Mukaiyama aldol addition to α-chloro-substituted aldehydes. Origin of the unexpected syn selectivity

Abstract

The addition of sterically demanding enolsilanes to alpha-chloro aldehydes results unexpectedly in preferential formation of the anti-PFA product (1,2-syn), while the addition of the corresponding boron enolate furnishes the expected polar Felkin-Anh product (1,2-anti). A stereoinduction model explaining these observations is proposed.

Diastereoselective Nucleophilic Addition to Aldehydes with Polar α‐ and α,β‐Substituents

“…It is also evident that both a-silyloxy aldehyde 3 [10] and a-fluoro aldehyde 4 follows a similar trend in diastereoselectivity when changing the size of the enol silane (Table 1, entries 7-9 and 10-12, respectively), and it is suggested that similar factors as those outlined in Scheme 4 also dictate the outcome for these substrates. [25] The higher anti selectivity obtained in the Mukaiyama aldol addition to 3 (X = O) and 4 (X = F) compared to 1 and 2 (X = Cl) could then be rationalized as a manifestation of the increased electronegativity of the a-heteroatom substituent, which should destabilize the TS structure corresponding to J, as is observed (Table 1, entries [7][8][9][10][11][12].…”

“…[12] Addition of E(O)-enolate 22 [16] to aldehyde 1 furnished adduct 24b in modest yield and selectivity, while the use of Z(O)-enolate 23 [16] afforded 25b in excellent yield and selectivity which indicates that also 1 prefers to react through a CornforthEvans TS in boron-mediated aldol reactions. Given these results it is then not clear why achloro-, a-alkoxy-and a-fluoro-substituted aldehydes react with poor Cornforth-Evans, or even anti-Cornforth-Evans, selectivity in the Mukaiyama aldol reaction (Table 1, entries [1][2][3][4][5][6][7][8][9][10][11][12]. It is generally accepted that the reaction proceeds through an open TS, [6a,17] having either antiperiplanar or synclinal TS conformations, although exceptions are known.…”

“…Minor isomer 18a. A C H T U N G T R E N N U N G (5R*,6S*)-6-(N-Benzyl-N-tosylamino)-5-hydroxy-2,2,7-trimethyloctan-3-one (19b) [12] Prepared from aldehyde 5 as described for 7a and 7b to afford 19b as a colorless oil; yield: 90 mg (85%); dr > 2:98 (syn:anti).…”

“…[12,13] Herein, we report our full investigation of the nucleophilic addition to a-and a,b-polar substituted aldehydes, including chloro-, fluoro-, alkoxy-and amino-substituted aldehydes. …”

Stereoselective Acetate Aldol Reactions

“…As shown in Scheme 1.18, addition of silyl ketene S,O-acetal (36a) to chiral α-OPMB aldehyde (37) in the presence of 1.1 equiv of TiCl 3 (i-PrO) gave 3,4-syn aldol (38) with exceptional diastereoselectivity in 64% yield [32]. Moreover, Forsyth reported that the addition of mild Lewis acid MgBr 2 · OEt 2 to a mixture of chiral silyl enol ether (39) and α-OPMB aldehyde (40) triggered a smooth aldol reaction that furnished 3,4-syn aldol (41) as a single diastereomer in 79% yield, which was further elaborated to a hapten for azaspiracids (Scheme 1. 19) [33].…”