Organocatalytic Stereoselective Direct Aldol Reaction of Trifluoroethyl Thioesters

Abstract

The first organocatalytic, stereoselective and direct aldol reaction of activated thioesters with aldehydes has been accomplished. The trichlorosilyl ketene thioacetal generated in situ by adding a tertiary amine to a trifluoroethyl thioester in the presence of tetrachlorosilane is activated by catalytic amounts of an enantiomerically pure biheteroaromatic phosphine oxide to react with different aldehydes, coordinated to as well as activated by the chiral cationic hypervalent silicon species. Starting from a variety of readily available thioesters, this Lewis acid-mediated Lewis base-catalyzed transformation allows the direct synthesis of syn-b-hydroxy thioesters in up to 95% ee.Keywords: aldol reaction; organocatalysis; phosphine oxides; tetrachlorosilane; thioesters The development of a direct diastereo-and enantioselective, catalytic aldol reaction of esters with carbonyl derivatives remains one of the unsolved challenges in organocatalysis.[1] The difficulty of successfully realizing such a transformation arises from the lower acidity of the a protons of carboxylic esters compared to those of a ketone or an aldehyde. Indeed, the pK a value for ester derivatives (ca. 19) [2] is significantly higher than that (ca. 16-17) necessary to activate a nucleophilic substrate via amine catalysis.[3] Since reactions with donors in the ester oxidation state via an enamine-based organocatalytic approach are not feasible, [4] and thioesters may react with a secondary amine to afford the corresponding amide, activation of the ester nucleophile is necessary. Taking inspiration from Nature, a few groups have recently studied the possibility to perform catalytic stereoselective transformations with malonic acid hemithioesters, exploiting either organometallic or metal-free catalysis. For the organometallic approach Shairs group and ours [5a,b] have investigated the use of chiral copper(II) complexes in the malonic acid hemithioester addition to aldehydes. Studying the metal-free methodology Riccis group has realized a decarboxylative addition to imines catalyzed by a readily available Cinchonabased compound to afford b-amino thioesters in up to 79% ee [6] At the same time, Wennemers showed that a bifunctional thiourea derivative of a Cinchona alkaloid could efficiently promote the enantioselective 1,4-addition of malonic acid hemithioesters to nitro-A C H T U N G T R E N N U N G olefins under mild conditions and in up to 90% ee [7] More recently, Ricci and Bernardi reported an efficient stereoselective Mannich reaction of sulfonylacetates with N-carbamoylimines under phase-transfer catalysis conditions in the presence of a quinine-derived chiral ammonium salt; [8] in this case, further synthetic elaboration was necessary to convert the reaction products into b-amino esters.An alternative approach has been recently investigated by Barbas who introduced the use of trifluoroethyl thioesters as activated nucleophilic substrates suitable for organocatalytic amine activation. [9] In the attempt to have access to a set of r...

Synthesis of novel chiral bithiophenebased phosphine oxides as Lewis bases in organocatalytic stereoselective reactions

“…[31] As previously reported, tetraMe-BITIOPO (6) can be employed as an efficient metal-free catalyst in many organic reactions giving often better results than when the corresponding binaphtyl analogue (S)-BINAPO (5) is employed. [15,16,25,26] The ability of tetraMe-BITIOPO to promote a reaction is related to its electronic properties; tetraMe-BITIOPO is indeed more electron rich than BINAPO because of the presence of two thiophene rings in place of the binaphthyl scaffold. This electronic difference is responsible for difference in chemical efficiency, as seen in the direct aldol addition of activated thioesters to benzaldehyde promoted by SiCl 4 (Scheme 2).…”

“…Phosphine oxides have been employed as organocatalysts in several chemical transformations including enantioselective addition of allyltrichlorosilanes to aldehydes [3][4][5], ring opening of meso-epoxides [3,[6][7][8], the Abramov-type phosphonylation of carbonyl compounds [8,9] and for the synthesis of γ-amino alcohols [10] and oxazines [11]. Furthermore, phosphine oxides are excellent catalysts for aldol reactions involving trichlorosilyl enolethers [12] and silyl ketene acetals, [13] and also for direct, cross, intermolecular, [14] and double aldol-type reactions involving aldehydes, ketones [15][16][17][18][19][20][21][22][23][24] or thioesters [25,26]. More recently, this class of compounds have found application in reductive aldol reactions in the presence of tertiary amines, [27,28] and in the Morita-Baylis-Hillman reaction [29].…”

Synthesis, Characterisation, and Organocatalytic Activity of Chiral Tetrathiahelicene Diphosphine Oxides

“…The direct addition of the activated thioester 5 to benzaldehyde, in the presence of a stoichiometric amount of tetrachlorosilane was first studied (Table 2). 15a…”

“…With enantiopure catalyst (+)‐ 2b , although only a marginal improvement in the enantioselectivity was observed [Table 2, entries 2 and 5; 12 % ee with catalyst (+)‐ 2a vs. 23 % ee with catalyst (+)‐ 2b ], 6 was obtained in high yield and excellent syn selectivity (Table 2, entry 5) 20. For comparison, with respect to phosphine oxides (+)‐ 2a and (+)‐ 2b , commonly used (–)‐BINAPO catalysed the reaction under the same reaction conditions in a significantly lower chemical yield, comparable syn / anti diastereoselectivity, but higher enantioselectivity (compare Table 2, entries 2 and 5 with entry 7) 15a…”

“…Solutions of n BuLi (1.6 M in hexane) were purchased and titrated prior to use. Tetrathiahelicene (±)‐ 1 ,10d thioester 5 ,15a,15e and N ‐benzyl‐1‐phenylethanimine ( 7 )15a,15e were prepared as described in the literature. Reactions were monitored by thin‐layer chromatography (TLC) on Merck precoated plates (silica gel 60 F254).…”