Pyranophane Transannular Diels−Alder Approach to (+)-Chatancin:  A Biomimetic Asymmetric Total Synthesis

Abstract

An asymmetric total synthesis of (+)-chatancin was achieved via a transannular Diels-Alder (TADA) reaction of an in situ generated macrocyclic pyranophane pseudobase. The presented route constitutes the second of two proposed biosynthetic pathways that involves a TADA reaction. It links this diterpene biogenetically to the cembranoids. A set of TADA selection rules that rationalize the formation of (+)-chatancin from a dynamic equilibrium of four 2-hydroxy-2H-pyrane bicycles and their 16 potential TADA transition states are also outlined. Beyond the TADA reaction, highlights of the synthetic work include the assembly of a chiral acyclic macrocyclization substrate from (S)-citronellol and an efficient macrocyclization via a beta-ketosulfoxyde/enone Michael addition.

Short, Enantioselective Total Synthesis of Chatancin

“…The compact structure of 1 , containing seven stereocenters (six of which are contiguous), has proven to be a formidable synthetic challenge that is further exacerbated by its extreme acid sensitivity; it rapidly dehydrates to anhydrochatancin ( 3 ) under even mildly acidic conditions. Gossinger and co‐workers reported the first synthesis of (±)‐ 1 in 33 chemical steps from thymoquinone (0.7 % overall yield),7 and in 2003, after significant chemical experimentation,8 the group of Deslongchamps reported a fundamentally disparate synthetic strategy to (+)‐ 1 (23 steps from cis ‐2‐butene‐1,4‐diol) 9. Guided by the biosynthetic hypothesis shown (Figure 1 a), chatancin was postulated to be of cembrane biosynthetic origins and its complex polycyclic skeleton the result of a transannular Diels–Alder cycloaddition (TADA) of pyranophane precursor 4 .…”

Total Syntheses of (+)‐Sarcophytin, (+)‐Chatancin, (−)‐3‐Oxochatancin, and (−)‐Pavidolide B: A Divergent Approach

“…These cembranoids feature two cis ‐decalin motifs possessing six or seven stereogenic centers, and are folded into an unprecedented polycyclic arrangement through a transannularly bridged hemiketal between a tertiary alcohol at C10 and a ketone at either C3 or C14. The highly congested architectures as well as the intriguing biological properties of the sarcophytin family members have stimulated several elegant total syntheses of their core structures and target molecules from the groups of Gössinger,, Deslongchamps,,– Maimone and Carreira …”

“…Although a biosynthetic origin of 5 based on an intramolecular Michael/aldol process was proposed, we were more intrigued by its distinctive carbon functional pattern similar to that of the sarcophytin family members. We hypothesized that a C5(10→11) Wagner–Meerwein rearrangement on the B/C rings of the sarcophytin/chatancin skeleton, which was postulated to be constructed through an transannular Diels–Alder cycloaddition of cembrane,,, might be involved in an alternative biosynthetic pathway to 5 . Therefore, a systematic investigation on the collective synthesis of these cembranoids is highly desirable to shed light on the biosynthetic relationship between their polycyclic skeletons.…”

Toward the Synthesis of the Antibiotic Branimycin: Novel Approaches to Highly Substituted cis‐Decalin Systems

“…To remedy this situation, we decided to inhibit such isomerizations by incorporating the triene into a macrolide ring, such as 24, and switch from IMDA to TADA [8] cyclization (Scheme 7). To achieve smooth macrocyclization, an (E)-enoate had to replace the former (Z)-enoate, and the former endo transition state had to be converted into the exo transition state.…”