Syntheses of C17–C27 fragments of 20-deoxybryostatins for assembly using Julia and metathesis reactions

Abstract

Two approaches to the synthesis of compounds corresponding to the C17-C27 fragment of the 20-deoxybryostatins are described. The first approach is based on the palladium(0) catalysed coupling of tin enolates, generated in situ from enol acetates using tributyltin methoxide, with vinylic bromides. The vinylic bromides were prepared using the Sharpless asymmetric dihydroxylation to introduce the hydroxyl groups corresponding to those at C25 and C26 in the bryostatins. Following several steps to introduce alkynyl ester functionality, the stereoselective addition of a tributyltin cuprate followed by tributyltin-bromine exchange gave the required vinylic bromides. The palladium(0) catalysed couplings worked very well for enol esters containing thioether substituents and gave products with retention of the position and geometry of the trisubstituted double bond derived from the vinylic bromide. These were taken through to compounds corresponding to fully developed C17-C27 fragments ready for assembly of the 16,17-double-bond of bryostatins by Julia reactions. This chemistry was also applied to prepare intermediates suitable for incorporation into bryostatins by ring-closing metathesis but, in this case, the coupling reaction gave mixtures of products including both the required βγ-unsaturated ketone and a conjugated diene formed by a competing Heck reaction. To avoid this problem, a second approach to compounds suitable for incorporation into a metathesis-based assembly of 20-deoxybryostatins was developed. In this organotin-free synthesis, the key step was the conjugate addition of an organic cuprate generated from allylmagnesium bromide to an alkynoate that gave the required (Z)-trisubstituted alkene with excellent stereoselectivity. This was converted into metathesis precursors in a few steps.

Towards 20,20-difluorinated bryostatin: synthesis and biological evaluation of C17,C27-fragments

“…The known alkene 71 35 was was ozonolysed with reduction of the intermediate ozonide using triphenylphosphine to give the aldehyde 72. The indium-mediated difluoroallylation of this aldehyde gave a mixture of the epimers of alcohol 73.…”

“…(60 mg, 0.17 mmol, 93%), R f = 0.2 (10:90 ether:light petroleum) (Found: M + + NH 4 , 348.1897. C 18 H 29 NO 35 ClF 2 requires M, 348.1900); ν max /cm -1 3428, 2954, 2926, 2855, 1599, 1576, 1467, 1433, 1199, 1163, 1079, 925 and 776; δ -1 3387, 2959, 2926, 2856, 1466, 1185, 1075, 1029, 964 and 922; δ H (400 MHz, CDCl 3 ) 0.89 (3 H, t, J 6.6, 14-H 3 ), 0.96 (3 H, t, J 7.0, 1-H 3 ), 1.21-1.38 (10 H, m, 5 × CH 2 ), 1.38-1.70 (6 H, m, 3 × CH 2 ), 1.85 (1 H, br. s, OH), 2.04-2.…”

Synthetic approaches to the C11–C27 fragments of bryostatins

“…Our early studies were concerned with syntheses of the C(1)-C(16) and C(17)-C (27) fragments in anticipation of developing a convergent synthesis. 9,10 However, following our difficulties encountered in using RCM for the synthesis of 20-deoxybryostatins, 6 a new strategy had to be devised for their assembly. In any new approach, we intended to use as much of the chemistry that we had already developed as possible.…”

“…Our earlier routes to this fragment had been based on stereoselective conjugate addition reactions of alkynyl esters. 10 However, a new route was envisaged in which the geometry of the trisubstituted double-bond would be controlled by a ring-closing metathesis, see Scheme 7.…”

“…50 : 50 mixture of the alcohols 43 and 44 in keeping with other reactions of this aldehyde. 10 However these isomers were relatively easy to separate and the less polar epimer was shown to have the required (4S)-configuration by comparison of the relative 1 H NMR chemical shifts of its (R)-and (S)-O-acetyl mandelates. 26 The more polar (4R)-epimer 43 was converted into the less polar (4S)-isomer 44 by a Mitsunobu reaction followed by saponification of the resulting nitrobenzoate making the required (4S)-epimer 44 available in an overall yield of ca.…”