1

Hydroxamate 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.

Nitro to AnilineBlaser, H.-U., "A golden boost to an old reaction." Science 2006, 313, 312-313.

Dr. P. Wipf Chem 2320 3/28/2007

2

Ester to Alcohol [DIBAL-H]

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

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.

Dr. P. Wipf Chem 2320 3/28/2007

3

Woodward, R. B. et al. J. Am. Chem. Soc. 1952, 74, 4223. Enone transposition.

Epoxide to Alcohol

Dr. P. Wipf Chem 2320 3/28/2007

4

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.

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).

Dr. P. Wipf Chem 2320 3/28/2007

5

Asymmetric Reductions

-LAH modified reagents: Mosher: LAH + darvon alcohol

Mukaiyama: LAH + chiral diamine

Noyori: Binal-H

- LAH modified reagents: Seebach: TADDOL

Dr. P. Wipf Chem 2320 3/28/2007

6

- NaBH4 modified reagents: Tartaric acid

Proline

Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J., "Asymmetricsynthesis of active pharmaceutical ingredients." Chem. Rev. 2006, 106,2734-2793.

Dr. P. Wipf Chem 2320 3/28/2007

7

- 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).

B-Chlorodiisopinocampheylborane (Ipc2BCl or DIP-chloride) is an excellentreagent for the asymmetric reduction of aryl alkyl ketones. (-)-DIP-chloride isdIpc2BCl, 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

Dr. P. Wipf Chem 2320 3/28/2007

8

Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J., "Asymmetricsynthesis of active pharmaceutical ingredients." Chem. Rev. 2006, 106,2734-2793.

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; Ph or alkene substituents occupy RLpositions).

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).

Dr. P. Wipf Chem 2320 3/28/2007

9

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.

Dr. P. Wipf Chem 2320 3/28/2007

10

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.

Noyori: BINAP-Ru(II)Cl2

BINAP-Ru diacetate catalyst

Dr. P. Wipf Chem 2320 3/28/2007

11

The history ofenantioselectivehydrogenation

Chiral environment of the (R)-BINAP-transition metal complex

Dr. P. Wipf Chem 2320 3/28/2007

12

Access to enantiomerically pure BINAP

Asymmetric hydrogenation of ketones by BINAP–rutheniumcomplexes

Halogen-containing BINAP–Ru(II) complexes are efficient catalysts for theasymmetric hydrogenation of a range of functionalized ketones.

Coordinative nitrogen, oxygen, and halogen atoms near C=O functions direct thereactivity and stereochemical outcome in an absolute sense.

(S)-BINAP–Ru(II)catalyst

Dr. P. Wipf Chem 2320 3/28/2007

13

Asymmetric hydrogenation of ketones by BINAP–rutheniumcomplexes

Asymmetric hydrogenation of β-keto esters

Dr. P. Wipf Chem 2320 3/28/2007

14

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.

Ali, S. M.; Georg, G. I. Tetrahedron Lett. 1997, 38, 1703.

Fine-tuned reactivity and stereoselectivity is a factor of the steric (bulkiness andchirality) and electronic properties of the auxiliaries.

Diamine-free BINAP–Ru complexes are totally ineffective.

Asymmetric hydrogenation of simple ketones byBINAP/diamine–ruthenium complexes

Dr. P. Wipf Chem 2320 3/28/2007

15

Asymmetric synthesis of various important pharmaceuticals

Asymmetric hydrogenation of simple ketones byBINAP/diamine–ruthenium complexes

Excellent enantioselectivity (90-100% ee).

Wide scope of substrates (C=O, C=C, C=N).

Rivals or exceeds enzymes: e.g. 2,400,000(TON), 228,000 h-1, 63 s-1 (TOF).

Development of pharmaceuticals and syntheticintermediates.

Successful industrial applications.

An enormous scientific or technological impactand even more general social benefits.

Significance of BINAP Chemistry

Dr. P. Wipf Chem 2320 3/28/2007

16

Asymmetric transfer hydrogenation catalyzed by RuH[(S,S)-YCH(C6H5)CH(C6H5)NH2](η6-arene)

R = alkyl or D; Y = O or NTs

Newer developments

Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R., "Asymmetric transferhydrogenation of α,β-acetylenic ketones." J. Am. Chem. Soc. 1997, 119, 8737.The use of chiral Ru(II) catalysts and 2-propanol as the hydrogen donor allowshighly selective reduction of structurally diverse acetylenic ketones to propargylicalcohols with ee’s approaching 99%. The 16-electron complexes 3 are preparedfrom the 18-electron precursors 4 by treatment with KOH. Less than 1% of catalystis necessary. A Ru-H is the reactive species, and catalyst deactivation occurs byaddition of Ru-H across the triple bond.

Dr. P. Wipf Chem 2320 3/28/2007

17

Asymmetric transfer hydrogenation of imines

HydrogenationsArene Hydrogenations: Hiscox, W. C.;Matteson, D. S. J. Org. Chem. 1996, 61, 8315.

Lindlar Hydrogenation: Taylor, R. E.; Ameriks, M. K.; LaMarche, M. J. Tetrahedron Lett. 1997,38, 2057.

Dr. P. Wipf Chem 2320 3/28/2007

18

Lindlar Hydrogenation: Wipf, P.; Venkatraman, S. J. Org. Chem. 1996, 61, 6517.

Wipf, P.; Graham, T. H., "Total synthesis of (-)-disorazole C1." J. Am. Chem. Soc. 2004, 126,15346-15347.

Asymmetric Hydrogenation with the DuPhos Catalyst: Hoerrner, R. S.; Askin, D.;Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998, 39, 3455. cf. Burk, M. J. et al. J.Am. Chem. Soc. 1995, 117, 9375.

Dr. P. Wipf Chem 2320 3/28/2007

19

Hayashi Asymmetric Hydrogenation: Schmid, R. et al. Chimia 1997, 51, 303. Pilotplant-scale synthesis of POSICOR®, a new type of calcium antagonist for treatmentof hypertension and angina pectoris.

Diimide Reductions: Heathcock, C. H.; Brown, R. C. D.; Norman, T. C., "Synthesisof petrosins C and D." J. Org. Chem. 1998, 63, 5013-5030. Raney-Ni hydrogenationwas slow, unreliable, and relatively low-yielding.

White, J. D.; Kim, T.-S.; Nambu, M., "Absolute configuration and total synthesis of (+)-curacinA, an antiproliferative agent from the cyanobacterium Lyngbia majuscula." J. Am. Chem. Soc.1997, 119, 103.

Dirat, O.; Kouklovsky, C.; Langlois, Y., "Oxazoline N-oxide-mediated [2+3] cycloadditions:Application to a total synthesis of the hypocholesterolemic agent 1233A." J. Org. Chem. 1998,63, 6634-6642. The use of KO2CN=NCO2K led to overreduction.

Dr. P. Wipf Chem 2320 3/28/2007

20

Birch and other (Dissolving) Metal Reductions

Mechanism of bond fission of single bonds with lithium-ammonia illustrated foralkyl halides:

Mechanism of multiple bond saturation with lithium-ammonia illustrated for ketones:

Mechanism of Birch reduction of benzene:

Dr. P. Wipf Chem 2320 3/28/2007

21

Regioselectivity in the Birch reductionof aromatic rings:

The radical and anion sites are always para to one another and tend to localize at sites on thering that stabilize charge. Regioselectivity is therefore controlled by the substituents on the ring.Electron-withdrawing groups stabilize the negative charge generated during the course of thereaction and increase the rate, leading to reduction at the position on the aromatic ring bearingthe stabilizing group. In contrast, electron donors are deactivating and direct protonation towardthe unsubstituted ortho- and meta-positions.Ring-fusions and electron-withdrawing groups have more influence in polysubstituted systems indirecting reduction than electron-donating groups. Of the electron-donating groups, the directingeffects of functional groups containing N or O outweigh alkyl groups. The empirical order ofdirecting power is carboxyl > amino, alkoxyl > alkyl. Hydrogen addition is para to an electron-withdrawing group and meta to the most strongly deactivating group, but preferentially not at aposition occupied by a deactivating substituent.

The acidity of the proton source used in the first protonation step is important to theoutcome of the reduction. Sometimes, a more acidic proton source than NH3 (pKa =35) is advantageous. According to House, Modern Synthetic Reactions, alcohols(pKa = 16-19) or ammonium salts (pKa = 10) may be added to the reaction mixture.Generally, the more acidic the proton source, the faster the reduction. If theprotonation of the radical anion is the rate limiting step, NH3 can be too weak anacid to allow reaction. An unactivated benzene ring is only slowly reduced withoutan added proton donor.

Reduction of an α,β-unsaturated ketone in NH3 stops at the saturated ketone stage; in thepresence of an added proton source, the saturated alcohol is obtained.

Dr. P. Wipf Chem 2320 3/28/2007

22

The formation of dimerization products of the intermediate radical anion can beprevented by more acidic proton sources.

Quenching: To avoid further reduction during the quenching step, NH4Cl or anotheracidic salt is used (not alcohol).

The presence of bulky substituents on an aromatic ring retards reduction,presumably because of steric interference with solvation of the radical anion. Theorder of stability for the anion radical from alkyl substituted benzenes is:

Stork, G.; Schulenberg, J. W. J. Am. Chem. Soc. 1962, 84, 284. Synthesis of dehydroabietic acid.

Wipf, P.; Lim, S. Chimia 1996, 50, 157.

Dr. P. Wipf Chem 2320 3/28/2007

23

Chemoselectivity:Ando, M.; Sayama, S.; Takase, K.Chem. Lett. 1981, 377.

Stereoselectivity:Huang, P. Q.; Arseniyadis, S.; Husson, H.-P. Tetrahedron Lett. 1987, 28, 547.

Truce, W. E.; Breiter, J. J. J. Am. Chem. Soc. 1962, 84, 1623.

Boeckman, R. K.; Thomas, E. W. J. Am. Chem. Soc. 1977, 99, 2805.

Stork, G.; Malhotra, S.; Thompson, H. J. Am. Chem. Soc. 1965, 87, 1148.

Ireland, R. E.; Anderson, R. C.; Badoud, R.; Fitzsimmons, B. J.; McGarvey, G. J.; Thaisrivongs,S.; Wilcox, C. S. J. Am. Chem. Soc. 1983, 105, 1988.

Ireland, R. E.; Wipf, P.; Miltz, W.; Vanasse, B. J. Org. Chem. 1990, 55, 1423. Use of a maskedaldol unit.

Dr. P. Wipf Chem 2320 3/28/2007

24

Deoxygenation: Ireland, R. E.; Wipf, P. Tetrahedron Lett. 1989, 30, 919.

Zinc reduction: Woodward, R. B. et al. J. Am. Chem. Soc. 1952, 74, 4223.

Dr. P. Wipf Chem 2320 3/28/2007