give acceptable yields of the required product. A more
satisfactory approach proved to be resolution of the racemic
acid.
Racemic trichloromethylbutanoic acid has been prepared
previously via radical addition of bromotrichloromethane to
crotonic acid followed by treatment of the resultant a-bromo
acid with zinc.17 The acid may then be resolved by separation of
the corresponding (2)-(R)-a-phenylglycinol derivatives by
HPLC giving 4 with 81% ee. However, there is some confusion
in the literature with the sign of the optical rotation for (S)- and
(R)-trichloromethylbutanoic acid.18 Thus, in order to remove
any possible ambiguity, the cinchonidine salt of 4 was prepared
and repeated crystallisation of the salt from methanol and
chloromethylbutanyl unit have been isolated from L. ma-
juscula.22 Unlike barbamide which is biosynthesised from
-
L
trichloroleucine and a derivative of
apparent that these metabolites are assembled from
chloroleucine and an -alanine derivative (as determined by
L
-phenylalanine,8 it is
-tri-
L
1
water16 gave a single diastereomer as determined by H- and
L
13C-NMR spectroscopy. X-Ray crystallography revealed the
(R)-configuration for C-3 of the trichloromethylbutanoic acid
portion of the salt 13. Treatment of the salt with potassium
hydroxide followed by 2 M HCl gave, after work up, (R) (+)-4
with [a]D +25 (c 1.8 in EtOH).
degradation studies). The 2S,5S,7S configurations of 18, 19 and
20 were assigned by chiral HPLC and comparison of their
optical rotations (which were all negative) to other poly-
chlorinated natural products.22 The synthetic studies described
herein confirm that barbamide 1 isolated from extracts of L.
majuscula, encompasses the (3S)-trichloromethylbutanyl unit
which is in accord with the assignment of the configuration of
the 2S and 7S stereocentres in these new structurally related
metabolites 18, 19 and 20 which have been isolated more
recently from L. majuscula.
We are very grateful to Dr Clive Smith, GlaxoSmithKline for
his kind assistance in the preparation of (S)-3-trichlorome-
thylbutanoic acid and Dr Lee Hall for the X-ray analysis. The
University of Bristol is thanked for a Scholarship (to
V.-A. N.).
For the synthesis of 4, the (4R,5S)-4-methyl-5-phenyl-
2-oxazolidinone19 derivative of racemic trichloromethylbuta-
noic acid was prepared and the diastereomers were separated by
column chromatography on silica. Following hydrolytic cleav-
age with lithium hydroxide–hydrogen peroxide the required (S)-
4 ([a]D 228.9, c 0.96 in EtOH; lit.15 228.09, c 2.12 in EtOH)
was isolated as well as recovered auxiliary, both in quantitative
yield. From the retrosynthetic analysis shown in Scheme 1, the
next stage of the synthesis of barbamide required a two carbon
homologation of (S)-trichloromethylbutanoic acid 4 to give a b-
keto acid derivative 3 with a suitable leaving group for reaction
with (S)-N-methyldolaphenine 2. Several approaches were
investigated to achieve these final steps and the most direct
route proved to be conversion of acid 4 to the corresponding
acid chloride 14 with thionyl chloride followed by coupling 14
with Meldrum’s acid to give the intermediate 15 (Scheme 3).20
Treatment of 15 with 2 gave 16 with the framework of
barbamide in 51% yield over the three steps from 4. Finally, the
(E)-enol ether was formed by reaction of b-keto amide 16 with
sodium hydride and dimethyl sulfate in the presence of HMPA.
A 1+1 mixture of two products was formed in this final stage of
the synthesis due to epimerisation at C-7 under the basic
reaction conditions. These compounds were readily separated
by HPLC21 giving the less polar product barbamide 1 and
7-epibarbamide 17, [a]D +73.4 (c 1.13 in CH3OH). The 1H- and
13C-NMR and mass spectra of the synthetic material 1 were
found to be identical with those of the natural product.7 The
optical rotation of synthetic barbamide was [a]D 281.9 (c 0.95
in CH3OH) whilst that of an authentic sample of the natural
product gave [a]D 282 (c 1.2 in CH3OH).
Notes and references
† Units of [a]D are 1021 deg cm2 g21 throughout.
1 M. D. Unson, C. B. Rose, D. J. Faulkner, L. S. Brinen, J. R. Steiner and
J. Clardy, J. Org. Chem., 1993, 58, 6336.
2 X. Fu, L.-M. Zeng, J.-Y. Su and M. Pais, J. Nat. Prod., 1997, 60, 695;
X. Fu, M. L. G. Ferreira, F. J. Schmitz and M. Kelly-Borges, J. Nat.
Prod., 1998, 61, 12 276.
3 W. Hofheinz and W. E. Oberhansli, Helv. Chim. Acta, 1977, 60, 660.
4 R. Kazlauskas, R. O. Lidgard, R. J. Wells and W. Vetter, Tetrahedron
Lett., 1977, 18, 3183.
5 J. B. MacMillan and T. F. Molinski, J. Nat. Prod., 2000, 63, 155.
6 W. D. Clarke and P. Crews, Tetrahedron Lett., 1995, 36, 1185.
7 J. Orjala and W. H. Gerwick, J. Nat. Prod., 1996, 59, 427.
8 N. Sitachitta, J. Rossi, M. A. Roberts, W. H. Gerwick, M. D. Fletcher
and C. L. Willis, J. Am. Chem. Soc., 1998, 120, 7131; N. Sitachitta, B. L.
Marquez, R. T. Williamson, J. Rossi, M. A. Roberts, W. H. Gerwick,
V.-A. Nguyen and C. L. Willis, Tetrahedron, 2000, 56, 9103.
9 A. Butler and J. V. Walker, Chem. Rev., 1993, 1937.
10 R. Pellegata, A. Italia, M. Villa, G. Palmisano and G. Lesma, Synthesis,
1985, 13, 517.
Recently three further metabolites (pseudodysidenin 18,
dysidenamide 19 and nordysidenin 20) containing the 3-tri-
11 C. J. Moody and M. C. Bagley, J. Chem. Soc., Perkin Trans. 1, 1998,
601.
12 W. P. McCann, L. M. Hall and W. K. Nonidez, Anal. Chem., 1983, 55,
1454.
13 M. W. Bredenkamp, C. W. Holzapfel, R. M. Snyman and W. J. van Zyl,
Synth. Comm., 1992, 22, 3029.
14 N. Irako, Y. Hamada and T. Shioiri, Tetrahedron, 1992, 48, 7251.
15 G. Helmchen and G. Wegner, Tetrahedron Lett., 1985, 26, 6047.
16 S. E. Brantley and T. F. Molinski, Org. Lett., 1999, 1, 2165.
17 (a) R. L. Huang, J. Chem. Soc., 1956, 1749; (b) S. E. de Laszlo and P. G.
Williard, J. Am. Chem. Soc., 1985, 107, 199.
18 For example, Helmchen and Wegner refer to (+)-(S)-3-trichloro-
methylbutyric acid in the discussion section of their paper but quote
[a]D 231.1 (c 1.1, CHCl3).15 Similarly, Williard and de Laszlo quote
(R)-(2)-3-methyl-4,4,4-trichloromethylbutanoic acid in the abstract but
[a]D +25.15 (c 1.36, CHCl3) in the experimental section.17b
19 D. A. Evans, J. Bartroli and T. L. Shih, J. Am. Chem. Soc., 1981, 103,
2127.
20 Racemic 15 has been prepared previously: P. G. Williard and S. E. de
Laszlo, J. Org. Chem., 1984, 49, 3489.
21 HPLC was performed on a Gilson Sphereclone 5m silica column using
Gilson 321 pumps with gradient control eluting with ethyl acetate–
petroleum ether 5–30%; UV detection was at 254 nm.
22 J. I. Jimenez and P. J. Scheuer, J. Nat. Prod., 2001, 64, 2000.
Scheme 3
Chem. Commun., 2001, 1934–1935
1935