[112068-01-6]  · C17H19NO  · a,a-Diphenyl-2-pyrrolidinemethanol  · (MW 253.37) (R)

[22348-32-9] ((S) .HCl)

[16226-54-3]  · C17H20ClNO  · a,a-Diphenyl-2-pyrrolidinemethanol Hydrochloride  · (MW 289.83)

(precursor to several chiral oxazaborolidine catalysts1 used for the enantioselective reduction of prochiral ketones2,3)

Alternate Name: diphenylprolinol.

Physical Data: mp 79-79.5 °C (hexane); 80-82 °C (EtOH). [a]589 -54.3° (c 0.261, MeOH); -68.1° (c 3.17, CHCl3) for the (S)-enantiomer.

Solubility: very sol THF, CH2Cl2, MeOH, toluene.

Preparative Methods: addition of Phenylmagnesium Bromide to (S)-proline-N-carboxyanhydride (73% overall from proline).4 Addition of N-benzyl-(S)-proline ethyl ester to phenylmagnesium chloride followed by catalytic hydrogenolysis (49% overall from proline).5 Addition of N-(benzyloxycarbonyl)-(S)-proline methyl ester to phenylmagnesium chloride (50% overall yield from proline).3a,c Addition of phenylmagnesium bromide to N-(ethyloxycarbonyl)-(S)-proline methyl ester followed by alkaline hydrolysis (65% overall yield from proline).6 Addition of (S)-proline ethyl ester hydrochloride to phenylmagnesium chloride (20-26% overall yield from proline, ca. 80% ee).7 Enantioselective deprotonation of N-Boc-pyrrolidine with s-Butyllithium/(-)-Sparteine followed by reaction with benzophenone to give (R)-diphenylprolinol (63% yield from pyrrolidine).8 Add ition of phenylmagnesium chloride to methyl pyroglutamate followed by reduction with borane to give racemic diphenylprolinol (51% yield) which can be resolved as its O-acetylmandelate salt to give the (R)- and (S)-enantiomers (30% yield from the racemate).3b Addition of lithiated N-nitrosopyrrolidine to benzophenone to give racemic diphenylprolinol (58-60% yield based on benzophenone).9

Purification: recrystallization from hexane, ethanol, or methanol/water.

Handling, Storage, and Precautions: no special information available. In general, however, it is advisable that all reactions with this reagent be conducted in a well ventilated fume hood. Care should be exercised to avoid contact of this reagent and the derived oxazaborolidine catalyst with the eyes and skin.

Enantioselective Ketone Reduction.

Following Itsuno's lead for enantioselective reductions using diphenylvalinol,10 Kraatz was the first to describe the use of a 1:2 mixture of (S)-diphenylprolinol (1) and Borane-Tetrahydrofuran for the stoichiometric enantioselective reduction of ketone (2) to obtain the plant growth regulator triapenthenol (3) (eq 1).2 Although not characterized at the time, the species responsible for the enantioselectivity observed was presumed to be an oxazaborolidine-borane complex.10b

Diphenylprolinol (1) and borane-THF react in a multistep process to give the unsubstituted oxazaborolidine-borane complex (7) (eq 2). Formation of amine-borane complex (4) is exothermic, and this intermediate can be isolated as a stable crystalline solid.4b Subsequent conversion to oxazaborolidine (6) requires heating the THF solution under pressure (1.7 bar) at 70-75 °C for 48-72 h. Corey isolated and characterized free oxazaborolidine (6) as a solid (mp 107-124 °C), which was reported to be a mixture of monomer and dimer (NMR).3a Finally, addition of borane-THF to a solution of oxazaborolidine (6) affords oxazaborolidine-borane complex (7) which was not isolated and was identified based on 11B NMR evidence.

Corey demonstrated that oxazaborolidine (6) can be used catalytically (2.5-100 mol %) with excess borane (60-200 mol %) for the enantioselective reduction of prochiral ketones (eq 3 Table 1).3a,c

The following catalytic cycle was proposed to explain the behavior of the oxazaborolidine catalyst (eq 4).3a,11 Oxazaborolidine (6) reacts with borane to give oxazaborolidine-borane complex (7). Coordination between the Lewis acidic ring boron and the carbonyl oxygen activates the ketone toward reduction. Intramolecular hydride transfer from the BH3 coordinated to the ring nitrogen then occurs via a six-membered ring chair transition state.12 Following hydride transfer, the alkoxy-BH2 dissociates, and oxazaborolidine (6) is free to begin the cycle again. For a more detailed discussion, see the entry for Tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole.

Problems with the preparation and stability of oxazaborolidine (6) led to the development of a series of B-substituted oxazaborolidines derived from diphenylprolinol. The B-methyl substituted oxazaborolidine (9a) was first prepared (eq 5) by reaction of diphenylprolinol (1) with methylboronic acid under dehydrating conditions (toluene at 23 °C in the presence of 4 Å molecular sieves or toluene at reflux using a Dean-Stark trap) followed by vacuum distillation (0.1 mmHg, 170 °C)3a,c Based on NMR evidence, the product (mp 74-87 °C) was reported to be a mixture of monomer and dimer.3a The corresponding B-butyloxazaborolidine (9c), prepared in a similar manner from n-butylboronic acid, was also reported to be a mixture of monomer and dimer.13 Subsequent investigations demonstrated that the reported dimers were in fact the intermediate (8) and the more stable disproportionation product (10) (eq 6).4 Furthermore, the presence of (8) or (10) was demonstrated to be deleterious to the enantioselectivity of the catalyst.14

A small-scale procedure, based on the reaction of bis(trifluoroethyl) alkylboronates with diphenylprolinol (eq 7) was reported for the preparation of the B-ethyl- (9b) and B-butyl- (9c) oxazaborolidines.15 The bis(trifluoroethyl) alkylboronates were prepared from the disproportionation of tris(trifluoroethyl) borate and the corresponding trialkylborane. Since trimethylborane is not commercially available, this procedure is not applicable for the preparation of B-methyloxazaborolidine (9a).

A practical large-scale process for the synthesis of B-methyloxazaborolidine (9a) was developed using commercially available trimethylboroxine (eq 8), which affords the product as an analytically pure, colorless crystalline solid (mp 79-81 °C).4,16 The B-ethyl- (9b), B-butyl- (9c), and B-phenyloxazaborolidines (9d) were also prepared from the corresponding triethyl-, tributyl-, or triphenylboroxine. The free oxazaborolidines, thus prepared, are stable if rigorously protected from moisture.

A significantly more stable form of the catalyst is the crystalline oxazaborolidine-borane complex (11).4b,16,17 This borane complex is readily prepared from oxazaborolidine (9a) and Borane-Dimethyl Sulfide complex (BMS) (eq 9).

The enantioselectivities reported for the reduction of acetophenone and a-tetralone using the different catalysts (5-10 mol %) and borane-THF or BMS are summarized in Table 2. The best results are obtained by slowly adding the substrate (neat or as a solution in dichloromethane) to a solution of borane complex (11) (5 mol %) and BMS (0.6-1.0 mol equiv) in dichloromethane at -20 °C.16

In addition to these simple examples, oxazaborolidines derived from diphenylprolinol have been used as enantioselective catalysts for the preparation of prostaglandins,3a PAF antagonists,3a a key intermediate of ginkgolide B,18 a key intermediate of forskolin,19 (R)- and (S)-fluoxetine,20 (R)- and (S)-isopreterenol,21 vitamin D analogs,22 the carbonic anhydrase inhibitor MK-0417,14 the dopamine D1 agonist A-77636,23 taxol,24 the LTD4 antagonists L-695,499 and L-699,392,25 the b-adenergic agonist CL 316,243,26 and MK-0499.27 Recently, Bringmann employed oxazaborolidines (9a) and (9c) to catalyze the atropo-enantioselective ring opening of achiral biaryl lactones (eq 10).28

Related Reagents.

2-Amino-3-methyl-1,1-diphenyl-1-butanol; Ephedrine-borane; Norephedrine-Borane; Tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole.

1. (a) Wallbaum S.; Martens, J. TA 1992, 3, 1475. (b) Singh, V. K. S 1992, 607. (c) Deloux, L.; Srebnik M. CRV 1993, 93, 763.
2. Kraatz, U. Ger. Patent 3 609 152, 1986 (CA 1978, 108, 56 111c).
3. (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. JACS 1987, 109, 5551. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C. P.; Singh, V. K. JACS 1987, 109, 7925. (c) Corey, E. J.; Shibata, S.; Bakshi, R. K. JOC 1988, 53, 2861.
4. (a) Mathre, D. J.; Jones, T. K.; Xavier, L. C.; Blacklock, T. J.; Reamer, R. A.; Mohan, J. J.; Jones, E. T. T.; Hoogsteen, K.; Baum, M. W.; Grabowski, E. J. J. JOC 1991, 56, 751. (b) Blacklock, T. J.; Jones, T. K.; Mathre, D. J.; Xavier, L. C. U.S. Patent 5 039 802, 1991. (c) Blacklock, T. J.; Jones, T. K.; Mathre, D. J.; Xavier, L. C. U.S. Patent 5 264 585, 1993.
5. Enders, D.; Kipphardt, H.; Gerdes, P.; Brena-Valle, L. J.; Bhushan, V. BSB 1988, 97, 691.
6. Kanth, J. V. B.; Periasamy, M. T 1993, 49, 5127.
7. (a) Kapfhammer, J.; Matthes, A. Hoppe-Seylers Z. Physiol. Chem. 1933, 223, 43. (b) Roussel-Uclaf Fr. Patent 3638M (CA 1969, 70, 106 375m).
8. Kerrick, S. T.; Beak, P. JACS 1991, 113, 9708.
9. (a) Seebach, D.; Enders, D.; Renger, B. CB 1977, 110, 1852. (b) Enders, D.; Pieter, R.; Renger, B. Seebach, D. OSC 1988, 6, 542.
10. (a) Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. CC 1983, 469. (b) Itsuno, S.; Hirao, A.; Nakahama, S.; Yamazaki, N. JCS(P1) 1983, 1673. (c) Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. JOC 1984, 49, 555. (d) Itsuno, S.; Nakano, M.; Miyazaki, K.; Masuda, H.; Ito, K.; Hirao, A.; Nakahama, S. JCS(P1) 1985, 2039. (e) Itsuno, S.; Nakano, M.; Ito, K.; Hirao, A.; Owa, M.; Kanda, N.; Nakahama, S. JCS(P1) 1985, 2615.
11. Evans, D. A. Science 1988, 240, 420.
12. Jones, D. K.; Liotta, D. C.; Shinkai, I.; Mathre, D. J. JOC 1993, 58, 799.
13. Corey, E. J.; Bakshi, R. K. TL 1990, 31, 611.
14. (a) Jones, T. K.; Mohan, J. J.; Xavier, L. C.; Blacklock, T. J.; Mathre, D. J.; Sohar, P.; Jones, E. T. T.; Reamer, R. A.; Roberts, F. E.; Grabowski, E. J. J. JOC 1991, 56, 763. (b) Shinkai, I. JHC 1992, 29, 627.
15. Corey, E. J.; Link, J. O. TL 1992, 33, 4141.
16. (a) Mathre, D. J.; Thompson, A. S.; Douglas, A. W.; Hoogsteen, K.; Carroll, J. D.; Corley, E. G.; Grabowski, E. J. J. JOC 1993, 58, 2880. (b) Blacklock, T. J.; Jones, T. K.; Mathre, D. J.; Xavier, L. C. U.S. Patent 5 189 177, 1993. (c) Carroll, J. D.; Mathre, D. J.; Corley, E. G.; Thompson, A. S. U.S. Patent 5 264 574, 1993.
17. Corey, E. J.; Azimioara, M.; Sarshar, S. TL 1992, 33, 3429.
18. Corey, E. J.; Gavai, A. V. TL 1988, 29, 3201.
19. Corey, E. J.; Jardine, P. D. S.; Mohri, T. TL 1988, 29, 6409.
20. Corey, E. J.; Reichard, G. A. TL 1989, 30, 5207.
21. Corey, E. J.; Link, J. O. TL 1990, 31, 601.
22. (a) Kabat, M.; Kiegiel, J.; Cohen, N.; Toth, K.; Wovkulich, P. M.; Uskokovic, M. R. TL 1991, 32, 2343. (b) Lee, A. S.; Norman, A. W.; Okamura, W. H. JOC 1992, 57, 3846.
23. DeNinno, M. P.; Perner, R. J.; Morton, H. E.; DiDomenico, S., Jr. JOC 1992, 57, 7115.
24. Nicolaou, K. C.; Hwang, C.-K.; Sorensen, E. J.; Clairborne, C. F. CC 1992, 1117.
25. (a) Labelle, M.; Prasit, P.; Belley, M.; Blouin, M.; Champion, E.; Charette, L.; DeLuca, J. G.; Dufresne, C.; Frenette, R.; Gauthier, J. Y.; Grimm, E.; Grossman, S. J.; Guay, D.; Herold, E. G.; Jones, T. R.; Lau, Y.; Leblanc, Y.; Leger, S.; Lord, A.; McAuliffe, M.; McFarlane, C.; Masson, P.; Metters, K. M.; Ouimet, N.; Patrick, D. H.; Perrier, H.; Piechuta, H.; Roy, P.; Williams, H.; Wang, Z.; Xiang, Y. B.; Zamboni, R. J.; Ford-Hutchinson, A. W.; Young, R. N. BML 1992, 2, 1141. (b) King, A. O.; Corley, E. G.; Anderson, R. K.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J.; Xiang, Y. B.; Belley, M.; Leblanc, Y.; Labelle, M.; Prasit, P.; Zamboni, R. J. JOC 1993, 58, 3731.
26. Bloom, J. D.; Dutia, M. D.; Johnson, B. D.; Wissner, A.; Burns, M. G.; Largis, E. E.; Dolan, J. A.; Claus, T. H. JMC 1992, 35, 3081.
27. Cai, D.; Tschaen, D.; Shi, Y.-J.; Verhoeven, T. R.; Reamer, R. A.; Douglas, A. W. TL 1993, 34, 3243.
28. Bringmann, G.; Hartung, T. AG(E) 1992, 31, 761.

David J. Mathre & Ichiro Shinkai

Merck Research Laboratories, Rahway, NJ, USA

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