Enantioselective Total Synthesis of Macfarlandin C, a Spongian Diterpenoid Harboring a Concave‐Substituted cis‐Dioxabicyclo[3.3.0]octanone Fragment

Abstract

The enantioselective total synthesis of the rearranged spongian diterpenoid (−)‐macfarlandin C is reported. This is the first synthesis of a rearranged spongian diterpenoid in which the bulky hydrocarbon fragment is joined via a quaternary carbon to the highly hindered concave face of the cis‐2,8‐dioxabicyclo[3.3.0]octan‐3‐one moiety. The strategy involves a late‐stage fragment coupling between a tertiary carbon radical and an electrophilic butenolide resulting in the stereoselective formation of vicinal quaternary and tertiary stereocenters. A stereoselective Mukaiyama hydration that orients a pendant carboxymethyl side chain cis to the bulky octahydronapthalene substituent was pivotal in fashioning the challenging concave‐substituted cis‐dioxabicyclo[3.3.0]octanone fragment.

Progress in the Total Synthesis of Natural Products Embodying Diverse Furofuranone Motifs: A New Millennium Update

“…Complex structural attributes along with Golgi-altering activity of its structurally related congeners [3,37] makes this natural product a challenging target for total synthesis. [38] Overman group has delineated a fragment coupling approach, involving stitching of a tertiary carbon radical (derived from 144) with an electrophilic butenolide partner 145 to accomplish an enantioselective synthesis of (À )-macfarlandin C (137) (scheme 13). [38] An easily accessible α-iodo-cyclohexen-1-one, 138 was subjected to enantioselective reduction by a modified CBS protocol to afford (S)-cyclohexenol which was converted to allylic phosphate 139.…”

“…Overman group has delineated a fragment coupling approach, involving stitching of a tertiary carbon radical (derived from 144 ) with an electrophilic butenolide partner 145 to accomplish an enantioselective synthesis of (−)‐macfarlandin C ( 137 ) (scheme 13). [38] An easily accessible α‐iodo‐cyclohexen‐1‐one, 138 was subjected to enantioselective reduction by a modified CBS protocol to afford ( S )‐cyclohexenol which was converted to allylic phosphate 139 . Phosphate derivative 139 was elaborated to ( E )‐ethylidene product 141 via sequential anti ‐S N 2' allylic displacement with organocuprate reagent 140 , Negishi vinylation and selective hydrogenation of the resulting terminal double bond.…”

General Access to Concave-Substituted cis-Dioxabicyclo[3.3.0]octanones: Enantioselective Total Syntheses of Macfarlandin C and Dendrillolide A

“…The linkage that joins the two fragments is freely rotatable, making identification of the relative configurations of these natural products challenging. X-ray crystallographic analysis and chemical synthesis have proven to be the only methods of establishing the relative and absolute configurations of this group of diterpenoids. − For many of these natural products, stereochemical assignments are based solely on their presumed biosynthetic relationship to the spongian diterpenoid skeleton ( 2 )…”

“…To synthesize the related diterpenoids in this series that display the bulky hydrocarbons substituent on the more-hindered concave face, 9 would need to be elaborated to a butyrolactone intermediate such as 10. The successful development of the divergent synthetic strategy outlined in Scheme and its use to accomplish enantioselective total syntheses of macfarlandin C ( 3 ) and dendrillolide A ( 4 ) are the subject of this report …”

Enantioselective Total Synthesis of Macfarlandin C, a Spongian Diterpenoid Harboring a Concave‐Substituted cis‐Dioxabicyclo[3.3.0]octanone Fragment

“…[13] Mukaiyama hydration of alkylidene lactone 12 took place with complete regioselectivity from the lactone face opposite the 1-methylcyclohexyl substituent to give alcohol intermediate 13. [14][15][16] The transformation of alcohol 13 to concavefunctionalized cis-2,8-dioxabicyclo[3.3.0]octan-3-one 17 was initially accomplished by way of three isolated intermediates. After initial silyl protection of the hydroxyl substituent, reaction with excess (iBu) 2 AlH provided a mixture of lactol epimers, which were directly oxidized to give cis-dioxabicyclooctanone 14 in high yield.…”