The long-term goal of the ongoing and proposed research project is to fundamentally innovate organic synthesis such that a wide variety of organic compounds of biological and medicinal significance can be prepared in efficient, selective, practically useful, and economical manners. Critically needed is to keep improving substantially and continuously organic synthesis through introduction of new and superior synthetically useful reactions, protocols, and procedures. In the NIH-supported research project, this goal has been pursued primarily through active and judicious incorporation of fundamentally superior reactions employing transition metals and their complexes primarily as catalysts, such as the Pd-catalyzed cross-coupling and the Zr-catalyzed carboalumination of alkynes. During the current grant period, the Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction hereafter) discovered by the PI has been developed into a general and potentially useful asymmetric carbon-carbon bond-formation reaction. Thus, the use of the ZACA reaction in target-guided development of protocols and procedures for the synthesis of chiral organic compounds, especially those alkenes, oligoenes, oligoenynes that contain one or more proximal asymmetric carbon centers is one of the main specific aims of the proposed research. It is fully intended to seek unprecedentedly high levels of efficiency and selectivity such that the preparation of the desired complex molecules would become genuinely practical for various purposes including medicinal screening and even industrial production. Some of the target compounds whose total syntheses will be attempted during the proposed grant period include mycolactones A and B, delactonmycin, ratjadone, lacrimin A, fluvirucinin A, as well as some (Z)-carotenoids and oligoynes. Equally important in the proposed research are syntheses of those fragments of compounds of biological and medicinal interest that are highly pertinent to the proposed methodological investigations. Being considered for this purpose are discodermolide, hennoxazole A, zincophorin, roselipins, apoptolidin, nafuredin, caIlystatin A, milbemycin p3, calyculin A, and amphotericin B.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Hagan, Ann A
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Purdue University
Schools of Arts and Sciences
West Lafayette
United States
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Wang, Guangwei; Xu, Shiqing; Hu, Qian et al. (2013) Search for highly efficient, stereoselective, and practical synthesis of complex organic compounds of medicinal importance as exemplified by the synthesis of the C21-C37 fragment of amphotericin B. Chemistry 19:12938-42
Xu, Shiqing; Lee, Ching-Tien; Wang, Guangwei et al. (2013) Widely applicable synthesis of enantiomerically pure tertiary alkyl-containing 1-alkanols by zirconium-catalyzed asymmetric carboalumination of alkenes and palladium- or copper-catalyzed cross-coupling. Chem Asian J 8:1829-35
Xu, Shiqing; Lee, Ching-Tien; Rao, Honghua et al. (2011) Highly(≥98%) Stereo- and Regioselective Trisubstituted Alkene Synthesis of Wide Applicability via 1-Halo-1-alkyne Hydroboration-Tandem Negishi-Suzuki Coupling or Organoborate Migratory Insertion Protocol. Adv Synth Catal 353:2981-2987
Wang, Guangwei; Yin, Ning; Negishi, Ei-ichi (2011) Highly stereoselective total synthesis of fully hydroxy-protected mycolactones A and B and their stereoisomerization upon deprotection. Chemistry 17:4118-30
Negishi, Ei-Ichi; Wang, Guangwei; Rao, Honghua et al. (2010) Alkyne elementometalation-Pd-catalyzed cross-coupling. Toward synthesis of all conceivable types of acyclic alkenes in high yields, efficiently, selectively, economically, and safely: ""green"" way. J Org Chem 75:3151-82
Wang, Chao; Xu, Zhaoqing; Tobrman, Tomas et al. (2010) Arylethyne Bromoboration-Negishi Coupling Route to E- or Z-Aryl-Substituted Trisubstituted Alkenes of ≥98% IsomericPurity. New Horizon in the Highly Selective Synthesis of Trisubstituted Alkenes. Adv Synth Catal 352:627-631
Negishi, Ei-Ichi; Tobrman, Tomas; Rao, Honghua et al. (2010) Highly(≥98%) Selective Trisubstituted Alkene Synthesis of Wide Applicability via Fluoride-Promoted Pd-Catalyzed Cross-Coupling of Alkenylboranes. Isr J Chem 50:696-701
Wang, Chao; Tobrman, Tomas; Xu, Zhaoqing et al. (2009) Highly regio- and stereoselective synthesis of (Z)-trisubstituted alkenes via propyne bromoboration and tandem Pd-catalyzed cross-coupling. Org Lett 11:4092-5
Wang, Guangwei; Huang, Zhihong; Negishi, Ei-Ichi (2008) Efficient and selective syntheses of (all-E)- and (6E,10Z)-2'-O-methylmyxalamides D via Pd-catalyzed alkenylation--carbonyl olefination synergy. Org Lett 10:3223-6
Wang, Guangwei; Zhu, Gangguo; Negishi, Ei-Ichi (2007) Zirconium-catalyzed methylalumination of heterosubstituted arylethynes. Factors affecting the regio-, stereo-, and chemoselectivities. J Organomet Chem 692:4731-4736