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Synthesis 2024; 56(14): 2223-2233
DOI: 10.1055/s-0042-1751552
short review

Stereodivergent Carbon–Carbon Bond-Forming Reactions

Alan R. Healy  ∗

A.R.H. thanks New York University Abu Dhabi (NYUAD) for funding.
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Abstract

Stereodivergent catalysis has emerged as a compelling strategy for achieving stereochemical diversity in small-molecule library design and natural product synthesis. In this short review, key examples of pioneering catalytic carbon–carbon bond-forming transformations that provide access to all stereoisomers of a given product are presented. Current trends and future directions in the field are discussed, highlighting ongoing initiatives to enhance the efficiency and broaden the scope of stereodivergent methodologies.

1 Introduction

2 Mono-catalysis

2.1 Change of Reaction Conditions

2.2 Change of Catalyst

3 Multi-catalysis

3.1 Bifunctional Catalysis

3.2 Sequential/Cascade Catalysis

3.3 Synergistic/Cooperative Catalysis

4 Conclusions and Outlook


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Key words

stereodivergent synthesis - dual catalysis - sequential catalysis - privileged catalysts - aldol reaction - carbon–carbon bond
1

Introduction

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Alan Healywas born in Co. Clare, Ireland. He completed his undergraduate studies in medicinal chemistry at Trinity College Dublin (TCD, Ireland) followed by an MSc in biomedical science from the University of Edinburgh (UK). He obtained a PhD from the University of St Andrews (UK) in 2014 under the guidance of Nicholas J. Westwood, and was a Charles H. Revson Senior Fellow with Seth B. Herzon and Jason M. Crawford at Yale University (USA) from 2015 to 2018. He began his independent career at New York University Abu Dhabi (NYUAD, UAE) in 2019 where he is currently an assistant professor in the chemistry program. His research group focuses on the development of novel methods to accelerate the discovery and study of dark matter metabolites.

The rise of asymmetric catalysis over the past half century can be attributed to its pivotal role in addressing the demand for enantiomerically pure building blocks in pharmaceutical, agrochemical, and natural product synthesis. The ability to selectively synthesize a single chiral product has become a hallmark of efficiency and precision. However, despite the vast and continuously growing collection of stereoselective bond-forming reactions, only a select few are routinely used in the synthesis of enantioenriched compounds. These privileged transformations share the common feature of high selectivity across a broad range of substrates. Yet, this desirable quality is often overlooked in modern discovery campaigns, which tend to optimize for a single substrate and reaction outcome (enantio- or diastereoselectivity), and thus select for high performance in a narrow region of structural and stereochemical space.

As the field of asymmetric catalysis continues to evolve, increased value is being placed on the development of more general synthetic methodologies.[1] [2] [3] [4] In particular, recent efforts have focused on the development of catalytic stereodivergent methods that provide complete control of both the relative and absolute configurations of multiple stereogenic centers in a bond-forming reaction.[5–7] The importance of developing these methods lies in their ability to provide access to all possible stereoisomers of a product from a given reaction, thus offering synthetic chemists greater flexibility and efficiency in constructing complex molecular structures.[8] This is of particular consequence in the field of drug discovery, where different drug stereoisomers can exhibit distinct biological activities and pharmacological properties.[9]

The development of stereodivergent bond-forming reactions is intrinsically challenging to achieve, as at least four reaction outcomes (enantioselectivity and diastereoselectivity in both diastereomers) must be identified and optimized. The challenges inherent to developing stereodivergent carbon–carbon bond-forming reactions is exemplified by the venerable aldol reaction. The aldol reaction is among the most powerful and widely used carbon–carbon bond-forming transformations in organic chemistry. As a result, the development of asymmetric aldol methods has been the focus of considerable efforts over the past 40 years. Despite the substantial attention devoted to this pursuit, the realization of a catalytic stereodivergent aldol reaction was achieved only recently (vide infra).[10]

The aldol reaction unites two carbonyl compounds (A and B) to generate a β-hydroxy carbonyl compound (C) with two vicinal stereocenters (Figure [1]). An extensive array of enantioselective aldol methods has been reported in which a single catalyst controls the absolute configuration of the new stereocenters in the bond-forming reaction to give a single enantiomer of the product (e.g., (S,S)-C).[11] While such transformations can often be made enantiodivergent by using the opposite enantiomer of the catalyst, switching the relative configuration of the product is more challenging because diastereochemical preference is largely governed by the inherent structural and stereoelectronic nature of the reactants. As a result, synthesis of either the syn- or anti-aldol product has mainly been achieved by changing the reactants, either the pronucleophilic carbonyl (A), as in the Mukaiyama aldol reaction,[12] [13] or in some cases alternate diastereomers were obtained from the same pronucleophile but with different acceptor aldehydes (B).[14–16] Diverging from conventional stereoselective methods, a stereodivergent process offers a distinct advantage by granting access to all four β-hydroxy carbonyl stereoisomers from identical reactants (A and B), and thus provides a singular approach for the synthesis of stereochemically diverse bioactive small molecules and polyketide natural products.

In this short review, select examples of catalytic stereodivergent carbon–carbon bond-forming reactions are highlighted. Only methods that can provide access to all possible stereoisomers of a product from identical starting materials are reviewed. The delineated stereodivergent reactions fall into two principal categories. Firstly, there is the modification of reaction parameters in a mono-catalytic transformation, involving the adjustment of the catalyst structure or reaction conditions. The second approach employs a multi-catalysis system, where two catalytic sites on a single catalyst, or two chiral catalysts, are utilized to establish multiple stereocenters. The ensuing sections highlight notable examples of each strategy. Furthermore, we explore how these cases can serve as a guiding framework for the future development of stereodivergent methodologies.

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Figure 1 Stereoselective (top) versus stereodivergent (bottom) approaches to the aldol reaction

# 2

Mono-catalysis

2.1

Change of Reaction Conditions

In traditional mono-catalytic systems, the catalyst interacts with one substrate to generate an activated complex which subsequently undergoes bond formation with a second, unactivated substrate to yield the target product. Conventional reaction discovery workflows begin with an exploratory catalyst and reaction condition screen. This initial screen typically leads to the identification of conditions that favor the formation of a single diastereomer. However, in select cases, during the preliminary screening process the complementary diastereomer is observed on adjustment of the catalyst system or reaction conditions (temperature, solvent or additive). Subsequent parallel optimization of each set of reaction conditions can lead to the successful development of a stereodivergent process. These stereodivergent methods can differ by just a single parameter, such as temperature or catalyst.[17] [18] [19] [20] [21] [22] However, in many cases, stereodivergence is achieved as a result of several different parameters.[23,24]

In this respect, Dong and co-workers have demonstrated that the diastereoselectivity of the Rh-catalyzed hydroacylation of diketones could be controlled by the careful selection of the reaction temperature, solvent, and counterion (Scheme [1]).[25] A preliminary screen guided by previously reported hydroacylation methods revealed that a combination of [Rh(C2H4)2Cl]2 and a JoSPOphos ligand furnished both the syn- and anti-bicyclic[5.3.0]lactone 1 as a 3:1 diastereomeric mixture. Through a systematic study of the reaction conditions, the authors demonstrated that polar aprotic solvents (DME), at low temperature (10 °C), and with a more strongly coordinating catalyst counterion (Cl–), favored the formation of the anti-lactone 1 (91% yield, 17:1 d.r., 99% ee). By contrast, the syn-lactone 1 (98% yield, >20:1 d.r, 97% ee) was the major product obtained in polar protic solvents (t-AmOH), at higher temperature (80 °C) and with a weakly coordinating catalyst counterion (SbF6 –).

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Scheme 1 Diastereodivergent Rh-catalyzed ketone hydroacylation

# 2.2

Change of Catalyst

Modification of the catalyst system by changing the chiral framework has proven to be a powerful method to develop stereodivergent processes. Such modifications to the catalyst structure have primarily been identified by catalyst screening, with the mechanistic insight governing the switch in stereoselectivity being elucidated at a later stage.[26] [27] However, in some cases, hypothesis-driven catalyst redesign has been used to develop stereodivergent transformations.[28] A notable example of the latter approach is the development of a direct and stereodivergent organocatalytic Mannich reaction by the Barbas group. An initial report documented an l-proline (2a) catalyzed Mannich reaction of isovaleraldehyde and N-PMP-protected α-imino ethyl glycolate to generate the syn-amino aldehyde 3 (Scheme [2]).[29] The authors rationalized that a reversal in the facial selectivity of either the enamine (generated by condensation of proline with the aldehyde) or the imine during the C–C bond-forming step was required to access the anti-product. They hypothesized that a pyrrolidine derivative bearing substituents at the 3- or 5-positions would favor the transition state required to generate the anti-Mannich product. Indeed, the ensuing study resulted in the identification of the novel pyrrolidine organocatalyst 2b, which afforded the anti-amino aldehyde product 3 in excellent diastereo- and enantioselectivity.[30]

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Scheme 2 Diastereodivergent organocatalyzed Mannich reactions
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Scheme 3 Diastereodivergent Mannich reactions of α-cyanocyclopentanone and N-Boc-benzaldimine

Chiral metal catalysts composed of a chiral ligand and a central metal have played a pivotal role in asymmetric catalysis. They also offer great opportunities towards the development of stereodivergent methods as their reactivity and selectivity can be tuned by varying the ligand or metal. Shibasaki and co-workers have developed several Mannich-type stereodivergent methods that combine a single chiral ligand with different metal cations.[31] [32] One such example is the diastereodivergent addition of α-cyanocyclopentanone to N-Boc-benzaldimine (Scheme [3]). In general, rigid, multidentate ligands are preferred for metal catalysis as they provide a stable and well-defined architecture for the asymmetric transformation. In contrast, Shibasaki and co-workers proposed that a conformationally flexible ligand in combination with different metal cations would allow the formation of alternative catalytic structures capable of inducing different stereochemical outcomes. Indeed, their ensuing study showed that complexation of the α-amino acid derived ligand 4 with the rare earth metals Sc(O i Pr)3 or Er(O i Pr)3 generated catalysts with different chiroptical properties capable of generating the anti-5 or syn-5 Mannich-type products respectively.[32]

The more common method to develop stereodivergent metal-catalyzed transformations has been through modification of the chiral ligand.[33] [34] [35] [36] In this context, Wu, Hou and co-workers reported a CuI-P,N-ferrocene-catalyzed diastereodivergent Mannich reaction (Scheme [4]).[37] Specifically, the Cu/ligand 6a-catalyzed reaction of glycine Schiff base 7 and N-tosyl-benzaldimine furnished the anti-α,β-diamine 8 in 99% ee and 96:4 d.r. The authors observed that a change in the electronic nature of the ligand resulted in a dramatic change in the diastereoselectivity of the reaction. Switching ligand 6a, containing an electron-donating p-methoxy group, for ligand 6b, that contains two electron-withdrawing fluorine substituents (3,5-F2C6H3), provided the syn-diamine 8 in 99% ee and >95:5 d.r.

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Scheme 4 Diastereodivergent Mannich reaction of glycine Schiff bases and N-tosylimines

While stereodivergent metal-ligand-catalyzed reactions have largely been discovered by screening, these studies have demonstrated that the ability to form functionally diverse three-dimensional catalyst structures is essential to obtain stereodivergent outcomes. As shown, this can be achieved by combining flexible ligands with different metals, or a single metal with electronic or sterically diverse ligands. In the latter case, metal-chiral phosphine catalyst systems have proven to be uniquely successful catalyst systems, as the diverse range of chiral bisphosphine, phosphoramidite, and P,N ligands available have enabled the development of a range of stereodivergent reactions.[38] [39] [40] [41] [42] [43]

Recently, our laboratory sought to develop a metal-chiral-ligand-catalyzed decarboxylative aldol reaction. With generality, both in the substrate and stereochemical outcome as the primary objective, we focused our attention on the privileged metal-chiral-salen catalyst system. The readily accessible, inexpensive and modular salen ligands have found widespread use across a variety of distinct enantioselective and stereodivergent reactions.[19] [44] [45] We began our studies by investigating the reaction of malonic acid half thioester (MAHT) and p-nitrobenzaldehyde (Scheme [5]). MAHTs have become increasingly popular as ester enolate surrogates in carbon–carbon bond-forming reactions as the mild conditions required to generate the enolate are tolerant of a wide variety of substrates.[46] [47] An initial reaction screen identified Ti(O i Pr)4-salen 9a as a competent catalyst for the decarboxylative aldol reaction, generating the syn-aldol product (S,S)-10 in high yield (97%), and high diastereo- and enantioselectivity (16:1 d.r., 99:1 e.r.).[10] A further ligand survey revealed that the dihydrosalen (salalen) ligand 9b, obtained by partial reduction of salen-9a, generated the anti-aldol adduct as the major product. Using the previously optimized conditions, ligand 9b provided the anti-product (S,R)-10 in high yield (98%) and selectivity (10:1 d.r., 98:2 e.r.). As both enantiomers of the chiral diamine are commercially available, all four stereoisomers of the aldol product are easily accessible from the same reactants by just varying the catalyst. The reaction was subsequently shown to be scalable and tolerant of a wide variety of functionalized substrates.[10]

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Scheme 5 A stereodivergent decarboxylative aldol reaction

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# 3

Multi-catalysis

Multi-catalysis has emerged as a promising strategy for the development of stereodivergent transformations.[48] Multi-catalytic systems include bifunctional catalysis, wherein a single catalyst activates both substrates (Nu and E) by interaction with discrete functional groups on the catalyst (Figure [2]A); or dual catalysis, wherein two catalysts and two catalytic cycles are in operation during the bond-forming step(s). Dual catalytic systems can be further classified as sequential/cascade catalysis or synergistic/cooperative catalysis. In sequential catalysis, one catalyst reacts with the reactant to produce an intermediate (E′) which subsequently is activated by the second catalyst to produce the target product (Figure [2]B). In contrast, when both reactants are simultaneously activated by two separate catalysts to enable the bond-forming transformation, this is classified as synergistic catalysis (Figure [2]C).[49] Multi-catalysis systems afford the ability to activate and control the chiral environment of both reactants compared to just one reactant in a mono-catalytic system. Intuitively, this should provide greater opportunity to control the formation of the new stereocenters during the bond-forming step.

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Figure 2 Classification of multi-catalysis systems
3.1

Bifunctional Catalysis

The field of bifunctional stereodivergent catalysis has largely been centered around the use of H-bonding/Bronsted base or H-bonding/enamine or iminium catalysts.[50] [51] [52] [53] [54] In a seminal report, Deng and co-workers disclosed the stereodivergent construction of two non-adjacent 1,3-stereocenters via a conjugate addition–protonation reaction with cinchona alkaloids as bifunctional catalysts.[55] An initial report outlined the syn-selective addition of α-cyanoketone 11 to α-chloroacrylonitrile (12) using the pseudo-enantiomeric phenanthryl-protected alkaloids 13a (Scheme [6]A). The authors proposed that a network of hydrogen bonds between the reacting substrates and the bifunctional catalyst controlled the stereoselective outcome of the reaction. Hence, they hypothesized that bifunctional catalysts containing the hydrogen bond donor and acceptor in different spatial arrangements could afford complementary diastereomers. Indeed, in a subsequent report, the authors demonstrated that 9-thiourea-functionalized chinchona alkaloids 14 led to the formation of the complementary anti-isomers 15 with excellent stereoselectivity.[56] Deng and co-workers further extended this approach through the development of a stereodivergent Diels–Alder reaction of 2-pyrone derivative 16 and the dienophile α-chloroacrylonitrile (12) to yield all four possible cycloadduct 17 stereoisomers (Scheme [6]B).[57]

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Scheme 6 Stereodivergent reactions catalyzed by bifunctional H-bonding catalysts. (A) Stereodivergent conjugate addition of α-cyanoketones to α-chloroacrylonitrile. (B) Stereodivergent Diels–Alder reaction of 2-pyrones and α-chloroacrylonitrile.

# 3.2

Sequential/Cascade Catalysis

In 2005, MacMillan and co-workers reported the sequential use of two distinct catalysts to control the configuration of two new stereocenters in a cascade reaction.[58] The first step in the transformation involved the iminium-catalyzed conjugate addition of a nucleophile to an α,β-unsaturated aldehyde. Following completion of this reaction, a second catalyst and electrophile are added to effect enamine-catalyzed α-functionalization of the aldehyde (Scheme [7]A). Importantly, as each amine catalyst controls the configuration of one chiral center, all possible stereoisomers can be obtained by selection of the suitable pairwise combination of amine catalysts. MacMillan and others have disclosed a wide range of stereodivergent methods focused on heteroatom α-functionalization of the enal using this elegant cycle-specific catalytic strategy, including hydrofluorination, hydroamination, hydrooxidation, alkyl amination, diamination, and aminooxidation.[6] [59]

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Scheme 7 Organocatalytic relay catalysis. (A) Cycle-specific sequential functionalization of α,β-unsaturated aldehydes. (B) Diastereodivergent dialkylation of 2-hexenal.

In a notable departure from these reports, Fréchet and colleagues disclosed a dialkylation of an enal employing this approach (Scheme [7]B).[60] Catalyst 18b-catalyzed addition of N-methylindole to 2-hexenal, followed by 2c-catalyzed α-conjugate addition to methylvinylketone yielded the dialkyl products 19 in high yields and excellent stereoselectivities. Central to the success of this process was the use of non-interpenetrating star-polymer encapsulated catalysts to isolate the individual transformations within the cascade sequence to prevent undesired side reactions.

Although cascade catalysis is a highly efficient and powerful strategy, the need for a common set of reaction conditions, which are compatible with both catalytic cycles and which maintain high yields and enantioselectivities for both catalytic transformations, is a challenge and has largely limited this method to iminium-enamine catalytic methods. In an important recent advance, Lautens and co-workers disclosed a cascade process involving the combination of two orthogonal asymmetric transition-metal-catalyzed transformations in one pot.[61] The transformation featured a Pd-catalyzed asymmetric allylic alkylation of allyl enol carbonate 20 (Scheme [8]). Both enantiomers of the α-quaternary stereocenter could be obtained in the presence of either enantiomer of the Pd ligand 21. A subsequent Rh-catalyzed enantioselective 1,4-addition of phenylboronic acid set the configuration of the δ-tertiary stereocenter to yield all stereoisomers of the chiral cyclic ketone 23.

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Scheme 8 The stereodivergent synthesis of cyclic ketones containing two remote stereocenters via sequential transition-metal-catalyzed reactions

# 3.3

Synergistic/Cooperative Catalysis

In 2013, Carreira and co-workers reported a stereodivergent α-allylation of aldehydes using a synergistic dual catalytic approach (Scheme [9]).[62] In this work, an iridium/(P,olefin) catalyst activates phenyl vinyl carbinol 24 to generate a putative electrophilic π-allyliridium species. Trapping of the electrophilic intermediate by an enantiopure nucleophilic enamine, derived in situ from hydratropaldehyde (25) and the cinchona-alkaloid-derived amine 26, affords the γ,δ-unsaturated aldehyde 27. All possible stereoisomers of the β-vinylaldehyde 27 were obtained in high yield and high stereoselectivity (>99% ee, 15:1 to >20:1 d.r.) by the selection of the appropriate combination of amine catalyst 26 and (P,olefin) ligand 28 enantiomers. The observed stereodivergence was rationalized through an outer-sphere transition state model, in which the two catalysts shield the opposite diastereofaces of their respective substrates. Such an arrangement permits the two activated intermediates to react in a stereocontrolled fashion with minimal matched or mismatch effects.

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Scheme 9 Dual Ir/chiral-amine-catalyzed α-allylation of branched aldehydes

Following Carreira’s approach, several dual metallo (Ir, Rh, Pd)-chiral amine systems have been reported for the hydroalkylation of alkynes and dienes, conjugate additions to α,β-unsaturated aldehydes, and [4+2] cycloadditions.[63] [64] [65] [66] [67] [68] [69] Hartwig and co-workers subsequently showed that the combination of a metalacyclic iridium complex and a chiral Lewis base (CLB) could catalyze the stereodivergent allylic alkylation of aryl acetic acid esters.[70] The Lewis basic chiral tertiary amine benzotetramisole (BTM) reacts with a pentafluorophenyl ester to form a C1-ammonium enolate that reacts with high facial selectivity with the electrophilic π-allyliridium species (Scheme [10]A). After the allylation reaction, the phenolate can displace the Lewis base to furnish the pentafluorophenyl ester product 29 and regenerate the BTM catalyst. The combination of the iridium ligand 30 and either (S)-BTM or (R)-BTM yielded syn- and anti-29, respectively, in excellent yields and selectivity. The alternate diastereomers were accessed by using the opposite enantiomer of ligand 30 to form the iridium complex. Recently, the scope of metal/organo dual catalysts has been expanded to include Pd/CLB,[71] [72] Ir/chiral phosphoric acid (CPA),[73] Ir/N-heterocyclic carbene (NHC),[74] [75] [76] Cu/NHC,[77] Ni/NHC,[78] and Ni or Rh/bifunctional H-bonding catalyst systems.[79] [80] These synergistic dual catalysts have been successfully applied in the hydroalkylation of dienes and alkoxyallenes, allyl–allyl coupling, propargylic substitution, [3+2]/[3+3] annulation, and in the stereodivergent synthesis of γ‑butyrolactones and 2,3-disubstituted dihydrobenzofurans.

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Scheme 10 (A) Stereodivergent α-allylation of aryl acetic acid esters by synergistic Ir/CLB catalysis (B) Stereodivergent α-allylation of α-hydroxyketones by synergistic dual metal Ir/Zn catalysis.

In 2016, Zhang and co-workers reported the first stereodivergent dual catalytic method consisting of two metal catalysts. The allylation of unprotected hydroxyketones was achieved under mild conditions by the synergistic action of a chiral iridium-phosphoramidite complex and a chiral zinc-ProPhenol complex (Scheme [10]B).[81] Complexation of hydroxyacetophenone and Zn-ProPhenol generates an activated 5-membered cyclic Zn-enolate. Simultaneous activation of cinnamyl methyl carbonate by the Ir-phosphoramidite complex forms an electrophilic π-allyliridium species that is trapped by the zinc-enolate to yield the α-allylated hydroxyacetophenone 31. As with previous examples, all four isomers of 31 were accessed under identical conditions by selection of the appropriate combination of catalyst enantiomers.

Following Zhang’s report, the stereodivergent allylic alkylation of azaaryl and fluorinated azaaryl esters, ketones and amides was reported by Hartwig and co-workers using a dual Ir/Cu catalytic system (Scheme [11]A).[82] [83] Subsequently, the Wang and Zhang groups independently reported the allylic alkylation of N-metalated azomethine ylides using a Ir/Cu catalytic system to generate α,α-disubstituted α-amino acids containing vicinal stereocenters (Scheme [11]B).[84] [85] In the ensuing years, the utility and scope of dual metal catalysis has been extended through the development and application of many synergistic dual metal catalyst systems.[86] [87] [88] [89] [90] [91] [92] Through these efforts, propargylic alkylation, the hydrofunctionalization of 1,3 dienes, allenes and enynes, and the challenging construction of non-adjacent 1,3-stereocenters has been achieved (Scheme [11]C).[93] [94] [95] [96] [97] [98] [99] [100] [101]

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Scheme 11 Dual-metal-catalyzed stereodivergent reactions. (A) Ir/Cu-catalyzed allylic alkylation of fluorinated azaaryl esters. (B) Ir/Cu-catalyzed allylic alkylation of N-metalated azomethine ylides. (C) The construction of 1,3-non-adjacent stereocenters via Pd/Cu-catalyzed dynamic kinetic asymmetric allenylation.

In contrast to the cooperative application of dual metal catalysts, the simultaneous and synergistic application of dual organocatalysts is underdeveloped. A recent advance in this area was the development of a synergistic Lewis base/iminium dual catalytic method for the Michael addition of phenyl acetic acid pentafluorophenyl ester to cinnamaldehyde (Scheme [12]).[102] The C–C bond formation occurs between an in situ generated nucleophilic ammonium enolate and an electrophilic iminium ion. The use of pentafluorophenyl esters as the nucleophile precursors enabled the use of a rebound strategy to provide the addition products 32 and regenerate the Lewis base catalyst.

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Scheme 12 Stereodivergent Michael addition of aryl acetic acid esters to α,β-unsaturated aldehydes enabled by synergistic organocatalysis

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# 4

Conclusions and Outlook

The field of stereodivergent catalysis has seen rapid growth in the past decade. This growth is expected to continue unabated, driven by the desire for more efficient and flexible strategies to synthesize chiral molecules. Nevertheless, some significant hurdles need to be overcome before stereodivergent catalysis becomes a mainstay of asymmetric synthesis. As summarized in this review, mono-catalytic and bifunctional catalytic methods have contributed significantly to the toolbox of methods for the synthesis of stereochemically diverse molecules. This strategy has led to the development of stereodivergent variants of many important C–C bond-forming reactions, such as the Mannich, aldol, and conjugate addition reactions, and the Diels–Alder cycloaddition. Although often seen as a strategy that is purely serendipitous and challenging to design, the examples in this review highlight some common patterns that can be utilized in the planning of stereodivergent method development campaigns.

Firstly, most mono- and bifunctional catalytic methods have arisen from a small number of privileged organocatalysts, or metal-ligand-catalyzed reactions using privileged ligands. These catalysts (e.g., cinchona alkaloids), and ligands (e.g., chiral phosphine, salen, etc.), are characterized by their modular nature, which allows for the screening of large libraries of related chiral frameworks with diverse geometric, steric and electronic properties. Secondly, the majority of these methods were discovered during preliminary screening campaigns. Typically, in asymmetric method development, only the most selective initial hit is prioritized for further optimization studies. As a result, conditions that favor an alternate diastereomer, but with lower selectivity, have likely not been pursued due to the significant resources required to optimize multiple different reaction conditions simultaneously using a one-variable-at-a-time approach (OVAT). High-throughput experimentation could provide a solution to this constraint by enabling the rapid parallel optimization of multiple reaction conditions. Finally, catalyst optimization is an essential but often tedious and costly step in the development of stereodivergent methods. In the absence of mechanistic insight, this process can often be slow and confounding, as many of the observed results cannot be explained. Data-driven approaches, in particular, multivariate regression analysis, can be used to identify the key features of the catalyst that contribute to the divergent stereochemical outcomes.[103] Indeed, numerous studies have demonstrated the benefits of using multidimensional correlation analysis as a predictive platform to guide effective and efficient catalyst optimization in asymmetric catalysis.[104]

We propose that the lessons gained from the examples in this review could provide a framework for discovering new mono-catalytic stereodivergent methods, one that is not reliant on serendipity, but rather achieved by the careful selection of the appropriate catalyst screening library coupled with technology-driven multi-reaction optimization.

In contrast to mono- and bifunctional catalytic methods, the main hurdle still facing dual catalysis is the narrow spectrum of compatible reaction types. The burgeoning field of synergistic dual catalysis has been the focus of much attention due to the intuitive nature of the approach and the ability to better predict and control the outcome of the transformation. The pace of progress in the field of dual catalysis is highlighted by the successful development of a range of dual metal, organocatalytic and combined catalytic methods, and important advances in controlling the configuration of distal stereocenters (1,3- and 1,4-relationships). Despite this rapid progress, the type of dual catalytic methods reported to date are largely limited to allylic and propargylic substitutions, and the hydroalkylation of olefins.[49] The challenge facing practitioners in this field is the identification of new carbon–carbon bond-forming reactions where each reactant can be activated by a unique catalyst, and where the two catalysts are compatible with each other and the substrates.

Overall, the ultimate challenge posed by stereodivergent synthesis is one of complexity. The successful development of a method that provides access to four (or more) stereoisomers of a product in high yield from a single set of reactants requires either the concurrent optimization of multiple reaction conditions, or catalytic cycles. The complexity of this task might be partially alleviated by the strategic implementation of high-throughput experimentation and data-driven catalyst optimization. As a result, we anticipate that the integration of these advanced methodologies has the potential to significantly impact the trajectory of stereodivergent method development.[105] However, as the legacy of stereoselective asymmetric transformations has shown us, new stereodivergent methods will need to demonstrate a broad substrate scope and versatility before they will make the leap from discovery to mainstay reactions.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

A.R.H. is grateful to Namitharan Kayambu, Torsten Cellnik, and Liban Saney for proofreading this manuscript.


Corresponding Author

Alan R. Healy
Chemistry Program, New York University Abu Dhabi
P.O. Box 129188, Abu Dhabi
UAE   

Publication History

Received: 15 December 2023

Accepted after revision: 03 January 2024

Article published online:
29 January 2024

© 2024. Thieme. All rights reserved

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Alan Healywas born in Co. Clare, Ireland. He completed his undergraduate studies in medicinal chemistry at Trinity College Dublin (TCD, Ireland) followed by an MSc in biomedical science from the University of Edinburgh (UK). He obtained a PhD from the University of St Andrews (UK) in 2014 under the guidance of Nicholas J. Westwood, and was a Charles H. Revson Senior Fellow with Seth B. Herzon and Jason M. Crawford at Yale University (USA) from 2015 to 2018. He began his independent career at New York University Abu Dhabi (NYUAD, UAE) in 2019 where he is currently an assistant professor in the chemistry program. His research group focuses on the development of novel methods to accelerate the discovery and study of dark matter metabolites.
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Figure 1 Stereoselective (top) versus stereodivergent (bottom) approaches to the aldol reaction
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Scheme 1 Diastereodivergent Rh-catalyzed ketone hydroacylation
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Scheme 2 Diastereodivergent organocatalyzed Mannich reactions
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Scheme 3 Diastereodivergent Mannich reactions of α-cyanocyclopentanone and N-Boc-benzaldimine
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Scheme 4 Diastereodivergent Mannich reaction of glycine Schiff bases and N-tosylimines
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Scheme 5 A stereodivergent decarboxylative aldol reaction
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Figure 2 Classification of multi-catalysis systems
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Scheme 6 Stereodivergent reactions catalyzed by bifunctional H-bonding catalysts. (A) Stereodivergent conjugate addition of α-cyanoketones to α-chloroacrylonitrile. (B) Stereodivergent Diels–Alder reaction of 2-pyrones and α-chloroacrylonitrile.
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Scheme 7 Organocatalytic relay catalysis. (A) Cycle-specific sequential functionalization of α,β-unsaturated aldehydes. (B) Diastereodivergent dialkylation of 2-hexenal.
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Scheme 8 The stereodivergent synthesis of cyclic ketones containing two remote stereocenters via sequential transition-metal-catalyzed reactions
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Scheme 9 Dual Ir/chiral-amine-catalyzed α-allylation of branched aldehydes
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Scheme 10 (A) Stereodivergent α-allylation of aryl acetic acid esters by synergistic Ir/CLB catalysis (B) Stereodivergent α-allylation of α-hydroxyketones by synergistic dual metal Ir/Zn catalysis.
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Scheme 11 Dual-metal-catalyzed stereodivergent reactions. (A) Ir/Cu-catalyzed allylic alkylation of fluorinated azaaryl esters. (B) Ir/Cu-catalyzed allylic alkylation of N-metalated azomethine ylides. (C) The construction of 1,3-non-adjacent stereocenters via Pd/Cu-catalyzed dynamic kinetic asymmetric allenylation.
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Scheme 12 Stereodivergent Michael addition of aryl acetic acid esters to α,β-unsaturated aldehydes enabled by synergistic organocatalysis