Total synthesis of (+)-intricarene using a biogenetically patterned pathway from (−)-bipinnatin J, involving a novel transannular [5+2] (1,3-dipolar) cycloaddition

Abstract

An asymmetric synthesis of the furanobutenolide-based macrocyclic diterpene (-)-bipinnatin J (4a) isolated from the gorgonian octocoral Pseudopterogorgonia bipinnata is described. The synthesis is based on elaboration of the chiral lactone-substituted vinyl iodide 26b from (+)-glycidol, followed by an intermolecular Stille coupling reaction with the stannylfurfural 27, leading to 28a, and then an intramolecular Nozaki-Hiyama-Kishi allylation reaction, 28b --> 4a. Treatment of (-)-bipinnatin J (4a) with VO(acac)2-tBuO2H followed by acetylation of the tautomeric hydroxypyranone product 7/8, next gave the acetoxypyrone 30. When the acetoxypyranone 30 was heated in acetonitrile in the presence of DBU, it gave (+)-intricarene 1, which is found in P. kallos, via a novel transannular [5+2] (or 1,3-dipolar) cycloaddition involving the butenolide-oxidopyrylium ion intermediate 31. We believe that this total synthesis of (+)-intricarene 1 mimics its most likely origin in nature via oxidation of (-)-bipinnatin J (4a), presumably involving photochemically generated singlet oxygen or possibly a P450 monooxygenase enzyme system.

Polycyclic Furanobutenolide-Derived Cembranoid and Norcembranoid Natural Products: Biosynthetic Connections and Synthetic Efforts

“…17 This proposal is supported by experimental work performed in both Pattenden 1,46–47 and Trauner 23,48–49 laboratories as well as by computational studies from the Tantillo laboratories. 50 Oxidative cleavage of the furan ring affords homoallylic alcohol 36 (Scheme 3).…”

“…The extremely limited examples of completed syntheses of members of this natural product family have been exclusively biomimetic synthetic (i.e., intricarene ( 7 ) by Pattenden 46–47 and Trauner 48–49 ) or semisynthetic (i.e., ineleganolide ( 9 ) and sinulochmodin C ( 10 ) by Pattenden 105 ). The de novo synthesis of only a single member of the polycyclic furanobutenolide-derived cembranoid and norcembranoid family has been completed to date (intricarene ( 7 ), Pattenden 46–47 and Trauner 48–49 ).…”

“…Synthesis of bishydroxyfuranobutenolide 189 was approached using the same NHK macrocyclization strategy employed in the synthesis of bipinnatin J ( 30 , Scheme 39A). 46–49 Unfortunately, only desbromo- 188 was observed under NHK coupling conditions without any trace of diol 189. In a complementary approach, furanobutenolide 191 was envisioned to arise via macrocyclic ring-closing metathesis (RCM, Scheme 39B).…”

Chemical Biology: What is Its Role in Drug Discovery?

“…The first total syntheses of many bioactive natural products was achieved in 2009 (Commeiras et al, 2009, Alvarez-Manzaneda et al, 2009, AlvarezManzaneda et al, 2009, Davis et al, 2009& Ribes et al, 2009) The synthesis of novel azaanalogues of staurosporine, K-252a and rebeccamycin have also been reported (McCortTranchepain, 2009). Total syntheses and new approaches to the total synthesis of many other natural products have also been reported (Yi Li et al, 2009, Garcia-Egido et al, 2009, Foster et al, 2009, Jiang & Hamada, 2009, Tang et al, 2009, Oh et al, 2009, Shing & Cheng, 2009, Poldy et al, 2009, Luo Yang et al, 2009, Ceccon et al, 2009, Coldham et al, 2009& Ayats et al, 2009. The isolation of several new natural products has also been achieved.…”

A strategy toward the synthesis of C13-oxidized cembrenolides

“…It is worth noting that this approach represents a significant improvement over the previously reported synthesis of compound 10 . 13 Treatment of 10 with LiHMDS/PhSeBr then afforded 11 in 76% yield. 7f,13 …”