The schiarisanrins are a structurally novel family of lignan natural products that exhibit potent cytotoxicity that were isolated from the fruit of the Chinese medicinal plant Schizandra arisanensis. These agents are derived from the well- represented dibenzocyclooctadiene class of lignans by an oxidative spirocyclization to form the unique 2,4- cyclohexadienone-6-spiro-3'-(2',3'-dihydrobenzo[b]furan) ring system. A synthetic approach to this family of natural products is proposed and is based on a biomimetic strategy for the formation of the spirodihydrobenzo[b]furan ring system. Two strategies for biaryl bond construction are proposed, the first based on an intermolecular coupling of an appropriately substituted 1,4-diarylbutane system, and the second based on novel synthetic methodology for an asymmetric intermolecular biaryl coupling reaction. In the first strategy, the three stereogenic centers of the cyclooctadiene ring will be introduced by an asymmetric allylboration reaction, and 1,4-diarylbutane construction will be completed by a stereoselective hydroboration/Suzuki coupling reaction sequence. In the second strategy, the cyclooctadiene ring will be formed by a ring- closing metathesis reaction of an appropriately substituted chiral biaryl system. The final spirocyclization is proposed to proceed regioselectively from a dioxepin precursor based on an inherent steric bias of the biaryl system. The oximidines are macrocyclic diene and triene lactone natural products that exhibit potent cytotoxicity that is selective for oncogene transformed cells. Studies are proposed for the total synthesis of these agents that feature a novel intramolecular Castro-Stephens coupling for macrolactone formation and a palladium catalyzed coupling between a (Z)-vinyl iodide and a lactam for installation of the enamide side chain.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA091904-02
Application #
6624122
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
2002-04-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$262,550
Indirect Cost
Name
Ohio State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
071650709
City
Columbus
State
OH
Country
United States
Zip Code
43210
Mitra, Soumya; Gurrala, Srinivas Reddy; Coleman, Robert S (2007) Total synthesis of the eupomatilones. J Org Chem 72:8724-36
Coleman, Robert S; Lu, Xiaoling; Modolo, Isabelle (2007) Total synthesis of 2'-O-methylmyxalamide D and (6E)-2'-O-methylmyxalamide D. J Am Chem Soc 129:3826-7
Coleman, Robert S; Walczak, Matthew C (2006) Total synthesis of gymnoconjugatins A and B. J Org Chem 71:9841-4
Coleman, Robert S; Lu, Xiaoling (2006) Total synthesis of strobilurin B using a hetero-bis-metallated pentadiene linchpin. Chem Commun (Camb) :423-5
Coleman, Robert S; Walczak, Matthew C (2005) Tandem Stille/Suzuki-Miyaura coupling of a hetero-bis-metalated diene. Rapid, one-pot assembly of polyene systems. Org Lett 7:2289-91
Coleman, Robert S; Gurrala, Srinivas Reddy (2005) Asymmetric synthesis of the dibenzocyclooctadiene lignans interiotherin a and gomisin R. Org Lett 7:1849-52
Coleman, Robert S; Gurrala, Srinivas Reddy; Mitra, Soumya et al. (2005) Asymmetric total synthesis of dibenzocyclooctadiene lignan natural products. J Org Chem 70:8932-41
Coleman, Robert S; Walczak, Matthew C; Campbell, Erica L (2005) Total synthesis of lucilactaene, a cell cycle inhibitor active in p53-inactive cells. J Am Chem Soc 127:16038-9
Coleman, Robert S; Gurrala, Srinivas Reddy (2004) Total synthesis of eupomatilones 4 and 6: structurally rearranged and atropisomerically fluxional lignan natural products. Org Lett 6:4025-8
Coleman, Robert S; Felpin, Francois-Xavier; Chen, Wei (2004) Mitomycin synthetic studies: stereocontrolled and convergent synthesis of a fully elaborated aziridinomitosane. J Org Chem 69:7309-16

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