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Among macrocyclic natural products, bryostatins have excellent bioactivities and unique structures that make them highly attractive to synthetic chemists. Particularly challenging for the total synthesis of bryostatins is the B-ring, which features a cis-tetrahydropyran containing a geometrically defined exocyclic Z-methyl enoate. Synthetic chemists have recently displayed great prowess in their efforts to construct this ring, and here we summarize the progress towards this goal.

The cyclization shows excellent cis and (Z) selectivity to form tetrahydropyrans containing a geometrically defined exocyclic vinylsilane.

This paper reports the synthesis of novel ring-expanded bryostatin analogues. By carefully modifying the substrate, a selective and high-yielding Ru-catalyzed tandem enyne coupling/Michael addition was employed to construct the northern fragment. A ring-closing metathesis was utilized to form the 31-membered macrocycle of the analogue. These ring-expanded bryostatin analogues possess anticancer activity against several cancer cell lines. Given the difficulty of forming the C16-17 olefin in the late stage, we also describe our development of a new-generation strategy to access the C7-C27 fragment containing both the B- and C-ring subunits.

Bryostatins, a family of structurally complicated macrolides, exhibit an exceptional range of biological activities. The limited availability and structural complexity of these molecules makes development of an efficient total synthesis particularly important. This article describes our initial efforts towards the total synthesis of bryostatins, in which chemoselective and atom-economical methods for stereoselective assembly of the C-ring subunit were developed. A Pd-catalyzed tandem alkyne-alkyne coupling/6-endo-dig cyclization sequence was explored and successfully pursued in the synthesis of a dihydropyran ring system. Elaboration of this methodology ultimately led to a concise synthesis of the C-ring subunit of bryostatins.

This article describes chemoselective and atom-economical methods for the stereoselective assembly of the A- and B-ring subunits of the bryostatins. A Ru-catalyzed tandem alkene-alkyne coupling/Michael addition was developed and applied to the synthesis of the bryostatin B-ring. We explored an acetylide-mediated epoxide-opening/6-exo-dig cyclization route to access the bryostatin A-ring; and the A-ring was eventually furnished via an acid-catalyzed tandem transketalization/ketalization sequence. In addition, a dinuclear zinc-catalyzed methyl vinyl ketone (MVK) aldol strategy was evaluated for the construction of the polyacetate moiety. Utilization of these methods ultimately led to the rapid assembly of a northern bryostatin fragment containing both the A- and B-ring subunits.

We review in part our computational, design, synthesis, and biological studies on a remarkable class of compounds and their designed analogs that have led to preclinical candidates for the treatment of cancer, a first-in-class approach to Alzheimer's disease, and a promising strategy to eradicate HIV/AIDS. Because these leads target, in part, protein kinase C (PKC) isozymes, they have therapeutic potential even beyond this striking set of therapeutic indications. This program has given rise to new synthetic methodology and represents an increasingly important direction of synthesis focused on achieving function through synthesis-informed design (function-oriented synthesis).

Progress on a total synthesis of the marine natural products, the bryostatins, is reviewed. Following studies aimed at the synthesis of the 1,16- and 17,27-fragments, procedures for the assembly of the macrocyclic ring of the bryostatins were investigated. Although ring-closing metathesis was not found to be useful for the synthesis of bryostatins with geminal dimethyl groups at C18, the modified Julia reaction was found to be useful for the stereoselective formation of the 16,17-double-bond and led to a synthesis of an advanced macrocyclic intermediate. Several novel synthetic procedures feature in this work.

Disconnection at C20-C21 leads to two fragments. The C21-C27 fragment is constructed from D-isobutyl lactate via chelation-controlled allylation. The C17-C20 fragment is obtained from D-pantolactone.

The α-bromo-alkyllithium compounds 5 are generated by diastereoselective bromine/lithium exchange on the dibromo-compound 4. The minor carbenoid 5b generated cyclizes spontaneously at −110°C to the bicyclo[3.1.0]hexane 6, thus, leaving the major carbenoid 5a in diastereomerically pure form. Application of the boronate extension reaction to this carbenoid 5a ed to 1,3- or 1,6-diol derivatives, viz. 9, 13, 6, with complete stereocontrol. This technique was applied to the synthesis of racemic 22, corresponding to the segment C-1/C-9 of the bryostatins.

On treatment with tributyltin hydride, the vinyl bromide 11 and the vinyl iodide 26 cyclize to give mixtures of the (E)- and (Z)-4-(alkoxycarbonylmethylene)tetrahydropyrans 12/13 and 27/28 in which the (E)-isomers 12 and 27 are the major components accounting for 80% of the products. Addition of triphenyltin hydride to the alkyne 34 similarly initiates cyclization giving a mixture of products 35–37, the composition of the mixture depending upon the concentration of the tin hydride. These results are consistent with faster cyclization of the (Z)-vinyl radical with kinetic formation of five-membered ring containing products which are either trapped by hydrogen transfer from the tin hydride or which rearrange to form a 4-methylenetetrahydropyran. This chemistry was applied to prepare the cis-2,6-disubstituted 4-(methoxycarbonylmethylene)tetrahydropyran 50 which may be useful for the introduction of the C(10)–C(16) fragment into the bryostatins. Cyclization of the p-methoxybenzyl protected vinyl iodide 58 is less stereoselective, perhaps because of intramolecular hydrogen transfer from the p-methoxybenzyl group.

The organolithium reagent generated from the vinyl iodide 8 reacts with aldehyde 13 to give a mixture of the anti- and syn-silyloxy alcohols 14 and 15 together with the regioisomeric syn-silyloxy alcohol 16, ratio 14 : 15 : 16 = 4 : 1 : 1. The major anti-alcohol 14 was taken through to the methoxyacetal 27 so confirming this strategy for the stereoselective synthesis of the C(17)–C(23) fragment of bryostatins. The diol 30, which has configurations at each of its three chiral centres corresponding to the C(23)–C(27) fragment of bryostatins, was prepared in two steps from the aldehyde 28 and converted into the vinylstannane 45.

The bryostatins are a unique family of cancer chemotherapeutic candidates isolated from marine bryozoa. While their molecular mode of action is not known, these macrolactones exhibit high affinities for protein kinase C (PKC) isozymes, compete for the phorbol ester binding site on PKC, and stimulate kinase activity in vitro and in vivo. Unlike the phorbol esters, they do not act as tumor promoters. Despite promising biological properties, the supply of these compounds is limited by the difficulty of their isolation from natural sources and their synthetic complexity. A new class of bryostatin analogues which retain the putative recognition domain of the bryostatins but are simplified through deletions and modifications in the C1-C14 spacer domain have been designed using computer models. A convergent synthesis has been realized for the production, in gram quantities, of these recognition and spacer domains whose coupling allows for the generation of a range of analogues. The final closure process involves a novel macrotransacetalization reaction which proceeds with complete stereoselectivity. The solution structures of two synthetic analogues were determined by NMR spectroscopy and found to be very similar to the previously reported structures of bryostatins 1 and 10. In addition, these structures appear to indicate that the stereochemistry of the C3 hydroxyl group plays a significant role in the conformation of the macrolactone. All analogues bound strongly to a mixture of PKC isozymes, and several exhibited significant levels of in vitro growth inhibitory activity against human cancer cell lines. Taken together, this work provides important steps toward the development and understanding of simplified, synthetically accessible analogues of the bryostatins as potential chemotherapeutic agents.

A new convergent synthetic approach to a pyran motif common to many naturally occurring structures is described. In this approach, two fragments are joined by esterification, and a subsequent intramolecular reductive cyclization affords the 2-hydroxypyran.

After a brief introduction that outlines our general strategy for the stereoselective synthesis of complex natural products, based on the rule of multiple asymmetric synthesis, this article will present a critical evaluation of reagents recently developed to effect asymmetric aldol and allyl- and crotylboration, perhaps the two most important carbon, carbon bond forming reactions in the synthesis of polyketide-type natural products. Some emphasis will be placed on the mechanistic and synthetic aspects of newly discovered (R-) and (S)-2-trimethylsilylborolane mediated reactions. The latter half of the article will deal with the application of these reactions as illustrated by our work directed towards the synthesis of bryostatin 1, C47H6sOll, a marine natural product isolated in minute quantities from Bulgula nerztzna. Bryostatins are potential anti-leukemic agents.