Synthetic efficiency: Using atom-economical and chemoselective approaches towards total syntheses of agelas alkaloids, terpestacin and bryostatins

Atom economy and chemoselectivity constitute two of the major challenges for enhancement of synthetic efficiency. The syntheses of biologically important complex natural products constitute the most demanding arena for exploration of such principles. Development and application of those atom-economical and chemo-selective methods, in the total synthesis of bioactive Agelas alkaloids, (--)-terpestacin and bryosotatins, are described herein.;New classes of nucleophiles, pyrroles and N-alkoxyamides, are developed for palladium-catalyzed asymmetric allylic alkylation (AAA) reactions. Application of those methods led to the total synthesis of agelastatin A, a marine natural product with exceptional anti-cancer activity. By tuning the reactivity of pyrrole nucleophiles, two rather different strategies for the total syntheses of both enantiomers of agelastatin A were accomplished, during the course of which we have developed a new copper catalyst for olefin aziridination and an In(OTf)3-DMSO system to oxidatively open an N-tosyl aziridine. As a unique feature of our syntheses, two routes to access both agelastatin A enantiomers use the same enantiomer of a chiral palladium catalyst.;In connection with the pyrrole-mediated Pd AAA reactions, a novel Pd-catalyzed asymmetric annulation between 5-bromopyrrole-2-carboxylate esters and vinyl aziridines has been developed to efficiently construct pyrrolopiperazinones, which serve as key intermediates in the enantioselective syntheses of pyrrole alkaloid natural products. The total synthesis of (--)-longamide B and the first total syntheses of agesamides A and B are illustrated.;Total synthesis of (--)-terpestacin, a sesterterpene with impressive anti-HIV/anti-cancer activity, is described. A strategy based on the unique reactivity of cyclic 1,2-diketones was developed, and total synthesis of (--)-terpestacin was accomplished in 20 longest linear steps from commercially available 3-methyl-1,2-cyclopentanedione. The key feature of our synthesis is represented by double usage of a "Pd AAA-Claisen" protocol, first in the early stage to generate the C1 quaternary center and second in the late stage to install the side chain. In addition, an unusual ene-1,2-dione moiety was synthesized and utilized as an excellent Michael acceptor to attach the C15 substituent. In this work, several interesting chemoselectivity issues have been addressed, such as a highly selective RCM and a challenging dihydroxylation.;Total syntheses of bryostatin 16, bryostatin 7 and 20-epi-bryostatin 7, as well as a promising route towards the structurally complicated bryostatin 3, are described. The overall length of these syntheses is significantly shorter than those previously reported. Notably, bryostatin 16 proved to be able to act as a pivotal parent structure to allow access to almost all other bryostatins and their analogues. Encouragingly, preliminary biological test indicated 20-epi-bryostatin 7 possessed nanomolar activities against several cancer-cell lines, suggesting that it could be a potent anticancer agent. The key features of our synthesis include (1) use of Pd-catalyzed alkyne-alkyne coupling as a novel macrocyclization method; (2) use of Ru-catalyzed tandem enyne isomerization/Michael addition to form the B-ring of bryostatin; (3) an acid-catalyzed one-pot transesterification-ketalization-desilylation; (4) chemoselective ester-hydrolysis; (5) a gold-catalyzed 6- endo-dig cyclization; and (6) a Re-catalyzed chemoselective oxidation of the C19-20 olefin.;In connection with bryostatin synthesis, we have developed a catalytic asymmetric method to synthesize chiral homopropargyl alcohols from the corresponding aldehydes without the use of toxic organotin reagents. A key feature of our methodology is that the reaction can be operated under a Barbier-type procedure without pre-generation of the allenylzinc nucleophile. Rather, the allenylzinc is formed in situ by means of zinc-halogen exchange. This asymmetric propargylation reaction has shown a relatively broad substrate scope: both aromatic aldehydes and aliphatic aldehydes including 0,43-unsaturated ones gave excellent yield (most >90%) and modest to excellent enantioselecitivity (47% to 92% ee). Application this method in the improved route of bryostatin synthesis is in progress.