Enantioselective Catalytic Reactions with N-Acyliden Penta-atomic

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Enantioselective Catalytic Reactions with N‑Acyliden Penta-atomic Aza-heterocycles. Heterocycles as Masked Bricks To Build Chiral Scaffolds Giovanni Desimoni,* Giuseppe Faita, and Paolo Quadrelli Department of Chemistry, University of Pavia, Viale Taramelli 10, 27100 Pavia, Italy S Supporting Information *

Downloaded by MONASH UNIV on August 26, 2015 | http://pubs.acs.org Publication Date (Web): August 26, 2015 | doi: 10.1021/acs.chemrev.5b00097

1. INTRODUCTION α,β-Unsaturated carbonyl derivatives are suitable substrates for the catalytic enantioselective reactions that, in general, are directed to functionalize either the activated double bond, or the entire CC−CO fragment, or the carbonyl group only. These reactions occur in the presence of a non-racemic catalyst (CC*), which can be either a [ligand/inorganic cation] complex acting as a Lewis acid, or a small non-racemic organic molecule behaving as activator (an organocatalyst). The basic mode of activation assumes that the lone electron pair of the carbonyl oxygen atom coordinates to the Lewis acid or is involved in hydrogen-bonding interactions. Hence, the activated reagent becomes the reacting complex involved in the catalytic cycle. Thereby, the activation of the substrate is the result of a lowered energy of its LUMO, which induces an easier reaction with a nucleophilic reagent. The characteristics of the substrate may influence the mode of coordination, and Figure 1, in which CC* is a chiral Lewis acid, illustrates the relationship between the structure of the reagent and the mode of activation. Compounds having a 4-ene-1,3-dione as the basic structure (A1) usually behave as bidentate reagents with the second

CONTENTS 1. 2. 3. 4.

Introduction Epoxidation Reactions Cyclopropanation Reactions Michael Reactions 4.1. Aza-Michael Reactions 4.2. Sulfa-Michael Reactions 4.3. Phospha-Michael Reactions 5. Radical Reactions 6. Diels−Alder Reactions 7. 1,3-Dipolar and Formal [3+2] Cycloaddition Reactions 8. Influence of Substituents on Reactivity and Selectivity 9. Comparison between Catalytic, Enantioselective Reactions with Different 1-(Nitrogen-heterocyclic)-Substituted Prop-2-en-1-ones 1−9 and the Aromatic Analogues 10 10. Relationship between Different [Chiral Ligand/ Inorganic Cation] Complexes or Non-Racemic Organocatalysts and the Stereochemical Outcome 11. Conclusions Associated Content Supporting Information Author Information Corresponding Author Notes Biographies Acknowledgments References

A D H I X AB AD AF AI AL AQ

AU

AV BC BD BD BD BD BD BD BD BE

Figure 1. α,β-Unsaturated carbonyl derivatives activated by a chiral catalyst (CC*) for enantioselective reactions. Received: February 18, 2015

© XXXX American Chemical Society

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DOI: 10.1021/acs.chemrev.5b00097 Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 1. Phospha-Michael Addition Catalyzed by the [Zn(II)/(S,S)-Ia] Complex

Chart 1. LUMO Energies (eV) of Enones with Different Substituents

to give five-membered chelated structures by involving the electron pairs of the oxygen carbonyl atom and the pyridine nitrogen one (B2).3 The corresponding N-oxide derivatives give six-membered chelated structures involving the electron pairs of both the oxygen atoms of the carbonyl group and the N-oxide (B1).3,4 One of the possible developments is represented by the use of 2-alkenyl ketones with a nitrogen-containing five-membered heterocyclic substituent. The position of the nitrogen atom in the heterocyclic ring is crucial for both the behavior of the substrate in the coordination with a chiral catalyst and the future use of the product as chiral synthetic scaffold. Figure 1 reports three paradigmatic examples. Substituted (E)-1-(1H-pyrrol-1-yl)prop-2-en-1-ones (C) allow only a mono-coordination, whereas (E)-1-(1H-pyrazol-1-yl)prop-2-en-1-ones (C2) and (E)-1-(1substituted-1H-imidazol-2-yl)prop-2-en-1-ones (C2′) may behave as bidentate ligands through the electron pairs of the carbonyl oxygen and the suitably placed nitrogen atom, which give, with the Lewis acid of the chiral catalyst, five-membered chelated structures. The importance of the coordination mode can be appreciated in the enantioselective phospha-Michael reaction

carbonyl group participating in stable six-membered chelated structures with the chiral Lewis acid; a typical example of this behavior is observed in substrates as 3-alkenoyl-2-oxazolidinone.1 4-Substituted 2-oxo-3-butenoates (A2) have an analogous advantage from the presence of the carbonyl group in the α position to the ester moiety, but the resulting 1,2dicarbonyl system forms a five-membered chelated structure with the chiral Lewis acid.2 The bicoordination to the Lewis acid with (A1)- and (A2)type reagents has some positive outcomes on both reactivity and stereoselectivity. It gives rigid structures with the catalyst, which allows higher level of selectivity in the concerned enantioselective reactions. The catalyst coordination to the electron-attracting substituent of the α,β-unsaturated carbonyl derivatives lowers the LUMO of the substrate, and favors the reactivity with electron-rich reagents. The specificity of unsaturated α- and β-dicarbonyl compounds to give five- and six-membered chelated structures with the Lewis acid can be found in other reagents. If the phenyl group of phenyl 2-alkenyl ketones (B) is substituted by 2pyridinyl or by 2-pyridinyl-N-oxide group (B2 and B1, respectively), a series of bicoordinating reagents are obtained. 1-(Pyridin-2-yl)alk-2-en-1-ones interact with the chiral catalyst B



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between either (E)-3-phenylacryloyl-oxazolidin-2-one (A1) or (E)-3-phenyl-1-(1H-pyrrol-1-yl)prop-2-en-1-one (C) with diphenylphosphinoxide in THF at ambient temperature. The reactions were catalyzed by the Zn(II) complex of (2S,2′S)1,1′-[(2-hydroxy-5-methyl-1,3-phenylene)bis(methylene)]bis[α,α-di-2-thienyl]-2-pyrrolidinmethanol [(S,S)-Ia] (Scheme 1).5 Two zinc cations coordinate the chiral ligand and the electrophiles (A1 or C, respectively) to give the corresponding reacting intermediates. Excellent yields were obtained in all of the cases, but the enantioselectivities were deeply different. Derivative C behaves as a monocoordinated ligand in the Lewis acid coordination; the obtained reacting intermediate does not discriminate the enantioface of the reagent to the approach of the deprotonated diphenylphosphine oxide affording a racemic product. On the contrary, the spatial conformation of A1, fixed by the bicoordination of the two carbonyl groups, gives rise to a reacting intermediate of the catalytic cycle inducing an appreciable enantioface discrimination. In addition to the characteristics of the chiral catalyst favoring the enantioselective approach on a specific reacting intermediate, a second factor must be taken into account. The reaction of a nucleophile to the β-position of an α,βunsaturated carbonyl moiety depends on the electron-withdrawing character of the substituents, whose enhancement lowers the LUMO and favors the reaction. Chart 1 reports the LUMO energies (eV) of enones differing for the residual substituent.6,7 Among them, (E)-3-phenylacryloyl-oxazolidin-2one (A1) and (E)-3-phenyl-1-(1H-pyrrol-1-yl)prop-2-en-1-one (C) have LUMO values that are nearly identical, as nearly identical is the reactivity of these reagents in the enantioselective reaction above reported. It is important that the cluster of the heterocyclic enones (g, h, i, and j in Chart 1) is characterized by compounds with the lowest LUMO energies, a property that should add reactivity to that induced by the catalyst. The above discussion concerns the activation of the substrates by the catalyst. However, C- and C2-type molecules in Figure 1 have an amide-type C(O)−N bond that, when cleaved after the enantioselective reaction, could allow the transformation of the products into a variety of functionalized chiral building blocks. The bond-cleavage between the carbonyl and the heterocyclic substituent X generates the heterocycle anion X−. The cleavage easiness is a function of the anion stability, and therefore a rough measure is given by the pKa values of the conjugated acids HX. Chart 2 lists the different (nitrogen-heterocyclic)-substituted prop-2-en-1-ones (1−9 and 11−13) that react in enantioselective catalyzed reactions. The pKa values of the heterocyclic HX derivatives are reported near the structures in Chart 2.8,9 For 3-substituted 1-(1H-pyrrol-1-yl)prop-2-en-1-ones (1), 1(1H-indol-1-yl)prop-2-en-1-ones (2), 1-(1H-pyrazol-1-yl)prop2-en-1-ones (3), 1-(1H-indazol-1-yl)prop-2-en-1-ones (4), 1(1H-imidazol-1-yl)prop-2-en-1-ones (5), 1-(1H-benzo[d]imidazol-1-yl)prop-2-en-1-ones (6), 1-(1H-1,2,4-triazol-1-yl)prop-2-en-1-ones (7), 1-(1H-benzo[d][1,2,3]triazol-1-yl)prop2-en-1-ones (8), and 1-(carbazol-9-yl)prop-2-en-1-ones (9), the cleavage concerns the amidic bond in which the conjugated bases of the heterocycles are the leaving groups (X−), and therefore the pKa values to be taken into account correspond to those of the conjugated acids (H−X). For 1-(1H-pyrrol-2-yl)prop-2-en-1-ones (11), 1-(1H-imidazol-2-yl)prop-2-en-1-ones (12), and 1-(thiazol-2-yl)prop-2-en-

Chart 2. pKa Values of Enones with Different Substituents

1-ones (13), the cleavage concerns a C−carbonyl bond, and hence the pKa values to be considered are those of the corresponding conjugated acids, in which a CH bond has to be dissociated. A reference for this class of ketones is chalcone 10 (R = Ph), and the assumed pKa value for the cleavage of the phenyl−carbonyl bond is added. On the basis of the pKa values, two clusters of compounds can be defined. The reagents in the first cluster (1−9) are expected to be suitable for modifications of their chiral products with substitution of the heterocycle fragment with other more useful functional groups. Among them, 7 (the derivative with the lowest LUMO) and 8 should have the most easily cleavable C−N bonds. The reagents in the second cluster of heterocyclic enones (11−13) are expected to generate stable chiral products in which the substitution of the heterocycle with other groups will be more difficult with respect to the compounds belonging to the first cluster. Higher difficulties will be expected for the substitution of the phenyl group in products derived from chalcone 10. Therefore, this Review will be limited to the reactions of the amides 1−9 listed in Chart 2, which afford non-racemic products when the reactions are performed in the presence of an optically active catalyst. As far as possible, the results of these reactions will be compared to those obtained under similar conditions with the corresponding chalcone (10) taken as a benchmark. The core of the discussion will be the reactivity and the stereoselectivity of these reagents, and the relationship between the configuration of the catalyst and that of the product, that is, the mechanism of transmission of the chiral information. When possible, the use of these reaction products as synthetic scaffolds for more or less complex natural or artificial chiral compounds will be described. C


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chiral intermediate enolate [(S)-C], from which epoxide (2S,3R)-14 is formed by ring closure. The epoxidation of five 3-phenylprop-2-en-1-one derivatives was performed with tert-butyl hydroperoxide in THF at −10 °C with [(R)-III/Sm(OiPr)3/Ph3AsO] as the catalyst (Scheme 3),7 whose results have been discussed in terms of LUMO energy of the substrate. Taking into account the LUMO energies reported in Chart 1 for 1-morpholino-3-phenylprop-2-en-1-one (a), 4-phenylbut-3en-2-one (d), 3-phenyl-1-(1H-pyrrol-1-yl)prop-2-en-1-one (1: R = Ph), chalcone (10a), and 3-phenyl-1-(4-phenyl-1Himidazol-1-yl)prop-2-en-1-one (5: R = R″ = Ph), a direct correlation between reactivity and LUMO energies has been observed. After 30 min, very little conversion was observed with the morpholine amide (a), while the conversion increased substantially with 4-phenylbut-3-en-2-one (d). The increase of the conversion then followed the order of the decrease of the LUMO energy for acylpyrrole and chalcone (1 and 10a, respectively). The best reactivity was that of acylimidazole (5), the derivative with the lowest LUMO energy (Figure 3). Among these results, those of (1H-pyrrol-1-yl)prop-2-en-1ones (1) and (1H-imidazol-1-yl)prop-2-en-1-ones (5) are the most attractive ones because of the versatility of the products after further transformations (Table 1). Hence, the epoxidation of different 1-(nitrogen-heterocycles)-substituted prop-2-en-1ones was studied.14 The best catalyst was [La(III)/BINOL (S)-IIb/Ph3AsO], and the reagents were either mono-coordinating substrates such as (E)-1-(1H-imidazol-1-yl)-3-phenylprop-2-en-1-ones (5) and (E)-1-(1H-benzo[d]imidazol-1-yl)-3-phenylprop-2-en-1-one (6), or a potentially bicoordinating reagent like (E)-3-phenyl-1(1H-1,2,4-triazol-1-yl)prop-2-en-1-one (7), Scheme 4.14 The reaction was tested also on 3-[(E)-3-phenylacryloyl]oxazolidin-2-one (A1) as a benchmark of bicoordinated reagent. The heterocyclic-substituted epoxides (A) cannot be isolated because of their high reactivity at the carbonyl carbon atom toward nucleophiles, and the product of all of the reactions is the peroxiester 15. This can be directly converted into the methyl 3-phenyloxirane-2-carboxylate [(2R,3S)-16a] by addition of methanol to the reaction (Scheme 4). Starting from these results, the epoxidation of several 3substituted (4-phenyl-1H-imidazol-1-yl)prop-2-en-1-ones (5f−

The reactions involving 1−9 may occur on the double bond either on both the α,β-positions (epoxidation, cyclopanations, and cycloaddition reactions) or in the β-position only (Micheal and radical reactions). To have a homogeneous comparison between the stereochemical results of these reactions, and to avoid different descriptors due to the different substituent priorities, the substituent R will be conventionally considered to be a phenyl group (Figure 2), and the preferred approached face will be referred to the β-carbon, with the α,β-unsaturated moiety in a s-cis conformation.


Figure 2. Addition to the enantiotopic faces at the double bond of (E)-1-(nitrogen-heterocyclic)-substituted prop-2-en-1-ones (1−9).

2. EPOXIDATION REACTIONS The first efficient catalytic enantioselective epoxidation reaction of enones was reported in 1997 by using BINOL lanthanoid complexes. In the early experiments, the reaction involving chalcone 10a (R = Ph) (Scheme 2) was catalyzed by the complex between La(OiPr)3 and (R)-3-hydroxymethyl-BINOL [(R)-IIa], with tert-butyl hydroperoxide (TBHP) as the oxidant. The chalcone epoxide (2S,3R)-14 was obtained with 93% yield and 91% ee.10 Later, the reaction was investigated in detail to optimize the experimental conditions and to infer the catalytic mechanism. The asymmetric amplification effect suggested that the catalyst had more than one ligand molecule bound to the lanthanide Lewis acid. The proposed mechanism reported in Scheme 2 is supported by experimental evidence: the positive effect of water,11 the presence of an intermediate enolate via conjugate addition of peroxide anion to enolate,12 the positive effect of triphenylarsine oxide as additive,13 and the X-ray analysis of the La(III)-BINOL complex [La/[(R)-IIa]2/(Ph3AsO)3] (A).13 The starting chalcone 10 is bound to lanthanum in the reacting intermediate (B) through mono-coordination. This gives the

Scheme 2. Proposed Mechanism for the La(III)-Catalyzed Epoxidation

D


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Scheme 3. Epoxidation Catalyzed by the [(R)-III/Sm(OiPr)3/Ph3AsO] Complex

en-1-one (7a) gives only a trace of the product (Table 1, entry 7), and this evidence contradicts the suggestive rationale advanced from the graph in Figure 3, but other factors can modify type and number of coordination around the Lewis acid center, which may influence the order of the reactivity. If a rationale simply based on MO interactions does not predict the reactivity, the pKa values of the conjugated acid related to the heterocyclic substituents of the substrates may help the rationalization of the cleavage facility of the carbonylheterocycle bond. The pKa values of 1H-imidazole- and 1Hbenzo[d]imidazole-derivatives 5 and 6 are 14.4 and 16.4, respectively (Chart 2), suggesting an easy cleavage of the Ncarbonyl bond. This is induced by tert-butyl-hydroperoxide in both heterocyclic-substituted epoxides A (Scheme 4) under the epoxidation conditions, and peroxiester 15 is the reaction product. This C−N bond lability is a property that justifies the common use of the above heterocyclic enones as reagents in enantioselective epoxidation because the peroxiesters 15 are the intermediates for the synthesis of useful chiral molecules and biologically important products. The synthesis of (2R,3S)-16a in high enantiomeric purity from 15 represents the best way to the epoxidation of cinnamate (Scheme 4).14 Furthermore, intermediate 15 can be converted to methyl 4,5-epoxy-3-oxo-5-phenylpentanoate [(4R,5S)-17], 3-phenyloxiranecarboxaldehyde (2R,3S)-18, and 3-phenyl-N-(phenylmethyl)oxiranecarboxamide [(2R,3S)-19], all in high enantiomeric purity.14 If L-leucine methyl ester is added to the product obtained from the reaction described in Table 1 (entry 5), in the presence of hexafluoroacetone, and the resulting epoxide-amidoester is opened under reductive conditions (Pd−C/H2), methyl 5-hydroxy-2-isobutyl-4-oxo-6phenylhexanoate [(2R,5S)-20] is obtained in very high enantiomeric purity (Scheme 5). If this procedure is applied to ent-15, obtained from the epoxidation with (R)-IIb, the diastereomer (2S,5S)-20 is achieved, which is a useful intermediate for the synthesis of neuropeptide AnthoRNamide.16 Furthermore, the epoxyester (2R,3S)-16h obtained from the reaction described in entry 11 of Table 1 is the key intermediate for the potent calcium antagonist Diltiazem (21).6 Methyl 3-phenethyloxirane-2-carboxylate [(2R,3S)-16i], obtained from the reactions in Table 1 (entries 14 or 30), is the starting material for the synthesis of natural product Strictifolione. When the epoxy-ester is treated with the lithium enolate of ethyl acetate, the epoxy-ketoester (4R,5S)-22 is obtained. The treatment with a selenium reagent prepared from PhSeSePh and NaBH4 leads to the reductive epoxide opening product (S)-23. This δ-hydroxy-ketoester can be either syn-

Figure 3. Correlation between the conversion yields (%) after 30 min of the epoxidation reaction of different α,β-unsaturated carbonyl derivatives, against their LUMO energies (eV).7

o) was investigated. The reaction yields were always good as well as the obtained enantioselectivities (Table 1, entries 9−12, 19, and 25−29).6,14,15 Taking constant the phenyl group as the substituent R in position 3, the best results in terms of yields and enantioselectivities were obtained with imidazole derivatives 5a,d,e as reagents (Table 1, entries 1, 4, 5), which may only give mono-coordination with La(III). The (1H-1,2,4-triazol-1yl)- and (oxazolidin-2-one)-derivatives 7 and A1 (Table 1, entry 7 and footnote b), which could both give bicoordination with the Lewis acid of the catalyst, give either a worse enantioselectivity or no reaction at all. Presumably, the heterocyclic ring is not involved in a bicoordination mode to La(III) in the reacting intermediate, and the catalytic cycle could be similar to that illustrated in Scheme 2. To optimize the Lewis acid, the epoxidation of both 1-(1Himidazol-1-yl)-5-phenylpent-2-en-1-one (5i) and 5j was performed with six different catalysts [(S)-IIb/Ln(OiPr)3/ Ph3AsO] in which the Ln(III) were La, Pr, Sm, Gd, Dy, and Yb (Table 1, entries 12, 14−18 for 5i; for 5j entries 19−24). The order of the cationic radius does not strictly follow the order of the enantioselectivity. Nevertheless, the best results are obtained with the larger cations [La(III) and Pr(III)], and the worst ones with the smaller Gd(III), Dy(III), and Yb(III) cations. (E)-1-(1H-Benzo[d]imidazol-1-yl)-3-phenylprop-2-en-1-one (6a), (E)-1-(1H-imidazol-1-yl)-3-phenylprop-2-en-1-one (5a), and (E)-3-phenyl-1-(4-phenyl-1H-imidazol-1-yl)prop-2-en-1one (5e) give yields and [ee’s %] of 80% [63], 86% [91], and 91% [94] (Table 1, entries 6, 1, and 5). This trend correlates with the same observed for their corresponding LUMO energies (−2.24, −2.34, and −2.37 eV, respectively). Unfortunately, (E)-3-phenyl-1-(1H-1,2,4-triazol-1-yl)prop-2E


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Table 1. Catalytic Epoxidation with tert-Butylhydroperoxide of Various 3-Substituted (1H-Imidazol-1-yl)-prop-2-en-1-ones (5) (Scheme 4)


16 entry

R

R′

R″

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

Ph Ph Ph Ph Ph Ph Ph Ph 4-Cl−C6H4 4-Br−C6H4 4-MeO−C6H4 3-phenethyl 3-phenethyl 3-phenethyl 3-phenethyl 3-phenethyl 3-phenethyl 3-phenethyl 3-phenylbutyl 3-phenylbutyl 3-phenylbutyl 3-phenylbutyl 3-phenylbutyl 3-phenylbutyl 3-(Z)-pent-3-enyl 3-(E)-pent-3-enyl 3-(Z)-4-phenylbut-3-enyl pentan-2-onyl cyclohexyl 3-phenethyl 4-TIPSO−C6H4

H Me Ph H H H H H H H H H H H H H H H H H H H H H H H H H H H H

H H H Me Ph H H Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph

5a 5b 5c 5d 5e 6a 7a 5e 5f 5g 5h 5i 5i 5i 5i 5i 5i 5i 5j 5j 5j 5j 5j 5j 5k 5l 5m 5n 5o 5i 5p

catalyst

time (h)

% yield

(S)-IIb/La(OiPr)3/Ph3AsOa,b (S)-IIb/La(OiPr)3/Ph3AsOa (S)-IIb/La(OiPr)3/Ph3AsOa (S)-IIb/La(OiPr)3/Ph3AsOa (S)-IIb/La(OiPr)3/Ph3AsOa (S)-IIb/La(OiPr)3/Ph3AsOa (S)-IIb/La(OiPr)3/Ph3AsOa (S)-IIb/La(OiPr)3/Ph3AsOc (S)-IIb/La(OiPr)3/Ph3AsOc (S)-IIb/La(OiPr)3/Ph3AsOc (S)-IIb/La(OiPr)3/Ph3AsOc (S)-IIb/La(OiPr)3/Ph3AsOc (S)-IIb/La(OiPr)3/Ph3POd (S)-IIb/Pr(OiPr)3/Ph3AsOc (S)-IIb/Sm(OiPr)3/Ph3AsOc (S)-IIb/Gd(OiPr)3/Ph3AsOc (S)-IIb/Dy(OiPr)3/Ph3AsOc (S)-IIb/Yb(OiPr)3/Ph3AsOc (S)-IIb/La(OiPr)3/Ph3AsOc (S)-IIb/Pr(OiPr)3/Ph3AsOc (S)-IIb/Sm(OiPr)3/Ph3AsOc (S)-IIb/Gd(OiPr)3/Ph3AsOc (S)-IIb/Dy(OiPr)3/Ph3AsOc (S)-IIb/Yb(OiPr)3/Ph3AsOc (S)-IIb/La(OiPr)3/Ph3AsOc (S)-IIb/La(OiPr)3/Ph3AsOc (S)-IIb/La(OiPr)3/Ph3AsOc (S)-IIb/La(OiPr)3/Ph3AsOc (S)-IIb/La(OiPr)3/Ph3AsOc (S)-IIb/Pr(OiPr)3/Ph3POc (S)-IIb/La(OiPr)3/Ph3POc

4 12 12 3 1 24 1 3.5 5 4 6 1 1 1.5 6 3 3 20 1 1.5 5 8 2 18 2 1.5 2 4 4 4 1.5

86 70 69 85 91 80 trace 86 91 86 80 86 84 87 81 81 79 78 93 88 88 84 85 71 93 92 85 81 72 82 95

% ee (conf) 91 77 87 92 94 63

(2R,3S) (2R,3S) (2R,3S) (2R,3S) (2R,3S) (2R,3S)

92 (2R,3S) 93 89 91 (2R,3S) 83 (2R,3S) 87 (2R,3S) 85 (2R,3S) 79 (2R,3S) 67 (2R,3S) 77 (2R,3S) 68 (2R,3S) 79 86 65 49 76 56 86 (2R,3S)e 79 (2R,3S)e 82 81e 88 (2R,3S)e 86 94 (2R,3S)

ref 6, 14, 15 6, 14, 15 6, 14 6, 14, 15 6, 14, 15 6, 14, 15 6, 14 6, 14, 15 6, 14, 15 6, 14, 15 6, 14, 15 6, 14, 15 6, 15 6, 17 6 6 6 6 6 6 6 6 6 6 6, 14, 15 6, 14, 15 6, 14, 15 6, 14, 15 6, 14, 15 17 18, 19

a 20% mol. bUnder the same conditions, 3-(E)-3-phenylacryloyl)oxazolidin-2-one (A1) (LUMO energy −2.05 eV) after 24 h gives (2R,3S)-16 in 73% yield and 87% ee.6,14,15 c10% mol. d30% mol of Ph3PO was used. eee determined after conversion to the corresponding 4-methoxybenzyl ester.

Scheme 4. Epoxidation of Enones with Different Substituents

selectively reduced to (3S,5S)-24, or anti-selectively reduced to (3R,5S)-24 (Scheme 6). The last dihydroxyester has the suitable (3R,5S) absolute configuration to be converted to the natural product Strictifolione (25).17

The catalytic enantioselective epoxidation with [(S)-IIb/ La(OiPr)3/Ph3PO] of 3-(4-TIPS-phenyl)-1-(4-phenyl-1H-imidazol-1-yl)prop-2-en-1-one (5p) (Table 1, entry 31), followed by the coupling reaction with D-leucin tert-butyl ester, affords F


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was lowered to 1% mol, the yield dropped due to probable binding competition of the leaving group (imidazole) as competitive ligand to Sm(III), Scheme 8.20 The interesting result was obtained with the new Sm(III) complex as epoxidation catalyst of (E)-3-phenyl-1-(1H-pyrrol-1-yl)prop-2en-1-one (1a). The product was (2S,3R)-2,3-epoxy-3-phenyl(1H-pyrrol-1-yl)propan-1-one [(2S,3R)-29] that was obtained in excellent yield and enantioselectivity even with 1% mol of catalyst.20 Scheme 8 clearly shows the different behavior of an heterocyclic substituent when the pKa of the heterocyclic conjugated acid is 14.4 (imidazole) and 23.0 (pyrrole): The 1imidazolyl-substituted epoxide (A in Scheme 4) under the reaction conditions gives nucleophilic substitution with the tbutylperoxide anion, whereas the 1-pyrrolyl-substituted epoxide 29 does not react with the involved nucleophile. From the above results, the flexibility of [(R)-III/Ln(OiPr)3] as epoxidation catalysts with variously 3-substituted 1-(1Hpyrrol-1-yl)prop-2-en-1-ones was tested. Among the lanthanide(III) cations screened, La, Pr, Nd, Gd, and Er gave yields >80% with >90% ee. Yb failed, while Sm(III) showed the best reactivity and selectivity. The preparation of the reagents was performed from 1-pyrrolylmethylenetriphenylphosphorane (28) and the required aldehyde to give 1, which were submitted, without workup, to the epoxidation reaction with cumenehydroperoxide at ambient temperature in toluene:THF 1:1, with 5% mol [(R)-III/Ln(OiPr)3/Ph3AsO] as the catalyst. Table 2 reports yields and ee’s of several 3-substituted 2,3epoxy-(1H-pyrrol-1-yl)propan-1-ones (29), all obtained in very good yields and excellent enantioselectivities (Table 2, entries 3, 5, 7, 9, 11−13, 15, 17, 18, 20−22, and 24). One exception is the epoxidation of (Z)-1h that proceeds slowly to give cisepoxide 29 with appreciable enantioselectivity, but in a poor yield (Table 2, entry 25).20,21 When the reactions were run on samples of isolated 1, yields and enantioselectivities improve, but not so significantly to make this route better than the previous one (Table 2, entries 4, 6, 8, 10, 14, 16, 19, and 23).22 The relatively weak C−N bond of (1H-pyrrol-1-yl) derivatives 29 allows the substitution of the pyrrolyl group, and the versatility of compounds (2S,3R)-29 is demonstrated by their transformations in useful chiral molecules. Phenyllithium adds to the carbonyl group to give a tetrahedral intermediate that, in the presence of DBU,23 looses the pyrrole affording the phenyl (3-phenyloxiran-2-yl) ketone [(2S,3R)14]. Analogously, the reaction of 29 with tert-butyl acetate and butyllithium gives tert-butyl 4,5-epoxy-3-oxo-5-phenylpentanoate [(2S,3R)-30], while that with 1-pentyne affords 1pentynyl (3-phenyloxiran-2-yl) ketone [(7S,8R)-31]. These transformations are compatible with different R substituents; hence (2S,3R)-29 (R = PhCH2CH2) can be reduced by LiBH4 and then NaBH4 to (2S,3R)-32, while (2S,3R)-29 (R = PMBOCH2CH2), when treated with LiBH4 and then with the required phosphonate, was converted to the epoxy heptenoate (4S,5R)-33 (Scheme 9).20−22 An interesting result derives from the diastereoselective epoxidation of chiral (E)-(5R,6R)-7-benzyloxy-5,6-(2,2-dimethyl-1,3-dioxolan-4-yl)-1-(1H-pyrrol-1-yl)hept-2-en-1-one 1 prepared in situ from aldehyde (2S,3R)-34 and 1-pyrrolylphosphorane 28. With 5% mol [(R)-III/Sm(OiPr)3/Ph3AsO], the “matching pair” between (5R,6R)-1 and (R)-III gives (2S,3R,5R,6R)-7-benzyloxy-2,3-epoxy-5,6-(2,2-dimethyl-1,3-dioxolan-4-yl)1-(1H-pyrrol-1-yl)heptan-1-one [(2S,3R,5R,6R)-


Scheme 5. Conversion of Peroxiesters 15 into EpoxyDerivatives and Synthesis of Diltiazem

Scheme 6. Synthesis of Strictifolione from (2R,3S)-16i

26 with the (2S,5S) absolute configuration, a significant moiety of Aeruginosin-298-A (27), Scheme 7, which is a potent thrombin and trypsin inhibitor isolated from the cyanobacterium Microcystis aeruginosa.18,19 Scheme 7. Synthetic Strategy toward Aeruginosin-298-A

The peroxidation of N-acylyden-imidazole was tested with different concentrations of the Sm(III) complex of 5,6,7,8tetrahydro-1-(1,2,3,4-tetrahydro-6-hydroxynaphthalen-5-yl)naphthalen-2-ol [(R)-III] with Ph3AsO as auxiliary ligand [(R)III/Sm(OiPr)3/Ph3AsO]. With 5% mol catalyst, the result is even better than that obtained with [(S)-IIb/La(OiPr)3/ Ph3AsO] (Table 1, entry 5). When the loading of the catalyst G


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Scheme 8. Different Leaving Behavior of the Heterocyclic Substituent in Epoxidation Reaction

Table 2. Catalytic Epoxidation with Cumenehydroperoxide of Various 3-Substituted 1-(1H-Pyrrol-1-yl)prop-2-en-1-ones (Scheme 8)a 29 1

entry

R

R

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Ph Ph Ph Phd 4-Me−C6H4 4-Me−C6H4d 4-MeO−C6H4 4-MeO−C6H4d 4-Cl−C6H4 4-Cl−C6H4d 2-Cl−C6H4 1-naphthyl 2-naphthyl 2-naphthyld 2-phenethyl 2-phenethyld 4-phenylbutyl cyclohexyl cyclohexyld (4-methoxybenzyloxy)ethyl 3-oxobutyl 9-decenyl 9-decenyld (E)-pent-1-enyl H

H H H H H H H H H H H H H H H H H H H H H H H H 2-phenethyl

1a 1a 1a 1a 1b 1b 1c 1c 1d 1d 1e 1f 1g 1g (E)-1h (E)-1h 1i 1j 1j 1k 1l 1m 1m 1n (Z)-1h

catalyst

time (h)

% yield

% ee (conf)

(R)-IIb/Sm(OiPr)3/Ph3AsOb,c (R)-III/Sm(OiPr)3/Ph3AsOb,c (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3POb (R)-III/Sm(OiPr)3/Ph3AsOc,f

0.5 0.5 0.3 0.2 2.5 0.2 0.5 0.2 0.5 0.2 0.5 0.5 2 0.2 0.5 0.5 0.8 2 0.2 0.5 0.5 0.5 0.3 2 1

85 95 96 98 92 98 87 91 100 97 83 85 100 93 84 91 83 75 90 91 93 82 95 72 32

96 (2S,3R) >99 (2S,3R) >99.5 (2S,3R) >99.5 (2S,3R) 99 (2S,3R)e >99.5 (2S,3R)e 98 (2S,3R)e 99 (2S,3R)e 99 (2S,3R)e >99.5 (2S,3R)e 97 (2S,3R)e 99 (2S,3R)e 99 (2S,3R)e >99.5 (2S,3R)e 97 (2S,3R)e 99 (2S,3R)e 96 (2S,3R)e 98 (2S,3R)e >99.5 (2S,3R)e 97 (2S,3R)e 96 (2S,3R)e 96 (2S,3R)e 99 (2S,3R)e 96 (2S,3R)e 86g

ref 20, 20, 20 22 20, 22 20, 22 20, 22 20, 20, 20, 22 20, 22 20 20, 22 20, 20, 20, 22 20, 20,

21 21

21 21 21 21 21 21 21

21 21 21 21 21 21

a Unless otherwise stated, the reagents 1 were synthesized from the required aldehyde and 1-pyrrolylmethylenetriphenylphosphorane at 100 °C in toluene and, without workup, submitted to the epoxidation at 25 °C in toluene:THF 1:1 with CHMP as peroxidant. b5% mol catalyst. cReaction run in THF with TBHP as peroxidant. dReaction carried out on isolated 1. eThe absolute configuration reported by analogy. f10% mol catalyst. gPhysical properties and [α] value not reported.

in the total synthesis of phorboxazole A, a macrolide isolated from the marine sponge Phorbas sp.

35] in a good yield and a diastereomeric ratio >99:1 (Scheme 10). The “mismatching pair” with (S)-III gives diastereomers (2R,3S,5R,6R)- and (2S,3R,5R,6R)-35 in the ratio 56:1.20,21 The above stereoselectivity is important because the (R) configuration of the chiral center in the 3-position is maintained during the epoxide opening to (3R,5R,6R)-36. The pyrrole substitution affords (3R,5R,6R)-37 maintaining the relevant (3S,5R,6R) absolute configuration of 38, an important fragment

3. CYCLOPROPANATION REACTIONS Very few examples of cyclopropanation reaction of heterocyclic enones have been reported in the literature, but, despite the small number, the argument deserves attention for the possible applications. 3-Phenyl-1-(1H-pyrrol-1-yl)prop-2-en-1-one (1a) reacts with dimethyloxosulfonium methyde 39 under catalysis with LaH


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Scheme 9. A Variety of Synthetic Elaborations from (2S,3R)-29

Scheme 11. “Star” Catalyst [3(S)-IV/La(OiPr)3/Li3] for Cyclopropanation Reactions


Scheme 10. New Results from the Diastereoselective Epoxidation of Chiral (E)-(5R,6R)-1

(III)/Li3/(biphenyldiolate)3 (S)-IV/NaI complex to give (2phenylcyclopropyl)(1H-pyrrol-1-yl) ketone [(1S,2S)-40], in low yield but excellent ee (98%). The conversion into the ethyl ester (1S,2S)-41 in the presence of EtONa occurs through an easy substitution of the pyrrolyl group (Scheme 11). The reactivity of 1a can be compared to that of chalcone 10a: The product achieved is (1S,2S)-42, obtained with a better yield (96% vs 68%), but with a slightly lower enantioselectivity (94% vs 98% ee).24 This result suggests for both of the reactions very similar reacting intermediates in which either 1 or 10 is bound to La. If the catalyst [3(S)-IV/La(OiPr)3/Li3], as suggested by the authors, has the “star” structure reported in Scheme 11,25 it is seems reasonable to imagine 1 or 10 axially bound to La, in an asymmetric environment in which the approach of the ylide is forced to the β-Si face, thus giving products with the (1S,2S) configuration.

significant variants involving both the chiral ligand and the Lewis acid. Initially, the ligand 3,3″-[oxybis(methylene)]-bis(1S,1″S)[1,1′-binaphthalene]-2,2′-diol [(S,S)-Va] and the Lewis acid Zn(II) give the precatalyst [Zn3/[(S,S)-Va]2/THF3], whose structure was determined by X-ray analysis (Scheme 12).26 The Michael reaction between aryl- and heteroarylsubstituted 1 and hydroxymethyl (2-methoxyphenyl) ketone (43) occurs easily at 0 °C with 10% mol catalyst and gives, as the main stereoisomer, the 3-substituted (2R,3R)-2-hydroxy-1(2-methoxyphenyl)-5-(1H-pyrrol-1-yl)pentane-1,5-diones [(2R,3R)-44] in good dr and yields, along with the excellent enantioselectivity (Table 3, entries 1−9). The result is not so good when R is an alkyl group (Table 3, entry 10).20 If the catalytic species is [Zn3/[(S,S)-Va]2/THF3], with the three Zn cations aligned in almost a straight line as reported by its X-ray analysis,26 both reagents can be linked on the catalyst. The enolate of 43 behaves as tridentate ligand coordinating two Zn, the third one linking the carbonyl group of 1 through a mono-coordination, affording the reacting intermediate A reported in Scheme 12. The nucleophilic addition of 43 to

4. MICHAEL REACTIONS The BINOL-based complexes used by Shibasaki and his group early in 1997 for the catalytic enantioselective epoxidation reaction of enones were later usefully applied to the Michael reaction of 3-substituted 1-(1H-pyrrol-1-yl)prop-2-en-1-ones (1). Different experiments were successively performed with I


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Scheme 12. Precatalyst X-ray Analysis Rationalizes the Michael Stereochemical Outcome

Table 3. Catalytic Enantioselective Michael Reaction between 3-Substituted 1-(1H-Pyrrol-1-yl)prop-2-en-1-ones (1) and 43, Catalyzed by [Zn3/[(S,S)-Va]2/THF3] (Scheme 12) entry b

1 2b 3c 4b 5b 6b 7b 8b 9b 10b 11d

R

1a

time (h)

yield (%)

dr (syn/anti)

Ph 4-Me−C6H4 4-MeO−C6H4 4-Cl−C6H4 4-Br−C6H4 3-Cl−C6H4 2-furyl 2-thienyl 4-pyridyl (4-methoxybenzyloxy)ethyl Ph

1a 1b 1c 1d 1o 1p 1q 1r 1s 1k 10a

17 12 24 12 13 13 17 17 13 12 3

85 82 77 84 94 93 80 74 97 89 93

91/9 93/7 95/5 89/11 91/9 86/14 90/10 95/5 81/19 69/31 78/22

44a ee (%) (config) 91 93 95 90 93 88 90 90 90 73 95

(2R,3R) (2R,3R) (2R,3R) (2R,3R) (2R,3R) (2R,3R) (2R,3R) (2R,3R) (2R,3R) (2R,3R) (2R,3R)

ref 20 20 20 20 20 20 20 20 20 20 27

Except entry 11 in which 10 is the reagent and 45 is the product. bReaction performed with 10% mol catalyst at 0 °C in THF with MS 3 Å. Reaction performed as (a) but with 15% mol catalyst. dReaction performed as (a) but at −20 °C with 5% mol catalyst. The product is (2R,3R)-45.

a c

Scheme 13. Malonate Michael Addition to Enones 1

the β-Re face of 1 gives (2R,3R)-44 as the main stereoisomer. The configuration of the catalytic intermediate A is supported by the reaction of chalcone 10 with 43 with the same catalyst. The higher reactivity of chalcone 10 allows a lower temperature and a shorter reaction time without any drop in stereoselectivity of product (2R,3R)-45 (Scheme 12, Table 3, entry 11).27 The same linked-BINOL (S,S)-Va, and the analogous chiral ligands (S,S)-Vb,c, but with La(III) as the Lewis acid, were tested as catalysts in the Michael reactions between dibenzylmalonate 46a and a series of (E)-3-substituted-1-

[1H-(2-acylpyrrolidin-1-yl)-pyrrol-1-yl)prop-2-en-1-ones 1. These compounds are interesting because they could behave as bidentate reagents due to the presence of the second carbonyl group on the pyrrole ring. The reaction products are dibenzyl 2-[1-substituted-3-oxo-3-(1H-(2-acylpyrrolidin-1-yl)pyrrol-1-yl)-propyl] malonates 47 (Scheme 13 and Table 4), in which the absolute configuration was determined to be (S) when the R substituent is p-chlorophenyl (Table 4, entry 13).28 Two conditions are required to obtain good stereoselectivities. First, the bulkiness around the lanthanide metal center is important for improving enantioselectivity; hence an J


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Table 4. Catalytic Enantioselective Michael Reaction between 3-Substituted 1-(1H-Pyrrol-1-yl)prop-2-en-1-ones (1) and Dibenzyl Malonate (46a) (Scheme 13)28 47


a

entrya

R

R′

5a

catalystb

% yield

% ee (conf)

1 2 3 4 5 6 7c 8c 9c 10c 11c 12c 13c

n-Pr n-Pr n-Pr n-Pr n-Pr n-Pr n-Pr Me cyclohexyl (E)-prop-1-enyl (E)-pent-1-enyl Ph 4-Cl−C6H4

H CO2Et CONMe2 2-acylpyrrolidin-1-yl 2-acylpyrrolidin-1-yl 2-acylpyrrolidin-1-yl 2-acylpyrrolidin-1-yl 2-acylpyrrolidin-1-yl 2-acylpyrrolidin-1-yl 2-acylpyrrolidin-1-yl 2-acylpyrrolidin-1-yl 2-acylpyrrolidin-1-yl 2-acylpyrrolidin-1-yl

1t 1u 1v 1w 1w 1w 1w 1x 1y 1z 1aa 1ab 1ac

[La(III)/(S,S)-Va] [La(III)/(S,S)-Va] [La(III)/(S,S)-Va] [La(III)/(S,S)-Va] [La(III)/(S,S)-Vb] [La(III)/(S)-Vc] [La(III)/(S,S)-Vb] [La(III)/(S,S)-Vb] [La(III)/(S,S)-Vb]d [La(III)/(S,S)-Vb]d [La(III)/(S,S)-Vb] [La(III)/(S,S)-Vb]d [La(III)/(S,S)-Vb]d

trace 70 40 50 23 83 78 85 87 80 83 76 80

8 32 41 86 40 80 90 88 96 92 78 86 (S)

40 h at −20 °C. b10% mol catalyst except otherwise reported. c0.1 equiv of 1,1,1,3,3,3-hexafluoroisopropanol added as additive. d20% mol catalyst.

Scheme 14. Cyanide Michael Addition to Enones 1

For the transmission of the specific stereochemical information from the catalyst to the product, the diphenylphosphinyl substituent bound to the methylene group of hexitol is crucial. The new ligand (1S,2S,6R)-2-diphenylphosphinyl-6-(4′,5′-difluoro-2′-phenoxy)cyclohexanol [(1S,2S,6R)VIIb] has the same configuration as VI, but the diphenylphosphinyl group is directly bound to the six-membered ring (Scheme 14). With 1 equiv of 2,6-dimethylphenol as additive, the cyanation of 1 gives again excellent results in terms of yields and enantioselectivities (Table 5, entries 12−18), but, while VIb gives (S)-48, the latter catalyst VIIb produces (R)-48 (Table 5, entry 12 vs 2).30 These catalysts prepared “in situ” from the above ligands and Gd(OiPr)3 show a peculiarity: Whereas the enantioselectivity with [VIb/Gd(III)] as catalyst depends on the ligand−Gd ratio, and it is maximized when the ratio is [2:1], that induced by [VIIb/Gd(III)] is constant independently from the ligand− Gd ratio. To infer the real structure of the catalysts, their X-ray crystallographic analyses were undertaken and revealed very complex structures. The crystal obtained from VIa and Gd showed a ligand:Gd ratio of [4:5] with a μ-oxo atom

OH of (S,S)-Va must be substituted with a phenyl group [(S,S)-Vb]. In any case, the ligand must retain the bis-chiral structure because, if the OH is substituted by an H atom as in (S)-Vc, the efficiency of the derived catalyst is lowered (Table 4, entry 5 vs 6). Second, two carbonyl groups are required in 1, and the 2-acylpyrrolidin-1-yl group attributes the best electronic and structural character to the substrate (Table 4, entry 4 vs entries 1−3). As an alternative to the linked-BINOLs discussed above, Shibasaki developed a second generation of catalysts based on 1,5-anhydro-2,6-dideoxy-3-O-(4,5-difluoro-2-hydroxyphenyl)6-(diphenylphosphinyl)-D-arabino-hexitol [(1S,2S,6R)-VIb] and Gd(OiPr)3 (Scheme 14).29 This catalyst, specific for the addition of cyanide to 1, is better than the non-fluorinated analogue [(1S,2S,6R)-VIa] (Table 5, entry 2 vs 1), and, with 2 equiv of HCN as additive, it gives excellent yield and enantioselectivity of (S)-48 (Table 5, entries 3−10).29 The catalyst is extremely flexible with a variety of substituents R, and only when the double bond of 1 is trisubstituted is the induced diastereoselectivity low (Table 5, entry 11). K


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Table 5. Catalytic Enantioselective Michael Addition of Cyanide to Various 3-Substituted 1-(1H-Pyrrol-1-yl)prop-2-en-1-ones (1) (Scheme 14)


48 entry

R

R1

R2

1a 2a 3b 4b 5b 6b 7b 8b 9b 10b 11b 12a 13a 14a 15a 16a 17a 18a 19a 20a 21a 22a 23a 24a 25a

Ph Ph Ph 4-MeO−C6H4 4-t-Bu−C6H4 2-phenethyl n-propyl i-butyl t-butyl 1-cyclohexenyl −(CH2 CH2 CH2)−(R2) Ph 4-t-Bu−C6H4 2-phenethyl n-propyl i-butyl t-butyl −(CH2 CH2 CH2)−(R2) i-Pr Me Ph Me n-Bu Me i-Pr

H H H H H H H H H H H H H H H H H H Me i-Pr Me Ph Me n-Bu Me

H H H H H H H H H H H H H H H H H H H H H H H

1a 1a 1a 1c 1ad 1h 1t 1ae 1af 1ag 1ah 1a 1ad 1h 1t 1ae 1af 1ah (E)-1ai (Z)-1ai (E)-1aj (Z)-1aj (E)-1ak (Z)-1ak (E)-10ai

catalyst (mol %)b

time (h)

% yield

[Gd(III)/2(1S,2S,6R)-VIa] (5) [Gd(III)/2(1S,2S,6R)-VIb] (5) [Gd(III)/2(1S,2S,6R)-VIb] (10) [Gd(III)/2(1S,2S,6R)-VIb] (10) [Gd(III)/2(1S,2S,6R)-VIb] (10) [Gd(III)/2(1S,2S,6R)-VIb] (5) [Gd(III)/2(1S,2S,6R)-VIb] (5) [Gd(III)/2(1S,2S,6R)-VIb] (5) [Gd(III)/2(1S,2S,6R)-VIb] (5) [Gd(III)/2(1S,2S,6R)-VIb] (20) [Gd(III)/2(1S,2S,6R)-VIb] (5) [Gd(III)/2(1S,2S,6R)-VIIb] (5) [Gd(III)/2(1S,2S,6R)- VIIb] (10) [Gd(III)/2(1S,2S,6R)- VIIb] (5) [Gd(III)/2(1S,2S,6R)- VIIb] (5) [Gd(III)/2(1S,2S,6R)- VIIb] (5) [Gd(III)/2(1S,2S,6R)- VIIb] (5) [Gd(III)/2(1S,2S,6R)- VIIb] (5) [Sr(II)/1.7(1R,2R,6S)-VIII] (0.5) [Sr(II)/1.7(1R,2R,6S)-VIII] (0.5) [Sr(II)/1.7(1R,2R,6S)-VIII] (10) [Sr(II)/1.7(1R,2R,6S)-VIII] (2.5) [Sr(II)/1.7(1R,2R,6S)-VIII(0.5) [Sr(II)/1.7(1R,2R,6S)-VIII] (2.5) [Sr(II)/1.7(1R,2R,6S)-VIII] (10)

43 40 98 98 88 43 42 42 88 139 8 38 20 24 2.5 5.5 2.5 1 16h 16h 16g 16g 16h 16h 1

34 34 90 85 91 92 91 89 87 78 99c 91 89 96 93 99 95 92e 100i 95i 92i 100i 100i 73i 100j

% ee (config)

ref

74 81 91 90 89 96 98 97 90 93 88 88 95 86 93 93 96 76 95 98 96 99 98 95 97

29 29 29 29 29 29 29 29 29 29 29 30 30 30 30 30 30 30 32 32 32 32 32 32 32

(S) (S) (S)

(R) (R)

(2R,3R)d (R)

(S) (S) (2S,3S)f (R) (S) (+) (−) (−) (+) (R)

a

Reaction with 2,6-dimethylphenol as additive. bReaction performed with 2 equiv of HCN. cThe ratio of [trans 48/cis 48] is 1.1:1. dee and absolute configuration of trans 48. The absolute configuration and the ee of cis 44 are (2S,3R), 83% ee. eThe ratio of [trans 48/cis 48] is 5.7:1. fee and absolute configuration of trans 48. The ee of cis 48 is 12% ee. gAt 50 °C. hAt 40 °C. iYield, ee, and absolute configuration refer to product 49. jYield, ee, and absolute configuration refer to product 50.

surrounded by 4 Gd(III).31 On the other hand, the crystal structure obtained from VIIb has a ligand:metal ratio of [4:3], with a [4(1S,2S,6R)-VIIb/3Gd(III)/2H2O] composition.30 The difference from the catalysts prepared “in situ” is so dramatic that the same reaction catalyzed by the “in situ” generated catalyst or by its crystal may reverse the stereochemical outcome of the reaction.31 The crystal itself, however, may act as a “pre-catalyst” if the suitable amount of Gd(III) is added to adjust the ligand−Gd ratio, by heating at 50 °C to destroy the supramolecular organization of the crystal. This intricate situation is schematically represented in Figure 4 in which a fundamental difference between the respective basic fragments of the crystal structures is put in evidence. The coordination in which both VI and VII act as tetradentate

ligands gives a [7-, 5-, 5-membered] fused chelation system for the former ligand, and a [6-, 5-, 5-membered] fused system for the latter one. To succeed in the construction of β-quaternary carbon stereocenters, the addition of cyanide to 3,3-disubstituted 1 was investigated taking (E)-3,4-dimethyl-1-phenyl-2-penten-1-one [(E)-10ai] as model reagent. Instead of ligands with the diphenylphosphinyl group, and lanthanides as metal, several carbinol derivatives were successively tested with several metals, and the best result was obtained with the Sr(II) complex of (1R,2R,6R)-6-di-p-tolyl(i-butoxy)methyl-2-(2′hydroxyphenoxy)cyclohexanol [Sr(II)/(1R,2R,6S)-VIII]. This catalyst was tested on three couples of (E)- and (Z)-1 (Scheme 14, Table 5, entries 19−24) with excellent results in terms of yields and enantiomeric excesses.32 The absolute configuration was determined for the products derived from (E)- and (Z)3,4-dimethyl-1-(pyrrol-1-yl)-2-penten-1-ones: The former gave (R)-49, while the latter gave its enantiomer (S)-49 (Table 5, entries 19 and 20). The transmission of the chiral information was the same in the case of the reaction of (E)-10ai to give (R)50 (Scheme 14, Table 5, entry 25), a result that strongly suggests similar reacting intermediates for the reactions involving reagents with 1-pyrrolyl or with 1-phenyl groups. Other catalysts have been applied to the Michael cyanation reaction. The Ru complex derived from (S)-(BINAP) and 2 equiv of (S)-phenylglycine [(S)-Phgly2/(S,S,S)-IX/Ru(II)] and MeOLi is a useful catalyst for the addition of HCN to pyrrolyl derivatives 1.33 The reaction of MeOLi with HCN leads to the

Figure 4. Representative modules of the bimetallic fragments derived from the X-ray structure of the complexes [5(1S,2S,6R)-VIa/μ-oxo atom/4Gd] and [4(1S,2S,6R)-VIIb/3Gd/2H2O] in which ligands act in a tetradentate mode. The tetracoordination of VIa gives a 7-, 5-, 5membered fused chelation system,31 whereas VIIb gives a 6-, 5-, 5membered fused chelation system.30 L


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Scheme 15. Michael Cyanation Reaction Catalyzed by (S)-Phgly2/(S,S,S)-IX/Ru(II) Complex

induced, and the opposite enantiomers are obtained again with excellent enantioselectivities.35 As suggested by the authors, these bifunctional phase-transfer catalysts bearing a hydrogen-bond-donor moiety could interact by hydrogen bonding with either the CN donor species (e.g., 53 in Scheme 17) and/or the CN-accepting substrate 1. These interactions, which could have a strong influence on the structure of the reacting intermediates, will be discussed in a forthcoming section. The use of the above described Cinchona alkaloid salts is infrequent because they do not behave as chiral bifunctional organocatalysts. In fact, if the hydroxy functionality on the quinoline ring is the hydrogen donor group, the nitrogen atom in the ammonium quinuclidine fragment is unable to act as a base. Hence, it is not surprising that Cinchona alkaloids are more popular as chiral scaffolds, in which the introduction of a thiourea moiety produces more valuable catalysts. An example is the Michael addition of either ethyl 1-oxo-2,3dihydro-1H-indene-2-carboxylate (54) or acetyl acetates 56a,b to 1-(pyrazol-1-yl)-4,4,4-trifluoro-2-buten-1-one (3p), with the latter compound coordinated to the epi-cinchonine-derived thiourea (R,R,R)-XII to give the active species (Scheme 18). The former nucleophile affords 55, a product that maintains in its structure the heterocyclic substituent. More interesting is the reaction with acetyl acetates because the Michael adducts undergo intramolecular nucleophilic substitutions to give 4(trifluoromethyl)-5,6-dihydro-2-methyl-6-oxo-4H-pyran-3-carboxylates (57a,b) with loss of the pyrazole auxiliary. The absolute configuration of the stereogenic center was determined to be (R) by X-ray crystallographic analysis. The stereochemical outcome is consistent with the approach of 56 to the β-Si face of 3p.36 Sometimes the Michael reaction has been tested on a single substrate. This obviously limits the synthetic perspectives, except when the comparison with the corresponding chalcone may give further insights on the nature of the reacting intermediates. Two examples are discussed below. The reactions between either (E)-3-phenyl-1-(1H-pyrrol-1yl)prop-2-en-1-one (1a), or chalcone 10a, with propyl malonate (46b) can be catalyzed by the Sr(II) complex of bis-sulphonamide (R,R)-XIII to give adducts 47 and 58 in excellent yields and enantioselectivities (Scheme 19).37 Furthermore, the stereochemical outcome of both reactions is identical. A detailed NMR investigation allowed one to detect the formation of the reacting intermediate [(R,R)-XIII/Sr(II)/

formation of the complex between [(S,S,S)-IX/Ru] and LiCN to give a bimetallic cyanide species [(S,S,S)-IX/Ru/LiCN], which catalyzes the hydrocyanation through an addition on the β-Re face of 1 affording (S)-48 (Scheme 15). The isolated yields and the enantioselectivities obtained for several products are reported in Table 6, entries 1, 4, 7−15; all of the results are excellent with the exception of the reaction of 1d bearing an aromatic group as substituent because a drop in the ee is observed (Table 6, entry 10). The interesting feature is that the same protocol used in the reaction of 1 was applied to the cyanation of both (E)-1-(3,5-dimethyl-1H-pyrazol-1-yl)but-2en-1-one (3c) and (E)-3-(but-2-enoyl)oxazolidin-2-one (A1: R = Me, Chart 1). The results are reported in Scheme 15, and their comparison with those of 1 shows that the enantioselectivities obtained for the three substrates are always excellent, the yields are almost quantitative for two of them, and moderate for 3n.33 The Mg(II) complex of (S)-(BINOL) [(S)-IIb/Mg(II)], obtained from Bu2Mg, is a highly effective catalyst for the Michael cyanation of 3-substituted 1-(3,5-dimethyl-1H-pyrazol1-yl)prop-2-en-1-ones (3) to afford (R)-51 (Scheme 16).34 An easy rationale of the stereochemical outcome can be derived from the tetrahedral reacting complex [(S)-IIb/Mg(II)/ TMSCN] in which 3 acts as a bicoordinating ligand, and Si is coordinated to the BINOL oxygen atom. The intramolecular nucleophilic approach of cyanide occurs to the β-Re face of 3 affording (R)-51 with moderate yields and enantioselectivities (Table 6, entries 24−37). The conjugate addition of cyanide can be also performed with acetone cyanohydrin 53 as cyanating agent and cupreidinium (S,R,R)-X or cupreinium (R,S,R)-XI salts as phase-transfer catalysts. The reactions work nicely with Rb2CO3 at ambient temperature with different 3-alkyl substituted 1-(1H-pyrrol-1-yl)propenones (1). The pseudoenantiomeric catalysts establish a facile access to both enantiomers of 48: (S,R,R)-X gives (S)-48, while (R,S,R)-XI affords the opposite enantiomer (R)-48 (Scheme 17).35 The excellent results are reported in Table 6 (entries 2, 3, 5, 6, 16− 23), and it is interesting to compare the results of 1al with three catalysts (Table 6, entries 1−3) and those of 1h with four catalysts (Table 6, entries 4−6 and Table 5, entry 6). In Table 6 (entries 38−41), the results of the cyanation of some substituted chalcones 10, taken as models, are also reported. With these reagents (S,R,R)-X and (R,S,R)-XI, with Cs2CO3 instead of Rb2CO3, the same enantioselection is M


Chemical Reviews

Review

Table 6. Catalytic Enantioselective Michael Cyanation of 3-Substituted 1-(1H-Pyrrol-1-yl)prop-2-en-1-ones (1), 3-Substituted 1-(3,5-Dimethyl-1H-pyrazol-1-yl)prop-2-en-1-ones (3), and 3-Substituted Chalcones (10) with Different Catalysts (Schemes 15−17)


48 entry

R

1/3/10

catalyst

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

Me Me Me 2-phenethyl 2-phenethyl 2-phenethyl n-propyl cyclohexyl t-butyl 4-Cl−C6H4 (CH2)2CO2Me CH2N(CH3)CO2tBu CH2−OBn CH(OCH3)2 CH2Cl Et Et i-Pr i-Pr n-pentyl n-pentyl i-butyl i-butyl Ph 2-Me−C6H4 3-Me−C6H4 4-Me−C6H4 4-Cl−C6H4 2,4-Cl2C6H3 4-Br−C6H4 4-CF3−C6H4 4-CN−C6H4 4-MeO−C6H4 2-naphthyl Ph−CHCH Me 3-N-methylindol Me Me i-butyl i-butyl

1al 1al 1al (E)-1h (E)-1h (E)-1h 1t 1j 1af 1d 1ap 1aq 1ar 1as 1at 1am 1am 1an 1an 1ao 1ao 1ae 1ae 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 10al 10al 10ae 10ae

[(S,S,S)-IX/Ru/LiOMe] [(S,R,R)-X/Rb2CO3] [(R,S,R)-XI/Rb2CO3] [(S,S,S)-IX/Ru/LiOMe] [(S,R,R)-X/Rb2CO3] [(R,S,R)-XI/Rb2CO3] [(S,S,S)-IX/Ru/LiOMe] [(S,S,S)-IX/Ru/LiOMe] [(S,S,S)-IX/Ru/LiOMe] [(S,S,S)-IX/Ru/LiOMe] [(S,S,S)-IX/Ru/LiOMe] [(S,S,S)-IX/Ru/LiOMe] [(S,S,S)-IX/Ru/LiOMe] [(S,S,S)-IX/Ru/LiOMe] [(S,S,S)-IX/Ru/LiOMe] [(S,R,R)-X/Rb2CO3] [(R,S,R)-XI/Rb2CO3] [(S,R,R)-X/Rb2CO3] [(R,S,R)-XI/Rb2CO3] [(S,R,R)-X/Rb2CO3] [(R,S,R)-XI/Rb2CO3] [(S,R,R)-X/Rb2CO3] [(R,S,R)-XI/Rb2CO3] [(S)-IIb/Mg(n-Bu)2] [(S)-IIb/Mg(n-Bu)2] [(S)-IIb/Mg(n-Bu)2] [(S)-IIb/Mg(n-Bu)2] [(S)-IIb/Mg(n-Bu)2] [(S)-IIb/Mg(n-Bu)2] [(S)-IIb/Mg(n-Bu)2] [(S)-IIb/Mg(n-Bu)2] [(S)-IIb/Mg(n-Bu)2] [(S)-IIb/Mg(n-Bu)2] [(S)-IIb/Mg(n-Bu)2] [(S)-IIb/Mg(n-Bu)2] [(S)-IIb/Mg(n-Bu)2] [(S)-IIb/Mg(n-Bu)2] [(S,R,R)-X/Cs2CO3] [(R,S,R)-XI/Cs2CO3] [(S,R,R)-X/Cs2CO3] [(R,S,R)-XI/Cs2CO3]

T/°C (t/h) −20 rt rt −20 rt rt −20 −20 −40 25 0 0 −20 0 −20 rt rt rt rt rt rt rt rt 10 10 10 10 10 10 10 10 10 10 10 10 10 10 rt rt rt rt

(25) (48) (24) (24) (96) (24) (27) (34) (72) (48) (24) (13) (24) (18) (16) (48) (24) (48) (24) (96) (24) (96) (24) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (24) (24) (72) (24)

% yield 94 79 77 88 75 70 91 97 94 55 40 86 99 90 93 83 94 83 71 87 84 78 80

51

% ee (conf) 96 97 92 96 95 93 97 88 >99 41 98 93 92 88 88 95 90 95 91 96 92 98 94

% yield

50

% ee (conf)

% yield

% ee (conf)

(S) (S) (R) (S) (S) (R) (S)

(S) (R) (S) (R) (S) (R) (S) (R) 61 65 68 71 68 63 58 75 79 71 76 69 62 88

76 (R) 75 70 74 70 82 40 72 76 60 64 50 37 48 78 92 80 91

97 91 97 93

(S) (R) (S) (R)

ref 33 35 35 33 35 35 33 33 33 33 33 33 33 33 33 35 35 35 35 35 35 35 35 34 34 34 34 34 34 34 34 34 34 34 34 34 34 35 35 35 35

46b], which is the chiral nucleophile that attacks the β-Re face of the uncoordinated substrates (1a or 10a) to give the observed (S)-products. The second example is the Michael addition of MOMOmalononitrile (59) to three reagents: (E)-1-(1H-benzo[d][1,2,3]triazol-1-yl)-3-phenylprop-2-en-1-one (8a), (E)-3-phenyl-1-(pyridin-2-yl)prop-2-en-1-one (B2: R = Ph), and chalcone 10a, the organocatalyst being the squaramide derivative (1R,2R)-XIV, to give products 60−62 (Scheme 20).38 The absolute configuration of (S)-62 was already known, while that of 60 was determined to be (S) through its conversion into the corresponding (S)-dimethyl 2-phenylsuccinate (63). The excellent enantioselectivities for all of the products can be rationalized through very similar reacting

Scheme 16. Catalyst for the Michael Cyanation of Enones 3

N


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Scheme 17. Cyanohydrin 53 as Cyanating Agent and Cupreidinium (S,R,R)-X or Cupreinium (R,S,R)-XI Salts as Phase-Transfer Catalysts

Scheme 19. Malonate Michael Addition Catalyzed by Sr(II)Based Complex

intermediates, in which the bifunctional organocatalyst coordinates the carbonyl group of the enones by double hydrogen bonding. A catalyst that found large application in enantioselective Michael reactions with 1-(1H-pyrazol-1-yl)prop-2-en-1-ones (3) is the nickel complex of (R,R)-4,6-dibenzo-furandiyl-2,2′bis(4-phenyloxazoline), [(R,R)-XV/Ni(II)/3 H2O] (Scheme 21). This ligand, usually known as DBFOX/Ph, was first applied in the reaction of 3 with derivatives of malononitrile (59) to give high yields of 64 whose absolute configuration was shown to be (S) by X-ray crystallographic analysis (Scheme 21, Table 7, entry 6). With the exception of a few R substituents (e.g., 2-furyl, Table 7, entry 10), the enantioselectivity ranges from very good to excellent ee’s.39−41 The reactivity is significantly influenced by the steric effect of the alkyl group R because the reaction time increases with the increase of the steric hindrance (Table 7, entries 2, 4−6).

Cyclic 1,3-diketones 65 and β-hydroxy lactones 68−70 are the second class of reagents whose Michael reaction with 3, catalyzed by [(R,R)-XV/Ni(ClO4)2], has been investigated. 1,3Diketones have a behavior dependent on the presence of a methyl group in the 2-position (Scheme 21).40 Compound 65b (R = Me) gives a normal Michael reaction, and the adduct 67 retains the pyrazolic residue into its structure (Table 8, entry 2), while 65a (R = H) gives a stepwise process in which the Michael reaction is the first step. After enolization, an intramolecular substitution at the amidic carbonyl group removes the pyrazole auxiliary affording 66 (Scheme 21, Table 8, entries 1, 3−15). The absolute configuration, shown to be (R) on the basis of X-ray crystallographic analysis (Table 8, entry 15), indicates that the nucleophile approaches the β-Re face of 3u in the initial Michael addition, the key step determining the final stereochemical outcome of the overall process.42 The same Michael reaction/lactonization sequence occurs with β-hydroxy lactones 68−70 to give 71−73 again with


Scheme 18. Organocatalyzed Michael Addition to Enone 3p

O


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Review


Scheme 20. Malononitrile Michael Addition to Different Enones

Scheme 21. Michael Addition of Several Nucleophiles to Enones 3

prop-2-en-1-one (1r) and butyrolactam 75 to give 76, which was obtained with moderate yield and appreciable ee.44 This Article focused on the reactivity of substituted chalcones, and 76 is the “orphan product” described as a “versatile” example of compound possessing a great synthetic utility for its easy tranformations. This versatility was described about the BINOL-catalyzed products derived from unusually substituted (1H-pyrrol-1yl)enones, which was applied in the synthesis of some natural products through the protocols illustrated in Scheme 23.45 The asymmetric conjugate addition of Me3Al to (E)-3-(3isopropylphenyl)-1-(1H-pyrrol-1-yl)prop-2-en-1-one (1au) was catalyzed by [(R)-IId/Cu(OTf)2], and (S)-77 was obtained in excellent yield and 96% ee. Within three steps, reductions with LiBH4 and NaBH4, and final Swern oxidation, (S)-77 was converted into (S)-Florhydral [(S)-78], a compound with a very floral, fresh, natural odor whose great

excellent enantioselectivity, Scheme 21 (Table 8, entries 16− 25).42 The overall result of the reaction catalyzed by [(R,R)-XV/ Ni(II)] is an excellent enantioselectivity with nearly all of the substituted 1-(pyrazol-1-yl)prop-2-en-1-ones (3). Only the reactivity (reaction time and yield) is quite sensitive to the steric hindrance of the alkyl substituent. Somewhat unusual is the [rhodium/chiral diene (S,S)-XVI] complex that catalyzes the Michael addition of phenylboronic acid to (E)-1-(1H-pyrrol-1-yl)but-2-en-1-one (1al), to give 3phenyl-1-(1H-pyrrol-1-yl)butan-1-one (74) (Scheme 22). The absolute (R) configuration of the reaction product derives from the approach to the β-Re face to avoid the steric hindrance created by the substituents on ligand (S,S)-XVI.43 The BINOL-based complex [(R)-IIc/Mg(II)], obtained from 3,3′-Ph2-BINOL and n-Bu2Mg, is the catalyst of the reaction between (E)-1-(1H-pyrrol-1-yl)-3-(thiophen-2-yl)P


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Table 7. Catalytic Enantioselective Michael Addition of Malononitrile 59 to Various Substituted 1-(Pyrazol-1-yl)prop-2-en-1ones (3), Catalyzed by [(R,R)-XV/Ni(II)] Catalyst (Scheme 21)


64

a

entry

R

R1

R′

R″

1a 2a 3b 4a 5a 6a 7a 8a 9a 10a 11b 12b 13b 14b 15b 16b 17b 18b

Me Me Me i-Pr c-C6H11 t-Bu Ph 4-Br−C6H4 4-Me−C6H4 2-furyl Me Me i-Pr Ph CO2Et CO2Et CO2Et CO2Et

H H H H H H H H H H H H H H H Me Me Me

Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me

H Br Br Br Br Br Br Br Br Br H H H H H H H H

3d 3aa 3aa 3q 3r 3s 3t 3u 3v 3w 3d 3d 3x 3b 3y 3z 3z 3z

59 R

t [h]

% yield

% ee (conf)

ref

H H H H H H H H H H Me Bn Me Me Me Me H Bn

5 6 4 7 24 120 12 12 24 48 8 12 36 36 1.5 48 36 48

94 92 98 94 88 82 87 94 91 78 90 92 33 82 91 55 94 77

81 88 92 93 90 91 (S) 88 85 78 55 97 95 91 92 99 72 85 76

39, 40 39 41 39 39 39 39 39 39 39 40 40 40 40 40 40 40 40

Reaction performed at rt in THF, Ac2O (10% mol) with 10 mol % catalyst. bReaction performed at rt in t-BuOH/THF with 10 mol % catalyst.

Table 8. Catalytic Enantioselective Michael Addition of Cyclic Diketones 65, or β-Hydroxy Lactones 68−70, to Various Substituted 1-(Pyrazol-1-yl)prop-2-en-1-ones (3), Catalyzed by [(R,R)-XV/Ni(II)] Catalyst (Scheme 21) 66 entry 1a 2b 3c 4b 5d 6d 7d 8d 9d 10d 11d 12d 13d 14d 15d 16d 17d 18d 19d 20d 21d 22d 23d 24d 25d

R Me Me Me CO2Et Me Me Et n-Pr i-Pr c-C6H11 1-propenyl 2-furyl CO2Me Ph 4-Br−C6H4 Me 5-Br-2MeOC6H3 3,5-Br2C6H3 Me Ph 4-Br−C6H4 5-Br-2MeOC6H3 3,5-Br2C6H3 Me 5-Br-2MeOC6H3

R1

R′

R″

3

65 R

t/h

H H H Me H H H H H H H H H H H H H

Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me

H H H H Br I Br Br Br Br Br Br Br Br Br Br Br

3n 3n 3n 3z 3aa 3ab 3ac 3ad 3q 3r 3ae 3w 3af 3t 3u 3aa 3ag

H Me H H H H H H H H H H H H H

29 48 3 48 5 6 8 24 96 96 48 168 3 12 12

H H H H H

Me Me Me Me Me

Br Br Br Br Br

H H H

Me Me Me

Br Br Br

% yield

67 % ee (conf)

78

71−73

% yield

% ee (conf)

42

91

68− 70

t/h

% yield

% ee (conf)

ref

94

68 68

12 166

85 23

98 84

40 40 41 40 42 42 42 42 42 42 42 42 42 42 42 42 42

3ah 3aa 3t 3u 3ag

68 69 69 69 69

24 2.5 144 96 168

60 66 64 65 53

96 93 96 95 84

42 42 42 42 42

3ah 3aa 3ag

69 70 70

24 96 96

80 81 31

97 91 89

42 42 42

100 35 93 62 73 94 71 53 85 73 77 94 99

75 59 96 98 93 92 96 95 90 89 n.d. 99 96 (R)

a c

Reaction in i-PrOH/THF, Ac2O (1 equiv), at rt, with 10% mol catalyst. bReaction in t-BuOH/THF, Ac2O (1 equiv), at rt, with 10% mol catalyst. Reaction in EtOH at rt, with 2% mol catalyst. dReaction in THF, Ac2O (2 equiv), at rt, with 10% mol catalyst and 2,2,6,6-tetramethylpiperidine.

Q


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Scheme 22. Phenylboronic Acid Michael Addition to Enones 1


Scheme 23. Enantioselective Conjugate Addition of Me3Al to Enones 1

product (R)-82 is the key intermediate for the synthesis of Frondosin B, a marine sesquiterpene with biological activity isolated from the sponge Dysidea frondosa (Scheme 23).45 The Michael additions between 3-hydroxy-1-methylindolin2-one (83) and (1H-pyrrol-1-yl) styryl (1a) or (1H-indol-1-yl) styryl (2a) derivatives, both catalyzed by the dinuclear ZincProPhenol complex [(R,R)-Ib/2Zn(II)], have been reported by Trost and Hirano.46 The intrinsic reactivity of the Michael adducts (A) avoids their isolation, because these adducts undergo transesterification to afford 1′-methyl-3-phenyl-3Hspiro[furan-2,3′-indoline]-2′,5(4H)-dione (84) (Scheme 24). This is the same product obtained from phenyl cinnamate 85, under the same conditions, a product whose configuration has been unambiguously determined to be (2R,3R)-84. Sometimes the literature offers the discovery of a new family of catalysts that breaks aged conventions and disclose new unbeaten paths that mix the art of the synthesis, the choice of the ideal selective catalyst, and the development of new

intensity makes it useful in all areas of perfumery. In comparison with the racemate, the (S)-enantiomer has a more green, less watery, and more powerful fragrance.45 Analogously, but starting from (E)-3-p-tolyl-1-(1H-pyrrol-1yl)prop-2-en-1-one (1b) and using [(R)-IIe/Cu(OTf)2] as catalyst, the Michael adduct (S)-79 was obtained with excellent ee. By using the protocol illustrated above, followed by the nucleophilic addition of a Grignard reagent and the MnO2mediated oxidation, (+)-ar-turmerone [(S)-80], a potent antivenom against snake bites, was obtained with 96% ee.45 Whereas the enantioselective methylations of 1au and 1b, catalyzed by [(R)-II/Cu(OTf)2], afford products whose stereochemistry is consistent with a β-Si face approach of the nucleophile to the coordinated substrate, the Cu(II) complex of ligand (S)-p-spinol-phos (S)-XVII induces an opposite enantioselectivity. A nice example is the addition of Me3Al to the β-Re face of (E)-3-(5-methoxybenzofuran-2-yl)-1-(1Hpyrrol-1-yl)prop-2-en-1-one (1av) to give (R)-81. Its reduction R


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Scheme 24. Michael Addition Catalyzed by Trost’s Dinuclear Zinc Catalyst

Scheme 25. Proposed Mechanism for the Catalyzed Michael Addition of Oxazolone 86a to Enones 8

Table 9. Michael Addition of 4-Isopropyloxazol-5(4H)-one (86a) to 1-(1H-Benzo[d][1,2,3]triazol-1-yl)prop-2-en-1ones (8), Catalyzed by [(S,S)-XVIII/(ArOH)n]a (Scheme 25)48

supramolecular architectures. The new chiral P-spiro triaminoiminophosphoranes (S,S)-XVIII (a, R′ = i-Pr; R″ = Ph; b, R′ = i-Bu, R″ = Ph; c, R′ = i-Bu, R″ = 4-Me−C6H4; d, R′ = i-Bu, R″ = 4-F−C6H4) were prepared from the suitable (S)-Nmethyl-1,1-diarylpropane-1,2-diamines and PCl5. (S,S)-XVIII then assembles with 3 equiv of ArOH to give the catalytic active supramolecular architecture (A) through intramolecular hydrogen bonding, whose structure was determined by X-ray diffraction analysis.47 This species is the effective catalyst of the Michael reaction that reacts with the 4-isopropyloxazol-5(4H)-one (86a), in its enolate form, to give a new supramolecular structure (B) [(S,S)-XVIII/(ArOH)2/86a] in which the dichlorophenoxide has been replaced. The intermediate (B) loses 2 equiv of 3,5-dichlorophenol affording the reacting intermediate (C). Both the supramolecular structures (B) and (C) are the catalysts of the Michael reaction, in which the addition of the chiral oxazolyl anion to the 3-substituted (E)-1-(1H-benzo[d][1,2,3]triazol-1-yl)prop2-en-1-ones leads to the adducts 87 in very high yields and excellent enantioselectivities, releasing (S,S)-XVIII (Scheme 25 and Table 9).48 Finally, the absolute configuration of 87 was unambiguously determined to be (R) in the case of R = Me (Table 9, entry 3) by conversion into (S)-2-methylsuccinic acid (88) within three steps. Note that the apparent change in the absolute configuration is only due to the change of the substituent priority from R = Ar to R = Me. The next step was the optimization of the organocatalyst by testing different substituents; the optimized organocatalyst was used in the Michael reaction of several substituted dienyl- and trienyl-1-(1H-pyrrol-1-yl)-1-ones 1 (Scheme 26). These substrates require a further level of selectivity, because they may undergo either 1,6- or 1,8-addition in competition with the

87 entry

R

1 2 3 4 5 6 7 8 9 10 11 12

Ph Ph Me n-pentyl 2-phenethyl cyclohexyl 4-MeO−C6H4 4-Br−C6H4 3−Br−C6H4 2-Me−C6H4 1-naphthyl 2-furyl

8a 8a 8b 8c 8d 8e 8f 8g 8h 8i 8j 8k

(S,S)-XVIII: R′,R″

t/h

% yield

% ee (conf)

a: i-Pr, Ph b: i-Bu, Ph b: i-Bu, Ph b: i-Bu, Ph b: i-Bu, Ph b: i-Bu, Ph b: i-Bu, Ph b: i-Bu, Ph b: i-Bu, Ph b: i-Bu, Ph b: i-Bu, Ph b: i-Bu, Ph

4 4 2 1 2 4 24 21 4 8 12 22

99 95 97 96 92 93 98 98 96 90 91 91

87 95 96 (S) 95 96 98 97 98 95 93 95 96

a

ArOH is 3,5-dichlorophenol. The reactions have been performed in toluene at −40 °C.

usual 1,4-addition that was verified on the Michael reaction involving 4-substituted-oxazol-5(4H)-ones 86. The P-spiro chiral triaminoiminophosphorane (S,S)-XVIIId, with R′ = iBu and R″ = 4-F−C6H4, was the best organocatalyst, affording the reaction products 89 (for n = 1) and 91 (for n = 2) in excellent yields with excellent chemoselectivity, and a very high level of diastereo- and enantioselectivities (Table 10).49 Oxazol5(4H)-ones 86 add selectively the ω-position of (2E,4E)-5substituted 1-(1H-pyrrol-1-yl)penta-2,4-dien-1-ones 1 (n = 1) to afford 89. The absolute configuration can be assigned by taking into account that the adduct from entry 8 of Table 10 was converted into 90, whose absolute configuration was determined to be (S,R) by X-ray diffraction analysis (Scheme S


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Michael reactions, among the different approaching modes of 1az, the absolute configuration (S,R) of the product and the face selectivity induced by the organocatalyst must be considered. These conditions can be satisfied with the frontside approach of the Re face of 86 to the δ-Re face of 1az. The structure of [(S,S)-XVIIId/86/1az] reported in Scheme 27 gives rise to (S,R)-89, confirming the proposed mechanism in which the electrophile 1 is not involved in the coordination of the reacting intermediate. The only one example of Mukaiyama−Michael reaction concerning this kind of substrates reported in the literature deals with the reaction between (E)-ethyl 4-(3,5-dimethyl-1Hpyrazol-1-yl)-4-oxobut-2-enoate (3y) and either silylketene acetals 92 and 94 or enolsilane 93. The catalyst is the Cu(OTf)2 complex of L-DOPA-derived monopeptide (S)-XIX, and the adducts 95−97 have been obtained with good yields and high enantioselectivities (Scheme 28).50 The application of this catalyst to the Diels−Alder reaction of 3 will be discussed later, together with the β-Re approach to the Cu(II)/3 complex. All of the Michael reactions above reported, along with the variants that will be discussed in next sections, involve 1heterocyclic substituted prop-2-en-1-ones behaving as electrophiles, which react with reagents having a nucleophilic character. Hence, to imagine a reaction between 1-(pyrrol-1yl)prop-2-en-1-ones (1) and 3-substituted acrylaldehydes 99, the umpolung of one of the two electrophiles is obviously required. This has been reported in a recent paper51 in which 1


Scheme 26. Chemoselective Asymmetric Michael Addition to Polyenic Enones 1

26). Analogously, the (2E,4E,6E)-(1H-pyrrol-1-yl)hepta-2,4,6trien-1-one homologues 1 (n = 2) give chemo-, diastero-, and enantio-selectively the product 91 with 99% ee (Table 10, entries 14−17).49 As evidenced from all of the data in Table 10, the reactions are very regioselective, and this selectivity appears to be astonishing in entries 14−17 when, having three distinct possibilities (the 1,8-, the 1,6-, or the 1,4-addition), the addition occurs at the ω-position of the polyene chain only. Taking the intermediate C in Scheme 25 as a model for the reacting species [(S,S)-XVIIId/86] of the above vinylog

Table 10. Vinylog Variants of Enantioselective Michael Addition of Azalactones (86) to Substituted Dienyl- and Trienyl-1-(1Hpyrrol-1-yl)-1-ones 1,a Catalyzed by [(S,S)-XVIIIb−d] (Schemes 26 and 27)49 89b

86 entry

a

(R) part of R−CHCH− (CHCH)n

91

n=

1

R1

R2

(S,S)-XVIII: R′ = iBu; R″ =

t/h

yield (%)

Ph Ph Ph 2-MeO−C6H4 2,6-(MeO)2− C6H3 2,6-(MeO)2− C6H3 2,6-(MeO)2− C6H3 2,6-(MeO)2− C6H3 2,6-(MeO)2− C6H3 2,6-(MeO)2− C6H3 2,6-(MeO)2− C6H3 2,6-(MeO)2− C6H3 2,6-(MeO)2− C6H3 2,6-(MeO)2− C6H3 2,6-(MeO)2− C6H3 2,6-(MeO)2− C6H3 2,6-(MeO)2− C6H3

Bn Bn Bn Bn Bn

b: Ph c: 4-Me−C6H4 d: 4-F−C6H4 d: 4-F−C6H4 d: 4-F−C6H4

2 2 2 2 2

95 93 99 96 97

13:1 11:1 12:1 14:1 >20:1

92 86 94 91 98

Bn

d: 4-F−C6H4

2

94

>20:1

98

Bn

d: 4-F−C6H4

2

84

>20:1

98

Bn

d: 4-F−C6H4

3

99

>20:1

98 (S,R)

Bn

d: 4-F−C6H4

2

95

>20:1

98

Bn

d: 4-F−C6H4

2

98

>20:1

98

Bn

d: 4-F−C6H4

2

93

>20:1

97

Bn

d: 4-F−C6H4

2

96

>20:1

94

i-Bu

d: 4-F−C6H4

3

97

>20:1

94

Bn

d: 4-F−C6H4

10

89

>20:20:1

99

Bn

d: 4-F−C6H4

10

94

>20:20:95%. T


Chemical Reviews

Review

Scheme 27. Schematic Stereochemical Model for the Vinylog Michael Reaction


Scheme 28. Mukaiyama−Michael Addition of Silylketene Acetals or Enolsilanes to Enone 3y

becomes the nucleophile that reacts with 99 in a Mukaiyama− Michael reaction. 1-(2,5-Dimethyl-1H-pyrrol-1-yl)but-2-en-1one (1bh) and the homologue pent-2-en-1-one (1bi) were converted by NaHMDS and DMPU to the corresponding enolates, which were trapped with the suitable chlorosilane, affording vinylketene silyl N,O-acetals (Z)-98bh (R ′= H) and (1Z,3Z)-98bi (R′ = Me), whose structures were determined by X-ray analyses. The reactions of these nucleophiles with 99 were catalyzed by diphenylprolinolsilylether [(S)-XX]. The major products derived from the γ-vinylogous Michael addition were (S,E)-100bh (R′ = H) and (3R,4S,E)-100bi (R′ = Me), together with 101bh and 101bi as the side products deriving from an α-Michael addition (Scheme 29 and Table 11).51 The results show that the chemoselectivity depends on the silyl group, and the reaction of DPMS-substituted dienolate, whose steric hindrance shields the α-position, maximizes the γvinylogous Michael addition (Table 11, entries 1−4). Under these conditions, both (S,E)-100bh and (3R,4S,E)-100bi were obtained with excellent diastereo- and enantioselectivities (Table 11, entries 4−25). Finally, several reactions give (S,E)100bh as a single nearly pure enantiomer (Table 11, entries 6− 8, 11, and 13). The adducts of this unusual Michael reaction have one or two chiral centers, and two groups suitable for transformations. To explore their synthetic potentials, the acyl-(2,5-dimethyl1H-pyrrole) group of (S,E)-100bh (from entry 4 of Table 11) was either converted into the acetal protected and saturated N-

Scheme 29. Umpolung of Enones 1 Reactivity in the Mukaiyama−Michael Addition to 99

U


Chemical Reviews

Review

Table 11. Enantioselective Mukaiyama−Michael Addition between the Vinylketene Silyl N,O-Acetals (Z)-98bh (R′ = H) and (1Z,3Z)-98bi (R′ = Me), Derived from 1, and 3-Substituted Acrylaldehydes 99, Catalyzed by Diphenylprolinolsilylether [(S)XX] (Scheme 29)51 98 a


entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

1bh 1bh 1bh 1bh 1bh 1bh 1bh 1bh 1bh 1bh 1bh 1bh 1bh 1bh 1bh 1bi 1bi 1bi 1bi 1bi 1bi 1bi 1bi 1bi 1bi

99

101bhb

101bib

(S,E)-100bh

R′

SiR3

R

% yield

% yield

H H H H H H H H H H H H H H H Me Me Me Me Me Me Me Me Me Me

TMS TES DMPS DPMS DPMS DPMS DPMS DPMS DPMS DPMS DPMS DPMS DPMS DPMS DPMS DPMS DPMS DPMS DPMS DPMS DPMS DPMS DPMS DPMS DPMS

Ph Ph Ph Ph 2-NO2−C6H4 3-MeO−-C6H4 4-MeO−C6H4 PhMe2Si 3-Me−C6H4 4-Me−C6H4 1-naphthyl 2-naphthyl 2-furyl 2-thienyl 3-thienyl Ph 4-MeO−C6H4 3-Me−C6H4 4-Me−C6H4 1-naphthyl 2-naphthyl 2-furyl 2-thienyl 2-Me−C6H4 4-Cl−C6H4

35 13 16 11 23 0 trace 0 14 15 trace 7 trace 15 13

55 67 70 80 55 81 80 75 74 68 83 69 95 75 61

% ee (conf) 95 97 >97 98 95 98 98 99 97 97 97 95 90 95 95

(3R,4S,E)-100bi

% yield

% yield

drc

% ee (conf)

6 2 14 11 trace 22 3 16 14 12

78 82 54 68 76 56 78 54 69 70

12:1 14:1 7:1 9:1 14:1 9:1 9:1 9:1 7:1 7:1

98 99 96 99 98 99 99 98 97 98

(S) (S) (S) (S) (S) (S) (S) (S) (S) (S) (S) (S) (S) (S) (S) (3R,4S) (3R,4S) (3R,4S) (3R,4S) (3R,4S) (3R,4S) (3R,4S) (3R,4S) (3R,4S) (3R,4S)

a Reaction performed with 10% mol (S)-XX, in toluene/ethanol (1:1), and 10% mol p-nitrobenzoic acid. bYields of chromatographically purified products. cThe diastereomeric ratio was determined by 1H NMR spectroscopy on crude product mixtures.

acyl pyrrole (S)-104, which was easily transformed into the corrresponding acid, ester, aldehyde, and keto derivatives (105−108), or into the tetrahydropyranyl derivatives [(2S,4R)-102 and (2S,4R)-103] with the formation of a new chiral center.51 The Michael addition to electron-deficient alkenes often concerns the nitronate nucleophiles derived from nitroalkanes. This variant affords adducts in which the reduction of the nitro group produces chiral amines, and the utility of these adducts in multiple useful transformations is enhanced by the presence of an easily removable heterocyclic auxiliary. An excellent catalyst for the reaction involving nitromethane (109: R1 = R2 = H) is the NiX2 complex of DBFOX/Ph [(R,R)XV/Ni(II)], which was previously encountered in other Michael reactions. The addition to various (E)-3-substituted 1-(3,5-dimethyl-1H-pyrazol-1-yl)prop-2-en-1-ones (3) affords the adducts 110 (Scheme 30).52 The data in Table 12 show that the enantioselectivity is excellent (up to >99% ee) and the catalyst is very flexible with many different substituents on 3, even if the bulky tert-butyl group depresses the reactivity (Table 12, entries 11 and 12). The octahedral structure of the complex [(R,R)-XV/NiX2/ 3H2O], determined by X-ray diffraction analysis,53,54 allows one to propose for the reacting complex the less sterically hindered structure [(R,R)-XV/Ni(II)/3]. Coordinated 3 is then approached by nitromethane to its β-Re face affording 110 with the observed (R) absolute configuration. Better results were obtained by using 4 Å MS as an additive, by the optimization of the solvent (nitromethane/tert-butanol),

Scheme 30. Enantioselective Nitromethane Michael Addition to Enones 3

and by taking acetate as the nickel counterion (Table 12, entries 2, 4, 9, 12, 15, and 17).41,55 V


Chemical Reviews

Review

Table 12. Catalytic Enantioselective Michael Reaction between Nitromethane 109 (R1 = H) and Various Substituted 1-(Pyrazol1-yl)prop-2-en-1-ones (3), Catalyzed by the NiX2 Complex of (R,R)-XV (Scheme 30)a


NiX2 entry

R

R′

R″

1b 2c 3b 4d 5b 6b 7b 8b 9c 10b 11b 12c 13b 14b 15c 16b 17c 18b 19b 20b 21b

Me Me Me Me Me Et n-Pr i-Pr i-Pr cyclohexyl t-Bu t-Bu (E)-MeCHCH CO2Me CO2Et Ph Ph 3,4-(OCH2O)C6H3 2-furyl 2-thienyl 3-(c-C5H9O)-4-MeOC6H3

Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me

H H Br Br I H H H H H H H H H H H H H H H H

3n 3n 3aa 3aa 3ab 3ai 3aj 3x 3x 3ak 3al 3al 3am 3an 3y 3b 3b 3ao 3ap 3aq 3ar

110

X=

T/°C (t/h)

yield (%)

% ee (conf)

ref

ClO4 OAc ClO4 OAc ClO4 ClO4 ClO4 ClO4 OAc ClO4 ClO4 OAc ClO4 ClO4 OAc ClO4 OAc ClO4 ClO4 ClO4 ClO4

−20 (96) rt (3) −20 (96) rt (24) −20 (96) 0 (24) −20 (96) −20 (168) rt (72) −20 (168) 0 (168) rt (72) −20 (96) rt (3) rt (2) −20 (168) rt (12) −20 (168) −20 (96) −20 (168) −20 (168)

85 quant 97 95 62 93 96 74 71 90 39 25 49 91 90 90 77 77 75 83 91

94 >99 95 98 96 94 91 97 96 91 95 98 77 83 98 93 >99 98 97 97 98 (R)

52 55 52 41 52 52 52 52 55 52 52 55 52 52 55 52 55 52 52 52 52

a

Reaction performed with 10% mol catalyst. bReaction carried out in nitromethane/THF (1:1 v/v). cReaction carried out in nitromethane/t-BuOH (1:1 v/v) with 4 Å MS. dReaction carried out in nitromethane/t-BuOH (1:1 v/v) with 5% mol catalyst.

Table 13. Catalytic Enantioselective Michael Reaction between Nitroalkanes 109 and Various Substituted 1-(Pyrazol-1-yl)prop2-en-1-ones (3) or 1-(Pyrrol-1-yl)prop-2-en-1-ones (1), with Cinchona-alkaloid-thiourea Organocatalyst (R,R,R)-XII and (S,S,R)-XXIa (Scheme 31)a 112b

109 entry

R

1 or 3 or 9 or 10

R1

R2

organocat.

t [h]

% yield

1a 2 3 4 5 6b 7c 8b 9b 10b 11b 12b 13b 14b 15b 16b 17b 18b

CF3 CF3 CF3 CF3 CF3 Ph Ph 4-MeO−C6H4 4-Cl−C6H4 2-furyl 2-thienyl (E)-2-phenethyl (Z)-2-phenethyl cyclohexyl CH2CH−(CH2)8 Ph−CHCH−CHCH 3-(c-C5H9O)-4-MeOC6H3 3-(c-C5H9O)-4-MeOC6H3

3p 3p 3p 3p 3p 1a 10a 1c 1d 1q 1r (E)-1h (Z)-1h 1j 1bj 1bk 1bl 9bl

H CO2Me CO2Me CO2Et CO2Et H H H H H H H H H H H H H

H Me Et Me Et H H H H H H H H H H H H H

(R,R,R)-XII (R,R,R)-XII (R,R,R)-XII (R,R,R)-XII (R,R,R)-XII (S,S,R)-XXIa (S,S,R)-XXIa (S,S,R)-XXIa (S,S,R)-XXIa (S,S,R)-XXIa (S,S,R)-XXIa (S,S,R)-XXIa (S,S,R)-XXIa (S,S,R)-XXIa (S,S,R)-XXIa (S,S,R)-XXIa (S,S,R)-XXIa (S,S,R)-XXIa

24 48 48 48 48 87 99 146 64 146 146 23 65 78 22 139 183 72

91 75 83 71 76 93 93 90 88 81 59 95 81 93 87 54 78 25e

dr

% ee (conf)

4.4:1 9.5:1 5.4:1 9.9:1

93 (R) 88 80 90 (R,R) 86 (R,R)

114 % ee

115/116 % ee (conf)

93 96 (R) 93 89 93 92 93 −34d 94 90 94 93 82e

ref 36 36 36 36 36 56 56 56 56 56 56 56 56 56 56 56 56 56

a

The reaction performed under the same conditions with 3-[(E)-4,4,4-trifluorobut-2-enoyl]oxazolidin-2-one afforded 3-[(R)-4,4,4-trifluoro-3(nitromethyl)butanoy]oxazolidin-2-one in 93% yield and 94% ee. bReaction carried out in nitromethane at 25−50 °C. cReaction carried out in toluene at 25 °C; the product was (R)-116. dEnantiomeric excess refers to the opposite enantiomer isolated from the reaction in entry 12. eThe product isolated was 115.

The synthetic potential of the adducts is successfully demonstrated by the short synthesis of the antidepressant and phosphodiesterase inhibitor (R)-Rolipram [(R)-111]. It was obtained from the adduct (R)-110 described in Table 12

(entry 21), which has the suitable (3-cyclopentyloxy-4methoxyphenyl) R substituent. Its reduction with hydrogen and Raney Ni gives 72% yield of 4-(3-cyclopentyloxy-4W


Chemical Reviews

Review


Scheme 31. Organocatalyzed Nitroalkane Michael Additions

one [(Z)-1h] that gives the opposite enantiomer obtained from (E)-1h, but in 34% ee only (Table 13, entry 13 vs 12). The same organocatalyst (S,S,R)-XXIa (Scheme 31) was tested in two other experiments regarding two specific substrates. First was the reaction between nitromethane and ( E ) - 1 - ( 9 H - c a r b a z o l - 9 - y l ) - 3 - [ 3 - ( c y c lo p e n t y l o x y ) - 4 methoxyphenyl]prop-2-en-1-one (9bl) to give 115 with 82% ee (Table 13, entry 18). Second was the reaction between nitromethane and chalcone (10a), which is more important because the (R) absolute configuration of the reaction product 116 suggests an approach of the nucleophile to the β-Re face of the electrophiles (Table 13, entry 7).56

methoxyphenyl)-2-pyrrolidinone [(R)-111] with an excellent enantiomeric purity (Scheme 30).52 When the Michael reaction with substituted nitroalkanes 109 (R1 ≠ R2 ≠ H) affords products with quaternary stereocenters, the catalyst, in addition to enantioselectivity, must also control diastereoselectivity. The epi-cinchonine-derived thiourea (R,R,R)-XII, which catalyzes the reaction between 1-(pyrazol1-yl)-4,4,4-trifluoro-2-buten-1-one (3p) and nitromethane to afford (R)-112 in 91% yield and 93% ee (Table 13, entry 1), is the organocatalyst suitable also for the reaction between 3p and substituted nitroacetic esters 109 (R1 = CO2Me or CO2Et, and R2 = Me or Et) (Scheme 31). The adducts 112 were obtained in about 85% ee, the diastereomeric ratio was between 4.4 and 9.9:1, and the major stereoisomer was (R,R)-112 (Table 13, entries 2−5).36 The absolute (R,R)-configuration of the adducts 112, obtained from the reactions of either nitropropanoates or nitrobutanoates, was determined by X-ray crystallographic analysis of their reduced derivatives 113a and 113b, and derives from the addition of the nucleophile to the β-Si face of 3p.36 The above results can be compared to those obtained from the reaction between nitromethane 109 (R1 = R2 = H) and substituted 1-(pyrrol-1-yl)prop-2-en-1-ones (1), catalyzed by the epi-quinidine-derived thiourea (S,S,R)-XXIa (R′ = Et), which afford adducts 114 in yields depending on the nature of R, but always with enantioselectivity above 90% ee (Scheme 31, Table 13).56 The ee was 93% also with 3-[(3-(cyclopentyloxy)4-methoxyphenyl)]-1-(1H-pyrrol-1-yl)prop-2-en-1-one (1bl), which was converted to Rolipram (111). The exception is the reaction with (Z)-5-phenyl-1-(1H-pyrrol-1-yl)pent-2-en-1-

4.1. Aza-Michael Reactions

Usually the Michael reactions form a new C−C bond, but the reaction may comprise other variants characterized by the formation of new C−X bonds in which X may be a nitrogen, an oxygen, a sulfur, or a phosphor atom.57−59 The aza-Michael reaction, with formation of a C−N bond, is interesting because it allows easy access to chiral β-amino acids. Useful catalysts for the reaction between methoxylamine (117a) and various substituted 1-(pyrrol-1-yl)prop-2-en-1ones (1) are the heterobimetallic complexes in which three (S)-BINOL are coordinated by one lanthanide [Y(III) or Dy(III)] and three lithium cations [3(S)-IIb/Ln(III)/Li3], giving the C3v symmetrical structure schematically reported in Scheme 32. With β-alkyl substituted (pyrrol-1-yl)propenones (Table 14, entries 5−14), the reaction proceeds smoothly with both Y(III) and Dy(III) catalysts and gives high yields (84− 96%) and high ee (83−94%). With β-aryl-substituted (pyrrol-1yl)propenones (Table 14, entries 1, 3, and 4), the reaction with the Dy(III)-based catalyst gives both lower yields and ee. Their reactivity is also significantly lower than that of chalcone 10a X


Chemical Reviews

Review

Scheme 32. Aza-Michael Route to β-Amino Acids and Aziridines

hydrogenation and the protection of the amino group gave the Boc-protected β-aminoester (S)-122 (Scheme 32).60 The aza-Michael reaction between benzyloxylamine (117b) and various 3-substituted (E)-1-(3,5-dimethyl-1H-pyrazol-1yl)prop-2-en-1-ones (3) can be catalyzed by the MgBr2 or Y(OTf) 3 complexes of (3aS,3′aS,8aR,8′aR)-2,2′cyclopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) [(S,R)-XXII]. Whereas the former catalyst favors the addition to the β-Si face of 3 affording (S)-123, the latter gives the opposite enantiomer (R)-123 through attack to the β-Re face of 3 (Scheme 33). The results are reported in Table 15 (entries 1,


Scheme 33. Box/Mg(II)-Catalyzed Aza-Michael Addition

(Table 14, entry 2).60 The absolute configuration of the products 118 and 119 was determined to be (S), which is the result of the approach of 117a to the β-Si face of either 1 or 10a. There is a close structural analogy between the complex structure of the above catalyst [3(S)-IIb/Ln(III)/Li3] and the “star” configuration of the catalyst [3(S)-IV/La(OiPr)3/Li3] used in the cyclopropanation of 1a and 10a (Scheme 11).24,25 Moreover, the approach of the nucleophilic species to the reacting intermediates of both of the reactions is always to the β-Si face of the coordinated reactants. The adduct (S)-118 (R = Ph), with TiCl4 and Et3N, afforded the corresponding chiral aziridine (2S,3R)-120; then the treatment with NaOMe converts the acyl-pyrrole group into an ester functionality affording (2S,3R)-121. The catalytic

2, 5, 8−10, and 12). The yields are usually acceptable, while the enantioselectivities obtained from the Mg(II)-based catalyst are better than those obtained by using Y(III) as the Lewis acid.61

Table 14. Catalytic Enantioselective Aza-Michael Reaction between Methoxylamine (117a) and Various Substituted 1-(Pyrrol-1yl)prop-2-en-1-ones (1), Catalyzed by the Ln(III)/Li(I) Heterobimetallic (S)-BINOL Complexes [3(S)-IIb/Ln(III)/Li3] (Scheme 32)60 entry

R

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Ph Ph 3-Cl−C6H4 4-CF3−C6H4 i-butyl i-butyl n-propyl n-propyl 2-phenethyl 2-phenethyl CH2CH−(CH2)6 CH2CH−(CH2)6 i-Pr i-Pr

1a 10a 1p 1bm 1ae 1ae 1t 1t 1h 1h 1bn 1bn 1an 1an

catalyst

t [h]

% yield

118 % ee (conf)

[3(S)IIb/Dy(III)/3Li] [3(S)IIb/Y(III)/3Li] [3(S)IIb/Dy(III)/3Li] [3(S)IIb/Dy(III)/3Li] [3(S)IIb/Y(III)/3Li] [3(S)IIb/Dy(III)/3Li] [3(S)IIb/Y(III)/3Li] [3(S)IIb/Dy(III)/3Li] [3(S)IIb/Y(III)/3Li] [3(S)IIb/Dy(III)/3Li] [3(S)IIb/Y(III)/3Li] [3(S)IIb/Dy(III)/3Li] [3(S)IIb/Y(III)/3Li] [3(S)IIb/Dy(III)/3Li]

165 24 107 107 38 62 38 38 38 38 38 62 106 114

53 94 63 49 96 92 91 97 86 94 84 89 94 91

81 (S)

Y

119 % ee (conf) 97 (S)

80 (S) 82 (S) 94 (R) 94 (R) 83 (R) 86 (R) 83 (R) 85 (R) 89 (R) 89 (R) 86 (R) 84 (R) DOI: 10.1021/acs.chemrev.5b00097 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

Table 15. Addition of Monosubstituted Hydroxylamines (117b−d) to 1-(3,5-Dimethyl-1H-pyrazol-1-yl)prop-2-en-1-ones (3) Catalyzed by Complexes of [(S,R)-XXII] and by (R,S)-XXIII as Organocatalyst (Schemes 33 and 34)


123

a

entry

R

1a 2b 3 4 5a 6 7 8a 9a 10a 11 12a 13 14 15 16 17

Me Me Me Me Et Et n-Pr CH2C6H11 CH2Ph i-Pr i-Pr Ph Ph cyclohexyl CO2Et CO2Et CH2OPMP

3n 3n 3n 3n 3ai 3ai 3j 3as 3at 3x 3x 3b 3b 3ak 3y 3y 3au

117 (R1)

catalyst or organocatalyst

t/h

% yield

Bn Bn Bn Ph2CH Bn Ph2CH Ph2CH Bn Bn Bn Ph2CH Bn Bn Ph2CH Ph2CH TBDMS Ph2CH

[(S,R)-XXII/MgBr2] [(S,R)-XXII/Y(OTf)3] (R,S)-XXIII (R,S)-XXIII [(S,R)-XXII/MgBr2] (R,S)-XXIII (R,S)-XXIII [(S,R)-XXII/MgBr2] [(S,R)-XXII/MgBr2] [(S,R)-XXII/MgBr2] (R,S)-XXIII [(S,R)-XXII/MgBr2] (R,S)-XXIII (R,S)-XXIII (R,S)-XXIII (R,S)-XXIII (R,S)-XXIII

22 22 72 96 22 168 138 22 22 22 216 72 72 288 96 96 24

80 67 82 86 74 92 84 53 80 76 68 24 19 59 50 42 98

% ee (config) 92 59 87 89 92 91 88 90 95 87 90 83 67 89 94 90 98

(R) (S) (S) (S)

(R)

ref 61 61 63 63 61 63 63 61 61 61 63 61 63 63 63 63 63

Reaction carried out at −60 °C with 0.3 equiv of catalyst. bReaction carried out at −60 °C with 1 equiv of catalyst.

Scheme 34. Proposed Mechanism for Thiourea-Organocatalyzed Michael Addition

octahedral coordination for Mg(II), and the different axial/ equatorial or equatorial/equatorial coordination for the Mg(II) versus the Y(III) complex.61,62 The aza-Michael reaction between 1-(3,5-dimethyl-1Hpyrazol-1-yl)prop-2-en-1-ones (3) and O-alkylhydroxylamines (117b−d: R1 = Bn, Ph2CH, and tert-butyldimethylsilyl) was performed with 1-(3,5-bis(trifluoromethyl)phenyl)-3-[(1R,2S)2,3-dihydro-2-hydroxy-1H-inden-1-yl]thiourea [(R,S)-XXIII] as organocatalyst. The reaction in Scheme 34 is suggested to occur through a mechanism schematized by the working model illustrated, in which both of the reagents are coordinated to the organocatalyst. The consequent addition of 117b to the β-Re face of 3b rationalizes the observed absolute configuration determined for (R)-123 (R = Ph), Table 15, entry 13.63 The results, listed in Table 15, are comparable to those obtained with [(S,R)-XXII/ MgBr2]. The limits of both of the reactions lie in the amount of catalyst required (30 mol %), because at a lower catalytic loading, selectivity decreases.61 A single example of aza-Michael reaction involving (E)-1(1H-imidazol-1-yl)-3-phenylprop-2-en-1-one (5a) and 1H-

The aza-Michael addition to (E)-1-(3,5-dimethyl-1H-pyrazol-1-yl)but-2-en-1-one (3n), catalyzed by [(S,R)-XXII/Mg(ClO4)2], was also tested by using benzylhydrazine (124) as the nucleophile to provide access to optically active pyrazolidinones. This is related to the easy cleavage of the pyrazole/carbonyl bond that occurs “in situ” on the major primary adduct (S)-125 that, spontaneously, undergoes intramolecular substitution losing pyrazole to give (S)-126 as the main product in 58% ee, together with the regioisomer 127 (55% ee) in a ratio [70:30] (Scheme 33). The enantioselectivity of the reaction may be increased by replacing the pyrazole moiety with the corresponding N-phenylamide: (S)126 was obtained in 92% yield, with a [98:2] dr, and in 84% ee.62 The opposite stereochemical outcome obtained by using the (S,R)-XXII-based catalysts requires a comment. The MgBr2based complex induces a β-Si face appoach, whereas the Mg(ClO4)2 gives rise to a β-Re face approach, the same induced by the Y(OTf)3-based complex. This has been rationalized as the result of a bidentate coordination of 3 to the Lewis acid that discriminates the different tetrahedral versus Z


Chemical Reviews

Review


Scheme 35. Organocatalyzed Benzotriazole Michael Addition

Scheme 36. Intramolecular Organocatalyzed Michael Addition

Table 16. Intramolecular Aza-Michael Reaction of 3aj−3av (Eventually Formed in Situ from 132 and DMP) That Give (S)-131 with (S,S,R)-XXIVa as Organocatalyst (Scheme 36)65 3 entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

3av 3av 3aw 3aw 3ax 3ay 3az 3ba 3ba 3bb 3bc 3bd 3be 3bf 3bg 3bh

m

n

1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1 1 2 1 1 1 1

1 1 1 1 1

Y

131 X

CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CCHCHCHCHC CCHCHCHCHC CCHCHCHCHC O CH2 CH2 CMe2 N-Bn CO C(CO2Et)2 CH2

Ar

protocol

solvent

% yield

% ee (config)

Ph Ph 4-Me−C6H4 4-Me−C6H4 4-MeO−C6H4 4-CF3−C6H4 Ph 4-Me−C6H4 4-Me−C6H4 4-Me−C6H4 4-Me−C6H4 4-Me−C6H4 4-Me−C6H4 4-Me−C6H4 4-Me−C6H4 4-Me−C6H4

A A A B A A A A B A A A B B B B

CHCl3 CPME CPME CPME CPME CPME CPME CPME CPME CPME CPME CPME CPME CPME CPME CPME

55 92 91 62 70 91 98 84 57 93 84 88 83 53 55 53

96 93 92 90 93 90 80 76 64 (S) 80 87 70 99 87 86 87

AA


Chemical Reviews

Review


Scheme 37. Organocatalyzed Sulfa-Michael Addition to Enones 3

benzo[d][1,2,3]triazole (128) was catalyzed with the epiquinidine-derived thiourea (S,S,R)-XXIb (R′ = vinyl),64 an organocatalyst very similar to the chiral thiourea (S,S,R)-XXIa described in Scheme 31 and used in the reaction between 1 and nitromethane. The result reported in Scheme 35 is certainly not astonishing from the point of view of yield and enantioselectivity, but it deserves attention. The adduct is the 3-1Hbenzotriazolyl-1-imidazolyl-3-phenylpropanone (129), similar to (R)-130, obtained from 10a, whose absolute configuration was determined by X-ray crystallography. If, by analogy, the absolute configuration (R) is assumed also for 129, the adducts of the reactions in Scheme 34 derive from an attack of the nucleophile 128 to the β-Re face of the electrophiles, the same observed in the Michael reaction of 1, catalyzed by (S,S,R)XXIa. Therefore, two different reactions, with different reagents (1, 5a, and 10a) all behaving as monodentate reagents, with two similar organocatalysts, give the same stereochemical result through transfer of the same stereochemical information by similar reacting intermediates. Recently, the intramolecular variant of the aza-Michael reaction has been reported.65 The (E)-1-(3,5-dimethyl-1Hpyrazol-1-yl)-7-(tosylamino)hept-2-en-1-one derivatives (3) have an NH group, whose acidity is increased by the tosyl substituent, suitable to give addition to the β-position of the α,β-unsaturated carbonyl moiety. The organocatalyst of choice is the squaramide incorporating cinchona alkaloid (S,S,R)XXIVa (R′ = ethyl) that, in cylopentyl methyl ether (CPME) at 50−90 °C, activates the approach to the β-Si face of the substrate to afford several derivatives with the (S)-1-(3,5dimethyl-1H-pyrazol-1-yl)]-2-(1-tosylpiperidin-2-yl)-1-ethanone scaffold (S)-131. The products were obtained in very good yields and with up to 96% ee (Scheme 36, protocol A, Table 16). The reaction can be also performed under the tandem peptide coupling conditions (protocol B) outlined in Scheme 36, in which the acid 132 is allowed to react with 3,5dimethylpyrazole (DMP) and diisopropyl carbodiimide (DIC). In the presence of the organocatalyst, the coupling product 3 undergoes the in situ intramolecular aza-Michael reaction

producing (S)-131 in moderate yields and appreciable enantioselectivities (Table 16). The transformation of the pyrazole moiety of the pyrrolidine derivative 131 reported in entry 9 of Table 16 into the ethyl ester derivative (S)-134 allows one to determine the absolute configuration of the aza-Michael reaction product. This conversion is paradigmatic of the philosophy of this Review: “the heterocycles as masked bricks to build chiral scaffolds”, because any attempt to perform a chiral aza-Michael reaction on ethyl 7-sulfonamido-2-heptenoate 133 with (S,S,R)-XXIVa as organocatalyst was unsuccessful and (S)-134 can be obtained only through a masked route. 4.2. Sulfa-Michael Reactions

The enantioselective sulfa variant of the Michael reaction allows the construction of chiral building blocks bearing a sulfur atom at the stereogenic center. Only a few recent examples with Nacyliden penta-atomic aza-heterocycles as Michael acceptors have been reported in the literature, all with excellent results. (E)-4,4,4-Trifluoro-1-(3,5-dimethyl-1H-pyrazol-1-yl)but-2en-1-one (3bi) can be considered the synthetic equivalent of the expensive cis-4,4,4-trifluorocrotonate, and hence an interesting candidate for the sulfa-Michael reaction with thiophenols 135. After a screening of several bifunctional amine-thiourea-based organocatalysts, the best one was found to be 1-[(1R,2R)-2-(dimethylamino)cyclohexyl]-3-[(1R,2R)-2(3,5-bistrifluoromethyl-1-benzenesulfonamido)-1,2diphenylethyl]thiourea [(R,R,R,R)-XXV] that catalyzes the conversion of 3bi into (S)-4,4,4-trifluoro-1-(3,5-dimethyl-1Hpyrazol-1-yl)-3-(arylthio)butan-1-ones (S)-136, Scheme 37.66 The results, reported in Table 17, show the excellent results in terms of yields and enantioselectivities obtained from 3bi with different arylthiophenols. The results show a collapse of the ee with benzylthiophenol (Table 17, entry 17) and allow one to evaluate the role of the halogen as pyrazole substituent (Table 17, entries 1, 4, and 5), and the importance of both the electron-withdrawing CF3 group (Table 17, entries 1−3) and the sulfur nucleophile in terms of reactivity and enantioselectivity. AB


Chemical Reviews

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Table 17. Catalytic Enantioselective Sulfa-Michael Reaction between Thiophenols 135, or 140, and Various Substituted 1(Pyrazol-1-yl)prop-2-en-1-ones (3), with Thiourea Organocatalysts (R,R,R,R)-XXV and (S,S,R)-XXIc (Schemes 37 and 38)


136 entry

R

R′

R″

1a 2b 3c

CF3 Me Ph CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 Me Et n-Pr i-Pr n-pentyl cyclohexyl n-octyl PhCH2CH2 Ph 2-Me−C6H4 3-Me−C6H4 4-Me−C6H4 4-MeO−C6H4 2-Cl−C6H4 3-Cl−C6H4 4-Cl−C6H4 4-Br−C6H4 2-naphthyl 2-furyl

Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me

H H H Br I H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H

4a,d 5a,d 6a 7a 8a 9a 10a 11a 12a 13a 14a 15a 16a 17a 18e 19e 20e 21e 22e 23f 24f 25e 26e 27e 28e 29e 30e 31e 32e 33e 34e 35e 36e

3bi 3n 3b 3bj 3bk 3bi 3bi 3bi 3bi 3bi 3bi 3bi 3bi 3bi 3bi 3bi 3bi 3n 3ai 3aj 3x 3bl 3ak 3bm 3bn 3b 3c 3d 3e 3k 3bo 3bp 3f 3h 3l 3ap

142

135 (R1) or 140

organocatalyst

% yield

% ee (conf)

Ph Ph Ph Ph Ph 2-Me−C6H4 3-Me−C6H4 4-Me−C6H4 2-MeO−C6H4 3-MeO−C6H4 4-MeO−C6H4 3-CF3−C6H4 4-F−C6H4 4-Cl−C6H4 3-Br−C6H4 2-naphthyl benzyl 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140

(R,R,R,R)-XXV (R,R,R,R)-XXV (R,R,R,R)-XXV (R,R,R,R)-XXV (R,R,R,R)-XXV (R,R,R,R)-XXV (R,R,R,R)-XXV (R,R,R,R)-XXV (R,R,R,R)-XXV (R,R,R,R)-XXV (R,R,R,R)-XXV (R,R,R,R)-XXV (R,R,R,R)-XXV (R,R,R,R)-XXV (R,R,R,R)-XXV (R,R,R,R)-XXV (R,R,R,R)-XXV (S,S,R)-XXIc (S,S,R)-XXIc (S,S,R)-XXIc (S,S,R)-XXIc (S,S,R)-XXIc (S,S,R)-XXIc (S,S,R)-XXIc (S,S,R)-XXIc (S,S,R)-XXIc (S,S,R)-XXIc (S,S,R)-XXIc (S,S,R)-XXIc (S,S,R)-XXIc (S,S,R)-XXIc (S,S,R)-XXIc (S,S,R)-XXIc (S,S,R)-XXIc (S,S,R)-XXIc (S,S,R)-XXIc

94 90 82 85 89 90 91 95 89 90 96 88 92 91 94 96 85

93 (S) 80 63 82 86 93 94 93 97 93 93 (S) 90 88 88 90 94 69

% yield

88 85 72 80 88 65 90 70 87 85 88 89 86 90 92 90 94 87 91

dr

98:2 97:3 97:3 93:7 96:4 96:4 98:2 94:6 99:1 98:2 97:3 98:2 97:3 97:3 95:5 98:2 98:2 97:3 95:5

% ee (conf)

ref

98 96 97 91 97 93 98 98 99 99 99 98 97 97 98 99 97 99 (2S,3R,4S) 95

66 66 66 66 66 66 66 66 66 66 66 66 66 66 66 66 66 67 67 67 67 67 67 67 67 67 67 67 67 67 67 67 67 67 67 67

a

Reactions carried out with 5% mol organocatalyst at rt for less than 10 min. bReaction carried out with 10% mol organocatalyst at rt for 15 h. Reaction carried out with 10% mol organocatalyst at rt for of 28 h. dReaction run in DCM. eReactions carried out with 1% mol organocatalyst at 0 °C in diethyl ether. fReactions carried out with 5% mol organocatalyst at −10 °C. c

Scheme 38. Domino Sulfa-Michael Reaction To Give Thiochromenyl Derivatives

reaction derives from a β-Si face approach of the nucleophile,

The absolute configuration of 136 was determined to be (S) by converting the adducts from entries 1 and 11 to the acids 137, which gave (S)-2-(trifluoromethyl)-7-arylthiochroman-4ones 138 that were reduced to (S,S)-139 of known configuration. Hence, the stereochemical outcome of the

and the reacting intermediate reported in Scheme 37 [(R,R,R,R)-XXV/3/135] rationalizes the obtained absolute configuration. AC



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Review

With 2-mercaptobenzaldehyde (140), derivatives 3 afford a domino sulfa-Michael reaction in which the primary products 141 undergo an intramolecular aldol reaction giving rise to 2substituted (3,4-dihydro-4-hydroxy-2H-thiochromen-3-yl)(1Hpyrazol-1-yl)methanones (142) (Scheme 38). The use of epi-quinidine-derived thiourea (S,S,R)-XXIc as the organocatalyst induces the (2S) absolute configuration in 141. The intramolecular addition then creates two further stereocenters to give 142 with an excellent control of the diastereo- and enantioselectivity either when the substituent R of the acceptor 3 is an alkyl (Table 17, entries 18−25) or an aryl group (Table 17, entries 26−36).67 For the product in Table 17, entry 35, the absolute configuration was unequivocally determined to be (2S,3R,4S) by X-ray crystallographic analysis. The results of the reactions in Schemes 37 and 38 show the efficiency of chiral thioureas as organocatalysts, with the pyrazole nitrogen and the CO group of 3 behaving as Hbond acceptors and the thiophenol as H-bond donor. These cooperative interactions give rise to a reacting intermediate that allows a very enantioselective intramolecular sulfa-Michael reaction. The discussion of this topic is completed with a domino sulfa-Michael reaction involving (E)-1-(1H-benzo[d][1,2,3]triazol-1-yl)but-2-en-1-one (8b) and thiophenol 135 through an addition/thioesterification process.68 With squaramide incorporating cinchona alkaloid (S,S,R)-XXIVb (R ′= vinyl) as organocatalyst, the first step is the addition of thiophenol to the β-position of enone, followed by the easy nucleophilic substitution of benzotriazole by thiophenol in the thioesterification step. The final product is therefore (S)-phenyl 3(phenylthio)butanethioate [(S)-143], whose absolute configuration derives from the β-Si face approach to 8b (Scheme 39, conventionally R is Ph, see Figure 2).

Scheme 40. Tautomeric Equilibrium Phosphonate− Phosphite or Phosphine Oxide−Phosphinous Acid

23, in 2009 Wang and coworkers investigated the reaction between 1 and phosphites 144 with the Zn(II) complex of (2S,2′S)-1,1′-[(2-hydroxy-5-methyl-1,3-phenylene)bis(methylene)]bis(diphenyl)-2-pyrrolidinemethanol [(S,S)-Ib] as catalyst, Scheme 41.71 The reaction can be applied to a wide Scheme 41. Phospha-Michael Addition Catalyzed by Trost’s Dinuclear Zinc Complex

Scheme 39. Sulfa-Michael Addition to Benzotriazole Enone 8b

4.3. Phospha-Michael Reactions

The enantioselective phospha-Michael addition consists of the reaction between an electrophilic double bond and the phosphorous atom of either dialkyl or diaryl phosphonates (144), or secondary alkyl or aryl phosphine oxides (145). These reagents may undergo phosphonate−phosphite (144/ 144′) or phosphine oxide−phosphinous acid tautomerization (145/145′), in which the second tautomer is the effective reacting nucleophile (Scheme 40). The phospha-Michael products are relevant chiral scaffolds because they can be easily converted into β- or γ-substituted phosphonates. For this reason, the identification of efficient chiral catalysts for the reaction involving substituted 1-(1H-pyrrol-1-yl)prop-2-en-1ones (1) was pursued, because these adducts are suitable for easy further elaborations.69 Starting from Trost’s dinuclear zinc-ProPhenol catalyst,70 already discussed in the Michael reaction reported in Scheme

range of substituents on both reagents, and the products 146, whose absolute configuration was determined to be (S), were always obtained with excellent yields and with up to >99% ee. The same catalyst was used in the reaction between 10a and 144 (R″ = Et), and the product was (S)-147, obtained again with excellent yield and enantioselectivity (Table 18, entry 3).72 Analogous results were obtained with dialkyl phosphine oxides 145, which afford substituted 3-(dialkylphosphine oxide)-1-(1H-pyrrol-1-yl)propan-1-ones (S)-153 (Scheme 42, Table 18).73 Toluene was the solvent of choice for the reactions in Schemes 41 and 42, and its importance will be emphasized later. The synthetic utility of (S)-146 was demonstrated by a series of modifications (Scheme 41). The pyrrolyl phosphonates were transformed into acids (S)-151, esters (S)-148, and amides (S)149. The acid 151 was reduced to β-amino phosphonates (S)AD


Chemical Reviews

Review

Table 18. Catalytic Enantioselective Phospha-Michael Reaction of Phosphites (144) or Phosphine-oxides (145) with Various Substituted 1-(1H-Pyrrol-1-yl)prop-2-en-1-ones (1), with 20 mol % [(S,S)-Ib/2Zn(II)] as Catalysts (Schemes 41 and 42) 146b


a

153c

entry

R

1 or 10

144 R″

% yield

% ee (conf)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

Ph Ph Ph Ph Ph Ph 4-Me−C6H4 4-MeO−C6H4 4-Cl−C6H4 4-Br−C6H4 4-F−C6H4 2-furyl 2-thienyl 3-thienyl 3-MeO−C6H4 2-MeO−C6H4 4-NO2−C6H4 1-naphthyl 2-naphthyl Ph−CHCH 2-phenethyl n-propyl i-propyl n-hexyl i-butyl 2-F−C6H4 3,4-(OCH2O)C6H3

1a 1a 10a 1a 1a 1a 1b 1c 1d 1o 1bo 1q 1r 1bp 1bq 1br 1bs 1f 1g 1bt (E)-1h 1t 1an 1bu 1ae 1bv 1bw

Me Et Et n-Pr i-Pr Ph Et Et Et Et Et Et Et Et Et Et Et Et Et Et Et Et Et Et Et

93 99 98d 98 95 96 99 99 96 98 96 99 99 94 94 94 96 95 97 91 96 93 99 98 92

95 >99 (S) 99 (S) >99 97 92 >99 >99 >99 >99 98 >99 >99 >99 99 98 98 98 >99 >99 >99 98 99 98 >99

145 R″

% yield

% ee (conf)

Et

99

97

n-Pr n-But allyl Et Et Et Et Et Et Et Et Et Et Et Et Et Et Et Et Et Et Et Et Et

96 99 99 98 98 97 99 99 96 98

98 >99 96 97 99 95 96 (S) 96 98 98

97 90

97 97

90 99

94 95

99

98

96 90 91 94 96

98 98 >99 95 98

ref 71 71, 72 71, 71, 71, 71, 71, 71, 71, 71, 71, 71, 71 71, 71, 71 71, 71, 71 71, 71 71, 71, 71, 73 73

73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73

a

Reactions usually run for 12 h at room temperature. bReaction carried out with 4 Å molecular sieves as additive. cReaction carried out with 10 equiv of pyridine as additive. dThe product of this reaction was (S)-147.

Scheme 42. Enantioselective Dialkyl Phosphine Oxide Michael Reaction

Scheme 43. Enantioselective Phospha-Michael Reaction of Diallyl Phosphine Oxide

152, while the amide 149 was converted under a standard protocol into the corresponding γ-amino derivative (S)-150.71 The asymmetric phospha-Michael reaction of diallyl phosphine oxide 145 (R″ = allyl) was also performed with 3,3-disubstituted-1-(1H-pyrrol-1-yl)prop-2-en-1-ones (1), whose products 154 have tetrasubstituted carbon stereocenters (Scheme 43).74 The catalyst was the zinc complex of (2S,2′S)1,1′-[(2-hydroxy-5-methyl-1,3-phenylene)bis(methylene)]bis[α,α-di-2-thienyl]-2-pyrrolidinemethanol [(S,S)-Ia], which was already encountered in the phospha Michael reaction of Scheme 1. The difference between this thienyl-substituted Ia and its phenyl analogue Ib mentioned above is the assumed possibility of thiophene sulfur atoms to participate in the coordination with zinc.5,74 Five (E)-3,3-disubstituted-1-pyrrolyl-propenones (Table 19, entries 1 and 5−9) were tested with very good results. The use of the stereoisomer (Z)-1ak instead of (E)-1ak allowed one to obtain the opposite enantiomer 154 in comparable yield and selectivity (Table 19, entries 8 and 9).

The same reaction with 20 mol % [(S,S)-Ia/2Zn(II)] was also performed between diallyl phosphine oxide and (E)-1,3diphenylbut-2-en-1-one [(E)-10aj] to afford (S)-155 (Scheme 43). The interesting feature is the different conditions under which the reaction catalyzed by [(S,S)-Ia/2Zn(II)] was performed: THF only, THF and 1 equiv of pyridine as additive, toluene and 1 equiv of pyridine (Table 19, entries 2− 4). The best yield was obtained with toluene and pyridine, but all of the conditions afforded excellent enantioselectivities (99% ee). The conclusion is that the zinc complexes of (S,S)-I are excellent catalysts for the phospha-Michael reaction between AE


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Review

Me2S·BH3 the borane-phosphine complex (S)-159 (Table 20, entry 3), and with S8 affords the phosphine sulfides (S)-160 (Table 20, entry 4), Scheme 44.75 Hence, the catalyst [(S,S)XXVI/Pd] coordinates 1 in such a selective fashion that the approach of the nucleophile occurs to its β-Si face. Among all of the reaction products listed in Table 20, a note is deserved to the reaction between (2E,4E)-5-phenyl-1-(1Hpyrrol-1-yl)penta-2,4-dien-1-one (1bt) and diphenylphosphine because it gives the 1,4-adduct 6-phenyl-3-(diphenylphosphino)-1-(1H-pyrrol-1-yl)pent-4-en-1-one [(S)-161] in a completely regioselective fashion (Table 20, entry 11).76 The excellent enantioselectivity of these phospha-Michael reactions is the starting point for a useful route to the synthesis of chiral phosphine-oxazoline ligands. The phosphine sulfide (S)-160 (Table 20, entry 4) was hydrolyzed to the acid (S)-162 that undergoes amidation with (R)-valine to give (R,S)-163. After the reduction of the carboxylic ester group, an intramolecular cyclization affords (5R,2′S)-164. The desulfurization with Raney-Ni produces (R)-4,5-dihydro-4-isopropyl-2[(S)-2-phenyl-2-(diphenylphosphino)ethyl]oxazole [(5R,2′S)165], a useful bidentate ligand in Pd-enantioselective catalyzed allylic alkylations. In conclusion, Tables 18−20 report more than 70 examples of enantioselective phospha-Michael reactions, with different catalysts, different P(III) and P(V) nucleophiles, and a variety of 1-(1H-pyrrol-1-yl)prop-2-en-1-ones (1); in all cases, the enantioselectivity was >90% ee.

Table 19. Catalytic Enantioselective Phospha-Michael Reaction of Diallyl-phosphine-oxides (145: R″ = Allyl) with 3,3-Disubstituted-1-(1H-pyrrol-1-yl)prop-2-en-1-ones (1) or Chalcone (10aj), with 20 mol % [(S,S)-Ia/2Zn(II)] as Catalyst (Scheme 43)74 154 or 155a


entry

R

R′

1b 2c

Ph Ph

Me Me

3c

Ph

Me

4c

Ph

Me

5b

4-MeO− C6H4 4-Cl−C6H4 2-naphthyl n-But Me

6b 7b 8b 9b

solvent (additive)

% yield

% ee (conf)

toluene (Py) THF

88 75

>99 99 (S)

THF (Py)

89

99 (S)

toluene (Py)

94

99 (S)

Me

(E)-1aj (E)10aj (E)10aj (E)10aj (E)-1bx

toluene (Py)

91

96

Me Me Me n-But

(E)-1by (E)-1bz (E)-1ak (Z)-1ak

toluene toluene toluene toluene

96 93 90 95

94 94 98 -97

(Py) (Py) (Py) (Py)

a

The reactions in entries 2−4 give 155 as product. bReaction carried out at 40 °C for 12 h. cReaction carried out at 60 °C for 12 h.

substituted 1-(1H-pyrrol-1-yl)prop-2-en-1-ones (1) and dialkyl phosphites 144, or secondary alkyl phosphine oxides 145. All of the above reactions have been run with P(V) reagents as nucleophiles. The tailor-made catalyst for the enantioselective phospha-Michael reaction of P(III) nucleophiles is the [(1S,1′S)-2,6-bis-[1-(diphenyl-phosphino)ethyl]phenyl]acetoxypalladium complex [(S,S)-XXVI/Pd] (usually known as PCP pincer−Pd complex). This catalyst allows one to obtain excellent results in terms of yield and enantioselectivity in the reaction between diarylphospines 156 and 1 to give 3substituted-3-(diarylphosphino)-1-(1H-pyrrol-1-yl)propan-1ones 157, whose absolute configuration was determined to be (S) (Table 20, entry 1). The reaction product was submitted to further transformations: with H2O2 it gives the corresponding phosphinoxides (S)-158 (Table 20, entries 2, 5−17), with

5. RADICAL REACTIONS In all of the previously described reactions, the substrate bound to a [chiral ligand/Lewis acid] complex is attached by a neutral or by a negatively charged nucleophile. The reactions discussed in this section have a radical species as the second reagent. In 1997 Sibi and co-workers developed a radical reaction performed on 1-(3,5-dimethyl-1H-pyrazol-1-yl)-3-phenylprop2-en-1-one (3b) with different alkyl iodides in the presence of Et3B/O2 and Bu3SnH, catalyzed by stoichiometric amounts of the Zn(OTf)2 complexes of (S,R)-XXVII and (S,R)-XXII.77

Table 20. Catalytic Enantioselective Phospha-Michael Reaction between Diarylphosphine (156) and 3-Substituted 1-(1HPyrrol-1-yl)prop-2-en-1-ones (1) with 2 mol % [(S,S)-XXVI/Pd] as Catalyst (Scheme 44)a entry

R

1

156 Ar

% yield

157 ee (%) (conf)

1b 2 3c 4d 5 6 7 8 9 10 11e 12 13 14 15 16 17

Ph Ph Ph Ph 4-Me−C6H4 4-MeO−C6H4 4-Cl−C6H4 3-Br−C6H4 2-naphthyl 2-furyl Ph−CHCH Me i-Pr i-butyl cyclohexyl Ph Ph

1a 1a 1a 1a 1b 1c 1d 1ca 1g 1q 1bt 1al 1an 1ae 1j 1a 1a

Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph 4-MeO−C6H4 4-Cl−C6H4

91 95 99 98 99 99 98 97 95 94 90 93 92 93 99 98 97

99 (S)

158 ee (%) (conf)

159 ee (%) (conf)

160 ee (%) (conf)

99 (S) 99 (S) 98 (S) 99 99 >99 (S) 99 99 97 96 (S) 91 94 96 96 97 98

ref 75 75 75 75 75 75 75 75 75 75 76 75 75 75 75 75 75

a

Reactions performed 2−24 h at rt in THF, with 2 mol % catalyst, then quenched with 30% H2O2. bReaction carried out without quenching reagents. cReaction quenched with 2 equiv of Me2S·BH3. dReaction quenched with 1 equiv of S8. eData referred to product 161. AF


Chemical Reviews

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Scheme 44. Enantioselective Phospha-Michael Reaction of P(III) Nucleophiles

The radical derives from the cleavage of the Alk−I bond promoted by Et3B/O2, and the new radical is quenched with Bu3SnH to give (S)-166 (Alk = I-Pr), which is formally the product of the conjugate addition of Alk-H to 3 (Scheme 45).

Addition of isopropyl radical to either 2-methyl-1-(1Hpyrazol-1-yl)prop-2-en-1-one (3bq) and its 3,5-dimethyl analogue (3br), or with 1-(1H-indazol-1-yl)-2-methylprop-2en-1-one (4b), was run with stoichiometric amounts of [(S,R)XXII/MgBr2] as the catalyst (Table 21, entries 9−11). The results were good in terms of reaction yields, but the enantioselectivities were again unsatisfactory. It is important to take into account that, in these reactions, the chiral center is generated in the second step of the process, when the H radical attaches the α-position of 3bq, 3br, or 4b. In all three examples, the configuration of the products 166 and 167 is always (R).79 What makes perhaps unsatisfactory the enantioselectivity of the radical alkylation reaction reported in Table 21 is not the efficiency of the Zn(II) or Mg(II) Box-based catalysts in coordinating 3 or 4, but the lack of a well-organized reacting intermediate around the Lewis acid. This aspect was exploited in the reaction involving 1-(3,5-dimethyl-1H-pyrazol-1-yl)-3phenylprop-2-en-1-ones (3) that react with alkyl iodides bearing a β- or γ-hydroxy group (168). Scheme 46 reports the reaction in which both 3 and 168 can be coordinated (3 by the carbonyl and one nitrogen atom, 168 by the hydroxy group) around the Lewis acid of the chiral catalyst to give the reacting intermediate 169. After quenching and ring closure of 169, the chiral lactones 170 were obtained.80 After testing different chiral ligands, such as (S)-XV that gave good results with Ni(II) as the Lewis acid, the ligand of choice was found to be (S,R)-XXII, and the accurate optimization of the Lewis acid led to the identification of Mg(NTf2)2 as the best salt for more efficient catalyst: the reaction product was (S)-170, which was obtained in good ee with different R substituents (Table 22).80 It is interesting to compare the results reported in Tables 21 and 22. In both cases, the reactions lead to products deriving from the approach of the radical species to the β-Si face of substrates 3, but the high level of enantioselectivity observed in the reaction involving the hydroxy-alkyl iodides 168 confirms

Scheme 45. Radical Addition Catalyzed by Box-Based Catalysts

The results, poor in terms of enantioselectivity, are reported in Table 21 (entries 1−6). The decrease of the catalyst concentration to 0.3 equiv leads to a further decrease of the enantioselectivity (Table 21, entry 3 vs 2). A variant of the catalyst, with (S,R)-XXII as the ligand and Mg(NTf2)2 or Mg(ClO4)2 as the Lewis acid, gives results even more disappointing than those with Zn(II) (Table 21, entries 7 and 8). These disappointing results are enforced by the comparison with the reaction of 3-(3-phenylacryloyl)oxazolidin-2-one (A1), because in this case the same catalyst allows one to obtain products with more than 90% yield with enantioselectivities ranging from 94% to 98% ee.78 AG


Chemical Reviews

Review

Table 21. Catalytic Enantioselective Radical Addition of Alkyl Iodides on Various Substituted 1-(Pyrazol-1-yl)prop-2-en-1-ones (3) or 1-(1H-Indazol-1-yl)-2-methylprop-2-en-1-ones (4b) Catalyzed by Zn(II) or Mg(II) Box Complexes (Scheme 45) 166 or 167 entrya

R

R2

R′

3 or 4

Alk-I, Alk =

ligand

Lewis acid

% yield

1a 2a 3b 4a 5a 6a 7b 8b 9a 10a 11a

Ph Ph Ph Ph Ph Ph Ph Ph H H H

H H H H H H H H Me Me Me

Me Me Me Me Me Me Me Me H Me H

3b 3b 3b 3b 3b 3b 3b 3b 3bq 3br 4b

iPr iPr iPr Et cyclohexyl cyclohexyl iPr iPr iPr iPr iPr

(S,R)-XXVII (S,R)-XXII (S,R)-XXII (S,R)-XXII (S,R)-XXVII (S,R)-XXII (S,R)-XXII (S,R)-XXII (S,R)-XXII (S,R)-XXII (S,R)-XXII

Zn(OTf)2 Zn(OTf)2 Zn(OTf)2 Zn(OTf)2 Zn(OTf)2 Zn(OTf)2 Mg(NTf2)2 Mg(ClO4)2 MgBr2 MgBr2 MgBr2

72 76 84 80 88 81 80 62 52 54 66c

% ee (conf) 43 51 39 39 43 81 14 2 15 38 15

ref

(S) (S) (S) (R)

77 77 77 77 77 77 78 78 79 79 79

(R) (R) (R)c


a Reaction performed with stoichiometric amount of ligand and Lewis acid. bReaction performed with 0.3 equiv of ligand and Lewis acid. cData refer to product 167.

the role of the OH group in the coordination of the Lewis acid giving rise to the well-organized reacting intermediate 169 (Scheme 46). Another approach to the radical addition was accomplished by using the CuCl complex of (4R,7S)-4,5,6,7-tetrahydro-7isopropyl-4-methyl-3-phenyl-1H-indazole [(R,S)-XXVIII] as the catalyst. The reaction between 3b and MeMgI with a stoichiometric amount of the square tetramer catalyst affords 1(3,5-dimethyl-1H-pyrazol-1-yl)-3-phenylbutan-1-one (171) in 60 % yield and 33% ee. The absolute configuration was determined by converting the product into the corresponding 3-phenylbutanoic acid [(S)-172] and is consistent with the reacting intermediate A reported in Scheme 47.81 As it can be evaluated from the above results, satisfactory catalytic conditions to perform an enantioselective conjugate radical addition on the substrates considered in this Review are not yet reported, and good results are obtained by using stoichiometric amounts of “catalyst” only. Further research in the field should be welcome.

Scheme 46. Catalytic Enantioselective Radical Addition of Hydroxy-Alkyl Iodides

Table 22. Catalytic Enantioselective Radical Addition of Hydroxy-Alkyl Iodides 168 to Various Substituted 1-(Pyrazol-1yl)prop-2-en-1-ones (3) Catalyzed by Complexes of (S,R)-XXII and (S)-XV (Scheme 46)80 168

a

entrya

R

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

PhCH2CH2 PhCH2CH2 PhCH2CH2 PhCH2CH2 PhCH2CH2 PhCH2CH2 Ph 2-furyl 4-CF3−C6H4 cyclohexyl PMPOCH2 PMPOCH2 4-CF3−C6H4 PhCH2CH2 4-CF3−C6H4

n 3bn 3bn 3bn 3bn 3bn 3bn 3b 3ap 3i 3ak 3au 3au 3i 3bn 3i

1 1 1 1 1 1 1 1 1 1 1 1 1 2 2

170 R1

Me Me

ligand

Lewis acid

% yield

(S,R)-XXII (S,R)-XXII (S,R)-XXII (S,R)-XXII (S,R)-XXII (S)-XV (S,R)-XXII (S,R)-XXII (S,R)-XXII (S,R)-XXII (S,R)-XXII (S,R)-XXII (S,R)-XXII (S,R)-XXII (S,R)-XXII

Zn(OTf)2 MgI2 Mg(OTf)2 Mg(ClO4)2 Mg(NTf2)2 Ni(ClO4)2 Mg(NTf2)2 Mg(NTf2)2 Mg(NTf2)2 Mg(NTf2)2 Mg(NTf2)2 Mg(NTf2)2 Mg(NTf2)2 Mg(NTf2)2 Mg(NTf2)2

40 33 58 53 50 38 48 40 81 68 85 71 53 68 64

% ee (conf) 55 55 32 44 85 88 85 79 80 81 48 40 28 92 87

(R) (S) (S) (S)

Reaction performed with stoichiometric amount of ligand and Lewis acid. AH


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XXVIII, already used in the radical reaction discussed in Scheme 47, were tested (Scheme 48). The Mg(ClO4)2 complex of bis [(4R,7R)-4,5,6,7-tetrahydro7-isopropyl-4-methylindazol-1-yl]methane [(R,R,R′,R′)-XXX] was tested in the D.A. reaction between cyclopentadiene 173 and acyl-substituted pyrazoles 3 bearing different substituents on either the acyl group or the pyrazole ring. The results are reported in Table 23 (entries 2−8), but yields, diastereo-, and enantioselectivities were unsatisfactory and lower than the results obtained with the PhBox-based catalyst (Table 23, entry 1).83 The methylene group, spacer of XXX, was then replaced with a 1,3-disubstituted phenyl or a 2,6-disubstituted pyridine affording (R,S,R′,S′)-XXXIa and (R,S,R′,S′)-XXXIb. 84 (4R,7S)-4,5,6,7-Tetrahydro-3-[6-(4R,7S)-4,5,6,7-tetrahydro-7isopropyl-2,4-dimethyl-2H-indazol-3-yl]pyridin-2-yl)-7-isopropyl-2,4-dimethyl-2H-indazole [(R,S,R′,S′)-XXXIb] was tested as chiral ligand in the D.A. reaction involving 3bs. The use of Zn(OTf)2 affords 174 with better enantioselectivities than those obtained by using Mg(ClO4)2 as Lewis acid (Table 23, entry 10 vs 11). Furthermore, this catalyst is less enantioselective than [(R,S,R′,S′)-XXXIa/Zn(OTf)2] because the ee was halved (Table 23, entry 10 vs 9). Other substituents on the pyrazole ring do not influence significantly the reaction enantioselectivity (Table 23, entries 13−15). The best enantioselectivity for 174 was obtained with [(R,S,R′,S′)XXXIb/Ni(ClO4)2] if 1 equiv of butyllithium is added to the reaction (Table 23, entry 12).84 Because the more complex new ligands XXX and XXXIb do not improve the results obtained with the more simple PhBoxbased catalyst, other studies involving the use of the IndaBox XXII as chiral ligand, one of the best Box ligands used in enantioselective catalysis, were performed. However, the enantioselectivity obtained by using [(S,R)-XXII/Cu(OTf)2] as the catalyst was worse than that observed by using (S)PhBox and Mg(ClO4)2 (see Scheme 48 and Table 23, entry 1), as demonstrated by the reaction between 3bs and cyclopentadiene because (S)-174 was isolated in 85% yield, with an endo/exo ratio of [38:1], but with an ee of 28% only (Scheme 49). The same catalyst gave a slightly better result in the reaction between 1-(1H-indazol-1-yl)prop-2-en-1-one (4c) and


Scheme 47. Radical Addition by Using Stoichiometric Amounts of Indazole/CuCl Complex

6. DIELS−ALDER REACTIONS The Diels−Alder reaction (D.A.) is generally a relevant section of reviews dealing with catalytic enantioselective reactions, because innovative and sophisticated catalysts are usually experimented in this cycloaddition before their extention to other enantioselective processes. This is true only in part for Nacyliden aza-heterocycles, and several classic catalysts discussed in the previous sections will be also applied to the D.A. reaction. As an extension of the study on the diastereoselective D.A. reaction of 2-(α,β-unsaturated)acyl-3-phenyl-l-menthopyrazoles,82 some exploratory experiments were performed between 1-(3,5-dimethyl-1H-pyrazol-1-yl)prop-2-en-1-one (3bs) and cyclopentadiene (173) with (S,S)-diphenyl-Box and Mg(ClO4)2 [(S)-XXIX/Mg(ClO4)2]. The reaction gave the endo product 174 in 69% yield and 60% ee, besides its exo isomer 175 (Scheme 48, Table 23, entry 1).83 Having concluded that acyl-substituted pyrazoles are promising dienophiles for the enantioselective D.A. reaction, different classes of chiral ligands were explored, and those derived from tetrahydro-1H-indazole Scheme 48. Enantioselective Diels−Alder Reaction of Enones 3

AI


Chemical Reviews

Review

Table 23. Catalytic Enantioselective Diels−Alder Reaction between Various Substituted 1-(Pyrazol-1-yl)prop-2-en-1-ones (3) and Cyclopentadiene Catalyzed by the Mg(II) Complexes of (S)-XXIX and (R,R,R′,R′)-XXX or the Zn(II) Complexes of (R,S,R′,S′)-XXXIa,b (Scheme 48) entrya


b

1 2b 3b 4b 5b 6b 7b 8b 9c 10c 11c 12c 13c 14c 15c

R

R′

H H Me Ph CO2Et Me H H H H H H H H H

Me Me Me Me Me H t-Bu Ph Me Me Me Me H t-Bu Ph

3bs 3bs 3n 3b 3y 3bt 3bu 3bv 3bs 3bs 3bs 3bs 3bw 3bu 3bv

ligand

Lewis acid

T/°C

% yield

[174]:[175]

% ee 174 (conf)

ref

(S)-XXIX (R,R,R′,R′)-XXX (R,R,R′,R′)-XXX (R,R,R′,R′)-XXX (R,R,R′,R′)-XXX (R,R,R′,R′)-XXX (R,R,R′,R′)-XXX (R,R,R′,R′)-XXX (R,S,R′,S′)-XXXIa (R,S,R′,S′)-XXXIb (R,S,R′,S′)-XXXIb (R,S,R′,S′)-XXXIb (R,S,R′,S′)-XXXIa (R,S,R′,S′)-XXXIa (R,S,R′,S′)-XXXIa

Mg(ClO4)2 Mg(ClO4)2 Mg(ClO4)2 Mg(ClO4)2 Mg(ClO4)2 Mg(ClO4)2 Mg(ClO4)2 Mg(ClO4)2 Zn(OTf)2 Zn(OTf)2 Mg(ClO4)2 Ni(ClO4)2d Zn(OTf)2 Zn(OTf)2 Zn(OTf)2

n.r. 0 30 0 0 30 0 0 0 0 0 0 0 0 0

80 81 42 7 85 62 40 51 98 84 58 82 60 44 62

86:14 84:16 76:24 85:15 71:29 73:27 91:9 87:13 95:5 92:8 92:8 94:6 95:5 91:9 85:15

60 40 (S) 25 15 0 12 21 35 33 67 13 75 48 33 23

83 83 83 83 83 83 83 83 84 84 84 84 84 84 83

a

Reactions performed in CH2Cl2 in the presence of 4 Å molecular sieves (MS). bReactions performed with 0.1 equiv of catalyst. cReactions performed for 5 h at 0 °C with 10% mol catalyst. dHexahydrate salt; the reaction requires an equimolar amount of butyllithium.

optimization of the different ligands then led one to choose the Cu(II) complex of (S)-2-(cyclopentylamino)-3-(3,4-dimethoxyphenyl)-1-(pyrrolidin-1-yl)propan-1-one [(S)-XIX] as the best catalyst giving (S)-174 in 97% yield, [98:2] dr, and 97% ee. Excellent diastereo- and enantioselectivities were also observed with all of the other dienes (Table 24, entries 8− 13). Finally, the Cu(OTf)2 or Cu[N(Tf)2]2 complexes of (S)XIX in dry acetonitrile were the optimized conditions for the reactions of six heterocyclic dienophiles with five dienes to give the products with enantioselectivity in the range 90−98% ee (Table 24, entries 14−23).50 The authors highlighted these results in two specific accounts,86,87 and the results were rationalized assuming the complex [(S)-XIX/Cu(II)/3], whose geometry was derived from the crystal structure of bis (L-tyrosinato)Cu(II) complex, as the reacting intermediate.88 The shielding of the 3,4dimethoxyphenyl group forces the diene cycloaddition to the βRe face of 3 (R = Ph) inducing the enantioselective formation of (S)-174 (Scheme 50). That the Cu(II) complexes of ligands (S)-XIX and (S)XXXII have other applications as catalysts in the D.A. reactions of a new family of reagents, 3-substituted 1-(3,5-dimethyl-1Hpyrazol-1-yl)prop-2-yn-1-one (3′), has to be introduced (Scheme 51). The D.A. reaction was first tested by using the [(S)-XIX/Cu(NTf2)2] as catalyst in MeCN to give 183 in high yield with good level of enantioselectivity (Table 25, entry 1). This satisfactory result was further improved by using (S)-2(cyclopentylamino)-3-(naphthalen-3-yl)-1-(pyrrolidin-1-yl)propan-1-one [(S)-XXXIIIa] as the chiral ligand. The optimized reaction condition required CH2Cl2 as the solvent and MS 4 Å as additive (Table 25, entry 4 vs 2 and 3).89 Under the optimized conditions, 3′n, 3′bs, and 3′bz (R = Me, H, I) were made to react with cyclopentadiene (173) and with other dienes 182a−d. The D.A. reaction with cyclopentadiene gave (1R,4S)-183 with 88−89% ee (Table 25, entries 4−6), while with cyclohexadienes 182a−d the products (1R,4S)-184a−c and 185 were obtained with enantioselectivities in the range 87−97% ee (Scheme 51, Table 25, entries 7− 13). These excellent results make [(S)-XXXIIIa/Cu(NTf2)2] the catalyst of choice for this reaction. The absolute

Scheme 49. IndaBox/Cu(II)-Catalyzed Diels−Alder Cycloadditions

cyclopentadiene, affording the endo product (S)-176 in good yield, with excellent endo/exo ratio, and appreciable ee (Scheme 49).85 The best catalyst for the D.A. reaction was the Cu(II) complex of L-DOPA-derived monopeptides (S)-XIX, already applied with success to the Mukaiyama−Michael reaction between 3y and silylketene acetals (Scheme 28). The reaction between substituted 1-(3,5-dimethyl-1H-pyrazol-1-yl)prop-2en-1-ones (3) and different dienes (173, 178a−c, and 179) was catalyzed with the Cu(II) complexes of (S)-XIX and also with three different variants of the basic ligand structure [(S)XXXIIa−c]. The results are described in Scheme 50 and Table 24.50 The first experiments were performed on the reaction between 3bs and 3n (Scheme 50, R = H and Me, respectively) with cyclopentadiene, which gave the endo adducts (S)-174 together with small amounts of exo-175. Two reaction conditions were employed: the Cu(NO3)2 complex of (S)XXXIIa in water as solvent (Table 24, entries 1 and 2) and the Cu(OTf)2 complex with the same ligand in wet MeCN solutions (Table 24, entry 3). The best results were obtained under the latter conditions, but an enantioselective D.A. reaction giving 85% ee in water is a very interesting result. The AJ


Chemical Reviews

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Scheme 50. Asymmetric Diels−Alder Reaction Catalyzed by Cu(II) Complex of L-DOPA-Derivatives

Table 24. Catalytic Enantioselective Diels−Alder Reaction between Substituted 1-(3,5-Dimethyl-1H-pyrazol-1-yl)prop-2-en-1ones (3) and Various Dienes Catalyzed by the CuX2 Complexes of L-DOPA-Derived Monopeptides (S)-XIX and (S)-XXXIIa−c (Scheme 50)50,86,87 entry a

1 2a 3a 4a 5a 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

R H Me H H Me H H H H H H H H Me Me Ph CO2Et CO2Et CO2Et CO2Et CO2Et OCOPh Cl

3bs 3n 3bs 3bs 3n 3bs 3bs 3bs 3bs 3bs 3bs 3bs 3bs 3n 3n 3b 3y 3y 3y 3y 3y 3bx 3by

dienes

ligand

X

solvent

T/°C (t/h)

173 173 173 173 173 173 173 173 173 173 178a 178b 179 173 173 173 173 178a 178c 178b 179 173 173

(S)-XXXIIa (S)-XXXIIa (S)-XXXIIa (S)-XXXIIb (S)-XXXIIb (S)-XXXIIb (S)-XXXIIc (S)-XIX (S)-XIX (S)-XIX (S)-XIX (S)-XIX (S)-XIX (S)-XIX (S)-XIX (S)-XIX (S)-XIX (S)-XIX (S)-XIX (S)-XIX (S)-XIX (S)-XIX (S)-XIX

NO3 NO3 OTf OTf OTf OTf OTf OTf OTf OTf OTf OTf OTf N(Tf)2 OTf N(Tf)2 OTf N(Tf)2 N(Tf)2 N(Tf)2 N(Tf)2 N(Tf)2 N(Tf)2

H2O H2O MeCNb MeCNb MeCNb MeCNb MeCNb MeCNb EtCNc MeCNc MeCNc MeCNc MeCNc MeCNc MeCNc MeCNc MeCNc MeCNc MeCNc MeCNc MeCNc MeCNg MeCNc

0 23 −40 −40 23 −40 −40 −40 −78 −40 −40 −40 0 −40 0 0 −20 0 23 −20 0 23 −20

(2) (8) (13) (13) (20) (7) (3.5) (0.7) (7) (6) (22) (7) (49) (24) (17.5) (40) (7) (39) (72) (5) (64) (6) (5)

% yield

dr

88 3 >99 >99 24 >99 30 97 99 >99 88 85 63 95 97 93 97 93 83 96 76 89 95

>90:10 >90:10 >90:10 >90:10 >90:10 98:2 98:2 98:2 99:1 98:2

174 % ee (conf) 85 72 78 92 76 87 66 97 98 97

180a−c % ee

181 % ee

(S) (S) (S) (S) (S) (S) (S) (S) (S) (S) 97d 97e 91

97:3 95:5 93:7 91:9

97 (S) 89 (S) 95 98 91d 87f 97e 93

93:7 >99:1

90 97

a Reaction run in the presence of base (NaOH or Et3N). bWet. cDried over MS 3 Å. dThe product is 180a. eThe product is 180b. fThe product is 180c. gThe solvent is MeCN/THF in the ratio 2:1.

AK


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Scheme 51. Diels−Alder versus [2+2] Cycloadditions of Enones 3′

7. 1,3-DIPOLAR AND FORMAL [3+2] CYCLOADDITION REACTIONS The Cu(NTf2)2 complex of 2-cyclopentylamino-3-(2-naphthyl)-1(pyrrolidin-1-yl)propan-1-one [(S)-XXXIIIa], previously used in D.A. and [2+2] cycloadditions, was also tested in the 1,3-dipolar cycloadditions between 3-substituted 1-(3,5dimethyl-1H-pyrazol-1-yl)prop-2-yn-1-one (3′) and several azomethine imines 192. The reaction gave 5,7-disubstituted6-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-2,3-dihydropyrazo[1,2-a]pyrazol-1(5H)-one derivatives [(R)-193], whose absolute configuration derives from the less hindered approach of 192 to 3′ bicoordinated to the Cu(II) complex of (S)-XXXIIIa (Scheme 52).90 The model of the reacting intermediate [(S)XXXIIIa/Cu(II)/3′], represented in Scheme 52, evidences the unfavorable steric interaction between the cyclopentyl moiety of the ligand (S)-XXXIIIa and the incoming 1,3-dipole. This suggested that one changes the cyclopentyl group Y with smaller alkyl groups. The reactivity and the enantioselectivity ameliorated when Y was a cyclobutyl group [(S)-XXXIIIb] (2.5 h, 95% ee), but further reductions of the size of Y [(S)XXXIIIc,d] were uneffective (Table 26, entries 1−4).90 The Cu(II) complex of (S)-XXXIIIb was used in the cycloadditions of other cycloaddends by changing R in 3′ and R′ in 192. The best results in terms of enantioselectivity (≥

configurations of products (1R,4S)-183 and (1R,4S)-184a suggest [(S)-XXXIIIa/Cu(II)/3′] as the reaction intermediate in which the shielding of the naphthyl group forces the approach of the dienes to the (CO)−Si face of 3′ through an exo-transition state (Scheme 51), affording the cycloadducts with the observed absolute configurations. Unexpectedly, when the reaction was performed with 2methoxy-5,5-dimethylcyclohexa-1,3-diene (186), [2+2] cycloadduct 189 was obtained with 80% ee in 65% yield (Table 25, entry 14) without any formation of D.A. product. This is probably due to the steric hindrance of 5,5-dimethyl substituents that depresses the diene character of 186. The [2+2] cycloaddition process is again the preferred pathway in reactions involving trialkylsilyloxy-1-cyclopentadienes 187a,b, and its 2-methyl analogue 188 to give 190 with about 80% ee and (1S,5R)-191 (83% ee), respectively.89 The formation of the [2+2] cycloadduct 191 could be due to a stepwise mechanism (Michael-aldol reaction pathway), but, if we consider the HOMO of 188 and the LUMO of 3′, the FMO interaction may also allow the concerted transition state schematized in Figure 5. AL


Chemical Reviews

Review

Table 25. Catalytic Enantioselective Diels−Alder Reaction between 3-Substituted 1-(3,5-Dimethyl-1H-pyrazol-1-yl)prop-2-yn-1one (3′) and Various Dienesa


Diels−Alder products entry

R

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

H Me H H Me I H I H I H I I H H H H

3′bs 3′n 3′bs 3′bs 3′n 3′bz 3′bs 3′bz 3′bs 3′bz 3′bs 3′bz 3′bz 3′bs 3′bs 3′bs 3′bs

dienes or enes

ligand

solvent

173 173 173 173 173 173 182a 182a 182b 182b 182c 182c 182d 186 187a 187b 188

(S)-XIX (S)-XXXIIIa (S)-XXXIIIa (S)-XXXIIIa (S)-XXXIIIa (S)-XXXIIIa (S)-XXXIIIa (S)-XXXIIIa (S)-XXXIIIa (S)-XXXIIIa (S)-XXXIIIa (S)-XXXIIIa (S)-XXXIIIa (S)-XXXIIIa (S)-XXXIIIa (S)-XXXIIIa (S)-XXXIIIa

MeCN MeCN CH2Cl2 CH2Cl2b CH2Cl2b CH2Cl2b CH2Cl2b CH2Cl2b CH2Cl2b CH2Cl2b CH2Cl2b CH2Cl2b CH2Cl2b CH2Cl2b CH2Cl2b CH2Cl2b CH2Cl2b

T/°C (t/h) −40 −40 −40 −40 −20 −40 −20 −20 −40 −20 −20 −20 −40 −78 −78 −78 −78

(7) (21) (7) (7) (45) (4) (28) (47) (42) (3) (168) (25) (1) (5) (32) (0.5) (0.75)

% yield 94 91 85 91 22 82 68 89 50 83 69 83 84 65 79 79 93

183 % ee (conf) 77 83 87 88 89 89

184a−c % ee (conf)

[2+2] cycloaddition products 185 % ee

189 % ee

190 % ee

191 % ee (conf)

(1R,4S) (1R,4S) (1R,4S) (1R,4S)

96 (1R,4S) 97 87 95 89 96 96 80 81 82 83 (1S,5R)

a

[2+2] cycloadditions between 3′ and various enes. Both reactions catalyzed by the Cu(NTf2)2 complex of 2-cyclopentylamino-3-(2-naphthyl)1(pyrrolidin-1-yl)propan-1-one (S)-XXXIIIa (Scheme 51).89 bMS 4 Å as additive.

and 195 were obtained with a very high control of the stereochemistry (de ≥ 99%, Scheme 52).90 The enantioselective 1,3-dipolar cycloaddition of 3-substituted 1-(3,5-dimethyl-1H-pyrazol-1-yl)prop-2-yn-1-ones (3′) was also performed with nitrones 196 and the complex [(S)XXXIIIa/Cu(NTf2)2] as the catalyst. The products are (2,3dihydroisoxazol-4-yl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone derivatives [(R)-197] (Scheme 53), and the results are excellent both for the yield and, even more, in terms of enantioselectivity (Table 27, entries 1−11).91 In only one example was the reaction yield unsatisfactory (reaction between 3′n and diphenylnitrone; Table 27, entry 5). All other reactions show yield above 70%, and the enantioselectivity is, in many cases, around or above 90% ee.91 The cycloadducts 197 are useful building blocks for βlactams. By a reductive cleavage of the N−O bond by using SmI2, (R)-197, from entries 1 (R″ = Ph) and 9 (R″ = 3-Me-2furyl) of Table 27, is converted into (3S,4S)-198a,b in 54% and 57% yield, respectively, and the new stereocenter is obtained with a diastereomeric excess >99%. The diastereoselective reduction of (3S,4S)-198b with L-Selectride gave the secondary alcohol (3S,4S)-199b that, in three steps, is converted into the interesting β-lactam derivative (2S,3S)-200b with >99% ee (Scheme 53).91 The above reaction is a paradigmatic example of the importance of the nitrone 1,3-dipolar cycloaddition to build useful chiral five-membered heterocycles, which are valid precursors for biologically relevant chiral compounds. For this reason, the complex [Cu(NTf2)2/(S)-XXXIIIa] was tested as the catalyst for the reaction between 3-substituted 1-(3,5dimethyl-1H-pyrazol-1-yl)prop-2-en-1-ones (3) and nitrones 196.91 The results were excellent because the endo-adducts 201 were obtained with good yields and excellent diastereoselectivities (except with 3y), and the enantioselectivity was in the range 83−94% ee (Scheme 53, Table 27, entries 12−17). The absolute configurations of 201 (R = H or Me) were determined to be (3S,4R) and (3S,4R,5S), respectively. The selectivity of

Figure 5. Proposed concerted transition state of the enantioselectively catalyzed reaction between 3′bs and (2-methylcyclopent-1-enyloxy)TBDMS (188) affording (1S,5R)-191.

Scheme 52. 1,3-Dipolar Cycloaddition Catalyzed by Cu(II) Complex of L-DOPA-Derivatives

90% ee) were obtained when R = H, CH2Cl, CH2OMe, and CH2OMs (3′bs, 3′ca, 3′cb, and 3′cc) and were unaffected by the aromatic substituents R′ of 192 (Table 26). The adduct (R)-193 from entry 14 (R = CH2OMe, R′ = Ph) with NaOMe gave the cleavage of the amidic bonds and was converted into methyl 1-(2-(methoxycarbonyl)ethyl)-4,5-dihydro-3-(methoxymethyl)-5-phenyl-1H-pyrazole-4-carboxylate [(4R,5S)-194], the intermediate to methyl 1-(2-(methoxycarbonyl)ethyl)hexahydro-4-(methoxymethyl)-2-oxo-6-phenylpyrimidine-5carboxylate [(4R,5S,6S)-195]. The new stereocenters in 194 AM


Chemical Reviews

Review


Table 26. Catalytic Enantioselective 1,3-Dipolar Cycloadditions between 3-Substituted 1-(3,5-Dimethyl-1H-pyrazol-1-yl)prop2-yn-1-one (3′) and Various Azomethyne Imines 192 Catalyzed by the Cu(NTf2)2 Complex of 2-Substituted-3-(2-naphthalen-2yl)-1(pyrrolidin-1-yl)propan-1-ones [(S)-XXXIII] (Scheme 52)90

a

entrya

R

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22b

H H H H H H H H H H H H CH2Cl CH2OMe CH2OMe CH2OMs CH2OMs CH2OMs CH2OMs CH2OBz (CH2O)2CH PhthalNCH2

3′bs 3′bs 3′bs 3′bs 3′bs 3′bs 3′bs 3′bs 3′bs 3′bs 3′bs 3′bs 3′ca 3′cb 3′cb 3′cc 3′cc 3′cc 3′cc 3′cd 3′ce 3′cf

192 (R′)

ligand

Y

time/h

% yield

Ph Ph Ph Ph 2-MeO−C6H4 3-MeO−C6H4 4-MeO−C6H4 4-NO2−C6H4 4-Br−C6H4 (2-naphthyl) (3-furyl) Ph−CHCMe Ph Ph 4-MeO−C6H4 Ph 4-MeO−C6H4 4-Br−C6H4 Ph−CHCMe 4-MeO−C6H4 Ph Ph

(S)-XXXIIIa (S)-XXXIIIb (S)-XXXIIIc (S)-XXXIIId (S)-XXXIIIb (S)-XXXIIIb (S)-XXXIIIb (S)-XXXIIIb (S)-XXXIIIb (S)-XXXIIIb (S)-XXXIIIb (S)-XXXIIIb (S)-XXXIIIb (S)-XXXIIIb (S)-XXXIIIb (S)-XXXIIIb (S)-XXXIIIb (S)-XXXIIIb (S)-XXXIIIb (S)-XXXIIIb (S)-XXXIIIb (S)-XXXIIIb

c-C5H9 c-C4H7 c-C3H5 i-Pr c-C4H7 c-C4H7 c-C4H7 c-C4H7 c-C4H7 c-C4H7 c-C4H7 c-C4H7 c-C4H7 c-C4H7 c-C4H7 c-C4H7 c-C4H7 c-C4H7 c-C4H7 c-C4H7 c-C4H7 c-C4H7

43 2.5 10 43 69 4 24 66 21 48 122 25 88 300 144 74 72 48 24 120 48 168

96 95 95 92 80 93 87 94 91 94 83 98 89 83 79 92 99 94 95 98 98 70

193 % ee (conf) 86 95 93 60 88 91 90 90 93 95 87 90 94 94 87 92 87 93 91 86 85 80

(R) (R) (R) (R)

Reactions performed with 2.5−30 mol % catalyst in CH2Cl2 at −40 °C with MS 4 Å as additive. bReaction at −20 °C.

Scheme 53. Nitrone Cycloaddition Catalyzed by Cu(II) Complex of L-DOPA-Derivatives

Sometimes an unsatisfactory catalyst in the D.A. reactions of 3 results to be even worse for the corresponding 1,3-dipolar cycloadditions. In Scheme 49, the Box complex [(S,R)-XXII/Cu(OTf)2] was used as catalyst in the D.A. reaction between 3bs (R = R2 = H) and cyclopentadiene to afford (S)-174 with good yield, excellent diastereoselectivity, but negligible ee.85 The MgI2 complex of the same Box (S,R)-XXII was used as catalyst in the 1,3-dipolar cycloaddition between 3n and the mesitonitrile

the catalyst in determining three contiguous defined stereocenters can be appreciated in the example reported in Table 27 (entry 16), in which (3S,4R,5S)-201 (R = Me, R′ = Bn, R″ = 2naphthyl) is obtained as a single diastereomer in 93% ee.91 This is an example in which the same catalyst promotes both the D.A. reaction and the 1,3-dipolar cycloaddition with 3, behaving as either a dienophile or a dipolarophile, always with the same excellent results. AN


Chemical Reviews

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Table 27. Catalytic Enantioselective 1,3-Nitrone Dipolar Cycloaddition between Nitrones 196 and 3-Substituted 1-(3,5Dimethyl-1H-pyrazol-1-yl)prop-2-yn-1-one (3′) or Substituted 1-(3,5-Dimethyl-1H-pyrazol-1-yl)prop-2-en-1-ones (3) catalyzed by the Complex [Cu(NTf2)2/(S)-XXXIIIa] (Scheme 53)91


dipolarophiles entry

R

3′

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

H H Me Me Me Me Me Me Me CH2Cl CH2Cl H H H Me Me CO2Et

3′bs 3′bs 3′n 3′n 3′n 3′n 3′n 3′n 3′n 3′ca 3′ca

a

nitrones 196 3

R′

R″

T/°C (t/h)

% yield

3bs 3bs 3bs 3n 3n 3y

Bn Bn Bn Me Ph 3,4-(MeO)2C6H3CH2 1-naphthylmethyl Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn

Ph 2-naphthyl Ph Ph Ph Ph Ph 2-naphthyl 3-Me-2-furyl Ph 2-naphthyl Ph 2-naphthyl 3-Me-2-furyl Ph 2-naphthyl Ph

−40 (1) −40 (2) −40 (5) −20 (1.5) −20 (28) −40 (1) −40 (48) −40 (19) −30 (61) −40 (2) −40 (3.5) −20 (3.5) −20 (1) -10 (89) 0 (7) 0 (13.5) rt (49)

89 80 94 81 39 82 91 97 96 79 70 71 81 79 78 82 41

197 % ee (conf) 92 94 87 74 80 87 91 94 84 89 94

201:202

201 % ee (conf)

97:3 95:5 85:15 98:2 >99:1 73:27

94 92 91 92 93 83

(R) (R) (R) (R) (R) (R) (R) (R) (S)a (R) (R) (3S,4R) (3S,4R) (3S,4R) (3S,4R,5S) (3S,4R,5S) (3S,4R,5R)a

Note the change of priority.

oxide 203. The products were obtained as a regioisomeric mixture of 204 and 205 in the ratio (1:5) with a 61% yield. The reduction with NaBH4 gave (4,5-dihydro-4-methyl-3-arylisoxazol-5-yl)methanol (206) and (4,5-dihydro-5-methyl-3-phenylisoxazol-4-yl)methanol (207) with very low enantioselectivities (Scheme 54).92 Even worse was the result of the 1,3-dipolar

Scheme 55. Pd(II)-Catalyzed Formal [3+2] Cycloaddition of Enone 1a

Scheme 54. 1,3-Dipolar Cycloadditions Catalyzed by Box/ Mg(II) Complexes

cycloaddition between nitrile imine 208 and 3br, catalyzed by [(S,R)-XXII/Mg(NTf2)2] because 209, obtained with 88% yield, was a racemate.93 3-Phenyl-1-(1H-pyrrol-1-yl)prop-2-en-1-one (1a), in the presence of the chiral complex from [Pd2(dba)3] and the imidazoline-phosphine ligand (aS,S,S)-XXXIV, smoothly reacts with the dipole derived from the ring opening of dimethyl 2vinylcyclopropane-1,1-dicarboxylate (210) to give the highly functionalized cyclopentane 211 in good yield and high stereoselectivity (Scheme 55).94 The almost complete control of the stereochemistry of the three contiguous stereocenters observed in the formation of (2S,3S,4R)-211 obtained with 97% ee suggests a highly ordered reacting intermediate that could be compatible with an enantioselective pericyclic process.

More realistically, the excellent diastereo- and enantioselectivity observed may be rationalized through a mechanism involving a zwitterionic (π-allyl) intermediate 212 with the allylic moiety bound to [Pd/(aS,S,S)-XXXIV]. The malonate anion attacks the β-Si face of 1a providing another (π-allyl) palladium complex 213 that gives the ring closure to (2S,3S,4R)-211 (Scheme 55). Hence, this reaction can be classified as a formal [3+2] cycloaddition occurring through a highly stereospecific multiAO


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strated to be (1S,2S), in accordance with the approach of [214b/Pd/XXXV] to the β-Si face of 1. The [3+2] cycloaddition was then extended to the reaction involving 1-cyano-2-[(trimethylsilyl)methyl]allyl acetate (217), an interesting CN-substituted TMM generator, which allows one to study the regioselectivity of the reaction and to obtain adducts with three adjacent stereocenters (Scheme 56). The regioselectivity of the reaction is controlled by the tautomeric equilibrium of the zwitterionic [217b/Pd/XXXV] complex in which the anion, adjacent to the nitrile, is resonance-stabilized and sterically favored as this form places the bulk of the palladium-ligand distal to the donor substituent. Its nucleophilic addition to 1 gives (1S,2R,3R)-218, again with excellent yields, diastereo-, and enantioselectivities (Table 28, entries 8−17).96 The absolute configuration can be rationalized by the geometry optimized structure of the [217b/Pd/XXXV] complex, in which one of the BINOL aryl rings acts as a wall, forcing the approach to the β-Re face of 1. The reaction between TMM donors and 1 is a versatile method for the construction of highly substituted fivemembered rings (with high chemo-, regio-, and diastereoselectivity), which are the ideal synthetic scaffolds for further manipulations. This opportunity inspired the search of novel TMM donors, and the reaction with tert-butyl 2[(trimethylsilyl)methyl]buta-2,3-dienyl carbonate (219) is a paradigmatic example in the field (Scheme 57). The reaction between 219 and 1 cannot be accomplished with [Pd(dba)2/XXXV] as catalyst, but, after testing different phosphoramidites, the Pd(dba)2 complex of (4S,4′S,5S,5′S)2,2′-[1,3-propanediylbis(oxy)]bis[1,3,4,5-tetraphenyl-1,3,2-diazaphospholidine [(S,S,S,S)-XXXVI] was found to be the best catalyst. The reaction was performed in toluene at 60 °C and gave 2-substituted (4-vinylidenecyclopentyl)(1H-pyrrol-1-yl)methanones (220), always with excellent enantioselectivities (Table 29).97 The synthetic utility was tested on adduct 220 (R = Ph) also to explore the nucleophilic addition to its allenic bond. The cycloadduct 220 was refluxed with benzylamine and then reduced to give the protected amine 221, whose Pd-catalyzed carboamination of the allene moiety afforded the bridged piperidine 222 with a tertiary amine stereocenter and a vinyl phenyl substituent (Scheme 57). Similarly, the acid 223, obtained from the NaOH treatment of 220, was carbolactonized, and the subsequent methanolysis of 224 afforded 225 in which the third chiral center bears a tertiary alcohol.97 The best example that allows one to emphasize the synthetic value of the adducts obtained from TMM-[3+2] cycloadditions as chiral building blocks is the reaction of alkynyl-substituted TMM donor 226 with 1-(1H-pyrrol-1-yl)propen-1-ones 1, catalyzed by the Pd(dba)2 complex of bisdiamidophosphite (S,S,R,R,S,S)-XXXVII (Scheme 58).98 The alkynyl-substituted cyclopentanes (1S,2S,3R)-227 are obtained in good yields, excellent diastereoselectivities (Table 30, entries 15−18), and enantioselectivities (19 of the 20 adducts reported in Table 30 were obtained with >90% ee). Three stereogenic centers were generated in a single step to give adducts bearing two substituents suitable for further modifications. The cyclopentanes (1S,2S,3R)-227 are the chiral precursors employed for the assembly of fused polycyclic hydrocarbons with hydroindene [(1S,2S,3R)-228, (1S,3aR,7aS)-230, and (1S,3aR,7aS)-231], and hydroazulene [(1S,3aR,7aS)-233] structures. Dienes 228 and 231 give consecutive Diels−Alder

step ionic process. This reaction is largely inspired by the palladium-catalyzed [3+2] cycloaddition of trimethylenemethane (TMM), disclosed by Trost, in which the reagent, instead of being generated by the ring opening of vinylcyclopropane, is a zwitterionic [Pd-TMM] species generated in situ by the metal-promoted ionization of the allylic acetate functionality of the silyl allylic acetate derivative 214 (Scheme 56). Trost in 2006 developed the enantioselective variant of the reaction, running the cycloaddition in the presence of a chiral phosphoramidite ligand.95


Scheme 56. Trost’s TMM Pd(II)-Catalyzed [3+2] Cycloaddition

Recently, the reaction with 2-[(trimethylsilyl)methyl]allyl acetate (214) was extended to a series of 3-substituted 1-(1Hpyrrol-1-yl)prop-2-en-1-ones (1), with the complex between Pd2(dba)3 and O,O′-(aR)-(1,1′-dinaphthyl-2,2′-diyl)-N-[(R,R)2,5-di(2-naphthyl)pyrrolidine]phosphoramidite [(aR,R,R)XXXV] as the catalyst. The adducts were 2-substituted (4methylencyclopentyl)(1H-pyrrol-1-yl)methanones (216) (Scheme 56). The results, reported in Table 28 (entries 1−7), show excellent yields and enantioselectivities for all of the substituents, except the case with R = 2-furyl (entry 6).96 The mechanism is outlined in the left part of Scheme 56 in which Pd(0) promotes ionization of the allylic acetate functionality in 214 to give [214a/Pd/XXXV], followed by desilylation, promoted by the displaced acetate, to afford the zwitterionic [214b/Pd/XXXV] complex. This nucleophilic PdTMM species adds to 1 giving the intermediate [(S)-215/Pd/ XXXV/1], which collapses through intramolecular cyclization to the product 216. Its absolute configuration was demonAP


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Table 28. Catalytic Enantioselective [3+2] Cycloaddition between Trimethylenemethane (TMM), from 2[(Trimethylsilyl)methyl]allyl Acetate (214) or Its 1-Cyano Derivative (217), and 1-(1H-Pyrrol-1-yl)prop-2-en-1-ones (1) with [Pd(dba)2/(aR,R,R)-XXXV] as Catalyst (Scheme 56)96

a

entrya

R

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Ph 2-naphthyl 4-F−C6H4 4-MeO−C6H4 3-furyl 2-furyl cyclohexyl Ph 2-naphthyl 4-MeO−C6H4 3-furyl 4-F−C6H4 4-Br−C6H4 3,5-Cl2−C6H3 Ph−CHCH Ph−(CH2)3 cyclopropyl

1a 1g 1bo 1c 1cb 1q 1j 1a 1g 1c 1cb 1bo 1o 1cc 1bt 1cd 1ce

TMM

T/°C

% yield

214 214 214 214 214 214 214 217 217 217 217 217 217 217 217 217 217

45 45 23 23 23 23 75 50 23 23 23 23 23 23 23 23 23

80 92 99 97 99 99 100 87 84 80 98 96 100 90 63 82 84

218b % ee (conf)

216 % ee (conf) 91 95 93 91 86

(1S,2S) (1S,2S) (1S,2S) (1S,2S) (1S,2S) 66 91 (1S,2R) 92 94 94 95 94 95 97 95 94 94

(1S,2R,3R) (1S,2R,3R) (1S,2R,3R) (1S,2R,3R) (1S,2R,3R) (1S,2R,3R) (1S,2R,3R) (1S,2R,3R) (1S,2R,3R) (1S,2R,3R)

Reaction performed in toluene as solvent with 5% Pd(dba)2 and 10% ligand (aR,R,R)-XXXV. bdr > 20:1.

Table 29. Catalytic Enantioselective [3+2] Cycloaddition between 219 and 1-(1H-Pyrrol-1-yl)prop-2-en-1-ones (1) with [Pd(dba)2/(S,S′,S,S′)-XXXVI] as Catalyst (Scheme 57)97

Scheme 57. Pd(II)/Phosphoramidite-Catalyzed TMM Cycloaddition

entrya

R

1

% yield

220 % ee

1 2 3 4 5 6 7 8b 9b 10b 11 12

Ph 4-MeO−C6H4 3-MeO−C6H4 2-Br−C6H4 3,5-Cl2−C6H3 3-pyridyl 3-furyl 2-(triisopropylsilyl)ethynyl hept-1-yn-1-yl phenylethynyl CH(OCH3)2 CHCH−CO2Et

1a 1c 1bq 1cf 1cc 1cg 1cb 1ch 1ci 1cj 1as 1ck

85 50 86 88 76 92 64 70 86 76 65 70

90 90 90 94 95 90 81 87 90 87 90 92

Reactions performed in toluene at 60 °C, for 12 h, with 5% Pd(dba)2 and 6% (S,S′,S,S′)-XXXVI. bReaction performed at 40 °C. a

suitable for further modifications. When one of these susbstituents is an alkynyl group, the proximity of the alkyne to other functional groups makes these adducts specific precursors for the rapid construction of fused polycyclic ring systems with a variety of hydrocarbon skeletons. It is easy to predict a prosperous future to this field.

reactions (with maleic anhydride and methyl acrylate, respectively) to afford 229 and 232 characterized by hydrocyclopentanaphthalene scaffolds containing six and five defined stereocenters, respectively. Furthermore, the TMS alkyne 227 from entry 18 of Table 30 was deprotected to (1S,2S,3R)-234, which was allowed to react with dimethyl acetylenedicarboxylate in the presence of [Cp*Ru(MeCN)3]PF6 to afford the tricyclic diester 235.98 In conclusion, the enantioselective Pd-catalyzed [3+2] cyloaddition reaction with TMM donors is a very powerful synthetic tool to achieve, with excellent diastereo- and enantioselectivities, highly functionalized cyclopentanes, with two or three well-defined stereocenters and some substituents

8. INFLUENCE OF SUBSTITUENTS ON REACTIVITY AND SELECTIVITY The previous sections discussed the reaction of 100 different subtrates having the 1-(1H-pyrrol-1-yl)prop-2-en-1-one (1) structure, 1 substrate with the 1-(1H-indol-1-yl)prop-2-en-1one (2) structure, 88 different subtrates having the 1-(1Hpyrazol-1-yl)prop-2-en-1-one (3) or (1H-pyrazol-1-yl)prop-2yn-1-one (3′) structure, 3 different subtrates having the 1-(1Hindazol-1-yl)prop-2-en-1-one (4) structure, 16 different subtrates having the 1-(1H-imidazol-1-yl)prop-2-en-1-one (5) structure, 1 substrate with the 1-(1H-benzo[d]imidazol-1AQ


Chemical Reviews

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Scheme 58. Chiral Building Blocks Obtained from Trost’s TMM-[3+2] Cycloadditions

Table 30. Catalytic Enantioselective TMM-[3+2] Cycloaddition between the TMM Donors 226 and 1-(1H-Pyrrol-1-yl)prop-2en-1-ones 1 with [Pd(dba)2/(S,S,R,R,S,S)-XXXVII] as Catalyst (Scheme 58)98

a

entrya

R

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Ph Ph Ph Ph 4-MeO−C6H4 3-MeO−C6H4 2-MeO−C6H4 4-Me−C6H4 3-Me−C6H4 2-Me−C6H4 4-Cl−C6H4 3-pyridyl 3-furyl Ph−CHCH 2-phenethyl i-butyl cyclopropyl 4-TMS-but-3-yn-1-yl but-3-yn-1-yl 2-methylpent-4-en-2-yl but-3-en-1-yl pent-4-en-1-yl

1a 1a 1a 1a 1c 1bq 1br 1b 1cl 1 cm 1d 1cg 1cb 1bt (E)-1h 1ae 1ce 1cn 1co 1cp 1cq 1cr

226 R′

time (h)

yield (%)

dr

cyclopropyl CH(OEt)2 CH2OTBS TMS TMS TMS TMS TMS TMS TMS TMS TMS TMS TMS TMS TMS TMS TMS TMS TMS CH2OTBS CH2OTBS

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 15 5 5 15 15

87 70 85 91 84 93 92 85 88 94 92 74 77 84 91 93 91 98 b 20:1 >20:1 >20:1 >20:1

227 % ee (conf) 95 96 95 99 98 90 98 96 97 94 97 >99 95 93 95 96 82 92

12:1 19:1

(1S,2S,3R) (1S,2S,3R) (1S,2S,3R) (1S,2S,3R) (1S,2S,3R) (1S,2S,3R) (1S,2S,3R) (1S,2S,3R) (1S,2S,3R) (1S,2S,3R) (1S,2S,3R) (1S,2S,3R) (1S,2S,3R) (1S,2S,3R) (1S,2S,3R) (1S,2S,3R) (1S,2S,3R) (1S,2S,3R)

94 (1S,2S,3R) 95 (1S,2S,3R)

Reactions performed in 1,4-dioxane at 60 °C, with 5% Pd(dba)2 and 6% (S,S,R,R,S,S)-XXXVI. bComplex reaction mixture.

yl)prop-2-en-1-one (6) structure, 3 different subtrates having the 1-(1H-1,2,4-triazol-1-yl)prop-2-en-1-one (7) structure, 11 different subtrates having the 1-(1H-benzo[d][1,2,3]triazol-1yl)prop-2-en-1-one (8) structures, and 4 different subtrates having the 1-(carbazol-9-yl)prop-2-en-1-one (9) structure. Heterocyclic enones 1, 3, 5, and 8 have a great variety of groups at the β-position of the alkenoyl moiety, and these

reagents have been employed in a lot of examples of different reactions. Have the substituents a leading influence on reactivity or enantioselectivity? To evaluate the effect of the different groups on reactivity and selectivity, the clusters of homogeneous reactions (i.e., same reaction, same reactants, and same catalyst) in which at least 10 different reagents have been tested are statistically AR


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Table 31. Statistical Analyses of Yield and Enantioselectivity of Clusters of Reactions Involving 1−9, Performed with the Same Catalyst and Under Homogeneous Conditions all reagents

reaction (Table)

1

epoxidation of 5 with tBuOOH (1) epoxidation of 1 with CumeneOOH (2) Michael of 1 with 43 (3)

4 (6)

Michael cyanation of 1 (5) Michael cyanation of 1 (6) Michael cyanation of 3 (6) Michael between 3 and R−CH(CN)2 (7) Michael of 8 with oxazolone 86a (9) Michael reaction between 3 and 109 (12) Michael reaction between 1 and 109 (13) sulfa-Michael between 3 and 135 (17) sulfa-Michael between 3 and 140 (17) phospha-Michael of 1 with 144 (18) phospha-Michael of 1 with 145 (18) [3+2]-cycl. of 1 with TMM (217) (28) [3+2]-cycl. of 1 with TMM (219) (29) [3+2]-cycl. of 1 with TMM (226) (30)

14 (29,30)

2 3 4 5 6 7


8 9 10 11 12 13 14 15 16 17 a

Scheme (ref)

n

8 (20−22) 12 (20)

15 (33) 16 (34) 21 (39,40) 25 (47,48) 30 (52,55)

catalyst (S)-IIb/ Ln(OiPr)3 (R)-III/ Sm(OiPr)3 Zn3/[(S,S)Va]2 2(S,S,R)-VIb/ Gd(III)a (S,S,S)-IX/Ru/ LiOMe (S)-IIb/Mg(nBu)2 (R,R)-XV/ Ni(II) (S,S)-XVI/ (ArOH)n (R,R)-XV/ Ni(ClO4)2

sub-clusters

no. of reag.

average yield % (s.d.)

average ee % (s.d.)

29

83.2 (6.6)

81.2 (11.1)

14

87.4 (8.5)

97.6 (1.3)

10

85.5 (7.6)

89.3 (6.1)

16

91.1 (5.2)

91.2 (5.4)

11

84.3 (18.9)

14

no. of. reag.

average yield % (s.d.)

average ee % (s.d.)

[(S)-IIb/ La(III)]

17

83.8 (7.7)

87.0 (5.5)

88.7 (16.4)

aliphatic subst.

10

87.2 (17.0)

93.5 (4.5)

69.6 (8.0)

63.9 (14.5)

aromatic subst.

11

68.6 (6.6)

69.0 (11.3)

12

83.5 (16.7)

87.3 (11.5)

only CH2(CN)2

8

88.3 (5.8)

83.5 (12.4)

11

94.3 (3.0)

95.8 (1.5)

13

79.5 (17.3)

92.7 (6.2) (Z)-1h excluded

10

81.8 (14.4)

92.4 (1.7)

31 (56)

(S,S,R)-XXIa

11

81.7 (13.7)

87.1 (17.7)

37 (66)

(R,R,R,R)XXIV (S,S,R)-XXIc

13

91.6 (3.3)

90.4 (6.9)

19

85.1 (7.9)

97.1 (2.1)

20

96.2 (2.6)

98.7 (0.5)

18

95.9 (3.4)

96.9 (1.5)

10

86.4 (10.8)

94.4 (1.3)

12

75.7 (12.4)

89.7 (3.6)

15

88.5 (6.6)

94.7 (4.4)

38 (67) 41 (71) 42 (73) 56 (96) 57 (97) 58 (98)

(S,S)-Ib/ 2Zn(II) (S,S)-Ib/ 2Zn(II) (aR,R,R)XXXV/Pd (S,S,S,S)XXXVI/Pd (S,S,R,R,S,S)XXXVII/Pd

more homogeneous conditions

And [2(S,S,R)-VIIb/Gd(III)].

The flexibility of the catalysts can be evaluated from the standard deviations of yield and enantioselectivity. Six clusters have the s.d. of the average yield higher than 10 (entries 5, 7, 9, 10, 15, and 16). Five clusters have the s.d. of the average ee higher than 10 (entries 1, 5, 6, 7, and 10). A simple consideration can be derived from the above data. The catalysts selected for the 17 reactions not only induce more homogeneous results on the enantioselectivity than on the yield of the reaction products, but the values of the average enantioselectivities are usually better than those of the corresponding average yields. To answer to the question “Have some of the substituents a leading influence on reactivity or enantioselectivity?”, we considered the clusters in which the s.d. of either yield or enantioselectivity has a value greater than 10, to evaluate if, in the sphere of one or more than one of them, there is an homogenous sub-cluster that has a significantly lower s.d., and, in this case, if there is a rationale in the lowering. The data resulting from these findings are reported in the right part of Table 31. Some of them are somewhat trivial, while some others are more sophisticated. To perform the epoxidation of 5 with t-BuOOH, [(S)-IIb/ La(III)] gives more homogeneous results than those obtained

analyzed. The average yield and its standard deviation (s.d.), the average enantiomeric excess and its s.d., for each set of reactions have been calculated, and the data are reported in Table 31. First, the average reactivity and enantioselectivity allow, at a first glance, one to evaluate the efficiency and flexibility of the catalyst in the presence of a variety of reagents. A significant s.d. then means that some substituents influence reactivity or selectivity. Seventeen clusters of reaction have been investigated, involving four different heterocyclic moieties: 1-(1H-pyrrol-1yl)prop-2-en-1-ones (1) (Table 31, entries 2−5, 10, 13−17), 1(1H-pyrazol-1-yl)prop-2-en-1-ones (3) (Table 31, entries 6, 7, 9, 11, and 12), 1-(1H-pmidazol-1-yl)prop-2-en-1-ones (5) (Table 31, entry 1), and 1-(1H-benzo[d][1,2,3]triazol-1yl)prop-2-en-1-ones (8) (Table 31, entry 8). The efficiency of the catalysts chosen to perform the enantioselective reactions can be appreciated from the average data of yields and enantioselectivities. Only three of 17 clusters have an average yield lower than 80% (Table 31, entries 6, 9, and 16), and only one cluster has an average enantioselectivity lower than 80% ee (Table 31, entry 6). AS


epoxidation epoxidation cyclopropan. Michael Michael CN Michael CNa Michael

Michael Michael Michaelb Michaelc aza-Michael phospha-Mic phospha-Micd radicale Diels−Alderf

1 2 3 4 5 6 7

8 9 10 11 12 13 14 15 16

20 24 (13) (13) 35 41 (18) 43 (19) 45 (21) 49

4 (1) 8 11 12 (3) 14 (5) 15 19

Scheme (Table)

(S)-IIb/La(OiPr)3 (R)-III/Sm(OiPr)3 (S)-IV/ La(OiPr)3 (S,S)-Va/Zn(II) (R,R,S)-VIII/Sr(II) (S,S,S)-IX/Ru(II) (R,R)-XIIIa/ Sr(OiPr)2 (1R,2R)-XIV (S,S)-Ib/Et2Zn (S,S,R)-XXIa (S,S,R)-XXIa (S,S,R)-XXIb (S,S)-Ib/Et2Zn (S,S)-Ia/Et2Zn (S,R)-XXII/MgBr2 (S,R)-XXII/ Cu(OTf)2

catalyst (99) (98) (91) (95) (96) (96)

99 (99) 88 (99)

91 (73) 93 (93) 78 (93)

95 68 85 100 94 93

1 % yield (% ee)

92 (79)

2 % yield (% ee)

52 (15) 85 (28)

44 (93)

3 % yield (% ee)

66 (15) 88 (59)

4 % yield (% ee)

51 (55)

86 (91) 82 (98)

5 % yield (% ee) 80 (63)

6 % yield (% ee) ∼0 (nd)

7 % yield (% ee)

96 (89)

8 % yield (% ee)

25 (82)

9 % yield (% ee)

67 (64) 98 (99) 94 (99)

93 (96)

98 (97)

92 (99)

96 (94) 93 (95) 100 (97)

10 % yield (% ee)

a Reactions performed on 1an and 3b. bReactions performed on 1a and 10a. cReactions performed on 1bl and 9bl. dReactions performed on 1aj and 10aj. eReactions performed on 3bq and 4b. fReactions performed on 3bs and 4c.

reaction

n

Table 32. Comparison between Reactivity and Selectivity of Catalytic Reactions Performed with Different 1-(Nitrogen-heterocyclic)-Substituted Prop-2-en-1-ones 1−9 and the Aromatic Analogues 10


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AT



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it was emphasized that the N-alkenoyl derivatives of pyrazole (3), indazole (4), 1,2,4-triazole (7), and benzo[d][1,2,3]triazole (8) may behave as bidentate ligands through the electron pairs of the carbonyl oxygen and the suitably placed nitrogen atom. Other reagents such as the corresponding derivatives of pyrrole (1), indole (2), imidazole (5), benzo[d]imidazole (6), and carbazole (9) can behave as monodentate ligands only, analogously to 1-phenyl-but-2-en-1-ones (10). The multiple binding ability of the substrate may have a specific effect on the transmission of chirality from the catalyst to the reaction product: This effect should become evident by comparing the reactivity observed with three classes of reagents [(3, 4, 7, and 8) vs (1, 2, 5, 6, 9, and 10)] by using the same catalyst and under homogeneous conditions. In the above sections, some reactions with more than one class of reactants have been encountered, and Table 32 collects 16 examples of these reactions, in which the conditions are strictly homogeneous (same organocatalyst or same chiral catalyst), and the substituent R in the β-position is also the same on the different reagents. Nine of the 16 listed reactions (Table 32, entries 3−5, 7, 8, 10, and 12−14) are reactions in which reactivity and selectivity of 10 are compared to those of at least one other 1-(nitrogenheterocyclic)-substituted prop-2-en-1-one, while the remaining seven examples concern the comparison within different 1(nitrogen-heterocyclic)-substituted prop-2-en-1-ones (Table 32, entries 1, 2, 6, 9, 11, 15, and 16). Within the reasonable variations of yields and enantioselectivities, which are familiar to researchers working in the field, for 10 of the 16 reactions (Table 32, entries 2, 4, 5, 7−10, and 12−14), the obtained results are almost superimposable and independent from the specific involved reagent. Concerning the remaining six reactions, three (Table 32, entries 3, 6, and 11) show different yields but similar enantioselectivities upon changing the reagent. Some of these variations can be the result of the different steric hindrance of the heterocyclic moiety: for example, the Michael reaction with 1-(carbazol-9-yl)prop-2-en-1-ones (9) gives 25% yield, whereas the yield with 1-(1H-pyrrol-1-yl)prop-2-en-1-ones (1) is 78% (Table 32, entry 11). In the epoxidation already discussed in Scheme 3, an influence of the heterocyclic substituent on the enantioselectivity is observed (Table 32, entry 1). The examples in entries 15 and 16 are a radical and a Diels−Alder reaction performed with similar catalysts on 1-(1H-pyrazol-1-yl)prop-2-en-1-one (3) and 1-(1H-indazol-1-yl)prop-2-en-1-one (4). Both of the substrates may behave as bidentate ligands, but the results are always poor. To evidence the eventual role of the heterocyclic moiety with respect to the phenyl derivative 10, the comparison of the enantioselectivity concerning products 1−9 versus 10 is shown in Table 33. From these data, it is clearly evident that the catalysts of these reactions do not discriminate between aromatic versus heterocyclic moieties, because the ee values are not dependent on the substituent. Only one example may discriminate between mono- versus bidentate coordination (Table 33, entry 8), but the best enantioselectivity observed in the reaction involving 10 does not support the behavior of 8 as a bidentate ligand.

with (S)-IIb coordinated by different lanthanides (Table 31, entry 1). In this sub-cluster (17 of 29 reactions), the yield does not change but the enantioselectivity ameliorates. The better enantioselectivity observed in the sub-cluster of the epoxidation of 5 with the La(III)-based catalyst may be rationalized by considering that the coordination number of lanthanides changes within the series. Clearly, La(III) coordinates 5 to give a reacting intermediate with a better discrimination of the nucleophilic addition to the β-Re face of the coordinated substrate, affording products with the expected configuration. In the case of the results of the Michael reaction between 3 and substituted R−CH(CN)2 (Table 31, entry 7), the subset limited to CH2(CN)2 evidenced an increase in reaction yields, but a lowering in the observed enantioselectivities (8 of 12 reactions). The enantioselectivity of the Michael cyanation of 3 with [(S)-IIb/Mg(n-Bu)2] as catalyst (Table 31, entry 6) slightly ameliorates when the R substituents of 3 were aromatic groups (sub-cluster of 11 on 14 reactions), while the yields were uneffected. Finally, two clusters of reactions have a single reagent that gives results largely divergent from the average. The Michael cyanation of 1 with [(S,S,S)-IX/Ru/LiOMe] as the catalyst (Table 31, entry 5) shows that (E)-3-(4chlorophenyl)-1-(1H-pyrrol-1-yl)prop-2-en-1-one (1d), the only aromatic derivative of the 11 reagents tested, affords compound 48 in very low yield (55%) and ee (41%). If this reagent is omitted, the average yield and ee obviously ameliorate, but the relevant variation is the decrease of s.d. of the ee, from 16.4 to 4.5. (Z)-5-Phenyl-1-(1H-pyrrol-1-yl)pent-2-en-1-one [(Z)-1h] is another reagent that deviates from the average data. The Michael reaction between 1 and nitromethane 109, with (S,S,R)-XXIa as organocatalyst (Table 31, entry 10), was performed on 11 reactants, and in the case of (Z)-1h the obtained enantioselectivity (34%) is the anomalous result and, when omitted, the average ee increases from 87.1% to 92.4% ee with a more narrowed distribution of enantioselectivities (s.d. decrases from 17.7 to 1.7). The rationale of some of these data can be found in a mismatching feeling between a certain substrate and the catalyst: a (Z) reagent can find more difficulty to coordinate the catalyst than its (E) analogue. The lower reactivity observed for (Z)-1h (reaction time, 65 h; 81% yield) with respect to that observed for the corresponding (E)-isomer (reaction time, 23 h; 95% yield) is consistent with the proposed rationalization. A last point deserves attention. 1-(1H-Pyrazol-1-yl)prop-2en-1-ones (3) and 1-(1H-benzo[d][1,2,3]triazol-1-yl)prop-2en-1-ones (8) may bind the catalyst in a bidentate fashion; 1(1H-pyrrol-1-yl)prop-2-en-1-ones (1) and 1-(1H-imidazol-1yl)prop-2-en-1-ones (5) can behave only as monodentate ligands. This different behavior cannot be discussed from the data in Table 31 because the involved catalysts are different, and this will be the topic of the next section.

9. COMPARISON BETWEEN CATALYTIC, ENANTIOSELECTIVE REACTIONS WITH DIFFERENT 1-(NITROGEN-HETEROCYCLIC)-SUBSTITUTED PROP-2-EN-1-ONES 1−9 AND THE AROMATIC ANALOGUES 10 In the introduction dealing with enantioselective reactions on 1-(nitrogen-heterocyclic)-substituted prop-2-en-1-ones (1−9), AU


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different descriptors referred to as the reactions at the βcarbon of the CC−CO moiety (Figure 2). The ligand (R,R)-4,6-dibenzo-furandiyl-2,2′-bis(4-phenyloxazoline), known as Ph-DBFOX, gives the Ni(II) complex [(R,R)-XV/Ni(II)/3H2O] with the octahedral structure reported in Scheme 29.54 This is an excellent catalyst of different reactions with 1-(1H-pyrazol-1-yl)prop-2-en-1-ones (3) affording the reacting complex [(R,R)-XV/Ni(II)/3]. The Michael reaction with malononitrile 59 gives (S)-64 with ee often >90%. With cyclic 1,3-cyclohexandione 65, the reaction follows different pathways if R is a methyl or an hydrogen atom. Compound 65b (R = Me) gives a normal Michael reaction, and the adduct (R)-67 retains the pyrazole residue; derivative 65a (R = H) gives a stepwise process in which the Michael reaction is the first step, followed by an intramolecular substitution removing the pyrazole auxiliary, to give product (R)-66. The same catalyst gives the Michael reaction with nitromethane 109 to afford (R)-110. The radical rection with 2-iodoethanol (168) is again a stepwise process with formation of the coordinated radical 169, which undergoes intramolecular ring closure with loss of pyrazole to produce (S)-tetrahydro-4-phenylpyran-2-one (170) obtained with 88% ee (Scheme 59). All of the reactions discussed in Scheme 59 have a common enantioselective pathway: All of the nucleophiles add the β-Re face of 3 in the common reacting intermediate [(R,R)-XV/ Ni(II)/3] to give products with the observed absolute configurations. Sometimes the same chiral ligand has been encountered along this Review in several catalysts with different Lewis acids. This is the case of Box (S,R)-XXII, the chiral ligand of catalysts for the aza-Michael reactions (Scheme 33) with MgBr2,61 Y(OTf)3,61 and Mg(ClO4)2.62 Furthermore, the same Box is the chiral ligand in the catalyst of the radical additions with either Zn(OTf)277 or with Mg(NTf2),80 Schemes 45 and 46,

Table 33. Comparison between the Enantioselectivity of Catalytic Reactions Performed with 1-(Nitrogenheterocyclic)-Substituted Prop-2-en-1-ones 1−9 and the Aromatic Analogues 10 entrya

reaction

3 4 7

cyclopropanation Michael Michael

8 10 12 13 14

Michael Michael aza-Michael phospha-Michael phospha-Michael


a

catalyst (S)-IV/ La(OiPr)3 (S,S)-Va/Zn(II) (R,R)-XIIIa/ Sr(OiPr)2 (1R,2R)-XIV (S,S,R)-XXIa (S,S,R)-XXIb (S,S)-Ib/Et2Zn (S,S)-Ia/Et2Zn

1−9 ee %

10 ee %

1 1 1

98 91 99

94 95 99

8 1 5 1 1

89 93 55 99 99

97 96 64 99 99

The entry numbers are those of Table 32.

10. RELATIONSHIP BETWEEN DIFFERENT [CHIRAL LIGAND/INORGANIC CATION] COMPLEXES OR NON-RACEMIC ORGANOCATALYSTS AND THE STEREOCHEMICAL OUTCOME This section deals with the relationship between the different chiral catalysts and the stereochemical outcome and is the core of this Review. It was certainly noted that some [chiral ligand/inorganic cation] complexes or some organocatalysts have been used and discussed several times throughout the text because they have been successfully applied in several reactions. If the chiral activator and a reactant give the reacting complex involved as the key intermediate in the chirality transmission, is the stereochemical outcome of the reactions always the result of the same facial approach to the coordinated reagents? To test this, as far as possible, the experimental conditions (solvent, counterion, additive, temperature, etc.) must be homogeneous. Therefore, this investigation will be limited to a few catalysts satisfying the above conditions, taking into account the

Scheme 59. Stereochemical Outcomes by Using the Ph-DBFOX/Ni(II) Catalyst

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Scheme 60. Stereochemical Outcome by Using the IndaBox Complexes with Different Cations

Figure 6. Proposed stereochemical models for the enantioselective reactions of different reactantants to 3 (Scheme 60), catalyzed by the complexes between box (S,R)-XXII and MgBr2, Mg(ClO4)2, Mg(NTf2)2, Zn(OTf)2, Cu(OTf)2, and Y(OTf)3.

Usually, in the conclusion of a paper describing an enantioselectively catalyzed reaction, the authors propose a model of the reacting intermediate to rationalize the stereochemical outcome, and Figure 6 summarizes the proposed different stereochemical models required to rationalize the results in Scheme 60. The geometry of the complex [(S,R)XXII/cation/3/counterion] with each specific cation is based on the reported X-ray crystal structure of the corresponding Box complexes:99,100 tetrahedral, cis-octahedral, and transoctahedral for Mg(II), depending on the coordination ability of the counterion; tetrahedral for Zn(II); distorted square planar for Cu(II); and trans-pentagonal bipyramid for Y(OTf)3. Matching the favored face of addition of 3 in each model of Figure 6 with the face of the attack that accounts for the observed products configuration in Scheme 60, a satisfying result is obtained. Certainly this is an oversimplification; some

respectively. Again, [(S,R)-XXII/Cu(OTf)2] is the catalyst of the Diels−Alder reaction (Scheme 49).85 The overall picture of these reactions is summarized in Scheme 60, which also reports the favored approached face that accounts for the observed product stereochemistry when the substituent R of 3 is conventionally considered to be a phenyl group (see Figure 2). It is evident that 3, when bound to the catalyst, has different sterically favored enantiofaces, not only depending on the coordinating cation, but also from the involved counterion. This depends on the stereochemistry of the reacting intermediate, whose geometries are well-known when the chiral ligand is a Box.99,100 A paradigmatic example is the schizophrenic behavior of Mg(II) that may give complexes with four and six as the coordination numbers, which give rise to either tetrahedral, cis-octahedral, or trans-octahedral complexes. AW


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Scheme 61. Stereochemical Outcome by Using BINOL-Based Chiral Catalysts

proposed reacting intermediate has one Ph3AsO axial, tertbutylhydroperoxide anion, and the BINOL equatorial, and the carbonyl group of 5 in the second axial position.13 When the ligand is (S)-IIb, the addition of t-BuOO¯ occurs to the β-Re face of 5, giving first the peroxide, then (2R,3S)-16, by ring closure, substitution of the heterocyclic moiety, and methanolysis of the intermediate. Compound 5i, in which R is the phenethyl group, was tested with different lanthanides, and the ee is in the order La > Pr > Sm > Dy > Yb > Gd. The interesting feature is that all of the lanthanides give the same (2R,3S) absolute configuration of the product, and this supports a somewhat similar reacting intermediate (Table 1).6 The same BINOL IIb forms an heterobimetallic complex with Y(III) or Dy(III) and 3 Li cations that catalyzes the azaMichael reaction of methoxylamine (117a) and 1. The crystal structure of the [3(S)-IIb/Y/3Li] complex has the “star” configuration simplified in the figure of Scheme 61.101 The authors suggest that the catalyst binds 1 at the seventh coordination site of the lanthanide and 117a at one Lithium cation. The intramolecular nucleophilic addition gives (S)-118, which is the precursor of aziridine (2S,3R)-120 (Scheme 32, Table 14).60 The key point is that the approach occurs to the βSi face of 1. Therefore, the same BINOL ligand (S)-IIb, with a lanthanide (III) Lewis acid, may give opposite enantioselectivity if lithium or Ph3AsO participates in the formation of the reacting intermediate. Trost’s dinuclear [Zn(II)-ProPhenol] complexes have been applied as enantioselective catalysts in the Michael reaction of 1 with 3-hydroxy-1-methylindolin-2-one (83),46 and in the

doubts remain for the configuration of the complex with Mg(ClO4)2 promoting the approach to the β-Re face of 3, but a faint light has been probably shed on the complex results in Scheme 60. In some cases, the reacting intermediates with different Lewis acids do not belong to the homogeneous cluster [(S,R)-XXII/ Lewis acid/3], illustrated in Figure 6. An example is the different behavior of BINOL (S)-IIb as ligand for catalysts of different reactions. The epoxidation of 5 with tert-butylhydroperoxides is catalyzed, with Ph3AsO as auxiliary ligand, with different lanthanide isopropylates (Scheme 4, Table 1).6,14,15,17 The Michael cyanation of 3 with TMSCN is catalyzed by the Mg(II) complex (Scheme 16, Table 6).34 The aza-Michael reaction of methoxylamine (117a) and 1 is catalyzed by Y(III) and Dy(III), with Li(I) as second Lewis acid of the heterobimetallic catalyst (Scheme 32, Table 14).60 All of these results are collected in Scheme 61. The cyanation reaction gives (R)-48, and the mechanism proposed by the authors assumes a tetrahedral reacting complex [(S)-IIb/Mg(II)/3] because the anhydrous conditions (Bu2Mg and 4 Å MS) do not allow a coordination number greater than 4. The oxygen atom of the ligand coordinates also TMSCN, and the intramolecular tranfer of the CN anion involves the addition to the β-Re face of 3, which justifies the absolute (R) configuration of the products.34 The reacting intermediate in the epoxidation of 5 can be proposed on the basis of the X-ray structure of the complex [2(R)-IIb/La(III)/3(Ph3AsO)], which the authors consider the pre-catalyst of the trigonal bipyramidal active species. The AX


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molecular nucleophilic addition of 83 to its β-Re face, and the final intramolecular transesterification gives (R,R)-84. The phospha-Michael reaction of either secondary alkyl phosphineoxides 145 (R″ = alkyl),74,75 or dialkylphosphites 14471,73 with 1a was catalyzed by (S,S)-Ib. 1a coordinates the zinc cations through its carbonyl group with an s-trans conformation, and the deprotonated phosphineoxide or dialkylphosphite is bound at the apical position of the less hindered zinc cation to give the corresponding reacting intermediate [(S,S)-Ib/2Zn/1a/P(O)X2]. The intramolecular nucleophilic approach of the phosphorous atom occurs on the β-Si face of 1a in its s-trans conformation to give (S)-146 and (S)-153, respectively. The use of a more sterically demanding diaryl phosphineoxide 145 (R″ = Ph)5 prevents its coordination to the Zn(II); hence the reacting intermediates involve only the coordination of 1a, which can be either in the s-cis or in the s-trans conformation, to give the catalysts [(S,S)-Ia/2Zn/1a]. This conformational uncertainty is an unfavorable factor to obtain good enantioselectivities, and the nucleophilic addition cannot take advantage of the stereodifferentiating properties of the bifunctional catalyst. In conclusion, all of the enantioselective reactions in Scheme 62, assuming the same (S,S) configuration for the catalyst I, occur on the β-Si face of 1a, which is coordinated in an s-trans conformation. The relationship between the absolute configuration of the products and the proposed reacting intermediates seems stable enough, even if some details about the difference between the role of the ligands in Ia and Ib remain unclear. A class of derivatives with large applications to the enantioselective reactions is that of non-racemic organic molecules able to interact with the reagent through hydrogen bonding (organocatalysts). After the “gold rush”,103 it is easy to find authors that justify the stereochemical result of an organocatalyzed reaction with a model of the reacting intermediate. Sometimes, the proposal derives from computational studies that led to models suitable to understand the enantioselective reactions involving organocatalysts.104 Often, the proposed model is simply an elegant structure, which may be useful not only to understand the catalytic cycle, but also to modify catalysts and/or reagents to improve the enantioselectivities. When the literature offers a crystal structure strongly related to the reacting intermediate, which involves organocatalyst and reagents, the proposal of a mechanism becomes much more than a simple hypothesis because it is based on stable data. The Michael cyanation of 3-alkyl-substituted 1-(1H-pyrrol-1-yl)prop-2-en-1-ones (1) and chalcones 10, performed with acetone cyanohydrin 53 and cupreidinium (S,R,R)-X or cupreinium (R,S,R)-XI salts as phase-transfer catalysts, allows one to discuss this approach.35 These pseudoenantiomeric organocatalysts establish facile access to both enantiomers of 48 and 50, because (S,R,R)-X gives (S)-48 and (S)-50, while (R,S,R)-XI produces the opposite enantiomers (R)-48 and (R)50 (Scheme 17). The crystal X-ray structures of cupreidinium (S,R,R)-X′ and cupreinium (R,S,R)-XI′ salts have been reported in the literature,35 and these structures are very similar to those of X and XI. Taking into account these crystal stuctures, an exercise is reported in Scheme 63 in which the reacting intermediates are reported, their structure being based on the models derived from (S,R,R)-X′ and (R,S,R)-XI′. Both have the carbonyl group


phospha-Michael reactions of 1 with either dialkylphosphites 14471,73 or secondary alkyl phosphineoxide and diaryl phosphinoxide 145.5,74,75 The ligands were (2S,2′S)-2,6-bis[2(hydroxydiphenylmethyl)pyrrolidin-1-ylmethyl]-4-methylphenol [(S,S)-Ib], its enantiomer [(R,R)-Ib], and the bis[α,α-di-2thienyl] analogue [(S,S)-Ia]. With Et2Zn, they give dinuclear complexes with two zinc atoms bound to two pyrrolidine nitrogens and the phenoxy anion. These complexes contain both Brønsted basic and Lewis acidic sites, and can therefore act as bifunctional catalysts, activating two reagents simultaneously. Figure 7 shows the X-ray structure of the complex [(S,S)-Ib/ 2Zn/para-nitrophenol/2THF],102 and the coordination sphere

Figure 7. X-ray structure of complex [(S,S)-Ib/2Zn/para-nitrophenol/2THF].102 Oxygens of nitrophenol and THF are in red, zinc cations are in magenta, nitrogens are in blue, and carbon atoms of pnitro phenol are in green.

around each zinc cation is approximately square pyramidal with the two bridging phenoxo oxygen atoms and the nitrogen and oxygen atoms of the chelating prolinol moieties forming the base, and a THF molecule at the apex of the pyramidal structure. The conversion of this complex into the reacting intermediate will require the displacement of the easily removable ligands (nitrophenol and THF) by the reactants involved in the reaction (the electrophile 1 and the nucleophile of choice). The coordination of the reagents in the complex depends upon the binding ability of 1 versus that of the nucleophile. If 1 is the strongest ligand, it will be coordinated through its carbonyl group as first to the zinc complex, and the remaining free coordination site may accommodate the nucleophile, only if its steric or electronic characters should be appropriate to fit the residual chiral pocket. Otherwise, if the nucleophile is the strongest ligand, then it will be first coordinated to the Zn complex, and 1 will enter in the apical position of the complex by replacing THF. This picture is summarized in Scheme 62, and the fit between the absolute configuration of the products and the plausibility of the proposed models will be the probe of the consistency of the assumed rationale. In the Michael reaction catalyzed by (R,R)-Ib between 1a and 3-hydroxy-1-methylindolin-2-one (83),46 the latter is deprotonated and coordinates to both the Zn cations. Compound 1a in the s-trans conformation coordinates to the less hindered zinc atom in the apical position. In this reacting intermediate, 1a is suitably placed to undergo the intraAY


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Scheme 62. Stereochemical Outcome by Using Trost’s Zn(II) Dinuclear Catalyst

Scheme 63. Stereochemical Outcome Comparison by Using Pseudoenantiomeric Organocatalysts

AZ


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62, respectively. These results can be rationalized if the reactions occur through the reacting intermediate reported in Scheme 64 for 10a, in which the bifunctional organocatalyst coordinates the CO group of 10a by a double hydrogen bonding and the amonium nitrogen binds the nucleophile anion. The proposed reacting intermediate gives two pieces of information. The structure of the bifunctional organocatalyst brings the nucleophile to approach the β-Si face of the electrophile, rationalizing the stereochemical outcome of the reaction. The electrophile behaves only as a monodentate ligand coordinated by a double hydrogen bonding to the organocatalyst. Therefore, the use of a potentially bicoordinating reagent as 8 cannot ameliorate the enantioselectivity of the reaction. The aza-Michael reaction between 1-(3,5-dimethyl-1Hpyrazol-1-yl)prop-2-en-1-ones (3) and O-benzylhydroxylamine 117b with the thiourea derivative [(R,S)-XXIII] as the organocatalyst, discussed in Scheme 34,63 occurs through a reacting intermediate involving a bicoordination, whose structure was investigated by theoretical calculations with the Jaguar 7.0 program at the M05-2/6-31G** level obtaining an original result.105 The most stable transition structure of the reacting intermediate [3/(R,S)-XXIII/117b] is (A), represented in Scheme 65, which involves the bifurcated H-bonds between the urea group and the pyrazole sp2 N atom. The role of the urea H-bonds is therefore different from that proposed in the original paper by the authors,63 in which the two NH thiourea groups coordinate the carbonyl of 3 to give the reacting intermediate (B). The key point is that both intermediates (A) and (B) favor the formation of the same enantiomer (R)-123, because the intramolecular approach of 117b always occurs to the β-Re face of the coordinated (pyrazol-1-yl)prop-2-en-1-ones 3. A group of compounds with a large application as organocatalysts is the family of natural Cinchona alkaloids, used as chiral scaffolds, with a thiourea function replacing the original 9-oxy group, to coordinate the reagent by multiple hydrogen bonding. Two examples have been encountered in previous sections: (R,R,R)-XII and (S,S,R)-XXI.

of 1 coordinated by hydrogen-bonding interaction to the quinolinic OH functionality. The cupreidinium cation (S,R,R)X has the cyanide anion bound by electrostatic interaction to the quaternary nitrogen, which is close (as evidenced by the Xray structure) to the β-Si face of 1 (or 10). The cupreinium (R,S,R)-XI salt may bind the cyanoalkoxide anion by hydrogen bonding to the 2-hydroxyethyl group, which is a specific feature of this catalyst, and the CN group is now close to the β-Re face of 1 (Scheme 63). A nice example of reacting intermediate has been proposed simply on the basis of the ability of the organocatalyst to establish multiple hydrogen bonding and to behave as a Lewis basic center. Scheme 64 summarizes this approach together with the stereochemical outcome of the Michael addition involving either 8a or 10a as electrophiles.


Scheme 64. Squaramide-Organocatalyzed Malononitrile Michael Addition

The Michael addition of MOMO-malononitrile (59) to (E)1-(1H-benzo[d][1,2,3]triazol-1-yl)-3-phenylprop-2-en-1-one (8a), and chalcone (10a), with squaramide derivative (1R,2R)XIV as the organocatalyst (Scheme 20),38 gives (S)-60 and (S)-

Scheme 65. Reaction Intermediates of Thiourea Organocatalyzed Aza-Michael Addition

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Scheme 66. Stereochemical Outcome of the Thiourea-Cinchonine-Catalyzed Michael Addition


Scheme 67. Stereochemical Outcome Comparison by Using Thiourea Organocatalysts

The Michael reaction of either chalcone (10a) or substituted 1-(pyrrol-1-yl)prop-2-en-1-ones (1) with nitromethane 109 (R1 = R2 = H) was catalyzed by (S,S,R)-XXIa, affording (R)116 and 114, respectively (Scheme 31).56 The aza-Michael reaction of either chalcone (10a) or (E)-1(1H-imidazol-1-yl)-3-phenylprop-2-en-1-one (5a) with 1Hbenzo[d][1,2,3]triazole (128) was catalyzed by (S,S,R)-XXIb, affording (R)-130 and (R)-129, respectively (Scheme 35),63 adducts that derive from an addition of the nucleophile 128 to the β-Re face of 10. Hence, two reactions of 1 and 10a, catalyzed by (S,S,R)-XXI organocatalysts, proceed with the same stereochemical approach to the β-Re face of the electrophile. (R,R,R)-XII and (S,S,R)-XXI are two pseudoenantiomers, and an approach induced from the former organocatalyst on 3p occurs on its βSi face (Scheme 66), while the latter organocatalyst favors the approach to the β-Re face of 1, 5a, and 10a (Scheme 67). This

(R,R,R)-XII, with the basic structure of 9-thiourea-epicinchonine, was the catalyst of two reactions. The Michael addition between acetyl acetates 56a,b and 1-(pyrazol-1-yl)4,4,4-trifluoro-2-buten-1-one (3p) affords (R)-57a,b after loss of the pyrazole auxiliary from the primary Michael adducts (Scheme 18).36 The Michael reaction between the same pyrazole 3p and nitromethane 109 afforded (R)-112 (Scheme 31).36 These results are grouped in Scheme 66, and, in our opinion, it is not astonishing that both of the reactions occur through nucleophilic addition to the same β-Si face of the electrophile. (S,S,R)-XXIa (R′ = ethyl, R″ = OMe), with the basic structure of 9-thiourea-epi-quinidine, and its derivatives (S,S,R)XXIb (R′ = vinyl, R″ = OMe), and (S,S,R)-XXIc (R′ = vinyl, R″ = H), are the organocatalysts of the three reactions reported in Scheme 66, whose discussion deserves attention. BB


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Chart 3. Significant Examples of Non-Racemic Products Described in This Review

means that the first two enantiomeric stereocenters of the organocatalysts are those inducing opposite stereochemical outcome in the reactions, while the third stereocenter does not have any active role in determining the stereochemistry. The domino sulfa-Michael reaction between 2-mercaptobenzaldehyde (140) and pyrazol-1-yl)prop-2-en-1-ones (3) was catalyzed with (S,S,R)-XXIc (Scheme 38). The primary products 141 undergo an intramolecular aldol reaction to give 2-substituted (3,4-dihydro-4-hydroxy-2H-thiochromen-3yl)(1H-pyrazol-1-yl)methanones (2S,3R,4S)-142, with simultaneous formation of two new stereocenters in positions 3 and 4.67 Hence, the absolute configuration of the primary products has to be (S), which derives from the addition of the nucleophilic thiol to the β-Si face of 3. During the peer-review process, one of the referees kindly attracted our attention to a paper published during the process of submission of this Review. The argument concerns the use of different masked unsaturated esters or amides in enantioselective organocatalysis, and one paragraph is dedicated to the α,β-unsaturated N-acyl heterocycles, the topic of this Review.106 The discussion of the six selected papers arrives to the same conclusions that we hope to have illustrated here. We recommend this concept article because it gives a bird view over the multiple reagents with many different templates, schematically illustrated in Figure 1 at the beginning of this Review, which may act as esters or amide surrogates, with outstanding results in terms of reactivity, stereoselectivity, and further synthetic manipulations.

N-Acyliden penta-atomic aza-heterocycles fulfill these conditions: they have the carbonyl group suitable for the coordination to the catalyst, and the leaving character of the heterocycle bound to the carbonyl group allows the conversion of the products into a variety of functionalized chiral building blocks. If the heterocycle has a further point of coordination to the catalyst, the reagent may behave as a bidentate ligand, making the reaction easier and the chiral product more stereoselective, as discussed for many reactions in the previous sections. The products of the enantioselective reactions are often useful intermediates for the syntheses of natural or biologically active compounds. Several of them have been encountered along this Review, and Chart 3 summarizes the significant examples, putting in evidence the parts deriving from the original enantioselective reaction and the importance that the chirality induced in this step has on the overall configuration of the final procuct. Adducts of epoxidation reactions were intermediates for the syntheses of the calcium antagonist Diltiazem (21) and the thrombin and trypsin inhibitor Aeruginosin 298-A (27), as well as of the natural product Strictifolione (25). The Michael alkylation was the starting step in the syntheses of (S)Florhydral (78), a compound with a floral odor useful in all areas of perfumery, of (+)-ar-turmerone (80), which is a potent antivenom against snake bites, and of 82, which is the intermediate in the synthesis of the marine sesquiterpene Frondosin B. Again, the Michael reaction affords the intermediate to the antidepressant and phosphodiesterase inhibitor (R)-Rolipram (111). Sometimes these reactions do not provide the syntheses of defined natural or industrial products, but the enantioselective nitrone 1,3-dipolar cycloaddition that gives useful building blocks for β-lactams, an example of which is 199b. Moreover, Trost [3+2] cycloaddition gives the alkynyl-substituted cyclopentane (1S,2S,3R)-227, having three stereogenic centers and

11. CONCLUSIONS Two characteristics are required for a reagent to be a useful partner in a chiral reaction: it must be able to bind to the catalyst to generate a reacting intermediate with a well-defined enantioface discrimination, and it must have substituents suitable for further modifications of the reaction products. BC



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the substituents required for the synthesis of (3aS,3bS,5aS,6S,8aR,10aR)-229 and (3aS,7aS,8S,10aR,10cS)-232, products having hydrocyclopentanaphthalene scaffolds. These examples clearly illustrate the power of a process that, within few steps, generates complex structures with up to six defined chiral stereocenters with almost complete diastereo- and enantioselectivities. In this Review, the authors have been fascinated by the complexity of the relationship between the structure of the catalyst and the stereochemical outcome in the products. Some [chiral ligand/inorganic cation] catalysts and organocatalysts, whose basic structures found multiple applications in the field, have been presented and discussed to tentatively correlate their structure with the stereochemical outcome of the reactions. The overall mechanism of the transmission of the chirality from the catalyst to the product is difficult to rationalize, but the attempt of this Review was to succeed in transmitting the character of perfection and beauty intrinsic in many chiral catalysts, functional to the reaction for which they were designed. This mixture of art and craft is not far from that of an harpsichord, elegant in its pure form, masterly constructed at the end of the XVIIIth century,107 whose magic sound is perfect to transmit the supreme Bach harmony. If this Review succeeded to build a link with the reader, made of admiration toward the art of the enantioselective synthesis, this is a great success.

of Organic Chemistry. His recent research interests concern the development of new catalysts for enantioselective reactions, especially those derived from optically active heterocycles used as chiral ligands, and the understanding of their mechanisms in inducing selectivity. Since 2010 he is Professor emeritus of the University of Pavia.

Giuseppe Faita received his degree in Chemistry in 1986 at the University of Pavia. In 1990 he obtained his Ph.D. at the same university under the supervision of G. Desimoni and he became a researcher in the Desimoni group in the Department of Organic Chemistry. In 2000 he became associate professor of Organic Chemistry. His research interests concern the optimization of asymmetric catalysts involving Box and Pybox as chiral ligands and solid-phase organic syntheses.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemrev.5b00097. Lists of substrates, catalysts, and organocatalysts discussed in this Review (PDF)

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

Paolo Quadrelli was born in 1961. He received his degree in chemistry in 1986 and Ph.D. in 1990 at the University of Pavia under the supervision of G. Desimoni. He then moved to the R&D Laboratories of ENI Group until 1992, when he returned as Researcher at the University of Pavia in P. Caramella group. In 1996, he joined the group of R. Grigg at the University of Leeds. He is currently Associate Professor of Organic Chemistry at the Department of Chemistry of the University of Pavia. His research interests center around pericyclic reactions as tools for the synthesis of antivirals and anticancer compounds, the chemistry of 1,3-dipoles, transition metal-catalyzed reactions, synthesis, and derivatization of steroids.

ACKNOWLEDGMENTS Financial support by the University of Pavia and MIUR (PRIN 2011, CUP: F11J12000210001) is gratefully acknowledged. Particular thanks are also due to CINMPIS for scientific support. Thanks are also due to Prof. Paolo Corsi and to Augusto Bonza for information about the Gregori’s harpsichord in the TOC.

Giovanni Desimoni was born in 1936. He received his laurea degree from the University of Pavia. After a research and teaching period at the same university and one year with Alan Katritzky at UEA, in 1975 he joined the Science Faculty at the University of Pavia as a full professor. He was Dean of the Faculty and Director of the Department BD


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(19) Fukuta, Y.; Ohshima, T.; Gnanadesikan, V.; Shibuguchi, T.; Nemoto, T.; Kisugi, T.; Okino, T.; Shibasaki, M. Enantioselective Syntheses and Biological Studies of Aeruginosin 298-A and Its Analogs: Application of Catalytic Asymmetric Phase-transfer Reaction. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5433−5438. (20) Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki, M. Catalytic Asymmetric 1,4-Addition Reactions Using α,β-Unsaturated N-Acylpyrroles as Highly Reactive Monodentate α,β-Unsaturated Ester Surrogates. J. Am. Chem. Soc. 2004, 126, 7559−7570. (21) Kinoshita, T.; Okada, S.; Park, S.-R.; Matsunaga, S.; Shibasaki, M. Sequential Wittig Olefination−Catalytic Asymmetric Epoxidation with Reuse of Waste Ph3P(O): Application of α,β-Unsaturated N-Acyl Pyrroles as Ester Surrogates. Angew. Chem., Int. Ed. 2003, 42, 4680− 4684. (22) Matsunaga, S.; Qin, H.; Sugita, M.; Okada, S.; Kinoshita, T.; Yamagiwa, N.; Shibasaki, M. Catalytic Asymmetric Epoxidation of α,βUnsaturated N-Acylpyrroles as Monodentate and Activated Ester Equivalent Acceptors. Tetrahedron 2006, 62, 6630−6639. (23) Evans, D. A.; Borg, G.; Scheidt, K. A. Remarkably Stable Tetrahedral Intermediates: Carbinols from Nucleophilic Additions to N-Acylpyrroles. Angew. Chem., Int. Ed. 2002, 41, 3188−3191. (24) Kakei, H.; Sone, T.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. Catalytic Asymmetric Cyclopropanation of Enones with Dimethyloxosulfonium Methylide Promoted by a La−Li3−(Biphenyldiolate)3 + NaI Complex. J. Am. Chem. Soc. 2007, 129, 13410−13411. (25) Shibasaki, M.; Yoshikawa, N. Lanthanide Complexes in Multifunctional Asymmetric Catalysis. Chem. Rev. 2002, 102, 2187− 2209. (26) Kumagai, N.; Matsunaga, S.; Kinoshita, T.; Harada, S.; Okada, N.; Sakamoto, S.; Yamaguchi, K.; Shibasaki, M. Direct Catalytic Asymmetric Aldol Reaction of Hydroxyketones: Asymmetric Zn Catalysis with a Et2Zn/Linked-BINOL Complex. J. Am. Chem. Soc. 2003, 125, 2169−2178. (27) Harada, S.; Kumagai, N.; Kinoshita, T.; Matsunaga, S.; Shibasaki, M. Direct Catalytic Asymmetric Michael Reaction of Hydroxyketones: Asymmetric Zn Catalysis with a Et2Zn/Linked-BINOL Complex. J. Am. Chem. Soc. 2003, 125, 2582−2590. (28) Park, S.-Y.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. Catalytic Asymmetric Michael Reactions of Dibenzyl Malonate to α,β-Unsaturated N-Acylpyrroles Using a La(O-iPr)3/Ph-linkedBINOL Complex. Tetrahedron Lett. 2007, 48, 2815−2818. (29) Mita, T.; Sasaki, K.; Kanai, M.; Shibasaki, M. Catalytic Enantioselective Conjugate Addition of Cyanide to α,β-Unsaturated N-Acylpyrroles. J. Am. Chem. Soc. 2005, 127, 514−515. (30) Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho, S.; Kanai, M.; Shibasaki, M. Toward a Rational Design of the Assembly Structure of Polymetallic Asymmetric Catalysts: Design, Synthesis, and Evaluation of New Chiral Ligands for Catalytic Asymmetric Cyanation Reactions. Tetrahedron 2007, 63, 5820−5831. (31) Kato, N.; Mita, T.; Kanai, M.; Therrien, B.; Kawano, M.; Yamaguchi, K.; Danjo, H.; Sei, Y.; Sato, A.; Furusho, S.; Shibasaki, M. Assembly State of Catalytic Modules as Chiral Switches in Asymmetric Strecker Amino Acid Synthesis. J. Am. Chem. Soc. 2006, 128, 6768− 6769. (32) Tanaka, Y.; Kanai, M.; Shibasaki, M. Catalytic Enantioselective Construction of β-Quaternary Carbons via a Conjugate Addition of Cyanide to β,β-Disubstituted α,β-Unsaturated Carbonyl Compounds. J. Am. Chem. Soc. 2010, 132, 8862−8863. (33) Sakaguchi, Y.; Kurono, N.; Yamauchi, K.; Ohkuma, T. Asymmetric Conjugate Hydrocyanation of α,β-Unsaturated NAcylpyrroles with the Ru(phgly)2(binap)−CH3OLi Catalyst System. Org. Lett. 2014, 16, 808−811. (34) Zhang, J.; Liu, X.; Wang, R. Magnesium Complexes as Highly Effective Catalysts for Conjugate Cyanation of α,β-Unsaturated Amides and Ketones. Chem. - Eur. J. 2014, 20, 4911−4915. (35) Provencher, B. A.; Bartelson, K. J.; Liu, Y.; Foxman, B. M.; Deng, L. Structural Study-Guided Development of Versatile PhaseTransfer Catalysts for Asymmetric Conjugate Additions of Cyanide. Angew. Chem., Int. Ed. 2011, 50, 10565−10569.


REFERENCES (1) Desimoni, G.; Faita, G.; Toscanini, M.; Boiocchi, M. A New CopperII/Isopropylidene-2,2-bis(oxazoline) Catalyst and Its Stable Reactive Complex with Acryloyloxazolidinone in Enantioselective Reactions. Chem. - Eur. J. 2009, 15, 9674−9677. (2) Desimoni, G.; Faita, G.; Quadrelli, P. Substituted (E)-2-Oxo-3butenoates: Reagents for Every Enantioselectively-Catalyzed Reaction. Chem. Rev. 2013, 113, 5924−5988. (3) Desimoni, G.; Faita, G.; Quadrelli, P. EnantioselectivelyCatalyzed Reactions with (E)-2-Alkenoyl-pyridines, Their N-Oxides, and the Corresponding Chalcones. Chem. Rev. 2014, 114, 6081−6129. (4) Livieri, A.; Boiocchi, M.; Desimoni, G.; Faita, G. Enantioselective Cycloadditions of 2-Alkenoylpyridine-N-oxides Catalysed by a Bis(oxazoline)/CuII Complex: Structure of the Reactive Intermediate. Chem. - Eur. J. 2011, 17, 516−520. (5) Zhao, D.; Wang, L.; Yang, D.; Zhang, Y.; Wang, R. Highly Efficient Asymmetric Michael Addition of Diaryl Phosphine Oxides to α,β-Unsaturated N-Acylated Oxazolidin-2-ones. Chem. - Asian J. 2012, 7, 881−883. (6) Ohshima, T.; Nemoto, T.; Tosaki, S.; Kakei, H.; Gnanadesikan, V.; Shibasaki, M. Catalytic Asymmetric Epoxidation of α,βUnsaturated Carboxylic Acid Imidazolides and Amides by Lanthanide−BINOL Complexes. Tetrahedron 2003, 59, 10485−10497. (7) Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki, M. Catalytic Asymmetric 1,4-Addition Reactions Using α,β-Unsaturated N-Acylpyrroles as Highly Reactive Monodentate α,β-Unsaturated Ester Surrogates. J. Am. Chem. Soc. 2004, 126, 7559−7570. (8) Bordwell, F. G. Equilibrium Acidities in Dimethyl Sulfoxide Solution. Acc. Chem. Res. 1988, 21, 456−463 and references therein.. (9) Baran, P. S.; Richter, J. M. Essentials of Heterocyclic Chemistry−I; retrieved from: http://www.scripps.edu/baran/heterocycles/ Essentials1-2009.pdf. (10) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai, H.; Shibasaki, M. Catalytic Asymmetric Epoxidation of α,β-Unsaturated Ketones Promoted by Lanthanoid Complexes. J. Am. Chem. Soc. 1997, 119, 2329−2330. (11) Watanabe, S.; Kobayashi, Y.; Arai, T.; Sasai, H.; Bougauchi, M.; Shibasaki, M. Water vs. Desiccant. Improvement of Yb-BINOL Complex Catalyzed Enantioselective Epoxidation of Enones. Tetrahedron Lett. 1998, 39, 7353−7356. (12) Watanabe, S.; Arai, T.; Sasai, H.; Bougauchi, M.; Shibasaki, M. The First Catalytic Enantioselective Synthesis of cis-Epoxyketones from cis-Enones. J. Org. Chem. 1998, 63, 8090−8091. (13) Nemoto, T.; Ohshima, T.; Yamaguchi, K.; Shibasaki, M. Catalytic Asymmetric Epoxidation of Enones Using La−BINOL− Triphenylarsine Oxide Complex: Structural Determination of the Asymmetric Catalyst. J. Am. Chem. Soc. 2001, 123, 2725−2732. (14) Nemoto, T.; Ohshima, T.; Shibasaki, M. Catalytic Asymmetric Synthesis of α,β-Epoxy Esters, Aldehydes, Amides, and γ,δ-Epoxy βKeto Esters: Unique Reactivity of α,β-Unsaturated Carboxylic Acid Imidazolides. J. Am. Chem. Soc. 2001, 123, 9474−9475. (15) Nemoto, T.; Tosaki, S.; Ohshima, T.; Shibasaki, M. Unique Reactivity of α,β-Unsaturated Carboxylic Acid Imidazolides: Catalytic Asymmetric Synthesis of α,β-Epoxy Esters and α,β-Epoxy Carboxylic Acid Derivatives. Chirality 2003, 15, 306−311. (16) Nemoto, T.; Kakei, H.; Gnanadesikan, V.; Tosaki, S.; Ohshima, T.; Shibasaki, M. Catalytic Asymmetric Epoxidation of α,βUnsaturated Amides: Efficient Synthesis of β-Aryl α-Hydroxy Amides Using a One-Pot Tandem Catalytic Asymmetric Epoxidation-PdCatalyzed Epoxide Opening Process. J. Am. Chem. Soc. 2002, 124, 14544−14545. (17) Tosaki, S.; Nemoto, T.; Ohshima, T.; Shibasaki, M. Catalytic Asymmetric Synthesis of Both syn- and anti-3,5-Dihydroxy Esters: Application to 1,3-Polyol/α-Pyrone Natural Product Synthesis. Org. Lett. 2003, 5, 495−498. (18) Ohshima, T.; Gnanadesikan, V.; Shibuguchi, T.; Fukuta, Y.; Nemoto, T.; Shibasaki, M. Enantioselective Syntheses of Aeruginosin 298-A and Its Analogues Using a Catalytic Asymmetric Phase-Transfer Reaction and Epoxidation. J. Am. Chem. Soc. 2003, 125, 11206−11207. BE



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(36) Wen, L.; Yin, L.; Shen, Q.; Lu, L. Enantioselective Organocatalytic Michael Addition of Nitroalkanes and Other Nucleophiles to β-Trifluoromethylated Acrylamides. ACS Catal. 2013, 3, 502−506. (37) Agostinho, M.; Kobayashi, S. Strontium-Catalyzed Highly Enantioselective Michael Additions of Malonates to Enones. J. Am. Chem. Soc. 2008, 130, 2430−2431. (38) Yang, K. S.; Nibbs, A. E.; Türkmen, Y. E.; Rawal, V. H. Squaramide-Catalyzed Enantioselective Michael Addition of Masked Acyl Cyanides to Substituted Enones. J. Am. Chem. Soc. 2013, 135, 16050−16053. (39) Itoh, K.; Oderaotoshi, Y.; Kanemasa, S. Enantioselective Michael Addition Reactions of Malononitrile Catalyzed by Chiral Lewis Acid and Achiral Amine Catalysts. Tetrahedron: Asymmetry 2003, 14, 635− 639. (40) Yanagita, H.; Kodama, K.; Kanemasa, S. Double Catalytic Enantioselective Michael Addition Reactions of Tertiary Nucleophile PrecursorsTertiary/quaternary and Quaternary/quaternary Carbon−carbon Bond Formations. Tetrahedron Lett. 2006, 47, 9353− 9357. (41) Ono, F.; Hasegawa, M.; Kanemasa, S.; Tanaka, J. Catalytic Activation of Nucleophile Precursors with Metal Acetates in Alcohol Media and Applications to Enantioselective Michael Addition Reactions. Tetrahedron Lett. 2008, 49, 5105−5107. (42) Itoh, K.; Hasegawa, M.; Tanaka, J.; Kanemasa, S. Enantioselective Enol Lactone Synthesis under Double Catalytic Conditions. Org. Lett. 2005, 7, 979−981. (43) Shintani, R.; Kimura, T.; Hayashi, T. Rhodium/Diene-catalyzed Asymmetric 1,4-Addition of Arylboronic Acids to α,β-Unsaturated Weinreb Amides. Chem. Commun. 2005, 3213−3214. (44) Lin, L.; Zhang, J.; Ma, X.; Fu, X.; Wang, R. Bifunctional 3,3′Ph2-BINOL-Mg Catalyzed Direct Asymmetric Vinylogous Michael Addition of α,β-Unsaturated γ-Butyrolactam. Org. Lett. 2011, 13, 6410−6413. (45) Endo, K.; Hamada, D.; Yakeishi, S.; Shibata, T. Effect of Multinuclear Copper/Aluminum Complexes in Highly Asymmetric Conjugate Addition of Trimethylaluminum to Acyclic Enones. Angew. Chem., Int. Ed. 2013, 52, 606−610. (46) Trost, B. M.; Hirano, K. Dinuclear Zinc Catalyzed Asymmetric Spirannulation Reaction: An Umpolung Strategy for Formation of αAlkylated-α-Hydroxyoxindoles. Org. Lett. 2012, 14, 2446−2449. (47) Uraguchi, D.; Ueki, Y.; Ooi, T. Controlled Assembly of Chiral Tetraaminophosphonium Aryloxide−Arylhydroxide(s) in Solution. Angew. Chem., Int. Ed. 2011, 50, 3681−3683. (48) Uraguchi, D.; Ueki, Y.; Ooi, T. Chiral Organic Ion Pair Catalysts Assembled Through a Hydrogen-Bonding Network. Science 2009, 326, 120−123. (49) Uraguchi, D.; Yoshioka, K.; Ueki, Y.; Ooi, T. Highly Regio-, Diastereo-, and Enantioselective 1,6- and 1,8-Additions of Azlactones to Di- and Trienyl N-Acylpyrroles. J. Am. Chem. Soc. 2012, 134, 19370−19373. (50) Ishihara, K.; Fushimi, M. Design of a Small-Molecule Catalyst Using Intramolecular Cation-π Interactions for Enantioselective DielsAlder and Mukaiyama-Michael Reactions: L-DOPA-Derived Monopeptide Cu(II) Complex. Org. Lett. 2006, 8, 1921−1924. (51) Basu, S.; Gupta, V.; Nickel, J.; Schneider, C. Organocatalytic Enantioselective Vinylogous Michael Reaction of Vinylketene SilylN,O-Acetals. Org. Lett. 2014, 16, 274−277. (52) Itoh, K.; Kanemasa, S. Enantioselective Michael Additions of Nitromethane by a Catalytic Double Activation Method Using Chiral Lewis Acid and Achiral Amine Catalysts. J. Am. Chem. Soc. 2002, 124, 13394−13395. (53) Kanemasa, S.; Oderaotoshi, Y.; Yamamoto, H.; Tanaka, J.; Wada, E.; Curran, D. P. Cationic Aqua Complexes of the C2Symmetric trans-Chelating Ligand (R,R)-4,6-Dibenzofurandiyl-2,2′bis(4-phenyloxazoline). Absolute Chiral Induction in Diels-Alder Reactions Catalyzed by Water-Tolerant Enantiopure Lewis Acids. J. Org. Chem. 1997, 62, 6454−6455. (54) Kanemasa, S.; Oderaotoshi, Y.; Sakaguchi, S.; Yamamoto, H.; Tanaka, J.; Wada, E.; Curran, D. P. Transition-Metal Aqua Complexes

of 4,6-Dibenzofurandiyl-2,2′-bis(4-phenyloxazoline). Effective Catalysis in Diels-Alder Reactions Showing Excellent Enantioselectivity, Extreme Chiral Amplification, and High Tolerance to Water, Alcohols, Amines, and Acids. J. Am. Chem. Soc. 1998, 120, 3074−3088. (55) Hasegawa, M.; Ono, F.; Kanemasa, S. Molecular Sieves 4A Work to Mediate the Catalytic Metal Enolization of Nucleophile Precursors: Application to Catalyzed Enantioselective Michael Addition Reactions. Tetrahedron Lett. 2008, 49, 5220−5223. (56) Vakulya, B.; Varga, S.; Soòs, T. Epi-Cinchona Based Thiourea Organocatalyst Family as an Efficient Asymmetric Michael Addition Promoter: Enantioselective Conjugate Addition of Nitroalkanes to Chalcones and α,β-Unsaturated N-Acylpyrroles. J. Org. Chem. 2008, 73, 3475−3480. (57) For a recent review on aza-Michael reactions, see: Enders, D.; Wang, C.; Liebich, J. X. Organocatalytic Asymmetric Aza-Michael Additions. Chem. - Eur. J. 2009, 15, 11058−11076. (58) For a recent review on sulfa-Michael reactions, see: Enders, D.; Lüttgen, K.; Narine, A. A. Asymmetric Sulfa-Michael Additions. Synthesis 2007, 2007, 959−980. (59) For a recent review on phospa-Michael reactions, see: Enders, D.; Saint-Dizier, A.; Lannou, M.-I.; Lenzen, A. The Phospha-Michael Addition in Organic Synthesis. Eur. J. Org. Chem. 2006, 2006, 29−49. (60) Yamagiwa, N.; Qin, H.; Matsunaga, S.; Shibasaki, M. Lewis Acid−Lewis Acid Heterobimetallic Cooperative Catalysis: Mechanistic Studies and Application in Enantioselective Aza-Michael Reaction. J. Am. Chem. Soc. 2005, 127, 13419−13427. (61) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. Chiral Lewis Acid Catalysis in Conjugate Additions of O-Benzylhydroxylamine to Unsaturated Amides. Enantioselective Synthesis of β-Amino Acid Precursors. J. Am. Chem. Soc. 1998, 120, 6615−6616. (62) Sibi, M. P.; Soeta, T. Enantioselective Conjugate Addition of Hydrazines to α,β-Unsaturated Imides. Synthesis of Chiral Pyrazolidinones. J. Am. Chem. Soc. 2007, 129, 4522−4523. (63) Sibi, M. P.; Itoh, K. Organocatalysis in Conjugate Amine Additions. Synthesis of β-Amino Acid Derivatives. J. Am. Chem. Soc. 2007, 129, 8064−8065. (64) Wang, J.; Zu, L.; Li, H.; Xie, H.; Wang, W. Cinchona Alkaloid Based Thiourea Promoted Enantioselective Conjugate Addition of NHeterocycles to Enones. Synthesis 2007, 2007, 2576−2580. (65) Sanchez-Rosello, M.; Mulet, C.; Guerola, M.; del Pozo, C.; Fustero, S. Microwave-Assisted Tandem Organocatalytic PeptideCoupling Intramolecular Aza-Michael Reaction: α,β-Unsaturated NAcyl Pyrazoles as Michael Acceptors. Chem. - Eur. J. 2014, 20, 15697− 15701. (66) Dong, X.-Q.; Fang, X.; Tao, H.-Y.; Zhou, X.; Wang, C.-J. Highly Efficient Catalytic Asymmetric Sulfa-Michael Addition of Thiols to trans-4,4,4-Trifluorocrotonoylpyrazole. Adv. Synth. Catal. 2012, 354, 1141−1147. (67) Dong, X.-Q.; Fang, X.; Tao, H.-Y.; Zhou, X.; Wang, C.-J. Organocatalytic Asymmetric Domino Sulfa-Michael-aldol Reactions of 2-Mercaptobenzaldehyde with α,β-Unsaturated N-Acylpyrazoles for the Construction of Thiochromane. Chem. Commun. 2012, 48, 7238− 7240. (68) Zhao, B.-L.; Du, D.-M. Chiral Squaramide-catalysed One-pot Enantioselective Sulfa-Michael Addition/thioesterification of Thiols with α,β-Unsaturated N-Acylated Succinimides. Org. Biomol. Chem. 2014, 12, 1585−1594. (69) Zhao, D.; Wang, R. Recent Developments in Metal Catalyzed Asymmetric Addition of Phosphorus Nucleophiles. Chem. Soc. Rev. 2012, 41, 2095−2108. (70) For a recent review, see: Trost, B. M.; Bartlett, M. J. ProPhenolCatalyzed Asymmetric Addition by Spontaneously Assembled Dinuclear Main Group Metal Complexes. Acc. Chem. Res. 2015, 48, 688−701. (71) Zhao, D.; Wang, Y.; Mao, L.; Wang, R. Highly Enantioselective Conjugate Additions of Phosphites to α,β-Unsaturated N-Acylpyrroles and Imines: A Practical Approach to Enantiomerically Enriched Amino Phosphonates. Chem. - Eur. J. 2009, 15, 10983−10987. BF



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Propioloylpyrazoles and Acryloylpyrazoles Induced by Chiral π-Cation Catalysts. J. Am. Chem. Soc. 2010, 132, 15550−15552. (92) Sibi, M. P.; Itoh, K.; Jasperse, C. P. Chiral Lewis Acid Catalysis in Nitrile Oxide Cycloadditions. J. Am. Chem. Soc. 2004, 126, 5366− 5367. (93) Sibi, M. P.; Stanley, L. M.; Soeta, T. Enantioselective 1,3-Dipolar Cycloaddition of Nitrile Imines to α-Substituted and α,β-Disubstituted α,β-Unsaturated Carbonyl Substrates: A Method for Synthesizing Dihydropyrazoles Bearing a Chiral Quaternary Center. Adv. Synth. Catal. 2006, 348, 2371−2375. (94) Mei, L.; Wei, Y.; Xu, Q.; Shi, M. Palladium-Catalyzed Asymmetric Formal [3+2] Cycloaddition of Vinyl Cyclopropanes and β,γ-Unsaturated α-Keto Esters: An Effective Route to Highly Functionalized Cyclopentanes. Organometallics 2012, 31, 7591−7599. (95) Trost, B. N.; Stambuli, J. P.; Silverman, S. M.; Schwörer, U. Palladium-Catalyzed Asymmetric [3+2] Trimethylenemethane Cycloaddition Reactions. J. Am. Chem. Soc. 2006, 128, 13328−13329. (96) Trost, B. M.; Silverman, S. M.; Stambuli, J. P. Development of an Asymmetric Trimethylenemethane Cycloaddition Reaction: Application in the Enantioselective Synthesis of Highly Substituted Carbocycles. J. Am. Chem. Soc. 2011, 133, 19483−19497. (97) Trost, B. M.; Maruniak, A. Enantioselective Construction of Highly Substituted Vinylidenecylopentanes by Palladium-Catalyzed Asymmetric [3+2] Cycloaddition Reaction. Angew. Chem., Int. Ed. 2013, 52, 6262−6264. (98) Trost, B. M.; Ehmke, V. An Approach for Rapid Increase in Molecular Complexity: Atom Economic Routes to Fused Polycyclic Ring Systems. Org. Lett. 2014, 16, 2708−2711. (99) Desimoni, G.; Faita, G.; Jørgensen, K. A. Update 1 of: C2Symmetric Chiral Bis(oxazoline) Ligands in Asymmetric Catalysis. Chem. Rev. 2011, 111, PR284−PR437. (100) Desimoni, G.; Faita, G.; Jørgensen, K. A. C2-Symmetric Chiral Bis(Oxazoline) Ligands in Asymmetric Catalysis. Chem. Rev. 2006, 106, 3561−3651. (101) Aspinall, H. C.; Dwyer, J. L. M.; Greeves, N.; Steiner, A. Li3[Ln(binol)3]·6THF: New Anhydrous Lithium Lanthanide Binaphtholates and Their Use in Enantioselective Alkyl Addition to Aldehydes. Organometallics 1999, 18, 1366−1368. (102) Xiao, Y.; Wang, Z.; Ding, K. Copolymerization of Cyclohexene Oxide with CO2 by Using Intramolecular Dinuclear Zinc Catalysts. Chem. - Eur. J. 2005, 11, 3668−3678. (103) Bertelsen, S.; Jørgensen, K. A. Organocatalysis-After the Gold Rush. Chem. Soc. Rev. 2009, 38, 2178−2189. (104) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H.-Y.; Houk, K. N. Theory of Asymmetric Organocatalysis of Aldol and Related Reactions: Rationalizations and Predictions. Acc. Chem. Res. 2004, 37, 558−569. (105) Simón, L.; Goodman, J. M. What is the mechanism of amine conjugate additions to pyrazole crotonate catalyzed by thiourea catalysts? Org. Biomol. Chem. 2009, 7, 483−487. (106) Monge, D.; Jiang, H.; Alvarez-Casao, Y. Masked Unsaturated Esters/Amides in Asymmetric Organocatalysis. Chem. - Eur. J. 2015, 21, 4494−4504. (107) Elpidio Gregori was a great harpsichord maker, active in Marche region (Italy) in the middle of the XVIII century, who built during the “Bach age” the elegant “falso levatore di cassa” harpsichord illustrated in this Review. We thank Prof. Paolo Corsi, owner of the harpsichord, for the kind permission to reproduce the picture of his instrument.

(72) Zhao, D.; Yuan, Y.; Chan, A. S. C.; Wang, R. Highly Enantioselective 1,4-Addition of Diethyl Phosphite to Enones Using a Dinuclear Zn Catalyst. Chem. - Eur. J. 2009, 15, 2738−2741. (73) Zhao, D.; Mao, L.; Wang, Y.; Yang, D.; Zhang, Q.; Wang, R. Catalytic Asymmetric Hydrophosphinylation of α,β-Unsaturated NAcylpyrroles: Application of Dialkyl Phosphine Oxides in Enantioselective Synthesis of Chiral Phosphine Oxides or Phosphines. Org. Lett. 2010, 12, 1880−1882. (74) Zhao, D.; Mao, L.; Wang, Y.; Yang, D.; Wang, R. Catalytic Asymmetric Construction of Tetrasubstituted Carbon Stereocenters by Conjugate Addition of Dialkyl Phosphine Oxides to β,βDisubstituted α,β-Unsaturated Carbonyl Compounds. Chem. Commun. 2012, 48, 889−891. (75) Du, D.; Duan, W.-L. Palladium-catalyzed 1,4-Addition of Diarylphosphines to α,β-Unsaturated N-Acylpyrroles. Chem. Commun. 2011, 47, 11101−11103. (76) Lu, J.; Ye, J.; Duan, W.-L. Palladium-catalyzed Asymmetric 1,6Addition of Diarylphosphines to α,β,γ,δ-Unsaturated Sulfonic Esters: Controlling Regioselectivity by Rational Selection of Electronwithdrawing Groups. Chem. Commun. 2014, 50, 698−700. (77) Sibi, M. P.; Shay, J. J.; Ji, J. Enantioselective Intermolecular Free Radical Conjugate Additions. Application of a Pyrazole Template. Tetrahedron Lett. 1997, 38, 5955−5958. (78) Sibi, M. P.; Petrovic, G. Enantioselective Radical Reactions: the Use of Metal Triflimides as Lewis Acids. Tetrahedron: Asymmetry 2003, 14, 2879−2882. (79) Sibi, M. P.; Sausker, J. B. The Role of the Achiral Template in Enantioselective Transformations. Radical Conjugate Additions to αMethacrylates Followed by Hydrogen Atom Transfer. J. Am. Chem. Soc. 2002, 124, 984−991. (80) Sibi, M. P.; Guerrero, M. A. Enantioselective Radical Methods for Lactone Synthesis: Use of Unprotected Haloalcohols as Radical Precursors. Synthesis 2005, 1528−1532. (81) Kashima, C.; Yokoyama, H.; Shibata, S.; Fujisawa, K.; Nishio, T. Asymmetric Conjugate Addition Reaction Using Pyrazole Derivatives as a Chiral Catalyst. J. Heterocycl. Chem. 2003, 40, 717−719. (82) Kashima, C.; Fukusaka, K.; Takahashi, K.; Yokoyama, Y. Diastereoselective Diels-Alder Reaction of 2-(α,β-Unsaturated)acyl-3phenyl-l-menthopyrazoles. J. Org. Chem. 1999, 64, 1108−1114. (83) Kashima, C.; Miwa, Y.; Shibata, S.; Nakazono, H. Asymmetric Diels Alder Reaction Using Pyrazole Derivatives as a Chiral Catalyst. J. Heterocycl. Chem. 2003, 40, 681−688. (84) Kashima, C.; Shibata, S.; Yokoyama, H.; Nishio, T. Preparation of 2,6-Bis(l-menthopyrzol-3-yl)pyridines and Their Catalytic Activity for Asymmetric Diels Alder Reaction. J. Heterocycl. Chem. 2003, 40, 773−782. (85) Sibi, M. P.; Chen, J.; Stanley, L. Enantioselective Diels-Alder Reactions: Effect of the Achiral Template on Reactivity and Selectivity. Synlett 2007, 2007, 298−302. (86) Ishihara, K.; Fushimi, M.; Akakura, M. Rational Design of Minimal Artificial Diels−Alderases Based on the Copper(II) Cation− Aromatic π Attractive Interaction. Acc. Chem. Res. 2007, 40, 1049− 1055. (87) Ishihara, K.; Sakakura, A.; Hatano, M. Design of Highly Functional Small-Molecule Catalysts and Related Reactions Based on Acid-Base Combination Chemistry. Synlett 2007, 2007, 686−703. (88) van der Helm, D.; Tatsch, C. E. The Crystal Structure of Bis-(Ltyrosinato)copper(II). Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1972, B28, 2307−2312. (89) Ishihara, K.; Fushimi, M. Catalytic Enantioselective [2 + 4] and [2 + 2] Cycloaddition Reactions with Propiolamides. J. Am. Chem. Soc. 2008, 130, 7532−7533. (90) Hori, M.; Sakakura, A.; Ishihara, K. Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Imines with Propioloylpyrazoles Induced by Chiral π−Cation Catalysts. J. Am. Chem. Soc. 2014, 136, 13198−13201. (91) Sakakura, A.; Hori, M.; Fushimi, M.; Ishihara, K. Catalytic Enantioselective 1,3-Dipolar Cycloadditions of Nitrones with BG


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