Enantioselective Synthesis of a Hydroxymethyl-cis-1,3-cyclopentenediol Building Block

Abstract

A brief, enantioselective synthesis of a hydroxymethyl-cis-1,3-cyclopentenediol building block is presented. This scaffold allows access to the cis-1,3-cyclopentanediol fragments found in a variety of biologically active natural and non-natural products. This rapid and efficient synthesis is highlighted by the utilization of the palladium-catalyzed enantioselective allylic alkylation of dioxanone substrates to prepare tertiary alcohols.

Preparation of 1,5‐Dioxaspiro[5.5]undecan‐3‐one

“…The procedure for the synthesis of 1,5-dioxaspiro [5.5]undecan-3-one is based on our previous report 2 and was originally adapted from the work of Forbes 3 and inspired by the work of Majewski, 4 Hoppe, 5 and Enders 6 on the synthesis of related ketodioxanone scaffolds. Using the procedure described herein, the synthesis of the analogous diethyl ketal product has been accomplished using 3,3-dimethoxypentane in place of 1,1-dimethoxycyclohexane.…”

Preparation of 1,5-Dioxaspiro[5.5]undecan-3-one

“…The procedure for the synthesis of 1,5-dioxaspiro[5.5]undecan-3-one is based on our previous report 2 and was originally adapted from the work of Forbes 3 and inspired by the work of Majewski, 4 Hoppe, 5 and Enders 6 on the synthesis of related ketodioxanone scaffolds. Using the procedure described herein, the synthesis of the analogous diethylketal product has been accomplished using 3,3-dimethoxypentane in place of 1,1-dimethoxycyclohexane.…”

“…8 It has been employed successfully as a nucleophile in palladium-catalyzed enantioselective allylic alkylation 2 as well as stereoselective aldol condensation. 9 As a synthetic building block, 1,5-dioxaspiro[5.5]undecan-3-one offers the advantage of a ketal that is significantly more stable to acidic reaction conditions in comparison to the acetonide and diethylketal orthologues.…”

“…For example, exposure of acetonide 1 to acidic oxidative α-bromination conditions furnished α-bromoketone 2 in widely variable yields, most typically between 0% and 20% (Scheme 1.A). 2 Although the conversion of α-bromoketone 2 to cyclopentenone 3 was accomplished, the labile nature of the acetonide contributed to the diminished yield.…”

Polycyclic Furanobutenolide-Derived Cembranoid and Norcembranoid Natural Products: Biosynthetic Connections and Synthetic Efforts

“…111,115–116 Oxidative cleavage of the resultant amino alcohol product provided ketodioxanone 368 in 94% over 3 steps. Condensation of cyclohexylamine onto ketone 368 prior to deprotonation and alkylation with methyl iodide enabled selective monomethylation.…”