Enantioselective aldol reactions with masked fluoroacetates

Abstract

Despite the growing importance of organofluorines as pharmaceuticals and agrochemicals, the stereoselective introduction of fluorine into many prominent classes of natural products and chemotherapeutic agents is difficult. One long-standing unsolved challenge is the enantioselective aldol reaction of fluoroacetate to enable access to fluorinated analogues of medicinally relevant acetate-derived compounds, such as polyketides and statins. Herein we present fluoromalonic acid halfthioesters as biomimetic surrogates of fluoroacetate and demonstrate their use in highly stereoselective aldol reactions that proceed under mild organocatalytic conditions. We also show that the methodology can be extended to formal aldol reactions with fluoroacetaldehyde and consecutive aldol reactions. The synthetic utility of the fluorinated aldol products is illustrated by the synthesis of a fluorinated derivative of the top-selling drug atorvastatin. The results show the prospects of the method for the enantioselective introduction of fluoroacetate to access a wide variety of highly functionalized fluorinated compounds.

An Enantio‐ and Diastereoselective Chemoenzymatic Synthesis of α‐Fluoro β‐Hydroxy Carboxylic Esters

“…In conclusion, we have developed ar obust chemoenzymatic synthesis of a-fluoro b-hydroxy esters.The scope of the approach is broad, enabling the conversion of many aromatic and heteroaromatic aldehydes into chiral products with > 98 % ee and high diastereoselectivity.C rucially,t he syn diasteroselectivity of the process complements the anti selectivity of ar ecent organocatalysed synthesis of a-fluoro thioesters. [12] Moreover,t he distinctive products have molecular properties suitable for application as high-quality fragments and building blocks for drug discovery. After 30 min of vigorous stirring,the reaction mixturewas cooled to 0 8 8Ca nd Na 2 S 2 O 5 (solid) was slowly added, before the water was removed in vacuo to reveal ac rude product.…”

“…[11] Very recently, an enantioselective organocatalysed reaction of fluoromalonic acid halfthioesters has been developed that yields the corresponding anti-configured a-fluoro thioester aldol adducts. [12] We therefore envisaged ac omplementary approach in which fluoropyruvic acid (4)w ould serve as an alternative synthetic equivalent for fluoroacetate in an aldolase-catalysed aldol reaction. [13] Aldolase-catalysed reaction of fluoropyruvate (4)and aldehydes 1 would result in the formation of a-keto acids 5 which might then be decarboxylated [14] to give the corresponding a-fluoro b-hydroxy carboxylic acids 6.T he approach would complement organocatalysed reactions that yield other classes of a-fluoro carbonyl compounds.…”

“…[13] Aldolase-catalysed reaction of fluoropyruvate (4)and aldehydes 1 would result in the formation of a-keto acids 5 which might then be decarboxylated [14] to give the corresponding a-fluoro b-hydroxy carboxylic acids 6.T he approach would complement organocatalysed reactions that yield other classes of a-fluoro carbonyl compounds. [12,15] TheC lass I( lysine-dependent) aldolase, N-acetyl neuraminic acid lyase (NAL), has been shown to accept fluoropyruvate as an alternative donor substrate to pyruvate. [16] The value of NALi nt he synthesis of fluorinated products is, however, limited by poor stereocontrol and narrow demonstrated substrate scope.M oreover,N AL accepts only polyhydroxylated substrates which often yield products as complex anomeric mixtures of both pyranose and furanose forms.…”

Decarboxylative aldol reaction of α,α-difluoro-β-ketocarboxylate salt: a facile method for generation of difluoroenolate

“…9 Wennemers has reported the rst decarboxylative process for the preparation of uorinated enolate using uoromalonic acid halhioesters (F-MAHT). 10 Recently, two groups have reported the synthesis of a,adiuoro-b-hydroxy ketones using 2,2-diuoro-3-oxo-3-phenylpropanoic acid (1). The rst route was based on an aldol reaction of 1 with aldehydes under metal-free conditions, from the Mao group.…”

Bicatalyzed Three-Component Stereoselective Decarboxylative Fluoro-Aldolization for the Construction of Elongated Fluorohydrins

“…6 Only very recently, the Wennemers group proposed an enantioselective organocatalyzed version of this approach, requiring five steps for the preparation of the fluorinated pro-nucleophile and suffering a substantial decreased enantiocontrol as soon as key aliphatic aldehydes are involved (Scheme 1b). 7 On the other side, the complementary aldolization on preformed enantioenriched fluorinated aldehydes has been largely overlooked and remains challenging, allowing access to only a limited number of vicinal fluorohydrins in lengthy stoichiometric sequences (Scheme 1c). 8,9 In view of a better incorporation of fluorine into polyols scaffolds, all of the abovementioned limitationsnotably, the single access to simple vicinal fluorohydrinsclearly highlight the need for moregeneral methods.…”