Stereoselective Tandem Synthesis of syn-1,3-Diol Derivatives by Integrating Olefin Cross-Metathesis, Hemiacetalization, and Intramolecular Oxa-Michael Addition

Abstract

Stereoselective tandem synthesis of syn-1,3-diol motifs, abundantly present in polyketide natural products and relevant pharmaceuticals, was achieved from homoallylic alcohols, α,β-unsaturated ketones, and aldehydes. Olefin crossmetathesis of homoallylic alcohols with α,β-unsaturated ketones, hemiacetalization of the resultant alcohols with aldehydes, and subsequent intramolecular oxa-Michael addition of the derived hemiacetals furnished syn-1,3-dioxane derivatives in good to excellent yields without isolation of any intermediates. The acetal moiety of the resultant syn-1,3-dioxanes could be cleaved chemoselectively/regioselectively under mild conditions in subsequent transformations.

Dynamic kinetic resolution of transient hemiketals: a strategy for the desymmetrisation of prochiral oxetanols

“…The overall high yield and selectivity can be rationalized by a dynamic kinetic resolution (DKR) of the racemic hemiketals. 20 This implies that hemiketal ent -9a reacts much slower than its enantiomer 9a while the rate of racemization remains relatively fast. About a dual role of the catalyst can only be speculated based on our current data, but it seems reasonable that the catalyst also acts as an inter- or intramolecular Lewis acid further facilitating oxetane-opening.…”

Six-membered ring systems: with O and/or S atoms

“…A palladium complex generated in situ from Pd 2 (dba) 3 •CHCl 3 and phosphoramidite 49 promotes asymmetric allylic cycloaddition reactions of vinyloxetanes with formaldehyde to afford a variety of 1,3-dioxanes, in moderate to excellent yields (Scheme 86) (19OL214). Further, syn-1,3-dioxanes can be obtained through hemiacetalization and subsequent intramolecular oxa-Michael addition reactions of d-hydroxy-a,b-unsaturated ketones with aldehydes promoted by camphorsulfonic acid in toluene at room temperature and through olefin cross-metathesis, hemiacetalization, and intramolecular oxa-Michael addition reaction of homoallylic alcohols with a,b-unsaturated ketones and aldehydes (19OL3730). Enantio-and diastereoselective synthesis of cyano-1,3-dioxanes is achieved via cascade reactions of d-oxo-a,b-unsaturated ketones with acetone cyanohydrin and trifluoromethyl ketones promoted by chiral bifunctional thiourea organocatalyst 50 (Scheme 87) (19OL2688).…”

Three-Pot Synthesis of Chiral Anti-1,3-diols through Asymmetric Organocatalytic Aldol and Wittig Reactions Followed by Epoxidation and Reductive Opening of the Epoxide

“…In fact, we recently reported a two-pot synthetic method for the synthesis of syn -1,3-diol units, through organocatalyst 1 -mediated aldol reaction, Wittig reaction, and acetalization, followed by Bi­(OTf) 3 -mediated oxy-Michael reaction (eq ). We also reported the three-pot synthesis of syn -α,γ-dihydroxycarbonyl units via organocatalyst 1 -mediated aldol reaction, Henry reaction, acetalization, Nef reaction, and epimerization (eq 2 ). In these reactions, chiral syn -1,3-diol units are synthesized from readily available starting materials.…”

“…Given that the first cross-aldol reaction proceeds with excellent enantioselectivity with a wide variety of substrates, the final 1,3-diols were obtained with excellent enantioselectivity. Given that we previously reported the synthesis of β,δ- syn -dihydroxy carbonyls based on an asymmetric cross-aldol reaction as one of the key steps (eq ), both anti - and syn -β,δ-dihydroxy carbonyl units can be prepared by using the same aldol reaction.…”