J. Nieto, C. Andrꢁs, and R. Infante
toester 2l afforded the corresponding product 3l with good
enantiocontrol and excellent isolated yield (96% yield,
84% ee). Even the cyclic ketoester 2m provided positive re-
sults when it was subjected to the methylation conditions
(75% yield, 86% ee; Table 4, entry 13). Interestingly, the
enantioselectivity was reversed for this substrate and the S
enantiomer was obtained as the major product.
Conclusion
We have shown that perhydro-1,3-benzoxazine-based ligand
1c is an excellent promoter for the construction of quaterna-
ry stereocenters by enantioselective methylation of a-ke-
toesters by using Me2Zn as the alkylating agent and
BACHTNUTRGENNG(U OEt)3 as an additive. The enantiocontrol achieved with
Ligand 1c was recovered in over 90% yield after chroma-
tographic purification. This recovered ligand was reused in
the methylation of 2b and produced essentially the same re-
sults as the freshly prepared ligand without any obvious de-
crease in chemical yield or enantiopurity (95% yield,
94% ee). In addition, the recovered ligand could be used to
perform the same reaction on a 5 mmol scale and the de-
sired product was isolated in 90% yield with 92% ee.
To demonstrate the potential value of the enantioenriched
hydroxyesters obtained by methylation, we decided to carry
out the synthesis of more complex and valuable structures,
in which the quaternary stereocenter previously generated
remained intact (Scheme 1). For example, azidoalcohols are
this catalytic system is high, and noticeably homogeneous,
for a wide range of aromatic and heteroaromatic a-ketoest-
ers, independent of the electronic nature of the substrate.
The steric hindrance of ortho-substituted aromatic ketoest-
ers is overcome by this ligand to afford the respective terti-
ary alcohols with up to 96% ee. Even the challenging cyclic
and acyclic aliphatic a-ketoester substrates provide the de-
sired hydroxyesters with good enantiocontrol. In addition,
some interesting applications of the obtained hydroxyesters
in the synthesis of valuable products are illustrated.
Experimental Section
All reactions were carried out in anhydrous solvents under argon atmos-
1
phere in dried glassware by using Schlenk techniques. H (300 MHz) and
13C NMR (75 MHz) spectra were recorded in CDCl3. Chemical shifts (d)
for are reported in ppm relative to tetramethylsilane with the residual
solvent signal as an internal reference. Three 13C NMR spectra are shown
for each compound (from top to bottom): DEPT90 (CH peaks only),
DEPT135 (CH and CH3 peaks up, CH2 peaks inverted), and {1H}-13C.
Data are reported as follows: chemical shift (d, ppm), multiplicity (s=
singlet, d=doublet, t=triplet, q=quartet, quint=quintet, sext=sextet
sp=septet, m=multiplet, br=broad), coupling constants (J, Hertz) and
integration. Specific rotations were measured with a 5 mL cell, 1 dm path
length, and sodium lamp, and the concentration is given in g/100 mL.
Flash chromatography was carried out on silica gel (230–240 mesh).
Chemical yields refer to pure isolated substances. TLC analysis was per-
formed on glass-backed plates coated with silica gel 60 and an F254 indica-
tor and plates were visualized either by UV irradiation or staining with I2
or phosphomolybdic acid solution. Chiral HPLC analysis was performed
by using a Daicel Chiralcel OD, Chiralpak AD-H, or Chiralpak AS-H
column. UV detection was monitored at l=220 or 254 nm. HRMS was
performed on a quadrupole spectrometer with TOF analyzer. Ketoesters
2a, 2b, 2l, and 2m were purchased from commercial sources and used as
received. Ketoesters 2c and 2d–k were synthesized from diethyl oxalate
and freshly prepared Grignard reagents by reported procedures.[7d,13]
Racemic hydroxyesters were isolated by addition of methylmagnesium
iodide (1.0m in Et2O, 1 equiv) to the corresponding ketoesters (1 equiv)
in Et2O at À408C. Ligands 1a, 1b, and 1d–f were prepared by literature
procedures.[8a,10] The reported synthesis of ligand 1c was optimized.[10a]
Scheme 1. Enantioselective synthesis of valuable building blocks from
a-hydroxyester 3b. Reagents and conditions: i) ClCO2Ph, Py, CH2Cl2, RT
overnight. ii) PhNHNH2, DMAP, HAcO, THF, reflux, 36 h. iii) NaOEt,
Urea, EtOH, reflux, 18 h. iv) TrCl, NEt3, CH2Cl2, RT, 1 h. v) LAH, Et2O,
08C, 30 min. vi) TsCl, NEt3, DMAP, CH2Cl2, 08C, 16 h. vii) NaN3,
nBu4NI, DMF, 808C, 5 h. viii) TsCl, NEt3, DMAP, CH2Cl2, 508C, 24h.
valuable building blocks for the synthesis of aziridines and
primary aminoalcohols.[9c] Conventional azidolysis of 2,2-di-
ACHTUNGTRENNUNGsubstituted epoxides was found to provide regioisomeric
mixtures of azidoalcohols, whereas enzymatic resolution of
the racemic epoxides afforded the products with high ee
values, although with poor chemical yields.[9c] Conversely,
when our catalytic system was used the high-value azidoal-
cohol
(R)-9b was easily isolated in 76% overall yield with 94% ee
(over four steps from commercially available 2b). Addition-
ally, the preparation of 2,2-disubstituted epoxide 10b was
accomplished in two simple steps in good yield. Two oxazo-
lidinediones, 5b and 6b, were also prepared in two steps
from the same hydroxyester 3b,[9a,b] in 70 and 90% overall
yield, respectively. It was confirmed by chiral HPLC that
the quaternary stereocenter was not modified to any signifi-
cant extent under the simple transformations described.
Typical procedure for enantioselective methylation of ketoesters: A solu-
tion of Me2Zn (1.2m, 2.5 mL, 3 mmol) in toluene was added dropwise to
a
solution of ligand 1c (32.1 mg, 0.1 mmol) in anhydrous toluene
(1.5 mL) under argon atmosphere at RT. The mixture was stirred for
10 min at RT, then triethyl borate (21 mL, 0.125 mmol) was added. The
resulting mixture was stirred for another 5 min at RT, then was cooled to
À358C. At À358C, the corresponding ketoester 2 (0.5 mmol) was added
slowly (30 min) and the reaction mixture was stirred at À358C for the in-
dicated time. Afterwards, the mixture was quenched with saturated aque-
ous solution of NH4Cl, extracted with Et2O (5ꢆ15 mL), dried over anhy-
drous MgSO4, filtered, and the solvents were evaporated under reduced
pressure. Purification by silica gel column chromatography (ethyl acetate/
hexane) gave the pure hydroxyesters. Enantiomeric excess was deter-
mined by chiral HPLC.
Compound 3a: Compound 3a was obtained from 2a (73 mL, 0.5 mmol)
after purification by flash chromatography (ethyl acetate/hexane 1:30) as
4378
ꢅ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 4375 – 4379