Phosphate Tether-Mediated Ring-Closing Metathesis for the Generation of P-Stereogenic, Z-Configured Bicyclo[7.3.1]- and Bicyclo[8.3.1]phosphates

Abstract

A phosphate tether-mediated ring-closing metathesis (RCM) study to the synthesis of Z-configured, P-stereogenic bicyclo[7.3.1]- and bicyclo[8.3.1]phosphates is reported. Investigations suggest that C3-substitution, olefin substitution, and proximity of the forming olefin to the bridgehead carbon of the bicyclic affect the efficiency and stereochemical outcome of the RCM event. This study demonstrates the utility of phosphate tether-mediated desymmetrization of C2-symmetric, 1,3-anti-diol-containing dienes in the generation of macrocyclic phosphates with potential synthetic and biological utility.

Figure 1

Ring-closing metathesis to medium- and large-ring containing bicyclo[n.3.1]phosphates

Figure 2

X-ray confirmation of olefin stereochemistry and revelation of distorted boat geometry in trans-33

Scheme 1

Ring-closing metathesis to bicyclo[7.3.1]phosphates via formation of C7–C8-trisubstituted olefins

Scheme 2

Synthesis of bicyclo[7.3.1]phosphates via formation of C6–C7-disubstituted olefins

Scheme 3

Synthesis of bicyclo[7.3.1]phosphates via formation of C6–C7-trisubstituted olefins

Scheme 4

Synthesis of bicyclo[7.3.1]phosphates via formation of C6–C7-trisubstituted olefins

Scheme 5

Synthesis of bicyclo[8.3.1]phosphates via formation of C7–C8-disubstituted olefins

Scheme 6

Synthesis of bicyclo[8.3.1]phosphates via formation of C7–C8-disubstituted olefins