Enantioselective synthesis of β-hydroxy carboxylic acids: Direct conversion of β-oxocarboxylic acids to enantiomerically enriched β-hydroxy carboxylic acids via neighboring group control

Article abstract of DOI:10.1016/S0957-4166(98)00502-3

β-Oxocarboxylic acids can be reduced to the corresponding β-hydroxy carboxylic acids employing DIP-Cl(TM) as a reducing agent. The β-carboxylic substituent exerts a remarkable neighboring group effect on the reduction. The reaction presumably proceeds in an intramolecular fashion through a 'rigid' bicyclic transition state assembly, which produces enantioselectivities approaching 99%.

Full text of DOI:10.1016/S0957-4166(98)00502-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 225–228
Enantioselective synthesis of β-hydroxy carboxylic acids: direct
conversion of β-oxocarboxylic acids to enantiomerically enriched
β-hydroxy carboxylic acids via neighboring group control
Zhe Wang,∗ Chunlin Zhao,† Michael E. Pierce and Joseph M. Fortunak
DuPont Pharmaceuticals Company, Research & Development, Chambers Works, Deepwater, NJ 08023, USA
Received 2 December 1998; accepted 7 December 1998
Abstract
™
β-Oxocarboxylic acids can be reduced to the corresponding β-hydroxy carboxylic acids employing DIP-Cl
as a reducing agent. The β-carboxylic substituent exerts a remarkable neighboring group effect on the reduction.
The reaction presumably proceeds in an intramolecular fashion through a ‘rigid’ bicyclic transition state assembly,
which produces enantioselectivities approaching 99%. © 1999 DuPont Pharmaceuticals Company. Published by
Elsevier Science Ltd. All rights reserved.
Optically active β-hydroxy acids are important building blocks in organic synthesis, for example, in
the syntheses of β-amino acids,1 β-lactams,2 and pheromones.3 β-Hydroxy acids are also important
subunits4 of polyketide natural products such as amphotericin B,5 tylosin6 and rosaramicin.7 Extensive
effort in this field has resulted in fruitful synthetic methods for the synthesis of optically active β-hydroxy
acids or their derivatives, utilizing, for example, aldol reactions,8 and hydrogenation reactions.9 We
have been interested in developing a simple, straightforward, and generally applicable method for the
enantioselective synthesis of β-hydroxy acids. Herein, we wish to report an efficient method to directly
convert β-oxocarboxylic acids to chiral β-hydroxy carboxylic acids employing DIP-Cl™ as the reducing
agent.
(1)
B-Chlorodiisopinocampheylborane is a remarkably versatile reducing agent in asymmetric
synthesis.10,11 This reagent has been successfully applied to a number of reduction reactions, including
asymmetric reduction of ketones,12 fluoroketones,13 diketones,14 α- and β-hydroxy ketones,15 and
∗
†
Corresponding author. E-mail: zhe.wang@dupontmerck.com
Current address: Pharmacy School, Temple University, 3307 N. Broad Street, Philadelphia, PA 19140, USA.
0957-4166/99/$ - see front matter © 1999 DuPont Pharmaceuticals Company. Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00502-3

226
Z. Wang et al. / Tetrahedron: Asymmetry 10 (1999) 225–228
ortho-substituted amino-, hydroxy- and carboxylic benzophenones.16 We have recently demonstrated
that α-oxocarboxylic acids can be reduced in a highly enantioselective manner employing DIP-Cl™ as
the reducing agent.17 The reactions apparently took place in an intramolecular fashion via a neighboring
group control, involving mixed boronate intermediates after ligand exchange.17–19 Applying the same
concept, we have achieved a methodology for the syntheses of enantiomerically enriched β-hydroxy
carboxylic acids using highly enantioselective DIP-Cl™ reduction of β-oxocarboxylic acids.
In a sharp contrast to the DIP-Cl™ reduction of β-keto esters,20 which occurred very sluggishly and
generated low enantioselectivities, the DIP-Cl™ reduction of β-oxocarboxylic acids, in the presence of
triethylamine, proceeds rapidly (in 1–5 h at −20–0°C) to afford the desired hydroxy carboxylic acids, with
high enantioselectivities (91–99% ee) and with predictable absolute configuration. As we reported earlier,
triethylamine significantly enhances the reaction rate.17–19 A plausible mechanism for this reduction
reaction may involve a ‘rigid’ bicyclic transition state assembly, as shown in Scheme 1.17–19 One of
the enantiotopic faces of the β-carbonyl is exposed to the reductive hydrogen via a ‘locked’ transition
state. Of the two approaches, only one face (Si-face, assuming –CH2COOH is >R) approach of the β-
carbonyl is favored since the R-group assumes an equatorial-like position in the six-membered ring which
minimizes steric interaction. The Re-face (assuming –CH2COOH is >R) approach, on the other hand, is
less favored due to the steric interaction between the axially (or axial-like) oriented R-group with the
endo-methyl of the campheyl ligand. The preferred facial approach yields β-hydroxy carboxylic acids
with the desired configuration shown in Eq. 1, which is consistent with the actual configuration observed
in our results.
Scheme 1.
As summarized in Table 1, β-oxocarboxylic acids21 in methylene chloride are treated with triethyla-
mine (1.0 equiv., −20°C, 5 min) and 1.2 equiv. of (−)-DIP-Cl™ (−20°C). Upon completion of the reaction
(−20°C to 0°C for 1–5 h), the mixture is quenched with water. After basic hydrolysis, followed by
acidic work-up, the desired optically active β-hydroxy carboxylic acids are obtained in 87–92% yield
and 91–99% ee (Table 1). The absolute configurations of the products are determined by optical rotation
through the comparison with literature.8
In summary, we have demonstrated that the β-carboxylic substituent exerts a remarkable neighboring
group effect on the reduction of β-oxocarboxylic acids to their corresponding β-hydroxy carboxylic acids
employing DIP-Cl™ as a reducing agent. This reaction presumably proceeds through a ‘rigid’ bicyclic
transition state assembly, which leads to their enantioselective excesses approaching 99%.22
Acknowledgements
CLZ would like to acknowledge her 1998 summer internship and the financial support from the DuPont
Merck summer intern program.

Z. Wang et al. / Tetrahedron: Asymmetry 10 (1999) 225–228
227
Table 1
Synthesis of β-hydroxy acids via DIP-Cl™ reduction of β-oxocarboxylic acids
References
1. (a) Thaisrivongs, S.; Pals, D. T.; Kati, W. M.; Turner, S. R.; Thomasco, L. M.; Watt, W. J. Med. Chem. 1986, 29, 2080. (b)
Thaisrivongs, S.; Schostarez, H. J.; Pals, D. T.; Kati, W. M.; Turner, S. R. J. Med. Chem. 1987, 30, 1837.
2. Schostarez, H. J. J. Org. Chem. 1988, 53, 3628.
3. Oertle, K.; Beyeler, H.; Duthaler, R. O.; Lottenbach, W.; Riediker, M.; Steiner, E. Helv. Chim. Acta 1990, 73, 353.
4. Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24, 1.
5. Nicolaou, K. C.; Chakraborty, T. K.; Ogawa, Y.; Furst, G. T. J. Am. Chem. Soc. 1988, 110, 4660.
6. Tatsuta, K.; Amemiya, Y.; Kanemura, Y.; Kinoshita, M. Tetrahedron Lett. 1982, 23, 3375.
7. Schlessinger, R. H.; Poss, M. A.; Richardson, S. J. Am. Chem. Soc. 1986, 108, 3112.
8. Duthaler, R. O.; Herold, P. Lottenbach, W.; Oertle, K.; Riediker, M. Angew. Chem., Int. Ed. Engl. 1989, 28, 495. (b)
Mioskowski, C.; Solladie, G. Tetrahedron 1979, 36, 227. (c) Meyers, A. I.; Knaus, G. Tetrahedron Lett. 1974, 15, 1333.
9. Noyori, R. Asymmetric Catalysis in Organic Chemistry; Wiley & Sons: New York, 1994; p. 62.
10. (a) Brown, H. C.; Ramachandran, P. V. Acc. Chem. Res. 1992, 25, 16. (b) Brown, H. C.; Ramachandran, P. V. Pure Appl.
Chem. 1994, 66, 201.
11. Zhao, M.; King, A. O.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1997, 38, 2641.
12. Brown, H. C.; Ramachandran, P. V. Organomet. Chem. 1995, 500, 1.
13. Ramachandran, P. V.; Malhotra, S. V.; Brown, H. C. Tetrahedron Lett. 1997, 38, 957.

228
Z. Wang et al. / Tetrahedron: Asymmetry 10 (1999) 225–228
14. Ramachandran, P. V.; Gong, B.; Brown, H. C. J. Org. Chem. 1995, 60, 41.
15. Sablong, R.; Osborn, J. A. Tetrahedron Lett. 1996, 37, 4937 and the references cited therein.
16. (a) Ramachandran, P. V.; Lu, Z.-H.; Brown, H. C. Tetrahedron Lett. 1997, 38, 761. (b) Ramachandran, P. V.; Gong, B.;
Brown, H. C. Tetrahedron Lett. 1994, 35, 2141. (c) Shieh, W.-C.; Cantrell, W. M.; Carlson, J. A. Tetrahedron Lett. 1995,
36, 3797. (d) Ramachandran, P. V.; Chen, G. M.; Brown, H. C. Tetrahedron Lett. 1996, 37, 2205.
17. Wang, Z.; La, B.; Fortunak, M. F.; Meng, X. J.; Kabalka, G. W. Tetrahedron Lett. 1998, 39, 5501.
18. Wang, Z.; Meng, X. J.; Kabalka, G. W. Tetrahedron Lett. 1991, 32, 1945.
19. (a) Wang, Z.; Meng, X. J.; Kabalka, G. W. Tetrahedron Lett. 1991, 32, 4619. (b) Wang, Z.; Meng, X.-J.; Kabalka, G. W.
Tetrahedron Lett. 1991, 32, 5677.
20. For example, treatment of 3-oxo-nonanoic acid benzyl ester with DIP-Cl™ for 5 h at 0°C, only less than 20% conversion
with <40% ee was observed.
21. Barnick, J. W. F. K.; van der Baan, J. L.; Bickelhaupt, F. Synthesis 1979, 787.
22. The synthesis of (R)-(−)-3-hydroxyl-5-methyl hexanoic acid serves as an example. A solution of 5-methyl-3-oxo-hexanoic
acid (2.0 g, 14.0 mmol, 1 equiv.) in CH2Cl2 (20 ml) was treated with Et3N (2.0 ml, 14.0 mmol, 1 equiv.) at −20°C and stirred
for 5 min followed by the addition of (−)-DIP-Cl™ (5.4 g, 16.7 mmol, 1.2 equiv. in 20 ml of CH2Cl2) slowly. The reaction
mixture was gradually warmed up to 0°C and stirred at 0°C for 2 h (monitored by TLC, hexane:ethyl acetate:formic acid,
1:1:0.05). Upon the completion of the reaction, it was quenched with water, and basified with NaOH (10%) to pH>12;
then extracted with t-butyl methyl ether (2×35 ml) and the organic layers were combined and washed with water (25 ml).
The aqueous layers were then combined and acidified with HCl (2 N) to pH∼2 and extracted with ethyl acetate (3×80
ml). The combined organic layers were washed with brine and dried with MgSO4. After filtration, removal of solvents,
the desired of (R)-(−)-5-methyl-hydroxyl hexanoic acid was obtained in 92% yield with >98% ee. [α]D= −15.8 (c=1.03,
CHCl3), 1H NMR (300 MHz, CDCl3, δ=ppm, J=Hz), 4.16 (m, 1H), 2.53 (m, 2H), 1.81 (m, 1H), 1.53 (m, 1H), 1.23 (m,
1H), 0.93 (d, J=6.6, 6H). 13C NMR (ppm), 177.6, 66.3, 45.5, 41.5, 24.4, 23.1, 22.0. The product (44 mg, 0.306 mmol, 1
equiv.) was treated with K2CO3 (46.4 mg, 0.336 mmol, 1.1 equiv.) and BnBr (57 mg, 0.336mmol, 1.1 equiv.) in DMF (2
ml) starting from 0°C to rt for 4 h; and then washed with saturated NaHCO3 and NH4Cl to obtain the desired benzylester
derivative. HPLC studies (Chiralcel OD column, Hex/IPA=94/6, peaks at R=6.21 min and 7.70 min) revealed 99% ee.