LETTER
A Direct Catalytic Aldol Route to Protected -Hydroxy- -amino Acids
1627
recrystallisation from dichloromethane/petroleum spirit 40–
60 °C.
(12) Small amounts of a by-product originating from the addition
of a second equivalent of ester 1 to the initially formed aldol
adduct could be isolated in several experiments when
conducted at r.t.
Acknowledgement
We thank the EPSRC, AstraZeneca (strategic research fund) and
Pfizer for funding. The EPSRC Mass Spectrometry Service at the
University of Wales Swansea is also thanked for their assistance.
(13) All new compounds were fully characterised. Selected data
for novel compounds:
References
(4R*,5R*)-Ethyl 5-(4-nitrophenyl)-2-thioxo-oxazolidine-
4-carboxylate. 1H NMR (400 MHz, CDCl3): = 8.28–8.24
(2 H, m), 7.71 (1 H, s), 7.57–7.54 (2 H, m), 6.19 (1 H, d, J =
9.8 Hz), 5.00 (1 H, d, J = 9.8 Hz), 3.87 (1 H, app. dq, J = 10.8
and 7.2 Hz), 3.72 (1 H, app. dq, J = 10.8 and 7.2 Hz), 0.89 (3
(1) (a) Vancomycin: Glycopeptide Antiobiotics; Nagarajan, R.,
Ed.; Marcel Dekker: New York, 1994. (b) Cyclosporine A:
Wenger, R. M. Prog. Chem. Org. Nat. Prod. 1986, 50, 123.
(c) Polyoxins : Isono, K.; Suzuki, S. Heterocycles 1979, 13,
333. (d) Cyclomarins: Renner, M. K.; Shen, Y.-C.; Cheng,
X.-C.; Jensen, P. R.; Frankmoelle, W.; Kauffman, C. A.;
Fenical, W. E.; Lobkovsky, E.; Clardy, J. J. Am. Chem. Soc.
1999, 121, 11273.
H, app. t, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3):
=
189.5, 166.6, 148.8, 140.2, 128.1, 124.0, 83.9, 62.9, 62.8,
14.1.
(4R*,5R*)-Ethyl 5-(4-cyanophenyl)-2-thioxo-oxazoli-
dine-4-carboxylate. 1H NMR (400 MHz, CDCl3): = 7.72–
7.46 (4 H, m), 7.36 (1 H, s), 6.12 (1 H, d, J = 9.8 Hz), 4.94
(1 H, d, J = 9.8 Hz), 3.85 (1 H, app. dq, J = 10.7 and 7.2 Hz),
3.72 (1 H, app. dq, J = 10.7 and 7.2 Hz), 0.88 (3 H, app. t, J
(2) For selected recent examples, see: (a) MacMillan, J. B.;
Molinski, T. F. Org. Lett. 2002, 4, 1883. (b) Loncaric, C.;
Wulff, W. D. Org. Lett. 2001, 3, 3675. (c) DeMong, D. E.;
Williams, R. M. Tetrahedron Lett. 2001, 42, 183. (d) Kim,
I. H.; Kirk, K. L. Tetrahedron Lett. 2001, 42, 8401.
(3) For example: (a) Horikawa, M.; Busch-Petersen, J.; Corey,
E. J. Tetrahedron Lett. 1999, 40, 3843. (b) Kobayashi, S.;
Ishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998, 120, 431.
(4) For the use of isocyanoacetates in direct catalytic aldol
additions, see: Ito, Y.; Sawamura, M.; Hayashi, T. J. Am.
Chem. Soc. 1986, 108, 6405.
(5) (a) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108,
6757. (b) Volkmann, R. A.; Davis, J. T.; Meltz, C. N. J. Am.
Chem. Soc. 1983, 105, 5946. (c) Hoppe, D.; Follmann, R.
Chem. Ber. 1976, 109, 3047.
(6) For examples, see: (a) Ji, J.; Barnes, D. M.; Zhang, J.; King,
S. A.; Wittenberger, S. J.; Morton, H. E. J. Am. Chem. Soc.
1999, 121, 10215. (b) Frantz, D. E.; Fassler, R.; Carreira, E.
M. J. Am. Chem. Soc. 1999, 121, 11245; ref. 5a.
= 7.2 Hz). 13C NMR (100 MHz, CDCl3–CD3OD, 66:33):
=
189.6, 167.0, 138.9, 132.2, 127.5, 118.0, 113.1, 83.7, 63.0,
62.1, 13.6.
(4S*,5R*)-Ethyl 5-(4-cyanophenyl)-2-thioxo-oxazoli-
dine-4-carboxylate. 1H NMR (400 MHz, CDCl3): = 8.09
(1 H, s), 7.75–7.54 (4 H, m), 6.03 (1 H, d, J = 6.2 Hz), 4.44
(1 H, d, J = 6.2 Hz), 4.41–4.29 (2 H, m), 1.37 (3 H, app. t,
J = 7.2 Hz). 13C NMR (100 MHz, CDCl3): = 188.2, 167.2,
141.6, 132.8, 126.1, 117.9, 113.4, 84.0, 64.4, 63.4, 14.2.
(4R*,5R*)-Ethyl 5-(4-bromophenyl)-2-thioxo-oxazoli-
dine-4-carboxylate. 1H NMR (400 MHz, CDCl3): = 7.58
(1 H, s), 7.53–7.50 (2 H, m), 7.23–7.18 (2 H, m), 6.04 (1 H,
d, J = 9.8 Hz), 4.90 (1 H, d, J = 9.8 Hz), 3.85 (1 H, app. dq,
J = 10.7 and 7.2 Hz), 3.74 (1 H, app. dq, J = 10.7 and 7.2 Hz),
0.89 (3 H, app. t, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3):
= 189.8, 166.9, 132.4, 132.0, 128.6, 124.2, 84.7, 62.9, 62.7,
14.0.
(7) For an example of alcohol additives aiding catalyst turnover,
see: Evans, D. A.; Scheidt, K. A.; Johnston, J. N.; Willis, M.
C. J. Am. Chem. Soc. 2001, 123, 4480.
(4S*,5R*)-Ethyl 5-(4-bromophenyl)-2-thioxo-oxazoli-
dine-4-carboxylate. 1H NMR (400 MHz, CDCl3): = 7.95
(1 H, s), 7.58–7.55 (2 H, m), 7.31–7.26 (2 H, m), 5.93 (1 H,
d, J = 6.2 Hz), 4.43 (1 H, d, J = 6.2 Hz), 4.39–4.27 (2 H, m),
1.35 (3 H, app. t, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3):
= 188.4, 167.5, 135.6, 132.2, 127.2, 123.6, 84.8, 64.5, 63.2,
14.2.
(4R*,5R*)-Ethyl 5-(3-bromophenyl)-2-thioxo-oxazoli-
dine-4-carboxylate. 1H NMR (400 MHz, CDCl3): = 7.54–
7.47 (3 H, m), 7.29–7.27 (2 H, m), 6.04 (1 H, d, J = 9.8 Hz),
4.91 (1 H, d, J = 9.8 Hz), 3.86 (1 H, app. dq, J = 10.8 and 7.2
Hz), 3.76 (1 H, app. dq, J = 10.8 and 7.2 Hz), 0.90 (3 H, app.
t, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3): = 189.8,
166.8, 135.5, 133.0, 130.5, 130.0, 125.5, 122.8, 84.4, 62.9,
62.8, 14.0.
(4S*,5R*)-Ethyl 5-(3-bromophenyl)-2-thioxo-oxazoli-
dine-4-carboxylate. 1H NMR (400 MHz, CDCl3): = 7.78
(1 H, s), 7.57–7.53 (2 H, m), 7.37–7.29 (2 H, m), 5.94 (1 H,
d, J = 6.2 Hz), 4.45 (1 H, d, J = 6.2 Hz), 4.41–4.28 (2 H, m),
1.36 (3 H, app. t, J = 7.0 Hz). 13C NMR (100 MHz, CDCl3):
= 188.7, 167.7, 139.1, 132.9, 131.0, 128.8, 124.4, 123.4,
84.8, 64.8, 63.6, 14.6.
(4R*,5R*)-Ethyl 5-(2-bromophenyl)-2-thioxo-oxazoli-
dine-4-carboxylate. 1H NMR (400 MHz, CDCl3): = 7.58–
7.23 (5 H, m), 6.41 (1 H, d, J = 9.0 Hz), 5.00 (1 H, d,
J = 9.0 Hz), 3.80 (1 H, app. dq, J = 10.7 and 7.2 Hz), 3.66
(1 H, app. dq, J = 10.7and 7.2 Hz), 0.82 (3 H, app. t, J = 7.2
Hz). 13C NMR (100 MHz, CDCl3): = 189.8, 166.9, 132.6,
132.3, 130.7, 127.8, 127.7, 122.1, 84.5, 62.2, 61.2, 13.6.
(8) For impressive recent examples of TMSCl being employed
as an additive in diastereoselective MgCl2 catalysed aldol
reactions, see: (a) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.;
Downey, C. W. J. Am. Chem. Soc. 2002, 124, 392.
(b) Evans, D. A.; Downey, C. W.; Shaw, J. T.; Tedrow, J. S.
Org. Lett. 2002, 4, 1127.
(9) A reaction using only Et3N (no metal salt or bipyridine)
provided an 8% yield of the aldol adducts after 48 h at r.t.
Reactions excluding Et3N provided no product.
(10) For a recent example of Lewis acid catalysed reaction in
which the addition of an external ligand was needed to
achieve reaction, see ref.6a
(11) The Preparation of 3 Serves as a Typical Procedure:
Mg(ClO4)2 (31 mg, 0.138 mmol) and bipyridine (22 mg,
0.138 mmol) were stirred for 10 min in dry THF (5.5 mL)
under nitrogen at r.t. Triethylamine (39 L, 0.276 mmol)
was then added and the mixture was cooled at 0 °C. After 10
min ethyl isothiocyanatoacetate (170 L, 1.38 mmol) and
benzaldehyde (150 L, 1.52 mmol) were added. After 20 h
at 0 °C, the reaction was quenched with a sat. aq ammonium
chloride solution (5 mL). The organic layer was separated
and the aq layer was extracted with dichloromethane (3 10
mL). The organic portions were washed with a sat. aq copper
sulphate solution (5 mL) and with brine (5 mL), dried
(MgSO4) and concentrated under reduced pressure. The
residue was purified by flash chromatography (SiO2,
EtOAc–DCM, 2:98) to give a mixture of the syn- and anti-
oxazolidinethiones, 3 (290 mg, 84%, syn:anti = 65:35), as a
viscous oil. Analytical samples were prepared by
Synlett 2002, No. 10, 1625–1628 ISSN 0936-5214 © Thieme Stuttgart · New York