(Ar), 128.6 (Ar), 127.7 (Ar), 79.9 (C-2A), 70.5 (C-5), 40.3 [C(CH3)3], 32.1
(NMe), 28.7 (C-2A), 26.1 [C(CH3)3]; Found: C, 56.18; H, 7.27; N, 9.21.
O(3)
C
17H22N2O3 requires: C, 56.29; H, 7.28; N, 9.27%.
F(1A)
§ Selected data for 5: (0.32 g, 67%): an oil; [a]D 213 (c 1, CHCl3); nmax
(CDCl3)/cm21 3360m (br), 2958s, 1675s, 1645m; dH(CDCl3) 8.10–7.60 (5
H, m, Ar), 5.62 (1 H, m, HCObz), 4.91 (2 H, dm, J 47, FH2C), 4.31 [1 H,
d, J 2.1, HC(2)], 4.15 [1 H, m, HC(5)], 3.02 (3 H, s, NMe), 1.15 (9 H, s, But;
dC(CDCl3) 172.5 (COPh), 165.4 (CO), 133.2 (Ar), 129.6 (Ar), 129.4 (Ar),
128.3 (Ar), 83.7 (C-2), 81.8 (C-2A, d, J 172.4, CH2F), 72.1 (C-1A, d, J 19.4,
COBz), 58.2 (C-5), 37.2 [C(CH3)3], 31.1 (NMe), 25.3 [C(cH3)3]; dF
(CDCl3) 2233.1 (dt, J 47.4, 25); Found: 323.17628. C17H23N2O3F
requires: 323.17709 (M + H+).
N
F(1B)
O(2)
O(1)
¶ Selected data for 1 (90 mg, 64%): white crystalline solid; mp 182–183 °C
(lit.,1,2 181–182 °C); [a]D 220 (c 5, H2O) [lit.,2 220 (c 0.06, H2O];
nmax(KBr)/cm21 3500s, 3000s, 2800s, 1435m, 1130m; dH (D2O) 4.52 (2 H,
ddd, J 46.5, 10.5, 3.9, CH2F), 4.22 (1 H, dq, J 25, 4.6, HC(3), 3.72 [1 H, d,
J 4.8, HC(2)]; dC(D2O) 175.5 (C-1), 87.8 (d, J 167.5, C-4), 70.8 (d, J 19.1,
C-3), 59.2 (C-2); dF(D2O) 2229.7 (dt, J 47, 25).
Fig. 2 X-Ray structure of synthetic (2S,3S)-4-fluorothreonine 1, showing
two positions for the disordered CH2F group with occupancies of 66(2)%
(solid) and 34(2)% (dashed)
∑ X-Ray diffraction experiments were performed on a Rigaku AFC6S
X-ray structural study∑ (Fig. 2). The 2S,3S assignment for 1
follows from the structure of 3 where the known absolute
stereochemistry of the auxiliary allows a 2S designation to be
made at C-5 and subsequently at the a-position of the amino
acid. All analytical data ([a]D 220, 19F NMR, HPLC, GC–MS
of MSTFA derivative) were identical to a sample of 4-fluoro-
threonine 1 isolated4 from Streptomyces cattleya, confirming
the absolute stereochemistry of the natural product. Addition-
ally this route to (2S,3S)-4-fluorothreonine is amenable to
isotope labelling and (2S,3S)-4-fluoro[3-2H]threonine 1a was
prepared by employing NaB2H4 in the reduction step. This
material is being used to probe the anabolic and catabolic flux
of (2S,3S)-4-fluorothreonine in S. cattleya.
4-circle diffractometer (graphite-monochromated Cu-Ka radiation,
l
= 1.54184 Å, w scan mode) for 1 and on a Siemens SMART 3-circle
diffractometer with a CCD area detector (graphite-monochromated Mo-Ka
radiation, l = 0.71073 Å, w scan mode in 0.3° frames) for 3 and 4. The
structures were solved by direct methods and refined by full-matrix least-
squares (non-H atoms anisotropic, H isotropic) against F2 of all data, using
SHELXTL ver. 5/VMS software (G. M. Sheldrick, Siemens Analytical
X-Ray Instruments Inc., Madison, WI, USA, 1995). Absolute configura-
tions were assigned according to those of the starting materials. CCDC
182/499.
Crystal data for 1: C4H8FNO3, M = 137.1, T = 296 K, orthorhombic,
space group P212121 (No. 19), a = 5.231(1), b = 7.870(2), c = 13.603(3)
Å, U = 560.0(2) Å3, Z = 4, Dx = 1.63 g cm23, m = 13.9 cm21, crystal size
0.15 3 0.15 3 0.05 mm, 730 data total (2q @ 100°), 549 unique, 447
observed with I
data) = 0.059, wR (F2, all data) = 0.163, goodness-of-fit S = 1.02,
Drmin,max = 0.27, 20.22 e Å23
For 3: C17H21FN2O3, M = 320.4, T = 296 K, orthorhombic, space group
> 2s(I), Rint = 0.029, 93 variables, R (F, obs.
OH
OH
D
F
.
–
–
CO2
CO2
D3C
P21212 (No. 18), a
= 13.294(1), b = 21.437(2), c = 6.037(1) Å,
+
+
NH3
1a
NH3
7a
U = 1720.5(3) Å3, Z = 4, Dx = 1.24 g cm23, m = 0.9 cm21, crystal size
0.4 3 0.2 3 0.15 mm, 12388 data total (2q @ 55°), 3916 unique, 2909
observed, Rint = 0.041, 225 variables, R = 0.050, wR = 0.142, S = 1.14,
Drmin,max = 0.19, 20.19 e Å23
For 4: C17H22N2O3, M = 302.4, T = 150 K, orthorhombic, space group
.
The modified methodology offers an alternative route to
threo amino acids and it displays a higher stereoselectivity to
that previously described for (2S,3R)-threonine.7b The method
has the additional advantage of using acid chlorides in place of
aldehydes when the requisite aldehyde is unavailable, as in the
case of fluoroacetaldehyde, or is expensive, as in the case of
P21212 (No. 18), a
= 12.636(1), b = 21.459(2), c = 6.059(1) Å,
U = 1642.9(3) Å3, Z = 4, Dx 1.22 g cm23, m = 0.8 cm21, crystal size 0.4
3 0.2 3 0.1 mm, 9842 data total (2q @ 50°), 2866 unique, 2289 observed,
Rint
= 0.064, 216 variables, R = 0.050, wR = 0.115, S = 1.14,
Drmin,max = 0.15, 20.19 e Å23
.
isotopic labelling. For example,
a sample of racemic
[4,4,4-2H3]threonine 7a was prepared from [2H3]acetyl chlo-
ride, a cheaper and more highly stereoselective route to the
labelled amino acid than that using [2H3]acetaldehyde with
racemic imidazolidinone 2.
References
1 M. Sanada, T. Miyano, S. Iwadare, J. M. Williamson, B. H. Arison,
J. L. Smith, A. W. Douglas, J. M. Liesch and E. Inamine, J. Antibiot.,
1986, 39, 259.
We thank Dr A. S. Batsanov (University of Durham,
Department of Chemistry) for help in the X-ray structural work.
We are also grateful to Drs Roy Bowden, Harry Eccles and
Peter Binks of BNFL for their interest in this work and to BNFL
Company Research Laboratories, Springfields, for financial
support.
2 M. Shimizu, T. Yokota, K. Fujimori and T. Fujisawa, Tetrahedron:
Asymmetry, 1993, 4, 835.
3 C. Scolastico, E. Conca, L. Prati, G. Guanti, L. Banfi, A. Berti, P. Farina
and U. Valcavi, Synthesis, 1985, 850.
4 K. A. Reid, J. T. G. Hamilton, R. D. Bowden, D. O’Hagan, L. Dasaradhi,
M. R. Amin and D. B. Harper, Microbiology, 1995, 141, 1385.
5 J. T. G. Hamilton, M. R. Amin, D. B. Harper and D. O’Hagan, Chem.
Commun., 1997, 797.
6 J. Nieschalk, J. T. G. Hamilton, C. D. Murphy, D. B. Harper and
D. O’Hagan, Chem. Commun., 1997, 799.
Footnotes
* E-mail: david.O’hagan@durham.ac.uk
† Selected data for 3: mp 197 °C; [a]D +140 (c 1, CHCl3); nmax(CDCl3)/
cm21 3360m, 2960s, 1715s, 1695s, 1665m; dH(CDCl3) 7.60–7.35 (5 H, m,
Ar), 5.75 [1 H, s, HC(2)], 5.39 [1 H, s, HC(5)], 4.45 (2 H, m, FCH2), 3.06
(3 H, s, NMe), 1.08 (9 H, s, But); dC(CDCl3) 197.7 (C-1A, d, JCF 18.6), 170.6
(COPh), 165.0 (C-4), 135.8 (Ar), 131.6 (Ar), 128.8 (Ar), 127.6 (Ar), 83.8
(C-2A, d, J 187), 80.4 (C-2), 66.2 (C-5), 40.3 [C(CH3)3], 32.2 (NMe), 26.1
[C(CH3)3]; dF(CDCl3) 2230.8 (t, J 46.3); Found: C, 63.52; H, 6.63; N, 8.63.
C17H21N2O3F requires: C, 63.68; H, 6.55; N, 8.74%.
7 (a) D. Blaser and D. Seebach, Liebigs Ann. Chem., 1991, 1067; (b)
D. Seebach, E. Juaristi, D. D. Miller, C. Schickli and T. Weber, Helv.
Chim. Acta, 1987, 70, 237; (c) D. Seebach, J. D. Aebi, R. Naef and
T. Weber, Helv. Chim. Acta., 1985, 68, 144.
8 G. Teutsch and A. Bonnet, Tetrahedron Lett., 1984, 25, 1561;
B. C. Saunders, G. J. Stacey and I. G. E. Wilding, J. Chem. Soc., 1949,
773.
9 Fluoroacetyl chloride is prepared in a straightforward manner from
fluoroacetic acid and thionyl chloride and can be distilled prior to use:
D. O’Hagan, J. White and D. A. Jones, J. Labelled Cmpd. Radiopharm.,
1994, 34, 871.
25
‡ Selected data for 4: mp 188–189 °C (decomp.); [a]D +120 (c 0.01,
CHCl3); nmax(CDCl3)/cm21 2984s (br), 2940s (br), 2287s (br), 1732s,
1700s, 1397s; dH(CDCl3) 7.60–7.23 (5 H, m, Ar), 5.64 (1 H, s, HC-2), 5.11
[1 H, s, HC(5)], 3.00 (3 H, s, NMe), 1.82 (3 H, s, CH3CO), 0.99 (9 H, s, But);
dC(CDCl3) 199.7 (C-1B), 171.3 (COPh), 165.3 (C-4), 136.3 (Ar), 131.3
Received in Cambridge, UK, 7th May 1997; 7/03121A
1472
Chem. Commun., 1997