Simple and efficient preparation of enantiopure alkyl α-hydroxyalkyl ketones

Article abstract of DOI:10.1055/s-2000-7611

The acylation reaction of organolithium reagents with pyrrolidine-derived α-benzyloxy and α-silyloxy carboxamides provides a simple and high-yielding method for the preparation of enantiopure α-benzyloxy and α-silyloxy ketones.

Full text of DOI:10.1055/s-2000-7611

1608
PAPER
Simple and Efficient Preparation of Enantiopure Alkyl a-Hydroxyalkyl
Ketones
Mònica Ferreró, Marta Galobardes, Ricardo Martín, Tomàs Montes, Pedro Romea,* Roser Rovira, Fèlix Urpí,* Jaume
Vilarrasa
Departament de Química Orgànica, Universitat de Barcelona, Martí i Franqués 1, 08028 Barcelona, Catalonia, Spain
Fax +34 3 3397878; E-mail: promea@qo.ub.es; furpi@qo.ub.es
Received 18 April 2000
Abstract: The acylation reaction of organolithium reagents with
O
O
O
O
pyrrolidine-derived a-benzyloxy and a-silyloxy carboxamides pro-
vides a simple and high-yielding method for the preparation of
enantiopure a-benzyloxy and a-silyloxy ketones.
N
H
S
OMe
OiBu
N
N
– MeOH
HO
HO
HO
Key words: a-benzyloxy ketones, a-silyloxy ketones, acylations,
pyrrolidine amides, organolithium reagents
1
N
H
R
– iBuOH
Enantiopure a-hydroxy ketones constitute a family of
chiral compounds whose members have played a key role
in many stereoselective processes.1-3 Recently, we
launched a project devoted to the study of the reactivity of
enolates of a-benzyloxy and a-silyloxy ketones derived
from lactic acid and other a-hydroxy acids.2c,g It was
therefore desirable to be provided with an easy and gener-
al method, suitable for small and large scale preparation of
this kind of structures. Among the different strategies de-
scribed to synthesize these ketones, acylation of organo-
metallic nucleophiles with carboxylic acids or any of their
derivatives has become the most useful one.4 Unfortunate-
ly, this transformation has often been plagued by the for-
mation of tertiary alcohols and by the loss of
stereochemical integrity at the a-center, so the develop-
ment of new acylation methods that are economical, effi-
cient and easy to perform are still appealing.
HO
ent-1
Scheme 1
TBDMS, PMB and TBDPS ethers can be accomplished in
high overall yields (see Scheme 2).
O
a
b
N
HO
1
O
O
N
N
PGO
PGO
It is well known that the addition of organolithium re-
agents to a-hydroxy acids affords the corresponding a-hy-
droxy ketones in good yields,5 however, this methodology
was not suited for our purposes because of the need to dry
commercially available aqueous solutions of lactic acid.6
Paterson et al.2e have satisfactorily solved this problem by
conversion of the lactate esters to their N-methoxy-N-me-
thyl carboxamides that give in turn the corresponding ke-
tones by reaction with organomagnesium nucleophiles. In
spite of being a very selective and high-yielding process,
the preparation of these amides involves high-cost starting
materials, which precludes its use on a large scale.7 To
overcome these shortcomings, we have developed a prac-
tical and simple procedure for the preparation of a-hy-
droxyalkyl ketones from their pyrrolidine amides.8-10
2a
2c
2b PG: TBDMS 93%
2d
PG: Bn
82%
PG: TBDPS 95%
PG: PMB 70%
Reagents and conditions: a) PhCH2Cl or p-MeOC6H4CH2Cl,
Oct3NMe+Cl–, NaOH, toluene, r.t.; b) TBDMSCl or TBDPSCl, Et3N,
DMAP, THF, r.t.
Scheme 2
Study of the reactivity of 2 was next addressed. Prelimi-
nary experiments showed that organolithium reagents af-
forded the desired ketones in good yields under very mild
conditions (THF, -78 °C), without being contaminated
by over-addition products. Higher temperatures, other
solvents (e.g. Et2O) or nucleophiles (e.g. Grignard re-
agents)12 proved to be less convenient. Eventually, addi-
tion of 1.0-1.25 equivalents of RLi to 2 afforded ketones
3-5 in good yields (Scheme 3, Table 1). In order to assess
if racemization of the a-stereocenter had taken place, sam-
ples of 3b, 3c, and 4b were converted to their tertiary al-
cohols, deprotected, and analyzed by chiral GC, showing
ee ≥ 99%.
Pyrrolidine is a low-cost, easy-to-handle amine and its
lactamide derivatives (1 or ent-1) can be obtained from
lactate esters with no need of solvent, as it was reported by
Terashima et al.11
Furthermore, we noticed that purification of 1 is not re-
quired and that protection of the hydroxyl group as Bn,
Synthesis 2000, No. 11, 1608–1614 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Simple and Efficient Preparation of Enantiopure Alkyl a-Hydroxyalkyl Ketones
1609
Table 2 Synthesis of Amides 8–9 and Ketones 10–11
Table 1 Acylation of RLi by Lactamides 2a–d
R’
PG
Amide Yield EtLi
(react. cond.)a
Ketone Yield
PG
Bn
Amide RLi (equiv)
Time
5 min
Ketone Yield
2a
EtLi (1.0)
3a
81%
Bn Bn
8a
75% 1.25, –78°C, 10a
85%
86%
88%
65%
TBDMS 2b
EtLi (1.2)
BuLi (1.2)
C7H15Li (1.2) 15 min
15 min
15 min
3b
4b
5b
84%
88%
77%
15 min
TBDMS 8b
91% 1.50, –78°C, 10b
15 min
PMB
2c
EtLi (1.0)
5 min
3c
78%
95%
iPr
Bn
9a
85% 1.25, –78°C, 11a
TBDPS
2d
EtLi (1.25)
30 min
3d
15 min
TBDMS 9b
85% 2.0, –40°C,
11b
60 min
a EtLi equiv., temperature, time.
O
O
+
RLi
N
R
previously described, and the protected amides 8 and 9
(Scheme 5) reacted smoothly with EtLi. Results are sum-
marized in Table 2. Enantiomeric excesses of 11a and 11b
were found to be greater than 98% by conversion of sam-
ples of the pure ketones to their tertiary alcohols, depro-
tection and GC analysis on a chiral column.
THF, –78 °C
PGO
PGO
2
3 R: Et
4 R: Bu
5 R: C7H15
Scheme 3
O
O
With the aim of extending the scope of this methodology,
we decided to test the effect of the alkyl chains on the
amide formation, hydroxyl protection and acylation steps
for other representative a-hydroxy esters such as methyl
(S)-2-hydroxy-3-phenylpropanoate and methyl (S)-2-hy-
droxy-3-methylbutanoate.
R'
R'
a
EtLi
6–7
N
THF
PGO
8–9
PGO
10–11
Reagents and conditions: a) BnCl, Oct3NMe+Cl–, NaOH, CH2Cl2 or
toluene, r.t. or TBDMSCl, imidazole, DMF, r.t.
The more bulky alkyl chains R¢ (Scheme 4) slowed down
the rate of the amide formation. Nevertheless, methyl
(S)-2-hydroxy-3-phenylpropanoate could be converted
into the corresponding a-hydroxy amide 6 by treatment
with 4 equivalents of pyrrolidine, without solvent, at room
temperature. Removal of the volatiles afforded a crude
mixture that was easily recrystallized to give pure 6 in ex-
cellent yield (93%). In the case of methyl (S)-2-hydroxy-
3-methylbutanoate, heating at 45 °C in the presence of 4
equivalents of pyrrolidine was required. A crude mixture
containing a-hydroxy amide 7 was isolated in quantitative
yield and was used in the next steps without further puri-
fication. In both cases, no racemization took place under
the aforementioned conditions as shown by HPLC analy-
sis of their Mosher esters (ee ≥ 99%).
Scheme 5
In summary, we have disclosed a simple and efficient
method for gaining access to alkyl a-hydroxyalkyl ke-
tones. Acylation reactions of alkyllithium reagents with
a-benzyloxy and a-silyloxy pyrrolidine amides take place
under very mild conditions in such a way that enantiomer-
ically pure ketones are obtained in good yields without be-
ing contaminated by over-addition products.
Mps were taken on a Gallenkamp apparatus and are uncorrected.
Specific rotations were determined at 20 °C at the Na D line (589
nm) on a Perkin-Elmer 241 MC polarimeter. IR spectra were re-
corded on either a Perkin-Elmer 681 or Nicolet 520 FT spectrome-
ters and only the more representative frequencies (cm-1) are
reported as follows: s, sharp; br, broad. 1H NMR (300 MHz) and 13
C
NMR (75.4 MHz) spectra were recorded on a Varian 300 Unity Plus
spectrometer; all spectra were obtained using CDCl3 as solvent and
referenced to internal TMS (d = 0) for 1H NMR and CDCl3 (d = 77)
for 13C NMR; data are reported as follows: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet. GC analysis were carried out on a
Shimadzu GC-14B/C-R6A equipment using a Beta-DexTM 120 col-
umn. Flash chromatography was performed on SDS silica gel (35-
70 mm). Analytical TLC was carried out using Merck Kieselgel 60
O
O
N
H
R'
R'
OMe
N
– MeOH
HO
HO
6
R': Bn
7
R': iPr
Scheme 4
F
254 plates. Elemental analyses were obtained by the Servei de Mi-
croanalisi (CID-CSIC, Barcelona). Low resolution mass spectra
were performed by the Servei d’Espectrometria de Masses, Univer-
sitat de Barcelona. High resolution mass spectra were obtained by
Protection of the hydroxyl groups as Bn or TBDMS ethers
was accomplished in good yields using the procedures
Synthesis 2000, No. 11, 1608–1614 ISSN 0039-7881 © Thieme Stuttgart · New York

1610
M. Ferreró et al.
PAPER
N-[(R)-2-tert-Butyldimethylsilyloxypropanoyl]pyrrolidine
the Centro de Apoio Cientifico Tecnoloxico a Investigacion
(C.A.C.T.I.), Universidad de Vigo.
(ent-2b)
Pyrrolidine (3.4 mL, 40 mmol) was added dropwise to a round bot-
tom flask containing isobutyl (R)-lactate 97% (3.015 g, 20 mmol) at
0 °C. The reaction mixture was stirred at 0 °C for 15 min and at r.t.
for 4 days, and concentrated in vacuo. The 1H NMR spectrum of the
crude revealed that it constituted mainly of a-hydroxy amide ent-1
and it was used without further purification.
All reactions were conducted under a N2 atm in anhyd solvents. The
following solvents and reagents were purified and dried according
to recommended procedures: THF, CH2Cl2, BnCl, Et3N and pyrro-
lidine.13 Ethereal solutions of EtLi and C7H15Li were prepared ac-
cording the reported procedures.14 Methyl (S)-2-hydroxy-3-
phenylpropanoate and methyl (S)-2-hydroxy-3-methylbutanoate
were prepared according the standard procedures from commercial-
ly available a-hydroxy acids (Aldrich). All other reagents were used
as received.
A solution of TBDMSCl (4.5 g, 30 mmol) in THF (10 mL) was add-
ed via cannula to a solution of crude ent-1 previously obtained, Et3N
(7 mL, 50 mmol) and DMAP (60 mg, 0.5 mmol) in THF (20 mL) at
0 °C. After stirring at 0 °C for 10 min and at r.t. for 3 days, the re-
action mixture was diluted with Et2O (250 mL) and H2O (40 mL).
The organic phase was washed with HOAc 15% (2 ¥ 40 mL), sat.
NaHCO3 (40 mL) and brine (40 mL). After drying (MgSO4), con-
centration in vacuo afforded a residue that was purified by flash
chromatography (hexanes/EtOAc, 30:70) to give the desired pro-
tected a-hydroxy amide ent-2b (4.835 g, 94%) as a colorless oil.
N-[(S)-2-Benzyloxypropanoyl]pyrrolidine (2a)
Pyrrolidine (4.6 mL, 55 mmol) was added dropwise to a round bot-
tom flask containing methyl (S)-lactate (5.215 g, 50 mmol) at 0 °C.
The reaction mixture was stirred at 0 °C for 15 min and at r.t. for
1
3 days, and concentrated in vacuo. The H NMR spectrum of the
crude revealed that it constituted mainly of a-hydroxy amide 1 and
it was used without further purification.15
Alternatively, imidazole and a catalytic amount of DMAP in DMF
can be used in the silylation step, with the same outcome.
The residue was diluted in toluene (15 mL) followed by addition of
BnCl (9.5 mL, 82 mmol) and [Oct3NMe]+ Cl- (1.025 g, 2.5 mmol).
This solution was added via cannula to a suspension of dry pow-
dered NaOH (7.1 g, 177 mmol) in toluene (20 mL) at 0 °C. After
stirring vigorously at 0 °C for 10 min and at r.t. for 12 h, the reaction
mixture was diluted with Et2O (750 mL) and H2O (100 mL). The or-
ganic layer was separated and washed with 1 M HCl (100 mL), sat.
NaHCO3 (100 mL) and brine (100 mL), dried (MgSO4) and concen-
trated in vacuo. Flash chromatography (hexanes/EtOAc, 40:60) af-
forded pure protected a-hydroxy amide 2a (9.652 g, 82%) as a
white solid.
Rf 0.30 (hexanes/EtOAc, 30:70); [a]D +18.2 (c 1.5, CHCl3).
IR (film): n = 1638 (s) cm-1.
1H NMR: d = 0.07 (s, 3H, SiCH3), 0.08 (s, 3H, SiCH3), 0.89 (s, 9H,
SiC(CH3)3), 1.37 (d, 3H, J = 6.7 Hz, CHCH3), 1.80-2.00 (m, 4H,
N(CH2CH2)2), 3.40-3.70 (m, 4H, N(CH2CH2)2), 4.46 (q, 1H,
J = 6.7 Hz, CHCH3).
13C NMR: d = -4.9, -4.8, 18.2, 20.6, 23.5, 25.8, 26.5, 46.2, 46.4,
70.6, 172.2.
LRMS (CI, NH3): m/z (%) = 200 (93), 242 (17), 258 [M+1]+ (100).
HRMS (+FAB): m/z calcd for C13H28NO2Si [M+1]+: 258.1889.
Mp: 40.3-41.2 °C (Lit.11 42.0-42.5 °C); Rf 0.15 (hexanes/EtOAc,
40:60); [a]D -63.3 (c 2.0, CHCl3) [Lit.11 -66.9 (c 1.72, CHCl3)].
Found: 258.1902.
IR (KBr): n = 1649 (s) cm-1.
1H NMR: d = 1.42 (d, 3H, J = 6.7 Hz, CHCH3), 1.75-1.95 (m, 4H,
N(CH2CH2)2), 3.30-3.60 (m, 4H, N(CH2CH2)2), 4.20 (q, 1H,
J = 6.7 Hz, CHCH3), 4.43 (d, 1H, J = 11.7 Hz, PhCHxHyO), 4.61 (d,
1H, J = 11.7 Hz, PhCHxHyO), 7.20-7.40 (m, 5H, ArH).
N-[(S)-2-tert-Butyldimethylsilyloxypropanoyl]pyrrolidine (2b)
Following the described procedures, 2b was obtained from methyl
(S)-lactate in 93% yield. [a]D -18.8 (c 2.0, CHCl3)
13C NMR: d = 17.3, 23.6, 26.3, 45.9, 46.2, 70.9, 74.6, 127.7, 127.9,
128.3, 137.7, 170.7.
N-[(S)-2-tert-Butyldiphenylsilyloxypropanoyl]pyrrolidine (2d)
2d was obtained as for 2b.
LRMS (CI, NH3): m/z (%) = 234 [M+1]+ (100).
White solid; mp: 69.0-71.0 °C; Rf 0.35 (hexanes/EtOAc, 40:60);
[a]D -15.8 (c 1.6, CHCl3).
IR (film): n = 1665 (s) cm-1.
Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C,
71.88; H, 8.25; N, 6.16.
1H NMR: d = 1.08 (s, 9H, SiC(CH3)3), 1.35 (d, 3H, J = 6.7 Hz,
CHCH3), 1.60-1.80 (m, 4H, N(CH2CH2)2), 2.90-3.40 (m, 4H,
N(CH2CH2)2), 4.36 (q, 1H, J = 6.7 Hz, CHCH3), 7.30-7.50 (m, 6H,
ArH), 7.60-7.70 (m, 4H, ArH).
13C NMR: d = 19.2, 20.5, 23.6, 26.2, 26.9, 45.8, 45.9, 69.4, 127.5,
127.6, 129.7, 129.7, 133.3, 133.6, 135.7, 135.9, 171.6.
N-[(S)-2-(p-Methoxybenzyloxy)propanoyl]pyrrolidine (2c)
2c was obtained as for 2a.
Pale yellow solid; mp: 79.1-80.3 °C; Rf 0.15 (hexanes/EtOAc,
30:70); [a]D -64.1 (c 1.3, CHCl3).
IR (KBr): n = 1635 (s) cm-1.
1H NMR: d = 1.40 (d, 3H, J = 6.7 Hz, CHCH3), 1.80-2.00 (m, 4H,
N(CH2CH2)2), 3.40-3.60 (m, 4H, N(CH2CH2)2), 3.80 (s, 3H,
OCH3), 4.17 (q, 1H, J = 6.7 Hz, CH CH3), 4.37 (d, 1H, J = 11.4 Hz,
ArCHxHyO), 4.53 (d, 1H, J = 11.4 Hz, ArCHxHyO), 6.80-6.90
(AA¢BB¢ system, 2H, ArH), 7.20-7.30 (AA¢BB¢ system, 2H, ArH).
13C NMR: d = 17.4, 23.7, 26.4, 45.9, 46.2, 55.2, 70.6, 74.4, 113.7,
129.6, 129.8, 159.3, 170.8.
LRMS (CI, NH3): m/z (%) = 121 (44), 264 [M+1]+ (100).
LRMS (CI, NH3): m/z (%) = 381 [M]+ (100), 382 [M+1]+ (31).
Anal. Calcd for C23H31NO2Si: C, 72.39; H, 8.19; N, 3.67. Found: C,
72.27; H, 8.19; N, 3.72.
Acylation of RLi: Typical Procedure; (S)-2-Benzyloxy-3-pen-
tanone (3a)
A solution of EtLi in Et2O (1.15 M, 8.8 mL, 10.1 mmol) was added
dropwise to a solution of 2a (2.330 g, 10.0 mmol) in THF (100 mL)
at -78 °C. After stirring for 5 min the reaction was quenched by ad-
dition of sat. NH4Cl (50 mL). It was then diluted with Et2O
(250 mL) and sat. NH4Cl (50 mL); the organic layer was separated,
washed with brine (50 mL) and dried (MgSO4). Concentration in
vacuo afforded a residue that was purified by flash chromatography
Anal. Calcd for C15H21NO3: C, 68.42; H, 8.04; N, 5.32. Found: C,
68.53; H, 8.14; N, 5.26.
Synthesis 2000, No. 11, 1608–1614 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Simple and Efficient Preparation of Enantiopure Alkyl a-Hydroxyalkyl Ketones
1611
(CH2Cl2) to give the desired ketone 3a (1.555 g, 81%), as a pale yel-
low oil; Rf 0.40 (CH2Cl2); [a]D -32.0 (c 1.0, CHCl3).
IR (film): n = 1715 (s) cm-1.
1H NMR: d = 1.05 (t, 3H, J = 7.2 Hz, CH2CH3), 1.34 (d, 3H, J = 6.9
Hz, CHCH3), 2.50-2.70 (m, 2H, CH2CH3), 3.94 (q, 1H, J = 6.9 Hz,
CHCH3), 4.50 (1H, AB system, J = 11.7 Hz, PhCHxHyO), 4.54 (1H,
AB system, J = 11.7 Hz, PhCHxHyO), 7.20-7.40 (m, 5H, ArH).
13C NMR: d = 7.2, 17.4, 30.5, 71.7, 80.5, 127.6, 127.8, 128.4, 137.6,
213.4.
LRMS (CI, NH3): m/z (%) = 210 [M+18]+ (100).
HRMS (EI): m/z calcd for C12H16O2 [M]+:192.1152. Found:
(S)-2-tert-Butyldimethylsilyloxy-3-heptanone (4b)
Colorless oil; Rf 0.35 (hexanes/EtOAc, 95:5); [a]D -7.7 (c 1.7,
CHCl3).
IR (film): n = 1720 (s) cm-1.
1H NMR: d = 0.08 (s, 6H, Si(CH3)2), 0.91 (t, 3H, J = 7.3 Hz,
CH2CH3), 0.92 (s, 9H, SiC(CH3)3), 1.27 (d, 3H, J = 6.7 Hz,
CHCH3), 1.25-1.40 (m, 2H, CH2CH3), 1.50-1.60 (m, 2H,
COCHxHyCH2), 2.52 (dt, 1H, J = 17.7, 7.3 Hz, COCHxHyCH2),
2.61 (dt, 1H, J = 17.7, 7.5 Hz, COCHxHyCH2), 4.13 (q, 1H, J = 6.7
Hz, CHCH3).
13C NMR: d = -5.1, -4.7, 13.8, 18.1, 20.8, 22.4, 25.3, 25.7, 36.5,
74.9, 214.2.
LRMS (CI, NH3): m/z (%) = 245 [M+1]+ (27), 262 [M+18]+ (100).
192.1157.
Ketones 3b-d, 4b and 5b were prepared in a similar way (see Table
1).
HRMS (EI): m/z calcd for C12H25O2Si [M-CH3]+: 229.1624.
Found: 229.1619; m/z calcd for C9H19O2Si [M-C(CH3)3]+:
187.1154. Found: 187.1160.
(S)-2-tert-Butyldimethylsilyloxy-3-pentanone (3b)
Caution: concentration in vacuo has to be carried out carefully in
order to prevent losses of product.
(S)-2-tert-Butyldimethylsilyloxy-3-decanone (5b)
Colorless oil; Rf 0.25 (hexanes/EtOAc, 97:3); [a]D -7.0 (c 2.0,
CHCl3).
IR (film): n = 1720 (s) cm-1.
1H NMR: d = 0.07 (s, 6H, Si(CH3)2), 0.85-0.95 (m, 3H,
(CH2)6CH3), 0.92 (s, 9H, SiC(CH3)3), 1.27 (d, 3H, J = 6.7 Hz,
CHCH3), 1.25-1.35 (m, 8H, (CH2)4CH3), 1.50-1.60 (m, 2H,
COCHxHyCH2), 2.52 (dt, 1H, J = 17.8, 7.3 Hz, COCHxHyCH2),
2.60 (dt, 1H, J = 17.8, 7.3 Hz, COCHxHyCH2), 4.13 (q, 1H, J = 6.7
Hz, CHCH3).
Colorless oil; Rf 0.50 (hexanes/Et2O, 90:10); [a]D -11.1 (c 2.0,
CHCl3).
IR (film): n = 1721 (s) cm-1.
1H NMR: d = 0.08 (s, 6H, Si(CH3)2), 0.92 (s, 9H, SiC(CH3)3), 1.04
(t, 3H, J = 7.3 Hz, CH2CH3), 1.28 (d, 3H, J = 6.9 Hz, CHCH3), 2.56
(dq, 1H, J = 18.6, 7.3 Hz, COCHxHyCH3), 2.65 (dq, 1H, J = 18.6,
7.3 Hz, COCHxHyCH3), 4.15 (q, 1H, J = 6.9 Hz, CHCH3).
13C NMR: d = -5.1, -4.7, 7.3, 18.0, 21.0, 25.7, 30.1, 74.8, 214.9.
LRMS (CI, NH3): m/z (%) = 217 [M+1]+ (54), 234 [M+18]+ (100).
13C NMR: d = -5.1, -4.7, 14.0, 18.1, 20.9, 22.6, 23.2, 25.7, 29.1,
29.3, 31.7, 36.9, 74.9, 214.4.
LRMS (CI, NH3): m/z (%) = 287 [M+1]+ (64), 304 [M+18]+ (100).
(S)-2-p-Methoxybenzyloxy-3-pentanone (3c)
Pale yellow oil; Rf 0.30 (hexanes/EtOAc, 90:10); [a]D -38.3 (c 2.0,
CHCl3).
IR (film): n = 1717 (s) cm-1.
HRMS (EI): m/z calcd for C15H31O2Si [M-CH3]+: 271.2093.
Found: 271.2092; m/z calcd for C12H25O2Si [M-C(CH3)3]+:
229.1624. Found: 229.1618.
1H NMR): d = 1.05 (t, 3H, J = 7.2 Hz, CH2CH3), 1.32 (d, 3H,
J = 6.9 Hz, CHCH3), 2.45-2.70 (m, 2H, CH2CH3), 3.81 (s, 3H,
OCH3), 3.92 (q, 1H, J = 6.9 Hz, CHCH3), 4.43 (AB system, 1H,
J = 11.35 Hz, ArCHxHy), 4.47 (AB system, 1H, J = 11.35 Hz,
ArCHxHy), 6.85-6.95 (AA¢BB¢ system, 2H, ArH), 7.20-7.30
(AA¢BB¢ system, 2H, ArH).
13C NMR: d = 7.3, 17.5, 30.5, 55.3, 71.5, 80.2, 113.9, 129.4, 129.7,
159.4, 213.6.
LRMS (CI, NH3): m/z (%) = 121 (100), 138 (21), 240 [M+18]+ (68).
HRMS (EI): m/z calcd for C13H18O3 [M]+: 222.1256. Found:
N-[(S)-2-Hydroxy-3-phenylpropanoyl]pyrrolidine (6)
Pyrrolidine (13.2 mL, 160 mmol) was added dropwise to a round
bottom flask containing methyl (S)-2-hydroxy-3-phenylpropanoate
(7.20 g, 40 mmol) at 0 °C. The reaction mixture was stirred at 0 °C
for 15 min and at r.t. for 5 days, and then concentrated in vacuo. The
residue was recrystallized from hexanes/EtOAc to give a-hydroxy
amide 6 (8.15 g, 93%) as a white crystalline solid.
Mp: 98.0-99.0 °C; Rf 0.40 (2% MeOH in CH2Cl2); [a]D +4.6 (c 2.0,
CHCl3).
IR (KBr): n = 3250 (b), 1630 (s) cm-1.
1H NMR: d = 1.70-1.90 (m, 4H, N(CH2CH2)2), 2.80-3.00 (m, 3H,
PhCH2 and 1 N(CH2CH2)2), 3.30-3.50 (m, 2H, 2 N(CH2CH2)2),
3.50-3.60 (m, 1H, 1 N(CH2CH2)2), 3.64 (d, 1H, J = 8.4 Hz, OH),
4.35-4.45 (m, 1H, CHOH), 7.20-7.40 (m, 5H, ArH).
13C NMR: d = 23.6, 25.7, 41.7, 45.7, 45.9, 70.5, 126.5, 128.2, 129.2,
136.8, 171.9.
222.1251.
(S)-2-tert-Butyldiphenylsilyloxy-3-pentanone (3d)
Colorless oil; Rf 0.35 (hexanes/EtOAc, 90:10); [a]D -12.0 (c 1.95,
CHCl3).
IR (film): n = 1719 (s) cm-1.
1H NMR: d = 0.97 (t, 3H, J = 7.3 Hz, CH2CH3), 1.10 (s, 9H,
SiC(CH3)3), 1.19 (d, 3H, J = 6.9 Hz, CHCH3), 2.58 (q, 2H, J = 7.3
Hz, CH2CH3), 4.22 (q, 1H, J = 6.9 Hz, CHCH3), 7.30-7.50 (m, 6H,
ArH), 7.60-7.70 (m, 4H, ArH).
LRMS (CI, NH3): m/z (%) = 220 [M+1]+ (100).
Anal. Calcd for C13H17NO2: C, 71.20; H, 7.81; N, 6.38. Found: C,
71.15; H, 8.05; N, 6.34.
13C NMR: d = 7.3, 19.2, 20.9, 26.9, 30.3, 75.5, 127.6, 127.7, 129.8,
129.9, 133.0, 133.7, 135.7, 214.0.
N-[(S)-2-Hydroxy-3-methylbutanoyl]pyrrolidine (7)
Pyrrolidine (6.6 mL, 80 mmol) was added dropwise to a round bot-
tom flask containing methyl (S)-2-hydroxy-3-methylbutanoate
(2.60 g, 20 mmol) at 0 °C. The reaction mixture was stirred at 0 °C
for 15 min and at 45 °C for 5 days. Concentration in vacuo afforded
a-hydroxy amide 7 (3.41 g, 99%) as a brown wax that was used in
LRMS (CI, NH3) : m/z (%) = 263 (100), 358 [M+18]+ (91).
HRMS (+FAB): m/z calcd for C17H19O2Si [M-C(CH3)3]+:
283.1154. Found: 283.1164.
Synthesis 2000, No. 11, 1608–1614 ISSN 0039-7881 © Thieme Stuttgart · New York

1612
M. Ferreró et al.
PAPER
the next step without further purification. Flash chromatography
(5% MeOH in CH2Cl2) of a sample gave pure 7 as a white wax.
Hy), 3.30-3.50 (m, 4H, N(CH2CH2)2), 4.46 (dd, 1H, J = 7.9, 5.2 Hz,
CHOTBDMS), 7.20-7.30 (m, 5H, ArH).
Rf 0.40 (5% MeOH in CH2Cl2); [a]D -9.9 (c 2.0, CHCl3).
IR (KBr): n = 3430 (b), 1640 (s) cm-1.
1H NMR: d = 0.84 (d, 3H, J = 6.9 Hz, CH(CH3)2), 1.06 (d, 3H,
J = 6.9 Hz, CH(CH3)2), 1.80-2.05 (m, 5H, N(CH2CH2)2 and
CH(CH3)2), 3.30-3.65 (m, 5H, N(CH2CH2)2 and OH), 4.07 (d, 1H,
J = 3.0 Hz, CHOH).
13C NMR: d = -5.4, -5.2, 18.2, 23.5, 25.7, 26.4, 41.3, 46.2, 46.35,
75.5, 126.5, 128.1, 129.8, 137.6, 171.1.
LRMS (CI, NH3): m/z (%) = 334 [M+1]+ (100).
N-[(S)-2-Benzyloxy-3-methylbutanoyl]pyrrolidine (9a)
The procedure described for 2a was followed.
13C NMR: d = 15.1, 19.6, 23.7, 25.9, 30.8, 45.9, 46.0, 73.6, 172.4.
LRMS (CI, NH3): m/z (%) = 172 [M+1]+ (100).
HRMS (EI): m/z calcd for C9H17NO2 [M]+: 171.1259. Found:
Yellow oil; Rf 0.40 (hexanes/EtOAc, 50:50); [a]D -62.3 (c 2.2,
CHCl3).
IR (film): n = 1636 (s) cm-1.
1H NMR: d = 0.92 (d, 3H, J = 6.9 Hz, CH(CH3)2), 1.06 (d, 3H,
J = 6.7 Hz, CH(CH3)2), 1.70-1.90 (m, 4H, N(CH2CH2)2), 2.00-
2.20 (m, 1H, CH(CH3)2), 3.25-3.60 (m, 4H, N(CH2CH2)2), 3.70 (d,
1H, J = 8.1 Hz, CHOBn), 4.40 (d, 1H, J = 12.0 Hz, PhCHxHyO),
4.63 (d, 1H, J = 12.0 Hz, PhCHxHyO), 7.25-7.40 (m, 5H, ArH).
13C NMR: d = 18.7, 19.0, 23.6, 26.4, 30.7, 46.0, 46.1, 71.6, 84.8,
127.6, 127.8, 128.3, 138.0, 170.3.
171.1261.
Anal. Calcd for C9H17NO2: C, 63.13; H, 10.01; N, 8.18. Found: C,
62.99; H, 9.95; N, 8.20.
N-[(S)-2-Benzyloxy-3-phenylpropanoyl]pyrrolidine (8a)
A solution of 6 (1.095 g, 5 mmol), BnCl (0.69 mL, 6 mmol) and
[Oct3NMe]+ Cl- (130 mg, 0.25 mmol) in CH2Cl2 (12 mL) was add-
ed via cannula to a suspension of dry powdered NaOH (700 mg,
17.5 mmol) in CH2Cl2 (1 mL) at 0 °C. After stirring vigorously at
0 °C for 15 min and at r.t. for 2 days, the reaction mixture was di-
luted with CH2Cl2 (300 mL) and washed with 1 M HCl (75 mL) and
brine (75 mL). The aqueous layers were further extracted with
CH2Cl2 (2 ¥ 50 mL); the combined organic extracts were washed
with H2O (30 mL), dried (Na2SO4) and concentrated in vacuo. Flash
chromatography (hexanes/EtOAc, 1:1) gave the desired protected
a-hydroxy amide 8a (1.156 g, 75%), as a white solid.
LRMS (CI, NH3): m/z (%) = 262 [M+1]+ (100).
HRMS (EI): m/z calcd for C16H23NO2 [M]+: 261.1729. Found:
261.1725.
N-[(S)-2-tert-Butyldimethylsilyloxy-3-methylbutanoyl]pyrroli-
dine (9b)
The procedure described for 8b was followed.
Colorless oil; Rf 0.40 (hexanes/EtOAc, 30:70); [a]D -45.8 (c 2.2,
CHCl3).
IR (film): n = 1638 (s) cm-1.
Mp: 121.0-122.0 °C; Rf 0.30 (hexanes/EtOAc, 1:1); [a]D -41.7 (c
2.0, CHCl3).
1H NMR: d = 0.04 (s, 3H, SiCH3), 0.06 (s, 3H, SiCH3), 0.90 (s, 9H,
SiC(CH3)3), 0.90 (d, 3H, J = 6.7 Hz, CH(CH3)2), 0.98 (d, 3H,
J = 6.6 Hz, CH(CH3)2), 1.70-1.95 (m, 4H, N(CH2CH2)2), 1.85-
2.05 (m, 1H, CH(CH3)2), 3.40-3.55 (m, 3H, N(CH2CH2)2), 3.70-
3.80 (m, 1H, N(CH2CH2)2), 3.90 (d, 1H, J = 8.1 Hz, CHOTBDMS).
13C NMR: d = -5.3, -4.9, 18.2, 18.6, 18.9, 23.4, 25.8, 26.5, 32.0,
46.0, 46.3, 80.6, 171.3.
IR (KBr): n = 1640 (s) cm-1.
1H NMR: d = 1.60-1.80 (m, 4H, N(CH2CH2)2), 2.80-2.90 (m, 1H,
1 N(CH2CH2)2), 3.00-3.20 (m, 3H, PhCH2CHOBn and 1
N(CH2CH2)2), 3.40-3.60 (m, 2H, 2 N(CH2CH2)2), 4.23 (t, 1H,
J = 6.9 Hz, PhCH2CHOBn), 4.39 (d, 1H, J = 12.1 Hz, PhCHxHyO),
4.63 (d, 1H, J = 12.1 Hz, PhCHxHyO), 7.20-7.40 (m, 10H, ArH).
13C NMR: d = 23.6, 26.1, 38.9, 45.9, 46.1, 71.2, 79.2, 126.6, 127.6,
127.8, 128.2, 128.3, 129.5, 137.2, 137.6, 169.7.
LRMS (CI, NH3): m/z (%) = 286 [M+1]+ (100).
LRMS (CI, NH3): m/z (%) = 310 [M+1]+ (100).
Ketones 10a, 10b, 11a and 11b were prepared in a similar way (see
Table 2).
Anal. Calcd for C20H23NO2: C, 77.64; H, 7.49; N, 4.52. Found: C,
77.80; H, 7.54; N, 4.50.
(S)-2-Benzyloxy-1-phenyl-3-pentanone (10a)
Colorless oil; Rf 0.50 (hexanes/CH2Cl2, 50:50); [a]D -74.5 (c 2.0,
CHCl3).
IR (film): n = 1710 (s) cm-1.
1H NMR: d = 0.99 (t, 3H, J = 7.2 Hz, CH2CH3), 2.40-2.55 (m, 2H,
CH2CH3), 2.92 (dd, 1H, J = 13.9, 7.7 Hz, PhCHxHyCHOBn), 3.01
(dd, 1H, J = 13.9, 4.7 Hz, PhCHxHyCHOBn), 4.03 (dd, 1H, J = 7.7,
4.7 Hz, CHOBn), 4.35 (AB system, 1H, J = 11.8 Hz, PhCHxHyO),
4.49 (AB system, 1H, J = 11.8 Hz, PhCHxHyO), 7.15-7.40 (m,
10H, ArH).
13C NMR: d = 7.0, 31.7, 38.6, 72.5, 85.5, 126.5, 127.6, 127.7, 128.2,
128.3, 129.4, 137.1, 137.3, 212.8.
LRMS (CI, NH3): m/z (%) = 286 [M+18]+ (100).
HRMS (+FAB): m/z calcd for C18H21O2 [M+1]+: 269.1542. Found:
N-[(S)-2-tert-Butyldimethylsilyloxy-3-phenylpropanoyl]pyrro-
lidine (8b)
A solution of 6 (627 mg, 2.8 mmol), imidazole (457 g, 6.6 mmol)
and a catalytic amount of DMAP in DMF (5 mL) was added via
cannula to a solution of TBDMSCl (596 mg, 3.9 mmol) in DMF
(1 mL) at 0 °C. After stirring at 0 °C for 5 min and at r.t. for 3 days,
the reaction mixture was diluted with CH2Cl2 (150 mL) and washed
with H2O (50 mL), 1 M HCl (50 mL), sat. NaHCO3 (50 mL) and
brine (50 mL). The aqueous layers were further extracted with Et2O
(3 ¥ 30 mL), and the combined organic extracts were dried
(Na2SO4). Concentration in vacuo afforded a residue that was puri-
fied by flash chromatography (hexanes/EtOAc, 40:60) to give the
desired protected a-hydroxy amide 8b (864 mg, 91%) as a colorless
oil.
Rf 0.30 (hexanes/EtOAc, 40:60); [a]D -19.0 (c 2.3, CHCl3).
IR (film): n = 1653 (s) cm-1.
1H NMR: d = -0.14 (s, 3H, SiCH3), -0.09 (s, 3H, SiCH3), 0.81 (s,
9H, SiC(CH3)3), 1.70-1.90 (m, 4H, N(CH2CH2)2), 2.92 (dd, 1H,
J = 13.3, 7.9 Hz, PhCHxHy), 3.00 (dd, 1H, J = 13.3, 5.2 Hz, PhCHx-
269.1538.
(S)-2-tert-Butyldimethylsilyloxy-1-phenyl-3-pentanone (10b)
Colorless oil; Rf 0.30 (hexanes/CH2Cl2, 75:25); [a]D -59.0 (c 2.0,
CHCl3).
IR (film): n = 1710 (s) cm-1.
Synthesis 2000, No. 11, 1608–1614 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Simple and Efficient Preparation of Enantiopure Alkyl a-Hydroxyalkyl Ketones
1613
1H NMR: d = -0.30 (s, 3H, SiCH3), -0.11 (s, 3H, SiCH3), 0.84 (s,
9H, SiC(CH3)3), 0.98 (t, 3H, J = 7.3 Hz, CH2CH3), 2.41 (dq, 1H,
J = 18.9, 7.3 Hz, CHxHyCH3), 2.54 (dq, 1H, J = 18.9, 7.3 Hz,
CHxHyCH3), 2.79 (dd, 1H, J = 13.4, 8.1 Hz, PhCHxHy), 2.91 (dd,
1H, J = 13.4, 4.0 Hz, PhCHxHy), 4.20 (dd, 1H, J = 8.1, 4.0 Hz,
CHOTBDMS), 7.10-7.30 (m, 5H, ArH).
Acknowledgement
Financial support from the DGICYT, Ministerio de Educación y
Cultura (PM95-0061 and PB98-1272), the Direcció General de
Recerca, Generalitat de Catalunya (1996SGR00102 and
1998SGR00040), and from the Universitat de Barcelona for a doc-
torate studentship to M. Galobardes is gratefully acknowledged.
Thanks are due to M. Mena for GC analysis of 3c derivatives.
13C NMR: d = -5.6, -5.3, 7.1, 18.0, 25.7, 30.9, 41.5, 79.9, 126.5,
128.1, 129.9, 137.1, 214.3.
LRMS (CI, NH3): m/z (%) = 310 [M+18]+ (100).
HRMS (+FAB): m/z calcd for C17H29O2Si [M+1]+: 293.1937.
References
Found: 293.1924.
(1) For 1,2-asymmetric induction, see:
a) Reetz, M. Acc. Chem. Res. 1993, 26, 462.
b) Mori, S.; Nakamura, M.; Nakamura, E.; Koga, N.;
Morokuma, K. J. Am. Chem. Soc. 1995, 117, 5055.
c) Kawatsura, M.; Matsuda, F.; Shirahama, H. J. Org. Chem.
1994, 59, 6900.
(S)-4-Benzyloxy-5-methyl-3-hexanone (11a)
Colorless oil; Rf 0.65 (CH2Cl2); [a]D -94.5 (c 2.0, CHCl3).
IR (film): n = 1710 (s) cm-1.
1H NMR: d = 0.89 (d, 3H, J = 6.9 Hz, CH(CH3)2), 0.97 (d, 3H,
J = 6.9 Hz, CH(CH3)2), 1.04 (t, 3H, J = 7.5 Hz, CH2CH3), 2.00-
2.10 (m, 1H, CH(CH3)2), 2.49 (dq, 1H, J = 18.5, 7.5 Hz,
CHxHyCH3), 2.55 (dq, 1H, J = 18.5, 7.5 Hz, CHxHyCH3), 3.48 (d,
1H, J = 6.9 Hz, CHOBn), 4.38 (d, 1H, J = 11.5 Hz, PhCHxHyO),
4.56 (d, 1H, J = 11.5 Hz, PhCHxHyO), 7.20-7.40 (m, 5H,ArH).
d) Marco, J. A.; Carda, M.; González, F.; Rodríguez, S.;
Castillo, E.; Murga, J. J. Org. Chem. 1998, 63, 698.
(2) For recent reviews on asymmetric aldol reactions, see:
a) Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994, 1,
317.
b) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.
For recent publications, see:
c) Figueras, S.; Martín, R.; Romea, P.; Urpí, F.; Vilarrasa, J.
Tetrahedron Lett. 1997, 38, 1637.
d) Palomo, C.; González, A.; García, J. M.; Landa, C.;
Oiarbide, M.; Rodríguez, S.; Linden, A. Angew. Chem., Int.
Ed. Engl. 1998, 37, 180.
e) Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998,
639.
13C NMR: d = 7.2, 18.1, 18.7, 31.1, 31.3, 72.9, 90.3, 127.6, 127.7,
128.3, 137.7, 213.8.
LRMS (CI, NH3): m/z (%) = 238 [M+18]+ (100).
(S)-4-tert-Butyldimethylsilyloxy-5-methyl-3-hexanone (11b)
Colorless oil; Rf 0.40 (hexanes/EtOAc, 90:10); [a]D -60.9 (c 2.0,
CHCl3).
IR (film): n = 1700 (s) cm-1.
f) Marco, J. A.; Carda, M.; Falomir, E.; Palomo, C.; Oiarbide,
M.; Ortiz, J. A.; Linden, A. Tetrahedron Lett. 1999, 40, 1065.
g) Esteve, C.; Ferreró, M.; Romea, P.; Urpí, F.; Vilarrasa, J.
Tetrahedron Lett. 1999, 40, 5083.
1H NMR: d = 0.02 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3), 0.85 (d, 3H,
J = 6.6 Hz, CH(CH3)2), 0.86 (d, 3H, J = 6.9 Hz, CH(CH3)2), 0.91 (s,
9H, SiC(CH3)3), 1.00 (t, 3H, J = 7.2 Hz, CH2CH3), 1.80-2.00 (m,
1H, CH(CH3)2), 2.45-2.55 (m, 2H, CH2CH3), 3.71 (d, 1H, J = 5.7
Hz, CHOTBDMS).
13C NMR: d = -5.1, -4.9, 7.2, 17.5, 18.1, 18.8, 25.7, 31.0, 32.7,
83.6, 214.4.
(3) For asymmetric Diels-Alder reactions, see:
a) Masamune, S.; Reed, L. A.; Davis, J. T.; Choy, W. J. Org.
Chem. 1983, 48, 4441.
b) Roush, W. R. In Comprehensive Organic Synthesis, Vol. 5;
Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991;. p
513.
LRMS (CI, NH3) : m/z (%) = 262 [M+18]+ (100), 279 [M+35]+ (34).
(4) a) O’Neill, B. T. In Comprehensive Organic Synthesis, Vol. 1;
Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991; p
397.
Enantiomeric Excess Determination
A solution of EtLi in Et2O (1.25 M, 1.2 mL, 1.5 mmol) was added
dropwise to a solution of 2b (145 mg, 0.7 mmol) in THF (3.5 mL)
at -78 °C. After stirring for 30 min, the reaction was quenched by
addition of sat. NH4Cl (15 mL) and the mixture was extracted with
tBuOMe (3 ¥ 25 mL). After drying (MgSO4), concentration in vac-
uo afforded an oil (152 mg), which was used in the next step without
further purification.
b) Dieter, R. K. Tetrahedron 1999, 55, 4177.
(5) Masamune, S.; Choy, W. Aldrichimica Acta 1982, 15, 47.
Van Draanen, N. A.; Arsenayidis, S.; Crimmins, M. T.;
Heathcock, C. H. J. Org. Chem. 1991, 56, 2499.
(6) In addition, pure lactic acid is not stable and polymerizes upon
standing, see: Van Ness, J. H. In Encyclopedia of Chemical
Technology, Vol. 13; Wiley: New York, 1981.
(7) Tillyer, R.; Frey, L. F.; Tschaen, D. M.; Dolling, U. -H. Synlett
1996, 225.
(8) For a preliminary communication, see: Martín, R.; Pascual,
O.; Romea, P.; Rovira, R.; Urpí, F.; Vilarrasa, J. Tetrahedron
Lett. 1997, 38, 1633.
(9) For acylation with other a-hydroxycarboxamides, see:
a) Honda, Y.; Ori, A.; Tsuchihashi, G. Chem. Lett. 1986, 13.
b) Larchevêque, M.; Petit, Y. Synthesis 1986, 60.
c) Achmatowicz, B.; Wicha, J. Bull. Pol. Acad. Sci. Chem.
1988, 36, 267.
This oil was diluted in CH3CN (6 mL) and aqueous HF (48%,
0.15 mL, 4.2 mmol) was added dropwise at r.t. After stirring for
1.5 h the mixture was diluted with EtOAc (70 mL), washed with
0.1 M NaOH (25 mL) and brine (25 mL), dried (Na2SO4), concen-
trated in vacuo and purified by flash chromatography (5% MeOH in
CH2Cl2) to give (S)-3-ethyl-2,3-pentanediol (75 mg, 83% overall
yield).
Its analysis by chiral GC was carried out using the following param-
eters: P = 130 kPa, Ti = 100 °C (10 min); rate = 5 °C min-1;
Tf = 150 °C; tR = 17.24 min and 18.46 min for S and R enantiomers,
respectively.
d) Ito, Y. N.; Ariza, X.; Beck, A. K.; Bohác, A.; Ganter, C.;
Gawley, R. E.; Kühnle, F. N. M.; Tuleja, J.; Wang, Y. M.;
Seebach, D. Helv. Chim. Acta 1994, 77, 2071.
e) Carreira, E.; Du Bois, J. J. Am. Chem. Soc. 1994, 116,
10825.
Synthesis 2000, No. 11, 1608–1614 ISSN 0039-7881 © Thieme Stuttgart · New York

1614
M. Ferreró et al.
PAPER
(12) TBDMS protected amides proved to be rather unreactive;
f) Martín, R.; Romea, P.; Tey, C.; Urpí, F.; Vilarrasa, J. Synlett
1997, 1414.
their acylation by EtMgX in several solvents (THF, Et2O or
CH2Cl2) at different temperatures (from -40 °C to r.t.) usually
afforded mixtures of the desired ketones, over-addition
products and/or the starting amides. In contrast, the chelating
ability of OBn group enhances the reactivity of the
carboxamide moiety and stabilizes the tetrahedral
intermediate, affording the corresponding ketones (84-92%)
contaminated by small amounts of tertiary alcohol derivatives
(approx. 5%).
(10) For acylation with other a-hydroxy carboxilic acid
derivatives, see:
a) Hopkins, M. H.; Overman, L. E.; Rishton, G. J. Am. Chem.
Soc. 1991, 113, 5354.
b) Trost, B. M.; Rodríguez, M. S. Tetrahedron Lett. 1992, 33,
4675.
c) Pégorier, L.; Petit, Y.; Mambu, A.; Larchevêque, M.
Synthesis 1994, 1403.
d) Cahiez, G.; Metais, E. Tetrahedron: Asymmetry 1997, 8,
1373; and references cited therein.
(13) Perrin, D. D.; Armarego, W. F. L. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon: Oxford, 1988.
e) Barluenga, J.; Baragaña, B.; Concellón, J. M. J. Org. Chem.
1997, 62, 5974; and references cited therein.
f) White, J. D.; Carler, R. G.; Sundermann, K. F. J. Org.
Chem. 1999, 64, 684.
(14) Brandsma, L.; Verkruijsse, H. Preparative Polar
Organometallic Chemistry; Springer: Berlin, 1987; Vol. 1.
(15) Alternatively it can be purified by distillation; see Ref. 11.
g) Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A.
Tetrahedron 1999, 55, 2431.
Article Identifier:
(11) Ito, Y.; Kobayashi, Y.; Kawabata, T.; Takase, M.; Terashima,
S. Tetrahedron 1989, 45, 5767.
1437-210X,E;2000,0,11,1608,1614,ftx,en;P03300SS.pdf
Synthesis 2000, No. 11, 1608–1614 ISSN 0039-7881 © Thieme Stuttgart · New York