accomplished with PPTS in MeOH, and the alcohol 5 was
oxidized to the acid with PDC (6 equiv) in DMF. Product 6
was purified by extraction with EtOAc and chromatography
on silica gel. Chromium residues were separated from the
product by passing a solution of 6 in MeOH through a short
pad of silica gel and sodium sulfite. Compound 6 was
transformed into dipeptide 8 which resulted, according to
NMR and HPLC analysis, as a single diastereoisomer.
Finally, the Cbz group was removed by microwave-induced
tranfer hydrogenation with HCOONH4 in i-PrOH and in the
presence of Pd/C11 to give enantiomerically pure (S)-cleonin
7.12
Scheme 1
propanol conversion7 applied to (R)-serine would not only
represent a straightforward approach to enantiomerically pure
cleonine but also give the opportunity for the preparation of
related new non-natural substituted cyclopropylglycines.
The desired hydroxycyclopropyl amino acid should be
obtained from a hydroxycyclopropyl oxazolidine, which can
be obtained by Kulinkovich reaction with EtMgBr and the
oxazolidine carboxylate derived from serine.
Scheme 3a
Therefore, we started from (R)-serine as a relatively
inexpensive starting material and decided to employ Cbz
protection for the amino group.8 Thus, methyl serine was
prepared from (R)-serine by reaction with SOCl2 in MeOH.
The so formed hydrochloride was reacted with Cbz-Cl under
basic conditions to give 1 in good overall yield (81%). Finally
the oxazolidine 2 was formed by reacting 1 with 2,2-
dimethoxypropane in acetone and in the presence of BF3‚
OEt2 (95% yield). Kulinkovich cyclopropanation was carried
out with 2.5 equiv of EtMgBr (freshly prepared) in the
presence of 0.5 equiv of Ti(Oi-Pr)4 in Et2O. Compound 2
was completely converted, and cyclopropanol 3 was isolated
in 64% yield after column chromatography on silica gel.
a (a) PPTS, MeOH, 12 h, rt, 83%; (b) PDC, DMF, 12 h, rt, 75%;
(c) HCOONH4, i-PrOH, Pd/C, microwaves, 5 min, 85%; (c) H-Ala-
OMe, DMTMM, DIPEA, THF, rt, 6 h, 86%.
1
The H NMR spectrum of the cyclopropyloxazolidine 3
showed two sets of signals at δ 0.8-0.6 indicating the
formation of the cyclopropyl group. The 1H NMR spectrum
was complicated by the existence of two conformers slowly
interconverting on the NMR time scale.9 The presence of
the OH group was confirmed by the strong IR band at 3330-
3100 cm-1. The 13C NMR spectrum, showing nine clean
singlets below 100 ppm, confirmed the proposed structure.10
Once the procedure to settle the cyclopropyl on the serine
structure and to transform the product into (S)-cleonin was
successfully concluded, we envisaged that the modified
Kulinkovich procedure based on the ligand exchange of the
intermediate titanacyclopropane with a terminal olefin13
would allow a convenient access to substituted cyclopropyl-
glycines.
Scheme 2a
(6) Demarcus, M.; Ganadu, M. L.; Mura, G. M.; Porcheddu, A.; Quaranta,
L.; Reginato, G.; Taddei, M. J. Org. Chem. 2001, 66, 697. Ciapetti, P.;
Mann, A.; Shoenfelder, A.; Taddei, M. Tetrahedron Lett. 1998, 39, 3843.
D’Aniello, F.; Mann, A.; Shoenfelder, A.; Taddei, M. Tetrahedron 1997,
53, 1447 and references therein.
(7) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pritytskaya,
T. S. Zh. Org. Khim. 1989, 25, 2244. Epstein, O. L.; Savchenko, A. I.;
Kulinkovich, O. G. Tetrahedron Lett. 1999, 40, 5935. Kulinkovich, O. G.;
de Meijere, A. Chem. ReV. 2000, 100, 2789.
(8) Extensive investigations of de Meijere and co-workers. showed that
cyclopropylcarbinols are more stable to hydrogenolysis conditions (Pd/C)
than to acidic mediums; see: de Meijere, A.; Ernst, K.; Zuck, B.; Brandl,
M.; Kozhushkov, S. I.; Tamm, M.; Yufit, D. S.; Howard, J. A. K.; Labahn,
T. Eur. J. Org. Chem. 1999, 3105, 5.
(9) Garner, P. Tetrahedron Lett. 1984, 25, 5855. Garner, P.; Park, J. M.
J. Org. Chem. 1987, 52, 2361. Garner, P.; Park, J. M. J. Org. Chem. 1988,
53, 2979.
a (a) MeOH, SOCl2, rt, 6 h, followed by Cbz-Cl, NaHCO3, H2O,
rt, 3 h, 81%; (b) 2,2′-dimethoxypropane, BF3OEt2, 95%; (c)
EtMgCl, Ti(Oi-Pr)4, Et2O, 12 h, rt, 64%.
(10) The enantiomeric integrity of compound 3 was confirmed by the
19F NMR spectrum of the (S)-MTPA 4 ester, which showed a single signal
at δ 7.02 (ext TFA).
(11) Daga, M. C.; Taddei, M.; Varchi, G. Tetrahedron Lett. 2001, 42,
5191.
Having successfully synthesized the cyclopropyl-isoxazo-
line 3, the next step was to selectively deprotect the OH and
carry out the oxidation. Oxazolidine ring opening was
(12) The enantiomeric integrity of cleonin was established by the 19F
NMR spectrum of the (S)-MTPA amide, which showed a single signal at
δ 9.74 (ext TFA).
3274
Org. Lett., Vol. 3, No. 21, 2001