Enantioselective Synthesis of Cyclohepta[b]indoles: Gram-Scale Synthesis of (S)-SIRT1-Inhibitor IV

Abstract

An enantioselective gram-scale synthesis of one of the most potent SIRT1-inhibitors has been accomplished by an unprecedented domino reaction sequence establishing the cyclohepta[b]indole core. This method was developed for application in natural product synthesis of a variety of indole alkaloids.

Indole‐derived Donor‐acceptor Cyclopropanes

“…The most general transformation of this type is the oxidation of (2‐indolylcyclopropyl)methanols 40 to the corresponding aldehydes 41 (Scheme ). [16,26,27,36–39] In some cases, the obtained aldehydes were immediately introduced into further transformations ,,,. Similarly, 2‐(1‐tosylindol‐3‐yl)‐1‐propionylcyclopropane was obtained by the oxidation of the corresponding secondary alcohol with 2‐iodoxybenzoic acid .…”

“…[16,26,27,36–39] In some cases, the obtained aldehydes were immediately introduced into further transformations ,,,. Similarly, 2‐(1‐tosylindol‐3‐yl)‐1‐propionylcyclopropane was obtained by the oxidation of the corresponding secondary alcohol with 2‐iodoxybenzoic acid . Precursor alcohols can be obtained by the reduction of esters, or other acid derivatives,, cyclopropanation of allylic alcohols, and their silyl ethers, or other methods …”

“…[16,27,36,39] Similarly,2-(1tosylindol-3-yl)-1-propionylcyclopropane was obtained by the oxidation of the corresponding secondary alcohol with 2-iodoxybenzoic acid. [39] Precursor alcohols can be obtainedb yt he reduction of esters [16,26] or other acid derivatives, [16,27] cyclopropanation of allylic alcohols [36,39] and their silyl ethers, [38] or other methods. [37] Thef irst approach to IDDAc yclopropanes that was based on the construction of the indole ring in the vicinal positiont ot he acceptor group in the cyclopropane scaffold was developed by Chibiryaev et al [40] To synthesize enantiopure cyclopropanes 43 and 44,t hey used Fischer indolization of ketone 42 obtained from (+)-car-3-ene [41] (Scheme20).…”

“…Gaich and coworkers reported the Wittig olefinationdivinylcyclopropane rearrangement cascadeo fo ptically active 2-(2/3-indolyl)cyclopropanecarbaldehydes 41,a s well as the corresponding ketone,a ffording cyclohepta-[b]indole derivatives 126 and 127 (Schemes 54 and 55). [39] They appliedt his transformation to gram-scale synthesis of (S)-SIRT1-inhibitor IV (Scheme56).…”

A computational triage approach to the synthesis of novel difluorocyclopentenes and fluorinated cycloheptadienes using thermal rearrangements

“…6 There have also been reports of related [3,3]-sigmatropic rearrangements, 7 including divinylcyclopropane to cycloheptadiene rearrangements, 8 being used in a similar fashion to generate molecular complexity. However, despite being utilised in the successful synthesis of marine sponge derived natural product frondosin B 6 9 and the highly potent SIRT-inhibitor 7 , 10 the [3,3]-rearrangements from our system are much less common (Fig. 1b).…”