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. 2008 Nov 7;73(21):8386-91.
doi: 10.1021/jo801453v. Epub 2008 Sep 27.

Synthesis and biological evaluation of a phosphonate analog of the natural acetyl cholinesterase inhibitor cyclophostin

Saibal Bandyopadhyay  1 , Supratik Dutta, Christopher D Spilling, Cynthia M Dupureur, Nigam P Rath
Affiliations

Synthesis and biological evaluation of a phosphonate analog of the natural acetyl cholinesterase inhibitor cyclophostin

Saibal Bandyopadhyay et al. J Org Chem. .

Abstract

Two diastereomers of a phosphonate analog 6 of the AChE inhibitor cyclophostin were synthesized. The substitution reaction of phosphono allylic carbonate 10a with methyl acetoacetate gave the vinyl phosphonate 9a. Attempted hydrogenation/debenzylation gave an unexpected enolether lactone. Alternatively, selective hydrogenation, demethylation, cyclization and debenzylation gave the phosphonate analog of cyclophostin as a separable mixture of diastereomers 6. The trans phosphonate isomer was more active than the cis isomer against AChE from two sources.

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Figures

Figure 1
Figure 1
Cyclophostin and Related Structures
Figure 2
Figure 2
Proposed Reaction with the Active Site Serine and a Phosphonate Analog of Cyclophostin
Scheme 1
Scheme 1
Retrosynthetic Analysis for the Phosphonate Analog of Cyclophostin.
Scheme 2
Scheme 2
Preparation of the Allylic Hydroxy Phosphonates
Scheme 3
Scheme 3
Hydrogenation and Debenzylation of the Vinyl Phosphonates
Scheme 4
Scheme 4
Synthesis of the Phosphonate Analog
Figure 3
Figure 3
Projection view of the Phosphonate 6b with 50% thermal ellipsoids
Scheme 5
Scheme 5
Synthesis of an Enol Phosphate Analog of Cyclophostin
See this image and copyright information in PMC

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