1083348-83-7Relevant academic research and scientific papers
Synthetic approaches to the C11-C27 fragments of bryostatins
Green, Anthony P.,Hardy, Simon,Thomas, Eric J.
, p. 9475 - 9496 (2017)
The modified Julia reaction and acyl carbanion chemistry, especially reactions of 2-lithiated dithianes, have been investigated for the synthesis of intermediates that are the synthetic equivalents of the C11-C27 fragments of bryostatins. The modified Julia reaction using 2-benzothiazolylsulfones was found to be more useful for the formation of the C16-C17 double-bond than the classical Julia reaction using phenylsulfones, and bulky sulfones gave very good (E)-stereoselectivity. The alkylation of a dithiane monoxide that corresponded to a C19-acyl carbanion using (E)-1-bromobut-2-ene was efficient but the use of a more complex allylic bromide corresponding to the C20-C27 fragment of the bryostatins was unsuccessful, possibly due to competing elimination reactions. This meant that the use of C19 dithianes for the synthesis of 20-deoxybryostatins would have to involve the stepwise assembly of the C20-C27 fragment from simpler precursors. However, lithiated C19 dithianes gave good yields of adducts with aldehydes and conditions were developed for the stereoselective conversion of the major adducts into methoxyacetals that corresponded to the C17-C27 fragment of 20-oxygenated bryostatins. A convergent synthesis of the C11-C27 fragment of a 20-deoxybryostatin was subsequently achieved using a 2-benzothiazolylsulfone corresponding to the intact C17-C27 fragment.
Total synthesis of 7-: Des-O -pivaloyl-7- O -benzylbryostatin 10
Green, Anthony P.,Hardy, Simon,Lee, Alan T. L.,Thomas, Eric J.
, p. 9497 - 9526 (2017/11/22)
The first total synthesis of a derivative of a 20-deoxybryostatin, namely 7-des-O-pivaloyl-7-O-benzylbryostatin 10 is described. Preliminary studies demonstrated that the modified Julia reactions of 2-benzothiazolylsulfones corresponding to the C17-C27 fragment with aldehydes corresponding to the C1-C16 fragment, provided an efficient and stereoselective assembly of advanced intermediates with the (E)-16,17-double-bond. The synthesis of the C1-C16 fragment was then modified so that the C1 acid was present as its allyl ester before the Julia coupling. A more efficient synthesis of the C17-C27 sulfone was developed in which a key step was the bismuth mediated coupling of an allylic bromide with an aldehyde in the presence of an acrylate moiety in the allylic bromide. A scalable synthesis of an advanced macrolide was completed using the modified Julia reaction followed by selective deprotection and macrolactonisation. The final stages of the synthesis required selective hydroxyl deprotection and the introduction of the sensitive C19-C21 unsaturated keto-ester functionality. Unexpected selectivities were observed during studies of the hydroxyl group deprotections. In particular, cleavage of tri-isopropylsilyl ethers of the exocyclic primary allylic alcohols was observed in the presence of the triethylsilyl ether of the secondary alcohol at C19. Model studies helped in the design of the methods used to introduce the C19-C21 keto-ester functionality and led to the completion of a total synthesis of a close analogue of bryostatin 10 in which a benzyloxy group rather than the pivaloyloxy group was present at C7.
