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. 2022 Nov 18;87(22):15693-15702.
doi: 10.1021/acs.joc.2c02205. Epub 2022 Nov 3.

Base-Mediated Nitrophenyl Reductive Cyclization for the Synthesis of Hexahydro-2,6-methano-1-benzazocines

Laura G Rodríguez  1 , Ana Delgado  2 , Carlos J Ciudad  2 , Véronique Noé  2 , Josep Bonjoch  1 , Ben Bradshaw  1
Affiliations

Base-Mediated Nitrophenyl Reductive Cyclization for the Synthesis of Hexahydro-2,6-methano-1-benzazocines

Laura G Rodríguez et al. J Org Chem. .

Abstract

A Diels-Alder reaction leading to 4-nitrophenylcyclohexanones followed by a newly developed base-mediated reductive cyclization of the resulting ketone tethered to the nitrobenzene moiety gives access to the hexahydro-2,6-methano-1-benzazocine ring system present in several biologically interesting natural products such as aspernomine. The scope of the reaction was explored with eight substituted nitrobenzenes, obtaining yields of up to 87%. The highest cytotoxicity was observed in benzazocine 4h, bearing an enone moiety, which was active against eight cancer cell lines.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structures of anominine and structurally related metabolites containing a 2,6-methano-1-benzazocine core.
Scheme 1
Scheme 1. (a) Proposed Retrosynthesis of Aspernomine; (b, c) Synthetic Precedents for Bridged Benzazocines Reported by Our Group
Scheme 2
Scheme 2. Synthesis of Substrates for the Base-Mediated Cyclization
Figure 2
Figure 2
Exploring the scope of the base-mediated reductive cyclization, and X-ray structure of compound 4e.
Scheme 3
Scheme 3. Protection of the Amino Group of the Benzazocine Framework
Scheme 4
Scheme 4. Proposed Mechanism for the Base-Mediated Reductive Cyclization involving a Grob Fragmentation
See this image and copyright information in PMC

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