A Concise Synthesis of Forskolin

Abstract

A 24-step synthesis of (±)-forskolin is presented, which delivered hundred milligram quantities of this complex diterpene in one pass. Transformations key to our approach include: a) a strategic allylic transposition, b) stepwise assembly of a sterically encumbered isoxazole ring, and c) citric acid-modified Upjohn dihydroxylation of a resilient tetrasubstituted olefin. The developed route has exciting potential for the preparation of new forskolin analogues inaccessible by semisynthesis.

Forskolin Editing via Radical Iodo- and Hydroalkylation

“…This was easily accomplished by protection of the 1,3-diol moiety in (-)-forskolin with 2,2-dimethoxypropane. 14 In this case, the I-ATRA reaction was carried out in the presence of a base (NaHCO 3 ) and gave the corresponding adduct 14 in a moderate isolated yield of 42% (dr 71:29) (Scheme 4). The relative configuration at C-14 of the major diastereomer of 14 was assigned by single crystal X-ray diffraction data analysis.…”

“…Since its isolation, the polyoxygenated, tricyclic skeleton of forskolin (1) has stimulated the development of different strategies for its synthesis. 13,14 Similarly, different routes have been explored for its hemisynthesis. For instance, This document was downloaded for personal use only.…”

Acetylene in Organic Synthesis: Recent Progress and New Uses

“…Introduced in the early 20th century by Favorskii [ 112 ] the reaction for obtaining propargyl alcohols by alkynylation of carbonyl compounds is still a heavy hitter [ 34 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 ]. Convenient and mild synthetic procedures for alkynylation of various aldehydes and ketones have been recently reported by Trofimov et al [ 34 , 113 , 114 ].…”

“…Alkynylation of carbonyl compounds with metal acetylides represents an alternative to the direct base-catalyzed alkynylation with gaseous acetylene [ 117 , 118 ]. Reaction of aldehydes and ketones with in situ generated ethynylmagnesium bromide is carried out in a commercially available falling film microreactor (FFMR) [ 117 ].…”

“…Lithium acetylide was used for the preparation of decalin-derived acetylenic alcohol 74 , an intermediate for the multistep synthesis of racemic forskolin [ 118 ]. Selective addition of monolithium acetylide to one of the two carbonyl groups in cis -decalin 73 and subsequent epimerization in the presence of aluminum oxide afforded trans -decalin 74 in overall yield 82% ( Scheme 41 ).…”