Six-Step Total Synthesis of Azaspirene

Abstract

The total synthesis of (±)-azaspirene (1) was achieved in a total of six steps from commercially available materials. Keys to the conciseness of our synthetic approach were the effective γ-lactam formation from linear precursor 36 and successful tandem epoxidations of γ-lactam 34 to afford α,β-epoxy-γ-hydroxy-γ-lactam intermediate 14. While our streamlined synthesis of azaspirene (1) sought inspiration from its biogenetic hypothesis, experimentally observed chemical reactivity of biosynthetically relevant precursors conversely provides insights to the biological origin of this natural product.

Biosynthetically Inspired Transformation of Iboga to Monomeric Post-iboga Alkaloids

“…Oxidations and Rearrangements: A Design Principle for Transforming Iboga to Post-iboga Alkaloids Our laboratory's interest in biosynthetically inspired total synthesis of complex natural products [30][31][32][33][34] prompted us to devise biogenetically relevant synthetic routes for voatinggine (10), tabertinggine (11), and dippinine B (15). To focus on the postmodification chemistry of the iboga scaffold, we made a strategic decision to start our synthesis from (+)-catharanthine (3), 35 the starting material for the industrial production of the anticancer drug navelbine.…”

Multifaceted Study on a Cytochalasin Scaffold: Lessons on Reactivity, Multidentate Catalysis, and Anticancer Properties

“…An explanation of this surprisingr esult came from the analysiso f 1 Ha nd 13 C, 1D and 2D NMR spectra of the unstableD iels-Alder substrate 5,s howingt he presence of a contaminant, which was partially assigned as enol isomer 19 (Scheme 5). This epimerization reaction, previously observed with similar unsaturated lactams [25] (and occasionally put to use in successful total syntheses,) [26] resultedi nt he loss of the chiral center originated from l-leucine, in enol 19,a nd explainst he racemic character of cycloadducts 16 and 17 (Scheme5,g rey box). To check the enantiomeric ratios of the cycloadducts,a lthough we were not able to derivatize debenzoylated cycloadducts by chiral reagents, both compounds 16 and 17 were separately analyzed by chiral HPLC (Cosmosil chiral 3B column, Figure S3).…”

Highly Oxidized γ-Lactam-Containing Natural Products: Total Synthesis and Biological Evaluation

“…In the presence of triethylamine, 302 and isobutyl glyoxal (286) were reacted to produce tautomers 303/304, which were used in the next reaction without purification because of their instability. Han's group reported the total syntheses of berkeleyamide D (142), 92 azaspirene (133), 93 FD-838 (141), 94 and cephalimysin A (138) 94 based on a strategy inspired by the biosynthetic origin of azaspirene 95 and the biomimetic synthesis of α,β-unsaturated γ-hydroxy-γ-lactam and α,β-epoxy-γ-hydroxy-γ-lactam ring systems reported by the Snider group. 96 Initially, they achieved the total synthesis of berkelyamide D (142) (Scheme 27).…”

“…Han's Total Synthesis of Berkeleyamide D Han's group used the same synthetic method 92 to achieve the total synthesis of azaspirene from β-ketoester 319, prepared from α,β,γ,δ-unsaturated aldehyde 152 and β-ketoester 318 (Scheme 28). 93 Oxidation of the secondary alcohol of 319 was followed by condensation with L-phenylalaninol (320) to produce amide 321. Amide 321 was subjected to a modified Pfitzner−Moffatt oxidation and treatment with base to afford lactam 322.…”

“…Spiro compounds consisting of an inseparable mixture of 330 and 331 or 332 were obtained in same manner as the previous azaspirene synthesis. 93 Treatment of spiro compounds 330 and 332 with camphorsulfonic acid in methanol produced only methoxy derivatives 333 or 334 as single diastereomer. After deprotection of TBS group and oxidation of the resultant alcohol, the total syntheses of FD-838 (141) and cephalimysin A (138) were completed.…”