1IE. ReductionsBoger Notes: p. 95 - 138 (Chapter VI)Carey/Sundberg: B p. 249-330 (Chapter B 5)Problem of the Week: How would you prepare this compound:I. Basic PrinciplesFukuda, N.; Sasaki, K.; Sastry, T. V. R. S.; Kanai, M.; Shibasaki,M., "Catalytic asymmetric total synthesis of (+)-lactacystin." J.Org. Chem. 2006, 71, 1220-1225.P. Wipf - Chem 232012/27/20062 Cell permeability Electrophillic carbonyl for acylation of proteasome Isolated by Fenical, 2003 More potent inhibitor than β-Lactone Cytotoxic activityFenical, W. et al. Angew. Chem. Int. Ed. 2003, 42, 355.β-Lactone : Important Feature for Activity1. Reductions - IntroductionThe most important practical difference between oxidation and reduction is thatthe reduction of unsymmetrical ketones generates chiral secondary alcohols.Reduction is treated extensively in most organic text and reference books. Morethorough treatises can be found in:- Comprehensive Organic Synthesis (Trost, B. M.; Fleming, I.; Eds.); Pergamon Press, Oxford1991, volume 8.- Paderes, G. D.; Metivier, P.; Jorgensen, W. L. J. Org. Chem. 1991, 56, 4718.- Sinclair, S.; Jorgensen, W. L. J. Org. Chem. 1994, 59, 762.- Seyden-Penne, J. Reductions by the Alumino- and Borohydrides in Organic Synthesis.;VCH: New York, 1991.-Reductions in Organic Synthesis; Abdel-Magid, A. F., Ed.; ACS: Washington, DC, 1996.- Daverio, P.; Zanda, M., "Enantioselective reductions by chirally modified alumino- andborohydrides." Tetrahedron: Asymmetry 2001, 12, 2225-2259.P. Wipf - Chem 232022/27/20063Hydrogen/Metal catalystsH2, Raney-NiH2, PtO2H2, RhH2, Pd/CH2, Lindlar-CatalystHydrides and Mixed HydridesAlH3 (LAH+AlCl3)LAHDIBAL-HLi(OMe)3AlH (LTMA)Li(O-t-Bu)3AlH (LTBA)NaH2Al(O(CH2)2OMe)2 (Red-Al, vitride, SMEAH; with CuBr→1,4-reductions)B2H6; BH3SMe2, BH3•THF, BH3 • NH3LiBH4 (LBH)LiEt3BH (super hydride)K(i- PrO)3BH (KIPBH)Li, Na, K, LS-SelectrideHydrides and Mixed Hydrides (cont.)NaBH4 (SBH)NaCNBH3 (stable at pH 3-4)NaBH4CeCl3 (Luche reagent, 1,2-reduction of enones)NaBH(OAc)3Zn(BH4)2Sia2BHBu3SnHDissolving Metal ReagentsNa/NH3/ROH (Birch)Li/NH3/ROHLi/NH3Zn/HOAcZn/HCl (Clemmensen)Na/HgZn/HgMiscellaneous ReductantsNH2NH2/KOHMeerwein-Ponndorf-Verley, i-PrOH, Al(i-Pro)3Diimide (H-N=N-H, prepared in situ from KOCON=NCOOK; adds to nonpolarizeddouble bonds)Et3SiH/BF3P. Wipf - Chem 232032/27/20064The reduction of hindered halides with LAH proceeds predominantly by a single electrontransfer pathway (Ashby, E. C.; Welder, C. O. J. Org. Chem. 1997, 62, 3542).Diastereoselectivity of ReductionsP. Wipf - Chem 232042/27/20065P. Wipf - Chem 232052/27/20066Acid to Alcohol [LAH]Wipf, P.; Kim, Y.; Fritch, P. C. J. Org. Chem. 1993, 58, 7195.Acid to Alcohol [BH3]Dymock, B. W.; Kocienski, P. J.; Pons, J.-M., "A synthesis of the hypocholesterolemic agent1233A via asymmetric [2+2] cycloaddition." Synthesis 1998, 1655.Ester to Alcohol [LiBH4]Hamada, Y.; Shibata, M.; Sugiura, T.; Kato, S.; Shioiri, T. J. Org. Chem. 1987, 52,1252.Wipf, P.; Xu, W. J. Org.Chem. 1996, 61, 6556.P. Wipf - Chem 232062/27/20067Lactone to LactolCorey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc.1969, 91, 5675.Wipf, P.; Kim, Y.; Fritch, P. C. J. Org. Chem. 1993, 58, 7195.Amide to AmineArmstrong, J. D.; Keller, J. L.; Lynch, J.; Liu, T.; Hartner, F. W.; Ohtake, N.; Ikada,S.; Imai, Y.; Okamoto, O.; Ushijima, R.; Nakagawa, S.; Volante, R. P. TetrahedronLett. 1997, 38, 3203.Godjoian, G.; Singaram, B. Tetrahedron Lett. 1997, 38, 1717.Tertiary amides require two equivalents of 9-BBN to give tertiary amines. Sterically morehindered dialkylboranes react in a 1:1 stoichiometry to give aldehydes.P. Wipf - Chem 232072/27/20068Amide to Amine [Raney-Nickel]Wipf, P.; Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117, 11106.Tian, X.; Hudlicky, T.; Königsberger, K. J. Am. Chem. Soc. 1995, 117, 3643.Amide to AldehydeHydroxyamide to Aldehyde [LAH]Wipf, P.; Kim, H. Y. J. Org. Chem. 1993, 58, 5592.Isocyanate to FormamideTaber, D. F.; Yu, H.; Incarvito, C. D.; Rheingold, A. L., "Synthesis of (-)-isonitrin B." J. Am.Chem. Soc. 1998, 120, 13285.P. Wipf - Chem 232082/27/20069β-Keto Ester to Enoate [Cp2ZrHCl]Trauner, D.; Schwarz, J. B.; Danishefsky, S. J., "Total synthesis of (+)-halichlorine:An inhibitor of VCAM-1 expression." Angew. Chem. Int. Ed. 1999, 38, 3542-3545.An application of a process developed by Ganem.Ester to Alcohol [DIBAL-H]Wipf, P.; Kim, Y.; Fritch, P. C. J. Org. Chem. 1993, 58, 7195.Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558; Wipf, P.; Lim, S. Chimia 1996, 50, 157.P. Wipf - Chem 232092/27/200610Enone to Allylic Alcohol or KetoneHard metal hydrides, e.g. LAH, add predominantly 1,2-, whereas softer hydrides,e.g. LiAl(t-BuO)3H, prefer 1,4-. 1,2-Addition also is the major pathway forreductions with electrophilic hydrides such AlH3.Luche reduction: Wipf, P.; Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117,11106.Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558; Wipf, P.; Lim, S. Chimia1996, 50, 157.Woodward, R. B. et al. J. Am. Chem. Soc. 1952, 74, 4223. Enone transposition.P. Wipf - Chem 2320102/27/200611Epoxide to AlcoholAlkyne to (E)-Alkene [LAH]Martin, T.; Soler, M. A.; Betancort, J. M.; Martin, V. S. J. Org. Chem. 1997, 62,1570.Consider also: Boeckman, R. K.; Thomas, E. W. J. Am. Chem. Soc. 1977, 99, 2805.P. Wipf - Chem 2320112/27/200612Allylic Ester to Alkene [Pd(0)]Wipf, P.; Spencer, S. R., "Asymmetric total syntheses of tuberostemonine,didehydrotuberostemonine, and 13-epituberostemonine." J. Am. Chem. Soc. 2005, 127, 225-235.Allylic Alcohol to Alkene - Allylic Diazene RearrangementWood, J. L.; Porco, J. A.; Taunton, J.; Lee, A. Y.; Clardy, K.; Schreiber, S. L. J. Am. Chem. Soc.1992, 114, 5898.P. Wipf - Chem 2320122/27/200613Reductive Dethionation [Et3SiH/Pd]Smith, A. B.; Chen, S. S.-Y.; Nelson, F. C.; Reichert, J. M.; Salvatore, B. A. J. Am.Chem. Soc. 1997, 119, 10935 (Fukuyama’s method).2. Asymmetric Reductions-LAH modified reagents: Mosher: LAH + darvon alcoholMukaiyama: LAH + chiral diamineNoyori: Binal-HP. Wipf - Chem 2320132/27/200614- (S)-Binal-H transition state:- (R)-Binal-H transition state:- LAH modified reagents: Seebach: TADDOL- Borane modified reagents: Alpine borane:The boat-TS conformation minimizes steric hindrance.DIP-Cl: (Ipc2B-Cl; better Lewis acid than Alpine borane, and more reactive).P. Wipf - Chem
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