Catalytic Enantioselective Aldol Additions with Chiral Lewis Bases

The advances that have taken place over the past five years in catalytic, enantioselective aldol addition reactions is evident in a number of important respects. The types of transition metals and their complexes that function competently as catalysts have been expanded considerably. Thus, in addition to B(III), Ag(I), Au(I), Sn(II), and La(III), chiral catalysts prepared from Cu(II), Ti(IV), Ln(III), Si(IV), Pt(II) and Pd(II) have been introduced. The expansion in the use of transition metals has taken place hand-in-hand with the design and synthesis of new bidentate and tridentate organic ligands based on nitrogen, oxygen, and phosphorus donors. Additionally, whereas the older methods primarily relied on the use of Lewis-acids for the activation of... 

The first catalytic, diastereoselective and enantioselective cross-aldol reactions of aldehydes have also been documented. Geometrically defined trichlorosilyl enolate derivatives of aldehydes undergo diastereoselective addition to a wide range of aldehyde acceptors with good enantioselectivity. The use of chiral Lewis base (138) was critical for achieving useful enantioselectivity. ... 

Introduction. The preparation of 1 was first reported by Baukov and co-workers in 1966. Thirty years later, Denmark et al. demonstrated its unique reactivity as an aldolizationreagent. Under catalysis by Lewis bases, a variety of aldehydes and ketones react smoothly with 1 at room temperature to afford the al-dol addition products in high yields. Catalytic, asymmetric aldol additions of 1 have also been demonstrated with both aldehyde and ketone substrates. However, the level of enantioselection is highly variable and dependent on the substrate. Synthetically useful enantioselectivities have been achieved with aldehydes using chiral phosphoramides and with aryl ketones using a chiral bipyridine bis-Ai-oxide catalyst. 

Catalytic, enantioselective addition of silyl ketene acetals to aldehydes has been carried out using a variant of bifunctional catalysis Lewis base activation of Lewis acids.145 The weakly acidic SiCU has been activated with a strongly basic phor-phoramide (the latter chiral), to form a chiral Lewis acid in situ. It has also been extended to vinylogous aldol reactions of silyl dienol ethers derived from esters. 

This concept of Lewis base catalysis has been widely developed by Denmark and coworkers in the asymmetric aldol additions of trichlorosilyl enolates on aldehydes. These reactions were shown to be highly susceptible to acceleration by catalytic quantities of chiral phosphoramides [69-77]. In particular, a phos-phoramide derived from (S,S)-stilbenediamine was remarkably effective not only in accelerating the reaction but also in modulating the diastereoselectivity and in providing the aldol addition products in good to excellent enantioselec-tivity. For example, trichlorosilyl enolate 61 reacts with benzaldehyde in very high enantio- and diastereoselectivity with 10 mol% of phosphoramide 62 in favor of the anti diastereomer (antifsyn 60/1). The catalyzed aldol reaction depends on the bulkiness and loading of the catalyst. On the other hand, the hindered phosphoramide (S,S)-63 afforded the syn aldol product in excellent diastereoselectivity (anti syn 1/97) but with modest enantioselectivity. 

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