Bryostatin total synthesis

Scheme 5.4 Total synthesis of bryostatin 3 by Nishiyama and Yamamura...

Scheme 10. Cu-catalyzed asymmetric aldol addition used in the enantioselective total synthesis of bryostatin 2 by Evans (1998).

Hale, K. J. and Manaviazar, S. (2010). New approaches to the total synthesis of bryostatin antitumor macrolides. Client. Asian J. 5, 704-754. 

Bryostatin 7 (3) was the first member of the bryostatin family that was accessible by total synthesis. Its preparation was described by Masamune et al. already briefly after its isolation from Bugula neritina [8]. Their concept was based on a combination of the four synthons 4-7 (Figure 2) The (R,R)-2,5-dimethylborolanyl triflate mediated aldol reaction of aldehyde 4 with the enolate derived from ketone 5 leads after a sequence of deprotection steps, cycliza-... 

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

Fig. 3. Total synthesis of bryostatin 2 by Evans et ai. [9]. All three ring fragments have a diol substructure in common which is highlighted.

Another example of this methodology has appeared recently from Masamune and coworkers in connection with a total synthesis of bryostatin (equation 67). The salient point here is the demonstrated utility of the thiol ester, prepared directly through stereoselective boron enolate aldol condensation. Notice Aat no further activation or removal of a chiral auxiliary is necessary for this transformation, unlike other related aldol methodology. 

Trost, B.M., Yang, H.,Thiel, O.R., Frontier, A.J. and Brindle, C.S. (2007) Synthesis of a ring-expanded bryostatin analogue. Journal of the American Chemical Society, 129, 2206-2207 Cook, C Guinchard, X., Liron, F. and Roulland, E. (2010) Total synthesis of (-)-exiguolide. Organic Letters, 12, 744-747. 

Application of the external chiral boron reagent (90) in the total synthesis of bryostatin, a natural product, is shown in Scheme 45.S8 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 die formation of the desired isomer (1 IS) in adduct (113). The use of chiral (2/ ,5fl)-dimethylborolanyl triflate in this reaction increases the selectivity to a 6 1 preference as... 

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