Highly Diastereoselective, Tandem, Three‐Component Synthesis of Tetrahydrofurans from Ketoaldehydes via Silylated β‐Lactone Intermediates

Abstract

Processes that form multiple bonds and stereocenters in a single reaction, without the isolation of intermediates, are known as tandem, domino, multicomponent, or cascade reactions.[1] They are powerful complexity-building reactions. We have developed stereoselective routes to both cis [2] and trans [3] b-lactones 5 through tandem Mukaiyama aldollactonization (TMAL) processes [4] between thiopyridyl ketene acetal 2 and aldehyde 1 (Scheme 1, pathway a). This methodology has been utilized in total syntheses of (À)-panclicin D, [5] orlistat and its congeners, [6] okinonellins, [7] brefeldin A, [8] and belactosin C. [9] In the course of these studies, we identified several by-products (e.g. b-chlorosilylester 4; Scheme 1, pathway b) that led us to propose the silylated b-lactone intermediate 3 in the TMAL process. Thus we considered methods for intercepting these intermediates to enable the study of useful complexity-building processes.Mead and Pillai have reported Lewis acid promoted reductive cyclizations of simple keto-b-lactones for tetrahydrofuran (THF) synthesis. This approach suggested the possibility of utilizing aldehyde substrates bearing pendant ketones that could undergo reductive cyclization in the TMAL process (Scheme 2).[10] The THF motif is commonly found in natural products, and while several approaches toward these heterocycles exist, many routes rely on CÀO bond formation of relatively complex substrates or proceed through oxocarbenium ions derived from O-glycosides.[11]Herein we describe the development of a tandem, threecomponent synthesis of THFs 9 from g-ketoaldehydes 6, thiopyridyl ketene acetals 2, and silyl nucleophiles in which up to two CÀC bonds, one CÀO bond, and three new stereocenters are generated.Initially, we sought further evidence for the postulated intermediacy of the silylated b-lactone 3 in the TMAL process. Previously we reported a correlation between the size of the silyl group of ketene acetals 2 a-c and product distribution leading to either b-lactone 5 a (20-66 %) or b-chlorosilyl esters 4 a-c (5-40 %; Scheme 3).[5] However, in Scheme 2. Proposed three-component synthesis of tetrahydrofuran 9 from ketoaldehyde 6, thiopyridyl ketene acetal 2, and a silyl nucleophile via a postulated silylated b-lactone intermediate 7.Scheme 3. Effect of varying the silyl group of ketene acetals 2 a-d on the product distribution of the TMAL process with octanal (1 a). SiR 3 : a: TES (triethylsilyl); b: TBS (tert-butyldimethylsilyl); c: TIPS (triisopropylsilyl); d: TBDPS (tert-butyldiphenylsilyl), R 1 = CH 3 (CH 2 ) 6 .

Counteranion‐Directed Catalysis in the Tsuji–Trost Reaction: Stereocontrolled Access to 2,5‐Disubstituted 3‐Hydroxy‐Tetrahydrofurans

“…[18] Many of these have very intriguing structures and/or interesting biological properties, hence the existence of a great number of strategies and methods that are aimed at their synthesis. [19] The very encouraging results mentioned above led us to subject complex allylacetates to this reaction in order to evaluate the scope of this transformation with regard to the synthesis of fragments of natural products. Thus, we synthesized 28, the C9-C19 fragment of (+)-oocydin A (1).…”