Enantioselectively-Catalyzed Reactions with (E)-2-Alkenoyl-pyridines

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Enantioselectively-Catalyzed Reactions with (E)‑2-Alkenoyl-pyridines, Their N‑Oxides, and the Corresponding Chalcones Giovanni Desimoni,* Giuseppe Faita, and Paolo Quadrelli Department of Chemistry, University of Pavia, Viale Taramelli 10, 27100 Pavia, Italy S Supporting Information *

1. INTRODUCTION α,β-Unsaturated carbonyl derivatives are suitable substrates for the enantioselective catalyzed reactions that, in general, are directed to functionalize the activated double bond. However, the reactions may also involve either the entire CC−CO fragment or the carbonyl group only. These reactions occur in the presence of a chiral catalyst (CC*), which can be either a [chiral ligand/inorganic cation] complex acting as a chiral Lewis acid catalyst or an organocatalyst behaving as a chiral activator. Their mechanism of activation assumes that the lone electron pair of the carbonyl oxygen atom coordinates to the Lewis acid or gives hydrogen bonding with the NH group of the organocatalyst. Thereby the activation of the substrate is the result of a lowered energy of the lowest unoccupied molecular orbital (LUMO), which easier reacts with the HOMO of an electronrich reagent. This model is deeply influenced on the characteristic of the substrate and Figure 1, in which for simplicity CC* is a chiral Lewis acid, illustrates three reagents that find wide applications as substrates. Besides the increased electrophilicity due to the presence of an electron-withdrawing ester substituent, the 4-substituted (E)-2oxo-3-butenoates (A) gain a specific advantage from the presence of the ester moiety, because the resulting 1,2-dicarbonyl system may form a five-membered chelated structure with the Lewis acid.1 Analogously, the α,β-unsaturated 1,3-dicarbonyl derivatives, an example of which are the 3-alkenoyl-2oxazolidinones (B),2 were used as the benchmark to compare the efficiency of different catalysts in asymmetric reactions. They behave again as bidentate reagents and the second carbonyl group participates to give an even more stable six-membered chelated structure with the Lewis acid. The bicoordination to the Lewis acid with A- and B-type reagents has several positive fall-outs on both reactivity and stereoselectivity. It gives rigid structures with the catalyst, which

CONTENTS 1. Introduction 2. Michael Reaction 2.1. Phospha- and Aza-Michael Reactions 2.2. Henry Reaction 2.3. Friedel−Crafts Reaction 3. Epoxidation Reaction 4. Radical Reaction 5. [3 + 2] Dipolar Cycloaddition Reaction 6. D.A. Reaction 6.1. Families of Unusual Catalysts for the D.A. Reaction 6.1.a. Natural and Artificial Metalloenzymes 6.1.b. DNA-Based Asymmetric D.A. Reaction 7. Hetero D.A. Reaction 8. Influence of Substituents on Reactivity and Selectivity 9. Relationship between Different Organocatalysts or Chiral Complexes and the Stereochemical Outcome 10. Comparison between the EnantioselectivelyCatalyzed Reactions with (E)-2-Alkenoyl-pyridines, Their N-Oxides, and the Corresponding Chalcones 11. Conclusions Associated Content Supporting Information Author Information Corresponding Author Notes Biographies Acknowledgments Dedication References

© XXXX American Chemical Society

A C H I K L M M O S S W AG AH

AI

AN AT AU AU AU AU AU AU AU AV AV

Figure 1. α,β-Unsaturated carbonyl derivatives activated by a chiral catalyst (CC*) for enantioselective reactions. Received: December 20, 2013

A

dx.doi.org/10.1021/cr4007208 | Chem. Rev. XXXX, XXX, XXX−XXX

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reaction occurs with excellent yield, diastereomeric ratio and enantiomeric excess giving (3R,4R)-5. Interestingly, the mechanism is a two-steps reaction. The first step is the formation of the octahedral reacting intermediate [3/(R,S)-I/Sc(OTf)3/ NBS] with NBS axial and 3 equatorial suitably arranged for a diastereoselective electrophilic bromination occurring to the Re face of the double bond that gives the chiral optically active bromonium ion (S,S)-4. In the second step, Ts-NH2 gives the nucleophilic ring-opening affording (3R,4R)-5 as the final product. The flexibility of the reaction was shown with 29 experiments in which the average yield was 95%, the d.r. 99:1, and the enantioselectivity 96% ee. These results are illuminating because: (a) the monocoordination does not correspond to a low stereoselectivity if the chiral catalyst is suitably chosen and the reacting complex is harmoniously organized; (b) the carbonyl coordination of the α,β-unsaturated carbonyl system still maintains an excellent reactivity of the double bond against the electrophiles. The reactions involving (E)-2-alkenoyl-pyridines (1) and (E)2-alkenoyl-pyridine-N-oxides (2) (as well as those on chalcone model compounds) may occur on the double bond either on their α,β-positions or in the β-position. To have a homogeneous comparison between the stereochemical results of these reactions and to avoid different descriptors due to different substituents inducing change of priority, the substituent R will be conventionally considered to be a phenyl group (1a and 2a), and the preferred approached face will be referred to the β-carbon (Figure 3).

usually makes a more selective diastereoface differentiation in the concerned enantioselective reaction. Moreover, the more electron attracting substituent of the α,β-unsaturated carbonyl derivatives, increasing the LUMO lowering, favors the reactivity with electron-rich reagents. All these advantages are absent if the substituent R′ of reagent C lacks of the characters that allow its participation to a bicoordination. Then, the monocoordination with the chiral catalyst makes less rigid (and usually less stereoselective) the reacting complex with the catalyst, and less electrophilic (and usually less reactive) the double bond. The peculiarity 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. Three families of reagent topologically similar to the above substrates are illustrated in Figure 2. (E)-2-Alkenoyl-pyridines (1), as A does, give a five-membered chelated structure with the chiral catalyst if

Figure 2. Activation by a chiral catalyst for enantioselective reactions of (E)-2-alkenoyl-pyridines (1), (E)-2-alkenoyl-pyridine-N-oxides (2), and chalcones (3).

the electron pairs of both the carbonyl and the pyridine nitrogen atom are involved. (E)-2-Alkenoyl-pyridine-N-oxides (2), as B does, give a six-membered chelated structure involving the electron pairs of both carbonyl and oxygen N-oxide. What can be expected for chalcones (3), in which the R substituent of C is a phenyl group, it has been therefore mentioned above, and it will be illustrated in the following and elegant example. The enantioselective aminobromination of chalcones is an outstanding topic in up-to-date organic synthesis,3 and it was elegantly solved by a one-pot reaction between chalcone (3, R=Ph), N-bromosuccinimide (NBS), and p-toluenesulfonamide (Ts-NH2), catalyzed by homoprolinebased N,N′-dioxide (R,S)-I and Sc(OTf)3 (Scheme 1).4 The

Figure 3. (E)-3-Phenyl-1-(pyridin-2-yl)prop-2-en-1-one (1a) and (E)3-phenyl-1-(pyridin-2-yl-N-oxide)prop-2-en-1-one (2a): addition to the enantiotopic faces of the double bond.

Scheme 1

B


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more rigid the reacting intermediate, the expected beneficial effects on stereoselectivity are not observed. Hence the statement that two-points binding corresponds to better enantioselectivity is not always true. More sophisticated catalysts have been recently designed to catalyze the reaction between the α,β-unsaturated carbonyl derivatives (1a or 3a) and N-(diphenylmethylene)glycine tertbutyl ester (8) (Scheme 3).6 The chiral core of the catalyst is again (S)-BINOL in its dimeric structure, containing two symmetric quaternary ammonium moieties annexed by means of a flexible linker [(S)-III]. One quaternary ammonium unit activates the electrophile by electrostatic interaction with the α,βunsaturated carbonyl group, while the second ammonium ion stabilizes the nucleophilic anionic enolate. The results are excellent and both chalcone 3a and its aza-analogue 1a give excellent yields and high diastereomeric ratios of (2R,3S)-9 and (2R,3S)-10, with 88 and 93% ee, respectively. The absolute configuration of the products implies that (S)-BINOL chiral environment induces a β-Si face attack of the nucleophile on 1a and 3a. The asymmetric catalysis of the Michael reaction has been developed with either urea or thiourea bifunctional organocatalysts. Three examples have been reported. The addition of malononitrile (11) to 1a can be catalyzed by cinchona alkaloid-based urea derivatives with different scaffolds and the interesting result is the relationship between scaffold and enantioselectivity of the product. If the 8-epi-quinidine-type catalysts (S,S,R)-IVa-d and the 8-epi-aminocinchonine-type ones (R,R,R)-Va-d are considered as clusters of pseudoenantiomeric catalysts, both enantiomers of the products can be achieved. (S,S,R)-IVa-d give (S)-12 and (R,R,R)-Va-d give (R)-12 (Scheme 4),7 both with excellent yields and degrees of enantioselectivity, even if the urea catalysts are superior over the corresponding thiourea ones. All the results obtained with the entire set of catalysts, with 1a as substrate, are listed in Table 1 (entries 1−8). The best of them, (R,R,R)-Va, was tested with a series of 17 4-substituted (E)-2-alkenoyl-pyridines (1a−q), changing the solvent from toluene to m-xylene (always at ambient temperature), and the results reported in Table 1 (entries 9−24) show the excellent flexibility of these catalysts that are compatible with a great variety of substituents, always with excellent yields and selectivities. The addition of ethyl α-cyanoacetate (13) to both 1d and to the analogue chalcone 3d was catalyzed by the dihydroquininebased thiourea (S,S,R)-VI (Scheme 5). The reaction in toluene at

The present review covers a narrow topic, being limited to the reactions of (E)-2-alkenoyl-pyridines (1) and (E)-2-alkenoylpyridine-N-oxides (2), which affords nonracemic products by performing the reactions in the presence of a chiral catalyst. As far as possible, the results of these reactions will be compared with those obtained with the analogous chalcone, only when obtained under similar conditions. The core of the discussion will be the reactivity and the stereoselectivity of these reagents, the relationship between the configuration of the catalyst and that of the product, i.e. the mechanism of transmission of the chiral information from catalyst to product.

2. MICHAEL REACTION In 1996 Feringa and co-workers,5 within an extensive research concerning enones, explored the first Michael reaction of diethylzinc to chalcone (3a) and to (E)-3-phenyl-1-(pyridin-2-yl)prop2-en-1-one (1a). The reactions were catalyzed by chiral copper(II) complex of phosphorus amidite (S)-II (Scheme 2). Scheme 2

Even if the absolute configurations of the products were not determined, this first research in the field allows inferring the scope of this review. Whereas chalcone gives 7 in excellent yield and 90% ee, the aza-analogue 1a gives 6 with low enantioselectivity (29% ee). Thus, in this reaction with this catalyst, the presence of a nitrogen atom in the reagent has a dramatic effect on the stereoselectivity. The authors advanced the hypothesis of a competitive binding of the copper catalyst to the pyridine moiety that depresses both the reactivity and the selectivity. Even if the representation in Figure 2 should make Scheme 3

C


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ambient temperature gives good yields, 80 and 88% with 1d and 3d, respectively, but the syn/anti diastereoselectivities were poor, [64:36] and [60:40]. 8 What deserves attention is the enantioselectivity. The absolute configuration of the syn products 14,15 is (2S,3S), while that of the anti adducts 16,17 is (2R,3S). This suggests that the poorly diastereoselective attack occurs on the β-Re face. The enantioselectivities of both diastereoisomers obtained from 1d (94 and 95% ee) are higher than the ee of the products obtained from 3d, probably due to a more efficient coordination of the reacting substrate to the catalyst. The same organocatalysts (S,S,R)-IVa-d and (R,R,R)-Va-d, used in the reaction with malononitrile (Scheme 4),7 were tested in the Michael reaction with 1,3-cyclohexandiones 18a,b.9 All eight urea- or thiourea-type molecules gave excellent results both in terms of yields and enantioselectivities: (S,S,R)-IVa-d induced the attack of the nucleophile onto the β-Re face to give (R)-19, while by using (R,R,R)-Va-d the attack was on the β-Si face and the product was (S)-19 (Scheme 6, Table 2, entries 2−9). With (R,R,R)-Va as the catalyst of choice, the reaction was tested with 1a−q and in all the cases the yields were above 90% and the ee in the range 90−95% with the exception of 1q (Table 2, entries 10− 26). When the reaction was performed without acetyl chloride, the unstable intermediate reacted with ammonium acetate to give 2-(pyridin-2-yl)-4,6,7,8-tetrahydroquinolin-5(1H)-ones [(S)-21], again with excellent yields and enantioselectivities. One further reaction deserves attention because it will allow in a late section to discuss the different stereoselective behavior of 1−3. The catalyst (S,S,R)-IVd was tested on the reaction between chalcone 3a and dimedone 18a (X=CMe2). Again the attack was on the β-Re face of 3a, but (R)-20 was obtained in only 55% yield and the ee was 72% (Table 2, entry 1).9 The Michael addition of dimethyl malonate (22a) to 1a depicted in Scheme 7 was catalyzed with the Cu(NO3)2 complex of a triazacyclophane scaffold decorated with three acetyl Lhistidine amino acid residues.10 Since the product 23 was obtained with 14% ee, and the same catalyst was tested on the Diels−Alder (D.A.) reaction between 1a and cyclopentadiene with better results (which we will consider in a further section of this review), this reaction is mentioned only for a matter of comprehensiveness. The above Michael reaction between 1a and 22a allows beginning the discussion of an unusual chiral catalyst that is commonly found only with enantioselective reactions dealing with 1. This catalyst is achieved by a noncovalent binding of an achiral copper complex [Cu(II)/(4,4′-dimethyl-2,2′-bipyridine)/(NO3)2] in a buffered solution of salmon testes DNA in base pairs. If 1a provides a bidentate coordination to copper(II), the chirality of DNA can be transmitted to the product, and the result is excellent since 23 is obtained in quantitative yield with 96% ee.11 The concerned Michael reaction is reported in Scheme 7 with the schematic representation of the DNA-based asymmetric catalyst that will also be used in the D.A. reaction between 1 and cyclopentadiene. If the Michael reaction is run in the presence of organic cosolvents, then the reactivity is significantly increased, while in the case of the D.A. reaction between 1a and cyclopentadiene the addition of organic cosolvents depresses the reaction rate. The enantioselective Michael addition of malonates 22 to 4substituted-2-enoylpyridine N-oxides (2) was catalyzed by the chiral Zn(OTf) 2 complex of (3aR,3′aR,8aS,8′aS)-2,2′cyclopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) [(3aR,8aS)-VIII] (Scheme 8). The corresponding Michael

Scheme 4

Table 1. Michael Addition of Malononitrile (11) to 1, with IVa-d and Va-d as Organocatalysts (Scheme 4)7 entrya

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

Ph Ph Ph Ph Ph Ph Ph Ph 4-MeO-C6H4 4-Me-C6H4 4-Cl-C6H4 3-Cl-C6H4 4-F-C6H4 3-NO2-C6H4 4-NO2-C6H4 4-CN-C6H4 4-CF3-C6H4 2-Cl-6-F-C6H3 3,4-OCH2O-C6H3 1-naphthyl 2-naphthyl 2-furyl (E)-PhCHCH cyclohexyl

1a 1a 1a 1a 1a 1a 1a 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 1m 1n 1o 1p 1q

organocatalyst

yield (%)

12 ee (%) (conf)

(S,S,R)-IVa (S,S,R)-IVb (S,S,R)-IVc (S,S,R)-IVd (R,R,R)-Va (R,R,R)-Vb (R,R,R)-Vc (R,R,R)-Vd (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va

93 94 94 94 95 94 92 94 85 90 92 91 90 80 94 93 79 82 81 86 89 80 78 80

94 (R) 82 (R) 93 (R) 92 (R) 94 (S) 93 (S) 88 (S) 84 (S) 94 94 95 95 95 93 96 95 95 94 92 95 94 94 94 97

a

Reactions in entries 1−8 were performed in toluene; those in entries 9−24 in m-xylene, both at ambient temperature. D


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Scheme 5

Scheme 6

Box-based copper(II) triflate complexes have been used as catalysts in the Mukaiyama−Michael reaction between 2benzilidenoylpyridine N-oxide (2a) and 2-(trimethylsilyloxy)furan (27). The reaction is highly stereoselective, since only the adduct anti-(+)-28 is obtained (Scheme 10).14 The interesting feature is that the Cu(OTf)2 complexes of two ligands with opposite configuration at C-4, (4R)-phenyl Box [(4R)-IX] and (4S,5S)-OTIPS-Box [(4S,5S)-X], give the same enantiomer. The same chiral complex [(4S,5S)-X/Cu(OTf)2] is the catalyst of the reaction between 4-substituted 2-enoylpyridine N-oxides (2a,v) and (1,2-dihydronaphthalen-4-yloxy)-trimethylsilane (29). The Mukaiyama−Michael reaction, which is in competition with a [4 + 2]-cycloaddition affording (4S,4aR,10bR)-30, later discussed, gives the syn and anti adducts (2S,3R)-31 and (2S,3S)-32 that are the products considered in this section (Scheme 11). The absolute configuration of all these adducts can be rationalized by assuming the approach of 29 to the β-Re face of 2.14 The reaction proceeds with almost quantitative yields, the enantioselectivity is always excellent, but regio- and diastereoselectivity are poor since the product ratios depend on temperature and reaction time (Table 5, entries 1−3). A simple explanation of these results was proposed by considering the ring-opening of the [4 + 2]-cycloadduct (4S,4aR,10bR)-30 (the primary reaction product) to give the

adducts 24, whose absolute configuration is (S), have been obtained in high yields and with up to 96% ee. The selectivity is very sensitive to the steric hindrance of both the malonate ester groups (Table 3, entries 1−5) and the R substituent of 2 (Table 3, entries 15 and 16).12 If 2 behave as bidentate ligands and coordinate to Zn(II) giving a tetrahedral complexes, the (S) absolute configuration requires the addition of malonates to the less hindered β-Re face. After testing several different Box ligands, the copper(II) triflate complex of (4R)-phenyl-Box [(4R)-IX/Cu(OTf)2] was found to be the best catalyst in the Mukaiyama−Michael reaction between 2-enoylpyridine N-oxides 2 and a variety of silyl enol ethers 25a−f (Scheme 9).13 The reaction occurs under smooth conditions and, with few exceptions, the yields are good and the average enantiomeric excess of (R)-26 in 20 experiments is 85% (Table 4). Surprising results are those obtained in the reaction of the cyclohexylsubstituted N-oxide 2q where only traces of the product were obtained after a long reaction time, while the tert-butyl substituted one 2s furnishes 26 in 88% yield and 91% ee (Table 4, entries 19 and 20). The absolute (R) configuration, determined for 26 (Ar=R=Ph), requires the attack of the silyl ether to the β-Re face of the coordinated 2. E


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Table 2. Michael Addition of 1,3-Cyclohexandione 18a to 1 and 3a, with IVa-d and Va-d as Organocatalysts (Scheme 6)9 entrya 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 26d

organocatalyst

yield (%)

19 ee (%) (conf)

3a 1a 1a 1a 1a 1a 1a 1a 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l

(S,S,R)-IVd (S,S,R)-IVd (S,S,R)-IVc (S,S,R)-IVb (S,S,R)-IVa (R,R,R)-Va (R,R,R)-Vb (R,R,R)-Vc (R,R,R)-Vd (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va

55b 95 95 93 94 97 94 95 92 95 96 88 96 95 94 90 87 94 97 86

72 (R)b 96 (R) 96 (R) 96 (R) 96 (R) 98 (S) 94 (S) 97 (S) 94 (S) 90 97 97 97 97 97 98 98 98 91 (R)c 92

1m 1n 1o 1p 1q 1a

(R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va (R,R,R)-Va

95 96 87 84 93 96

93 97 96 86 70 95

R Ph Ph Ph Ph Ph Ph Ph Ph Ph 4-MeO-C6H4 4-Me-C6H4 4-Cl-C6H4 3-Cl-C6H4 4-F-C6H4 3-NO2-C6H4 4-NO2-C6H4 4-CN-C6H4 4-CF3-C6H4 2-Cl-6-F-C6H3 3,4-OCHH2OC6H3 1-naphthyl 2-naphthyl 2-furyl (E)-PhCHCH cyclohexyl Ph

Scheme 8

Table 3. Michael Addition of Malonates 22 to 2 with Complex [(3aR,8aS)-VIII/Zn(OTf)2] as the Catalyst (Scheme 8)12 entry

R

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

Ph Ph Ph Ph Ph 4-MeO-C6H4 4-Cl-C6H4 3-Cl-C6H4 2-Cl-C6H4 4-F-C6H4 3-NO2-C6H4 1-naphthyl 2-furyl (E)-PhCHCH cyclohexyl t-Bu

a

Reactions in entries 1−9 were performed in toluene, those in entries 10−26 in CH2Cl2, both at ambient temperature, with 10% mol organocatalyst, and the reaction time was in the range 6−72 h. bYield, ee, and absolute configuration refer to 20. cNote the change in priority. d Reaction run with 18b.

Scheme 7

a

R′ 2a 2a 2a 2a 2a 2b 2d 2e 2r 2f 2g 2m 2o 2p 2q 2s

Me Et i-Pr Bn t-Bu Me Me Me Me Me Me Me Me Me Me Me

22a 22b 22c 22d 22e 22a 22a 22a 22a 22a 22a 22a 22a 22a 22a 22a

yield (%)

24 ee (%) (conf)

96 90 86 84 60 87 97 96 95 95 92 83 96 75 70 n.r.a

92 (S) 85 79 74 16 88 91 87 96 90 88 96 94 86 92

No reaction.

The Michael pathway is the only reaction between α-tetralone (33) and 2a,v, with complex [(4S,5S)-X/Cu(OTf)2] as the catalyst, and (2S,3R)-31 is obtained with very good stereoselectivity (Table 5, entries 5 and 6). Again, the absolute configuration of the product suggests the reaction to occur through the approach of 33 to the β-Re face of 2 (Scheme 11).14 Valuable alternatives to the [Box/Cu(II)] complexes as catalysts of the Michael reactions between 2-enoylpyridine-Noxides 2 and β-dicarbonyl derivatives are the catalysts in which the chiral ligand is Pybox and the Lewis acid is Zn(II). After testing several ligands, the most efficient was found to be 2,6bis[(4S)-4,5-dihydro-4-isopropyl-5,5-diphenyloxazol-2-yl]pyridine [(4S)-XI], hence its Zn(OTf)2 complex was applied to

Michael derivatives. A clear proof of this rearrangement was obtained by converting the cycloadduct (4S,4aR,10bR)-30 (Ar Ph) at ambient temperature and in the presence of Cu(OTf)2 into compound (2S,3R)-31 (ArPh) with complete retention of the configuration. Thus, the suitable location of this reaction should be in the section of this review dealing with [4 + 2]cycloaddition. F


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Scheme 9

Scheme 10

Table 4. Mukaiyama−Michael Addition of Silyl Enol Ethers 25a−f to 2 with Complex [(4R)-IX/Cu(OTf)2] as the Catalyst (Scheme 9)13 entry

R

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

Ph Ph Ph Ph Ph Ph 4-F-C6H4 3-F-C6H4 2-F-C6H4 4-Br-C6H4 4-Cl-C6H4 4-NO2-C6H4 3-NO2-C6H4 2-NO2-C6H4 4-Me-C6H4 2-naphthyl 2-furyl (E)-PhCHCH cyclohexyl t-Bu

2a 2a 2a 2a 2a 2a 2f 2t 2u 2v 2d 2h 2g 2w 2c 2n 2o 2p 2q 2s

25a 25b 25c 25d 25e 25f 25a 25a 25a 25a 25a 25a 25a 25a 25a 25a 25a 25a 25a 25a

yield (%)

26 ee (%) (conf)

93 90 88 75 86 35 88 90 85 91 90 92 92 91 82 86 80 80 trace 88

96 (R) 82 75 80 91 (R) 35 (R) 90 97 82 95 92 96 97 84 92 93 83 72 n.d. 91

idine N-oxide (2s) that gives no product after 4 days (Table 6, entry 18). The same catalyst [(4S)-XI/Zn(OTf)2] was successfully applied to the Michael reaction between 2-enoylpyridine Noxides 2 and different coumarin derivatives or coumarin analogues (35a−e).16 The reaction, which requires the presence of a basic additive (DBU is the best) to improve rate and enantioselectivity, gives the open chain product whose absolute configuration is (4R)-36, in rapid equilibrium with the hemiketal form (4R)-36′ (Scheme 12). This result can be again rationalized through the approach of 35 to the β-Re face of 2. The results are reported in Table 6 and 14 experiments with different reagents give an average yield of 93%. Again, 2s gave no product after 3 days (Table 6, entry 18). Some reactions give only satisfactorily ee (Table 6, entries 5, 13, and 14); therefore the average ee is 80% only, but the enantioselectivity may be strongly improved simply washing the products with ethyl acetate. To illustrate the synthetic utility of this method, (R)-36 (R=Ph, X=O), purified at 97% ee, was converted into the acid (R)-37. This latter was transformed into either the anticoagulant (R)-Warfarin by reaction with MeLi, or the enol lactone (R)-38 upon treatment with acetic anhydride, in any cases without losing the enantiopurity (Scheme 13).16 The [(4S)-XI/Zn(OTf)2] catalyst was also successfully used in the Mukaiyama−Michael reaction between 2-enoylpyridine N-oxides 2 and different acyclic silyl enol ethers 39 (Scheme 14).17 If R″ in silyl ethers 39 is hydrogen, then the reaction is compatible with a wide series of substituents R of 2enoylpyridine N-oxides (Table 7, entries 1−12 and 14−16). When the substituent R or R′ is a tert-butyl group, the increased reagent hindering determines a complete loss of reactivity (Table 7, entries 13 and 17). Another limit is the low diastereoselectivity of the reaction when R″ in 39 is a methyl group (Table 7, entries 18−20). The product 40 of the reaction in Table 7 (entry 1), under basic conditions, was converted into the carboxylic acid 41, which was then oxidized to the synthetically useful α-pyrone 42 without appreciable loss of the original chirality (Scheme 14). The X-ray crystal structure of the product described in entry 15, and the comparison of the optical rotation of 41 with the value reported in the literature, allowed to determine the absolute configuration of the Michael products. The (R) configuration derives from the attack of silyl enol ethers 39 to the β-Re face of 2

a

The same reaction catalyzed with the Cu(OTf)2 complex of (4S)-tertbutyl Box gives 91% yield of (R)-26 with 54% ee.

the reaction of several 4-substituted 2-enoylpyridine N-oxides 2 with dimedone, 1,3-cyclohexanone, and 1,3-cyclopentanone (18a−c), respectively (Scheme 12).15 The reactions occur smoothly and the different dicarbonyl compounds 18a−c have little influence on reactivity and enantioselectivity, since the corresponding adducts 34 are obtained with comparable yields and enantiomeric purities (Table 6, entries 1−3). The Michael adduct 34 is found to exist in rapid equilibrium with a diastereomeric hemiketal form 34′. The crystal structure of the hemiketal product 34′ in Table 6 (entry 6), where X is CMe 2 and R is 4-Br-C 6 H 4 , has the (2S,4R) absolute configuration. Attention must be given to the absolute configuration of its open chain product that, for priority reasons, is (4S)-34. This result means that the reaction occurs through the approach of 18 to the β-Re face of 2. Changing the nature of R, yields and enantioselectivities are always excellent since 14 experiments with different reagents give an average yield of 91% and an average ee of 93% (Table 6). An anomaly is the reaction with (E)-4,4-dimethyl-2-pentenoylpyrG


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Scheme 11

Table 5. Competition between the Michael Addition and the [4 + 2]-Cycloaddition in the Reactions between 2a,v and (1,2Dihydronaphthalen-4-yloxy)-trimethylsilane (29) or α-Tetralone (33) with [(4S,5S)-X/Cu(OTf)2] as the Catalyst (Scheme 11)14 entry

R

1 2 3 4 5 6

Ph Ph Ph 4-Br-C6H4 Ph 4-Br-C6H4

2a 2a 2a 2v 2a 2v

29 29 29 29 33 33

T/°C

t/h

yield (%)

[30:31:32]

30 ee (%) (conf)

31 ee (%) (conf)

−20 −20 −70 −20 r.t. r.t.

1 15 140 60 96 72

82 94 99 67 99 99

71:22:7 20:69:11 85:13:2 20:66:14 0:92:8 0:88:12

99.9(4S,4aR,10bR) 99.9(4S,4aR,10bR) 99.9(4S,4aR,10bR) 99.8(4S,4aR,10bR)

n.d. 99(2S,3R) n.d 98(2S,3R) 94(2S,3R) 92(2S,3R)

when coordinated to the Zn(II) cation of (4S)-XI, a result that has been already found in the reactions with the same catalyst reported in Scheme 12. To our opinion these two last examples (Schemes 13 and 14) are of a great relevance since they allow to consider the pyridine N-oxide of the addition products as a masked carboxylic group, with a great increase of the possible synthetic applications for these enantioselective Mukaiyama−Michael adducts.

Scheme 12

2.1. Phospha- and Aza-Michael Reactions

The Michael additions implying the formation of a new C−C bond have been discussed in the previous part of this section. Two other variants of the reaction with formation of new C-X bonds have been reported: the phospha- and aza-Michael reactions with formation of C−P and C−N bonds, respectively. The phospha-Michael reaction is interesting because the hydrophosphination of 1 allows the synthesis of chiral tertiary phosphines that, in addition to PR′3 and CO groups, have a nitrogen atom allowing them to behave as potentially tridentate chiral ligands. The chiral catalyst of the reaction with diphenylphosphine is the phosphapalladacycle (R)-XII,18 and the interesting feature is that the reaction was performed both with 1a and with chalcone 3a (Scheme 15). Both reagents gave quantitative yields and the enantioselectivities of (S)-43 and (S)44 were 92 and 98% ee, respectively.19 The catalytic cycle begins with the high affinity of phosphines to palladium. The solvent molecules weakly bound to (R)-XII are displaced by the free phosphine to give the chiral bis(diphenylphosphine) complex (A). Then one phosphine is displaced by the ketonic oxygen atom of 1a (or 3a) to give complex (B). The external base Et3N converts (B) into the corresponding phosphido species (C), which then undergoes the H


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Table 6. Enantioselective Michael Addition of Cyclic 1,3-Dicarbonyls (18) or 4-Hydroxycoumarin Derivatives (35) with 2, Catalyzed by the Complex [(4S)-XI/Zn(OTf)2] (Scheme 12)15,16 reaction 2 + 18a entry

R

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

Ph Ph Ph Ph Ph 4-Br-C6H4 4-Cl-C6H4 3-Cl-C6H4 2-Cl-C6H4 4-NO2-C6H4 3-NO2-C6H4 2-NO2-C6H4 4-MeO-C6H4 1-naphthyl 2-furyl (E)-PhCHCH CO2Et t-Bu

yield (%) 2a 2a 2a 2a 2a 2v 2d 2e 2r 2h 2g 2w 2b 2m 2o 2p 2x 2s

reaction 2 + 35b

34 ee (%) (conf)

18a 18b 18c

96 95 85

92 (S) 97 96

18a 18a 18a 18a 18a 18a

95 93 97 93 92 90

>99 (S) 92 95 77 94 95

18a 18a 18a 18a 18a 18a

89 85 92 90 80 n.r.c

92 87 98 94 96

yield (%)

36 ee (%) (conf)

35a 35b 35c 35d 35e

99 97 93 93 87

88 85 80 97 70

35a

98

88 (R)

35a 35a 35a 35a 35a 35a 35a 35a 35a

98 96 95 87 95 99 85 80 n.r.d

89 89 91 67 53 78 69 79

a Data taken from ref 15. bThe reactions require the presence of 10% mol DBU as basic additive and the data are taken from ref 16. cNo reaction after 100 h. dNo reaction after 70 h.

Scheme 13

Scheme 14

moderate, the enantioselectivities poor. Through the X-ray structure of the salt with (1S)-(+)-10-camphosulfonic acid, the absolute configuration of the major enantiomer of the reaction with 45d was determined to be (S)-46d. This means that the reaction, to give the intermediate (A), occurs through the approach of 45 to the β-Si face of 1a. 2.2. Henry Reaction

When the stabilized carbanion involved in the conjugate Michael addition to 1 derives from a nitroalkane, the variant is known as the Henry reaction. The subsequent possible manipulation of the nitro group makes these addition products very interesting for further synthetic applications. The enantioselective reaction between nitromethane (47) and different (E)-2-alkenoyl-pyridines (1) has been usefully performed with the La(OTf)3 complex of 2,6-bis{(S)-4,5dihydro-4-[(naphthalen-1-yl)methyl]oxazole-2-yl}pyridine [(S)-XIV/La(OTf)3] (Scheme 17). The reactions run on 14 different substrates gave good yields and enantioselectivities (Table 8, average values: 70% yield and 79% ee). It is worthwhile to note that the reactions involving (E)-1-(pyridin-2-yl)but-2-en-

desired intramolecular 1,4-addition to the β-Si face of the activated enones affording (D), with phosphine completing the catalytic cycle (Scheme 15). Assuming this mechanism, there is no participation of the pyridine ring of 1 to ameliorate the stereochemistry of the reacting intermediate, because 1a and 3a always behave as monodentate ligands only as confirmed by the observed enantioselectivities. The second variant is the aza-Michael reaction and consists in the enantioselective addition of some arylhydrazines 45a−d to 1a, catalyzed by the Ni(II) complex of 2,2′-methylenebis[(3aS,8aR)-3a,8a-dihydro-8H-indeno[1,2-d]oxazole] [(3aS,8aR)-XIII/Ni(OAc)2] (Scheme 16).20 The yields are I


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Table 7. Enantioselective Mukaiyama−Michael Reaction of Silyl Ethers 39 with 2, Catalyzed by the Complex [(4S)-XI/Zn(OTf)2] (Scheme 14)17

a

entry

R

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

Ph 4-MeO-C6H4 4-Cl-C6H4 3-Cl-C6H4 2-Cl-C6H4 4-NO2-C6H4 3-NO2-C6H4 2-NO2-C6H4 4-F-C6H4 1-naphthyl 2-furyl (E)-PhCHCH t-Bu Ph Ph 4-Cl-C6H4 4-Cl-C6H4 Ph 4-Cl-C6H4 2-Cl-C6H4

2a 2b 2d 2e 2r 2h 2g 2w 2f 2m 2o 2p 2s 2a 2a 2d 2d 2a 2d 2r

R′

R″

yield (%)

Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph 4-F-C6H4 2-thienyl 4-Br-C6H4 t-Bu Ph Ph Ph

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

92 86 88 89 91 88 88 87 89 82 81 80 n.r.a 82 88 83 n.r.c 91 92 90

dr

40 ee (%) (conf) 95 (R) 92 95 90 83 90 95 92 96 90 90 83 91 81 (S)b 87

3:2 3:1 4:1

97/64d 98/68d 65/ndd

No reaction after 98 h. bNote the change in priority. cNo reaction after 96 h. dee of the major/minor isomers.

Scheme 15

poor [anti/syn average 68:32]. With the exception of the products from 1v (Table 8, entries 13 and 14), which give low enantiomeric excesses, the enantioselectivities of both anti-50 and syn-50 are not far from those obtained with nitromethane (Table 8). The enantioselective Henry reaction can be efficiently promoted by the organocatalyst (S)-XV, synthesized by exo(−)-bornylamine and Cbz-protected L-phenylalanine, in the presence of Boc-L-phenylalanine. This reaction is interesting because it was tested on both 1a and 3a with 2-nitropropane (51), and the products were (S)-52 and (S)-53 (Scheme 18).22 Since, under identical conditions, the yields of both products were good and the enantiomeric excesses for both products were

1-one (1ac) and (E)-4,4-dimethyl-1-(pyridin-2-yl)pent-2-en-1one (1s), despite the different steric hindrances that sometimes may have a dramatic effect (Table 2, entry 16 and Table 6, entry 10), give fully comparable results (Table 8, entry 19 vs 12).21 The absolute configuration was determined by X-ray crystallographic analysis of the 4-bromo-phenyl derivative 48 (Table 8, entry 13) and was found to be (S), suggesting the approach of the nucleophile on the β-Si face of 1. The same reaction, using with the same catalyst and performed with other nitroalkenes such as nitroethane or nitropropane (49: R′=Me or Et) (Scheme 17), leads to the formation of two diastereoisomers: anti-50 and syn-50.21 The yields are moderate (average of 10 experiments 59%) and the diastereoselectivity is J


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major enantiomer can be rationalized as the result of the attack of indole to the β-Si face of 1a, 3a, and 55. Whereas the results of 1 and 3 were disappointing in terms of enantioselectivity, the same reaction between indoles (54) and 4substituted (E)-2-alkenoyl-pyridine-N-oxides (2) gave excellent results when catalyzed by the copper triflate complex of 2,6bis[(4S)-4,5-dihydro-4-isopropyl-5,5-diphenyloxazol-2-yl]pyridine, [(4S)-XI/Cu(OTf)2].24 The product was shown to be (R)-59 (Scheme 20) and the results, reported in Table 9, have an average yield of 95% and an average enantioselectivity of 93% ee. (E)-4-Cyclohexyl-2-propenoyl-pyridin-N-oxide (2q) (Table 9, entry 33) gave a nearly racemic product; other substituents on enones and indole have influence only on the reaction time. An electron attracting substituent on indole lowers reactivity (Table 9, entry 8), but if it is on the 4-aryl group of 2, it does not influence the reaction rate (Table 9, entries 2, 15, 21−24, 27, and 31). The absolute configuration of the products from the catalysis with the Cu(II) complex of (4S)-XI derives from indole approach to the β-Re face of 2. This complex catalyzes also the reaction involving 1a, but the results (89% yield and 16% ee, Table 9, entry 1) suggest an inappropriate coordination between substrate and catalyst when the N-oxide group is lacking. The synthetic utility of the process was shown by the N−O reduction of 59a (obtained as reported in the entry 2 of Table 9) with indium and NH4Cl. (R)-60 was thus obtained, without any loss of enantioselectivity, in 73% yield. Furthermore, the pyridine ring of 59a can be cleaved under basic conditions and the enantiomerically pure acid (R)-61, was obtained in 75% yield (Scheme 20). The same Pybox ligand, but with zinc triflate as the Lewis acid, [(4S)-XI/Zn(OTf)2], was the catalyst of election for the Friedel−Crafts reaction with pyrroles (62). As observed in the reaction catalyzed by [(4S)-XI/Cu(OTf)2], the products 63 have the (R) absolute configuration, which derives from the attack of indole to the β-Re face of 2 (Scheme 20).25 Not only the enantioselectivity of these reactions are better that those with indole, since seldom the products have the enantiomeric excess lower than 90%, but substrates unreactive with indole [(E)-4octenoyl-2-pyridin-N-oxide (2ad), (Table 9, entry 34)] gave excellent results with pyrrole. Again, (R)-63 are excellent synthons for the preparation of interesting products [(R)-64 and (R)-65], without any loss of enantiomeric purity (Scheme 20). Finally, the excellent flexibility of [(4S)-XI/Zn(OTf)2] as the catalyst for enantioselective Friedel−Crafts reactions is illustrated in Scheme 21, in which 2-methoxyfuran (66) and two

Scheme 16

excellent, this can be considered a proof of the absence of any interaction involving the nitrogen atom of 1a in the reacting intermediate. 2.3. Friedel−Crafts Reaction

A very popular variant of the Michael addition is the Friedel− Crafts reaction that involves the C−C bond formation between the β-position of enones and an aromatic or heteroaromatic ring. Obviously, a large part of the efforts concerns heteroaromatic substrates, mainly indoles, for the possible biological applications of the reaction products. Pybox is the ligand of choice for the chiral catalysts in the first example mentioned in an article by Evans and co-workers23 in which the Friedel−Crafts reaction between indoles (54) and different enones [1ab and 3ab, argument of this review, and (E)1-(1-methyl-1H-imidazol-2-yl)but-2-en-1-one (55)] has been catalyzed by the Sc(OTf)3complex of (3aS,8aR)-Inda-Pybox, (Scheme 19). The results reported in Scheme 19 account 55 as the reagent that coordinates in a bidentate mode to Sc(III) giving the rigid reacting intermediate [(3aS,8aR)-XVI/Sc(OTf)3/55], and (R)58 is obtained in 99% yield and 92% ee. On the contrary, the disappointing results achieved with both 1ab and 3ab suggest a possible behavior as monodentate reagents to give less defined reacting intermediates from which (R)-56 and (R)-57 are formed in 68% and 14% yields, with enantioselectivities of 31% and 30% ee, respectively.23 In any case, the absolute configuration of the Scheme 17

K


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Table 8. Enantioselective Henry Reaction between 1 and Nitroalkanes (47 or 49) Catalyzed by the Complex [(4S)-XIV/La(OTf)3] (Scheme 17)21 reaction 1 + 47 entry

R

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

Ph Ph 4-MeO-C6H4 4-MeO-C6H4 4-Cl-C6H4 3-Cl-C6H4 4-NO2-C6H4 4-NO2-C6H4 1-naphthyl 2-furyl 2-Cl-C6H4 t-Bu 4-Br-C6H4 4-Br-C6H4 3-Br-C6H4 2-thienyl 3-thienyl 3-thienyl Me

yield (%) 1a 1a 1b 1b 1d 1e 1h 1h 1m 1o 1r 1s 1v 1v 1y 1z 1aa 1aa 1ab

reaction 1 + 49

48 ee (%) (conf)

74

79

65

78

73 58 70

77 82 74

68 68 69 72 74

77 79 73 81 79 (S)

68 72 69

78 81 81

65

87

R′

yield (%)

anti:syn

anti-50 ee (%)

syn-50 ee (%)

Me Et Me Et

68 50 60 50

73:27 64:36 69:31 56:44

81 80 77 64

71 72 71 61

Me Et

66 54

72:28 65:35

81 83

79 57

Me Et

67 53

76:24 65:35

57 51

55 54

Me Et

66 51

62:38 73:27

81 75

70 71

dimethylamino benzenes (68a,b) reacts with 2a with very good yields and excellent ee. The products [(R)-67 and (R)-69a,b, respectively] derive from the attacks of the electron rich aromatic and heteroaromatic reagents to the β-Re face of 2a.25 As an alternative to the above Pybox-based catalysts, the copper(II) complex of gluco-Box (3aR,4aR,7R,8aS,9R,9aR)XVII, a Box already applied for the preparation of efficient chiral catalysts,26 was tested on the Friedel−Crafts reaction of 2 with indoles 54 and pyrrole 62 (Scheme 22).27 The reaction was exploited with several 4-substituted (E)-2alkenoyl-pyridine-N-oxides (2) and different indoles (54) (Table 9). Over 22 experiments, whereas the average yield of all other reactions was 91% and the average enantiomeric excess was 92%, only (E)-4-cyclohexyl-2-propenoyl-pyridin-N-oxide (2q) failed to react and (E)-4,4-dimethyl-1-(pyridin-2-yl)pent-2-en-1-one (2s) since the product was obtained with a discrete yield but with a poor enantioselectivity (Table 9, entry 33 and 32, respectively). The data in Table 9 show that, whereas yields and enantioselectivity with catalysts [(4S)-XI/Cu(OTf)2] and [(3aR,4aR,7R,8aS,9R,9aR)-XVII/Cu(OTf)2] are nearly comparable, the former gives (R)-59, the latter the opposite enantiomer (S)-59. The basic difference between the catalysts is that Pybox is a tridentate ligand and its Cu(II) complex must have an octahedral geometry, while the bidentate Box gives a distorted planar Cu(II) complex.26 The former induces the attack of indole to the β-Re face of coordinated 2, and the latter favors the attack of indole to the β-Si face of coordinated 2. As a consequence, the catalysts give products with the opposite absolute configuration.

Scheme 18

Scheme 19

3. EPOXIDATION REACTION The epoxidation reaction of (E)-3-phenyl-1-(pyridin-2-yl)prop2-en-1-one (1a) was accomplished in the early 1996, following the Juliá-Colonna triphasic protocol for asymmetric epoxidation of enones: aqueous basic peroxide, dichloromethane, and poly-Lleucine (S)-XVIII.28 Under these conditions, at ambient temperature, the reaction on 1a proceeds with the formation of 2,3-epoxi-1-phenyl-3-(2-pyridyl)propan-1-one [(2R,3S)-70] in 74% yield and 79% ee.29 L


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Review

Scheme 20

compatible with different alkyl radicals, generated from the corresponding alkyl iodides with Bu3SnH, but the enantioselectivity lowers when alkyl groups are the substituents on the double bond (Table 10, entries 9−11). The absolute configuration was determined for the product 72 reported in entry 1 of Table 10 and shown to be (S). This suggests the attack of the radical on the β-Re face of 1a.32 Two interesting experiments have been performed. In order to understand if (E)-2-alkenoyl-pyridines 1 assume an s-trans conformation in the reacting intermediate, (E)-1-(3-methylpyridin-2-yl)-3-phenylprop-2-en-1-one (1ag) was tested in the reaction. This reagent, which suffers severe interactions to assume the concerned configuration, indeed gives 73% yield and a modest enantioselectivity. The product has the same absolute (S) configuration (Table 10, entry 12). Then, the same reaction was performed on 3a and the result (Table 10, entry 13) was only a trace of the desired product 73. This is a clear proof that the nitrogen atom of the pyridine is of fundamental importance in the reactivity allowing a bicoordination of the reagent to Zn(II) in the formation of the reacting intermediate.32

These conditions were later ameliorated running the reaction under PTC conditions, adding tetra-n-butylammonium bromide (TBAB) and changing CH2Cl2 with toluene. The reaction performed with 1a gave (2R,3S)-70 in 99% yield and 84% ee, when 3a was the substrate, (2R,3S)-71 was obtained in 96% yield and 90% ee (Scheme 23).30 To decipher the role of poly-L-leucine (pLl), which evidently acts as an organocatalyst of the peroxidation, the early step of the reaction must be the formation of a complex between enone and pLl, which then also coordinates the hydroperoxide anion. The significant part of the computed model (A), with pLl coordinating the carbonyl group of 3a (or 1a) with two NH groups, is represented in the lower part of Scheme 23.31 The hydroperoxide anion is then hydrogen bonded to the complex giving the reacting intermediate (B) in which the hydroperoxide attacks intramolecularly the β-Re face of the enone, thus giving (2R,3S)-70 [or (2R,3S)-71]. This model can interfere with the pyridine nitrogen atom, hence an enantioselectivity lower with 1a than with 3a is not unexpected.

4. RADICAL REACTION The enantioselective conjugate radical additions have been performed on (E)-2-alkenoyl-pyridines 1 by using [(4S)-IX/ Zn(OTf)2] as the catalyst (Scheme 24). The reaction is

5. [3 + 2] DIPOLAR CYCLOADDITION REACTION The 1,3-dipolar cycloaddition is certainly one of the most important pericyclic reactions because of the possibility to M


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Table 9. Enantioselective Friedel-Crafts Reactions of 2 with Indoles (54), Catalyzed by Complexes [(4S)-XI/Cu(OTf)2]24 and [(3aR,4aR,7R,8aS,9R,9aR)-XVII/Cu(OTf)2],27 or with Pyrroles (62) Catalyzed by the Complex [(4S)-XI/Zn(OTf)2]25 (Schemes 20 and 22) reaction 2 + 54

reaction 2 + 62 [(3aR,4aR,7R,8aS,9R,9aR)XVII/Cu(OTf)2]b

[(4S)-XI/Cu(OTf)2]a entry

R

R′/R″

time

yield (%)

ee (%) (conf)

time (h)

yield (%)

ee (%) (conf)

1

97

99 (S)

2 2

94 91

92 93

2

84

70

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

Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph

1a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a

H/H H/H

24 h 15 min

89 97

16 (R) 99 (R)

H/5-F H/5-Cl H/5-Br H/5-OMe H/5-CN Me/H Bn/H

1h 1h 6h 15 min 7d 30 min 3h

97 92 93 98 86 97 94

97 96 97 95 83 86 87

13

4-MeOC6H4 4-Me-C6H4 4-Cl-C6H4 4-Cl-C6H4 4-Cl-C6H4 4-Cl-C6H4 4-Cl-C6H4 4-Cl-C6H4 3-Cl-C6H4 4-F-C6H4 3-NO2-C6H4 4-NO2-C6H4 1-naphthyl 2-furyl 2-Cl-C6H4 2-F-C6H4 4-Br-C6H4 2-Br-C6H4 2-NO2-C6H4 t-Bu cyclohexyl n-pentyl

2b

H/H

3h

97

94

2c 2d 2d 2d 2d 2d 2d 2e 2f 2g 2h 2m 2o 2r 2u 2v 2ac 2w 2s 2q 2ad

H/H H/H

15 min

97

94

14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

H/5-Br H/5-Cl H/4-OMe Me/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

15 min 15 min 15 min 15 min 2h 3h 15 min

98 96 97 95 83 97 96

93 95 98 99 89 87 91

15 min

96

97

3d

75

5

4 1

87 94

94 97

2 2 2 7

88 94 94 88

90 94 85 77

1 2 1 4 2 1 1 1 2 1 24 200

94 94 98 88 91 92 98 91 94 96 65 trace

95 99 96 90 94 99 94 92 96 98 33 n.d.

[(4S)-XI/Zn(OTf)2]c time

yield (%)

ee (%) (conf)

H/H H/Hd

9h 4h

95 88

>99 (R) 85 (S)

1-Me 3-Ac-2,4(Me)2 H/H

3d 20 h

87 97

95 (R) >99

18 h

54

99

H/H H/Hd

3h 4h

86 92

>99 86 (S)

H/H H/H H/H H/H H/H H/H H/H

5h 3h 3h 3h 9h 18 h 5h

96 90 99 96 71 82 88

98 98 98 85 99 95 98

H/H

5h

98

97

H/H H/H

12 h 5h

76 74

94 95

R′/R″

a Data taken from ref 24. bData taken from ref 27. cData taken from ref 25. dReaction performed with [(3aR,4aR,7R,8aS,9R,9aR)-XVII/Cu(OTf)2] as catalyst (ref 27).

construct useful chiral five-membered heterocyclic synthons. In its enantioselective variant, when the 1,3-dipole is a nitrone, the reaction with alkenes affords isoxazolidines with three contiguous stereocenters, which are valid precursors for biologically relevant chiral compounds. Among the chiral ligands suitable to catalyze efficiently this reaction, Box have a pivotal role also when the dipolarophiles are 4-substituted (E)-2-alkenoyl-pyridine-N-oxides (2). The copper triflate complex with (4S,5S)-OTIPS-Box, [(4S,5S)-X/Cu(OTf)2/H2O], whose structure was determined by X-ray analysis and found to have the square-pyramidal structure (A) reported in Scheme 25, was studied in details.33 The reaction between diphenyl nitrone 74 and 2a,h,v, performed in CH2Cl2 at −20 °C, gave a mixture of endo and exo products in nearly quantitative yields: (3S,4R,5R)-75 and exo-76, the former with excellent enantioselectivities (Table 11).34

The interesting point of this research is that, in addition to the structure of the catalyst, the structure of the reacting intermediate [(4S,5S)-X/Cu(OTf)2/2a] was determined by X-ray analysis [Scheme 25, (B)].34 Its distorted octahedral structure makes fully consistent the approach of nitrone 74 to the less hindered βRe face of the coordinated 2, thus rationalizing the absolute configuration of the adduct determined to be (3S,4R,5R)-75 (Scheme 25). The enantioselective 1,3-dipolar cycloaddition reaction of several (E)-2-alkenoyl-pyridine-N-oxides (2) with a variety of different nitrones 74 was also catalyzed by t-Butyl Box [(4S)XIX] and Cu(OTf)2 (Scheme 26).35 The reactions were performed in ethyl acetate with 4 Å MS and the yields were largely depending on the substituents of both reagents [from 94% for the reaction between 2a and diphenyl nitrone (Table 11, entry 1) to 16% for the reaction between 2a and 1-cyclohexyl-2N


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Scheme 21

Scheme 24

Table 10. Enantioselective Radical Addition on (E)-2Alkenoyl-pyridines 1 and Chalcone 3a, Catalyzed by the Complex [(4S)-IX/Zn(OTf)2]32 entry 1 2 3 4 5 6 7 8 9 10 11 12 13

Scheme 22

a

1a 1b 1d 1ae 1b 1b 1b 1b 1ab 1ab 1af 1ag 3a

R

R′

R1

yield (%)

ee (%) (conf)

Ph 4-MeO-C6H4 4-Cl-C6H4 4-CO2Me-C6H4 4-MeO-C6H4 4-MeO-C6H4 4-MeO-C6H4 4-MeO-C6H4 Me Me 3-Ph-propyl Ph Ph

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

i-Pr i-Pr i-Pr i-Pr Et t-Bu c-Pent c-Hex c-Pent c-Hex i-Pr i-Pr i-Pr

97 97 99 60 50 88 79 59 92 91 92 73 99 >99 >99 >99

88:12 87:13 85:15 81:19

93 94 97 94 (3S,4R,5R)

52 n.d. 65 62

94

94:6

95

61

56 82 69 43 68 52 98 77 81 36 16 59 62

87:13 90:10 93:7 >99:1 94:6 93:7 92:8 86:14 91:9 94:6 74:26 66:34 61:39

96 96 96 95 91 (3S,4R,5R) 93 86 90 94 89 60 88 80

21 22 n.d. n.d. 33 45 42 45 79 29 78 75

a

Reactions performed with 10% mol of (4S,5S)-X and 10% mol of Cu(OTf)2. Data taken from ref 34. bData taken from ref 35. cReaction catalyzed by crystalline complex [(4S,5S)-X/Cu(OTf)2/H2O] with the structure A reported in Scheme 25.

Scheme 26

N-Methyl-L-tyrosine (whose structure is reported in Scheme 27) and L-abrine. The comparison between these catalysts and those derived from L-tryptophan (Table 12, entry 10 vs 8) and Ltyrosine (Table 12, entry 5 vs 4) show the large influence of Nmethylation on the enantioselectivity. Multiple methylation or other substituents have little effect. To evaluate the effect of water as solvent, the D.A. reaction catalyzed by the Cu(II) complex of L-abrine was performed in

several organic solvents (Table 12, entries 11−16). The reaction time in water is considerably shorter than in other solvents and the enantioselectivity significantly better. The great limit avoiding any deep investigation of the mechanism is the uncertainty of the absolute configuration of 78. To try to solve this problem other enantiocatalysed D.A. reactions between 2 and cyclopentadiene must be discussed. P


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Cu(OTf)2 complex of (4S)-Ph-Box [(4S)-IX/Cu(OTf)2], which was also tested in the reaction between (E)-3-phenyl-1-(pyridin2-yl)prop-2-en-1-one (1a) and 77.38 Whereas the results with this last reagent were unsatisfactory, the [endo-78]:[exo-79] was [86:14] and the enantiomeric excesses were 19% for 78 and 11% for 79, the results for the D.A. reaction between 2 and 77 were excellent. Interestingly, the same reactions were also carried out with the Zn(OTf)2 complex of the same ligand, with results almost comparable to those obtained with copper(II). The overall picture of these reactions is reported in Scheme 28 and the results in Table 13. When the D.A. reaction was performed with the Cu(OTf)2 complex of (4S)-t-Bu-Box [(4S)-XIX/ Cu(OTf)2], the opposite enantiomer was obtained (Table 13, entry 5).38 From the data in entry 4 of Table 13, the best overall result has been obtained with [(4S)-IX/Cu(OTf)2] as the catalyst. Hence the D.A. reaction was performed with 2b, 2h, and 2s, and with a series of different dienes: cyclohexadiene, 2,3-dimethylbutadiene, 2-methylbutadiene, 1,3-pentadiene, and 1-phenylbutadiene.38 The results of all these reactions are reported in Table 14, and yields, diastereo-, and enantioselectivities were always excellent, showing the great flexibility of this catalyst with both dienes and dienophiles. The absolute configuration of none of the products described by the authors has been determined, but an important correlation has been achieved. The optically active pyridine N-oxide adduct (+)-80 (R = Ph) was deoxygenated to the corresponding pyridine adduct (+)-78 by treatment with indium powder/ NH4Cl without loss of enantiomeric purity (Scheme 28).38 This compound was the opposite enantiomer of the product obtained by Engberts37b from 1a and 77 upon catalysis with Cu(II)/Nmethyl-L-tyrosine. Hence, the determination of the absolute configuration of one enantiomer of 80 should be enough to propose the structure of the reacting intermediate allowing to rationalize the stereochemical outcome of such catalyzed DA reactions. In the section of this review devoted to nitrone 1,3-dipolar cycloaddition, the complex [(4S,5S)-X/Cu(OTf)2] was shown to be an excellent catalyst for the reactions of 2. Hence, the D.A. reaction between 2 and 77 was tested with this catalyst (Scheme 29) and the excellent results with 2a, 2h, and 2v, in terms of yields (quantitative), diastereo- (80:81 about 99:1) and enantioselectivity (ee of 80 in the range 96−97%) are reported

Table 12. Enantioselective D.A. Reaction between 1a and Cyclopentadiene 77, Catalyzed by Cu(II) Complexes of Different Amino Acids (Scheme 27)37 entrya 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

time (days)

78 ee (%)

water water water water water

n.r n.r n.r n.r n.r

3 3 17 36 74

water water

n.r n.r

73 67

water water water

n.r n.r 3

33 29 74

1,1,1trifluoroethanol ethanol

12

40

10

39

acetonitrile

7

17

THF

8

24

chloroform

11

44

dichloromethane

12

17

amino acid L-valin L-leucin L-phenylalanin L-tyrosine

N-methyl-L-tyrosine, (S)-XX N,N-dimethyl-L-tyrosine N-methyl-p-methoxy-Lphenylalanine L-tryptophan 5-hydroxy-L-tryptophan Nα-methyl-L-tryptophan (L-abrine) Nα-methyl-L-tryptophan (L-abrine) Nα-methyl-L-tryptophan (L-abrine) Nα-methyl-L-tryptophan (L-abrine) Nα-methyl-L-tryptophan (L-abrine) Nα-methyl-L-tryptophan (L-abrine) Nα-methyl-L-tryptophan (L-abrine)

solvent

a Entries from 1 to 10 were performed with Cu(NO3)2; entries from 11 to 16 with Cu(OTf)2

Scheme 27

An excellent catalyst for the D.A. reaction between (E)-2alkenoyl-pyridine-N-oxides 2 and cyclopentadiene (77) is the Scheme 28

Q


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Table 13. Enantioselective D.A. Reactions of 1a or 2a with Cyclopentadiene at 0 °C in CH2Cl2 Catalyzed by 10% mol of Box Complexes (Scheme 28)38 entry 1 2 3 4 5

1a 2a 1a 2a 2a

catalyst

t/h

yield (%)

endo:exo

endo ee % (conf)

exo ee %

[(4S)-IX/Zn(OTf)2] [(4S)-IX/Zn(OTf)2] [(4S)-IX/Cu(OTf)2] [(4S)-IX/Cu(OTf)2] [(4S)-XIX/Cu(OTf)2]

22 2.5 22 0.3 1

99 99 99 98 99

81.5:18.5 96:4 86:14 97.5:2.5 96.5:3.5

(+)-23a (+)-91c (+)-19a (+)-96c (−)-96c

41b 35d 11b 81d −94d,e

a Data refer to product 78. bData refer to product 79. cData refer to prouct 80. dData refer to product 81. eProduct 81 was the enantiomer opposite to that obtained from entries 2 and 4.

Table 14. Enantioselective D.A. Reactions of 2 with Cyclopentadiene (77) and Other Dienes, Catalyzed by the Complexes [(4S)IX/Cu(OTf)2]38 and [(4S,5S)-X/Cu(OTf)2]34 (Schemes 28 and 29) [(4S)-IX/Cu(OTf)2]a entry

R

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

Ph Ph 4-MeO-C6H4 4-NO2-C6H4 4-Br-C6H4 t-Bu Ph Ph Ph Ph Ph

2a 2a 2b 2h 2v 2s 2a 2a 2a 2a 2a

[(4S,5S)-X/Cu(OTf)2]b

diene

yield (%)

[80]:[81]

80 ee % (conf)

81 ee %

yield (%)

[80]:[81]

80 ee % (conf)

81 ee %

77 77 77 77 77 77 cyclohexadiene 2,3-diMe-butadiene 2-Me-butadiene 1,3-pentadiene 1-Ph-butadiene

98 94c 95 93

97.5:2.5 97:3 97:3 95:5

(+) 96 (2S,3S) (+) 95 (2S,3S) 95 96

81

99 99d

99:1 98:2

(−) 97 (2R,3R) (−) 97 (2R,3R)

n.d. n.d.

99 99

98:2 99:1

97 (−) 96 (2R,3R)

n.d. n.d.

92 99 95 93 97 99

78:22 85:15 96:4 >99:1 >99:1

93 96 93 92 94 94

81 n.d. 70 47

a

Reactions performed with 1% mol of (4S)-IX and 10% mol of Cu(OTf)2. Data taken from ref 38. bData taken from ref 34. cReaction carried out with a ratio of [2a]:[catalyst] = [100:1]. dReaction catalyzed by crystalline complex [(4S,5S)-X/Cu(OTf)2/H2O] with the configuration (A) reported in Scheme 25. eThe products have the formula conceivable with the diene used in the reaction.

Scheme 29

attack of cyclopentadiene on the lower face of 1a (the β-Re face) rationalizes the obtained (1S,2R,3R,4R) configuration of 78.

in Table 14.34 Luckily, the crystal structure of the endo (−)-80 adduct from 2v (R = 4−Br-C6H4) was determined to have the (1S,2R,3R,4R) absolute configuration (Table 14, entry 5), as expected if cyclopentadiene attacks the β-Re face of the coordinated 2 in the reacting intermediate (B) of Scheme 25. From this steady attribution, following the analogy principle, the product from 2a obtained by using the [(4S,5S)-X/Cu(OTf)2] catalyst with the [α]D25 of −258.3 is (1S,2R,3R,4R)-80 (R = Ph),34,39 while that obtained by using the [(4S)-IX/Cu(OTf)2] catalyst in Scheme 28, having an [α]D25 of +262.4, had the (1R,2S,3S,4S) absolute configuration.38 The N−O reduction of (1R,2S,3S,4S)-80 gives (−)-78 with the same (1R,2S,3S,4S) absolute configuration.38 These attributions allow to assign to the product (−)-78 (R=Ph), obtained by Engberts by using (S)-XX as the chiral ligand (Scheme 27),37b the (1S,2R,3R,4R) absolute configuration, identifying the reaction pathway involved in this catalytic process. The reacting intermediate [(S)-XX/Cu(II)/1a] has the trans/cisoid geometry reported in Scheme 30 and the endo

Scheme 30

An excellent catalyst for the D.A. reaction between 1a and 1,3cyclohexadiene (82) was the copper(II) triflate complex of a new Box bearing the tert-butylcarbamoyl group at the oxazoline 4position [(4S)-XXIa/Cu(OTf)2]. The reaction gives the enantiomerically pure endo adduct 83 in 78% yield (Scheme 31), and the important role of the amido-induced interligand interactions in the catalytic performance can be appreciated R


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Scheme 31

Table 15. Enantioselective D.A. Reactions of 1 with Cyclopentadiene Catalyzed by [(S)-XXII/Ti(OiPr)4],41 [(S,S)-XXIII/Cu(OTf)2],42 and [(S,S,S)-XXIV/Cu(NO3)2]10 Complexes (Scheme 32) entry Ph

1a

2

1b

4

4-MeOC6H4 4-MeC6H4 4-Cl-C6H4

5

3-Cl-C6H4

1e

6

2-Cl-C6H4

1r

7

4-NO2C6H4 3-NO2C6H4 2-NO2C6H4 2-Br-C6H4

1h

1ah

14

2-MeOC6H4 2-MeC6H4 1naphthyl 2-furyl

15a

Ph

1a

4-MeOC6H4 4-NO2C6H4 Ph

1b

8 9 10 11 12 13

6.1. Families of Unusual Catalysts for the D.A. Reaction

In the previous section, the catalysts of the D.A. reactions between a diene and 1 or 2 were simple or sophisticated complexes made from a cation, acting as a Lewis acid, and a chiral ligand. Some ligands belong to common families, suitable and very popular for every enantioselectively catalyzed reaction. Some are very unusual organic molecules designed for the specific purpose. All have at least a chiral center, and this very defined chirality is transmitted to the final product of the reaction. However, the catalysis of the D.A. reactions with 1 or 2, in addition to transition metal catalysis, to organocatalysis, or to biocatalysis, offer to the chemist a further option, making the field very attractive. The enantioselective D.A. can be performed with a hybrid catalyst in which the [ligand/Lewis acid] complex is achiral and the chirality derives from a complex bionatural chiral

a

16

17a 18 a

catalyst

1

3

when the same D.A. reaction is catalyzed by the ester-Box complex [(4S)-XXIb/Cu(OTf)2].40 Several other catalysts consisting of a chiral ligand and a cation acting as Lewis acid have been tested in the D.A. reaction between 1 and cyclopentadiene. In spite of some good results, their limitation is the indeterminate absolute configuration of the adducts. Scheme 32 reports the reaction catalyzed with (S)Binol/Titanium complex, [(S)-XXII/Ti(OiPr)4],41 with the cyclic dipeptide cyclo-(S)-His(Tr)-(S)-His(Tr)/Cu(II) complex, [(S,S)-XXIII/Cu(OTf)2],42 and the triazacyclophane scaffold decorated with three (S)-histidine residues/Cu(II) complex, [(S,S,S)-XXIV/Cu(NO3)].10 The results with different (E)-2-alkenoyl-pyridines 2 are listed in Table 15, the majority of which refers to catalyst [(S)-XXII/Ti(OiPr)4].41 Certainly, some results in terms of yield (entries 4−6), or concerning yield and enantioselectivity (entries 7−9) are not easily explainable.

R

1c 1d

1g 1w 1ac

1ai 1m 1o

1h 1a

[(S)-XXII/ Ti(OiPr)4] [(S)-XXII/ Ti(OiPr)4] [(S)-XXII/ Ti(OiPr)4] [(S)-XXII/ Ti(OiPr)4] [(S)-XXII/ Ti(OiPr)4] [(S)-XXII/ Ti(OiPr)4] [(S)-XXII/ Ti(OiPr)4] [(S)-XXII/ Ti(OiPr)4] [(S)-XXII/ Ti(OiPr)4] [(S)-XXII/ Ti(OiPr)4] [(S)-XXII/ Ti(OiPr)4] [(S)-XXII/ Ti(OiPr)4] [(S)-XXII/ Ti(OiPr)4] [(S)-XXII/ Ti(OiPr)4] [(S,S)-XXIII/ Cu(OTf)2] [(S,S)-XXIII/ Cu(OTf)2] [(S,S)-XXIII/ Cu(OTf)2] [(S,S,S)-XXIV/ Cu(NO3)2]

yield (%)

[78]:[79] 78 ee %

>99

96:4

64

67

91:9

64

77

95:5

79

18

93:7

72

52

95:5

78

76

94:6

72

>99

89:11

52

11

99.5:0.5

40

92

88:12

70

53

99:1

70

91

95:5

87

43

98.5:1.5

74

63

94:6

65

49

95:5

79

79

95:5

45

19

98:2

26

70

90:10

60

n.r.

n.r.

55

Reaction performed at −40 °C.

molecule that somewhat binds the [achiral ligand/Lewis acid] complex to give a suprachiral catalyst. 6.1.a. Natural and Artificial Metalloenzymes. The first family of these suprachiral catalysts is constituted by the achiral water-soluble ambiphilic phthalocyanine/copper(II) complex,

Scheme 32

S


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subdomain of the protein to give the supramolecular complex catalyst. The reaction conditions were: water (sometimes acetonitrile) and formate buffer (pH ∼4), 10% mol of [XXV/ Cu(II)] and serum albumin. Different commercially available serum albumins were tested: bovine serum albumin (BSA), human serum albumin (HSA), sheep serum albumin (SSA), and rabbit serum albumin (RSA). The results in Table 16 show that BSA and HSA were the best albumins, while SSA was less efficient, and RSA gave unsatisfactory results (Table 16, entries 1−4). The enantioselective D.A. reaction can be performed with analogous results on different 3-aryl-1-(pyridin-2-yl)prop-2-en1-ones 1 (Table 16, entries 5−8).43 The results of these catalysts, sometimes astonishing, will be given below, but first we wish to point out the major limit of this type of catalysts: the uncertainty of the chiral domain of the catalyst and hence the difficulty to correlate the chirality of the catalyst with that of the product. The further step in the field of metalloenzymes was to test other proteins, suitably modified to have the copper binding site at the appropriate position. The synthase subunit from Thermotoga marittima (tHisF), which is an enzyme essential in the biosynthesis of histidine, was chosen as the host protein. Its X-ray structure reveals a typical TIM-barrel structure 8-fold α/β motif having a wide “top” open.45,46 The presence in this site of an aspartate residue at position 11 suggested to consider engineering a 2-His-1-carboxylate motif (His/His/Asp) at the top of the TIM-barrel. With the alanine protection of four histidines across the surface of the protein, which could compete for Cu(II) coordination, a standard site-specific mutagenesis

[XXV/Cu(II)], and serum albumins as the protein host that acts as chirality messenger (Scheme 33).43,44 These robust and easy Scheme 33

to handle proteins are present at high concentration in blood plasma and the phthalocyanine complex is able to bind a

Table 16. Enantioselective D.A. Reactions of 1 or 3 with Cyclopentadiene, Catalyzed by Natural or Artificial Metalloenzymes (Schemes 33 and 35) entry

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 Ph 4-MeO-C6H4 4-Me-C6H4 4-Cl-C6H4 4-NO2-C6H4 Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph 3-MeO-C6H4 Me Ph

1a 1a 1a 1a 1b 1c 1d 1h 1a 1a 1a 3a 1a 1a 1a 1a 1a 1a 3a 1a 1a 1a 1aj 1ab 1a

metalloenzyme [ligand/Cu(II)/protein]

conditions (buffer pH)

conv. (%)

[78]:[79]

78 ee % (conf)

ref

[XXV/Cu(II)/BSA]a [XXV/Cu(II)/HSA]c [XXV/Cu(II)/SSA]d [XXV/Cu(II)/RSA]e [XXV/Cu(II)/BSA] [XXV/Cu(II)/BSA] [XXV/Cu(II)/BSA] [XXV/Cu(II)/BSA] [HHD-4xala/Cu(II)] [NC-4xala/Cu(II)] [HHA-4xala/Cu(II)] [HHD-4xala/Cu(II)] [bPP/Cu(II)]f [7H,10E-bPP/Cu(II)]f [4-PA,10E-bPP/Cu(II)]f [3PA-bPP/Cu(II)]f [3PA,10E-bPP/Cu(II)]f [3PA,10E,24Ala-bPP/Cu(II)]f [bPP/Cu(II)]g [LmrR/Phenanthroline/Cu(II)] [LmrR N19C-XXVIII/Cu(II)] [LmrR M89C-XXVIII/Cu(II)] [LmrR M89C-XXVIII/Cu(II)] [LmrR M89C-XXVIII/Cu(II)] [LmrR M89C-XXIX/Cu(II)]

water (4.0)b water (4.0)b water (4.0)b water (4.0)b water (4.0)b water (4.0)b MeCN (4.0) MeCN (4.0) water water water water water (4.0)g water (4.0)g water (4.0)g water (4.0)g water (4.0)g water (4.0)g water (4.0)g water (7.0)h water (7.0)h water (7.0)h water (7.0)h water (7.0)h water (7.0)h

78 89 76 69 71 84 89 91 73 61 56 80 100 100 100 100 100 90 100 31 68 29 100 85 72 46 50 55 75 100 >80 97 97 98 95 60 97 100 100 100 100 100 ≈50 ≈50 ≈50 100 ≈50 ≈50 ≈50 ≈50 99 ≈50 ≈50 ≈50 n.d. n.d. n.d. n.d. 7 15 >80 >80

98:2 98:2 96:4 98:2 97:3 98:2 92:8 92:8 n.d. n.d. n.d. n.d. n.d. n.d. n.d. 88:12 78:22 73:27 95:5 90:10 98:2 99:1 99:1 88:12 99:1 97:3 96:4 n.d. 86:14 n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. 96:4 95:5 96:4 98:2 97:3 >99:1 98:2 >99:1 99:1 92:8 93:7 95:5 n.d. n.d. n.d. n.d. >98:2 >98:2 >98:2 >98:2

49 (2S,3S) 47 (2S,3S) 48 (2R,3R) 33 (2S,3S) 80 >80 >80 >80 >80 >80 >80 100 100 100 100 100 23 20 100 17 25 10

>98:2 >98:2 >98:2 >98:2 >98:2 >98:2 >98:2 >98:2 >98:2 >98:2 n.d. 99:1 98:2 95:5 98:2 89:11 92:8 94:6 92:8 >99:1 92:8

78 (2S,3S) 83 (2S,3S) 78 (2S,3S) 82 (2S,3S) 90 (2S,3S) 95 (2S,3S) 98 (2S,3S) 99 (2S,3S) >99 (2S,3S) 97 (2S,3S) 99 (2S,3S) 95 (2S,3S) 92 (2S,3S) 40 (2R,3R) 89 (2S,3S) 60 (2R,3R) 79 (2R,3R) 28 (2R,3R) 71 (2R,3R) >+99 −92

ref 57 57 57 57 57 57 57 57 57 57 11 60 60 60 60 60 60 60 60 60 60

a The Cu(II) source is copper nitrate. bThe absolute configuration reported is based on the relationship between the [α]D value and the chiral HPLC determination reported in the ref 38: Chiralcel OD-H column, 2% isopropanol:98% hexane, the endo enantiomer eluted first is (2R,3R)-78, the second eluted endo enantiomer is (2S,3S)-78. In many referenced publications the chiral HPLC data of the enantioselectively catalyzed D.A. reactions can be found in the Supporting Information. “+” and “−” correspond respectively to the enantiomer eluted first and second on the HPLC analyses. cSolvent water (MOPS buffer, pH 6.5). d100 mM NaCl. es.s. is single stranded. fReactions performed in the presence of water/cosolvents (MeCN, or DMF, or MeOH, or EtOH, or i.PrOH, or 1,4-dioxane, or DMSO) at T ≤ 0 °C.

15). Surprisingly, the enantioselectivity is influenced by interchanging the order of the G and C nucleobases (Table 19, entries 12 and 14). A random distribution of nucleobases gives very low enantioselectivity. In conclusion, the role of DNA is simply that of a chiral scaffold; the induced enantioselectivity affords always to (2R,3R)-78, and the optimal sequence to induce high enantioselectivity is that with an alternate sequence of GC nucleotides. The role of the pyridine in the interaction with DNA was evaluated by introducing a methyl substituent in three different positions of 1 (1ag, 1ak, and 1al), and testing the enantioselectivity of the different substrates with four different catalysts in which the chiral source was always the salmon testes DNA, linked to the XXXa,b and XXXIa,b Cu(II) complexes (Scheme 37). The absolute configuration of the endo products is unknown, but the nature of the ligand may influence the observed stereochemistry. For three ligands (XXXb and XXXIa,b) the stereochemical outcome for all the 2-alkenoylpicolines overlaps that previously observed with the corresponding pyridine derivatives (Table 19, entries 16−18, 20−22, and 24−26). The results with ligand XXXa depend upon the specific picoline involved in the reaction. Starting from substrates 1ak and 1al it is always obtained the forecasted opposite enantiomer (Table 19, entries 23 and 27), while with 1ag the observed stereochemistry reversed to the opposite enantiomer (Table 19, entry 19). This unusual behavior is tentatively rationalized by the authors by proposing a different cisoid conformation in which 1ag is forced to react due to the steric interaction with the 3-methyl group in the picoline.54 A further structure optimization of the ligand binding copper to DNA was performed by synthesizing a long series of

observed in going from XXXa (n = 3) to XXXd (n = 5) (Table 19, entries 1, 4, and 5). In contrast, a decrease of the spacer length from XXXa (n = 3) to XXXb (n = 2) (Table 19 entries 1 vs 3) gave an opposite sense of the stereoinduction and XXXb (n = 2) gives (2R,3R)-78, whereas XXXa (n = 3) gives the opposite enantiomer (2S,3S)-78.53,54 When the intercalating ligand is XXXI (n = 2 or 3) the major enantiomer is always (2R,3R)-78, obtained in 37% ee (Table 19, entries 6 vs 7). After that the above research optimized the copper ligands, further investigations to infer other parameters involved in the catalytic process were planned. Since the source of chirality is the DNA, emphasis was placed in determining the effect of different fragments of DNA (from salmon testes DNA) on the catalytic process of the D.A. reaction between 1a and cyclopentadiene. The research was initially based on the first generation DNAbased catalysts, in which the copper binding site is connected by a linker to 9-acrydine (Scheme 36). After testing DNA fragment from different natural sources, linked to [XXXIb/Cu(II)] complex (Table 19, entries 7 and 8), a series of synthetic self-complementary oligonucleotides of defined sequence were tested.54 The sequences were selected to cover a broad range of oligonucleotides. From the data reported in Table 19 some general patterns can be detected. The AT-base enriched sequences give rise to very poor enantioselectivities (Table 19, entries 9 and 10). The best results are obtained with GC-base enriched sequences, in particular with alternating GC sequences (Table 19, entries 11−14). The result obtained with d(GC)6 sequence is influenced by the presence of NaCl, since in the absence of salt the enantioselectivity is lower (Table 19, entries 13 vs 12). A truncation from dodecamer to octamer led to a lower enantioselectivity (Table 19, entries 13 vs Y


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catalysts based on salmon testes DNA, Cu(NO3)2, and simple achiral polyaromatic heterocyclic bidentate ligands were tested (Scheme 39).56,57

Scheme 37

Scheme 39

derivatives, based always on 9-aminoacridine as the DNA intercalator and on 2-ethylamine as the spacer. Taking constant 3,5-dimethoxybenzyl as the decoration substituent (R′), the modifications interested the ligand binding site and the substituents of XXXIc-h are listed in Scheme 38. Then, taking Scheme 38

The condensed penta-, tetra- and triaromatic heterocycles dipyrido[3,2-a:2′,3′-c]phenazine (XXXIIIa), pyrazino[2,3-f ][1,10]phenanthroline (XXXIIIb), and [1,10]phenanthroline (XXXIIIc), induced good diastereoselectivities, although with moderate enantioselectivities of (2S,3S)-78 (Table 19, entries 39−41). 2,2′-Bipyridine (XXXIVa) was a very simple ligand that gave, with different DNA and some alkenoyl-pyridines (1a, 1b, and 1s), very good results since (2S,3S)-78 were obtained with up to 90% ee (Table 19, entries 42 and 43). Three analogous 2pyridinyl derivatives were then tested: 2-(1H-Imidazol-2-yl)pyridine (XXXIVc) and 2-(pyridin-2-yl)-1H-benzo[d]imidazole (XXXIVd), which gave again excellent results (Table 19, entries 44 and 45), and (2S,3S)-78 was obtained in more than 90% ee. 4,4′-Dimethyl-2,2′-bipyridine (XXXIVb) was the best ligand for the purpose, at a level even better than the best results of the literature. With 1a, 1b, and 1s the diastereoselectivity [endo-78]: [exo-79] was >99:99% ee, and (2S,3S)-78 was obtained with almost complete stereochemical control (Table 19, entry 46).56−58 These valuable results suggested the attempt to immobilize [stDNA/Cu(II)/XXXIVb] on SiO2 solid support.59 The result was excellent, (2S,3S)-78 was obtained in 94% ee (Table 19, entry 47), and, since the supported catalyst was reused in several cycles, this opens a possible future for the industrial applications of the DNA-based asymmetric syntheses. When this polyheterocyclic model was abandoned, and pyridine (XXXVa) or (pyridin-2-yl)methanamine (XXXVb) were tested; the resulting catalysts did not provide any significant enantioselectivity (Table 19, entries 48 and 49). These results were similar to that obtained in the absence of ligand [i.e., only DNA and Cu(II)], but in which the major enantiomer was (2R,3R)-78 (Table 19, entry 50).56

constant the ligand binding site (L″), which was always 2pyridine, several decorative substituents were introduced in ligands XXXIIa-e, whose structures are also reported in Scheme 38.55 The results of the D.A. reaction between 1a and 77, with catalyst made with the different ligands, copper(II) nitrate, and salmon testes DNA, are reported in Table 19 (entries 28−38). The absolute configuration of the endo adduct is not the same for every catalyst: Those deriving from ligands XXXIc, XXXIIc, and XXXIId give (2S,3S)-78 (Table 19, entries 28, 36, and 37), the last two in 49 and 43% ee, respectively. All the other catalysts give the enantiomer (2R,3R)-78 with an enantiomeric excess of 56 and 75% for ligands XXXId and XXXIIe, respectively (Table 19, entries 29 and 38). An important modification in the concept of [DNA-based/ Cu(II)] catalysts was the introduction of the second generation of ligands in which the bidentate copper binding site and the DNA intercalating agent are integrated into the same heterocyclic system. The spacer is no longer required, and the reactive site of the coordinated 1 is brought closer to the source of the chirality, the DNA helix. Following this approach, several Z


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In conclusion, these results demonstrate that a ligand able to bind Cu(II) to DNA is necessary, and the shorter is the distance between DNA and the copper binding site, the better the enantioselectivity. Among the ligands with these characteristics, the best one was 4,4′-dimethyl-2,2′-bipyridine (XXXIVb) and, when coupled with copper nitrate, it was chosen for an in deep investigation of DNA, to optimize this important part of the catalyst.57 First, it was stated that a single stranded DNA gives a worse enantioselectivity than the double stranded DNA-based catalysts (Table 19, entries 51−53), even if the length of the strand may become an important parameter (Table 19, entry 54). Together with salmon testes DNA, that is a polymer of high molecular weight having a random sequence (Table 19, entry 46), a set of self-complementary oligonucleotides covering a great range of sequences, was tested: [Poly d(AT):poly d(AT)] and [poly d(GC):poly d(GC)] (Table 19, entries 55 and 56), 16mers d(GACTGACTAGTCAGTC)2 and d(CAGTCAGTACTGACTG)2 (Table 19, entries 59 and 60), alternating dGC sequences of different length (Table 19, entries 57 and 58), variations of the d(TCGGGATCCCGA)2 (Table 19, entries 61−68). With the exception of poly d(AT) that gives (2R,3R)-78 in 15% ee, all other nucleosides give from high to excellent enantiomeric excesses of (2S,3S)-78.57 The conclusion of this accurate analysis is that salmon testes DNA is the best starting material for DNA-based catalysts. Along this line of research, the complex [salmon testes-DNA/ XXXIVb/Cu(NO3)2] was tested in [water/water miscible cosolvents] in the D.A. reaction of 1a with cyclopentadiene. The reaction media were therefore aqueous 3-(N-morpholino)propanesufonic acid (MOPS) buffer (pH 6.5) with 1/3 volume of different solvents [MeCN, DMF, EtOH, MeOH, DMSO, 1,4dioxane, 2-propanol]. The presence of organic cosolvents allows for the reaction temperatures to be 85 >85 >85 >85 >85 >85 >85 >85 99 55 55 97 33 23 >90 >90 >90 >90 >90 >90

96:4 91:9 92:8 92:8 95:5 94:6 94:6 93:7 98:2 95:5 93:7 97:3 90:10 93:7 n.d. n.d. n.d. n.d. n.d. n.d.

24 (2S,3S) 9 (2R,3R) 7 (2S,3S) 97:3.

An interesting result was obtained substituting KCl with NaCl in the buffer (Table 22, entry 2 vs 3). With [XXXVIIIa/ Cu(NO3)2] enantioselectivity drops from 58 to 10% ee, but the result is even more dramatic when the reaction is catalyzed with only Cu(NO3)2. With KCl (2R,3R)-78 is obtained in 44% ee, with NaCl the enantioselectivity is inverted and (2S,3S)-78 is obtained with 53% ee, a result that implies a conformational change of the G-quadruplex.67 This Na +/K+ switch of enantioselectivity in G4 catalysis has been recently observed in the D.A. reaction between (E)-1-(1-phenyl-1H-imidazol-2yl)but-2-en-1-one (already mentioned in Scheme 19) and

cyclopentadiene and this unusual change in stereocontrol, to our opinion, is a virgin field to be explored.69 This investigation was completed testing the Cu(II) complexes of the different cationic porphyrin, reported in Figure 9, with five G-quadruplex, and the results are reported in Table 23. The catalysts based on XXXIX and XL gave disappointing results and enantioselectivity dropped when compared with the results of [XXXVIIIa/Cu(NO3)2] (Table 23, entries 3, 4, 7, and 14 vs 1, 5, and 12). Conversely, XXXVIIIb was an excellent ligand and the enantiomeric excesses of (2R,3R)-78 were similar, AE


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Scheme 42

Table 24. Enantioselective Hetero D.A. Reactions between 1 or 2 with Electron Rich Alkenes Catalyzed by [Box/Cu(OTf)2] Complexes in CH2Cl2 (Scheme 42)71 entry

R

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

Ph Ph Ph Ph 4-MeO-C6H4 4-NO2-C6H4 2-furyl t-Bu 4-Br-C6H4 3-furyl Ph Ph Ph 4-Br-C6H4 Ph Ph

1a 2a 2a 2a 2b 2h 2o 2s 2v 2am 2a 2a 2a 2v 2a 2a

dienophile

box

T/°C (t/h)

yield (%)

[endo:exo]

endo ee % (conf)

exo ee %

86 86 86 86 86 86 86 86 86 86 91 94 97 97 100 103

(4S)-IX (4S)-IX (4S)-XIX (3aR,8aS)-XLI (4S)-IX (4S)-IX (4S)-IX (4S)-IX (4S)-IX (4S)-IX (4S)-IX (4S)-IX (4S)-IX (4S)-IX (4S)-IX (4S)-IX

rt (90) −40 (20) 0 (0.5) 0 (1.0) −40 (48) −20 (3) −40 (70) −40 (18) −40 (14) −40 (70) −40 (7) −40 (7) −40 (7) −40 (5) −40 (21) −40 (25)

>99 >99 >99 >99 80 85 99 99 99 98 99 92 98 99 99 93

85:15 >99:1 94:6 98:2 >99:1 >99:1 99:1 95:5 >99:1 99:1 >99:1 66:34 >99:1 98:2 >97:3 >99:1

87: 16 (4S,6S) 89: 96 (4S,6S) 89: 75 (4R,6R) 89: 79 (4S,6S) 89: 94 89: 96 89: 96 89: 96 89: 96 89: 96 92: 99 95: 94 98: 96 98: 97 (4S,6R) 101: 77 104: >99

88: 15 90: nd 90: nd 90: nd 90: nd 90: nd 90: nd 90: 37 90: nd 90: nd 93: nd 96: 95 99: nd 99: nd 102: nd 105: nd

comments are required. These “families of unusual catalysts for the D.A. reactions” within a short time gave several dozens of different catalysts applied to more than 210 examples described in Tables 16−23. With one exception concerning the Michael reaction,10 these D.A. catalysts have never been applied to any

or even better, than those obtained with XXXVIIIa (Table 23, entries 2, 6, 9, 11, and 13 vs 1, 5, 8, 10, and 12).67 This is the end of a chapter in which a topic, once rather unusual dealing with chiral enantioselective catalysts, but that is the subject of a specific review,70 has been discussed. Two AF


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other reaction involving 1 (or 2). Perhaps not all the catalysts will give results comparable to those of the more traditional literature, but certainly this new kind of catalysts is “the new entry” in the field.

Scheme 43

7. HETERO D.A. REACTION The hetero D.A. reaction (H.D.A.) is a good occasion, after a fruitful trip in the field of biocatalysis, to come back to more traditional chiral catalysts. In this reaction reagents 1−3 may behave either as heterodiene (CC−CO) or as heterodienophile with CO reacting with a diene. The enantioselective reaction of 1 and 2 as heterodiene in the inverse electron demand H.D.A. with electron rich alkenes is the only up-to-now reported in the literature.71 To optimize the conditions, the reaction of 1a and 2a with ethyl vinyl ether (86) was catalyzed with the complexes of three Boxes [(4S)-IX, (4S)-XIX, and (3aR,8aS)-XLI], with Cu(OTf)2, Zn(OTf)2, and Mg(OTf)2, in CH2Cl2, toluene, MeNO2, or THF (Scheme 42). The best solvent was CH2Cl2, and the best Lewis acid was Cu(II). The reaction with 1a, catalyzed by [(4S)-IX/ Cu(OTf)2], was sluggish at ambient temperature (90 h) and gave endo-87 and exo-88 in the ratio 85:15, with 16 and 15% ee, respectively (Table 24, entry 1). Moving to the reactions with 2a, these were easily performed at 0 °C (or even better at −40 °C) to give endo-89 and exo-90 from good to excellent enantiomeric excesses and a configuration that depends on the Box (Table 24, entries 2−4): [(4S)-IX/Cu(OTf)2] and [(3aR,8aS)-XLI/Cu(OTf)2] gave as major isomer (4S,6S)-89 in 96 and 79% ee, respectively, whereas [(4S)-XIX/Cu(OTf)2] gave (4R,6R)-89 in 75% ee.71 With [(4S)-IX/Cu(OTf)2] as the most efficient catalyst, the reaction was extended to different 2-alkenoylpyridine-N-oxides and the results were always excellent in terms of yield, diastereoand enantioselectivity, with the adduct endo-89 that often was the only reaction product (Table 24, entries 5−10). Later, the reaction was performed with several different alkenes (Table 24, entries 11−16) and, among them, the reaction between 2v and ethyl vinyl thioether (97) must be mentioned because it gave 2[(4S,6R)-6-(ethylthio)-5,6-dihydro-4-phenyl-4H-pyran-2-yl]pyridine-N-oxide [(4S,6R)-98] whose absolute configuration was unequivocally determined by X-ray crystallographic analysis. The above absolute configuration of the endo adduct (4S,6R)98, as well as that of the endo adduct (4S,6S)-89, derives from the attack of the electron rich dienophile to the β-Si face of 2 (Scheme 42). The asymmetric reactions involving 2-alkenoylpyridine-Noxides 2 and cyclic enol silyl ethers show good yields and excellent enantioselectivities (up to 99.9% ee) when catalyzed by Box/Cu(II) complexes. Different reaction pathways can be followed by different enol silyl ethers. In a previous section the reaction with 2-(trimethylsilyloxy)furan (27) was shown to give a Mukaiyama−Michael reaction (Scheme 10). With (cyclohexenyloxy)trimethylsilane (106) the reaction of 2a proceeds with moderate yield to give a mixture of the diastereomeric products of the H.D.A. reaction 107 and 108 (Scheme 43).14 The two adducts were isolated, but it was impossible to determine the relative configurations of the C4, C4a, and C8a stereocenters. However, the relative ratio of the two adducts and their enantiomeric excesses were determined. Despite the opposite configurations of the C4 stereocenters of the oxazoline rings, the catalyst [(4S,5S)-X/Cu(OTf)2] and [(4R)-IX/Cu(OTf)2] produced the same dextrorotatory

enantiomer of 107, which was obtained with the former catalyst in 99% ee.14 Moving back to the reaction between (3,4-dihydro-1naphthyloxy)-trimethylsilane (29) and 2a,v, which was also considered in the section dedicated to the Michael reaction, it proceeds with almost quantitative yields with the copper(II) catalysts derived from (4R)-IX, (4S)-IX, (4S)-XIX, and (4S,5S)X Box ligands (Table 25, entries 1−5). The isolated products were the hetero D.A. adducts 30 and the syn/anti Michael products 31 and 32 (Scheme 43). The best catalyst was again [(4S,5S)-X/Cu(OTf)2], which gave (4S,4aR,10bR)-30 as pure enantiomers, whose cis configuration of the 4a and 8a substituents is in agreement with a hetero D.A. mechanism in which the dienophile 29 approaches endo to the less hindered βRe face of 2. When the reaction with 2a was performed at −20 °C for a short reaction time (1h), or at −70 °C, the major product obtained was (4S,4aR,10bR)-30 with excellent diastereo- and enantioselectivities (Table 25, entry 4 and 6). The application of prolonged reaction time shifts the selectivity toward the formation of the Michael product (+)-31 (Table 5, entry 5). A simple explanation of these results may be proposed by considering (4S,4aR,10bR)-30 as a primary reaction product that, under prolonged reaction times at higher temperatures, opens into (+)-31. This rationale was easily confirmed by converting (4S,4aR,10bR)-30 into (+)-31 at ambient temperature with a catalytic amount of Cu(OTf)2. Since the conversion occurs with total retention of the enantiomeric purity (99.9% ee), these data allow to assign the absolute configuration (2S,3R) to 31 (Scheme 43).14 A new approach to the enantiocatalyzed H.D.A. reaction takes advantage from a new emerging area of organocatalysis: the Nheterocyclic carbene family. In the presence of triethylamine, the precatalyst carbene precursor (5aR,10bS)-2-(2,4,6-trimethylphenyl)-5a,10b-dihydro-4H,6H-indeno[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazinium tetrafluoroborate gives the N-heterocyclic AG


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Table 25. [4 + 2]-Cycloaddition Reaction between 2 with (3,4-Dihydro-1-naphthyloxy)-trimethylsilane (29) Catalyzed by Different [Box/Cu(OTf)2] Complexes (Scheme 43)14 entry

R

1 2 3 4 5 6 7

Ph Ph Ph Ph Ph Ph 4-Br-C6H4

2a 2a 2a 2a 2a 2a 2v

box

T/°C

t/h

yield (%)

[30:31:32]

30 ee (%) (conf)

31 ee (%) (conf)

(4R)-IX (4S)-IX (4S)-XIX (4S,5S)-X (4S,5S)-X (4S,5S)-X (4S,5S)-X

−20 −20 −20 −20 −20 −70 −20

70 70 15 1 15 140 60

99 99 95 82 94 99 67

65:29:6 71:25:4 49:44:7 71:22:7 20:69:11 85:13:2 20:66:14

35 (4R,4aS,10bS) 36 (4S,4aR,10bR) 99 (4S,4aR,10bR) 99.9 (4S,4aR,10bR) 99.9 (4S,4aR,10bR) 99.9 (4S,4aR,10bR) 99.8 (4S,4aR,10bR)

65 (2S,3R) 70 (2R,3S) 75 (2S,3R) n.d 99 (2S,3R) n.d. 98 (2S,3R)

reactants 1 or 2, and same catalyst) in which at least 10 experiments have been performed, are statistically 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 for all the data, and for those of the reagents bearing an aromatic substituent in the β-position. The results are reported in Table 26, the complete set of data being in columns 5−7, and those for the aryl substituted derivatives in columns 8− 10. From the overall data reported in columns 5−7, the efficiency and the flexibility of the catalyst for each single reaction can be easily evaluated. Excellent average yields and enantioselectivities for a large number of reactants are a good measure for the efficiency of the catalysts, while small s.d.s are an index of the catalyst flexibility. Examples of reactions catalyzed by efficient and flexible catalysts are those reported in Table 26, entries 1−5, 7, 15, and 17. Sometimes the catalyst is flexible, but not too efficient (Table 26, entries 8, and 9), sometimes is efficient, but not flexible (Table 26, entries 6, 10−14), sometimes neither too efficient nor too flexible (Table 26, entry 16). The clusters reported in entries 15 and 17 deserve a further comment: The former cluster reports the data for the D.A. reaction of 2, which behaves as dienophile, with six different dienes, and in 10 different reactions the catalyst [(4S)-IX/ Cu(OTf)2] gives yields and enantiomeric excesses always around 95%.38 The same chiral complex catalyzes the hetero D.A. reaction of 2 behaving as heterodiene, with six different dienophiles, and in 10 different reactions yields and ees around 95% are again obtained.71 Hence, the role of 2 as 2π or 4π component in a D.A. cycloaddition does not influence the efficiency and flexibility of [(4S)-IX/Cu(OTf)2] as chiral catalyst. The comparison of the data obtained for all the reagents (Table 26, columns 5−7) with those for the subset of the aryl substituted derivatives (columns 8−10) may evidence the role of the alkyl/heterocyclic vs the aryl substituents in determining the efficiency/flexibility of the catalyst. The catalyst [(3aR,4aR,7R,8aS,9R,9aR)-XVII/Cu(OTf)2] of the Friedel−Crafts reaction between 2 and 54 (Table 26, entry 11) gives better results when the reaction involves only β-aryl-substituted reactants.27 On the contrary, in many cases the efficiency/flexibility of the catalyst is not dependent on the nature of the substituent (alkyl, heterocyclic, or aryl group) (Table 26, entries 1, 3, 4, 7−9, 12, 14, and 17). This does not mean that an aryl, an heterocyclic, or an alkyl group in the β-position of 1 or 2 always give comparable results in the same reaction and with the same catalyst. Since reactivity and selectivity of an enantioselective reaction often depend on steric factors, one could expect that a methyl or a tert-butyl (or a cyclohexyl) substituent in the β-position may give similar or

carbene (5aR,10bS)-XLII, which is the catalyst of the redox reaction between (E)-trifluoro-1-(pyridin-2-yl)but-2-en-1-one (1ap) and 2-benzoyloxypentanal (109). The product, 3-butyl4-(trifluoromethyl)-3,4-dihydro-6-(pyridin-2-yl)pyran-2-one, is obtained in 63% yield, the diastereoselectivity is 92:8, and the nearly pure enantiomer (3S,4S)-110 is obtained with >99% ee. The same reaction occurs with (E)-trifluoro-1-phenylbut-2-en-1one (3ap) and, interestingly, (3S,4S)-111 is obtained in 63% yield, the d.r. is >95:5, and the ee is >99% (Scheme 44).72 Hence, Scheme 44

this is one of the few reactions in which alkenoyl-pyridines and the corresponding chalcones, with a chiral catalyst, give rise to the same result in terms of reactivity and selectivity.

8. INFLUENCE OF SUBSTITUENTS ON REACTIVITY AND SELECTIVITY The previous sections discussed the reaction of 38 (E)-2alkenoyl-pyridines (1), 24 (E)-2-alkenoyl-pyridines-N-oxides (2), and 4 chalcones (3). The majority of pyridines and pyridine N-oxides have a substituted aryl group in the β-position of the alkenoyl group, 8 have an alkyl group, 3 a heterocyclic substituent, and these reactants have been employed in about 500 examples of several reactions. Have some of the substituents on the aryl group, or the different alkyl or heterocyclic groups a leading influence on the enantioselectivity of the reactions? Furthermore, the pyridine ring of 1 may have a methyl group in the 3-, 4-, or 5-positions. Have these substitutions an influence on the stereoselectivity of the reactions? To evaluate the effect on reactivity and selectivity of the different groups in the β-position of the alkenoyl moiety, the clusters of homogeneous reactions (i.e., same reaction, same AH


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Table 26. Statistical Analyses of Yields and Enantioselectivities of Reaction Clusters Involving 1 or 2, Performed with the Same Catalyst and Under Homogeneous Conditions all substrates entry

reaction (ref)

1 2 3

Michael 1 + 11 (7) Michael 1 + 18 (9) Michael 2 + 22a (12)

4

Muk.-Mich. 2 + 25a (13) Michael 2 + 18a (15) Michael 2 + 35a (16) Muk.-Mich. 2 + 39 (17) Henry 1 + 47 (21) Henry 1 + 49 (21) Friedel−Crafts 2 + 54 (24) Friedel−Crafts 2 + 54 (27) Friedel−Crafts 2 + 62 (25) Radical reac. 1 + RI (32) 1,3-DC 2 + 74 (35) D.A. 2 + dienes (38) D.A. 1 + 77 (41) H.D.A. 2 + dienophiles (71)

5 6 7 8 9 10 11 12 13 14 15 16 17

catalyst

table

reagent number

average yield % (s.d.)

aryl substituted substrates average ee % (s.d.)

reagent number

average yield % (s.d.)

average ee % (s.d.)

(R,R,R)-Va (R,R,R)-Va [(3aR,8aS)-VIII/ Zn(OTf)2] (4R)-IX/Cu(OTf)2]

1 2 3

17 17 11

86.1 (5.9) 92.4 (4.3) 89.3 (9.4)

94.5 (1.1) 93.6 (7.0) 90.9 (3.5)

14 14 8

87.6 (5.4) 93.3 (3.8) 92.6 (5.0)

94.4 (1.0) 95.7 (2.9) 91.0 (3.5)

4

14

87.7 (4.5)

90.0 (7.3)

11

89.1 (3.4)

92.2 (5.5)

[(4S)-XI/Zn(OTf)2] [(4S)-XI/Zn(OTf)2] [(4S)-XI/Zn(OTf)2]

6 6 7

12 10 12a

87.7 (4.5) 93.2 (6.7) 86.8 (3.8)

90.0 (7.3) 79.1 (12.6) 90.9 (4.3)

9 7 10

92.2 (3.8) 95.4 (4.0) 88.0 (2.7)

91.4 (6.3) 80.7 (14.8) 91.8 (3.9)

[(4S)-XIV/La(OTf)3] [(4S)-XIV/La(OTf)3] [(4S)-XI/Cu(OTf)2]

8 8 9

14 10 19

68.9 (4.3) 58.5 (7.7) 93.7 (6.0)

79.7 (4.7) 73.0 (11.4)b 88.5 (20.7)

9 8 17

68.8 (4.9) 58.5 (7.7) 94.6 (4.2)

77.4 (2.7) 71.8 (12.5)b 93.5 (4.8)

[XVII/Cu(OTf)2]c

9

21

91.0 (7.0)

89.4 (14.8)

17

92.4 (3.9)

92.1 (7.6)

[(4S)-XI/Zn(OTf)2]

9

17

86.4 (11.9)

95.2 (5.0)

14

88.4 (12.2)

95.4 (5.5)

[(4S)-IX/Zn(OTf)2]

10

11

85.1 (16.0)

49.5 (17.1)

8

82.6 (18.4)

56.6 (12.8)

[(4S)-XIX/Cu(OTf)2] [(4S)-IX/Cu(OTf)2] [(S)-XXII/Ti(Oi-Pr)4] [(4S)-IX/Cu(OTf)2]

11 14 15 24

14 10 14 13

63.8 (22.6) 95.7 (2.7) 63.6 (27.9) 95.3 (6.2)

89.2 (9.6) 94.3 (1.5)d 69.0 (11.9) 94.8 (5.5)e

10 10 13 10

63.2 (23.3) 95.7 (2.7) 64.7 (28.7) 94.3 (6.8)

88.4 (11.2) 94.3 (1.5)d 68.2 (12.0) 94.4 (6.3)e

a

The reaction with 2s gives no product after 98 h and the data is not considered in the analysis. bData for anti-50, the major product. cThe catalyst is [(3aR,4aR,7R,8aS,9R,9aR)-XVII/Cu(OTf)2]. dData for endo-adducts, the major products. eData for endo adducts, the major products, whose structures are reported in Scheme 42

Table 27. Comparison of Yields and Enantioselectivities of the Reactions Involving 1 or 2 where R is a Methyl, a Cyclohexyl, or a tert-Butyl Group R = Me entry

reaction

1 2 3 4 5

Henry Michael Mukaiyama-Mich. Friedel−Crafts Oxa-Michael

1 + 47 2 + 22a 2 + 25a 2 + 54 1 + H2 O

R = cyclohexyl

table

yield %

ee %

8 3 4 9 18

65

87

different results depending on their steric hindrance. Few data are available in the literature, and those in which at least two such alkyl groups have been involved in the same reaction are reported in Table 27. The single example in entry 1 shows an unexpected identical result for methyl and tert-butyl reagents. On the contrary, the examples in entries 2−5 evidence that the tert-butyl group may be better (entries 3 and 5) or worse than the cyclohexyl substituent (entry 2). An example in which a relationship is observed between the steric bulk of R and the enantioselectivity [n-pentyl (1ad) (57%) < cyclohexyl (1q) (64%) < i-Pr (1aq) (77%) 30% ee will be evaluated (Table 28 and Scheme 51). Two clusters of ligands have been considered: those with 9aminoacridine as intercalator connected through a spacer to the Cu(II) ligand (XXXa-c, XXXIa,b,d, and XXXIIc-e), and those in which an heterocyclic aromatic structure acts at the same time as intercalator and as Cu(II) ligand (XXXIIIa-c, XXXIVa-h, and XXXVIa,b,d). In the first cluster (Table 28, entries 1−9) some factors may influence the enantioselectivity, some easy to rationalize, some AM


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Review

Scheme 50

ligand in the coordination to copper(II). To shed some light on these geometries, DFT calculations of the structure of [XXXIVb/Cu(II)/1am/(H2O)2] and [XXXVIa/Cu(II)/1am/ (H2O)] were performed in the absence of DNA, and the most stable structures of these complexes are depicted in Figure 11. The complex with the bidentate ligand (A) has a pentacoordinate trigonal bipyramidal geometry with an additional water molecule hydrogen bridged with both the carbonyl group and the aqua ligand. The complex (B) with the tridentate ligand has an octahedral structure with four pyridine nitrogen atoms equatorial, and the carbonyl group and the water molecule in the axial positions.60 If the right handed helix of the salmon testes DNA is added to these complexes and steric factors are avoided (Table 28, entry 19), then the denticity connected to trigonal bipyramidal structure has a synergic effect on the face selectivity induced by DNA, and (2S,3S)-78 is obtained with a very good ee (Table 28, entries 13−18, and 20). On the contrary, when the denticity related to the octahedral structure competes with the chirality induced by DNA, (2R,3R)-78 is obtained with lower enantiomeric excesses (Table 28, entries 21−23).76 Certainly, much researches are required for a more comprehensive rationale of a new, original and fascinating field of enantioselective catalysis.

Table 28. Enantioselective D.A. Reactions between 1a and Cyclopentadiene with Salmon Testes DNA-Based Cu(II) Catalysts Inducing Enantioselectivity >30% eea entry

a

ligand

entry in Table19

yield (%)

[78:79]

78 ee % (conf)

1

XXXa

1

>80

98:2

49 (2S,3S)

2 3 4

XXXb XXXc XXXIa

3 4 6

>80 >80 >80

96:4 98:2 98:2

48 (2R,3R) 33 (2S,3S) 37 (2R,3R)

5

XXXIb

7

>80

92:8

37 (2R,3R)

6 7 8 9 10 11 12 13

XXXId XXXIIc XXXIId XXXIIe XXXIIIa XXXIIIb XXXIIIc XXXIVa

29 36 37 38 39 40 41 42

97 100 100 100 ≈50 ≈50 ≈50 100

86:14 n.d. n.d. n.d. 96:4 95:5 96:4 98:2

56 (2R,3R) 49 (2S,3S) 43 (2S,3S) 75 (2R,3R) 49 (2S,3S) 61 (2S,3S) 73 (2S,3S) 90 (2S,3S)

14

XXXIVb

46

≈50

>99:1

99 (2S,3S)

15 16 17 18 19 20 21 22 23

XXXIVc XXXIVd XXXIVe XXXIVf XXXIVg XXXIVh XXXVIa XXXVIb XXXVId

44 45 70 71 72 73 74 75 77

≈50 ≈50 100 100 100 100 23 20 17

>99:1 98:2 99:1 98:2 95:5 98:2 89:11 92:8 92:8

91 (2S,3S) 92 (2S,3S) 95 (2S,3S) 92 (2S,3S) 40 (2R,3R) 89 (2S,3S) 60 (2R,3R) 79 (2R,3R) 71 (2R,3R)

ref 53, 55, 58 53, 58 53, 55 53, 55, 58 53-55, 58 55 55 55 55 56 56 56-58 56-58, 60 56-58, 60 56 56 60 60 60 60 60 60 60

10. COMPARISON BETWEEN THE ENANTIOSELECTIVELY-CATALYZED REACTIONS WITH (E)-2-ALKENOYL-PYRIDINES, THEIR N-OXIDES, AND THE CORRESPONDING CHALCONES Dealing with enantioselective reactions involving reagents having the R−CC−CO group, bearing a β-nitrogen atom [(E)-2alkenoyl-pyridines 1], or a β N−O group [their N−oxides 2] as further potential ligands, the binding ability in a bidentate fashion may have a specific effect on the transmission of chirality from the

Data taken from Table 19.

AN


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Scheme 51

catalyst to the product; this specific effect may become evident when a comparison with the monocoordinating chalcone is performed. It is not easy to find the same reaction, performed under the same experimental conditions, on 1, 2, and the corresponding chalcone 3. The scope of this section is to review and to compare the reactions with at least two of these reagents and to discuss the difference, if any, on reactivity and stereoselectivity. The results of these comparisons are reported in Table 29 and four different behaviors can be evidenced. First of all, four reactions (Table 29, entries 1−4) compare the results obtained by using 1 or 2. In the D.A. reactions of entries 1 and 2, in the Friedel−Crafts reaction of entry 3, and in the H.D.A. reaction of entry 4, the stereoselectivity is always better when the reaction is run with N-oxides 2. All the other cases compare the results of 1 with those of the corresponding chalcone 3 (Table 29, entries 5−16). The radical addition and the D.A. reaction involving 1 (Table 29, entries 5 and 6) give yields and enantioselectivities by far better than those for the chalcone reaction. Nearly similar is the result of the Friedel−Crafts reaction mentioned in entry 7, in which the enantioselectivities are similar, but the yield of the reaction with 3 is negligible. In seven reactions (Table 29, entries 9−15) there is no significant difference in the yields and stereoselectivities between the reactions carried out with either 1 or 3, and, even with some distinction, the Michael reaction described in entry 8 can be considered part of the same group.

Figure 11. DFT optimized geometries of [XXXIVb/Cu(II)/1am/ (H2O)2] (A) and [XXXVIa/Cu(II)/1am/(H2O)] (B) without the DNA fragments.60

Figure 12. X-ray crystal structures of [(4S)-IX/CuCl2] and [(4S)-IX/ ZnCl2] (ref 75).

AO


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Table 29. Comparison between Reactivity and Selectivity of Enantioselective Catalytic Reactions Performed with (E)-2-Alkenoylpyridines (1), Their N-Oxides (2), and the Corresponding Chalcones (3) reaction of 1 entry

reaction

reagent (scheme)

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

D.A. D.A. Friedel−Crafts Hetero D.A. Radical D.A. Friedel−Crafts Michael Michael Michael Michael

77 (28) 77 (28) 54 (20) 86 (42) i.PrI (24) 77 (33) 54 (19) 18a (6) 13 (5) 13 (5) 8 (3)

12 13 14 15 16

Henry Phospha Michael Hetero D.A. Epoxidation Michael

51 (18) PPh2H (15) 109 (44) H2O2 (23) Et2Zn (2)

catalyst or organocatalyst [(4S)-IX/Cu(OTf)2] [(4S)-IX/Zn(OTf)2] [(4S)-XI/Cu(OTf)2] [(4S)-IX/Cu(OTf)2] [(4S)-IX/Zn(OTf)2] [HHD-4xala/Cu(II)] [(3aS,8aR)-XVI/Sc(OTf)3] (S,S,R)-IVd (S,S,R)-VI (syn products) (S,S,R)-VI (anti products) (S)-III: ArC6H3[3,5(CF3)2] (S)-XV (R)-XII (5aR,10aS)-XLII (S)-XVIII (S)-II/Cu(OTf)2

yield (%)

ee % (conf)

99 99 89 85 97 73 68 95 48 32 92

19 (2S,3S) 23 (2S,3S) 16 (R) 16 (4S,6S) 64 (S) 46 31 (R) 96 (R) 94 (2S,3S) 95 (2R,3S) 88 (2R,3S)

61 99 63 >99 n.d.

90 (S) 92 (S) >99 (3S,4S) 84 (2R,3S) 29

reaction of 2 yield (%)

ee % (conf)

98 99 97 >99

96 (2S,3S) 91 (2S,3S) 99 (R) 96 (4S,6S)

reaction of 3 yield (%)

ee % (conf)

ref

99% ee (Scheme 57).18 The absolute configuration of 115 was determined to be (S,S) through X-ray analysis of the complex between 115 and 2 equiv of (R)-XII.18 Two considerations can be derived from these results. The reagents 112 and 113 behave as monodentate ligands and therefore there is no participation of the pyridine nitrogen of 112 to determine the stereochemical outcome of the reaction. The absolute (S,S)-configuration of the products derives from the first β-Si face attack of phosphorus on the first β-carbon atom that gives the first (S)-chiral center. The selectivity of the second AR


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Scheme 58a

a

See Scheme 18.

Scheme 59a

a

See Scheme 3.

From the results discussed above, when does a reaction show no significant difference in yield and stereoselectivity if carried out with 1 or 3? The catalysts in Schemes 55−60 have a common feature, since all give reacting intermediates in which the coordinated enone reagent behaves as a monodentate ligand. Generally this corresponds to a less rigid structure expected to induce poor enantioselectivities, but this limitation can be overwhelmed by an appropriate choice of the catalyst. In a recent study, three inactivated ketones [methyl 2-pyridylketone (117), methyl 2-pyridyl-N-oxide-ketone (118), and acetophenone (119)] have been tested in the enantioselective aldol reaction with isatin (120).78 The organocatalyst was the epiaminocinchonine-based urea (R,R,R)-Va, and the products were 121−123 (Scheme 61). Isatin behaves as the electrophile, the ketones as the nucleophile, and even if reagents 117−119 do not fit the topic of this review, they can be taken as models of compounds 1−3 to rationalize the differences in reactivity and stereoselectivity. The authors proposed an interesting model of the reacting intermediate (A) that is represented in Scheme 61. The urea hydrogens bond the two isatin carbonyl groups,79 activating the bound substrate; the enol tautomers of 117−119 protonate the cinchona tertiary nitrogen, being the resulting enolates bound to the ammonium ion in a monodentate fashion. Therefore, the geometry of the resulting reacting intermediate is not affected by the ketone substituent (pyridyl, or the

reacting intermediate is schematically represented in Scheme 59. This is the key point that rationalizes the result because the enone is the part of the reagent (1a or 3a) interacting with the catalyst. Thus, a phenyl or a 2-pyridyl group does not modify the structure of the reacting intermediate favoring the β-Si face attack of 8. Hence, yields and enantioselectivities of (2R,3S)-9 and (2R,3S)-10 are comparable. The hetero D.A. reaction between 1ap or 3ap with 2benzoyloxypentanal (109), catalyzed by the N-heterocyclic carbene (5aR,10bS)-XLII, is the paradigmatic example of a reaction in which the reactivity of alkenoyl-pyridines and chalcones is identical (Table 29, entry 14). Both the reactions give 63% yield, their diastereoselectivity is around [95:5], and the (3S,4S)-products are obtained in more than 99% ee.72 A mechanistic insight in the catalytic cycle allows to rationalize these results (Scheme 60). Initially the organocatalyst adds to 109 to give the Breslow intermediate A, which looses pnitrobenzoic acid affording the azolium enolate B. This electronrich dienophile attacks the β-Re face of the heterodiene 1ap or 3ap to give the zwitterionic intermediate D. This latter releases the reaction products, and the catalyst begins a further catalytic cycle. Obviously, the eventual presence of pyridine nitrogen in the heterodienophile does not affect both reactivity and selectivity. AS


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Scheme 60a

Table 30. Enantioselective Aldol Reaction between 117−119 and Isatin (120) with (R,R,R)-Va as Organocatalyst78 entry

reagent

X

product

time (d)

yield (%)

ee (%) (conf)

1 2 3

117 118 119

N N−O CH

121 122 123

4 4 7

91 85 92

78 91 91 (R)

zinc catalyzed by the Cu(II) complex of the (S)-BINOL-based phosphorus amidite [(S)-II/Cu(OTf)2], because 3a gives yield and enantioselectivity better than those obtained with 1a as the reactant (Table 29, entry 16).5 Furthermore, the optimized conditions require the use of two equiv of (S)-II, indicating that in the catalytic cycle two ligands are bound to Cu(II). A suggestive rationale derives from the result achieved by the authors with the dimeric bis[(S)-(BINOL-phospamidite)] ligand (S,S)-XLIII. With the catalyst derived from this bidentate ligand and Cu(II) salt in the ratio (1:1), the reaction yields and the enantiomeric excesses of 6 and 7 were the same obtained by using two equiv of the (S)-II ligand (Scheme 62).5 Scheme 62a

a

See Scheme 44.

Scheme 61

a

See Scheme 2.

This indicates that among the four coordination sites of Cu(II), two are occupied by 2 equiv of (S)-II (or one equiv of (S,S)-XLIII), one by an ethyl fragment transferred from zinc, and the last one by the enone’s double bond through π-complexation. Hence, the pyridyl-substituted reagent 1a gives low yield and stereoselectivity presumably due to the competitive binding of the pyridine nitrogen to the copper cation.5

11. CONCLUSIONS This review discussed the enantioselective reactions of two classes of reagents, (E)-2-alkenoyl-pyridines 1, and their corresponding N-oxides 2, substrates able to behave as bidentate ligands in the coordination with a chiral catalyst. The reacting intermediates are characterized either by a five-membered ring in the case of 1 or by a six-membered chelate for N-oxides 2. When possible, their reaction results were compared with those obtained by using the monocoordinating chalcones 3. This recent field that was pioneered 15 years ago is now accounted for about 60 reagents, tested in more than 500 examples of enantioselective reactions. The chiral products, which retain functional groups for further transformations, are

corresponding N-oxide, or a phenyl group), and the enolates of 117−119 must attack the CO-Si-face of isatin to give products 121−123 with the same (R) absolute configuration. Table 30 reports the results of the above aldol reactions: the products 121−123 have been obtained with yields in the range 85−92%, the enantiomeric excesses were in the range 78−91%, and the absolute configuration of 123 was (R). In conclusion, since 117−119 behave as monodentate ligands in the reacting intermediate, reactivity and stereoselectivity are constant. To conclude the analysis of the behavior of 1 and 3, an unexpected result is found in the Michael reaction with diethylAT


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useful synthons for natural products and molecules with potential biological interest. The authors were first stimulated, and then fascinated, in this topic by three features of these reactions. (a) Some significant catalysts found multiple applications in the field, and it is intriguing to try to correlate their structure with the stereochemical outcome of the reactions. (b) It is hard to believe that one single reagent, the (E)-3-phenyl-1-(pyridin-2-yl)prop-2-en1-one (1a), has found enormous applications as reagent in the field of the enantioselective reactions with artificial metalloenzymes and DNA-based chiral catalysts. This is a field that is considered borderline with enantioselective catalysis, which prefers small, defined, robust, and cheap chiral molecules as the base for the catalyst. On the other hand, thinking at the DNA structure (not limited to duplex but even in a more sophisticated quadruplex structure) as an equivalent of a Box or a Pybox, this opens further perspectives in a new world. (c) The attempt to rationalize the reason why, in terms of reactivity and stereoselectivity, sometimes 1 is better than 3, or 2 is better than 1, or 1 is similar to 3, is a game that appears as intriguing as the solution of the Rubik’s cube. In conclusion, the admirable perfection of many chiral catalysts, functional to the reaction for which they were designed, gives the same sensation of the pure elegance and magic artcraft of an Amati violin,80 perfect in the form, and magic in the sound. Perhaps, the admiration toward the art of the enantioselective synthesis that moved this research could contagiously stimulate the interest of the reader.

joined the Science Faculty at the University of Pavia as a full professor. He was Dean of the Faculty and Director of the Department 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 *

Tables with a list of 4-substituted (E)-2-alkenoyl-pyridines (1), their N-oxides (2), and the corresponding chalcones (3), with the catalysts used in the enantioselectively catalyzed reactions. This material is available free of charge via the Internet at http:// pubs.acs.org.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Paolo Quadrelli graduated in Chemistry at the University of Pavia in 1986 and received the Ph.D. in Chemical Sciences at the same University, studying the use of copper(II) complexes in enantioselective organic syntheses under the guidance of Prof. Desimoni. He spent a couple of years in Eniricerche Company in Milan working in the field of heterogeneous catalysis. As Marie Curie Fellow, he joined the School of Chemistry, University of Leeds in the research group of Prof. Ronald Grigg and then he continued his work as a Researcher in the group of Prof. Caramella at the Department of Chemistry of the University of Pavia. Actually, he is Associate Professor and his research interests are in the field of pericyclic reactions and their applications in the synthesis of biologically active molecules. He is member of the Italian Chemical Society (SCI) and of the American Chemical Society (ACS) and collaborates with some chemical companies in Italy in the field of antivirals, antitumorals, and steroids.

Biographies

ACKNOWLEDGMENTS We thank the University of Pavia for supporting the research that made this review possible and the Ministry of University

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 AU


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(MIUR) for financial support (PRIN 2011, CUP F11J12000210001). A warm thanks to all our co-workers who contributed to the development of the topic presented in this review.

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(69) Wang, C.; Jia, G.; Li, Y.; Zhang, S.; Li, C. Chem. Commun. 2013, 49, 11161. (70) Park, S.; Sugiyama, H. Molecules 2012, 17, 12792. (71) Barroso, S.; Blay, G.; Muñoz, M. C.; Pedro, J. R. Adv. Synth. Catal. 2009, 351, 107. (72) Davies, A. T.; Taylor, J. E.; Douglas, J.; Collett, C. J.; Morrill, L. C.; Fallan, C.; Slawin, A. M. Z.; Churchill, G.; Smith, A. D. J. Org. Chem. 2013, 78, 9243. (73) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev. 2003, 103, 3119. (74) Evans, D. A.; Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc. 2000, 122, 1635. (75) Thorhauge, J.; Roberson, M.; Hazell, R. G.; Jørgensen, K. A. Chem.Eur. J. 2002, 8, 1888. (76) The enantiodivergent reactions, with DNA as single chiral messenger, catalyzed with [achiral ligands/salmon testes DNA/Cu(II)] complexes can be considered a new type of dual stereocontrol of asymmetric reactions, argument of the comprehensive recent review: Escorihuela, J.; Burguete, M. I.; Luis, S. V. Chem. Soc. Rev. 2013, 42, 5595. (77) (a) Landa, A.; Minkkilä, A.; Blay, G.; Jørgensen, K. A. Chem. Eur. J. 2006, 12, 3472. (b) Landa, A.; Richter, B.; Johansen, R. L.; Minkkilä, A.; Jørgensen, K. A. J. Org. Chem. 2007, 72, 240. (78) Allu, S.; Molleti, N.; Panem, R.; Singh, V. K. Tetrahedron Lett. 2011, 52, 4080. (79) (a) Guo, Q.; Bhanushali, M.; Zhao, C.-G. Angew. Chem., Int. Ed. 2012, 49, 9460. (b) Xu, D.-Q.; Wang, Y.-F.; Zhang, W.; Luo, S.-P.; Zhong, A.-G.; Xia, A.-B.; Xu, Z.-Y. Chem.Eur. J. 2010, 16, 4177. (80) Nicolò Amati (1596−1684), a lutier from Cremona (Italy), was the great violin maker that gave to the instrument the perfect form illustrated in the cover of this review and the magic sound that we still admire today. The Serdet violin, the first instrument made by Stradivari has inside the label “Antonius Stradivarius Cremonensis Alumnus Nicolaij Amati”.

AW


Enantioselectively-Catalyzed Reactions with (E)-2-Alkenoyl-pyridines

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