Bryostatin natural products, synthesis

Fig. 1. Molecular structures of bryostatin natural products which are accessible by total synthesis.

In studies related to the synthesis of bryostatin natural products, it was shown that stereocontrolled cyclizations could be achieved in silyl-terminated Prins cyclizations (Scheme 5). ° Thus, the syn-P-hydroxy allyl silane (13) reacts with propionaldehyde to provide the cw-2,6-disubstituted 4-alkylidenetetrahydropyran (14) in excellent yield and stereocontrol of the olefin geometry (>95 5). The chemistry was examined by DPT (density functional theory) calculations, which suggested that the cyclization step occurs through a chair-like structure (15). Stereocontrol of the exocyclic double bond is thought to be a consequence of steric and electronic effects, in particular maximization of -silyl stabilization of forming carbocation center (16). 

The synthesis of bryostatins and related congeners contains some of the most complex examples of Prins cyclizations in natural products synthesis. Simultaneous reports by both Wender and coworkers and Keck et al. illustrate the power and tolerance of Prins cyclization on complex bryostatin analogs (Scheme 42)... 

Evans synthesis of bryostatin 2 (113) also relied upon asymmetric aldol reactions for the introduction of most of the 11 stereocenters [58], At different points, the synthesis used control from an auxiliary, a chiral Lewis acid, chiral ligands on the enolate metal and substrate control from a chiral aldehyde. Indeed, this represents the current state of the art in the aldol construction of complex polyketide natural products. 

As already illustrated, the AD reaction still requires some investigation to obtain good selectivity other than that with simple substrates. Another example is in work toward the synthesis of Bryostatin-C where reasonable selectivity was seen with 9 as a substrate for an AD reaction with AD-mix [3. However, the selectivity fell significantly with the more substituted cyclic and acyclic analogues of 9 required for the synthesis of the natural product. A survey of commercially... 

Application of the external chiral boron reagent (90) in the totd synthesis of bryostatin, a natural product, is shown in Scheme 45. The convergent approach adopted involves coupling of the boron enolate derived from (111) with aldehyde (112). The reaction mediated by an achiral boron reagent (Et2BOTf) provides only a 2 1 preference for the formation of the desired isomer (115) in adduct (113). The use of chiral (2/ ,5 )-dimethylborolanyl triflate in this reaction increases the selectivity to a 6 1 preference as... 

Several studies were dedicated to the construction of the tetrahydropy-ran scaffold in the total synthesis of natural products, namely (—)-brevisamide (130BC6751), (—)-blepharocalyxin D (13OL2046), bryostatins... 

Owing to the reliability and versatility of this reagent, it has been extensively utilized in the synthesis of complex natural products and some of the very recent examples include sominone 29, lauli-malide 30, macrosphelide 31, bryostatin 32, superstolide 33, hyptolide 34, and so on (Figure 25.4). ... 

Kageyama, M., and S. Masamune Studies Toward the Total Synthesis of Bryostatin 7. 31st Symposium on the Chemistry of Natural Products, Nagoya, Japan, 1989, 227. 

The THP rings contained within the bryostatin family of natural products have also succumbed to synthesis by Michael-type cyclization. Yadav et al. reported the tandem desilylation and conjugate addition to give the B ring of bryostatin 1 [27]. TBAF-mediated deprotection of silyl ether 27 resulted in 67 % isolated yield of 2,6-cis THP 28 (Scheme 8, Eq. 1). Thomas and coworkers described a similar approach on a related substrate to that of Yadav et al. (Scheme 8, Eq. 2) [28]. Cleavage of TES and TMS ethers with HF/pyridine resulted in diol 29, and a subsequent cyclization with catalytic base proceeded stereoselectively to 2,6-cis-4-methylene THP 30 (48 % yield over three steps). 

Green, A.P., Hardy, S Lee, A.T.J., and Thomas, E.J. (2010) Approaches to the total synthesis of biologically active natural products studies directed towards bryostatins. Phytochem. Rev., 9, 501-513. 

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