Research Article

Enantio- and Diastereodivergent Dual Catalysis: α-Allylation of Branched Aldehydes

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Science  31 May 2013:
Vol. 340, Issue 6136, pp. 1065-1068
DOI: 10.1126/science.1237068

Independent Chiral Catalysts

Synthetic catalysts can be prepared in their mirror-image form and thereby furnish the mirror-image (enantiomer) of the reaction product. In practice, however, this versatility is largely limited to products featuring a single stereocenter that accounts for the dissymmetry. Krautwald et al. (p. 1065; see the Perspective by Schindler and Jacobsen) now report a pair of chiral catalysts—an iridium complex and an amine—that operate in concert to facilitate carbon-carbon bond formation, while retaining independent stereoselectivity toward their respective sides of the bond.


An important challenge in asymmetric synthesis is the development of fully stereodivergent strategies to access the full complement of stereoisomers of products bearing multiple stereocenters. In the ideal case, where four products are possible, applying distinct catalysts to the same set of starting materials under identical conditions would in a single step afford any given stereoisomer. Herein, we describe the realization of this concept in a fully stereodivergent dual-catalytic synthesis of γ,δ-unsaturated aldehydes bearing vicinal quaternary/tertiary stereogenic centers. The reaction is enabled by chiral iridium and amine catalysts, which activate the allylic alcohol and aldehyde substrates, respectively. Each catalyst exerts high local stereocontrol irrespective of the other's inherent preference.

The field of asymmetric synthesis has experienced considerable progress over the past three decades, and a wide range of enantiopure compounds can now be readily prepared using enantioselective methods based on bio-, transition metal-, and organocatalysis (1). In addition, chemists can rely on a number of structural elements, such as stereoelectronic, steric, or directing effects, to exert diastereocontrol in the reactions of chiral substrates (2). Although enantiomers can be prepared by simply selecting between a pair of enantiomeric catalysts, a notable challenge associated with the synthesis of molecules bearing multiple stereogenic centers is access to any stereoisomer at will from the same set of starting materials with full absolute and relative stereocontrol.

Access to the complete set of stereoisomers of a compound from the same substrates has been realized through a number of strategies. These include change of solvent, the use of additives, and selection of distinct catalysts (39). In a different approach termed cycle-specific aminocatalysis, a pair of chiral amine catalysts may be employed in a two-step sequence of reactions with enamine after iminium activation (10). A characteristic feature of this approach is that the two stereogenic centers are formed sequentially: After enantioselective formation of the first stereocenter, the second catalyst needs to overcome the stereochemical bias present in the chiral product of the first step. Thus, the overall strategy combines an enantioselective reaction with a catalyst-controlled diastereoselective step.

In a conceptually different construct aimed at the synthesis of compounds with a pair of stereogenic centers, two chiral catalysts employed concurrently could dictate the configuration of the stereocenters in the product. Ideally, these would operate independently and set both configurations in a single transition state with minimal matched/mismatched interactions. Herein, we report the realization of this concept in the development of a method for the stereodivergent dual-catalytic α-allylation of aldehydes.

Dual catalysis involves the concurrent activation of both nucleophile and electrophile using distinct catalysts (Fig. 1A) and has recently emerged as an attractive strategy for enantioselective synthesis (1113). Its implementation relies on the combination of chiral and achiral catalysts to furnish products enantioselectively (1418). We reasoned that a dual-catalytic system in which both catalysts are chiral (*Cat1 and *Cat2) and each is capable of exercising full control over the configuration of its corresponding stereocenter would provide stereodivergent access to the full matrix of stereoisomeric products simply by using the four available permutations (Cat1R + Cat2R, Cat1R + Cat2S, Cat1S + Cat2R, and Cat1S + Cat2S) (Fig. 1B).

Fig. 1 Dual and stereodivergent dual catalysis.

(A) Dual catalysis. Simultaneous activation of two reactants, A and B, by two distinct catalysts leading to reaction. (B) Stereodivergent dual catalysis. The use of two distinct chiral catalysts enables access to the full complement of stereoisomeric products by simple catalyst permutation. The specific example illustrates the proposed coupling of amine and iridium catalysis.

Dual Catalysis by Chiral Ir and Chiral Amine

Ir-catalyzed allylic substitution has become a useful method for the synthesis of chiral building blocks (1922). A salient feature of these processes is the formation of the branched product resulting from addition of the nucleophile to the more substituted carbon of the allyl moiety. In this context, our own studies have demonstrated direct substitution of allylic alcohols using an Ir/(P,olefin) complex in combination with Brønsted acid promoters (23, 24). We anticipated that intercepting a reactive allyliridium intermediate such as I with a nucleophile (II) activated by a second chiral catalyst could result in an allylation process that permits control of the configuration of both stereocenters (Fig. 1B). Amines are known to readily and reversibly form nucleophilic enamines from the corresponding aldehydes (25, 26). Specifically, cinchona-alkaloid–derived primary amines such as A2 and A3 have been shown to be useful activators in the stereoselective functionalization of carbonyls (2729). A particularly attractive feature of the reaction involving I and II is that the two reactive species are planar in the region where C–C bond formation ensues, potentially minimizing matched-mismatched effects at the transition state. Consequently, we began our study by examining the reaction of hydratropaldehyde (1a) and phenyl vinyl carbinol (2a) mediated by the various combinations of amine catalysts A1 and A2 and Ir/(P,olefin) complexes L1 and (R)-L (Fig. 2). The first set of experiments examined the effect of using a pair of catalysts in which only one is chiral (#1 and #2). The results demonstrate the ability of the amine A2 and the Ir/(R)-L catalyst to control the α or β configuration, respectively (30). The observed relative stereocontrol in each case indicates that neither catalyst is able to control the configuration of both stereocenters. This is consistent with the observations of the experiment involving achiral catalysts (#3). The observation of poor relative stereocontrol in both cases suggested to us that the combined use of amine A2 and Ir/(R)-L could result in highly diastereoselective formation of the product. In the experiment (#4), product 3a was indeed isolated with excellent relative [>20:1diastereomeric ratio (d.r.)] and [absolute >99% enantiomeric excess (ee)] stereocontrol. Although these experiments established the feasibility of a diastereoselective process, they left unanswered the question of whether a stereodivergent dual-catalytic method could be realized.

Fig. 2 Key experiments in the evaluation of diastereocontrol.

We then set out to examine whether the full array of stereoisomers of 3a might be accessible (31). The experiments involving the complete set of catalyst permutations A2 and its pseudoenantiomer A3 along with (R)-L and (S)-L establish the operation of a stereodivergent process (Fig. 3). Thus, from the same set of starting materials 1a and 2a, all four stereoisomers of 3a are obtained in good yields (71 to 80%) and superb enantio- (>99% ee) and diastereoselectivity (d.r. 15:1 to >20:1).

Fig. 3 Stereodivergent dual catalytic synthesis of all stereoisomers of 3a.

Substrate Scope

The scope of allylic alcohols in the α-allylation was explored using hydratropaldehyde 1a (Fig. 4). A range of allylic alcohols substituted with arenes bearing halogens, electron-withdrawing, electron-donating, and alkyl substituents furnish products (3b to 3m) in excellent selectivities (14:1 to >20:1 d.r., >99% ee). In addition, allylic alcohols incorporating other arenes such as naphthyl (3n) and thiophene (3o) proved to be good substrates for the reaction. An electrophilic aldehyde in the arene did not interfere with the process, and 3f was obtained in 72% yield. Under the reaction conditions described, no potentially competitive aldol process was observed.

Fig. 4 Allylic alcohol scope of the allylation.

We then turned our attention to investigating the scope of the reaction with regard to the aldehyde component (Fig. 5). A range of aldehydes bearing common functional groups affords products (3p to 3t) in good yield and 4:1 to >20:1 diastereoselectivity. Finally, symmetrical aldehydes (3u to 3w) can also be allylated in good yield and excellent enantioselectivity.

Fig. 5 Aldehyde scope of the allylation.

After exploring the substrate scope, we sought to further demonstrate the stereodivergence of the reaction with hydratropaldehyde (1a) under the conditions described above. Substrates 2f, 2k, and 2o were chosen as representative examples based on their diverse electronic properties (Fig. 6), including electron-poor, electron-rich, and hetarenes. In each case, the corresponding stereoisomeric products were isolated in good yields, with >99% ee and 10:1 to >20:1 d.r.

Fig. 6 Representative examples of stereodivergence.

We subsequently subjected the substitution reaction to a highly challenging substrate by examining the use of diallyl alcohol 2x (Fig. 7). In the experiment, 2x afforded diene 3x in 57% yield (98% ee, 5:1 d.r.). This example underscores that the process we have described displays both enantio- and diastereoselectivity in the generation of vicinal quaternary/tertiary stereocenters (32, 33) as well as regiocontrol, resulting from substitution at the more hindered end of the of the pentadienyl system. This observation in combination with those described above lead us to suggest a conceptual model to account for the high degree of stereodivergence in this dual-catalytic process. In this respect, the operation of an outer sphere mechanism in which the stereocontrol elements are positioned opposite the reactive diastereofaces for each reactant allows two independent catalysts with a high degree of local diastereofacial differentiation to participate in a single transition state with minimization of matched and mismatched effects.

Fig. 7 Synthesis of diene 3x and analysis.


We have disclosed an enantioselective α-allylation of branched aldehydes that proceeds through iridium-catalyzed allylic substitution of allylic alcohols with in situ–generated enamines. The method delivers products bearing quaternary stereocenters in a vicinal relationship to tertiary stereocenters in good yields and excellent selectivities. The successful coupling of amine and Ir-catalysis via chiral enamine and allyl metal intermediates serves as proof of concept for stereodivergent dual catalysis in which two distinct and highly face-selective catalytic cycles are merged and provide access to all possible stereoisomers of a target compound in enantiomerically pure form. We expect the broader consequences of this concept to be applicable to the development of other stereodivergent dual-catalytic asymmetric reactions.

Supplementary Materials

Materials and Methods

Supplementary Text

Tables S1 to S8

References (3441)

References and Notes

  1. Materials and methods are available as supplementary materials on Science Online.
  2. Acknowledgments: We are grateful to the Swiss National Science Foundation for a grant supporting this work (200020_135224). S.K. thanks the Fonds der Chemischen Industrie for support (Chemiefonds-Stipendium). We thank S. Müller for insightful discussions. Structural parameters for a carbamate derived from (R,R)-3a are available free of charge from the Cambridge Crystallographic Data Centre under reference number CCDC 933469.
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