Phosphate tether-mediated ring-closing metathesis for the generation of medium to large, P-stereogenic bicyclo[n.3.1]phosphates

Abstract

A phosphate tether-mediated ring-closing metathesis study towards the synthesis of P-stereogenic bicyclo[6.3.1]-, bicyclo[7.3.1]-, and bicyclo[8.3.1]phosphates is reported. This study demonstrates expanded utility of phosphate tether-mediated desymmetrization of C2-symmetric, 1,3-anti-diol dienes in generating complex medium to large, P-stereogenic bicyclo[n.3.1]phosphates..

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

“…12,16 However, as the RCM of analogous monocyclic Si-tethered systems proceeds with predominantly Z -configured olefin formation—even at larger ring sizes, 17 there was some interest in attempting to perturb the stereoselectivity of the phosphate tether-mediated RCM to provide 10- and 11-membered rings to broaden the scope of the molecules accessible by this method. Thus, trienes 3 and 4 were chosen as model substrates to assess the effect of olefin substitution on the phosphate tether-mediated RCM to generate bicyclo[7.3.1]phosphates (Scheme 1).…”

“…Treatment of triene 7 with Grubbs first generation catalyst (G-I), added in 1 mol % portions over 7 hours (6 mol %, total), provided the corresponding bicyclo[7.3.1]phosphates trans - 11 20 in 61% combined yield of a separable 2:1 mixture of Z / E -stereoisomers (with Z - trans - 11 as the major stereoisomer). 21 Notably, the formation of the analogous equivalent of this trans -bicyclo[7.3.1]phosphate via C7–C8 olefin formation was unsuccessful under a variety of RCM conditions, 16 suggesting that the extension of the forming olefin from C7–C8 to C6–7 could provide for conformational flexibility that allows for the reaction of the latter to proceed (albeit with lower stereoselectivity). Conversely, RCM of triene 8 with G-I (3 mol %) provided Z -olefin-containing cis - 12 in 88% as a single stereoisomer (dr > 20:1).…”

“…To separate the effect of olefin substitution from C3-substitution, we first synthesized simple triene 13 via the coupling of monochlorophosphate ( R , R )- 14 12,16 with 4-penten-1-ol (Scheme 3). Exposure of 13 to Grubbs second-generation catalyst (G-II) provided the corresponding bicyclic phosphate 15 as the Z-isomer in 87% yield.…”

“…Earlier this year, we published a continuation of these efforts to provide a number of stereochemically complex bicyclo[6.3.1]­phosphates, along with a few simple examples of bicyclo[7.3.1]- and bicyclo[8.3.1]­phosphates (Figure ). , However, the complexity of large ring dynamicscombined with the small sample size of bicyclo[7.3.1]- and bicyclo[8.3.1]­phosphates in both studiescan complicate the generalization of those findings, and since the previous work represented some of the first reports of RCM to afford phosphates of this ring size, much remains to be discovered in this particular area of macrocyclic phosphate synthesis. The work reported herein expands upon previous efforts by focusing on the formation of bicyclo[7.3.1]- and bicyclo[8.3.1]­phosphates (10- and 11-membered RCM), with a special emphasis on the effect of olefin- and C3-substition (Figure ), as well as proximity of the forming olefin to the bridgehead carbon of the resultant bicyclic phosphate, on the success and stereochemical outcome of the macrocyclic, RCM event.…”

Stereoselective Synthesis of 2Z,4E-Configured Dienoates through Tethered Ring Closing Metathesis

“…23 In most of these transformations, the tether is hydrolytically removed after the metathesis step. [24][25][26][27] In our diene synthesis, however, it remains in the target molecule as a carboxylic acid group. The synthesis starts from allyl butenoates 1, which undergo RCM, followed by base induced elimination to the carboxylates 3.…”