Asymmetric Pudovik Reactions

Scheme 19.60 Asymmetric Pudovik reactions catalysed by an Al-Schiff base or tethered Al-bis(8-quinolinato).

The base-catalysed hydrophosphonylation of aldehydes or imines (Pudovik reaction) [58] as a convenient method was widely used for the synthesis of 1-hydrox-yalkylphosphonates. Since the pioneering work of Shibuya [50] and Spilling [51] was reported, much attention has been devoted to developing enantioselective catalysts for the synthesis of chiral 1 -hydroxy alkylphosphonates. Chiral aluminium complexes were shown to be more effective chiral catalysts [59-62]. Based on the success of using A1 (salen) and A1 (salcyen) as asymmetric catalysts, Al-Schiff base complexes [63, 64] have been developed to catalyze the asymmetric addition reaction of dial-kylphosphonates and aldehydes. Tridentate Schiff base metal complexes, such as vanadium, chromium, and iron [65], have been successfully applied in many asymmetric synthetic reactions. We noticed that Al(III) complexes could catalyse the asymmetric Pudovik reaction and these ligands could be easily synthesized [66-70]. 

Yokomatsu T, Yamagishi T, Shibuya S (1997) Enantioselective synthesis of a-hydroxyphosphonates through asymmetric Pudovik reactions with chiral lanthanoid and titaniumaikoxides. J Chem Soc Perkin Trans 1 1527-1534... 

Metal-catalyzed asymmetric addition of dialkyl phosphites to aldehydes (Pudovik reaction) has been extensively developed since the initial reports in 1993 by Shibuya. Scheme 5-25 illustrates the use of TiCh to promote diastereoselective addition of diethyl phosphite to an a-amino aldehyde. 

The most successful asymmetric variants of the Abramov reaction employ chiral substrates, either chiral carbonyl compounds or aldimines, or chiral phosphorus(III) reagents.5,51,86,88 However, the Pudovik reaction using chiral catalysts is a superior route for the asymmetric synthesis of a-hydroxy- and a-aminophosphonates (Section 6). 

Asymmetric catalysis of the Pudovik reaction is an area of active study with numerous success stories, mostly featuring chiral Lewis acid catalysts, and further developments are anticipated.39,86,87 Shibasaki and co-workers heterobimetallic catalysts108 are the best developed in this field, for both aldehyde and aldimine substrates. 

A bimetallic catalyst prepared from BINOL and lithium aluminum hydride has been found to result in useful asymmetric induction in the Pudovik reaction [17]. The (f )-ALB catalyst 64 (10 mol %) facilitates the addition of dimethyl phosphite to a variety of electron-rich and electron-poor aryl aldehydes in high yield with induction in the range 71-90 % ee. The nature of the solvent is important in this reaction—the induction for addition to benzaldehyde dropped from 85 % ee to 65 % ee when the solvent was changed from toluene to dichloromethane. Aluminum seems to be a key to the success of this reaction, because reaction with benzaldehyde was not as successful with other bimetallic catalysts. BINOL catalysts with lanthanum and potassium gave only 2 % ee, a catalyst with lanthanum and sodium gave a low 32 % ee, and a catalyst with lanthanum and lithium gave only a 28 % ee [18]. Aliphatic aldehydes were not successfully hydrophosphonylated with dimethyl phosphite by catalyst 64 (Sch. 9). Induction was low (3-24 % ee) for unbranched and branched substrates. a,/3-Unsaturated aldehydes were, however, reported to work nearly as well as aryl aldehydes with four examples in the range 55-89 % ee. The failure of aliphatic aldehydes with this catalyst can be overcome by reduction of the product obtained from reactions with a,)3-unsaturated aldehydes. As illustrated by the reduction of 67 with palladium on carbon, this can be done without epimerization of the a-hydroxy phos-phonate. 

Enantioselective addition of various nucleophiles to carbonyl compounds has received significant attention in modem asymmetric synthesis. This objective has been accomplished with the aid of chiral organoaluminum complexes. Kee et al. examined organoaluminum-chiral salen complex 55 catalyzed addition of dialkylphosphites 56 to aldehydes, known as Pudovik reaction, to give a-hydroxyphosphonates 57 (Scheme 39) [70, 71]. 

Asymmetric versions of these reactions, in which a stereocenter adjacent to the phosphorus is created in a controlled fashion, have been also developed " These rely either on diastereoselective reactions involving optically active starting material (a carbonyl compound or a phosphite) or on chiral catalysis. The Pudovik reaction with enantiopure nucleophiles containing a chiral phosphorus atom was found to occur without epimerization however, this feature has not been exploited yet in the synthesis of natural products or their analogs. ... 

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