The Total Synthesis of the Galbulimima Alkaloid GB 13

Abstract

This contribution describes a synthetic approach to alkaloid GB 13, previously isolated from the North Australian and Papua New Guinean rain forest tree Galbulimima belgraveana. A Birch reductive alkylation of 2,5-dimethoxybenzoic acid by 3-methoxybenzyl bromide, followed by an acid-catalyzed cyclization was used to synthesize the [3.3.1]bicyclononane 8. A ring contraction performed on the diazo derivative 9 of the [3.3.1]bicyclononane led to [3.2.1]bicyclooctane 10. This [3.2.1]bicyclooctane was converted into a dienophile and subjected to a Diels-Alder reaction to generate a pentacyclic intermediate 13 with a carbon skeleton closely resembling the target alkaloid. The surplus substituent, required for activation and regioselectivity in the Diels-Alder reaction, was removed using Birch reductive conditions to effect a decyanation. It was discovered that a Birch reduction of the aromatic ring also present in the molecule could be performed at the same time to give the enone 15, which was cleaved by means of an Eschenmoser fragmentation. The piperidine ring found in the natural product was formed by reductive cyclization of the bis-oxime 18 derived from the alkynyl ketone 17 and the resulting material further elaborated to GB 13 (1) via ketone 20.

Total Synthesis of the Galbulimima Alkaloid (−)‐GB17

“…While early work focused on himbacine ( 1 ), most recent efforts have been directed at preparing the more complex members of the family. The first synthesis of GB13 ( 2 ) was reported by Mander and MacLachlan in 2003,6a with subsequent reports from the groups of Movassaghi, Chackalamannil, Evans, Sarpong, and Ma 6b–f. Himgaline ( 3 ) can be synthesized from GB13 ( 2 ), as shown by the groups of both Chackalamannil6c and Evans 6d.…”

Total Synthesis of (±)-Goniomitine via a Formal Nitrile/Donor−Acceptor Cyclopropane [3 + 2] Cyclization

“…14 The reaction time for this debenzylation proved to be critical in order to avoid elimination of the nitrile to give the C3 methyl indole. 15 The successful deprotection of 19 to give 18 again merged the sequence back into the synthetic stream pioneered by Takano.…”

A Convergent Route to the Galbulimima Alkaloids (−)‐GB 13 and (+)‐GB 16

“…In the previous reports, formation of the D ring,6a B ring,6b,d,e or A ring6c was set up at a late stage to complete the total synthesis of GB 13. Apparently, if formation of the C‐ring of GB 13 could be conducted at the late stage, this molecule would be disconnected into two equally complex fragments, thereby offering a more convergent approach to the natural product.…”