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Synthesis
DOI: 10.1055/a-2788-6538
DOI: 10.1055/a-2788-6538
Paper
Synthesis of (+)-Dehydrobulbispermine Analogs
Authors
Abstract
An eight-step synthesis of a (+)-dehydrobulbispermin analog was developed. Starting from optically active 4-alkylidene-tetrahydroisoquinoline, the Eschenmoser–Claisen rearrangement enabled the introduction of the central quaternary center with complete remote stereocontrol. Subsequent iodolactonization, N-BOC group cleavage, and D-ring closure delivered the key quaternary stereotriads as present in (+)-bulbispermine and (+)-hamayne. Then, methyl lithium addition and protection of the resulting OH group allowed completion of the carbon skeleton. OTBS group removal and TEMPO oxidation afforded a ketoaldehyde, which finally underwent an intramolecular aldol condensation, building up the C ring and the α-crinan-11-ol tetracycle derivatives, which will be used as key intermediates in the bulbispermine and 11-hydroxyvittatine-type α-crinane alkaloid total syntheses.
Keywords
4-Alkylidene-tetrahydroisoquinoline - Eschenmoser–Claisen rearrangement - Iodolactonization - Quaternary stereotriad - Methyl lithium addition - Intramolecular aldol condensation - α-Crinan-11-ol derivativesPublication History
Received: 23 December 2025
Accepted after revision: 14 January 2026
Accepted Manuscript online:
15 January 2026
Article published online:
26 January 2026
© 2026. Thieme. All rights reserved.
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(+)-α-Crinane [4aS-(4aα,5β,11bβ)]:
(−)-β-Crinane [4aR-(4aα,5β,11bβ)]:
Syntheses of (+) and (−)-Crinane
Related alkaloids displaying a stereotriad 4a, 10b, 1 are less well known:
Synthesis of (+)-Amabiline (ent-VIb):
Apohaemanthamine:
For a comprehensive review see:
For a review focusing on the generation of the quarternary center see:
For an N5–C12 ring closure incorporating C6 and C11 carbonyl groups, see:
For an N5–C12 ring closure incorporating C6 and C11 CH2 groups, see:
Aldol reactions including the installation of the quaternary C10b center are unknown so far. For a C2–C3 bond formation via an aldol reaction (C11 CH2), see:
For a Claisen rearrangement to generate an alkaloid quaternary center, see:
Side product methyl thiomethyl ether formation
Alternative C1 nucleophile
Initial attempts employing a Weinreb amide formation and a subsequent methyl Grignard reagent addition to synthesize ketone 26a failed. For data of the Weinreb amid see supporting information:
Remark: Initial investigations attempting C-ring closure focused on intramolecular enolate alkylation. In this connection, the OH group of enol ether 24 was activated as mesylate (standard conditions). However, all runs pointing on intramolecular enolate alkylation to generate a cyclohexanone C ring failed. For data of the mesylate see supporting information. Furthermore, substitution of the mesylates with thiophenolate and subsequent sulfoxide generation would have introduced a substitution pattern ready for a Pummerer rearrangement:
Starting from endo enolether 24 most (electrophilic) oxidation reagents primarily addressed the enol ether function and the OH function served as a nucleophile leading to ketals 23 and 25, respectively:
For data of the mesylate see supporting information. Intramolecular enolate alkylation:
A first attempt running a one pot Ru-catalyzed HAT/intramolecular Aldol condensation following a procedure of Cho and Shim. failed: