Bryostatins [1] are a class of complex macrolides produced by a bacterial symbiont of the marine bryozoan Bugula neritina (Figure 1). [2] Since the first isolation of bryostatin 1 by Pettit and co-workers in 1982, [3] some 20 members of this family have been described. The bryostatins have shown remarkable biological activity against a range of cancers [4] and other diseases such as Alzheimers. [5] They have also been used extensively in clinical trials against these diseases. [1a, 6] Because of their attractive biological activities and unusual structures, bryostatins have remained popular synthetic targets for three decades. [7] The main challenge presented by the bryostatins is the construction of the cistetrahydropyran rings B and C, which contain geometrically defined exocyclic methyl enoates. It is noteworthy that a similar ring skeleton can be found in the structure of (À)exiguolide ( Figure 1), [8] which is thought to be a structurally simpler naturally occurring analogue of the bryostatins. [9] In recent total syntheses of bryostatins, ring B was generally formed by a stepwise strategy, in which the cis-tetrahydropyranone was constructed first with a subsequent asymmetric Horner-Wadsworth-Emmons reaction using Fujis chiral binol phosphonate 2 [10] (Scheme 1 a). Although the exocyclic methyl enoate was produced in good yield, the Z/E selectivity was only in the range of 4:1 to 8:1. In the total synthesis of bryostatin 16, Trost and Dong constructed ring B using an approach based on a ruthenium-catalyzed tandem alkyneenone coupling/Michael addition (Scheme 1 b). [7e,f] While the cis stereochemistry and Z configuration were established in one step, the reaction showed only moderate efficiency and gave 6 in 34 % yield (80 % based on recovered starting material).Bis(silyl) compounds, [11] a special type of organosilane, are attractive synthons because of their great potential for bifunctional reactivity. As part of our continuing efforts to explore bis(silyl) chemistry, [12] we became intrigued by a proposal to form ring B of the bryostatins by using the new strategy shown in Scheme 1 c. In this approach, the bis(silyl) group in 7 plays a bifunctional role: one silyl group reacts as an allylsilane, which undergoes a Prins cyclization [13] Figure 1. Structures of bryostatin 1 and (À)-exiguolide. Scheme 1. Strategies towards the synthesis of ring B of the bryostatins. a) Strategy used by Evans et. al. (bryostatin 2); Yamamura et al. (bryostatin 3); Keck et. al. (bryostatin 1); Wender et al. (bryostatin 9); Krische et al. (bryostatin 7). b) Strategy used by Trost et al. (bryostatin 16). c) This work: Prins cyclization of bis(silyl) homoallylic alcohol with aldehyde. Cp = cyclopentadienyl, HMDS = hexamethyldisilazide, NBS = N-bromosuccinimide.

Convergent total synthesis of bryostatin 8 has been accomplished by an organosilane-based strategy. The C ring is constructed stereoselectively through a geminal bis(silane)-based [1,5]-Brook rearrangement, and the B ring through geminal bis(silane)-based Prins cyclization, thus efficiently joining the northern and southern parts of the molecule.

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Geminal bis(silyl) compounds, a special type of organosilane, are attractive synthons because of their great potential for bifunctional reactivity. This article outlines our recent efforts to develop a practical method to synthesize geminal bis(silane) compounds and to explore their interesting bifunctionality.