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IE. Reductions

Boger 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 Principles

Fukuda, 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.

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Cell permeability Electrophillic carbonyl for acylation of proteasome

Isolated by Fenical, 2003 More potent inhibitor than β-Lactone Cytotoxic activity

Fenical, W. et al. Angew. Chem. Int. Ed. 2003, 42, 355.

β-Lactone : Important Feature for Activity

1. 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.

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Hydrogen/Metal catalystsH2, Raney-NiH2, PtO2

H2, RhH2, Pd/CH2, Lindlar-Catalyst

Hydrides 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 • NH3

LiBH4 (LBH)LiEt3BH (super hydride)K(i- PrO)3BH (KIPBH)Li, Na, K, LS-Selectride

Hydrides and Mixed Hydrides (cont.)NaBH4 (SBH)NaCNBH3 (stable at pH 3-4)NaBH4CeCl3 (Luche reagent, 1,2-reduction of enones)NaBH(OAc)3Zn(BH4)2Sia2BHBu3SnH

Dissolving Metal ReagentsNa/NH3/ROH (Birch)Li/NH3/ROHLi/NH3Zn/HOAcZn/HCl (Clemmensen)Na/HgZn/Hg

Miscellaneous ReductantsNH2NH2/KOHMeerwein-Ponndorf-Verley, i-PrOH, Al(i-Pro)3Diimide (H-N=N-H, prepared in situ from KOCON=NCOOK; adds to nonpolarized

double bonds)Et3SiH/BF3

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The 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 Reductions

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Acid 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.

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Lactone to Lactol

Corey, 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 Amine

Armstrong, 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.

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Amide 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 Aldehyde

Hydroxyamide to Aldehyde [LAH]

Wipf, P.; Kim, H. Y. J. Org. Chem. 1993, 58, 5592.

Isocyanate to Formamide

Taber, D. F.; Yu, H.; Incarvito, C. D.; Rheingold, A. L., "Synthesis of (-)-isonitrin B." J. Am.Chem. Soc. 1998, 120, 13285.

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β-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.

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Enone to Allylic Alcohol or Ketone

Hard 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.

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Epoxide to Alcohol

Alkyne 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.

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Allylic 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.

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Reductive 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 alcohol

Mukaiyama: LAH + chiral diamine

Noyori: Binal-H

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- (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).

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B-Chlorodiisopinocanpheylborane (Ipc2BCl or DIP-chloride) is an excellent reagentfor the asymmetric reduction of aryl alkyl ketones. (-)-DIP-chloride is dIpc2BCl,derived from (+)-pinene.For an in situ protocol, see: Zhao, M.; King, A. O.; Larsen, R. D.; Verhoeven, T. R.;Reider, P. J. Tetrahedron Lett. 1997, 38, 2641-4.

Ramachandran, P. V. et al. Tetrahedron Lett. 1996, 37, 2205; Tetrahedron Lett.1997, 38, 761

Oxazaborolidines: The systematic studies of Hirao, Itsuno, and coworkersrevealed the catalytic nature of the aminoalcohol-borane system. Corey and co-workers identified the catalyst as oxazaborolidine (CBS = Corey-Bakshi-Shibata,diphenyloxazaborolidine). The transition state model shown below was proposedby Liotta (J. Org. Chem. 1993, 58, 799).

Preparation of the catalyst: Xavier, L. C.; Mohan, J. J.;Mathre, D. J.; Thompson, A. S.; Carroll, J. D.; Corley, E.G.; Desmond, R. Org. Syn. 1996, 74, 51.Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37,1986 (review).

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Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc.1969, 91, 5675.

• Corey, E. J. et al. J. Am. Chem. Soc.1987, 109, 7925. Asymmetric reductionto achieve diastereoselectivity.

Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1997, 38, 7511. Enantioselective:Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986 (review).

Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558; Wipf, P.; Lim, S. Chimia 1996, 50, 157.

Wipf, P.; Weiner, W. J. Org. Chem. 1999, 64, 5321-5324.

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Comparison of oxazaborolidine catalysts:Hett, R. H.; Senanayake, C. H.; Wald, S. A., "Conformational toolbox ofoxazaborolidine catalysts in the enantioselective reduction of α-bromo-ketone forthe synthesis of (R,R)-formoterol." Tetrahedron Lett. 1998, 39, 1705.

Asymmetric Reduction of Ketones to Alcohols [Meerwein-Ponndorf-Verley].Evans, D. A.; Nelson, S. G.; Gagne, M. R.; Muci, A. R. J. Am. Chem. Soc. 1993,115, 9800. One of the critical characteristics of the reduction is the special affinityexhibited by the catalyst for 2-propanol as the hydride source. Other alcohols suchas benzhydrol are not practical reductants. Accordingly, product enantiomeric purityis maintained in all instances even after prolonged exposure to the catalytic system.

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Enzymatic reductions: Baker’s yeast, lactate dehydrogenase (both L- and D-LDH are available). Review: Roberts, S. M., "Preparative biotransformations." J.Chem. Soc., Perkin Trans. 1 2001, 1475-1499.

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