Vinylogous, chiral aldol reactions

Scheme 28 Vinylogous Mukaiyama aldol reaction using chiral aldehydes...

Using chiral catalysts, not only various enantioselective Mukaiyama and vinylogous Mukaiyama aldol reactions have been developed but also asymmetric reactions of a,a-difluoro silyl enol ethers (1) with carbonyl compounds have been reported ... 

A range of chiral pre-organized diols have been studied to assess their potential to catalyse vinylogous Mukaiyama aldol reactions enantioselectively via hydrogen bonds.141... 

A ternary chelate of TiCU, sparteine and the A-acetyl derivative of the tricyclic thiazoli-dinethione 74 acts as a chiral donor in aldol reaction with aldehydes. The tryptophan-derived oxazaborolidinone 75 is serviceable in completing the vinylogous Mukaiyama aldol reaction to furnish chiral products. ... 

A silver salt dramatically reverses the diastereoselectivity of a titanium-chloride-mediated vinylogous Mukaiyama aldol reaction of a chiral vinylketene silyl N, 0-acetal with ethyl glyoxolate. ° ... 

The synthesis of the carboxylic acid 9a commenced with silylation of known alcohol 16 followed by reductive removal of the chiral auxiliary to give the aldehyde 17 (Scheme 3). Vinylogous Mukaiyama aldol reaction" " of 17 with Chan s diene 18" afforded the alcohol 19 in 95% yield with 10 1 diastereoselectivity. Treatment of 19 with PPTS in MeOH resulted in cleavage of the silyl ether and spontaneous methyl acetalization to provide the methyl acetal 20. Protection of the hydroxyl group of 20 by using MPM trichloroacetimidate in the presence of La(OTf >3" gave the MPM ether 21. Hydrolysis of the methyl ester of 21 afforded the carboxylic acid 9a. 

Remote asymmetric induction can be obtained through the use of chiral auxiliaries, such as valine derived oxazolidinones, within the framework of the vinylogous Mukaiyama aldol reaction. During the synthesis of khafrefungin, an antifungal agent, Kobayashi and coworkers reacted the vinylketene silyl A. O-acetal 56 with the aldehyde 57 to yield the a r/-aldol adduct 58 in excellent yield (98%) and high diastereoselectivity (> 20 1). ... 

Scheme 1.7 Total synthesis of (-)-rasfonin through diastere-oselective vinylogous Mukaiyama aldol reaction promoted by chiral BLA (2b).

As practiced in the preceding syntheses by Evans and Nishiyama and Yamamura, the A-ring fragment 43 is formed through substrate-directed vinylogous aldol reaction of the Brassard-type diene 19 and the chiral aldehyde 42, which is prepared using Brown s protocols for enantioselective allylation [53], followed by hydroxy-directed nnn-diastereoselective reduction of the C3 ketone (Me4NB(OAc)3H) [41],... 

Scheme 18 Vinylogous aldol reactions with chiral aldehyde 44...

The Rawal group next applied diol catalysis to the enantioselective vinylogous Mukaiyama aldol (VMA) reaction of electron-deficient aldehydes [105]. Screening of various known chiral diol derivatives, including VANOL, VAPOL, BINOL, BAMOL, and TADDOL, revealed that 38a was the only catalyst capable of providing products in acceptable levels ofenantioselection (Scheme 5.55). Subsequent to this work, Scettri reported a similar study of TADDOL-promoted VMA reactions with Chan s diene [106]. 

Campagne and Bluet recently reported the catalytic asymmetric vinylogous Mukaiyama aldol (CAVM) reaction of aldehydes with dienol silyl ether 15 using chiral ammonium fluorides as an activator. For example, the CAVM reaction of isobutyr-aldehyde with 15 in the presence of 10 mol% of 4b in THF at room temperature led to the formation of the vinylogous aldol product 16 in 70% yield with 20% ee. The ee-value was improved to 30% by conducting the reaction at 0 °C (Scheme 9.6) [16]. 

Chiral sulfoximines liganded to copper(II) give highly enantioselective vinylogous Mukaiyama-type aldol reactions under mild conditions.137 A chiral sulfinyl group has been used to achieve 1,5- and 1,6-asymmetric induction in Mukaiyama aldols, using Yb(OTf)3 catalysis.138... 

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. 

Scheme 19.55 Direct vinylogous aldol reaction promoted by a chiral bifunctional primary amine-thiourea.

The observed excellent stereoselectivities (dr=91 9 to >95 5, 94 to >99% ee) could be ascribed to the steric hindrance created by the employed catalyst in each step of the catalytic cycle reported below (Scheme 2.56). Once the chiral amine (S)-70 activates the acrolein 131 as electrophile by generating the vinylogous iminium ion A, the indole 171 performs an intermolecular Friedel-Crafts-type reaction. The resulting enamine B acts as nucleophile in the Michael addition of the nitroalkene 140 leading to the iminium ion D, which upon hydrolysis liberates the catalyst and yields the intermediate aldehyde 173. The latter compound enters in the second cycle by reacting with the iminium ion A, previously formed by the free catalyst. The subsequent intramolecular enamine-mediated aldol reaction of E completes the ring closure generating the intermediate F, which after dehydration and hydrolysis is transformed in the desired indole 172. 

A versatile y-vinylogous aldol reaction of a dioxinone-derived silyl enol ether, by enolate activation with an appropriate Lewis base, has been developed. Using chi- ral 2-(methylsulfinyl)benzaldehyde, adduct (69) has been obtained in high de and ee. 0 This 1,4-asymmetric induction features a dual role for the sulfinyl group chiral inductor and activator of a silyloxydiene. 

In addition to the studies mentioned above, chiral alcohols have been used as H-bonding catalysts in a vinylogous aldol reaction of Chan s diene with aldehydes [73], in an enantioselective Strecker reaction [74], and in the enantioselective addition of aza-enamines to imines [75]. Taddol has also found use as a memory of chirality enhancer in the stereoselective synthesis of (i-lactams from amino acid derivatives [76, 77]. 

Terada and coworkers reported, in 2010, an enantioselective, direct vinylogous aldol reaction of furanone derivatives with aromatic aldehydes catalyzed by axiaUy chiral guanidines (Scheme 10.49) [142]. Initial catalyst screening revealed that both the buUdness and the electronic nature of the G substituent on the guanidine had a large influence on catalytic activity as well as enantio- and diastereoselectivity. 

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