A short highly stereoselective synthesis of the fluorinated natural product (2S,3S )-4-fluorothreonine

Article abstract of DOI:10.1039/a703121a

A three step stereoselective route to the fluorinated natural product (2S,3S)-4-fluorothreonine is described; the route is amenable to the preparation of (2S,3S)-4-fluoro[3-²H]threonine and (2S,3R)-[4,4,4-²H₃]threonine.

Full text of DOI:10.1039/a703121a

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A short highly stereoselective synthesis of the fluorinated natural product
(2S,3S)-4-fluorothreonine
Muhammad R. Amin,a David B. Harper,b Janet M. Moloney,a Cormac D. Murphy,b Judith A. K. Howarda and
David O’Hagan*a
a Department of Chemistry, University of Durham, Science Laboratories, South Road, Durham, UK DH1 3LE
b Department of Food Science, The Queen’s University of Belfast, Newforge Lane, Belfast, UK BT9 5PX
A three step stereoselective route to the fluorinated natural
product (2S,3S)-4-fluorothreonine is described; the route is
amenable to the preparation of (2S,3S)-4-fluoro[3-2H]threo-
nine and (2S,3R)-[4,4,4-2H3]threonine.
system is non-planar. This is an important feature as C-5 is
rendered configurationally stable, a situation that is revealed
again in the X-ray structure of the analogous defluorohydro
compound 4,‡ an intermediate in our synthesis of (2S,3R)-
threonine (Fig. 1). It was not clear at the outset if the subsequent
reduction of the b-carbonyls of 3 and 4 would be stereoselective
and deliver the desired threo products, however in the event this
proved to be the case. Treatment of 3 and 4 with NaBH4 in
MeOH generated the benzoate esters 5§ and 6 respectively as
single diastereoisomers. The benzoates 5 and 6 and not the
N-benzoyl derivatives were the sole products, indicating a facile
transacylation after carbonyl reduction. This transacylation is
consistent with Seebach’s observations7b after the direct
condensation of 2 with acetaldehyde. The allo-diastereoisomers
were not detectable by 13C, 1H and 19F (for 5 only) NMR
spectroscopy of the crude reaction products, indicating that the
reduction is highly stereoselective with hydride delivered
exclusively to the si face of 3 (re face of 4 due to a change in
assignment priorities). If the transition state conformation of 3
bears a resemblence to the ground state structure as shown in
Fig. 1 then the si face of the carbonyl is the more exposed of the
two as the N-benzoyl aromatic ring hinders access to the re
face.
4-Fluorothreonine 1 is a secondary metabolite of Streptomyces
cattleya and is one of the few natural products that contain
fluorine. The compound was first isolated1 in 1986 in the course
of studies aimed at improving thienamycin production by the
organism. It was reported to be a single stereoisomer but the
relative or absolute stereochemistry was not established at that
time. Two syntheses of (2S,3S)-4-fluorothreonine 1 have been
reported,2 one prior3 to its isolation from S. cattleya, and in each
case the optical rotation values were close to that of the natural
amino acid 1 ([a]D 220) implying a 2S,3S absolute configura-
tion. In our current programme4–6 focused on evaluating the
biosynthetic origin of fluoroacetate and 4-fluorothreonine in S.
cattleya it proved necessary to confirm the absolute ster-
eochemistry of 1. As the two published syntheses are lengthy we
have developed a new and more direct approach to (2S,3S)-
4-fluorothreonine 1 which exploits Seebach’s imidazolidinone
methodology for the synthesis of a-amino-b-hydroxy acids.7
This appeared attractive at the outset as a straightforward
condensation between 2 and fluoroacetaldehyde should deliver
the required framework. However, fluoroacetaldehyde is not
readily prepared and despite several attempts we were not able
to devise a suitable synthesis. The literature preparations8 for
fluoroacetaldehyde generated aqueous solutions which are
inadequate for the current purpose.
The benzoates 5 and 6 were subjected to hydrolysis (10 m
HCl at 100 °C) and the resultant (2S,3S)-4-fluorothreonine 1¶
and (2S,3R)-threonine 7 [identical in all respects to natural
(2S,3R)-threonine] were recovered after purification on Dowex
H+. The threo relative stereochemistry of 1 was confirmed by an
The route was therefore modified as shown in Scheme 1 such
that 2 was treated with fluoroacetyl chloride9 (WARNING:
highly toxic) to generate the resultant b-ketone 3,† a crystalline
solid. From the X-ray structure of 3 it is noteworthy that the
geometry at C-5 is fully tetrahedral and that the b-carbonyl
(a)
O(1)
F
C(5)
N(3)
O(2)
N(1)
Me
N
Me
N
But
O
But
O
i
5
N
Bz
N
Bz
O
2
O(3)
R
(b)
3 R = F
4 R = H
O(1)
ii
C(5)
Me
N
OH
But
O
O(2)
N(3)
–
CO2
iii
H
N
Bz
N(1)
OBz
+
R
NH3
R
1 R = F
7 R = H
5 R = F
6 R = H
O(3)
Scheme 1 Reagents and conditions: i, LDA, FCH2COCl (acetyl chloride for
4), THF, 2100 °C, 57%; ii, NaBH4, MeOH, 20 °C, 5 min, 67%; iii, 10 m
HCl, 100 °C, 72 h, 64%
Fig. 1 X-Ray structures of 3 (a) and 4 (b). The geometry at C-5 of the
b-ketone is tetrahedral in each case.
Chem. Commun., 1997
1471

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(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
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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.
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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