Stereodivergence in Asymmetric Catalysis - Journal of the American

Perspective pubs.acs.org/JACS

Stereodivergence in Asymmetric Catalysis Simon Krautwald† and Erick M. Carreira* Eidgenössische Technische Hochschule Zürich, 8093 Zürich, Switzerland use of two distinct chiral catalysts, Cat1 and Cat2, each of which exerts complete and independent control over the configuration of one of the stereogenic centers. Access to any given product stereoisomer C is possible from the same set of starting materials (A and B) under otherwise identical reaction conditions by selection of the appropriate pairwise combination of catalyst configurational isomers. The first part of this Perspective discusses the advantages and opportunities associated with a stereodivergent approach to synthesis, and the second part summarizes the state of the art, placing particular focus on the concept of stereodivergent dual catalysis and its application in synthesis. We conclude by providing an outlook of how we anticipate the field may develop in the future. In order to understand the concept of stereodivergent catalysis, it is important to highlight its distinction from nonstereodivergent approaches to asymmetric catalysis. A representative example of a reaction in which a single catalyst controls both the absolute and relative configuration of two stereocenters is the direct cross-aldol reaction of aldehydes reported by Northrup and MacMillan.3 As shown in Scheme 2,

ABSTRACT: This Perspective presents an overview of catalytic enantioselective transformations that allow convenient access to all stereoisomers of a given product with multiple stereogenic centers. Particular focus is placed on discussion of the concept of stereodivergent dual catalysis and its application in target-oriented synthesis. The potential of this concept in the development of new transformations as well as implications for achieving stereochemical diversity in library design and diversityoriented synthesis are also discussed.

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INTRODUCTION Despite remarkable progress in the field of asymmetric catalysis over the past 30 years, complete control of both absolute and relative configuration in catalyst-controlled reactions that form multiple stereogenic centers remains a challenge.1 While high selectivity for one diastereomer may be achieved in a given transformation, access to the complementary diastereomer(s) is usually not possible, so that the reaction is not stereodivergent.2 In the context of asymmetric synthesis, a stereodivergent process is one that allows access to any given stereoisomer of a product with multiple stereocenters from the same set of starting materials. Ideally, such a process would use the same set of catalysts and reaction conditions to access the various diastereomers. However, in the limited number of methods that allow preparation of the full complement of stereoisomeric products from a single set of precursors, stereodivergence is typically the result of ad hoc adjustment of the structure of the catalyst or reaction conditions.2c Hence, the strategies developed to this end cannot readily be applied to the design of other stereodivergent transformations. In 2013, our laboratory introduced an approach for the selective synthesis of all stereoisomers of a molecule with two stereogenic centers termed stereodivergent dual catalysis (Scheme 1).2a,b In general terms, this involves the simultaneous

Scheme 2. Proline-Catalyzed Direct Cross-Aldol Reaction of Aldehydes

Scheme 1. Concept of Stereodivergent Dual Catalysis anti-aldol product (R,R)-4 was prepared in >99% enantiomeric excess (ee) and 24:1 diastereomeric ratio (dr) by L-prolinecatalyzed reaction of propanal (1) and iso-butyraldehyde (2). As with any catalytic enantioselective transformation, the enantiomeric product, (S,S)-4, can be synthesized in the same yield and selectivity by using the enantiomeric form of the catalyst, (R)-3. However, the corresponding syn-isomers cannot Received: December 29, 2016 Published: April 6, 2017 © 2017 American Chemical Society

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DOI: 10.1021/jacs.6b13340 J. Am. Chem. Soc. 2017, 139, 5627−5639

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Journal of the American Chemical Society be prepared selectively by this method. According to the definition set forth above, this remarkable aldol addition reaction is thus not stereodivergent. This limitation is not restricted to the aldol addition in Scheme 2; in fact, many asymmetric transformations that create multiple stereocenters allow access to only one enantiomeric couple of product diastereomers.2 In this respect, modern screening strategies are partly responsible, because the ideal reaction processes are optimized for high diastereo- and enantiocontrol. Stereodivergence in asymmetric catalysis is a matter of practical consequence and a worthwhile objective. Its relevance is highlighted in the following section by discussion of two syntheses of biologically active molecules. For example, when the isolation and structural characterization of acyltetramic acid natural product β-lipomycin (5, Scheme 3) were reported more

Scheme 4. Synthesis of Both Diastereomers of Mefloquine via Borylative Alkene Isomerization

Scheme 3. Synthesis of All Stereoisomers of Key Intermediate 6 en Route to β-Lipomycin (5)

isomerization step was directly treated with aldehyde 14 to give protected amino-alcohol 15 in 99% ee. Hydrogenation in the presence of Crabtree’s catalyst furnished (R,R)-16, which represented the branch point in the synthesis of the two diastereomers of mefloquine. While cleavage of the Boc protecting group gave (−)-threo-mefloquine, access to the corresponding diastereomer required inverting the configuration of the hydroxyl-bearing stereocenter through an oxidation/reduction sequence ((R,R)-16 to (S,R)-16), adding two steps to the synthesis of (+)-erythro-mefloquine. In both of the examples discussed above, more streamlined syntheses would have been possible had various stereodivergent methods been available for the synthetic steps in which stereocenters are set in a pairwise manner. While the syntheses of β-lipomycin and mefloquine were undoubtedly effective, the two case studies highlight that additional labor and time had to be invested in designing and implementing a second route to access a diastereomeric target. Access to an advanced intermediate with two stereocenters (e.g., 6) by a single stereodivergent method could, in principle, allow the synthesis of all targeted stereoisomers to be completed via a single route, with an attendant increase in efficiency and sustainability. Both examples also illustrate how stereodivergent synthesis can impact drug discovery. The absolute and relative configuration of a given molecule directly influence its biological activity.7 As such, evaluation of the therapeutic as well as toxicological properties of all stereoisomers of a drug candidate are required by regulatory agencies as a routine part of the lead optimization process.7 In addition, access to all stereoisomers of a drug

than 40 years ago,4 the configuration of the stereogenic centers in the polyene side chain (highlighted in blue) could not be determined using the available spectroscopic methods and chemical degradation studies. Hofferberth and Brückner recently reported the synthesis of the four relevant stereoisomers of 5 and thus identified the configuration of the two stereocenters in the natural product. The authors’ strategy rested on using the four stereoisomers of (E)-vinyl iodide 6 as key intermediates (Scheme 3).5 The isomers (R,S)-6 and (S,R)6 were prepared from the corresponding anti-aldols 4, which in turn were obtained via the proline-catalyzed asymmetric aldol reaction highlighted in Scheme 2. The two syn-isomers of (E)6, however, were accessed via an auxiliary-based strategy involving Evans aldol reaction of 7 with isobutyraldehyde (2). The syn-aldol products 8 were then advanced to the corresponding vinyl iodides in a seven-step sequence. Racemic erythro-mefloquine is used as an antimalarial under the trade name Lariam, and while both enantiomers are active against the malaria parasite, (−)-erythro-mefloquine is known to cause psychotropic side effects. In 2013, Ding and Hall reported the synthesis and evaluation of all four stereoisomers of mefloquine (9, Scheme 4) for antimalarial activity.6 Hall’s synthesis featured a tandem process involving Pd-catalyzed borylative alkene isomerization and aldehyde allylation. The 3:1 mixture of boron compounds 12 and 13 produced in the 5628


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Journal of the American Chemical Society candidate may be necessary for use as authentic standards in assaying purity associated with a manufacturing process. As such, stereodivergent synthesis methods can reduce the time and effort required for preparation of the various stereoisomers of a lead compound. Stereodivergence and Polypharmacology. It is now well-established that certain drugs interact with more than one biological target, a phenomenon referred to as polypharmacology.8 While unintended multi-target interactions can lead to side effects, deliberate modulation of a group of targets by a molecule can result in an improved therapeutic profile.8b Study of a drug candidate’s polypharmacology thus is not only important from the perspective of drug safety, but it also offers opportunities for developing more effective treatments for human disease. Stereodivergent synthesis can make a contribution in this area by enabling access to small molecule drug stereoisomers whose on- and off-target interactions can then be studied (Scheme 5).

Scheme 6. Phosphoramide-Catalyzed Cross-Aldol Reaction

Scheme 5. General Schematic Drawing Showing Polypharmacology of Drug Stereoisomers

Scheme 7. Merck’s Synthesis of β,β′-Diarylamino Acid Derivatives

Researchers at Merck reported a three-step process for the synthesis of all stereoisomers of β,β′-diaryl-α-amino acid derivatives of type 21 (Scheme 7).11 Starting from ketones of

Catalytic asymmetric reactions are typically optimized to favor formation of a single enantio- and diastereomer (e.g., Scheme 2). Therefore, adapting catalysts or reaction conditions to achieve a reversal of the sense of diastereoselectivity to favor formation of the complementary diastereomer can be challenging. The following section presents specific examples of catalytic stereodivergent transformations, and rather than comprehensively reviewing each individual case reported in the literature, we focus on key examples that are representative of a given approach or strategy.

type 22, the corresponding enol tosylates (E)-23 and (Z)-23 were prepared stereoselectively by variation of base, solvent, and temperature. The second aryl group was then introduced by Suzuki−Miyaura cross-coupling, and asymmetric hydrogenation of olefins 24 furnished the desired β,β′-diaryl-α-amino acid derivatives. This effective approach combined a robust stereocontrolled synthesis of enol tosylates with two of the most reliable and well-developed reactions currently available to synthetic chemists, in order to deliver products with commonly used functional groups (CO2Me, NHBoc) in three steps from 22. The Merck example in particular emphasizes the power of leveraging alkene geometry to access all stereoisomers of a target molecule. However, this study required identification of two distinct protocols for stereoselective enolization of the ketone starting materials. Although the approach was effective, the need for more than one starting material can complicate synthetic efforts since the preparation of certain precursors may be difficult, and in any case requires the expense of additional time and effort. The following section features discussion of a few key examples of stereodivergent transformations that rely on a single set of starting materials. Catalyst Redesign. Redesign of catalyst structure, in some cases guided by a hypothesis on the origin of stereocontrol, has been used as a strategy to develop stereodivergent transformations. In this context, work by Deng and co-workers on

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STRATEGIES FOR ACHIEVING STEREODIVERGENCE Change in Structure of Starting Material. The sense of diastereoselectivity of a transformation can in some cases be altered by changing the structure of the starting material(s). Although the definition of stereodivergence given in the introduction specified that the same set of starting materials be used, this approach is widely employed, and select examples are briefly discussed here for context. Transformations that are rendered stereodivergent through structural modification of the substrate have been termed pseudo-diastereodivergent.2c For instance, control of the geometry of an enolate or enolate equivalent in carbonyl, imine, and conjugate addition reactions can be used to influence diastereoselectivity.9 A representative example is the phosphoramide-catalyzed addition of trichlorosilyl enolates to aldehydes reported by Denmark (Scheme 6).10 While reaction of (E)-18 and benzaldehyde (17) catalyzed by 19 gave anti-product (R,S)-20, the use of isomeric enol silane (Z)-18 resulted in formation of the diastereomer, (S,S)-20. 5629


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Journal of the American Chemical Society cinchona alkaloid derivative-catalyzed conjugate addition of αcyanoketones to α-chloroacrylonitriles is of particular note (Scheme 8). An initial report documented the highly syn-

Scheme 9. Stereodivergent, Amine-Catalyzed 1,4-Addition of Thiols to α,β-Unsaturated Ketones

Scheme 8. Stereodivergent Conjugate Addition of αCyanoketones to α-Chloroacrylonitriles

selective synthesis of (R,S)-29 and (S,R)-29 through the use of pseudo-enantiomeric phenanthryl-protected alkaloids 27 as bifunctional catalysts.12 A transition state model involving an array of hydrogen bonds between the catalyst, ketone, and acrylonitrile was proposed to rationalize the observed stereochemical outcome.12 The authors hypothesized that a different spatial arrangement of the components of this network of noncovalent interactions might enable the synthesis of the complementary diastereomer. Indeed, the ensuing study resulted in identification of 9-thiourea-substituted cinchona alkaloids 28 as suitably modified catalysts for the highly stereocontrolled synthesis of anti-isomers (S,S)-29 and (R,R)29.13 As shown in Scheme 8, all four stereoisomers of adduct 29 were prepared with outstanding stereoselectivity (93−99% ee, 9:1−20:1 dr) simply by selecting the appropriate cinchona derivative (Q-27/QD-27 and Q-28/QD-28). One feature that distinguishes this work from most other examples highlighted in this Perspective is that products with two non-adjacent stereocenters (in 1,3-relationship) are accessed selectively. Change of Reaction Conditions. Select reports have described how the sense of diastereoselectivity enforced by a catalyst can be altered through additives/co-catalysts and solvent effects. In this respect, Melchiorre and co-workers have demonstrated that the sense of diastereoselectivity induced by a single chiral catalyst can be controlled by the nature of the acid and solvent. As shown in Scheme 9, cinchona alkaloids 32 and 33 were found to catalyze the asymmetric 1,4addition of benzylthiol (31) to α,β-unsaturated ketone 30.14 When the reaction was run in chloroform in the presence of 2fluorobenzoic acid, catalyst 32 promoted formation of synisomer (S,R)-35. By contrast, anti-stereoisomer (R,R)-35 was the major product when the 1,4-addition was performed in acetone in the presence of chiral phosphoric acid 34. The remaining two stereoisomers were synthesized using pseudoenantiomeric catalyst 33. The fact that a single chiral catalyst (i.e., 32) could be “re-purposed” simply by choice of an

appropriate additive and solvent is a highly remarkable aspect of this work. The authors tentatively proposed that the use of different acids and solvents resulted in iminium ion intermediates with distinct geometries, thus leading to different stereochemical outcomes. Change of Ligand. An approach that is closely related to the catalyst redesign strategy exemplified by Deng’s report entails changing the ligand in a transition metal-catalyzed transformation. In this context, Maulide and co-workers have developed a method for the stereodivergent synthesis of cyclobutene derivatives through palladium-catalyzed allylic substitution. Specifically, Pd/phosphoramidite-catalyzed reaction of racemic lactone 36 with sodium diethylmalonate 37 resulted in formation of the cis-isomer of cyclobutene 40 in 96% ee and >95:5 dr (Scheme 10).15 The corresponding transisomer was obtained with equally impressive stereoselectivity when phosphine-oxazoline ligand 39 was used instead of 38. The authors’ initial mechanistic experiments suggested that the formation of cis-40 was a consequence of a double inversion, as is typical for Pd-catalyzed allylic substitutions with stabilized nucleophiles. Furthermore, the mechanistic experiments suggested that a change of mechanism may be responsible for formation of trans-40 with the Pd/39 catalyst system, wherein ionization of lactone 36 proceeded, unusually, with retention of configuration. Change of Metal Cation. Another strategy used for achieving stereodivergence involves the use of different metal cations with the same chiral ligand. Shibasaki and co-workers have developed a stereodivergent method for the addition of isothiocyanato esters to ketimines, as illustrated by the two reactions shown in Scheme 11. The different stereochemical outcomes of the two reactions highlight that the sense of diastereoselectivity induced by chiral ligand 43 was controlled by the metal cation used. While magnesium-catalyzed addition 5630


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Journal of the American Chemical Society Scheme 10. Stereodivergent Pd-Catalyzed Synthesis of Cyclobutenes

Scheme 12. Strategy of Cycle-Specific Amine Catalysis in Formal Hydrofluorination of Enals

Scheme 11. Stereodivergent Mannich-Type Reaction to a chiral α,β-unsaturated iminium ion formed from enal 45 and amine catalyst (R)-46. Following complete consumption of 47, NFSI (50) and the appropriate enantiomer of amine catalyst 49 were added to promote catalyst-controlled αfluorination. Crucially, both diastereomers of fluorinated aldehyde 51 are accessible with a high degree of stereocontrol through this sequential approach to catalysis, in which each of the two catalysts controls the configuration of one of the stereogenic centers. The remaining two stereoisomers of 51 are readily accessed by using (S)-46 in the initial reduction step. This elegant demonstration of the power of sequential catalysis provided a blueprint for the development of other predictably stereodivergent transformations. Indeed, MacMillan and coworkers subsequently disclosed methods for a wide range of transformations based on this cascade catalysis strategy, including formal hydroamination, hydro-oxidation, and amino-oxidation of enals.22,23 A similar approach for the synthesis of all stereoisomers of a set of 1,3-amino alcohols involving copper-catalyzed enantioselective hydrosilylation of enones followed by catalystcontrolled diastereoselective formal hydroamination was reported by Buchwald and co-workers in 2016 (Scheme 13).24 The hydrosilylation step enantioselectively produced allylic alcohols 53, which were isolated when a ligand switch for the subsequent step was required. Copper-catalyzed formal hydroamination then gave the 1,3-amino alcohol products 54. By harnessing both catalyst control and the stereospecific nature of the hydroamination step, all eight stereoisomers of amino alcohol 56 were prepared from either (E)-55 or (Z)-55

of 41 to protected ketimine 42 furnished syn-isomer (S,R)-44, the corresponding strontium-catalyzed transformation proceeded with anti-selectivity to give (R,R)-44 (Scheme 11).16 Thus far, the discussion has focused on approaches involving ad hoc changes to reaction conditions or catalyst systems as a means of rendering a given reaction stereodivergent. Although these methods were effective in the cases described, they lack the generality or predictability that would allow their application to the development of other stereodivergent transformations. This is also the case for a number of examples of stereodivergence based on the ad-hoc approaches discussed above (structural adjustment of the catalyst system,17 and the use of different additives18,19 or solvents20) that are not specifically discussed in this Perspective.2c Cascade (Sequential) Catalysis. As an alternative to these disparate approaches, in 2005, MacMillan and co-workers implemented a strategy of two distinct catalysts acting sequentially to control the configuration of two stereocenters in the formal hydrofluorination of enals (Scheme 12).21 In contrast to the instances covered in the preceding sections, this approach is characterized by predictable control over the sense of diastereoselectivity. The first step of the transformation involved 1,4-addition of hydride, supplied by a Hantzsch ester,

Scheme 13. Cascade-Catalysis Strategy for Synthesis of 1,3Amino Alcohols

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Journal of the American Chemical Society

by MacMillan and Buchwald, a chiral intermediate B is formed in a reaction of A catalyzed by Cat1. Upon completion of the first reaction, the second catalyst, Cat2, activates B, which undergoes a catalyst-controlled diastereoselective transformation to give C. In principle, a cascade approach can be developed to incorporate more than two catalysts. In contrast to the sequential operation of catalysts in the cascade approach, the concept of dual catalysis (also referred to as synergistic or cooperative catalysis) relies on simultaneous activation of two substrates by two distinct catalysts. In such a case, product C is formed directly from the reaction of the resulting activated intermediates (Cat1-A and Cat2-B, Scheme 15).25 While many dual-catalytic reactions that rely on one chiral and one achiral catalyst have been developed,25 transformations involving simultaneous use of two chiral catalysts have received relatively little attention. In this context, Jacobsen and coworkers reported a dual-catalyst system consisting of 62 and 63 to enable the highly enantioselective addition of cyanide to unsaturated imides in up to 97% ee (Scheme 16).26 Control

(Scheme 14). This example is particularly impressive since it involves the creation of three contiguous stereocenters using a single copper/bisphosphine catalyst system. Scheme 14. Synthesis of All Stereoisomers of Amino Alcohol 56

Scheme 16. Cooperative Use of Two Chiral Catalysts in Enantioselective 1,4-Addition of Cyanide

experiments established that both metal complexes were required for the transformation to proceed and that the enantioselectivity was influenced by the absolute configuration of both ligands. Although the transformation shown in Scheme 16 generated only one stereocenter, it represented an early example of simultaneous activation of nucleophile and electrophile by two distinct enantiopure catalysts. In an additional salient example of substrate activation by two enantiopure catalysts, Jørgensen reported a method based on concurrent use of a cinchona alkaloid and a copperbisoxazoline complex to effect addition of nitro-esters to imines (Scheme 17).27 The authors proposed that the cinchona alkaloid activated the nitro-ester, while the copper complex activated the imino-ester toward addition of the nucleophile. Specifically, reaction of ester 64 and imine 65 in the presence of catalytic amounts of quinine and Cu complex (R)-68 resulted in formation of 69 in 98% ee and 14:1 dr. The same reaction run with quinidine (67) instead of quinine was reported to predominantly give the same diastereomer of the product, albeit with slightly diminished selectivity. As a result, the transformation depicted in Scheme 17 is not stereodivergent. Nevertheless, these two examples demonstrate that simultaneous activation of two substrates through the action of two distinct, enantiopure catalysts has considerable potential in asymmetric synthesis.

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DUAL CATALYSIS A diagram summarizing the general features of cascade catalysis is shown at the top of Scheme 15. In the processes developed Scheme 15. Schematic Representation of the Concepts of Cascade Catalysis and Dual (Synergistic/Cooperative) Catalysis

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C could be accessed at will through selection of the suitable pairwise combination of amine catalyst and (P,olefin) ligand enantiomers. In the stereodivergent dual-catalytic approach described above and visualized conceptually in Scheme 18, the catalysts control the two stereochemical outcomes simultaneously and independently of one another. These key features distinguish the approach from the sequential catalysis strategy, which involves two catalysts controlling stereochemical outcomes one af ter the other. Since the creation of the second stereogenic center is a catalyst-controlled diastereoselective reaction of a chiral substrate, which is typically subject to matched/mismatched effects, the first catalyst indirectly influences the stereoselectivity of the second step.1 Successful application of this approach to dual catalysis was demonstrated in the α-allylation of branched aldehydes (Scheme 19). An iridium complex bearing (P,olefin) ligand

Scheme 17. Jørgensen’s Dual-Catalytic Addition to Imines

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STEREODIVERGENT DUAL CATALYSIS Our laboratory has been studying direct enantioselective allylic substitutions of allylic alcohols in the presence of an iridium/ (P,olefin) ligand complex and Brønsted or Lewis acid promoters.28 In the context of this research program, we envisioned that the putative electrophilic π-allyliridium intermediate central to these transformations (I) might be intercepted by an enantiopure enamine (II) to afford (after hydrolysis) γ,δ-unsaturated aldehyde C (R=H,Scheme 18). The requisite chiral enamines could be readily derived in situ from the corresponding aldehydes A and a suitable amine catalyst. In principle, the simultaneous activation of the aldehyde A and alcohol B substrates by two distinct catalysts would enable independent control of the configuration of both stereogenic centers in the product. As such, any given product stereoisomer

Scheme 19. Stereodivergent Dual Ir/Primary AmineCatalyzed α-Allylation of Hydratropaldehyde

Scheme 18. Stereodivergent Dual Catalysis As Envisioned for Dual Amine/Ir-Catalyzed α-Allylation of Aldehydes

73 and either of the pseudo-enantiomeric cinchona alkaloidderived primary amines 74 and 75 were used to activate allylic alcohol 70 and aldehyde 71, respectively. In the presence of trichloroacetic acid as promoter, all four stereoisomers of 2methyl-2,3-diphenylpent-4-enal 72 were accessed in good yields (71−80%) and in excellent enantio- and diastereoselectivities (>99% ee, 15:1 to >20:1 dr).29 Importantly, this process allowed the configuration of the two stereogenic centers in 72 to be controlled at will by selection of the appropriate combination of enantiomer of 73 and amine catalyst pseudoenantiomers 74/75. The reaction conditions otherwise remained unchanged. Scheme 18 illustrates the defining feature of the concept of stereodivergent dual catalysis, namely that two catalysts independently induce stereoselectivity at their respective stereocenters. In our working model, the key to achieving a high degree of stereodivergence was the use of two catalysts that are capable of effectively shielding opposite diastereofaces of their respective substrates, thereby allowing 5633


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Journal of the American Chemical Society the two coupling partners to come together in highly stereocontrolled fashion, as illustrated for intermediates I and II in Scheme 18. Bhaskararao and Sunoj subsequently reported a computational study on the origin of stereodivergence in the transformation shown in Scheme 19.30 In addition to investigating the activation of aldehyde and alcohol as enamine and π-allyliridium, respectively, the authors presented an indepth analysis of the C−C bond-forming transition states. A key finding was that both enantiomers of allylic alcohol 71 yielded a single diastereomer of a reactive allyliridium complex when a given enantiomer of ligand 73 was used. The configuration at the β-carbon of product 72 thus was set in the formation of the π-allyl species. However, transition-state modeling showed that the diastereoselectivity of the reaction was controlled in the C−C bond-forming step. The quinoline ring was shown to play an important role by stabilizing the transition state through a π-stacking interaction with the phenyl ring of the π-allyliridium when (R)-73 and 74 were used, as illustrated in Scheme 20.31 This model accurately predicted formation of (R,R)-72 as the major product stereoisomer.

Scheme 21. Stereodivergent Dual Ir/Primary AmineCatalyzed α-Allylation of Hexanal

of a stereodivergent approach to catalysis in the context of target-oriented synthesis. We specifically targeted Δ9-tetrahydrocannabinol (79, Scheme 22) since both trans-isomer (R,R)-

Scheme 20. Schematic, Simplified Representation of the Computed Transition State Leading to Formation of (R,R)72a

Scheme 22. Retrosynthetic analysis of Δ9-THCs

a

Adapted from ref 30.

Importantly, the lowest-energy transition state identified for the reaction involving (R)-73 and pseudo-enantiomeric amine 75 gave rise to the diastereomeric product (S,R)-72, in line with the experimental findings reported previously. In this diastereomeric transition structure, the quinoline was shown to engage in a C−H···π interaction with the phosphoramidite (not shown). The study by Sunoj emphasized how computational methods may aid in understanding the factors governing stereocontrol and stereodivergence when two enantiopure catalysts are used simultaneously. Accordingly, mechanistic insights obtained through computational studies may guide the development of novel stereodivergent dual-catalytic transformations.32 The scope of the dual Ir/amine-catalyzed α-allylation was subsequently expanded to include linear aldehydes. Using Jørgensen/Hayashi catalyst 78 in the presence of dimethylhydrogen phosphate as promoter, all four isomers of γ,δunsaturated aldehyde 77 were obtained in >99% ee and 7:1 or >20:1 dr (Scheme 21).33 The development of a stereodivergent allylation of linear aldehydes presented the opportunity to demonstrate the power

79 and cis-isomer (S,R)-79 are natural products. Both diastereomers could be traced back to aldehyde 80 and allylic alcohol 81 by retrosynthetic analysis. The concept of retrosynthetic analysis and the logic of chemical synthesis upon which it is based have long been fundamental to the practice of organic synthesis.34 One of the central tenets of retrosynthetic analysis is that the type of molecular complexity inherent to a target governs the strategy chosen for its synthesis. This complexity comes in a number of forms, and can be derived from skeletal complexity, the number or type of functional groups (such as a high degree of oxygenation), or stereochemical intricacy.34,35 Stereodivergent dual catalysis can be viewed as a design principle for retrosynthetic analysis of systems in which the full complement of stereoisomers is targeted. In the forward sense, this application entailed an initial dual-catalytic stereodivergent step followed by a uniform sequence of steps by which each of the four stereoisomers resulting from the initial step would be advanced to the four stereoisomers of Δ9-THC. 5634


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Scheme 24. Synthesis of the Four Stereoisomers of Δ9-THC by a Uniform Sequence of Stepsa

Through dual Ir/amine-catalyzed reaction of 80 and 81, all four stereoisomers of 82 were prepared in comparable yield, at least 15:1 dr, and >99% ee (Scheme 23).36 Scheme 23. Stereodivergent Dual Ir/Amine-Catalyzed Synthesis of Aldehyde Intermediate 82

Each of the four stereoisomers of 82 was then subjected to the same sequence of steps, culminating in the total synthesis of the four stereoisomers of Δ9-THC (Scheme 24).36 In contrast to traditional methods for accessing a diastereomeric series of products (as described in the Introduction of this Perspective), stereodivergent dual catalysis offers a streamlined approach to target-oriented synthesis. Scheme 25 summarizes the characteristics of the two strategies. Protected α-hydroxy and α-aminoaldehydes37 as well as α,βunsaturated aldehydes38 also participated in dual Ir/aminecatalyzed allylations, as shown by our group and that of Jørgensen, respectively (Scheme 26). The work on α- and γ-allylation of aldehydes described above established that stereodivergent processes involving an organocatalyst and a metal catalyst are feasible and display remarkable generality across different classes of substrate and organocatalyst. The power of the concept of dual catalysis, however, rests in the notion that essentially any combination of two catalysts may be used to promote a given reaction, as long as they are compatible with each other and the substrates used.25 This considerably increases the number of possibilities for the development of novel stereodivergent reactions. In this context, Zhang and co-workers recently reported the first example of stereodivergent dual catalysis involving two metal catalysts (Scheme 27).39 Hydroxyketone 90 was activated by formation of a zinc-ProPhenol complex, with the five-membered chelate involving the two oxygen atoms of the substrate ensuring that an enolate of well-defined geometry forms. According to the authors’ hypothesis, such a zinc enolate might react with a πallyliridium complex of phosphoramidite ligand 94. In analogy to the previous examples of stereodivergent dual catalysis, all four isomers of ketone 92 were prepared from the same set of starting materials by selection of the appropriate catalyst combination under otherwise identical conditions. The results reported by Zhang illustrate that reactions involving dual activation by two metal complexes are also amenable to stereodivergent catalysis, and thus considerably extended the

a

Reagents and conditions: (a) Grubbs’s second-generation catalyst (3 mol %), CH2Cl2, rt, 92% for (S,S)-83, 87% for (R,S)-83, 90% for (S,R)-83, 85% for (R,R)-83; (b) NaClO2 (2.3 equiv), NaH2PO4 (2.0 equiv), 2-methyl-2-butene (30 equiv), t-BuOH/H2 O, rt; (c) Me3SiCHN2 (1.1 equiv), C6H6/MeOH (1:1), 0 °C, 66% for (S,S)84, 60% for (R,S)-84, 61% for (S,R)-84, 65% for (R,R)-84; (d) MeMgI (10 equiv), Et2O, 0 to 160 °C, ambient pressure to 150 mmHg; then addition of ZnBr2, MgSO4 upon workup in CH2Cl2, rt, 57% for (S,S)79, 41% for (R,S)-79, 45% for (S,R)-79, 65% for (R,R)-79. R = C5H11. Adapted from ref 36.

Scheme 25. General Comparison of Stereodivergent and Traditional Approaches to Synthesis

utility of this concept. In this respect, a key goal of future efforts should be the expansion of stereodivergent dual catalysis to transformations that involve substrate activation via noncovalent interactions, such as hydrogen-bonding and π−π interactions.40 Following Zhang’s report, Hartwig and co-workers disclosed a method for stereodivergent allylic alkylation of aryl acetic acid esters that relied on dual iridium and Lewis base catalysis (Scheme 28).41 As a representative example, allylation of ester 95 with allyl carbonate 96 proceeded at room temperature in 5635


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Journal of the American Chemical Society Scheme 26. Dual Ir/Amine-Catalyzed Allylation of αHeteroatom-Substituted and α,β-Unsaturated Aldehydes

Scheme 28. Stereodivergent Allylic Substitutions by Dual Iridium and Lewis Base Catalysis

displace the Lewis base catalyst after allylation of the activated substrate, thus regenerating free catalyst. In a conceptually different approach toward α-allylation of carbonyls, Cruz and Dong reported the stereodivergent reaction of aldehydes and internal alkynes through synergistic rhodium and amine catalysis.42 As shown in Scheme 29, both Scheme 27. Stereodivergent Dual Catalysis with Two Metal Complexes

Scheme 29. Stereodivergent Dual-Catalytic Coupling of Branched Aldehydes and Alkynes

diastereomers of aldehyde 103 were accessed in >99% ee and high diastereoselectivity by using the appropriate combination of amine catalyst 104 and phosphine ligand enantiomer 105.

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OUTLOOK The past few years have witnessed considerable advances in the field of stereodivergent synthesis, as summarized in the preceding sections. Yet, opportunities for further development remain. The vast majority of stereodivergent processes currently available generate vicinal stereocenters; in this regard, future studies should focus on the development of transformations that allow complete control over two or more distal

the presence of catalytic amounts of iridium complex 99 and chiral Lewis base 100. Each of the four stereoisomers of product 97 was obtained in effectively quantitative yield, 99% ee, and >20:1 dr. A key feature of this work was the use of pentafluorophenyl esters as nucleophiles in a so-called “rebound” strategy. The electron-deficient phenolate can 5636


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Journal of the American Chemical Society stereocenters (e.g., in 1,3- or 1,4-relationship). Furthermore, no stereodivergent dual-catalytic variants of several powerful reactions have been reported yet. For example, the aldol reaction is one of the fundamental transformations in organic synthesis and involves the reaction of two carbonyl compounds to give β-hydroxycarbonyls. The development of asymmetric variants has been the subject of considerable scientific efforts,43 which have primarily been motivated by the relevance of asymmetric aldol reactions in the total synthesis of polyketides and small, highly functionalized building blocks.44 Catalytic asymmetric aldol reactions are typically either syn- or antiselective, as exemplified by the direct aldol reaction developed by Northrup and MacMillan (Scheme 2). Due to the increasing importance of stereochemical diversity in the design of compound libraries for drug discovery45 and in diversityoriented synthesis,46 a method for a general, stereodivergent aldol reaction would represent an important advance. In fact, this has been a longstanding goal in the field. In asymmetric aldol reactions based on stoichiometric chiral auxiliaries, stereoselectivity can be influenced by controlling enolate geometry and the manner of facial approach of enolate and aldehyde.47 In an early example of stereodivergent synthesis illustrating these aspects, Heathcock and co-workers devised protocols for the preparation of all four stereoisomers of βhydroxyacid 108 from a single chiral ketone (Scheme 30).47

Although this approach was impressively effective, the need for four distinct sets of conditions and reagents makes it somewhat cumbersome. Arguably one of the most powerful transformations available to synthetic chemists is the Evans aldol reaction,49 which is based on amino acid-derived chiral oxazolidinones such as 109. In its original form, it involves addition of a boron enolate of 109 to an aldehyde such as isobutyraldehyde, affording synaldol (S,R)-110 with high stereoselectivity. Heathcock and coworkers subsequently discovered that by pre-mixing the aldehyde with diethylaluminum chloride, the Evans aldol reaction could be rendered anti-selective, as exemplified by the synthesis of (R,R)-110 in 95:5 dr (Scheme 31).50 By adjusting the reaction conditions, both aldol diastereomers could be accessed from the same oxazolidinone starting material. Scheme 31. Syn- and Anti-Selective Evans Aldol Reactions

Scheme 30. Synthesis of All Four Aldol Stereoisomers from a Single Enantiopure Ketone

While the two auxiliary-based approaches to achieving stereodivergence in the aldol reaction are effective, we anticipate that the concept of stereodivergent dual catalysis will lead to the development of the next generation of these processes. A stereodivergent aldol reaction involving two chiral catalysts that independently control the stereochemical outcome would be synthetically valuable by enabling rapid, streamlined access to a host of versatile building blocks. These could be used in stereodivergent syntheses of polyketide natural products or drug candidates,7,42 and serve as stereochemically diverse elements of compound libraries.43,44 Importantly, the concept of stereodivergent dual catalysis can in principle also be applied to many other reactions that unite two fragments, such as the Diels−Alder reaction, and thus offers numerous opportunities for further development. Work in this area will lead to useful processes as delineated in this Perspective. Importantly, in a broader sense, the investigations will shed light on mechanistic details of catalytic asymmetric processes. They will compel researchers to question just how much they really know about various proposed transition states and may offer opportunities for preferred choice among alternatives as well as identification of new catalyst design criteria.

Through judicious choice of base and reaction conditions, control over the transition state of the aldol reaction between an enolate of ketone 106 and isobutyraldehyde (2) was achieved. Deprotection and oxidation with sodium periodate of the aldol products then furnished all stereoisomers of acid 108. A detailed analysis of the transition states that are thought to give rise to the observed stereochemical outcomes is beyond the scope of this Perspective and can be found elsewhere.47,48

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Erick M. Carreira: 0000-0003-1472-490X 5637


Perspective

Journal of the American Chemical Society Present Address

14793. (h) Li, X.; Lu, M.; Dong, Y.; Wu, W.; Qian, Q.; Ye, J.; Dixon, D. J. Nat. Commun. 2014, 5, 4479. (18) Nojiri, A.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 3779. (19) (a) Gao, J.; Bai, S.; Gao, Q.; Liu, Y.; Yang, Q. Chem. Commun. 2011, 47, 6716. (b) Kanayama, T.; Yoshida, K.; Miyabe, H.; Takemoto, Y. Angew. Chem., Int. Ed. 2003, 42, 2054. (20) Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305, 1752. (21) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051. (22) Simmons, B.; Walji, A. M.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2009, 48, 4349. (23) For a report on the use of polymers as additives allowing the mixing of otherwise incompatible catalysts and reactants in stereodivergent cascade catalysis, see: Chi, Y.; Scroggins, S. T.; Fréchet, J. M. J. J. Am. Chem. Soc. 2008, 130, 6322. (24) Shi, S.-L.; Wong, Z. L.; Buchwald, S. L. Nature 2016, 532, 353. (25) For reviews, see: (a) Inamdar, S. M.; Shinde, V. S.; Patil, N. T. Org. Biomol. Chem. 2015, 13, 8116. (b) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633. (c) Du, Z.; Shao, Z. Chem. Soc. Rev. 2013, 42, 1337. (d) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745. (26) Sammis, G. M.; Danjo, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 9928. (27) Knudsen, K. R.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 1362. (28) (a) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 3139. (b) Schafroth, M. A.; Sarlah, D.; Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc. 2012, 134, 20276. (c) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. J. Am. Chem. Soc. 2013, 135, 994. (d) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. Angew. Chem., Int. Ed. 2013, 52, 7532. (e) Jeker, O. F.; Kravina, A. G.; Carreira, E. M. Angew. Chem., Int. Ed. 2013, 52, 12166. (f) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. J. Am. Chem. Soc. 2014, 136, 3006. (g) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. Angew. Chem., Int. Ed. 2015, 54, 7644. (h) Rössler, S. L.; Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc. 2017, 139, 3603. (29) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Science 2013, 340, 1065. (30) Bhaskararao, B.; Sunoj, R. B. J. Am. Chem. Soc. 2015, 137, 15712. (31) For optimized geometries of the stereocontrolling transition states with the various catalyst combinations, see the article cited in ref 30. (32) Jindal, G.; Kisan, H. K.; Sunoj, R. B. ACS Catal. 2015, 5, 480. (33) Krautwald, S.; Schafroth, D.; Sarlah, D.; Carreira, E. M. J. Am. Chem. Soc. 2014, 136, 3020. (34) The Logic of Chemical Synthesis; Corey, E. J., Cheng, X.-M., Eds.; Wiley-Interscience: New York, 1995. (35) Organic Synthesis: The Disconnection Approach, 2nd ed.; Warren, S., Wyatt, P., Eds.; Wiley: Weinheim, 2009. (36) Schafroth, M. A.; Zuccarello, G.; Krautwald, S.; Sarlah, D.; Carreira, E. M. Angew. Chem., Int. Ed. 2014, 53, 13898. (37) Sandmeier, T.; Krautwald, S.; Zipfel, H. F.; Carreira, E. M. Angew. Chem., Int. Ed. 2015, 54, 14363. (38) Næsborg, L.; Halskov, K. S.; Tur, F.; Mønsted, S. M. N.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2015, 54, 10193. (39) Huo, X.; He, R.; Zhang, X.; Zhang, W. J. Am. Chem. Soc. 2016, 138, 11093. (40) Knowles, R. R.; Jacobsen, E. N. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20678. (41) Jiang, X.; Beiger, J. J.; Hartwig, J. F. J. Am. Chem. Soc. 2017, 139, 87. (42) Cruz, F. A.; Dong, V. M. J. Am. Chem. Soc. 2017, 139, 1029. (43) (a) Modern Methods in Stereoselective Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2013;. (b) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600. (c) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004; Vols. 1−2. (44) (a) Zheng, K.; Xie, C.; Hong, R. Front. Chem. 2015, 3, 32. (b) Brodmann, T.; Lorenz, M.; Schäckel, R.; Simsek, S.; Kalesse, M. Synlett 2009, 2009, 174. (c) Li, J.; Menche, D. Synthesis 2009, 2009,

†

Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the ETH Zürich and the Swiss National Science Foundation (200020_152898) for financial support. This Perspective is based in part on S. Krautwald’s Ph.D. thesis entitled “Stereodivergent Dual Catalysis” (ETH Zürich, 2016).

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REFERENCES

(1) (a) Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999; Vols. I−III, Suppl. I−II. (b) Comprehensive Chirality; Carreira, E. M., Yamamoto, H., Eds.; Elsevier Science: Amsterdam, 2012; Vols. 1−9. (2) For perspectives on stereodivergent transformations in asymmetric catalysis and the concept of stereodivergent dual catalysis, see: (a) Schindler, C. S.; Jacobsen, E. N. Science 2013, 340, 1052. (b) Oliveira, M. T.; Luparia, M.; Audisio, D.; Maulide, N. Angew. Chem., Int. Ed. 2013, 52, 13149. For a comprehensive review of many individual examples of diastereodivergent catalysis, see: (c) Bihani, M.; Zhao, J. C.-G. Adv. Synth. Catal. 2017, 359, 534. (3) (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798. For the seminal report on enantioselective prolinecatalyzed aldol reactions of acetone, see: (b) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395. (4) Kunze, B.; Schabacher, K.; Zähner, H.; Zeeck, A. Arch. Microbiol. 1972, 86, 147. (5) Hofferberth, M. L.; Brückner, R. Angew. Chem., Int. Ed. 2014, 53, 7328. (6) (a) Ding, J.; Hall, D. G. Angew. Chem., Int. Ed. 2013, 52, 8069. For another report of a synthesis of both diastereomers of mefloquine, see: (b) Rastelli, E. J.; Coltart, D. M. Angew. Chem., Int. Ed. 2015, 54, 14070. (7) (a) Drug Stereochemistry: Analytical Methods and Pharmacology, 3rd ed.; Józw ́ iak, K., Lough, W. J., Wainer, I. W., Eds.; CRC Press: Boca Raton, FL, 2012. (b) The Practice of Medicinal Chemistry, 3rd ed.; Wermuth, C. G., Ed.; Elsevier: Amsterdam, 2008. (8) (a) Anighoro, A.; Bajorath, J.; Rastelli, G. J. Med. Chem. 2014, 57, 7874. (b) Peters, J.-U. J. Med. Chem. 2013, 56, 8955. (9) Classics in Stereoselective Synthesis:; Carreira, E. M., Kvaerno, L., Eds.; Wiley-VCH: Weinheim, 2009. (10) Denmark, S. E.; Ghosh, S. K. Angew. Chem., Int. Ed. 2001, 40, 4759. (11) Molinaro, C.; Scott, J. P.; Shevlin, M.; Wise, C.; Ménard, A.; Gibb, A.; Junker, E. M.; Lieberman, D. J. Am. Chem. Soc. 2015, 137, 999. (12) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928. (13) Wang, B.; Wu, F.; Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2007, 129, 768. (14) Tian, X.; Cassani, C.; Liu, Y.; Moran, A.; Urakawa, A.; Galzerano, P.; Arceo, E.; Melchiorre, P. J. Am. Chem. Soc. 2011, 133, 17934. (15) Luparia, M.; Oliveira, M. T.; Audisio, D.; Frébault, F.; Goddard, R.; Maulide, N. Angew. Chem., Int. Ed. 2011, 50, 12631. (16) Lu, G.; Yoshino, T.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2011, 50, 4382. (17) (a) Eitel, S. H.; Jautze, S.; Frey, W.; Peters, R. Chem. Sci. 2013, 4, 2218. (b) Mechler, M.; Peters, R. Angew. Chem., Int. Ed. 2015, 54, 10303. (c) Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem. Soc. 2007, 129, 12396. (d) Yan, X.-X.; Peng, Q.; Li, Q.; Zhang, K.; Yao, J.; Hou, X.-L.; Wu, Y.-D. J. Am. Chem. Soc. 2008, 130, 14362. (e) Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2000, 39, 2327. (f) Verrier, C.; Melchiorre, P. Chem. Sci. 2015, 6, 4242. (g) Uraguchi, D.; Yoshioka, K.; Ooi, T. Nat. Commun. 2017, 8, 5638


Perspective

Journal of the American Chemical Society 2293. (d) Schetter, B.; Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45, 7506. (45) (a) Harrison, B. A.; Gierasch, T. M.; Neilan, C.; Pasternak, G. W.; Verdine, G. L. J. Am. Chem. Soc. 2002, 124, 13352. (b) Kim, Y.; Arai, M. A.; Arai, T.; Lamenzo, J. O.; Dean, E. F.; Patterson, N.; Clemons, P. A.; Schreiber, S. L. J. Am. Chem. Soc. 2004, 126, 14740. (c) Gao, Y.; Kodadek, T. Chem. Biol. 2013, 20, 360. (d) Gerard, B.; Duvall, J. R.; Lowe, J. T.; Murillo, T.; Wei, J.; Akella, L. B.; Marcaurelle, L. A. ACS Comb. Sci. 2011, 13, 365. (e) Misske, A. M.; Hoffmann, H. M. R. Chem. - Eur. J. 2000, 6, 3313. (f) Gierasch, T. M.; Shi, Z.; Verdine, G. L. Org. Lett. 2003, 5, 621. (g) Kumagai, N.; Muncipinto, G.; Schreiber, S. L. Angew. Chem., Int. Ed. 2006, 45, 3635. (46) (a) O’ Connor, C. J.; Beckmann, H. S. G.; Spring, D. R. Chem. Soc. Rev. 2012, 41, 4444. (b) Nielsen, T. E.; Schreiber, S. L. Angew. Chem., Int. Ed. 2008, 47, 48. (c) Tan, D. S. Nat. Chem. Biol. 2005, 1, 74. (d) Schreiber, S. L. Science 2000, 287, 1964. For a report on a pseudo-stereodivergent approach to the avermectins involving “super silyl” aldol reactions, see: (e) Brady, P. B.; Oda, S.; Yamamoto, H. Org. Lett. 2014, 16, 3864. (47) Van Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.; Heathcock, C. H. J. Org. Chem. 1991, 56, 2499. (48) Classics in Total Synthesis II: More Targets, Strategies, Methods; Nicolaou, K. C., Snyder, S. A., Eds.; Wiley-VCH: Weinheim, 2003; Chapter 3. (49) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127. (50) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56, 5747.

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