Diastereo- and Enantioselective Reductive Aldol Reaction with Trichlorosilane Using Chiral Lewis Bases as Organocatalysts



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Chiral Lewis base organocatalysts activate trichlorosilane to promote the tandem conjugate reduction/aldol reaction of α,β-unsaturated ketones with aldehydes to give optically active β-hydroxy ketones with good to high syn diastereo- and enantioselectivities. The reaction tolerates α,β-unsaturated aldehydes owing to the chemoselective conjugate reduction of enones in the presence of enals.

The catalytic enantioselective tandem reaction is an efficient synthetic methodology in which optically active compounds are assembled from simple prochiral substrates via two (or more) distinct catalytic processes taking place under the same conditions.1 The synthetic efficiency is enhanced by avoiding the time-intensive and yield-reducing isolation and purification of synthetic intermediates and by decreasing the amounts of chemicals and solvents used. The asymmetric catalytic reductive aldol reaction is an efficient tandem transformation involving conjugate reduction of α,β-unsaturated carbonyl compounds followed by aldol reaction of the enolate intermediate with aldehydes or ketones. Chiral transition-metal catalysts have been used to control the stereochemistry of these transformations.2, 3 We recently reported that achiral phosphorus oxides function as Lewis base organocatalysts4 to promote both the conjugate reduction of enones with trichlorosilane and the reductive aldol reaction of enones with aldehydes.5 Herein we report that enantioselective catalysis of this tandem reaction by chiral Lewis bases provides good to high diastereo- and enantioselectivities.

Scheme 1 outlines the current catalytic method. Our previous study had shown that the Lewis base catalyzed conjugate reduction with trichlorosilane proceeds via a six-membered transition state with an enone in the s-cis conformation to give the (Z)-trichlorosilyl enolate exclusively.5 Therefore, high syn selectivity is expected for the subsequent aldol process, assuming that the reaction proceeds through a chair-like cyclic transition state. Moreover, high enantioselectivity could also be achieved by judicious selection of chiral Lewis base catalysts (LB*).6, 7

Scheme 1.

The enantioselective reductive aldol reaction with trichlorosilane catalyzed by a chiral Lewis base catalyst.

We first examined various chiral Lewis base catalysts (Figure 1) for the reductive aldol reaction of chalcone (1 a) and benzaldehyde (2 a) with trichlorosilane at −78 °C (Table 1). With (S)-BINAPO, the reaction in dichloromethane gave aldol adduct 3 a with respectable stereoselectivities (Table 1, entry 1). By simply changing the solvent from dichloromethane to propionitrile, both the stereoselectivities and chemical yield dramatically improved (Table 1, entry 2). Other Lewis base catalysts were then examined using this solvent (Table 1, entries 3–6). (R,R)-DIOPO showed a comparable activity to BINAPO to afford similar enantioselectivity with a slight loss of diastereoselectivity (Table 1, entry 3). Although structurally similar to BINAPO, (S)-SEGPHOSO was found to significantly lower the reactivity and selectivities (Table 1, entry 4). On the other hand, (R)-BQNO, a bisquinoline N,N′-dioxide developed in our laboratory8 exhibited good activity and selectivity, while (R)-BIQNO, a bisisoquinoline N,N′-dioxide,9 afforded low enantioselectivity (Table 1, entries 5 and 6).10, 11

Figure 1.

Chiral Lewis base catalysts used in this study.

Table 1. Optimization of reaction conditions for the enantioselective reductive aldol reaction of chalcone (1 a) and benzaldehyde (2 a).[a]inline image
EntryLB*ConditionsYield [%]syn/antiee [%] (syn[b])
  1. [a] All reactions were carried out by addition of trichlorosilane (1.0 mmol, ca. 3 M solution in CH2Cl2) to a solution of chalcone (0.5 mmol), benzaldehyde (0.6 mmol), and a Lewis base catalyst (10 mol %) in a solvent (2 mL) at −78 °C. [b] 2R, 3R configuration. [c] 2S, 3S configuration.

1(S)-BINAPOCH2Cl2, 30 h6885:1584
2(S)-BINAPOEtCN, 24 h8796:492
3(R,R)-DIOPOEtCN, 5 h8092:892
4(S)-SEGPHOSOEtCN, 24 h1772:2861
5(R)-BQNOEtCN, 24 h6894:680[c]
6(R)-BIQNOEtCN, 24 h7595:54

Having discovered several effective catalysts, we next investigated the reductive aldol reaction of a variety of substrates (Table 2). The reactions of several β-monosubstituted enones (1 b-d) with benzaldehyde (2 a) were smoothly catalyzed by (S)-BINAPO to afford the corresponding adducts in good yields with high syn diastereo- and enantioselectivities (Table 2, entries 1–4).11 Dichloromethane was found to provide a higher yield and enantioselectivity than did propionitrile in the reaction of β-ionone, although diastereoselectivities were comparable in the two solvents (Table 2, entries 2 vs. 3). The rapid transformation of enone 1 d, which bears a bulky isopropyl group, presumably results from the substrate’s preference for the s-cis conformation, which is favorable for the conjugate reduction (Table 2, entry 4).12, 13

Table 2. Enantioselective reductive aldol reaction of various enones and aldehydes.[a]inline image
EntryEnoneAldehydet [h]ProductYield [%]syn/antiee [%] (syn)
  1. [a] Unless otherwise noted, reactions were carried out by addition of trichlorosilane (1.0 mmol, ca. 3 M solution in CH2Cl2) to a solution of an enone (0.5 mmol), an aldehyde (0.6 mmol), and (S)-BINAPO (10 mol %) in EtCN (2 mL) at −78 °C. [b] R=2,6,6-trimethyl-1-cyclohexenyl (β-ionone). [c] With benzaldehyde (2 equiv) in CH2Cl2 instead of EtCN. [d] With (R,R)-DIOPO (10 mol %) instead of (S)-BINAPO.

11 b2 a243 b7094:691
21 c2 a243 c3799:191
3[c]1 c2 a213 c6799:196
41 d2 a1.53 d7499:197
51 a2 b83 e7295:585
61 a2 c63 f8499:190
71 a2 d243 g7897:394
81 a2 e243 h5895:596
91 a2 f243 i9195:551
101 a2 g83 j7198:250
11[d]1 a2 f4.53 i7195:585
12[d]1 a2 g243 j9299:198

Using chalcone (1 a) as the enone component, (S)-BINAPO-catalyzed reactions with other aldehydes were investigated (Table 2, entries 5–10).10, 11p-Anisaldehyde (2 b) and 2-furaldehyde (2 c) having electron-rich aromatic rings showed higher reactivity than benzaldehyde (2 a; see Table 1, entry 2), but the enantioselectivity was slightly decreased (Table 2, entries 5 and 6). On the other hand, an opposite tendency was observed for p-bromobenzaldehyde (2 d) and p-nitrobenzaldehyde (2 e) having electron-withdrawing substituents, which resulted in higher enantioselectivity (Table 2, entries 7 and 8). In all cases, high syn diastereoselectivities were observed. The reaction tolerated α,β-unsaturated aldehydes to give the corresponding adducts in good yields with high syn diastereoselectivity and moderate enantioselectivity (Table 2, entries 9 and 10). For the reaction of these enals, significantly improved enantioselectivity was obtained by using (R,R)-DIOPO instead of (S)-BINAPO (Table 2, entries 11 and 12). It is noteworthy that the enone was chemoselectively reduced with trichlorosilane in the presence of enals. The low reactivity of α,β-unsaturated aldehydes in the conjugate reduction might be attributed to unfavorable conformations of enals in the reaction (see Figure 2).13 As shown in Figure 2 a, the s-trans conformer predominates for enals. Furthermore, the trichlorosilane–Lewis base complex predominantly coordinates to the sterically less hindered lone pair of the carbonyl oxygen leading to anti complex B, even in the s-cis conformation (Figure 2 b). Both the s-trans conformation and anti complex B are unfavorable for the six-membered transition state required for the conjugate reduction.

Figure 2.

Conformational preference of α,β-unsaturated aldehydes and their trichlorosilane complexes.

Preliminary investigation has indicated that the current method can be applied to an intramolecular process (Scheme 2).14 The (S)-BINAPO-catalyzed reaction of keto-enone 414c with trichlorosilane proceeded smoothly at −40 °C to give the expected cyclized product cis-5 in a good yield, but with low enantioselectivity. The enantioselectivity was improved when (R)-BIQNO was used instead of BINAPO, although the yield was moderate.15 Further improvement of the intramolecular transformation is under investigation.

Scheme 2.

Intramolecular enantioselective reductive aldol reaction.

In summary, we have demonstrated that the reductive aldol reaction of enones and aldehydes with trichlorosilane is catalyzed by chiral Lewis base organocatalysts to afford optically active β-hydroxy ketones with good to high diastereo- and enantioselectivities. Further investigations including extension of the scope of the reaction and application to natural product synthesis are currently underway.

Experimental Section

General procedure for enantioselective reductive aldol reaction with trichlorosilane: To a solution of a chiral Lewis base (10 mol %), an enone (0.5 mmol), and an aldehyde (0.6 mmol, 1.2 equiv) in dry propionitrile (2 mL) was added dropwise trichlorosilane (ca. 3 M CH2Cl2 solution, 2 equiv) at −78 °C. The reaction was monitored by TLC analysis. After the enone was consumed or no significant change was observed, the reaction was quenched with sat. aqueous NaHCO3 (3 mL). After addition of ethyl acetate (10 mL), the mixture was stirred for 1 h, filtered through a celite pad and extracted with ethyl acetate (3×). The combined organic layers were washed with brine (1×), dried over anhydrous MgSO4, filtered, and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20:1–3:1) to give the corresponding aldol product.


This work partially supported by a Grant-in-Aid of Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.