We propose to continue our research in the area of acyclic diastereoselective synthesis, with emphasis on novel allylmetalation reactions and fragment assembly aldol reactions which will be developed in the context of the total synthesis of structurally complex, biologically active natural products. Specific goals for the next grant period are: (1)Completion of a Total Synthesis of Tedanolide. The key step of the proposed synthesis was successfully modeled in the previous grant period, thus defining the strategy that will be pursued for completion of the total synthesis. (2) Allylation of Oxonium Ions; Synthesis of the Pyran Nucleus of Scytophycin C. A new strategy for the synthesis of the 2,6-trans dihydropyran unit of scytophycin C will be developed based on the reactions of allylsilanes and oxonium ions followed by ring closing metathesis. (3) Completion of a Total Synthesis of Scytophycin C. The total synthesis of scytophycin C will be completed. The key fragment assembly aldol step was successfully modeled in the previous grant period. (4) Total Synthesis of Spongistatin 1. A synthesis of the E-F bis-pyran unit was completed in the preceding grant period. Studies in the coming grant period will focus on the bifunctional gamma-silylallylborane for the convergent coupling of two aldehydes to generate l,5-anti-pent-2(E)-1,5- diols, which will serve as precursors to the A-B and C-D spiroketals. A strategy for the stereocontrolled synthesis of the C-D spiroketal via inversion of the C(l9) stereocenter also will be developed. (5) Total Synthesis of Apoptolidin. Fragment assembly aldol reactions of alpha- alkoxy ketones will be developed for the synthesis of the C(12)-C(28) segment of apoptolidin. (6) Total Synthesis of Amphidinol 3. Bifunctional allylboranes will be developed for the convergent coupling of two aldehydes to generate l ,5-syn-pent-2(Z)- l ,5-diols, which will serve as key intermediates for the synthesis of the tetrahydropyran units of amphidinol 3. This methodology also provides an alternative strategy for synthesis of the scytophycin C dihydropyran nucleus.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM038436-16
Application #
6498661
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1988-02-01
Project End
2004-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
16
Fiscal Year
2002
Total Cost
$237,973
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Doherty, Joanne R; Yang, Chunying; Scott, Kristen E N et al. (2014) Blocking lactate export by inhibiting the Myc target MCT1 Disables glycolysis and glutathione synthesis. Cancer Res 74:908-20
Chen, Ming; Roush, William R (2013) Enantiodivergent Hydroboration Reactions of a Racemic Allenylsilane with Diisopinocampheylborane and Curtin-Hammett Controlled Double Asymmetric Crotylboration Reactions of (S)-E-?-phenyldimethylsilyl( d diisopinocamp Tetrahedron 69:5468-5475
Nuhant, Philippe; Allais, Christophe; Roush, William R (2013) Diisopinocampheylborane-mediated reductive aldol reactions: highly enantio- and diastereoselective synthesis of syn aldols from N-acryloylmorpholine. Angew Chem Int Ed Engl 52:8703-7
Nuhant, Philippe; Roush, William R (2013) Enantio- and diastereoselective synthesis of N-acetyl dihydrotetrafibricin methyl ester. J Am Chem Soc 135:5340-3
Allais, Christophe; Nuhant, Philippe; Roush, William R (2013) (Diisopinocampheyl)borane-mediated reductive aldol reactions of acrylate esters: enantioselective synthesis of anti-aldols. Org Lett 15:3922-5
Chen, Ming; Roush, William R (2013) Crotylboron-based synthesis of the polypropionate units of chaxamycins A/D, salinisporamycin, and rifamycin S. J Org Chem 78:3-8
Kister, Jeremy; Ess, Daniel H; Roush, William R (2013) Enantio- and diastereoselective synthesis of syn-*-hydroxy-*-vinyl carboxylic esters via reductive aldol reactions of ethyl allenecarboxylate with 10-TMS-9-Borabicyclo[3.3.2]decane and DFT analysis of the hydroboration pathway. Org Lett 15:5436-9
Abbott, Jason R; Roush, William R (2013) Stereoselective synthesis of the disaccharide unit of incednine. Org Lett 15:62-4
Chen, Ming; Roush, William R (2013) Enantioselective synthesis of (Z)- and (E)-2-methyl-1,5-anti-pentenediols via an allene hydroboration-double-allylboration reaction sequence. J Am Chem Soc 135:9512-7
Tsai, Andy S; Chen, Ming; Roush, William R (2013) Chiral Brønsted Acid Catalyzed Enantioselective Synthesis of anti-Homopropargyl Alcohols via Kinetic Resolution-Aldehyde Allenylboration Using Racemic Allenylboronates. Org Lett 15:2325

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