Applications of Iridium-Catalyzed Asymmetric Allylic Substitution

Article Cite This: Acc. Chem. Res. 2017, 50, 2539-2555

pubs.acs.org/accounts

Applications of Iridium-Catalyzed Asymmetric Allylic Substitution Reactions in Target-Oriented Synthesis Jianping Qu† and Günter Helmchen*,‡ †

Institute of Advanced Synthesis, Nanjing Tech University, Nanjing 211816, China Organisch-Chemisches Institut der Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany

‡

CONSPECTUS: Metal catalyzed allylic substitution is a cornerstone of organometallic and synthetic chemistry. Enantioselective versions have been developed with catalysts derived from transition metals, most notably molybdenum, nickel, ruthenium, rhodium, iridium, palladium, and copper. The palladium- and the iridium-catalyzed versions have turned out to be particularly versatile in organic synthesis because of the very broad scope of the nucleophile and great functional group compatibility. Assets of the iridium-catalyzed reaction are the formation of branched, chiral products from simple monosubstituted allylic substrates, high degrees of regio- and enantioselectivity, and use of modular, readily available chiral ligands. The possibility to use carbon, nitrogen, oxygen, and sulfur compounds as well as fluoride as nucleophiles allows a wide range of chiral building blocks to be prepared. Our Account begins with the presentation of fundamental reaction schemes and chiral ligands. We will focus our discussion on reactions promoted by phosphoramidite ligands, though numerous chiral ligands have been employed. The subsequent section presents a brief overview of reaction mechanism and experimental conditions. Two versions of the iridium-catalyzed allylic substitution have emerged. In type 1 reactions (introduced in 1997), linear allylic esters are commonly used as substrates under basic reaction conditions. In type 2 reactions (introduced in 2007), environmentally friendly branched allylic alcohols can be reacted under acidic conditions; occasionally, derivatives of allylic alcohols have also been applied. A unique feature of the type 2 reactions is that highly electrophilic allylic intermediates can be brought to reaction with weakly activated alkenes. The subsequent text is ordered according to the strategies followed to transform allylic substitution products to desired targets, most of which are natural products or drugs. Syntheses starting with an intermolecular allylic substitution are discussed first. Some fairly complex targets, for example, the potent nitric oxide inhibitor (−)-nyasol and the drug (−)-protrifenbute, have been synthesized via less than five steps from simple starting materials. Most targets discussed are cyclic compounds. Intermolecular allylic substitution with subsequent ring closing metathesis is a powerful strategy for their synthesis. Highlights are stereodivergent syntheses of Δ9-tetrahydrocannabinols (THC), wherein iridium- and organocatalysis are combined (dual catalysis). The combination of allylic alkylation with a Diels−Alder reaction was utilized to synthesize the ketide apiosporic acid and the drug fesoterodine (Toviaz). Sequential allylic amination, hydroboration and Suzuki−Miyaura coupling generates enones suitable for conjugate addition reactions; this strategy was employed in syntheses of a variety of alkaloids, for example, the poison frog alkaloid (+)-cis-195A (pumiliotoxin C). Intramolecular substitutions offer interesting possibilities to build up stereochemical complexity via short synthetic routes. For example, in diastereoselective cyclizations of chiral compounds, substrate control can be overruled by catalyst control in order to generate cis- and trans-isomers selectively from a given precursor. This approach was used to prepare a variety of piperidine and pyrrolidine alkaloids. Finally, complex polycyclic structures, including the structurally unusual indolosesquiterpenoid mycoleptodiscin A, have been generated diastereo- and enantioselectively from olefins by polyene cyclizations and from electronrich arenes, such as indoles, in dearomatization reactions.

1. INTRODUCTION

2. Ir-CATALYZED ALLYLIC SUBSTITUTION: BACKGROUND

The development of reaction methodology is booming, benefiting synthetic chemistry as well as the pharmaceutical industry. From 1997 onward,1,2 Ir-catalyzed asymmetric allylic substitution has been a significant part of the new developments and remains an attractive field of research.3 Meanwhile, a considerable body of work focusing on the application of this reaction in the enantioselective synthesis of bioactive compounds has emerged. In this Account, we attempt to present a survey of the state of the field. © 2017 American Chemical Society

The early work was modeled on Pd-catalyzed allylic substitution, with the distinction that linear allylic esters were used as substrates (Scheme 1, type I). Privileged chiral ligands are still L1−L4,4,5 which upon reaction with [Ir(cod)Cl]2 under basic conditions yield catalysts that induce high enantio- and Received: June 15, 2017 Published: September 22, 2017 2539

DOI: 10.1021/acs.accounts.7b00300 Acc. Chem. Res. 2017, 50, 2539−2555

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Accounts of Chemical Research Scheme 1. Ir-Catalyzed Allylic Substitution: Privileged Ligands

Scheme 2. One-Step Preparation of (π-Allyl)Ir Complexes

Scheme 3. Catalytic Cycle of Type II Allylic Substitutions

Figure 1. Catalyst preparation and catalytic cycle of type I allylic substitution reactions. Adapted with permission from ref 9a. Copyright 2010 Wiley-VCH.

A fundamentally new approach was introduced in 2007 by Carreira et al. (Scheme 1, type II), who discovered that branched allylic alcohols can be reacted under acidic conditions with Ir catalysts prepared in situ from ligand L6.8 High degrees of regioand enantioselectivity in favor of the branched product are generally obtained. Intermediary allyl complexes are markedly stronger electrophiles than those occurring in reactions of type I. For example, olefins are reactive nucleophiles in type II reactions, while they are inert under type I conditions. High regioselectivity in favor of branched products is generally observed; however, adequate explanations are lacking for both types.

regioselectivity with a broad variety of nucleophiles. However, this is not the case for allylic derivatives containing an orthosubstituted aryl substituent R, which commonly react with low enantioselectivity. For these compounds, ligand L5 developed by You et al.6 often gives satisfactory results. Cod (cycloocta-1,5diene) serves as the standard ancillary ligand. In addition, catalysts derived from dbcot (dibenzo[a,e]cyclooctene) are employed; these are more stable and induce higher regioselectivity, even under aerobic conditions.7

Figure 2. Ir-complexes used as catalysts for allylic substitutions. 2540


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Accounts of Chemical Research 2.1. Mechanism and Conditions of Type I Reactions

The in situ preparation of (cod)Ir catalysts is sensitive toward oxygen and water, and dry, degassed THF is the optimal solvent. Cyclometalation is commonly effected by propylamine, which is subsequently removed by evaporation, or substoichiometric amounts of TBD, DBU, and related strong bases. The presence of an additional base (for example, Cs2CO3) in a stoichiometric amount is often beneficial. In the case of sufficiently acidic pronucleophiles, such as malonates and N,N-diacylamines, an additional base for salt formation is not required with carbonates as allylic substrates (“salt-free conditions”); this procedure allows solubility problems to be avoided in the case of weakly polar solvents.10

Mechanistic aspects of type I reactions are well established and are summarized in Figure 1.9 In situ catalyst preparation is described on the left. Mixing of [Ir(diene)Cl]2 with ligands L* spontaneously yields complexes C1. Treatment of these with base results in cyclometalation to give iridacycles of type C2 that have been characterized and are active catalysts.3g The entry into the catalytic cycle (enclosed field of Figure 1) likely occurs via a complex of type C′ (16 valence electrons at Ir), for which no example has been isolated to date. Coordination of the substrate and oxidative addition gives π-allyl complexes C3 that react with a nucleophile to produce olefin complexes C4. Dissociation completes the catalytic cycle.

Figure 3. (Pro)nucleophiles and allylic substrates that have been used in intermolecular target-directed Ir-catalyzed allylic substitutions. 2541


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2.3. Scope of Substrates Used in Target Oriented Synthesis

(π-Allyl)Ir complexes (Figure 2) can be prepared by the simple method described in Scheme 2.7,11 The procedure is applicable to cod as well as dbcot complexes and complexes of ligand L5 that undergo cyclometalation at an aryl-H.6 (π-Allyl)Ir complexes are air stable, can be purified by chromatography, and are excellent single-species catalysts.

The substrate scope of the allylic substitutions is very broad. For a rapid overview, a survey of the substrates occurring in the subsequently discussed syntheses are given in Figure 3.

3. INTERMOLECULAR ALLYLIC SUBSTITUTIONS IN VERY SHORT ROUTES TO TARGETS Carreira et al. have reported type II substitutions with nonstabilized carbon acids as nucleophiles, furnishing fairly demanding targets in just two or three steps (Scheme 4). Note that different acids for activation of the allylic alcohol were used in four similar reactions. In the first example, the nucleophile is a geminallyl disubstituted alkene, which likely reacted via a carbenium ion intermediate to give a biallylic substitution product with high selectivity (Scheme 4a).13 Two simple further steps furnished the drug candidate JNJ-40418677 with potential activity against Alzheimer’s disease. This example also underlines the considerably different properties of (allyl)Ir intermediates in type I and II substitutions because participation of an olefin was never observed in a type I reaction. In the examples of Scheme 4b, potassium (Z)- or (E)alkenyltrifluoroborates were used as nucleophilic vinylation agents. The additive nBu4NHSO4 functioned both as a phase transfer catalyst for potassium alkenyltrifluoroborates and as a Brønsted

2.2. Mechanistic Aspects and Conditions of Type II Reactions

Recently, Carreira et al. published a well-founded proposal of the catalytic cycle of type II reactions (cf. Scheme 3).12 Mixing of allylic alcohol, [Ir(cod)Cl]2, and ligand L6 gives rise to the loss of cod and formation of complex I. Treatment of I with acid, for example, triflic acid, induces the formation of a mixture of two diastereomeric (π-allyl)Ir complexes II yielding the (putative) product complex III from which the product then dissociates. The details of the mode of the addition of the nucleophile and the origin of the generally very high selectivity still need to be elucidated. The preparation of the catalyst requires mixing of reactants in the order [Ir(cod)Cl]2, ligand L6, allylic alcohol, and a catalytic amount of acid [Brønsted acid, such as CF3COOH, or Lewis acid, such as Zn(OTf)2 or Sc(OTf)3]. As solvents, toluene, ethers, and haloalkanes are commonly used, and the exclusion of moisture and air is not necessary.

Scheme 4. Ir-Catalyzed Alkylations with Nonstabilized C-Nucleophiles

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oborates were used in combination with nBu4NBr as a phase transfer catalyst. As mentioned above, success with type II reactions requires the optimization of the acid. Here, trifluoroacetic acid was used, and HF was replaced by the less hazardous

acid. The targeted norlignans (−)-nyasol and (−)-hinokiresinol are potent inhibitors of eicosanoid and nitric oxide production.14 A similar procedure has been developed for Ir-catalyzed alkynylation reactions (Scheme 4c).15 Potassium alkynyltrifluor-

Scheme 5. Ir-Catalyzed Allylic Substitutions with Heteroatom Nucleophiles

Figure 4. Biologically active compounds via allylic substitution in combination with RCM. 2543


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Accounts of Chemical Research KHF2. The value of this procedure has been demonstrated by the synthesis of the drug candidate AMG 837 for the treatment of type 2 diabetes. Sc(OTf)3 was used as an acidic additive in the case of the allylation with trimethylallylsilane (Scheme 4d). The crude product was subjected to hydroboration/Suzuki−Miyaura coupling and cyclopropanation to furnish the insecticide (−)-protrifenbute.16

Several short syntheses were also reported for heteroatom nucleophiles. The antiepilepsy drug (S)-vigabatrin was prepared by allylic amination under salt-free conditions with an N,Ndiacylamine as the pronucleophile and subsequent deprotection (Scheme 5a).17 Allylic hydroxylations with bicarbonate as the nucleophile in conjunction with single component Ir catalysts C3 or ent-C3 were used for the preparation of an analog of the

Scheme 6. Ir-Catalyzed Alkylation with a Weinreb-type Malonic Acid Derivative and Applicationsa

a

THT = tetrahydothiophene.

Scheme 7. Ir-Catalyzed Alkylation Using a Silyl Enol Ether as Pronucleophile

Scheme 8. Ir-Catalyzed Alkylation in Combination with Brown Allylation and RCM

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subsequent step using Grubbs II catalyst proceeded in ≥85% yield. 4.1.2. Reactions with Heteronucleophiles. Allylic aminations with alkenylamines were applied in syntheses of tobacco alkaloids. As an example, a synthesis of (S)-nicotine is shown (Scheme 10).25 The main encountered problem was the racemization in the olefin reduction step. All attempted transition metal-catalyzed hydrogenations caused racemization to some degree. It was found that reduction with diimide generated from TsNHNH2 is a safe method with regard to the enantiomeric excess. N-Boc-N-methylhydroxylamine is an excellent pronucleophile in allylic substitutions to give N-protected hydroxamic acid derivatives. These could be used for alkaloid syntheses by deprotection, acylation with unsaturated carboxylic acids, and RCM (Scheme 11).26 Resultant Weinreb-type amides were treated with Grignard or organolithium reagents to give hemiaminals that could be reduced diastereoselectively via acyliminium intermediates to give cis-2,6- and cis-2,5-disubstituted piperidines or pyrrolidines, respectively. A variety of prosophis, spruce, and poison frog alkaloids were synthesized in this manner. A similar route had been used earlier to prepare γ-lactams, one of which was transformed into a baclofen analog (Figure 4), a potential monoamine oxidase inhibitor.27

antibiotic brefeldin A, (15R)-15-desmethyl-15-vinylbrefeldin A, which displayed strong replication inhibition of the enterovirus coxsackievirus B3 (CVB3). Stereoselectivity was completely controlled by the Ir catalyst (Scheme 5b).18 Zhao et al. have applied sodium sulfite as an S-nucleophile in an Ir-catalyzed allylic sulfonation reaction. The subsequent oxidative degradation with ozone gave (R)-2-phenyl-2-sulfoacetic acid, which has been used in the synthesis of cefsulodin, a semisynthetic antibiotic (Scheme 5c).19 Nguyen et al. have developed the first highly enantio- and regioselective fluorination utilizing the chiral diene ligand L7 (Scheme 5d).20 Although slightly outside the scope of this Account with respect to the ligand, we want to illustrate this method by an application in the synthesis of a 15-fluoro-prostaglandin precursor.

4. INTERMOLECULAR ALLYLIC SUBSTITUTIONS EN ROUTE TO CYCLIC TARGETS 4.1. Allylic Substitution in Combination with Ring Closing Metathesis (RCM)

Given the vinyl group, RCM is perhaps the most often employed reaction subsequent to an allylic substitution. The partner alkenyl group is usually introduced with the nucleophile. An important aspect of RCM is that it often proceeds without racemization on substrates bearing allylic stereogenic centers. The list of target compounds in Figure 4 demonstrates the considerable structural variety accessible by the combination of allylic substitution and RCM. 4.1.1. Allylic Alkylation. Early examples of the combination of allylic substitution and RCM are presented in Scheme 6.21 A fairly flexible preparation of cyclopentenones was developed through the use of the sodium salt of a Weinreb-type malonamide in conjunction with CuI and THT as additives. Saponification and decarboxylation of the products gave Weinreb-type amides that could be transformed into α,β-unsaturated ketones by the addition of alkenylmagnesium halides. Subsequent RCM led to a variety of chiral cyclopentenones. This procedure was applied in the total synthesis of the carbonucleoside 2′-methylcarbovir and the prostaglandin analogue TEI-9826. The group of Hartwig has developed allylic substitutions with silyl enol ethers as pronucleophiles. Among these, enol ethers derived from α,β-unsaturated ketones are interesting because a considerable level of complexity is introduced in the substitution step (Scheme 7). Liberation of the active nucleophile requires fairly complex reaction mixtures that are prone to induce side reactions and low dr. In the present example, KF/18-crown-6 was identified as an effective reagent. The resultant substitution product was directly suited for RCM to give cyclopentenones of which one was then transformed into ent-TEI-9826 (Scheme 7).22 Combining several stereoselective steps gives rise to products with enhanced enantiomeric excess due to double asymmetric induction. An example is presented in Scheme 8, in which a combination of an allylic alkylation and a Brown allylation that both proceeded with high stereoselectivity is described. As a consequence, the target compounds (+)-infecto- and (+)-cryptocaryone were obtained with >99% ee.23 A highlight in the field of allylic substitutions is Carreira’s divergent synthesis of the full set of stereoisomeric Δ9-tetrahydrocannabinols (Δ9-THC) (Scheme 9).24 Perfect dual asymmetric catalysis was realized by combining an Ir-catalyzed allylic substitution and an enamine type asymmetric organocatalysis. The results are all the more remarkable in view of the unusually sterically shielded allylic reaction center. RCM as the

4.2. Allylic Substitution and Subsequent Diels−Alder Reaction

Combining an allylic substitution with an RCM reaction is straightforward because the vinyl group itself is a given reactive site. The combination with a Diels−Alder (DA) reaction is less obvious but nevertheless is quite readily achieved through the transformation of the moiety introduced with the nucleophile. Chen and Hartwig28 have employed a silyl enol ether as a pronucleophile in order to produce an enone that could be transformed by a one-step silylation into a dienylic unit that in turn was combined with a dienophile to give an aryl group (Scheme 12). Stereochemical complexity is preserved in this synthesis. An impressive increase can be achieved with an intramolecular Diels−Alder reaction (IMDA). A pertinent example is provided by a synthesis of apiosporic acid that was carried out in our group (Scheme 13).29 Also in this case, the moiety introduced with the nucleophile was transformed into the dienylic part via four steps. A shorter route to a dienylic moiety was developed in syntheses of the hexahydroindene cores of the antibiotics indanomycin and stawamycin (Scheme 14).30 An α-sulfonylacetic ester was used as a pronucleophile to give allylic substitution products with 92−95% ee. Subsequent Krapcho reaction and E-selective Julia−Kocienski olefination furnished trienes that were suitable for selective hydroboration with 9-BBN and Suzuki−Miyaura coupling to give the diene/enoate precursor of the subsequent Lewis acid catalyzed IMDA reaction. This was controlled by a chiral auxiliary and proceeded, due to double asymmetric induction, with good to excellent diastereoselectivity and in situ removal of the protecting and the chiral auxiliary groups. The corresponding methyl ester furnished low yield and diastereoselectivity. 4.3. Suzuki−Miyaura Reaction in Syntheses of Alkaloids

The vinyl group of allylic substitution products is well suited for the combination with a RCM. As illustrated in the previous section, it serves similarly well as a C2 connector via hydroboration, usually with 9-BBN, and the Suzuki−Miyaura cross 2545


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Accounts of Chemical Research coupling. Both reactions are compatible with a wide variety of functional groups including vicinally substituted double bonds as was demonstrated above in conjunction with the allylic alkylation and DA reactions. More applications of this strategy have been used in alkaloid synthesis based on allylic amination (Scheme 15). A protecting group-free route to tetrahydroquinolines is described in Scheme 16.31 Another route to angustureine, based on Ir-catalyzed allylic substitution with o-vinylaniline and RCM, was developed by You et al.32

Hydroboration of an N-protected allylic amine followed by a Suzuki−Miyaura coupling and an intramolecular aza-Michael addition constitutes a broadly applicable route to trans-2,5disubstituted pyrrolidines. As an example, the synthesis of the pyrrolizidine alkaloid (+)-xenovenine is described in Scheme 17.33 The crucial aza-Michael reaction proceeded with very high E/Z-diastereoselectivity under kinetic control, with low selectivity under thermodynamic control. Reduction with DIBAL-H followed by a Wittig reaction and a reductive amination also gave good results.

Scheme 9. Stereodivergent Syntheses of Δ9-Tetrahydrocannabinols (THC) Based on Dual Catalysis with Phosphoramidite L6 and Hayashi−Jørgensen Organocatalyst HJ

Scheme 10. Synthesis of (S)-Nicotine Using Ir-Catalyzed Allylic Amination and RCM

Scheme 11. Synthesis of Alkaloids via Hydroxamic Acid Derivatives

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Accounts of Chemical Research As a more intricate application of this strategy, a five-step synthesis of the poison frog alkaloid cis-195A (pumiliotoxin C) was carried out, in which every bond-forming step was controlled by catalysis (Scheme 18).34 Key steps are an Ir-catalyzed allylic

amination and, for introduction of the methyl group at C-5, a Cu-catalyzed conjugate addition according to Alexakis. Because of double asymmetric induction, enantiomeric excess of the final product was very high (≥99% ee), while diastereoselectivity

Scheme 12. Ir-Catalyzed Allylic Substitution in Combination with a Diels−Alder Reaction

Scheme 13. Synthesis of Apiosporic Acid via Allylic Substitution and IMDA Reaction

Scheme 14. Ir-Catalyzed Allylic Alkylation in Combination with an IMDA Reaction

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4.4. Allylic Substitution Followed by a Carbonylation Reaction

Scheme 15. Various Structural Motifs Generated by Suzuki−Miyaura Coupling

Similar to the Diels−Alder reaction, carbonylation reactions are atom economic and are prone to fast buildup of molecular complexity (Scheme 19). Two corresponding syntheses have been reported. One example is a synthesis of (S)-nicotine (Scheme 20), which is significantly shorter than that based on the RCM (Scheme 10).35 The ring-closing step is a rhodium-catalyzed hydroaminomethylation, which is essentially a hydroformylation of an allylamine, followed by in situ condensation and reduction. Whereas the allylic amination proceeded with remarkably high selectivities, ring closure was swathed by the competing formation of the lactam (S)-nicotinine, which is also an alkaloid. This could be completely avoided with the use of the particularly bulky ligand Biphephos. Several years ago, the kainic acid biomedical reagent was in demand. This provided an incentive for the development of its total syntheses. Our synthesis is based on an Ir-catalyzed allylic amination with a propargylic amine, which proceeded with high enantioselectivity. Subsequent N-protection and intramolecular Pauson−Khand reaction furnished a cyclopentenone that was transformed into (−)-(R)-kainic acid via eight steps (Scheme 21).36

Scheme 16. Use of ortho-Iodoaniline as Nucleophile for Ir-Catalyzed Allylic Substitutions in Syntheses of Tetrahydroquinolines

4.5. Miscellaneous Cyclization Reactions

In addition to the systematic use of cyclization methods, several procedures have been employed ad hoc. The corresponding targets are listed in Figure 5. Formal syntheses of (+)-sertraline and (−)-preclamol relied on allylic substitutions with organozinc compounds (Scheme 22). The Alexakis group have investigated mainly arylzinc compounds formed in situ from Grignard reagents and ZnBr2/LiBr.37 Whereas enantioselectivities were moderate to high, regioselectivities were generally low. In application to the synthesis of (+)-sertraline, cross metathesis with methyl acrylate followed by copper-catalyzed reduction gave a known methyl γ,γ-diarylbutyrate that had previously been transformed by Friedel− Crafts cyclization into a tetralone en route to the target. Reformatsky type alkylzinc bromides have been successfully employed in type II Ir-catalyzed allylic alkylation by Carreira et al.38 Instead of branched allylic alcohols that would require

was only 5:1, requiring the removal of the minor isomer by chromatography. Complete control of diastereoselectivity for giving a diastereomeric alkaloid (trans-195A) can be achieved with the enantiomeric Cu catalyst.

Scheme 17. Ir-Catalyzed Amination as Basis of Syntheses of trans-2,5-Disubstituted Pyrrolidines

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Accounts of Chemical Research Scheme 18. Pumiliotoxin C via Ir-catalyzed Amination in Combination with Cu-Catalyzed Conjugate Additiona

a

TC = thiophene-2-carboxylate.

(−)-preclamol, a drug candidate with antipsychotic effects (Scheme 22). Piperidine formation was achieved by 2-fold SN2-type substitution. The Carreira group has reported a stereodivergent synthesis of (−)-paroxetine based on dual catalysis (Scheme 23). The piperidine ring was formed by an intramolecular Mitsunobu reaction.39a An earlier formal enantioselective synthesis of (−)-paroxetine based on an Ir-catalyzed allylic alkylation of methyl 4-fluorophenylallyl carbonate with dimethyl malonate was reported by Hamada et al.39b As a part of an extensive study of allylic aminations of benzimidazoles, imidazoles, and purines, Stanley and Hartwig40

Scheme 19. Carbonylation Reactions in Combination with Allylic Substitution Products

acidic conditions, Boc derivatives were used in conjunction with the Carreira catalyst. Most reactions proceeded with very high enantioselectivity, and branched products were obtained exclusively. This method has been used for the synthesis of Scheme 20. Synthesis of (S)-Nicotine via Hydroaminomethylation

Scheme 21. Total Synthesis of (−)-(R)-Kainic Acid via Ir-Catalyzed Allylic Amination

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Accounts of Chemical Research reported the synthesis of an intermediate of Bergman and Ellman’s synthesis of a JNK3 inhibitor (Scheme 24). They successfully reproduced a rhodium-catalyzed oxidative

Heck-type coupling to give an annulated cyclopentene in a single step.

5. INTRAMOLECULAR ALLYLIC SUBSTITUTIONS 5.1. Stereodiversity via Substrate and Catalyst Control

As outlined above, double asymmetric induction allows a significant enhancement of enantioselectivity and stereodivergency to be realized. Several examples involving substrate control in combination with catalyst controlled intramolecular allylic substitution to yield heterocycles were reported. The targets described in Schemes 25 and 26, piperidine and pyrrolidine alkaloids, display great stereochemical diversity. Thus, modular, stereodivergent syntheses are of interest. Stereogenic centers C2 and C3 of 2,6-substituted piperidines (Scheme 25) were set up by asymmetric allylic substitution and diastereoselective epoxidation, respectively. Intramolecular aminations with P(OPh)3 as a ligand showed that substrate control is weak. Indeed, the use of chiral ligands L1 and ent-L1

Figure 5. Targets assessed by allylic substitution followed by various cyclization reactions.

Scheme 22. Ir-Catalyzed Alkylations with Organozinc Reagents as Nucleophiles

Scheme 23. Formal Synthesis of (−)-Paroxetine Based on Dual Catalysis

Scheme 24. Ir-Catalyzed Amination Followed by CH Activation Leading to Ring Closure

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Accounts of Chemical Research Scheme 25. Stereodivergent Synthesis of Piperidine Alkaloids

with useful selectivity. Intramolecular allylic substitutions with O-nucleophiles also gave good results, though target directed syntheses were not pursued to the best of our knowledge.41,43

Scheme 26. Stereodivergent Syntheses of Pyrrolidine Alkaloidsa

5.2. Polyene Cyclizations

a

Carreira’s type II intermolecular allylic substitutions with olefins as nucleophiles are presented in Scheme 4a. The intramolecular version was first successfully realized in the form of polyene cyclizations terminated by an aryl group.44a Later other terminating nucleophiles were identified. The first target oriented application was a synthesis of the labdane-type diterpenoid asperolide C (Scheme 27).44b The high electrophilicity of the proposed allylic intermediate renders this method a supplement to the biomimetic polyene cyclization initiated by carbocation formation. Li et al. have achieved the total syntheses of the terpenoids taiwaniadduct B, C, and D by the coupling of enantiomerically pure (>99% ee) components that had been prepared by application of polyene cyclization with aryl as well as OH termination (Scheme 28).45a Using this strategy, they also completed the first total synthesis of mycoleptodiscin A, a structurally unusual indolosesquiterpenoid possessing an orthobenzoquinone motif.45b

Ns = 2-nitrobenzenesulfonyl.

led to cis- and trans-diastereomeric piperidines, respectively, with >97:3 diastereoselectivity and >99% ee. In other examples, substrate control also slightly favored the cis-isomer. Total syntheses of several prosopis, spruce, and dendrobate alkaloids were carried out using this approach.41 Similar results were obtained for corresponding pyrrolidines (Scheme 26).42 However, reactions were generally slow, and a high load of catalyst was required. In addition, in unpublished work of our group, substrate control was found to favor the transdiastereomers. Nevertheless, catalyst control enforced generation of both trans- and cis-2,5-substituted pyrrolidines, such as those found in alkaloids (+)-bulgecinine and (+)-preussin,

5.3. Arenes as Nucleophiles: Friedel−Crafts-type Reactions, Aminations, and Dearomatizations

Electron-rich arenes, notably indoles, pyrroles, and phenols, are excellent nucleophiles in Ir-catalyzed intramolecular allylic substitutions. Their investigation has been particularly pursued by You et al. Here, space limitations only permit us to provide a small impression of the enormous amount of work. This was mostly carried out with indoles. These display high nucleophilicity in Friedel−Crafts-type reactions, preferably at C3, even in competition with nitrogen. A typical example is given in Scheme 29a.46 In contrast, nitrogen was the nucleophilic center in an analogous 2551


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Accounts of Chemical Research Scheme 27. Ir-Catalyzed Polyolefin Cyclization in a Synthesis of Asperolide C

Scheme 28. Applications of the Carreira Ir-Catalyzed Polyolefin Cyclization

Scheme 29. Friedel−Crafts-type Ir-Catalyzed Allylic Alkylationsa

a

DMB = 2,4-dimethoxybenzyl.

cyclization with a pyrrole derivative47a that had previously served as a starting material of alkaloid syntheses (Scheme 29b).47b

An intramolecular type II Ir-catalyzed Friedel−Crafts alkylation of an indole was utilized in the total synthesis of the stereochemically 2552


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example containing an unusual reaction course in the total synthesis of (−)-debromoflustramine B is described in Scheme 31.50 Preference for the linear regioisomer in a type II allylic substitution is unusual. Furthermore, the marked discrimination of the enantiotopic faces of the prochiral nucleophile is notable. Based on a dearomatization reaction, Yang et al. accomplished the first enantioselective total synthesis of the alkaloid (−)-aspidophylline A (Scheme 32).51 An enantioselective type II allylic alkylation of an indole followed by an in situ nucleophilic addition at the resultant iminium ion gave a 5:1 mixture of inseparable diastereomers. Following an oxidative degradation, a diastereomerically pure ketone was obtained, which was an excellent starting material for eight further steps to the target. You et al. reported allylic dearomatization reactions of electron-poor arenes, such as pyridines and quinolines, by the initiation of a reaction cascade with the nitrogen center followed by a deprotonation step enabled by an appropriate EWG (Scheme 33).52 The value of this method was demonstrated by the formal synthesis of (+)-gephyrotoxin.

complex alkaloid (−)-alstoscholarisine (Scheme 30). The allylic substitution proceeded with excellent enantioselectivity. In the subsequent part of the route, a highly diastereoselective tandem 1,4addition-aldol reaction was applied.48 A dearomatization reaction can be realized if an electrophilic addition at an aromatic ring occurs at a carbon atom bearing a substituent. To date, very few natural product targets have been addressed using this otherwise broadly pursued concept.49 An Scheme 30. Total Synthesis of (−)-Alstoscholarisine A

6. CONCLUSION Whereas the Ir-catalyzed allylic substitution was introduced as late as 1997, two completely different versions have been established, one using linear allylic esters and the other using Scheme 31. Ir-Catalyzed Asymmetric Dearomatization and Application

Scheme 32. Application of a Dearomatization Reaction in Total Synthesis of (−)-Aspidophylline Aa

a

FFC = flash column chromatography. 2553


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Scheme 33. Formal Synthesis of (+)-Gephyrotoxin

branched allylic alcohols, with both yielding branched substitution products with high regio- and enantioselectivity. Cyclization reactions do not require low concentration. Very broad scope with respect to the allylic substrate as well as the nucleophile and convenient reaction conditions have allowed a considerable number and variety of target oriented applications.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Günter Helmchen: 0000-0003-3125-4313 Notes

The authors declare no competing financial interest. Biographies Jianping Qu received Ph.D. at Shanghai Institute of Organic Chemistry and was an Alexander von Humboldt Fellow in the Helmchen laboratory. She is currently a Principle Investigator at Nanjing Tech University. Günter Helmchen received his Dr. sc. techn. under the mentorship of V. Prelog at the ETH Zürich. He then moved to the TU Stuttgart for a habilitation (1980). Subsequently, he became associate and full professor at the universities of Würzburg and Heidelberg, respectively. Today, he is a Senior-Professor at the latter institution.

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ACKNOWLEDGMENTS This work was supported by the Deutsche Forschungsgemeinschaft (SFB 623) and the Dr. Rainer Wild-Stiftung. J. Qu thanks the Alexander von Humboldt Foundation for a scholarship and the National Natural Science Foundation of China NSFC (21602001). We thank Professor J.A. Raskatov, UC Santa Cruz, for linguistic improvement of the conspectus.

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REFERENCES

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