Asymmetric synthesis of aldol products derived from unsymmetrical ketones: Assignment of the absolute configuration of antibody aldol products

Article abstract of DOI:10.1016/S0957-4166(02)00410-X

Compounds 1-7 are the products formed by aldol condensation of p-nitrobenzaldehyde with a series of unsymmetrical ketones, the reaction occurring at the less substituted carbon. The asymmetric synthesis of 1-7 using the Evans's asymmetric aldol methodology is described in detail. These syntheses were completed to allow us to assign the absolute configuration of products 1-3, obtained in a single step in the presence of the aldolase I antibody 84G3.

Full text of DOI:10.1016/S0957-4166(02)00410-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1789–1798
Asymmetric synthesis of aldol products derived from
unsymmetrical ketones: assignment of the absolute configuration
of antibody aldol products
V. Maggiotti,a J.-B. Wong,a R. Razet,a A. R. Cowleyb and V. Gouverneura,*
aUniversity of Oxford, The Dyson Perrins Laboratory, South Parks Road, OX1 3QY Oxford, UK
bUniversity of Oxford, Chemical Crystallography Laboratory, 9 Parks Road, OX1 3PD Oxford, UK
Received 5 July 2002; accepted 18 July 2002
Abstract—Compounds 1–7 are the products formed by aldol condensation of p-nitrobenzaldehyde with a series of unsymmetrical
ketones, the reaction occurring at the less substituted carbon. The asymmetric synthesis of 1–7 using the Evans’s asymmetric aldol
methodology is described in detail. These syntheses were completed to allow us to assign the absolute configuration of products
1–3, obtained in a single step in the presence of the aldolase I antibody 84G3. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
ab84G3 operates with moderate to high catalytic profi-
ciencies and both enantiomers are accessible using
either an antibody-catalysed aldol or retro-aldol reac-
tion. In the presence of antibody 84G3, compounds 1–3
are typically obtained with enantiomeric excesses
greater than 94% (Scheme 1, Table 1).3
The aldol reaction has emerged as one of the most
powerful methods for stereocontrolled carbonꢀcarbon
bond formation.1 An inherent challenge with the use of
unmodified unsymmetrical ketones in cross aldol reac-
tions is the simultaneous control of regio- and stereose-
lectivity and as such, access to enantiomerically pure
aldol products derived from unsymmetrical ketones
remains difficult. Recently, we have found that, in
contrast to other known biocatalysts, the commercially
available aldolase type I antibody 84G3 (ab84G3)2
catalyses the aldol condensations of p-nitrobenzalde-
hyde with a series of unsymmetrical donor ketones by
preferential formation of the less substituted enamine.
The presence of heteroatoms such as sulfur or oxygen
in the donor ketones does not affect the regioselectivity
of these antibody-catalysed reactions. The catalyst
Table 1. E.e. for the antibody-catalysed aldol and retro-
aldol reactions
Entry
R
Method
Product
e.e. (%)
1
2
3
4
5
6
CH2CH2CH3 Aldol
(R)-1
(R)-2
(R)-3
(S)-1
(S)-2
(S)-3
98
98
97
94
97
96
OMe
SMe
Aldol
Aldol
CH2CH2CH3 Retro-aldol
OMe
SMe
Retro-aldol
Retro-aldol
Scheme 1. Antibody catalysed aldol and retro-aldol reactions.
* Corresponding author. Fax: 00 44 1865 275 644; e-mail: veronique.gouverneur@chem.ox.ac.uk
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00410-X

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V. Maggiotti et al. / Tetrahedron: Asymmetry 13 (2002) 1789–1798
Transamination of compound (+)-9a to give the N-
methoxy-N-methylamide (−)-8,9 followed by silylation
of the secondary alcohol with tert-BuMe2SiCl in the
presence of imidazole provides intermediate (−)-10 in
78% overall yield. This compound was enantiomerically
pure (e.e. >99%) as verified by chiral high performance
liquid chromatography (HPLC) analysis. For the
preparation of compound (−)-1, it was hoped that the
addition of n-butyllithium or the Grignard reagent
derived from n-bromobutane to the Weinreb amide
(−)-10 might directly afford the desired protected aldol
product (−)-12. Unfortunately, model studies showed
the addition of organomagnesium, organolithium or
organocopper reagents to the Weinreb amide (−)-10 or
its corresponding aldehyde or acyl chloride to be prob-
lematic.5 Analyses of the crude mixtures revealed only
products of decomposition with concomitant loss or
reduction of the nitro group as well as unwanted substi-
tution of the aromatic ring. It is well known that in
some cases, the Pd-catalysed reactions of acyl halides
with organometallic reagents give higher yields and
selectivities than the non-catalysed reactions. Therefore,
we turned to organozinc chemistry in the presence of a
palladium-based catalyst.10 This methodology relies on
transmetallation between the acylpalladium complex
and the organozinc reagent followed by reductive elimi-
nation. Carboxylic acid (−)-11 was obtained in two
Herein, we report the independent asymmetric synthesis
of the aldol products 1–3 that allowed us to assign the
absolute configuration of the antibody aldol products.4
In conjunction with our efforts to study the scope and
limitation of the biological versus the chemical
approach for the preparation of aldol products derived
from unsymmetrical methyl ketones, we have also pre-
pared compounds 4–7. A major concern in the planning
of the syntheses of 1–7 is the potential sensitivity of the
p-nitrophenyl group to organometallic reagents.5 It was
anticipated that compounds 1–7 could be prepared in
enantiomerically pure form from a common precursor,
8, by functional group manipulation of the N-methoxy-
N-methylamide group, although we were somewhat
apprehensive as the addition of highly reactive
organometallic reagents to compound 8 might be prob-
lematic. However, the highly convergent nature of this
approach stimulated the exploration of this synthetic
strategy as the absolute configuration of compound 8
could be easily secured through use of the Evans’s
asymmetric aldol methodology (Scheme 2).6
2. Results and discussion
The aldol reaction between (4S)-4-benzyl-3-acetyl-2-
oxazolidinone7 with p-nitrobenzaldehyde was achieved
via a boron enolate and gave the expected product in
66% yield as a mixture of two diastereomers (+)-9a and
(+)-9b (d.e.=45% as assigned by HPLC). These two
diastereomers could be cleanly separated by column
chromatography. The absolute configuration of the
major diastereomer (+)-9a was determined unambigu-
ously by X-ray diffraction with reference to the known
absolute configuration of the asymmetric carbon atom
of the oxazolidinone ring and was found to be (3%S,4S)
(Scheme 3, Fig. 1).8
Figure 1. X-Ray crystallography of diastereomer (+)-9a.
Scheme 2. Retrosynthetic approach for the preparation of compounds 1–7.
Scheme 3. Synthesis of compounds (+)-9a and (+)-9b. Reagents and conditions: (i) Et3N, n-Bu2BOTf, DCM, −78°C then rt, 66%.

V. Maggiotti et al. / Tetrahedron: Asymmetry 13 (2002) 1789–1798
1791
steps from (+)-9a by silylation followed by the
hydrolytic removal of the chiral auxiliary.11 The
ketones (−)-12 and (−)-13 were obtained in an overall
yield of 45 and 51%, respectively, by treatment of
(−)-11 with oxalyl chloride followed by addition of
dimethyl- or di-n-butylzinc on the crude acyl chloride
in the presence of 4 mol% of Pd(PPh3)4 in benzene. The
cleavage of the tert-butyldimethylsilyloxy group of
ketone (−)-12 was best achieved using TBAF in the
presence of acetic acid to afford compound (−)-1 in a
chemical yield of 87%.12 Other common reagents such
as BF3·OEt2, TFA or TBAF in the absence of acetic
acid, failed to afford the deprotected product (−)-1 with
an acceptable yield (Scheme 4).13
trimethylsilyltriflate. Oxidation of compound 15 with 3
mol% OsO4 and 2 equiv. of N-methylmorpholine-N-
oxide (the Upjohn process) introduces the requisite
hydroxyl group alpha to the carbonyl, affording com-
pound (−)-4 after a final deprotection step, with an
overall yield of 41% from ketone (−)-13.14 Exposure of
the silyl enol ether 15 to N-chlorosuccinimide in wet
acetonitrile at room temperature yielded the chlorinated
compound (−)-16. The nucleophilic substitution of the
chlorine group of 16 with sodium thiomethoxide in
toluene at 0°C proceeded smoothly to afford compound
17 in 79% yield. Cleavage of the tert-butyldimethylsilyl
group of both compounds 16 and 17 afforded our
targets (−)-3 and (−)-5 with respective yields of 98 and
75%. Finally, the methylation of (−)-18 followed by
deprotection of the corresponding ether afforded com-
pound (−)-2 in an acceptable overall yield of 50%.
The protected ketone (−)-13 via its corresponding less
substituted silyl enol ether 15 is an obvious precursor of
compounds 2–5 (Scheme 5). Ketone (−)-13 was there-
fore converted into the corresponding kinetic enolate
by treatment with 2,6-lutidine in dichloromethane at
−78°C, and then to the silyl enol ether 15 by
trimethylsilylation of the enolate oxygen with
It was anticipated that compounds 6 and 7 could
conceivably be prepared from the same enone interme-
diate (−)-19 using a Michael addition reaction. Unfor-
tunately, the addition of the vinyl Grignard to the
Scheme 4. Asymmetric synthesis of compound (−)-1 and intermediate (−)-13. Reagents and conditions: (a) HN(OMe)Me·HCl,
AlMe3 (2 M in toluene), THF, 0°C, 4 h, 78%; (b) TBSCl, imidazole, DMF, rt, 12 h, 100%; (c) n-BuMgBr or n-BuLi, several
conditions; (d) same conditions as b, 84%; (e) 6 equiv. H2O2, 6 equiv. LiOH, THF, 0°C then rt, 91%; (f) 1.8 equiv. (COCl)2, cat.
DMF, DCM then Me2Zn, Pd(PPh3)4, benzene, rt, 51%; (g) 1.8 equiv. (COCl)2, cat. DMF, DCM then n-Bu2Zn, Pd(PPh3)4,
benzene, rt, 45%; h: 10 equiv. TBAF, 10 equiv. AcOH, 15 h, 87%.
Scheme 5. Asymmetric synthesis of compounds (−)-2, (−)-3, (−)-4 and (−)-5. Reagents and conditions: (a) 2 equiv. TMSOTf, 4
equiv. 2,6-lutidine, DCM, −78°C then 0°C; (b) 2 equiv. NMO, 3 mol% OsO4, DCM/H2O, rt, 53%; (c) 10 equiv. TBAF, 10 equiv.
AcOH, rt, 15 h, 78%; (d) 1 equiv. NCS, CH3CN, rt, 35%; (e) 1 equiv. NaSMe, toluene, 0°C, 79%; (f) as in c, 100%; (g) as in c,
75%; (h) 4 equiv. Ag2O, 8 equiv. MeI, CH3CN, reflux, 62% then same conditions as in c, 81%.

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V. Maggiotti et al. / Tetrahedron: Asymmetry 13 (2002) 1789–1798
Weinreb amide (−)-10 to form the enone (−)-19 proved
to be problematic. All our attempts to isolate the enone
from the Weinreb amide (−)-10 failed. The use of
organozinc chemistry as described above was not suc-
cessful, as the addition of divinylzinc15 to the acyl
chloride prepared in situ from the carboxylic acid (−)-
11 afforded only decomposition products. We found
that the enone (−)-19 could be obtained from the
protected Weinreb amide (−)-10 in three steps. The
reductive removal of the N-methoxy-N-methylamide
with diisobutylaluminium hydride followed by the addi-
tion of vinyl Grignard to the resulting aldehyde (−)-20
furnished the diols 21a and 21b as a mixture of the syn
and anti stereoisomers with a chemical yield of 53%
(d.e.=25%). Subjecting the mixture of the two
diastereomers to oxidation using PDC in the presence
observed by Lerner et al. for other substrates.2 For the
retro-aldol reactions, HPLC analysis confirmed that at
approximately 50% conversion, the isolated uncon-
verted aldol substrates 1–3 are of (S)-configuration.
3. Conclusions
In conclusion, we have prepared compounds 1–7 by
independent asymmetric synthesis. This work has
revealed that the presence of the p-nitrophenyl group
can cause problems if these products are to be prepared
using a chemical method based on an asymmetric aldol
reaction followed by functional group manipulation
involving highly reactive organometallic reagents.
Indeed, the use of alkyl Grignard or alkyllithium
reagents is not always compatible with compounds
possessing a p-nitrophenyl group within their structure.
For the preparation of alkyl ketones, the best route
relies on the addition of the corresponding organozinc
reagents to the acyl chloride in the presence of a
palladium catalyst. If an alkenyl ketone or enone such
as (−)-19 has to be generated, our three-step sequence
via the aldehyde is the best approach, since the one-step
process based on the addition of divinylzinc to the acyl
chloride did not afford the desired product. Interest-
ingly, we have found previously that in contrast to the
chemical approach, products (R)-1–3 could be readily
prepared in one step with enantiomeric excesses of
greater than 97%, from the corresponding unmodified
ketones and p-nitrobenzaldehyde in the presence of the
commercially available aldolase antibody 84G3. Both
enantiomers are accessible using either the forward or
reverse aldol reaction. Indeed, compounds (S)-1–3 were
obtained by kinetic resolution of the corresponding
racemic aldol products via a retroaldolisation process.
With the enantiomerically pure compounds 4–7 in
hand, further studies are now in progress including the
,
of 3 A molecular sieves afforded the desired enone
(−)-19 in 85% yield. The overall yield from the Weinreb
amide (−)-10 is 42%. The Michael addition of sodium
thiomethoxide in toluene or sodium methoxide in
methanol to the enone (−)-19 afforded the desired
products in 76 and 60% yields, respectively. For these
Michael additions, it is important to carry out the
reactions at 0°C to avoid product decomposition. For
both Michael adducts, the cleavage of the tert-
butyldimethylsilyl group was accomplished in quantita-
tive yield in the presence of TBAF and acetic acid to
afford compounds (−)-6 and (−)-7 as single enantiomers
(Scheme 6).
For compounds 1–3, an authentic racemic mixture was
prepared and both enantiomers were in each case sepa-
rated by HPLC. Comparison of the retention times of
the antibody-products and the products obtained by
independent asymmetric syntheses established the (R)-
configuration of the stereogenic center of the antibody
aldol products, which is consistent with addition of the
ketone to the si face of the aldehyde, as was previously
Scheme 6. Asymmetric synthesis of compounds (−)-6 and (−)-7. Reagents and conditions: (a) CH2ꢁCHMgBr, several conditions;
(b) 1.8 equiv. (COCl)2, cat. DMF, DCM then (CH2ꢁCH)2Zn, Pd (PPh3)4, benzene, rt, 0%; (c) 1.2 equiv. DIBAL-H (1 M in
hexane), −78°C, 45 min, 94%; (d) 1.1 equiv. CH2ꢁCHMgBr (0.55 M in THF), −78°C then 0°C then rt, 53%; (e) 1.2 equiv. PDC,
,
3 A MS, DCM, rt, 3 h, 85%; (f) Na, MeOH, 0°C, 30 min, 60%; (g) 10 equiv. TBAF, 10 equiv. AcOH, 100%; (h) MeSNa, toluene,
0°C, 5 h, 76%; (i) 10 equiv. TBAF, 10 equiv. AcOH, 100%.

V. Maggiotti et al. / Tetrahedron: Asymmetry 13 (2002) 1789–1798
1793
use of antibody 84G3-catalysed reactions for the prepa-
ration of natural products.
C19H18N2O6: C, 61.62; H, 4.90; N, 7.56. Found: C,
61.27; H, 4.83; N, 7.54%; [h]2D5=+29.5 (c 1, DCM).
1
Analytical data for 9b: Rf 0.1; mp 116°C; H NMR
(CDCl3): l 8.23 (d, J=9.2, 2H), 7.62 (d, J=8.4, 2H),
7.38–7.21 (m, 5H), 5.38 (m, 1H), 4.72 (m, 1H), 4.24 (m,
2H), 3.58 (d, J=4.4, 1H), 3.45 (dd, J=18 and 2.8, 1H),
3.33 (dd, J=14 and 3.6, 1H), 3.28 (dd, J=18 and 9.4,
1H), 2.82 (dd, J=14 and 9.6, 1H); 13C NMR (CDCl3):
l 171.5, 153.3, 149.6, 147.4, 134.8, 129.3, 129.1, 127.6,
126.6, 123.8, 69.2, 66.6, 55.1, 44.3, 37.7; IR (neat): w
3506br, 1780, 1694, 1520, 1391, 1348, 1212, 1111, 1072;
4. Experimental
Melting points were determined in a capillary and are
uncorrected. NMR spectra were recorded on a Bruker
DPX-400 or Bruker AMX-500 spectrometer. The
1
experiments were performed at 400 MHz for H and
100 MHz for 13C, except when otherwise specified.
Chemical shifts (l) are reported in parts per million
(ppm) and coupling constants (J) are given in hertz. IR
spectra were recorded on a Perkin–Elmer Paragon 1000
FT-IR spectrometer. Principal absorption bands are
reported in wavenumbers (cm−1). Mass spectra (m/z)
and HRMS were recorded on a Micromass GCT in
Chemical Ionisation (NH3, CI), Electronic Impact (EI+)
or Field Ionization (FI) modes. Optical rotations were
determined on a Perkin–Elmer 241 polarimeter in a 1
dm cell. Concentrations are given in g/100 mL. Micro-
analyses were performed by ‘Elemental Microanalysis
Limited’, Devon. Thin layer chromatography (TLC)
was performed using Merck aluminium foil backed
sheets precoated with Kieselgel 60F254. Column chro-
matography was carried out on Merck Silica gel C60
(40–60 mM). All Rf values are given for the solvent
system used for the preparative chromatography.
MS (CI+): m/z 403.2 (M+NH4 ), 388.2 (M+H+), 195.2
+
(M+H+−oxazolidinone), 178.1 (oxazolidinone+H+).
Anal calcd for C19H18N2O6: C, 61.62; H, 4.90; N, 7.56.
Found: C, 61.14; H, 4.82; N, 7.55%; HRMS:
[C19H18N2O6+H]+ requires 388.1509. Found 388.1508;
[h]2D5=+90.5 (c 1, DCM).
4.2. (3S)-3-Hydroxy-N-methoxy-N-methyl-3-(4-nitro-
phenyl)propionamide (−)-8
To a suspension of N,O-dimethylhydroxylamine hydro-
chloride (1.75 g, 17.8 mmol) in THF (60 mL) at 0°C
was added a solution of trimethylaluminium in toluene
(2 M, 8.9 mL, 17.8 mmol). After 30 min at 0°C and 20
min at rt, the solution was cooled to −15°C and a
solution of 9a (2.2 g, 5.9 mmol) in THF (40 mL) was
added dropwise. The cloudy mixture was warmed to
0°C and stirred for 4 h. The solution was quenched by
addition of saturated 0.5 M HCl (100 mL). The
aqueous layer was washed three times with DCM. The
combined organic layers were dried over MgSO4 and
concentrated. Purification by column chromatography
on silica (AcOEt/hexane, 55/45) afforded (−)-8 as a
4.1. (3%S,4S)-4-Benzyl-3-[3%-hydroxy-3%-(4-nitrophenyl)-
propionyl]oxazolidin-2-one 9a and (3%R,4S)-4-benzyl-
3-[3%-hydroxy-3%-(4-nitrophenyl)propionyl]oxazolidin-2-
one 9b
1
white solid (1.18 g, 78%); Rf 0.25; mp 81°C; H NMR
To a solution of (4S)-3-acetyl-4-benzyl oxazolidin-2-
one (3.5 g, 16 mmol) in DCM (25 mL) cooled at −78°C
were successively added di-n-butylboron triflate in
DCM (1 M, 17.6 mL, 17.6 mmol) and triethylamine
(2.7 mL, 19.2 mmol). The mixture was stirred at −78°C
for 30 min then at 0°C for 1 h. After cooling the
mixture to −78°C, a solution of p-nitrobenzaldehyde
(2.4 g, 16 mmol) in DCM (30 mL) was added dropwise.
The solution was quenched after 30 min at −78°C and
1 h at rt by addition of saturated NH4Cl (20 mL). The
aqueous layer was washed with DCM (3×15 mL). The
combined organic layers were dried over Na2SO4 and
concentrated. Purification by column chromatography
on silica (DCM/hexane/AcOEt, 70/25/5) afforded two
diastereomers 9a and 9b (d.e.=45%) as white solids
(2.95 g, 66%). Analytical data for 9a: Rf 0.15; mp
(CDCl3, 500 MHz): l 8.23 (d, J=8.7, 2H), 7.60 (d,
J=8.6, 2H), 5.25 (dt, J=9.6 and 3.0, 1H), 4.53 (d,
J=3.1, 1H), 3.66 (s, 3H), 3.23 (s, 3H), 2.93 (dd, J=17.0
and 2.2, 1H), 2.75 (dd, J=17.0 and 9.7, 1H); 13C NMR
(CDCl3, 125 MHz): l 173.0, 150.7, 147.8, 127.0, 124.2,
69.9, 61.8, 40.5, 32.4; IR (neat): w 3414br, 1640, 1520,
1348, 1070; MS (CI+): m/z 255.1 (M+H+). Anal calcd
for C11H14N2O5: C, 51.97; H, 5.55; N, 11.02. Found: C,
51.83; H, 5.70; N, 10.91%; HRMS: [C11H14N2O5+H]+
requires 255.0981. Found 255.0988; [h]2D5=−57.5 (c 1,
DCM).
4.3. (3S)-3-(tert-Butyldimethylsilanyloxy)-N-methoxy-
N-methyl-3-(4-nitrophenyl)propionamide (−)-10
Imidazole (1.45 g, 21 mmol) and TBSCl (1.6 g, 10.6
mmol) were added to a solution of (−)-8 (1.12 g, 4.4
mmol) in DMF (15 mL) at room temperature. The
mixture was stirred overnight and quenched with
NH4Cl (pH 6), extracted with DCM and the combined
organic layers were washed with brine and dried over
MgSO4. Purification by chromatography on silica
(DCM/hexane/EtOAc, 20/70/10) afforded (−)-10 as a
1
133°C; H NMR (CDCl3): l 8.24 (d, J=8.8, 2H), 7.61
(d, J=8.4, 2H), 7.37–7.19 (m, 5H), 5.34 (m, 1H), 4.73
(m, 1H), 4.26 (dd, J=9.2 and 7.2, 1H), 4.23 (dd, J=9.2
and 3.2, 1H), 3.68 (d, J=4, 1H), 3.37 (m, 2H), 3.29 (dd,
J=13.6 and 3.4, 1H), 2.82 (dd, J=13.6 and 9.2, 1H);
13C NMR (CDCl3): l 171.7, 153.3, 149.6, 147.4, 134.7,
129.4, 129.0, 127.5, 126.6, 123.8, 69.2, 66.5, 55.1, 44.2,
37.7; IR (neat): w 3446br, 1760, 1702, 1516, 1392, 1346,
1
white solid (1.7 g, 100%) Rf 0.2; mp 45°C; H NMR
+
1211, 1115, 1071; MS (CI+): m/z 403.2 (M+NH4 ),
(CDCl3): l 8.19 (d, J=8.7, 2H), 7.57 (d, J=8.6, 2H),
5.36 (dd, J=8.3 and 4.8, 1H), 3.64 (s, 3H), 3.17 (s, 3H),
3.02 (dd, J=14.9 and 8.3, 1H), 2.53 (dd, J=14.9 and
4.6, 1H), 0.85 (s, 9H), 0.05 (s, 3H), −0.11 (s, 3H); 13C
388.2 (M+H+), 353.2 (M+−OH), 237.2 (M+−C9H10O),
220.1 (M+−C9H10O−OH), 195.2 (M+H+−oxazolidi-
none), 178.1 (oxazolidinone+H+). Anal calcd for

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V. Maggiotti et al. / Tetrahedron: Asymmetry 13 (2002) 1789–1798
NMR (CDCl3): l 170.7, 152.3, 147.2, 126.7, 123.6, 71.1,
61.3, 42.9, 31.9, 25.6, 18.0, −4.9, −5.1; IR (neat, cm−1):
w 2930, 2857, 1662, 1607, 1523, 1472, 1388, 1348, 1089,
831; MS (CI+): m/z 369.2 (M+H+), 237.2 (M+−
OSiC6H15), 195.2 (M+H+−SiC6H15−NOC2H6). Anal.
calcd for C17H28N2O5Si: C, 55.41; H, 7.66; N, 7.60.
Found: C, 55.04; H, 7.70; N, 7.52%; HRMS:
[C17H28N2O5Si+H]+ requires 369.1846. Found 369.1848;
[h]2D5=−69.6 (c 1, DCM).
54.94; H, 7.41; N, 4.28%; HRMS: [C15H23NO5Si+NH4]+
requires 343.1689. Found 343.1693; [h]2D5=−49.8 (c 1,
DCM).
4.6. (1S)-1-(tert-Butyldimethylsilanyloxy)-1-(4-nitro-
phenyl)heptan-3-one (−)-12
Oxalyl chloride (75 mL, 0.86 mmol) was added at 0°C
to a solution of (−)-11 (165 mg, 0.51 mmol) in DCM (3
mL). The reaction was initiated by addition of two
drops of DMF. After 30 min at 0°C, the mixture was
allowed to warm to rt and stirred for an additional
hour. Solvents were evaporated. The solid residue was
dissolved in benzene (2.5 mL) and palladium tetrakis
(25 mg, 0.02 mmol) was added. After cooling to 0°C,
di-n-butylzinc (1 M in heptane, 0.5 mL, 0.5 mmol) was
added dropwise, the mixture was stirred at rt for 1 h
and quenched by addition of water. The aqueous layer
was extracted with EtOAc and the combined organic
layers were dried over MgSO4. Purification by chro-
matography on silica (DCM/hexane, 50/50) afforded
(−)-12 as a white solid (82 mg, 45%). Rf 0.16; mp
4.4. (3%S,4S)-4-Benzyl-3-[3%-(tert-butyldimethyl-
silanyloxy)-3%-(4-nitrophenyl)propionyl]oxazolidin-2-one
Imidazole (3.5 g, 51.8 mmol) and TBSCl (3.9 g, 25.9
mmol) was added to a solution of 9a (4 g, 10.8 mmol)
in DMF (40 mL) at room temperature. The reaction
was stirred overnight. The product was filtered off and
washed with Et2O to afford a white solid (4.4 g, 84%).
1
Mp 173°C; H NMR (CDCl3): l 8.21 (d, J=9.2, 2H),
7.61 (d, J=8.8, 2H), 7.38–7.22 (m, 5H), 5.40 (dd,
J=8.4 and 4.8, 1H), 4.66 (m, 1H), 4.18 (m, 2H), 3.46
(dd, J=15.6 and 8.0, 1H), 3.31 (dd, J=14.0 and 3.6,
1H), 3.23 (dd, J=15.6 and 4.4, 1H), 2.79 (dd, J=13.6
and 9.6, 1H), 0.88 (s, 9H), 0.09 (s, 3H), −0.12 (s, 3H);
13C NMR (CDCl3): l 169.5, 153.4, 151.5, 147.4, 135.0,
129.4, 129.0, 127.5, 126.9, 123.7, 70.4, 66.2, 55.1, 46.5,
37.7, 25.7, 18.0, −4.8, −5.1; IR (neat, cm−1): w 2926,
2852, 1789, 1695, 1598, 1518, 1476, 1390, 1347, 1248,
1
decomposition; H NMR (CDCl3): l 8.19 (d, J=9.2,
2H), 7.52 (d, J=8.4, 2H), 5.30 (dd, J=8.4 and 4.4, 1H),
2.91 (dd, J=15.6 and 8.4, 1H), 2.52 (dd, J=15.6 and
4.4, 1H), 2.44 (dt, J=17.6 and 7.5, 1H), 2.37 (dt,
J=17.6 and 7.6, 1H), 1.51 (m, 2H), 1.30 (m, 2H), 0.89
(t, J=7.4, 3H), 0.85 (s, 9H), 0.03 (s, 3H), −0.15 (s, 3H);
13C NMR (CDCl3): l 208.3, 152.2, 147.2, 126.6, 123.7,
70.7, 53.0, 44.4, 25.6, 25.4, 22.2, 18.0, 13.8, −4.8, −5.2;
IR (neat): w 2931, 2858, 1717, 1608, 1524, 1347, 1258,
1095; MS (CI+): m/z 366.3 (M+H+), 308.2 (M+−C4H9);
HRMS: [C19H31NO4Si+H]+ requires 366.2101. Found
366.2115; [h]2D5=−64.4 (c 1, DCM).
+
1201, 1048; MS (CI+): m/z 502.2 (M+NH4 ), 485.2
(M+H+), 323.1 (M+−SiC6H15−NO2), 195.1 (M+H+−
SiC6H15−oxazolidinone). Anal calcd for C25H32N2O6Si:
C, 61.96; H, 6.66; N, 5.78. Found: C, 61.79; H, 6.91; N,
6.12%; HRMS: [C25H32N2O6Si+H]+ requires 485.2108.
Found 485.2109; [h]2D5=+24.0 (c 1, CHCl3).
4.5. (3S)-3-(tert-Butyldimethylsilanyloxy)-3-(4-nitro-
phenyl)propionic acid (−)-11
4.7. (4S)-4-(tert-Butyldimethylsilanyloxy)-4-(4-nitro-
phenyl)butan-2-one (−)-13
To
a
solution of (3%S,4S)-4-benzyl-3-[3%-(tert-
butyldimethylsilanyloxy)-3%-(4-nitrophenyl)propionyl]-
oxazolidin-2-one (2 g, 4.1 mmol) in THF (40 mL)
at 0°C were added aqueous hydrogen peroxide (27.5%
wt, 3.1 mL, 24.8 mmol) and aqueous lithium hydroxide
(0.8 M, 31 mL, 24.8 mmol). After stirring at 0°C for 1
h, the solution was allowed to warm to rt and was
stirred for an additional 3 h. Then Na2S2O3·5H2O was
added (5.1 g, 20.7 mmol), the solution was extracted
with EtOAc, then acidified to pH 3 and extracted again
with EtOAc. The combined organic layers were dried
over MgSO4. Purification by chromatography on silica
(EtOAc/hexane, 50/50) afforded (−)-11 as a white solid
(1.2 g, 91%) (a few drops of acetic acid were added
before the column to dissolve completely the product);
Rf 0.32; mp 142°C; 1H NMR (CDCl3): l 8.22 (d,
J=8.4, 2H), 7.55 (d, J=8.8, 2H), 5.26 (dd, J=8.8 and
4.4, 1H), 2.78 (dd, J=15.6 and 8.4, 1H), 2.65 (dd,
J=15.6 and 4.4, 1H), 0.87 (s, 9H), 0.07 (s, 3H), −0.13
(s, 3H); 13C NMR (CDCl3): l 176.4, 150.9, 147.5, 126.6,
123.8, 70.9, 45.6, 25.6, 18.0, −4.7, −5.3; IR (neat): w
3434br, 1645, 1520, 1345, 1101; MS (CI+): m/z 343.1
Oxalyl chloride (595 mL, 6.8 mmol) was added at 0°C
to a solution of (−)-11 (1.23 g, 3.8 mmol) in DCM (20
mL). The reaction was initiated by addition of three
drops of DMF. After 30 min at 0°C, the mixture was
allowed to warm to rt and was stirred for an additional
hour. The solvents were evaporated under anhydrous
conditions. The solid residue was dissolved in benzene
(20 mL) and palladium tetrakis(triphenylphosphine)
(150 mg, 0.13 mmol) was added. After cooling to 0°C,
dimethylzinc (2 M in toluene, 1.6 mL, 3.3 mmol) was
added dropwise, the mixture was stirred at rt for 1 h
and quenched by addition of water. The aqueous layer
was extracted with EtOAc and the combined organic
layers were dried over MgSO4. Purification by chro-
matography on silica (DCM/hexane, 50/50) afforded
(−)-13 as a white solid (626 mg, 51% for both steps). Rf
1
0.26; mp 36°C; H NMR (500 MHz, CDCl3): l 8.19 (d,
J=9.0, 2H), 7.52 (d, J=9.0, 2H), 5.28 (dd, J=8.5 and
4.5, 1H), 2.94 (dd, J=15.5 and 8.5, 1H), 2.58 (dd,
J=15.5 and 4.5, 1H), 2.16 (s, 3H), 0.86 (s, 9H), 0.04 (s,
3H), −0.14 (s, 3H); 13C NMR (125 MHz, CDCl3): l
206.0, 151.9, 147.2, 126.6, 123.7, 70.7, 53.8, 31.7, 25.6,
18.0, −4.8, −5.3; IR (neat): w 2990, 1720, 1608, 1523,
(M+NH4 ), 326.1 (M+H+), 164.0 (M+−NO2−SiC6H15),
+
120.4 (M+−NO2−SiC6H15−COOH). Anal calcd for
C15H23NO5Si: C, 55.36; H, 7.12; N, 4.30. Found: C,
+
1347, 1257, 1090; MS (CI+): m/z 341.2 (M+NH4 ),

V. Maggiotti et al. / Tetrahedron: Asymmetry 13 (2002) 1789–1798
1795
324.2 (M+H+), 266.1 (M+−C4H9), 162.1 (M+−NO2−
[C17H27NO4SSi+H]+
370.1513; [h]2D5=−81.3 (c 1, DCM).
requires
370.1508.
Found
SiC6H15); Anal calcd for C16H25NO4Si: C, 59.41; H,
8.27; N, 4.40. Found: C, 59.70; H, 8.27; N, 4.40%;
HRMS: [C16H25NO4Si+H]+ requires 324.1631. Found
324.1643; [h]2D5=−70.0 (c 1, DCM).
4.10. (4S)-4-(tert-Butyldimethylsilanyloxy)-1-hydroxy-4-
(4-nitrophenyl)butan-2-one (−)-18
Trimethylsilyl triflate (112 mL, 0.62 mmol) was added to
a solution of (−)-13 (100 mg, 0.31 mmol) and lutidine
(144 mL, 1.24 mmol) in 1 mL of DCM at −78°C. The
reaction mixture was stirred for 2 h at −78°C, 30 min at
0°C and then diluted with cold DCM and washed with
cold sat. NaHCO3. The aqueous layer was extracted
three times with cold DCM. The combined organic
layers were washed with cold sat. NaCl, dried over
Na2SO4 and concentrated to give the corresponding
silyl enol ether 15 (128 mg) which was used in the next
step without purification. Osmium tetroxide (0.2 M in
toluene, 51 mL, 0.01 mmol) and aqueous NMO (50%
(w/w), 180 mL, 0.77 mmol) was added sequentially to a
solution of the crude silyl enol ether in DCM (1.5 mL)
and the mixture was stirred at rt for 2 h. Then a 50%
(w/w) solution of Na2S2O5 (1 mL) was added and the
reaction was stirred for 15 min. The mixture was
extracted with DCM, washed with brine and dried over
Na2SO4. Removal of solvents and purification by chro-
matography on silica (EtOAc/hexane, 15/85) afforded
(−)-18 as a colourless oil (56 mg, 53% for both steps).
4.8. (4S)-4-(tert-Butyldimethylsilanyloxy)-1-chloro-4-(4-
nitrophenyl)butan-2-one (−)-16
Trimethylsilyl triflate (434 mL, 2.4 mmol) was added to
a solution of (−)-13 (385 mg, 1.2 mmol) and lutidine
(560 mL, 4.8 mmol) in 4 mL of DCM at −78°C. The
reaction mixture was stirred for 2 h at −78°C, 30 min at
0°C and then diluted with cold DCM and washed with
cold sat. NaHCO3. The aqueous layer was extracted
three times with cold DCM. The combined organic
layers were washed with cold sat. NaCl, dried over
Na2SO4 and concentrated to give the corresponding
silyl enol ether 15 which was used in the next step
without purification. A solution of the residue in
CH3CN (4 mL) at 0°C was successively treated with
N-chlorosuccinimide (160 mg, 1.2 mmol) and water (0.5
mL). The mixture was warmed to rt and stirred for 3 h.
Water was added, and the solution was extracted with
EtOAc, washed with brine and dried over Na2SO4.
Purification by chromatography on silica (hexane/Et2O,
80/20) afforded (−)-16 as a white solid (150 mg, 35% for
1
Rf 0.19; H NMR (CDCl3): l 8.22 (d, J=9.2, 2H), 7.54
1
both steps). Rf 0.13; mp 54°C; H NMR (CDCl3): l
(d, J=8.7, 2H), 5.32 (dd, J=8.9 and 3.8, 1H), 4.32 (dd,
J=19.5 and 4.8, 1H), 4.16 (dd, J=19.5 and 4.8, 1H),
3.06 (t, J=4.8, 1H), 2.87 (dd, J=14.7 and 8.9, 1H),
2.56 (dd, J=14.8 and 3.8, 1H), 0.86 (s, 9H), 0.02 (s,
3H), −0.15 (s, 3H); 13C NMR (CDCl3): l 207.3, 151.0,
147.4, 126.5, 123.9, 70.9, 69.9, 49.0, 25.6, 18.0, −4.8,
−5.4; IR (neat): w 3416, 2923, 1723, 1606, 1518, 1349,
8.22 (d, J=8.4, 2H), 7.54 (d, J=8.8, 2H), 5.30 (dd,
J=8.4 and 4.0, 1H), 4.15 (d, J=15.8, 1H), 4.11 (d,
J=15.8, 1H), 3.06 (dd, J=15.6 and 8.6, 1H), 2.70 (dd,
J=15.6 and 4.2, 1H), 0.86 (s, 9H), 0.04 (s, 3H), −0.15
(s, 3H); 13C NMR (125 MHz, CDCl3): l 199.5, 151.0,
147.4, 126.5, 123.8, 70.8, 50.0, 49.4, 25.6, 17.9, −4.8,
−5.4; IR (neat): w 2990, 1738, 1608, 1523, 1348, 1254,
1074; MS (CI+): m/z 357.1 (M+NH4 ), 340.1 (M+H+),
+
1093; MS (CI+): m/z 375.0 (M+NH4 ), 358.0 (M+H+),
+
178.0 (M+−NO2−SiC6H15); HRMS: [C16H25NO5Si+
NH4]+ requires 357.1846. Found 357.1849 [h]2D5=−94.7
(c 1, DCM).
195.9 (M+−NO2−SiC6H15), 162.0 (M+H+−NO2−
SiC6H15−Cl); HRMS: [C16H24ClNO4Si+H]+ requires
358.1241. Found 358.1235 [h]2D5=−101.2 (c 1, DCM).
4.9. (4S)-4-(tert-Butyldimethylsilanyloxy)-1-methylsul-
fanyl-4-(4-nitrophenyl)butan-2-one (−)-17
4.11. (4S)-4-(tert-Butyldimethylsilanyloxy)-1-methoxy-
4-(4-nitrophenyl)butan-2-one
To a solution of (−)-16 (100 mg, 0.27 mmol) in toluene
(3 mL) was added sodium thiomethoxide (20 mg, 0.27
mmol) at 0°C. After stirring at 0°C for 3 h, the solution
was quenched by addition of aqueous NH4Cl. The
aqueous phase was extracted three times with EtOAc
and the combined organic layers were dried over
MgSO4. Removal of solvents and purification by chro-
matography on silica (hexane/Et2O, 80/20) afforded
A mixture of (−)-18 (50 mg, 0.15 mmol), silver(I) oxide
(140 mg, 0.6 mmol) and methyl iodide (75 mL, 1.2
mmol) in CH3CN (1 mL) was heated under reflux for
20 h in the dark. After cooling, the solution was diluted
with EtOAc and filtered through Celite. Removal of
solvents and purification by chromatography on silica
(EtOAc/hexane, 20/80) afforded a white solid (33 mg,
1
62%). Rf 0.22; mp 56°C; H NMR (CDCl3): l 8.20 (d,
1
(−)-17 as a pale yellow oil (78 mg, 79%). Rf 0.22; H
J=8.8, 2H), 7.53 (d, J=8.4, 2H), 5.33 (dd, J=8.4 and
3.6, 1H), 4.04 (d, J=17.4, 1H), 3.98 (d, J=17.4, 1H),
3.41 (s, 3H), 2.93 (dd, J=15.6 and 8.4, 1H), 2.54 (dd,
J=15.6 and 4.0, 1H), 0.86 (s, 9H), 0.04 (s, 3H), −0.15
(s, 3H); 13C NMR (CDCl3): l 205.6, 151.7, 147.3, 126.6,
123.7, 78.6, 70.4, 59.3, 49.3, 25.6, 18.0, −4.8, −5.3; IR
(neat): w 2955, 2930, 1731, 1523, 1347, 1092; MS (CI+):
NMR (CDCl3): l 8.20 (d, J=8.8, 2H), 7.54 (d, J=8.4,
2H), 5.30 (dd, J=8.2 and 4.5, 1H), 3.20 (d, J=13.6,
1H), 3.14 (d, J=13.6, 1H), 3.14 (dd, J=15.9 and 8.1,
1H), 2.77 (dd, J=15.9 and 4.5, 1H), 1.99 (s, 3H), 0.86
(s, 9H), 0.05 (s, 3H), −0.15 (s, 3H); 13C NMR (125
MHz, CDCl3): l 202.2, 151.7, 147.2, 126.6, 123.6, 70.8,
50.4, 44.1, 25.6, 17.9, 15.4, −4.9, −5.3; IR (neat): w 2929,
2857, 1711, 1608, 1523, 1347, 1258, 1094; MS (CI+):
m/z 371.2 (M+NH4 ), 354.2 (M+H+), 239.1 (M+H+−
+
SiC6H15) 222.1 (M+−OSiC6H15), 192.1 (M+−NO2−
m/z 387.1 (M+NH4 ), 370.2 (M+H+), 208.1 (M+−NO2−
SiC6H15);
HRMS:
[C17H27NO5Si+H]+
requires
+
SiC6H15), 162.1 (M+H+−NO2−SiC6H15−SCH3); HRMS:
354.1737. Found 354.1726; [h]2D5=−61.2 (c 0.5, DCM).

1796
V. Maggiotti et al. / Tetrahedron: Asymmetry 13 (2002) 1789–1798
4.12. (3S)-3-(tert-Butyldimethylsilanyloxy)-3-(4-nitro-
phenyl)propionaldehyde (−)-20
4.14. (5S)-5-(tert-Butyldimethylsilanyloxy)-5-(4-nitro-
phenyl)pent-1-en-3-one (−)-19
To a solution of (−)-10 (2.5 g, 6.8 mmol) in THF (80
mL) at −78°C was added a solution of DIBAL-H in
hexane (1 M, 8.2 mL, 8.2 mmol). The reaction was
stirred at −78°C for 45 min and then quenched with sat.
NH4Cl. The aqueous layer was extracted with EtOAc
and the combined organic layers were washed with
brine and dried over MgSO4. Removal of solvents and
purification by chromatography on silica (hexane/
EtOAc, 90/10) afforded (−)-20 as a white solid (1.98 g,
To a solution of 21a and 21b (674 mg, 2 mmol) in
,
DCM (13 mL) was added 3 A molecular sieves (2.7 g)
and PDC (908 mg, 2.4 mmol). After stirring for 3 h,
Et2O was added and the precipitate was filtered and
washed with Et2O. Removal of solvents and purifica-
tion by chromatography on silica (hexane/DCM, 50/50)
afforded (−)-19 as a colourless oil (570 mg, 85%). Rf
1
0.32; H NMR (CDCl3): l 8.20 (d, J=8.8, 2H), 7.55 (d,
J=8.4, 2H), 6.35 (dd, J=17.6 and 10.4, 1H), 6.21 (dd,
J=17.6 and 1, 1H), 5.88 (dd, J=10.6 and 1, 1H), 5.35
(dd, J=8.2 and 4.6, 1H), 3.15 (dd, J=15.6 and 8, 1H),
2.69 (dd, J=15.6 and 4.4, 1H), 0.84 (s, 9H), 0.03 (s,
3H), −0.13 (s, 3H); 13C NMR (CDCl3): l 197.8, 152.1,
147.2, 137.1, 129.2, 126.6, 123.7, 70.8, 49.9, 25.7, 18.0,
−4.8, −5.2; IR (neat, cm−1): w 2930, 2857, 1662, 1607,
1523, 1472, 1388, 1348, 1089, 831; MS (CI+): m/z 336.2
(M+H+), 278.1 (M+−C4H9), 266.1 (M+−CH2CH(O)-
1
94%); Rf 0.27; mp 47°C; H NMR (CDCl3): l 9.79 (t,
J=2.0, 1H), 8.22 (d, J=8.4, 2H), 7.54 (d, J=8.8, 2H),
5.34 (dd, J=7.7 and 4.4, 1H), 2.90 (ddd, J=16.0, 7.6
and 2.0, 1H), 2.68 (ddd, J=16.0, 4.4 and 1.6, 1H), 0.88
(s, 9H), 0.08 (s, 3H), −0.10 (s, 3H); 13C NMR (CDCl3):
l 199.7, 151.2, 147.4, 126.5, 123.8, 69.6, 53.6, 25.6, 18.0,
−4.7, −5.2; IR (neat, cm−1): w 2956, 2858, 1727, 1608,
1523, 1472, 1348, 1095, 838; MS (CI+): m/z 327.3
(M+NH4 ), 310.3 (M+H+), 252.2 (M+NH4 −NO2−
CH2CHO). Anal calcd for C15H23NO4Si: C, 58.22; H,
7.46; N, 4.53. Found: C, 57.84; H, 7.58; N, 4.58%;
HRMS: [C15H23NO4Si+NH4]+ requires 327.1740.
Found 327,1743; [h]2D5=−50.2 (c 1, DCM).
CHCH2),
174.0
(M+−NO2−SiC6H15);
HRMS:
+
+
[C17H25NO4Si+H]+ requires 336.1631. Found 336.1635;
[h]2D5=−73.4 (c 1, DCM).
4.15. (1S)-1-(tert-Butyldimethylsilanyloxy)-5-methyl-
sulfanyl-1-(4-nitrophenyl)pentan-3-one
4.13. (5S)-5-(tert-Butyldimethylsilanyloxy)-5-(4-nitro-
phenyl)pent-1-en-3-ol 21a and 21b
To a solution of (−)-19 (175 mg, 0.52 mmol) in toluene
(6 mL) was added small portions of sodium
thiomethoxide (40.2 mg in total, 0.57 mmol) at 0°C.
The reaction mixture was stirred for 5 h at 0°C and
then quenched with NH4Cl, extracted with DCM and
the combined organic layers washed with brine and
dried over MgSO4. Removal of solvents and purifica-
tion by chromatography on silica (hexane/DCM, 20/80)
A solution of vinyl-magnesium bromide in THF (0.55
M, 10 mL, 5.5 mmol) was added at −78°C to a solution
of (−)-20 (1.7 g, 5 mmol) in THF (50 mL). After 1 h at
−78°C, the solution was stirred at rt for 2 h and
quenched by addition of sat. aqueous NH4Cl. The
aqueous layer was extracted with EtOAc and the com-
bined organic layers were washed with brine and dried
over Na2SO4. Removal of solvents and purification by
chromatography on silica (DCM/hexane, 75/25)
afforded a mixture of 21a and 21b as a colourless oil
(892 mg, 53%, d.e=25%); Noesy and Goesy experi-
ments suggest that the major diastereomer 21a is the
syn and the minor diastereomer 21b is the anti. Rf 0.20;
1H NMR (CDCl3): 21a l 8.14 (d, J=8.4, 2H), 7.45 (d,
J=8.8, 2H), 5.85 (ddd, J=16.8, 10.4 and 6.0, 1H), 5.18
(dt, J=16.8 and 1.5, 1H), 5.05 (dt, J=10.4 and 1.5,
1H), 4.92 (dd, J=8.8 and 6.2, 1H), 4.13 (m, 1H), 2.63
(d, J=2.0, 1H), 1.90 (dt, J=13.0 and 8.8, 1H), 1.78
(ddd, J=13.0, 6.8 and 3.2, 1H), 0.91 (s, 9H), 0.09 (s,
3H), −0.18 (s, 3H); 21b (deduced from the mixture syn
and anti ) l 8.14 (d, J=8.4, 2H), 7.52 (d, J=8.8, 2H),
5.85 (m, 1H), 5.18 (dm, J=16.8, 1H), 5.05 (m, 2H),
4.23 (m, 1H), 2.44 (d, J=3.2, 1H), 1.90 (dt, J=13.0 and
8.8, 1H), 1.74 (m, 1H), 0.93 (s, 9H), 0.11 (s, 3H), −0.12
(s, 3H); IR from the mixture (neat): w 3428br, 1522,
1348, 1086, 838; 13C NMR (CDCl3, 125 MHz): 21a l
152.0, 147.2, 140.0, 126.7, 123.6, 114.9, 73.7, 71.1, 47.0,
25.6, 17.9, −4.6, −5.1; 21b l 152.3, 147.0, 140.5, 126.4,
123.6, 114.4, 71.7, 69.0, 46.5, 25.6, 18.0, −4.8, −5.3; IR
(neat, cm−1): w 3428, 2954, 2858, 1607, 1523, 1348, 1086,
838; MS (CI+): m/z 338.2 (M+H+), 266.1 (M+−
CH2CH(OH)CHCH2), 188.1 (M+−OH−OSiC6H15),
1
afforded a yellow oil (150 mg, 76%). Rf 0.23; H NMR
(CDCl3): l 8.20 (d, J=8.8, 2H), 7.53 (d, J=8.8, 2H),
5.30 (dd, J=8.4 and 4.4, 1H), 2.94 (dd, J=16.0 and
8.4, 1H), 2.82–2.65 (m, 4H), 2.58 (dd, J=15.6 and 4.0,
1H), 2.10 (s, 3H), 0.85 (s, 9H), 0.04 (s, 3H), −0.15 (s,
3H); 13C NMR (CDCl3): l 206.2, 151.8, 147.3, 126.6,
123.7, 70.7, 53.2, 44.3, 27.5, 25.7, 18.0, 15.8, −4.8, −5.2;
IR (neat, cm−1): w 2955, 2929, 2857, 1717, 1608, 1523,
1472, 1408, 1347, 1094, 839. MS (CI+): m/z 384.2
(M+NH4 ), 384.2 (M+H+); HRMS: [C18H29NO4SSi+
+
NH4]+ requires 401.1930. Found 401.1932. [h]2D5=−71.4
(c 1, DCM).
4.16. (1S)-1-(tert-Butyldimethylsilanyloxy)-5-methoxy-
1-(4-nitrophenyl)pentan-3-one
To a solution of sodium methoxide (formed by dissolv-
ing sodium (12 mg, 0.52 mmol) in MeOH (6 ml)) at 0°C
was added (−)-19 (85 mg, 0.25 mmol) in MeOH (2.8
mL). After stirring for 30 min at 0°C, the reaction was
acidified to pH 6–7 by addition of HCl (1N in MeOH).
Removal of solvents and purification by chromatogra-
phy on silica (DCM/hexane, 70/30) afforded a colour-
1
less oil (54 mg, 60%). Rf 0.13; H NMR (500 MHz,
CDCl3): l 8.19 (d, J=8.8, 2H), 7.53 (d, J=8.4, 2H),
5.31 (dd, J=8.0 and 4.4, 1H), 3.62 (m, 2H), 3.30 (s,
3H), 2.97 (dd, J=16.1 and 8.0, 1H), 2.65 (m, 3H), 0.85
(s, 9H), 0.04 (s, 3H), −0.14 (s, 3H); 13C NMR (125
176.1
(M+−NO2−SiC6H15),
95
(81).
HRMS:
[C17H27NO4Si+H]+ requires 338.1788. Found 327.1783.

V. Maggiotti et al. / Tetrahedron: Asymmetry 13 (2002) 1789–1798
1797
MHz, CDCl3): l 206.2, 151.9, 147.1, 126.5, 123.6, 70.3,
67.0, 58.7, 53.5, 44.2, 25.5, 17.9, −4.9, −5.2; IR (neat,
cm−1): w 2957, 2955, 2857, 1717, 1608, 1523, 1347, 1259,
1093, 835; MS (FI): m/z 368.2 (M+H+); HRMS:
[C18H29NO5Si+H]+ requires 368.1893. Found 368.1895;
[h]2D5=−56.1 (c 1.04, DCM).
4.17.4. (4S)-4-Dihydroxy-4-(4-nitrophenyl)butan-2-one
(−)-4. Column chromatography (DCM/EtOAc, 80/20)
1
afforded (−)-4 as a colourless oil (78%). Rf 0.12; H
NMR (CD3OD): l 8.21 (d, J=8.4, 2H), 7.63 (d, J=8.4,
2H), 5.28 (dd, J=8.9 and 4.2, 1H), 4.26 (d, J=18.7,
1H), 4.22 (d, J=18.7, 1H), 2.88 (dd, J=15.8 and 8.9,
1H), 2.75 (dd, J=15.8 and 4.2, 1H); 13C NMR
(CD3OD): l 208.5, 152.2, 147.5, 126.8, 123.4, 68.9,
68.5; IR (neat, cm−1): w 3413br, 2913, 1703, 1605, 1512,
1348, 1035; MS (FI): m/z 225.1 (M+), 207.1 (M+−H2O),
151.0 (p-nitrobenzaldehyde); HRMS: [C10H11NO5]+
requires 225.0637. Found 225.0638; [h]2D5=−38.7 (c 0.5,
DCM).
4.17. General procedure for the deprotection of the
aldol compounds
A stock solution was prepared by addition of AcOH
(0.15 mL) to
a solution of tetrabutylammonium
fluoride in THF (1 M, 2.5 mL). The TBDMS ether (1
equiv.) was dissolved in THF (0.1 M) and treated by a
portion of stock solution (10 equiv.). After 15 h at rt,
the reaction mixture was quenched by addition of sat.
aqueous NaHCO3 (pH 8). The aqueous layer was
extracted with EtOAc and the combined organic layers
were washed once with sat. NH4Cl and dried over
MgSO4. Removal of solvent and purification by chro-
matography on silica gave the corresponding alcohol.
4.17.5. (4S)-1-Chloro-4-hydroxy-4-(4-nitrophenyl)butan-
2-one (−)-5. Column chromatography (hexane/EtOAc,
65/35) afforded (−)-5 as a white solid (75%). Rf 0.21;
1
mp 94°C; H NMR (CDCl3): l 8.23 (d, J=8.0, 2H),
7.57 (d, J=8.0, 2H), 5.34 (m, 1H), 4.14 (s, 2H), 3.15 (d,
J=3.6, 1H), 3.03 (m, 2H); 13C NMR (CDCl3): l 202.1,
149.4, 147.5, 126.4, 123.9, 68.9, 48.4, 48.2; IR (neat,
cm−1): w 3390br, 2912, 1726, 1601, 1509, 1344; MS
4.17.1.
(1S)-1-Hydroxy-1-(4-nitrophenyl)heptan-3-one
(CI+): m/z 261.1 (M+NH4 ), 150.0 (M+−COCH2Cl−
+
(−)-1. Column chromatography (EtOAc/hexane, 30/70)
OH), 122.1 (NO2−Ph+); HRMS: [C10H10ClNO4+NH4]+
requires 261.0642. Found 261.0645; [h]2D5=−30.4 (c 0.5,
DCM).
1
afforded (−)-1 as a colourless oil (87%); Rf 0.28; H
NMR (CDCl3): l 8.16 (d, J=8.8, 2H), 7.52 (d, J=8.8,
2H), 5.25 (m, 1H), 3.80 (d, J=2.4, 1H), 2.81 (m, 2H),
2.44 (t, J=7.6, 2H), 1.55 (m, 2H), 1.28 (m, 2H), 0.88 (t,
J=7.6, 3H); 13C NMR (CDCl3): l 211.1, 150.2, 147.2,
126.4, 123.7, 69.0, 50.5, 43.3, 25.5, 22.2, 13.8; IR (neat,
cm−1): w 3466br, 2959, 1709, 1605, 1520, 1347, 1081,
856; MS (EI+): m/z 251.1 (M+), 194.0 (M+−C4H9),
4.17.6.
(1S)-1-Hydroxy-5-methoxy-1-(4-nitrophenyl)-
pentan-3-one (−)-6. Column chromatography (DCM/
EtOAc, 80/20) afforded (−)-6 as a colourless oil
1
(quant.). Rf 0.27; H NMR (500 MHz, CDCl3): l 8.22
(d, J=8.7, 2H), 7.55 (d, J=8.9, 2H), 5.29 (m, 1H), 3.67
(m, 3H), 3.35 (s, 3H), 2.88 (d, J=7.2, 2H), 2.71 and
2.72 (2t, J=6.0, 2H); 13C NMR (125 MHz, CDCl3): l
209.7, 150.4, 147.8, 126.9, 124.2, 69.4, 67.9, 59.4, 52.1,
43.9; IR (neat, cm−1): w 3470, 2857, 1710, 1600, 1516,
1345, 1260, 1106, 854; MS (FI): m/z 253.1 (M+), 221.1
(M+−MeOH); HRMS: [C12H15NO5]+ requires 253.0950.
Found 253.0955; [h]2D5=−42.6 (c 1, DCM).
152.0 (M+−CH2C(O)C4H9), 57.4 (C4H9 ); HRMS:
+
[C13H17NO4]+ requires 251.1158. Found 251.1162;
[h]2D5=−55.3 (c 1, DCM).
4.17.2.
(4S)-4-Hydroxy-1-methoxy-4-(4-nitrophenyl)-
butan-2-one (−)-2. Column chromatography (DCM/
Et2O, 90/10) afforded (−)-2 as a white solid (81%). Rf
1
0.20; mp 78°C; H NMR (CDCl3, 500 MHz): l 8.21 (d,
J=7.2, 2H), 7.55 (d, J=6.8, 2H), 5.31 (t, J=4.8, 1H),
4.05 (d, J=13.8, 1H), 4.01 (d, J=13.8, 1H), 3.48 (s,
1H), 3.42 (s, 3H), 2.90 (d, J=5.2, 2H); 13C NMR
(CDCl3, 125 MHz): l 208.5, 149.9, 147.2, 126.3, 123.7,
77.7, 68.7, 59.3, 47.2; IR (neat, cm−1): w 3436br, 2936,
1726, 1606, 1519, 1348, 1088; MS (FI): m/z 239.1 (M+),
207.1 (M+−MeOH). Anal calcd for C11H13NO5: C,
55.23; H, 5.48; N, 5.86. Found: C, 55.01; H, 5.57; N,
5.83%; HRMS: [C11H13NO5]+ requires 239.0794. Found
239.0789; [h]2D5=−37.5 (c 0.5, DCM).
4.17.7.
(1S)-1-Hydroxy-5-methylsulfanyl-1-(4-nitro-
phenyl)pentan-3-one (−)-7. Column chromatography
(hexane/Et2O, 40/60) afforded (−)-7 as a yellow solid
(quant.); Rf 0.21; mp 47°C; 1H NMR (500 MHz,
CDCl3): l 8.23 (d, J=7.7, 2H), 7.56 (d, J=8.1, 2H),
5.31 (m, 1H), 3.48 (d, J=3.3, 1H), 2.87 (d, J=6.5, 2H),
2.77 (m, 4H), 2.12 (s, 3H); 13C NMR (125 MHz,
CDCl3): l 208.7, 149.7, 147.3, 126.3, 123.7, 68.8, 51.0,
43.0, 27.6, 15.7; IR (neat, cm−1): w 3423br, 2919, 1710,
1603, 1519, 1347, 1077; MS (FI): m/z 269.1 (M+), 151.0
(p-nitrobenzaldehyde); HRMS: [C12H15NO4S]+ requires
269.0722. Found 269.0719; [h]2D5=−47.2 (c 1, DCM).
4.17.3.
(4S)-4-Hydroxy-1-methylsulfanyl-4-(4-nitro-
phenyl)butan-2-one, (−)-3. Column chromatography
(DCM/Et2O, 98/2) afforded (−)-3 as a pale yellow solid
1
(98%). Rf 0.19; mp 86°C; H NMR (CDCl3): l 8.21 (d,
4.18. Determination of enantiomeric purity for
compounds 1, 2, 3, 5, 6 and 10
J=8.8, 2H), 7.57 (d, J=8.5, 2H), 5.28 (t, J=6.3, 1H),
3.57 (s, 1H), 3.19 (s, 2H), 3.05 (d, J=6.4, 2H), 2.05 (s,
3H); 13C NMR (CDCl3): l 204.7, 149.9, 147.3, 126.5,
123.7, 69.3, 48.0, 43.4, 15.6; IR (neat, cm−1): w 3468br,
2921, 1706, 1605, 1519, 1348, 1063; MS (CI+): m/z
Determination of enantiomeric purity was performed
by high performance liquid chromatography (HPLC) at
270 nm using a waters HPLC system (626 pump, 600S
controller, 996 photodiode array detector, millennium32
software). Chiralcel OD or OD-R Daicel column (10
mm particle size, 4.6×50 mm, flow rate 0.5, 1 or 1.5
mL/min, solvent A: hexane, solvent B: iso-propanol,
273.1 (M+NH4 ), 255.1 (M+H+), 122.1 (NO2−Ph+).
+
Anal calcd for C11H13NO4S: C, 51.75; H, 5.13; N, 5.49.
Found: C, 51.96; H, 5.19; N, 5.49%; [h]2D5=−32.2 (c 1,
DCM).

1798
V. Maggiotti et al. / Tetrahedron: Asymmetry 13 (2002) 1789–1798
solvent C: water, solvent D: MeOH) was used as chiral
stationary phase. The different retention times of the
racemic mixture are for compound 1: on OD column
(1.5 mL/min), Isocratic 96% A/4% B, tR ((R)-1)=18.0
min, tR ((S)-1)=19.3 min; for compound 2: on OD
column (1.0 mL/min), Isocratic 80% A/20% B, tR ((S)-
2)=13.9 min, tR ((R)-2)=17.2 min; for compound 3:
on OD column (1.0 mL/min), Isocratic 88% A/12% B,
tR ((S)-3)=17.2 min, tR ((R)-3)=19.1 min; for com-
pound 6: on OD-R column (0.5 mL/min), Isocratic 15%
C/85% D, tR ((S)-6)=10.0 min, tR ((R)-6)=11.0 min;
for compound 7: on OD column (1.0 mL/min), Iso-
cratic 85% A/15% B, tR ((S)-7)=15.7 min, tR ((R)-7)=
16.8 min; for compound 10 on OD column (1.0
mL/min), Isocratic 99.5% A/0.5% B, tR ((S)-10)=14.5
min, tR ((R)-10)=15.6 min; in all cases, the R enan-
tiomer in the independent synthesis was not observed.
References
1. For general reviews on the catalytic enantioselective aldol
reaction: (a) Carreira, E. M. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.,
Eds.; Springer: Heidelberg, 1999; Vol. 3, Chapters 29–1; (b)
Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357; (c)
Groger, H.; Vogl, E. M.; Shibasaki, M. Chem. Eur. J. 1998,
4, 1137; (d) Machajewski, T. D.; Wong, C.-H. Angew.
Chem., Int. Ed. 2000, 39, 1352.
2. (a) Zhong, G.; Lerner, R. A.; Barbas, C. F., III Angew.
Chem., Int. Ed. 1999, 38, 3738; (b) Sinha, S. C.; Sun, J.;
Miller, G. P.; Wartmann, M.; Lerner, R. A. Chem. Eur.
J. 2001, 7, 1691; (c) Sinha, S. C.; Sun, J.; Miller, G. P.;
Barbas, C. F., III; Lerner, R. A. Org. Lett. 1999, 10, 1623.
3. Maggiotti, V.; Resmini, M.; Gouverneur, V. Angew.
Chem., Int. Ed. 2002, 41, 1012.
4. For a paper on the enantioselective synthesis of aldol
products derived from methyl ketones and aliphatic alde-
hydes, see: Paterson, I.; Goodman, J. M.; Lister, M. A.;
Schumann, C.; McClure, C. K.; Norcross, R. D. Tetra-
hedron 1990, 46, 4663. This methodology was not applied
to methyl ketones including heteroatoms such as S or O
in combination with the p-nitro substituted aromatic
aldehydes.
5. (a) Adam, W.; Makosza, M.; Zhao, C.-G.; Surowiec, M.
J. Org. Chem. 2000, 65, 1099 and references cited therein;
(b) Lin, S.-T.; Yang, F.-M. J. Chem. Res. (S) 1994, 292;
(c) Le Guilly, L.; Setton, R.; Tatibouet, F. J. Organomet.
Chem. 1972, 40, C5.
6. (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem.
Soc. 1988, 110, 1238; (b) Evans, D. A.; Nelson, J. V.; Taber,
T. Topics in Stereochemistry; John Wiley and Sons, 1982;
Vol. 13, p. 1.
7. (a) McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm,
M. J. Org. Chem. 1993, 58, 3568; (b) Lewanowicz, A.;
Lipinski, J.; Siedlecka, R.; Skarzewski, J.; Baert, F. Tetra-
hedron 1998, 54, 6571; (c) Matsunaga, H.; Ishizuka, T.;
Kunieda, T. Tetrahedron 1997, 53, 1275; (d) Ager, D. J.;
Allen, D. R.; Schaad, D. R. Synthesis-Stuttgart 1996, 1283.
8. The crystallographic data were deposited at the Cambridge
Crystallographic Data Centre.
4.19. X-Ray crystallography
Crystals of 9a suitable for X-ray analysis were grown
from methylene chloride. A single crystal of 9a was
mounted on a glass fibre using perfluoropolyether oil
and cooled rapidly to 220 K in a stream of cold N2
using an Oxford Cryosystems CRYOSTREAM unit.
Diffraction data were measured using an Enraf–Nonius
KappaCCD diffractometer (graphite-monochromated
,
MoKa radiation, u=0.71073 A). Intensity data were
processed using the DENZO-SMN package. The struc-
ture was solved using the direct-methods program
SIR92, which located all non-hydrogen atoms. Subse-
quent full-matrix least-squares refinement was carried
out using the CRYSTALS program suite. Coordinates
and anisotropic thermal parameters of all non-hydro-
gen atoms were refined. The hydroxyl hydrogen atom
was located in a difference Fourier map and subse-
quently its coordinates and isotropic thermal parameter
were refined. Other hydrogen atoms were positioned
geometrically after each cycle of refinement. A 3-term
Chebychev polynomial weighting scheme was applied.
Refinement converged satisfactorily to give R=0.0268,
wR=0.0278. Crystal data: colourless orthorhombic
crystal (0.20×0.20×0.40 mm) in space group P21221;
9. (a) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron
Lett. 1977, 4171; (b) Levin, J. I.; Turos, E.; Weinreb, S. M.
Synth. Commun. 1982, 12, 989.
,
a=6.8117(1), b=7.1052(1), c=37.3863(6) A, h=i=
3
k=90°C; V=1809.4 A ; Z=4; Dcalad=1.359 Mg/m3;
,
10. (a) Baba, S.; Negishi, E. J. Am. Chem. Soc. 1976, 98, 6729;
(b) Negishi, E.; Takahashi, T.; Baba, S. Org. Synth. 1987,
66, 60; (c) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Tsubaki,
K.; Yoshiba, Z. Tetrahedron Lett. 1985, 26, 5529; (d)
Negishi, E.; Bagheri, V.; Chatterjee, S.; Lue, F. T.; Miller,
J. A.; Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181.
11. Naganawa, A.; Ichikawa, Y.; Isobe, M. Tetrahedron 1994,
50, 8969.
F(000)=776.254; absorption coefficient=0.103 mm−1;
reflections measured=7558, unique reflections=1529
(Rint=0.031); observations [I>3|(I)]=1232; parame-
ters=248; goodness-of-fit=1.0665; R=0.0268; Rw=
0.0278.
12. Smith, A. B., III; Chen, S. S.-Y.; Nelson, F. C.; Reichert,
J. M.; Salvatore, B. A. J. Am. Chem. Soc. 1995, 117, 12013.
13. The use of these reagents afforded a mixture of products
arising from competitive processes such as dehydration and
retroaldolization.
Acknowledgements
Financial support was provided by the University of
Oxford (grant B(RE)9862 to R.R. and grant to V.M.)
and the Royal Society of Chemistry (RSRG 20750
grant to V.G.). The authors gratefully acknowledge
Professor R. A. Lerner for supplying a very generous
quantity of antibody 84G3 as well as Dr. B. Odell for
assistance with NMR.
14. VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron
Lett. 1976, 1973.
15. For the preparation of divinylzinc, see: Boshetti, A.;
Nicotra, F.; Panza, L.; Russo, G. J. Org. Chem. 1988, 53,
4181.