Synthesis of β-CF2-D-mannopyranosides and β-CF 2-D-galactopyranosides by Reformatsky addition onto 5-ketohexoses

Article abstract of DOI:10.1055/s-2006-958414

The first synthesis of β-CF₂-D-manno- and β-CF ₂-D-galactopyranosylesters 1a and 1b is reported. It involves an oxidation-Reformatsky addition sequence on carbohydrate-derived diols and a dehydroxylation of the resulting cyclized com

Full text of DOI:10.1055/s-2006-958414

LETTER
123
Synthesis of b-CF2-D-Mannopyranosides and b-CF2-D-Galactopyranosides by
Reformatsky Addition onto 5-Ketohexoses
S
b
-
CF
a
-
D
-Mannosvide 2
s
and
b
-
C
n
F
-
D
-Galacto
a
side
s
th P. Karche, Camille Pierry, Florent Poulain, Hassan Oulyadi, Eric Leclerc,* Xavier Pannecoucke,
Jean-Charles Quirion
Laboratoire d’Hétérochimie Organique and Laboratoire de Résonance Magnétique Nucléaire, UMR 6014 CNRS, IRCOF,
INSA et Université de Rouen, 1 rue Tesnière, 76821 Mont Saint-Aignan Cedex, France
Fax +33(2)35522959; E-mail: eric.leclerc@insa-rouen.fr
Received 13 October 2006
OBn
F
F
F
F
Abstract: The first synthesis of b-CF2-D-manno- and b-CF2-D-ga-
lactopyranosylesters 1a and 1b is reported. It involves an oxida-
tion–Reformatsky addition sequence on carbohydrate-derived diols
and a dehydroxylation of the resulting cyclized compounds. The ex-
pected b-CF2-D-glycoside and an undesired b-CF2-L-glycoside are
obtained from this sequence. An application of this methodology to
the synthesis of some fluorinated pseudo-glycopeptides, potential
selectin inhibitors, is also described.
OH
O
O
CO2Et
BnO
BnO
CO2Et
OBn
BnO
OBn
OBn
OBn
1
2
F
OZnX
OEt
F
Key words: fluorinated C-glycosides, CF2-glycopeptides, biomi-
metic synthesis, addition reactions, stereoselectivity
OBn
OBn
OBn
O
O
O
O
O
O
or
or
BnO
OBn
BnO
OBn
BnO
OBn
Glycoconjugates are known to play a crucial role in many
biological events, such as protein structure modulation or
cell–cell recognition, and thus became highly attractive
OBn
OBn
OBn
3c
3b
3a
targets for drug research.1 For example, tumor-associated Scheme 1
glycopeptide antigens (TN, STN) have stimulated an in-
tense research interest in recent years as they might allow
the development of potent anti-cancer vaccines.2 How-
ever, as with many carbohydrate-based drugs, glyco-
peptides might often suffer from a low metabolic stability
due to hydrolytic cleavage of the glycosidic link. In this
context, the development of synthetic tools to access hy-
drolytically stable glycoconjugates remains an attractive
task.3
difluoromethylene glycosides 2. Standard anomeric dehy-
droxylation conditions would result in a two-step synthe-
sis of 1 (Scheme 1).
Ketoaldehydes 3a–c in the mannose, galactose and glu-
cose series were obtained by a double Swern oxidation of
diols 4, prepared from the corresponding O-methyl-D-pyr-
anosides.7 Despite our efforts, the poor stability of these
aldehydes did not allow any purification and the crude ox-
idation products were directly subjected to Reformatsky
reactions with ethyl bromodifluoroacetate. These reac-
tions were first tested on the mannose-derived ketoalde-
hyde 3a. To begin with, standard conditions (aldehyde,
bromoacetate, and activated zinc in THF) – efficient for
the addition on other substrates – were used.4 Unfortu-
nately, this procedure happened to be unsatisfactory on
such unstable aldehydes, whatever the reaction condi-
tions. Analysis of the crude mixture by TLC and 19F NMR
revealed the presence of many fluorinated compounds
from which no addition/cyclization product could be iso-
lated. We then turned our attention to the use of a rhodi-
um(I)-catalyzed reaction recently described for the
addition of bromoacetates and bromodifluoroacetates on
carbonyl electrophiles.8 Addition of diethylzinc to a mix-
ture of crude 3a and ethyl bromodifluoroacetate in the
presence of Wilkinson’s rhodium(I) complex led to a
complete conversion of the aldehyde within 30 minutes at
0 °C in THF. 19F NMR spectrum of the crude mixture
revealed the presence of two major products 5a and 6a
(58:42 ratio) with signals consistent with the addition of a
difluoroacetate onto the aldehyde function.
Our group had a long-standing interest in the synthesis of
difluoromethylene-containing compounds.4 If not re-
ferred to as a strict isosteric and isoelectronic replacement
of oxygen, the difluoromethylene group has been often in-
troduced into bioactive compounds to serve as a mimic of
a labile P–O or C–O bond.5,6 We thus focused on the syn-
thesis of C-glycosides such as 1, where the ester function-
ality would allow us further synthetic transformations
towards glycoconjugate mimetics.4a We wish to present
herein a simple procedure for the synthesis of a b-CF2-D-
mannopyranoside and a b-CF2-D-galactopyranoside and
the application of this methodology to the preparation of
fluorinated pseudo-glycopeptides.
Our strategy is based on the Reformatsky-type addition of
ethyl bromodifluoroacetate on 5-ketohexoses 3, readily
available from the corresponding sugars. It was hoped that
the resulting zinc alkoxides would readily cyclize to yield
SYNLETT 2007, No. 1, pp 0123–0126
0
4.
0
1.
2
0
0
7
Advanced online publication: 20.12.2006
DOI: 10.1055/s-2006-958414; Art ID: G30406ST
© Georg Thieme Verlag Stuttgart · New York

124
N. P. Karche et al.
LETTER
OBn
OBn
F
F
F
F
OH
O
OH
O
OH OH
O
O
b
BnO
BnO
CO2Et
OBn
a
BnO
BnO
CO2Et
OBn
+
BnO
OBn
BnO
OBn
OBn
OBn
OBn
OBn
6a
4a
3a
5a
c
c
OBn
OBn
F
F
F
F
CO2Et
OBn
O
O
CO2Et
OBn
BnO
BnO
OBn
OBn
β-1a
7a
Scheme 2 Synthesis of CF2-mannosides. Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2; (b) Et2Zn, BrCF2CO2Et, RhCl(PPh3)3,
THF, 28% (2 steps; 5a:6a = 58:42); (c) Et3SiH, TMSOTf, CH2Cl2, 54% (b-1a), 58% (7a).
Purification by column chromatography allowed the sep- correlations between H1 and H3 and between H3 and H5
aration of these two diastereomers in 28% cumulated and (Figure 1). The second diastereomer 7a was expected to
overall yield from diol 4a (Scheme 2).9 Many reaction be the corresponding a-CF2-D-mannopyranoside result-
parameters (amounts of BrCF2CO2Et and Et2Zn, tempera- ing from the same stereoselective reduction but, to our
ture, reaction time, catalyst loading) have been examined dismay, NMR data were in complete contradiction with
but no improvement in yield could be reached for this this structure. To begin with, a large 3JH1–H2 coupling con-
two-step reaction involving an unstable ketoaldehyde in- stant (9.9 Hz) was consistent with a trans-diaxial relation-
termediate. The two diastereomers 5a and 6a were first ship between these two protons, which is compatible with
1
expected to result from a non-selective addition at C1 fol- the expected S configuration at C1 but only under a C4
lowed by a reversible O-cyclization leading to the most chair conformation. Moreover, a NOESY correlation be-
stable diastereomer i.e. the one with the hydroxy group in tween H1 and H5 proved that the configuration at C5 was
3
axial position. The measurement of a large JH1–H2 cou- S, indicating that 7a was a b-CF2-L-gulopyranoside
pling constant (10.0 Hz) in 6a was, however, not compat- (Figure 1).
4
ible with a classical C1 chair conformation for this
This stereodivergent pathway can be explained if we con-
compound. Despite this contradiction, the relative config-
sider that the conformational switch occurred just after the
urations of 5a and 6a were not determined at this stage and
addition of the Reformatsky reagent, during the reversible
cyclization step (Scheme 3). If we examine the case of a
Reformatsky addition leading to an R configuration at C1,
there is no doubt that cyclized compound (1R)-A is the
diastereomer offering the greatest steric and stereoelec-
tronic stabilization. The situation is more balanced in the
case of an addition leading to an S configuration at C1. The
axial position of the difluoroacetate group in (1S)-A is
each diastereomer was subjected to a classical dehydrox-
ylation reaction using triethylsilane as the reducing agent
in the presence of trimethylsilyl triflate. Dilution proved
to be a critical parameter for this reaction and CF2-glyco-
sides b-1a and 7a could be obtained in 54% and 58% yield
from 5a and 6a, respectively, with a concentration of the
substrate higher than 0.25 M (Scheme 2).10,11
The relative configuration of these two compounds was probably highly disfavored and steric repulsions induce
3
assigned thanks to JH–H measurements and NOESY an equilibrium shift towards (1S)-B.
experiments. All coupling constants in b-1a were in
The conformational change and the inversion at C5 (R to
agreement with a b-mannoside configuration (4C1 chair
S) leave the CF2CO2Et group of (1S)-B in equatorial posi-
conformation) which was further confirmed by NOESY
tion to minimize steric repulsion and the hydroxy group in
Figure 1 NOESY maps for b-1a and 7a.
Synlett 2007, No. 1, 123–126 © Thieme Stuttgart · New York

LETTER
Synthesis of b-CF2-D-Mannopyranosides and b-CF2-D-Galactopyranosides
125
F
OBn
OBn
OBn
OBn
OM
OBn
CO2Et
F
F
BnO
F
OM
OBn
O
O
F
F
BnO
O
BnO
BnO
CO2Et
BnO
BnO
OBn
O
CO2Et
OBn
OM
OM
OBn
F
CO2Et
OBn
F
(1R)-A
(1S)-A
(1S)-B
(1R)-B
5a (4C1)
6a (1C4)
Scheme 3 Conformational and configurational equilibriums leading to 5a and 6a.
axial position thanks to anomeric effect stabilization. A sponding a-CF2-glycopeptides and the evaluation of all
stereoselective reduction of 6a based on an axial attack of these molecules for E- and P-selectin inhibition will be
the hydride thus provided the undesired b-CF2-L-gulo- reported in due course.
pyranoside (7a).12 If the S configuration of the C5 center
3
OBn
in 6a remains speculative, the large JH1–H2 coupling
CO2H
F
F
OH
1
F
F
O
constant is consistent with the C4 chair conformation of
H
CO2Et
OBn
N
O
a–c
this compound.
BnO
O
OH
CO2H
The same sequence was applied to the galactose deriva-
tive 4b. The oxidation–Reformatsky reaction procedure
afforded once again a mixture of two diastereomers
(40:60 ratio) in 32% overall yield. These two diastere-
omers were this time not separable at that stage and the
mixture was subjected to a dehydroxylation reaction al-
lowing the formation and the separation of b-CF2-D-ga-
lactopyranoside (b-1b) and b-CF2-L-altropyranoside (7b)
in 58% yield (Scheme 4).13 The assignment of the config-
uration at C1 and C5 and the determination of the favored
conformation of each diastereomer was carried out, as for
b-1a and 7a, on the basis of NMR data. The same stereo-
divergent pathway was thus observed in this series and
could be rationalized by a similar conformational switch
occurring during the O-cyclization step.
HO
OBn
OH
β-1a
8
a, d–f
F
OH
F
H
CO2H
N
O
O
OH
HO
OH
9
Scheme 5 Synthesis of fluorinated pseudo-glycopeptides. Reagents
and conditions: (a) LiOH, THF–H2O, 95%; (b) H-Glu(OBn)-OBn,
EDCI, HOBt, NMM, CH2Cl2; (c) H2, Pd/C 67% (2 steps); (d) 3-ami-
nobenzoic acid methyl ester, BOPCl, DIPEA, MeCN; (e) LiOH,
THF–MeOH–H2O; (f) H2, Pd/C 40% (3 steps).
In conclusion, we reported the first synthesis of ethyl b-D-
manno- and b-D-galactopyranosyldifluoroacetates b-1a
and b-1b. Despite a low yield in the first step of this syn-
thesis, this methodology provides an access to CF2 ana-
logues of b-O-glycoconjugates, the ester function of such
CF2-glycosides allowing further elaboration of the side
chain. A first example of this potential was illustrated by
the synthesis of pseudo-glycopeptides 8 and 9 which are
CF2 analogues of selectin inhibitors.
CO2Et
CO2Et
OBn
OBn
OBn
O
OH OH
O
F
F
F
F
a–c
+
BnO
OBn
BnO
OBn
BnO
OBn
OBn
OBn
OBn
7b (1C4)
4b
β-1b (4C1)
Scheme 4 Synthesis of CF2-galactosides. Reagents and conditions:
(a) (COCl)2, DMSO, Et3N, CH2Cl2; (b) Et2Zn, BrCF2CO2Et,
RhCl(PPh3)3, 32% (2 steps); (c) Et3SiH, TMSOTf, CH2Cl2, 58%.
Acknowledgment
This strategy was unfortunately unsuccessful in the glu-
cose series. In our hands, the double Swern oxidation af-
forded a crude ketoaldehyde 3c which appeared even less
stable than its mannose and galactose counterparts. The
Reformatsky addition on this intermediate afforded a
complex mixture from which the expected compound
could not be isolated.
We thank the Ministère de l’Enseignement Supérieur et de la
Recherche for a post-doctoral grant to N.K. and Perigene Inc. for a
PhD grant to F.P.
References and Notes
(1) Essentials of Carbohydrate Chemistry and Biochemistry,
2nd ed.; Lindshorst, T. K., Ed.; Wiley-VCH: Weinheim,
2002.
(2) (a) Keding, S. J.; Danishefsky, S. J. In Carbohydrate-Based
Drug Discovery, Vol. 1; Wong, C.-H., Ed.; Wiley-VCH:
Weinheim, 2003, 381–406. (b) Dziadek, S.; Hobel, A.;
Schmitt, E.; Kunz, H. Angew. Chem. Int. Ed. 2005, 44,
7630. (c) Buskas, T.; Ingale, S.; Boons, G.-J. . Angew. Chem.
Int. Ed. 2005, 44, 5985.
Despite the moderate yields obtained with the oxidation–
Reformatsky sequence, this strategy was applied to the
synthesis of pseudo b-glycopeptides 8 and 9 derived from
b-1a (Scheme 5). This work is part of a project dealing
with the synthesis and the evaluation of a-CF2 and b-CF2
analogues of E- and P-selectin inhibitors designed accord-
ing to the strategy of using small molecules to mimic
host–enzyme interaction.14 The synthesis of the corre-
Synlett 2007, No. 1, 123–126 © Thieme Stuttgart · New York

126
N. P. Karche et al.
LETTER
(3) (a) Postema, M. H. D.; Piper, J. L.; Betts, R. L. Synlett 2005,
1345. (b) Marcaurelle, L. A.; Bertozzi, C. R. Chem. Eur. J.
1999, 5, 1384. (c) Sears, P.; Wong, C.-H. Angew. Chem. Int.
Ed. 1999, 38, 2300.
(4) (a) Marcotte, S.; D’Hooge, F.; Ramadas, S.; Pannecoucke,
X.; Feasson, C.; Quirion, J.-C. Tetrahedron Lett. 2001, 42,
5879. (b) Quirion, J.-C.; Pannecoucke, X.; D’Hooge, F.;
Marcotte, S.; Castelot-Deliencourt, G.; Jubault, P.; Gouge,
V. WO 014928A2, 2004. (c) Cuenca, A. B.; D’Hooge, F.;
Gouge, V.; Castelot-Deliencourt, G.; Oulyadi, H.; Leclerc,
E.; Jubault, P.; Pannecoucke, X.; Quirion, J.-C. Synlett 2005,
2627.
(5) (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-
VCH: Weinheim, 2004. (b) Burke, T. R. Jr.; Lee, K. Acc.
Chem. Res. 2003, 36, 426. (c) Blackburn, G. M.; Jakeman,
D. L.; Ivory, A. J.; Williamson, M. P. Bioorg. Med. Chem.
Lett. 1994, 4, 2573.
(6) For pioneering or recent syntheses of CF2-glycopyranosides,
see: (a) Houlton, J. S.; Motherwell, W. B.; Ross, B. C.;
Tozer, M. J.; Williams, D. J.; Slawin, A. M. Z. Tetrahedron
1993, 49, 8087. (b) Berber, H.; Brigaud, T.; Lefebvre, O.;
Plantier-Royon, R.; Portella, C. Chem. Eur. J. 2001, 7, 903.
(c) Wegert, A.; Miethchen, R.; Hein, M.; Reinke, H.
Synthesis 2005, 1850.
(7) (a) Adinolfi, M.; Barone, G.; De Lorenzo, F.; Iadonisi, A.
Synlett 1999, 336. (b) Boiron, A.; Zillig, P.; Faber, D.;
Giese, B. J. Org. Chem. 1998, 63, 5877.
(8) (a) Sato, K.; Tarui, A.; Kita, T.; Ishida, Y.; Tamura, H.;
Omote, M.; Ando, A.; Kumakadi, I. Tetrahedron Lett. 2004,
45, 5735. (b) Kanai, K.; Wakabayashi, H.; Honda, T. Org.
Lett. 2000, 2, 2549.
(9) To a stirred solution of Wilkinson’s catalyst (0.019 g, 0.021
mmol, 0.025 equiv) in dry THF (10 mL) at 0 °C was added
ethyl bromodifluoroacetate (0.144 mL, 1.22 mmol, 1.5
equiv) and a solution of dry 5-ketohexose 3a (0.437 g, 0.81
mmol, 1 equiv) in anhyd THF (13 mL). A ca. 1.0 M hexane
solution of diethylzinc (2.43 mL, 2.43 mmol, 3 equiv) was
then added dropwise to the mixture at 0 °C. After stirring for
1 h at this temperature, the reaction was quenched with sat.
NH4Cl (15 mL). The aqueous layer was extracted with
EtOAc (3 × 15 mL) and the collected organics were washed
with brine (10 mL), dried over MgSO4 and evaporated under
reduced pressure. Purification by column chromatography
(6% to 10% EtOAc in cyclohexane) allowed the separation
of the two diastereomers 6a (11%) and 5a (17%).
Rf(6a) = 0.45 and Rf(5a) = 0.37 (25% EtOAc in
128.5, 138.0, 138.2, 138.3, 138.6, 162.9 (dd, 2J = 32.8 Hz,
2J = 29.9 Hz). 19F NMR (282.5 MHz, CDCl3): d = –117.2
(dd, 2J = 268.8 Hz, 3J = 12.9 Hz), –111.4 (dd, 2J = 266.2 Hz,
3J = 6.4 Hz). MS (ESI+): m/z = 669 [MNa+]. IR: 3032, 2915,
1767 cm–1. Anal. Calcd for C38H40F207: C, 70.58; H, 6.19.
Found: C, 70.41; H, 6.31.
(11) The procedure described in ref. 10 was applied to 6a
allowing the isolation of 7a (58%): Rf = 0.50 (25% EtOAc in
cyclohexane). [a]D20 +3.26 (c 1.50, CHCl3). 1H NMR (300
MHz, CDCl3): d = 1.10 (t, 3 H, 3J = 7.2 Hz), 3.42–3.56 (m,
3 H), 3.60 (app t, 1 H, 3Japp = 3.2 Hz), 3.86 (dd, 3J = 10.0 Hz,
3J = 2.8 Hz), 3.92–4.18 (m, 3 H), 4.21–4.59 (m, 9 H), 7.09–
7.26 (m, 20 H). 13C NMR (75.5 MHz, CDCl3): d = 13.9, 62.6,
68.6,72.0, 73.1, 73.3, 73.5, 73.6 (t, 2J = 23.9 Hz), 73.8, 74.8,
75.0, 114.2, 127.8, 127.88, 127.9, 128.0, 128.1, 128.2,
128.4, 128.5, 128.6, 137.6, 138.0, 138.1, 138.2, 163.0 (t,
2J = 31.0 Hz). 19F NMR (282.5 MHz, CDCl3): d = –119.2 (d,
2J = 261.7 Hz), –118.2 (d, 2J = 261.7 Hz). MS (ESI+): m/z =
669 [MNa+]. IR: 3040, 2914, 1765 cm–1. Anal. Calcd for
C38H40F207: C, 70.58; H, 6.19. Found: C, 70.55; H, 6.18.
(12) For information on the stereoselectivity of the hydride
reduction of pyran oxoniums, see: (a) Lewis, M. D.; Cha, J.
K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4976.
(b) Dondoni, A.; Scherrmann, M.-C. J. Org. Chem. 1994, 59,
6404.
(13) The procedure described in ref. 9 was applied to 3b allowing
the isolation of 5b and 6b as an unseparable mixture (32%).
This mixture was subjected to the dehydroxylation
procedure described in ref. 10 to afford b-1b (23%) and 7b
(35%).
Compound b-1b: Rf = 0.43 (25% EtOAc in cyclohexane).
[a]D20 +29.09 (c 1.10, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 1.06 (t, 3 H, 3J = 7.2 Hz), 3.48–3.55 (m, 3 H), 3.59 (dd,
1 H, 3J = 9.2 Hz, 3J = 2.8 Hz), 3.80–4.02 (m, 4 H), 4.09 (tapp
1 H, 3J = 9.8 Hz), 4.28–4.40 (m, 2 H), 4.50–4.69 (m, 4 H),
4.83–4.89 (m, 2 H), 7.15–7.28 (m, 20 H). 13C NMR (75.5
MHz, CDCl3): d = 13.7, 62.7, 68.5, 72.3, 73.1, 73.5, 73.6,
74.5, 74.8, 77.5 (t, 2J = 23.2 Hz), 77.7, 84.3, 113.5 (t,
,
1J = 255.9 Hz), 127.6, 127.75, 127.8, 127.85, 127.9, 128.15,
128.2, 128.35, 128.4, 128.5, 137.8, 137.9, 138.0, 138.5,
162.7 (t, 2J = 31.1 Hz). 19F NMR (282.5 MHz, CDCl3): d =
–118.3 (dd, 2J = 259.0 Hz, 3J = 9.7 Hz), –116.7 (dd,
2J = 259.0 Hz, 3J = 12.9 Hz). MS (ESI+): m/z = 669 [MNa+].
IR: 3034, 2920, 1768 cm–1. Anal. Calcd for C38H40F207: C,
70.58; H, 6.19. Found: C, 70.69; H, 6.17.
Compound 7b: Rf = 0.50 (25% EtOAc in cyclohexane).
[a]D20 –2.65 (c 2.00, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 1.18 (t, 3 H, 3J = 7.2 Hz), 3.69–3.72 (m, 1 H), 3.74–3.77
(m, 1 H), 3.79–3.84 (m, 2 H), 3.94 (dd, 1 H, 3J = 10.0 Hz,
3J = 2.6 Hz), 4.02 (app dt, 1 H, 3J = 10.0 Hz, 3J = 2.6 Hz),
4.09–4.20 (m, 2 H), 4.27–4.74 (m, 9 H), 7.15–7.39 (m, 20 H,
Har). 13C NMR (75.5 MHz, CDCl3): d = 13.7, 62.7, 69.0,
71.7, 71.8, 72.0, 72.7, 72.9, 73.2 (d, 3J = 2.9 Hz), 73.4, 74.2
(t, 2J = 28.2 Hz), 76.3, 113.3 (dd, 1J = 257.0 Hz, 1J = 251.8
Hz), 127.75, 127.8, 127.85, 127.9, 128.0, 128.1, 128.3,
128.4, 137.5, 137.85, 137.9, 138.6, 163.0 (dd, 2J = 33.3 Hz,
2J = 30.5 Hz). 19F NMR (282.5 MHz, CDCl3): d = –117.9
(dd, 2J = 267.6 Hz, 3J = 14.0 Hz), –111.9 (dd, 2J = 267.6 Hz,
3J = 7.5 Hz). MS (ESI+): m/z = 669 [MNa+], 685 [MK+]. IR:
3032, 2915, 1768 cm–1. Anal. Calcd for C38H40F207: C,
70.58; H, 6.19. Found: C, 70.45; H, 6.13.
cyclohexane).
(10) To a solution of 5a (1.278 g, 1.92 mmol, 1 equiv) and Et3SiH
(6.2 mL, 38.5 mmol, 20 equiv) in CH2Cl2 (6 mL) was added
dropwise TMSOTf (1.05 mL, 5.7 mmol, 3 equiv). The
mixture was stirred at r.t. for 24 h and then neutralized with
sat. NaHCO3 (25 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 10 mL) and the collected organics were washed
with brine (10 mL), dried over MgSO4 and evaporated under
reduced pressure. Purification by column chromatography
(4% to 6% EtOAc in cyclohexane) afforded b-1a (54%) as a
20
colorless oil. Rf = 0.45 (25% EtOAc in cyclohexane). [a]D
–21.1 (c 0.84, CHCl3). 1H NMR (300 MHz, CDCl3): d = 1.08
(t, 3 H, 3J = 7.2 Hz), 3.46–3.50 (m, 1 H), 3.62 (dd, 1 H,
3J = 9.3 Hz, 3J = 2.4 Hz), 3.75–3.82 (m, 3 H), 3.92–4.03 (m,
2 H), 4.08 (tapp, 1 H, 3J = 9.6 Hz), 4.17 (br s, 1 H), 4.49–4.97
(m, 8 H), 7.19–7.23 (m, 20 H). 13C NMR (75.5 MHz,
CDCl3): d = 13.8, 62.9, 68.9, 72.0 (d, 3J = 2.9 Hz), 72.4,
73.5, 74.2, 74.6, 75.4, 77.6 (t, 2J = 28.7 Hz), 81.1, 84.0,
112.7 (dd, 1J = 256.4 Hz, 1J = 252.4 Hz), 127.4, 127.5,
127.6, 127.8, 127.9, 128.0, 128.1, 128.2, 128.3, 128.4,
(14) (a) Wong, C.-H.; Moris-Varas, F.; Hung, S.-C.; Marron, T.
G.; Lin, C.-C.; Gong, K. W.; Weitz-Schmidt, G. J. Am.
Chem. Soc. 1997, 119, 8152. (b) Kaila, N.; Thomas, B. E.;
Thakker, P.; Alvarez, J.; Camphausen, R. T.; Crommie, D.
Bioorg. Med. Chem. Lett. 2001, 11, 151.
Synlett 2007, No. 1, 123–126 © Thieme Stuttgart · New York

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