Asymmetric, Organocatalytic, Three-Step Synthesis of α-Hydroxy-(E)-β,γ-unsaturated Esters

Abstract

An efficient and enantiocontrolled 3-step synthesis of α-hydroxy-(E)-β,γ-unsaturated esters is reported. Enantioenriched α-selenyl aldehydes, prepared in one step by asymmetric, organocatalytic α-selenylation of aldehydes, were directly subjected to a Wittig reaction followed by allylic selenide to selenoxide oxidation and final spontaneous [2,3]-sigmatropic rearrangement to yield the target compounds in 43-65 % overall yield and in 94-97 % ee.Asymmetric synthesis utilizing organoselenium compounds has become increasingly popular in recent years. 1 Selenium incorporation can be done in either a nucleophilic or an electrophilic fashion. 2 Once selenium is introduced into the molecule, many different chemical transformations can occur including oxidations leading to either syn-elimination 3 or, in the case of an allylic selenide, [2,3]-sigmatropic rearrangement to give an allylic alcohol. 4 Pursuing our recently published work preparing chiral non-racemic γ-hydroxy-(E)-α,β-unsaturated sulfones and esters, 5 we have developed a complementary asymmetric synthetic method producing α-hydroxy-(E)-β,γ-unsaturated esters.α-Hydroxy esters and their corresponding acids are key structural units of valuable synthetic intermediates as well as natural products. 1,6 Based on the utility of these structural units, we set out to design a simple, asymmetric general strategy for their synthesis. Suprisingly, most reports of selenium oxidation and [2,3]-sigmatroptic rearrangements have been done utilizing chiral oxidants as opposed to installing chirality prior to oxidation. 7 There have been a few reports involving diastereoselective oxidations of selenides containing chiral moieties, 8 but the scope is quite limited, with low to moderate yields and only modest diastereomeric excess (de). Other methods have also been reported using conformationally locked ring systems to induce stereocontrol. 9 ghp@jhu.edu. Supporting Information Available: Experimental procedures and full spectroscopic data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. Recent reports on the organocatalytic, asymmetric α-selenenylation of aldehydes in high yields (> 85 %) and high enantiomeric excess (> 95 %) 10,11 gave an excellent method for controlling the absolute stereochemistry of our α-hydroxy-(E)-β,γ-unsaturated target systems. NIH Public AccessWe chose a variety of aldehydes (3-phenylpropanal, 2-cyclohexylethanal, N-Boc-4-piperidineethanal, hexadecanal, and 6-benzyloxyhexanal) as well as three different ester functional groups (OMe, O-t-butyl, and O-benzyl) to determine the generality of this reaction. α-Selenyl aldehydes 3a-e, prepared according to an Italian protocol, 11 were immediately subjected in situ to a Wittig reaction to give the enantiomerically enriched compounds 5-11 (Scheme 1, A) in 48-83 % yields. Oxidation of the γ-seleneyl-(E)-α,β-unsaturated esters to the selenoxide using hydrogen peroxide caused spontaneous [2,3]-sigmatropic rearrangement to give the final enantioenric...

Total Synthesis of Symbioramide: a Flexible Approach for the Efficient Preparation of Structural Isomers

“…More recently, Posner et al. achieved a formal synthesis of symbioramide by using an elegant asymmetric organocatalytic approach to α‐hydroxy ( E )‐β,γ‐unsaturated esters 6…”

Organocatalysis in Total Synthesis

“…Among other examples, α-oxidation is the most frequent one: 7,8-O-isopropylidene iriomoteolide-3a [15], (+)-neosymbioimine [16], (+)-and ()-disparlure [17], ()-(5R,6S)-6-acetoxy-5-hexadecanolide [18], and Hagen's gland lactones [19]; followed by α-amination: chloptosin [20], (S)-AIDA [21], and Licopodium alkaloids [22]. Sometimes α-heterofuntionalization of carbonyl compounds is necessary to form a temporal reactive intermediate, as is the case of α-selenylation: (+)-symbioramide [23], and α-chlorination: ripostatin B [24]. Moreover, organocatalytic Michael addition is other main C-C bond-forming strategy widely used in natural product synthesis.…”

Chiral Cobalt(II) Complex Catalyzed Asymmetric [2,3]-Sigmatropic Rearrangement of Allylic Selenides with α-Diazo Pyrazoleamides

“…9,12 Despite the great efforts that have been devoted to the construction of C-Se stereocenters with chiral starting materials, [1][2][3][4][5][6][7][8][15][16][17][18][19][20][21][22] the enantioselective catalytic route to novel optically active organoselenium compounds is less known and investigated. [23][24][25][26][27][28][29][30] The asymmetric catalytic methods are appealing in terms of versatile reactivity and interesting stereochemistry of selenium during the process. Asymmetric α-selenenylation of aldehydes and β-keto esters have been reported by the use of electrophilic selenium sources (Scheme 1a).…”

“…Asymmetric α-selenenylation of aldehydes and β-keto esters have been reported by the use of electrophilic selenium sources (Scheme 1a). [24][25][26][27][28] The kinetic resolution of selenocarbonates via a chiral palladiumcatalyzed decarboxylative coupling to provide optically active allylic selenides was achieved (Scheme 1b). 29 Recently, an asymmetric hydroselenation of heterobicyclic alkenes was developed to afford chiral selenolincorporated adducts.…”