Total Synthesis of (−)-Himandrine

Abstract

We describe the first total synthesis of (−)-himandrine, a member of the class II galbulimima alkaloids. Noteworthy features of this chemistry include a diastereoselective Diels-Alder reaction in the rapid synthesis of the tricycle ABC-ring system in enantiomerically enriched form, the use of a formal [3+3] annulation strategy to secure the CDE-ring system with complete diastereoselection, and successful implementation of our biogenetically inspired oxidative spirocyclization of an advanced intermediate. The successful and direct late-stage formation of the F-ring in the hexacyclic movassag@mit.edu. Supporting Information Available: Experimental procedures, spectroscopic data, copies of 1 H and 13 C NMR spectra, and X-ray structure of (−)-1. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript J Am Chem Soc. Author manuscript; available in PMC 2010 July 22. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript core of himandrine drew on the power of biogenetic considerations and fully utilized the inherent chemistry of a plausible biosynthetic intermediate.The galbulimima alkaloid (−)-himandrine (1) is a topologically fascinating compound isolated from the bark of Galbulimima belgraveana, a tree indigenous to Papua New Guinea and northern Australia. 1 The promise that natural and synthetic derivatives of galbulimima alkaloids have shown for treatment of human ailments 2 has resulted in substantial attention in both academia and industry. We previously reported the first enantioselective total synthesis of (−)-galbulimima alkaloid 13 (class III) 3 and revised the absolute stereochemical assignment of the class II and III derivatives. 4 While there have been several outstanding syntheses of class I 5 and III 6 galbulimima alkaloids, no total synthesis of the class II 7 galbulimima alkaloids possessing the unique N-C9 spirofused polycyclic framework has been reported. Herein we describe our total synthesis of class II alkaloid 1 guided by our previously disclosed hypothesis for its biogenesis, 3b featuring a final stage oxidative spirocyclization to secure the BCF ring juncture.Inspired by Mander, Ritchie and Taylor's 1967 proposal relating all galbulimima alkaloids to a single polyacetate precursor, 1d and consistent with our specific hypothesis for the biogenesis of class II and III galbulimima alkaloids, 3b we identified aminoketoester 3 (Scheme 1) as a plausible point of divergence en route to more complex alkaloids. Our retrosynthetic analysis of (−)-1 follows this hypothesis, 3b in which the N-C9 bond is introduced by a late stage oxidative spirocyclization of the pentacyclic aminoketoester 3. We envisioned that oxidation of 3, potentially facilitated by dienol formation, would afford allylic alcohol 2, which is poised for the critical condensative spirocyclization. We expected that application of our annulation methodology 8 to enone 4 and iminium chloride 5 would convergently assemble a pentacycle primed for our...

Mild and Highly Efficient Copper(I) Inspired Acylation of Alcohols and Polyols

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Substrate‐Controlled, Phosphine‐Catalyzed Domino Reactions of Activated Conjugated Dienes: Highly Diastereoselective Synthesis of Bicyclic Skeletons

“…The latter can be stabilized by an appendant enone (or enoate) and therefore has potential to trigger subsequent chemical reactions with appropriate substrates. Polycyclic dihydrofuran skeletons are widespread among various natural products of important biological activities [10] and also serve as very useful precursors for the construction of molecular complexity such as (À)-himandrine [11] and cyathin A 3 . [12] At present, however, the formation of the bicyclic dihydrofuran framework generally involves building a second five-or six-membered ring onto a preformed dihydrofuran moiety in several steps, which dramatically weakens the overall efficiency.…”

Biomimetic Syntheses of Alkaloids with a Non‐Amino Acid Origin

“…Inspired by this putative biosynthetic pathway, the authors achieved the total synthesis of both alkaloids of Class II (himandrine) [10] and Class III (Galbulimima alkaloid 13 or GB 13) [7]. During these investigations, they obtained exciting results that support their hypothesis.…”