Stereoselective Construction of cis-2,6-Disubstituted Tetrahydropyrans via the Reductive Etherification of δ-Trialkylsilyloxy Substituted Ketones:  Total Synthesis of (−)-Centrolobine

Abstract

[reaction: see text] The stereoselective intramolecular reductive etherification of delta-trialkylsilyloxy substituted ketones with catalytic bismuth tribromide and triethylsilane provides a convenient method for the construction of cis-2,6-disubstituted tetrahydropyrans. This method was highlighted in the key step of an expeditious total synthesis of the antibiotic, (-)-centrolobine.

Lipase-Catalyzed Resolution of 1-[4-(Benzyloxy)phenyl]hex-5-en-3-ol: Synthesis of (-)-Centrolobine

“…The compound (S)-5b upon esterificaton using acryloyl Determined by HPLC (Chiracel AS-H column; Daicel) employing nhexane:iso-propanol (9:1) as mobile phase at 0.5 mL/min and monitored at UV (254 nm); e Calculated according to Chen et al [69,70] Et2O afforded the optically pure (-)-centrolobine 1 (Scheme-I). The spectral data of 1 H and 13 C NMR as well as its optical rotation closely match with the previously reported data of the natural product 1 [54,55].…”

“…The enantiomerically pure core unit of tetrahydropyran unit has been constructed by various methods like Prinscyclization [39,40], ring rearrangement metathesis [41], asymmetric allylation [42][43][44][45], asymmetric hydrogenation [46][47][48], chelation controlled diastereoselective synthesis from carbohydrate [49], intramolecular amide enolate alkylation [50], enantioselective hetero Diels-Alder reaction (HDA) [51], the reduction of a β-ketosulfoxide [52,53], intra molecular reductive etherification [54], asymmetric reduction [55]. However, most of these reported methods have certain limitations like use of expensive chiral reagents, low selectivity and moderate yields.…”

A Stereodivergent Synthesis of All Stereoisomers of Centrolobine: Control of Selectivity by a Protecting‐Group Manipulation

“…[20] A major advantage of the reagents (R,R)-and (S,S)-4, derived from C2-symmetric 1,2-cyclohexanediamine, relative to the alternative reagent derived from pseudoephedrine, is the convenient access to both enantiomers. Thus, by using (R,R)-4, the homoallylic alcohol (R)-5 was obtained, whereas (S,S)-4 gave the enantiomer (S)-5 [13] in good yield and with excellent enantioselectivity. The enantiomeric ratio was determined to be > 98:2 by using Moshers method: [21] in the 1 H NMR spectrum of the Mosher esters derived from rac-5, the signals for the AB system of the TBS-protected phenols are baseline separated.…”

“…Since then, further enantioselective syntheses were published by using various key steps, [11] such as [4+2] cycloaddition, [12] cross-metathesis with a reductive etherification, [13,14] a Prins cyclization, [15,16] and a diastereoselective ring rearrangement metathesis. [17,18] In contrast to the 5,6-dehydro-4''-de-O-methylcentrolobines (2) from Alpinia blepharocalyx, no trans-configured epimers of the centrolobines have been isolated from natural sources so far.…”

Chemoselective Reduction and Alkylation of Carbonyl Functions Using Phosphonium Salts as an <i>in Situ</i> Protecting Groups

“…[36][37][38] Asymmetric syntheses of centrolobine have been reported by several groups, but they involve multiple steps and/or give low yields. [39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55] Our synthetic route is summarized in Chart 7. This enantioselective synthesis was accomplished in five steps from commercially available cyclopentene 3; the overall yield was 75%, which is the highest total yield reported for the asymmetric synthesis of (+)-centrolobine.…”