Stereoselective Protection-Free Asymmetric Total Synthesis of (+)-Chamuvarinin, a Potent Anticancer and Antitrypanosomal Agent: Substrate-Controlled Construction of the Adjacently Linked Oxatricyclic Core by Internal Alkylation

Abstract

A stereoselective protection-free asymmetric total synthesis of (+)-chamuvarinin (1), a potent anticancer and antitrypanosomal agent, has been accomplished. The adjacently linked [bis­(tetrahydrofuran)]­tetrahydropyran (THF–THF–THP) core of this natural product with seven stereogenic centers was constructed in a completely substrate-controlled fashion. The inter-ring stereochemistry (threo,threo,threo) of the oxatricyclic core was established in a stereoselective fashion by a chelation-controlled Keck allylation, whereas the intraring cis or trans relative stereochemistry was controlled by a stereoselective internal alkylation.

Evolution of Strategies in Protecting‐Group‐Free Synthesis of Natural Products: A Recent Update

“…It shows strong anti‐proliferative activity against KB‐3–1, a multidrug resistant cervical cancer cell line (GI 50 = 0.8 n m ) [ 103 ] and antitrypanosomal activity. [ 104 ] Lee and co‐workers [ 105a ] tactically synthesized chamuvarinin by iterative allylation/internal alkylation strategy (Scheme 35). The chiral alcohol 287 (prepared in two steps from 1‐epoxyoctane via kinetic resolution and Grignard opening) was subjected to chloroacetamide reaction, olefin cleavage and reduction to alcohol 288 .…”

“…The iterative allylation, internal alkylation worked well with a good level of substrate control in most steps to complete the PGF synthesis of (+)‐chamuvarinin ( 298 ) in 22 steps and 2 % overall yield from racemic 1‐epoxyoctane. The earlier first total synthesis of (+)‐chamuvarinin ( 298 ) by Florence [ 105b ] was completed from ( S )‐TBS‐glycidol ether (may require to be prepared) in 20 steps with involvement of several protecting groups and 1.4 % overall yield.…”

Highly Stereoselective Asymmetric Total Synthesis of (−)-Jimenezin via Sequential Intramolecular Amide Enolate Alkylation

“…On the basis of the insights acquired during our recent synthesis of the confamilial acetogenin (+)-chamuvarinin, we set out to examine the feasibility of a strategy based on a stereoselective construction of the adjacent oxacycles in this natural product using sequential intramolecular amide enolate alkylation (IAEA). More specifically, the 2,3- erythro -2,6- cis -trisubstituted THP ring system would be elaborated employing chelation-controlled nucleophilic addition (CCNA) and IAEA as key steps.…”

“…The inverted alcohol 11 was elaborated to the first IAEA substrate 7 by a straightforward three-step sequence in good overall yield (83%): (1) Williamson ether synthesis with N , N -dimethyl chloroacetamide, (2) desilylation, and (3) tosylation. Upon treatment with potassium bis­(trimethylsilyl)­amide (KHMDS), ω-tosyl α-alkoxy amide 7 underwent a smooth cyclization to give THP 6 in 92% yield (cis/trans 180:1 by weight). ,, The first IAEA reaction presumably proceeded via the chairlike transition-state geometry B with both the bulky R and OBn groups in equatorial positions to yield the desired cis product 6 . The relative stereochemistry of 6 was elucidated through analysis of its rotating frame Overhauser enhancement spectroscopy (ROESY) spectra, as indicated in the scheme.…”

“…In particular, the stereoselective formation of the adjacent oxacycles of 1 has been considered as the key challenge, and the elegant pathways attempted for this purpose to date include the use of intramolecular Williamson ether synthesis, radical cyclizations, and intramolecular allylboration. 3−5 On the basis of the insights acquired during our recent synthesis of the confamilial acetogenin (+)-chamuvarinin, 6 we set out to examine the feasibility of a strategy based on a stereoselective construction of the adjacent oxacycles in this natural product using sequential intramolecular amide enolate alkylation (IAEA). More specifically, the 2,3-erythro-2,6-cistrisubstituted THP ring system would be elaborated employing chelation-controlled nucleophilic addition (CCNA) and IAEA as key steps.…”