A Domino Approach to the Enantioselective Total Syntheses of Blennolide C and Gonytolide C

Abstract

The first enantioselective total syntheses of the tetrahydroxanthenone (-)-blennolide C (ent-4) and related γ-lactonyl chromanone (-)-gonytolide C (ent-3) are reported. Key to the syntheses is an enantioselective domino-Wacker/carbonylation/methoxylation reaction to set up the stereocentre at C-4a. Various chiral BOXAX ligands were investigated, including novel (S,S)-iBu-BOXAX, and allowed access to chromane 8 in an excellent enantioselectivity of 99 %. The second stereocentre at C-4 was established employing a diastereoselective Sharpless dihydroxylation. An extensive survey of (DHQ)- and (DHQD)-based ligands enabled the preparation of both the anti-isomer 14 a and the syn-isomer 14 b in very good to reasonable selectivities of 13.7:1 and 1:3.7, respectively. While 14 a was further converted to ent-3 and ent-4, 14 b was elaborated to syn-acid 25 and 2'-epi-gonytolide C 28.

Scope and Limitations of the Domino Vinylogous Aldol/oxa‐Michael Reaction

“…This product was not purified but directly converted into the methyl ester 37 . The latter can serve as a building block for the methyl ester series of tetrahydroxanthones like 38 …”

A Convergent Synthesis of Gonytolide C Using an Intramolecular Oxa‐Michael Addition

“…Gonytolide C (2a) and epi-gonytolide C (2b) proved readily separable by chromatography and were isolated in a combined yield of 45 % over the three steps; spectroscopic and specific rotation data were in excellent agreement with previously reported data sets. [2,7,8] Diastereoselective formation of gonytolide C (2a) was observed by Sudhakar and co-workers upon cyclisation of aldol intermediates in the presence of pyridine at high temperature (Scheme 1). [7] However, when the same conditions were applied to our oxa-Michael cyclisation of enone 31, only a low conversion to the chromanone product resulted, with no change in the observed diastereoselectivity.…”

“…Recently, a number of reports of synthetic work towards gonytolide C (2a) have been published (Scheme 1). [5][6][7][8] A racemic synthesis of (±)-gonytolide C (2a) and (±)-epi-gonytolide C (2b) was incidentally reported by the Porco group in 2011 en route to a different natural product, before the gonytolides had been isolated. [5] A vinylogous addition of ners were established.…”

“…Also concurrent with our work, Tietze published a 23-step synthesis of (-)-gonytolide C (ent-2a) based on an asymmetric domino-Wacker/carbonylation/methoxylation reaction. [8] synthesis of the desired keto phosphonate for the HWE reaction, orcinol (8) was first converted into its bis-EOM (ethoxymethyl) ether 11 using EOMCl and NaH. The EOM group was chosen due to its expected stability to basic HWE conditions and its anticipated ability to direct ortho-metallation.…”

Crystal structure of 8-[7,8-bis(4-chlorobenzoyl)-7H-cyclopenta[a]acenaphthylen-9-yl]naphthalene-1-carboxylic acid

“…In this reaction, multiple C-C or C-H bonds are formed in the same vessel, including different reaction mechanisms to form complex molecules without the purification of intermediates. These reactions are often used in medical or combinatorial chemistry to synthesize complex active drug molecules (Sudhapriya et al, 2014;Tietze et al, 2014;Fu et al, 2013;Shestopalov et al, 2013;Zohreh & Alizadeh, 2013;Renault et al, 2007). Domino reactions are classified as homo-domino processes and hetero-domino processes (Nesi et al, 1999).…”