3756
G. Blay et al.
PRACTICAL SYNTHETIC PROCEDURES
MS (EI, 70 eV): m/z (%) = 241 (2, [M+]), 107 (79), 91 (100), 79
(92), 77 (57).
da has reported lower yield (71%) and enantioselectivity
(84%). Keto ester 1n bearing an aliphatic chain linked to
the ketone carbonyl group reacts readily under the catalyt- HRMS (EI): m/z calcd for C15H15NO2 [M+]: 241.1103; found:
241.1031.
ic conditions but with lower enantioselectivity (entry 14).
As with Shibashaki’s system, the reaction is also limited
(S)-Ethyl 2-Hydroxy-2-(4-methoxyphenyl)propanoate (2g);
Typical Procedure
to dimethylzinc as the organozinc reagent. Treatment of
ethyl oxo(phenyl)acetate (1b) with diethylzinc yielded the
corresponding racemic reduction product.
A commercially available 2 M solution of Me2Zn in toluene (3 mL,
6 mmol) was added to a solution of ligand 3 (48 mg, 0.2 mmol) in
anhyd toluene (5 mL), under N2 at r.t. After stirring for 30 min, the
solution was cooled to 0 °C and ethyl (4-methoxyphenyl)oxoacetate
(1g; 208 mg, 1 mmol) was added. After 2.5 h, aq 1 M HCl (20 mL)
was added dropwise while keeping the mixture in the ice bath (Cau-
tion! Gas evolution). The mixture was extracted with Et2O (3 × 20
mL) and the organic layer was washed with brine (2 × 20 mL), dried
(MgSO4), and concentrated under reduced pressure. Purification by
flash chromatography eluting with hexane–EtOAc (9:1) gave 2g as
In summary, this is an operationally simple and practical
procedure for the enantioselective addition of dimethyl-
zinc to a-keto esters. Additional advantages of this proce-
dure are the simplicity and easy preparation of the ligand
(also both enantiomers of the ligand are available starting
from the proper mandelic acid) and the not requirement
for additional Lewis acids. The yields and enantioselectiv-
ities with most substrates are comparable to those ob-
tained with other procedures, which require more
elaborated ligands and more operationally complicated
processes.
25
a slightly yellow oil; yield: 184 mg (82%); [a]D +39 (c 0.51,
CHCl3, ee 90%).
1H NMR (300 MHz, CDCl3): d = 7.46 (d, J = 8.7 Hz, 2 H), 6.85 (d,
J = 8.7 Hz, 2 H), 4.29–4.11 (m, 2 H), 3.78 (s, 3 H), 1.73 (s, 3 H),
1.24 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 175.8, 159.1, 135.0, 126.4, 113.5,
75.2, 62.3, 55.2, 26.6, 14.0.
Herein we describe the procedure for the preparation of mandel-
amide ligand 3 and the procedure for the addition of dimethylzinc
to ethyl (4-methoxyphenyl)oxoacetate (1g) as representative exam-
ple for the substrates described in Table 1.
MS (EI, 70 eV): m/z (%) = 224 (3, [M+]), 151 (100).
HRMS (EI): m/z calcd for C12H16O4 [M+]: 224.1049; found:
224.1055.
All reactions were carried out with a magnetic stirring in oven-dried
(120 °C) glassware under N2. Melting points were measured on a
Büchi B-535 apparatus and are uncorrected. Optical rotations were
measured on a PerkinElmer 243. NMR spectra were recorded in
CDCl3 at 300 MHz for 1H NMR and at 75 MHz for 13C NMR in a
Bruker Avance 300 DPX spectrometer, and referenced to the sol-
vent as internal standard. Mass spectra were recorded on a Fisons
Instruments VG Autospec GC 8000 series spectrometer (EI, 70 eV).
Chiral GLC analyses were carried out in a Thermo Quest Trace GC
2000 series instrument equipped with a flame ionization detector.
Chiral HPLC analyses were performed in an Agilent 1100 series in-
strument equipped with a refraction index detector.
Enantiomeric Excess Determination
GLC (Supelco b-dex-225): Tinjector = 220 °C, Tdetector = 220 °C,
Tcolumn = 130 °C, N2 (1 mL/min), minor enantiomer (R) tR = 81.8
min, major enantiomer (S) tR = 85.3 min.
HPLC (Chiralpack AD-H): Hexane–i-PrOH (95:5), 1 mL/min, ma-
jor enantiomer (S) tR = 11.3 min, minor enantiomer (R) tR = 12.5
min.
Acknowledgment
Support from the Ministerio de Educación y Ciencia (Grant CTQ
2006-14199), Generalitat Valenciana (Grant grupos 03/168) and the
Universitat de València (Grant UV-AE-20060244) is acknowl-
edged. A.M-A. thanks the MEC for a pre-doctoral grant (FPU pro-
gram).
(+)-N-Benzyl-(S)-mandelamide (3)
To a stirred solution of (S)-(+)-mandelic acid (5.0 g, 32.9 mmol) in
anhyd THF (140 mL) under N2 was added benzylamine (3.6 mL, 3.5
g, 32.9 mmol) via a syringe followed by N-hydroxysuccinimide (4.2
g, 36.1 mmol).11 The resulting mixture was cooled to 0 °C and N,N¢-
dicyclohexylcarbodiimide (7.5 g, 36.1 mmol) was added. After 15
min, the cooling bath was removed and the solution was stirred at References
r.t. under N2 overnight (ca 20 h). After this time, the mixture was fil-
(1) (a) Bennet, G. B.; Houlihan, W. J.; Mason, R. B.; Engstrom,
tered through a sintered glass plate and the dicyclohexylurea cake
washed with THF (2 × 10 mL). The solvent was removed under re-
duced pressure, and the residue was dissolved in EtOAc (300 mL).
The organic layer was washed successively with sat. aq Na2CO3 (70
mL), H2O (70 mL), aq 1 M HCl (70 mL), H2O (70 mL), and brine
(70 mL) and dried (MgSO4). After filtration, the solvent was re-
moved under reduced pressure and the crude product was purified
by flash chromatography on silica gel eluting with hexane–EtOAc
(8:2) to give 3 as a white solid: yield: 6.3 g (80%); mp 134–135 °C
R. G. J. Med. Chem. 1976, 19, 709. (b) Zalkow, L. H.;
Glinski, J. A.; Gelbaum, L. T.; Moore, D.; Melder, D.;
Powis, G. J. Med. Chem. 1988, 31, 1520. (c) Comins, D. L.;
Hong, H.; Saha, J. K.; Jianhua, G. J. Org, Chem. 1994, 59,
5120. (d) Senanayake, C. H.; Fang, Q. K.; Grover, P.;
Bakale, R. B.; Vandenbossche, C. P.; Wald, S. A.
Tetrahedron Lett. 1999, 40, 819. (e) Shilova, E. V. Pharm.
Chem. J. 2000, 34, 419. (f) Okumura, Y.; Ando, A.;
William Stevens, R.; Shimizu, M. Tetrahedron 2002, 58,
8729. (g) Sergeeva, N. N.; Golubev, A. S.; Henning, L.;
Burger, K. Synthesis 2003, 915. (h) Zha, C.; Brown, G. B.;
Brouillette, W. J. J. Med. Chem. 2004, 47, 6519.
(i) Tchilibon, S.; Zhang, J.; Yang, Q.-F.; Eidelman, O.; Kim,
H.; Caohuy, H.; Jacobson, K. A.; Pollard, B. S.; Pollard, H.
B. Biochem. Pharmacol. 2005, 70, 381. (j) Tokuda, O.;
Kano, T.; Gao, W.-G.; Ikemoto, T. Org. Lett. 2005, 7, 5103.
(k) Tangirala, R. S.; Antony, S.; Agama, K.; Pommier, Y.;
25
25
(MeOH); [a]D +83.2 (c 0.54, CHCl3); [a]D +45.7 (c 0.52,
MeOH).
1H NMR (300 MHz, CDCl3): d = 7.41–7.28 (m, 8 H), 7.19 (dd,
J = 7.8, 1.8 Hz, 2 H), 6.60 (s, 1 H, NH), 5.06 (d, J = 3.7 Hz, 1 H),
4.43 (AA¢ system, 2 H), 3.78 (d, J = 3.7 Hz, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 172.2 139.4, 137.7, 128.8, 128.7,
128.6, 127.5, 126.8, 74.2, 43.4.
Synthesis 2007, No. 23, 3754–3757 © Thieme Stuttgart · New York