of the rhodium catalyst 8 [SbF6]- under 40 psi of hydrogen
pressure gave the (S)-2-(2-nitro-4-methoxyphenyl)alanine
derivative 10a in 98% yield and ∼98% ee.11 The enantio-
selectivity of this product can be enhanced, if desired,
by further recrystallization. Reduction of the ester with
LiHB(Et)3 (Super hydride), conversion of the resulting
primary alcohol (11a) to the mesylate (11b),15 and its
subsequent hydrogenation using 10% palladium on carbon
in THF gave the unstable 3-acetamido-1,2,3,4-tetrahydro-
quinoline (12a). This compound was protected as its tosyl-
amide by treatment with TsCl in the presence of Et3N.16 The
catalytic hydrogenation of intermediate nitro-mesylate 11b
is a capricious reaction, leading to, for example, the
corresponding N-ethoxy compound 12c when the reaction
was carried out in ethanol.
4 Å molecular sieve, 24 h) gave consistently poor results.18
When the reaction was performed at -20 °C, with 5 to 20
mol % of catalyst, a nearly constant ratio of product to
starting material was observed at 6, 12, and 24 h. Prompted
by reports19 that 3-aryl-2,3-epoxypropanols were prone to
facile ring opening mediated by Ti(IV), we concluded that
lower temperatures and higher catalyst loadings would be
needed for this substrate. In the event, the asymmetric
epoxidation reaction was carried out at -30 °C using ∼10
mol % of the catalyst for 6 days to obtain the desired
epoxyalcohol 16 in >90% ee and an isolated yield of 60%.
The enantiomeric excess was determined by 19F NMR of
the Mosher ester of the epoxyalcohol. To confirm this high
selectivity, authentic samples of the racemic epoxyalcohols
and the corresponding diastereomeric Mosher esters were
prepared via m-CPBA epoxidation of the allylic alcohol 15.
Attempts to separate the diastereomeric esters by chiral GC
and HPLC have not been successful.
Catalytic hydrogenation of 7 using the catalyst Rh+(9)-
-
(COD) SbF6 gave the opposite enantiomer (R) of the
2-nitrophenylalanine derivative in >96% ee and 99% yield,
thus providing access to both enantiomers of the heterocyclic
system in excellent yields and selectivity.
The epoxyalcohol 16 was readily converted into the
corresponding tosylate 17 at low temperature in 80% yield.
Two well-precedented reactions, viz., the regioselective
benzylic C-O cleavage of 1-phenyl-1,2-epoxy-3-tosyloxy-
propane20 and the reductive cyclization of a (2-nitrophenyl)-
propoan-1-yl methanesulfonate,21 prompted us to explore the
tandem reduction-cyclization strategy for the conversion of
the epoxytosylate to the final tetrahydroquinoline 19.21c
However, catalytic hydrogenation under a variety of condi-
tions, using Pd and Pt, led to none of the expected products.
Regioselective opening of the allylic alcohols using DIBAL22
or LiBH423 in the presence of of Ti(O-i-Pr)4 have also been
reported. Reaction of 16 with LiBH4 gave small amounts of
the desired alcohol, whereas the DIBAL gave mixtures of
products. The regioselective opening of the epoxide in 17
The Asymmetric Epoxidation Route. The iodide 5 was
subjected to Heck reaction using the classical procedure17
published by Heck (Pd(OAc)2, Et3N, acetonitrile, methyl
acrylate, sealed tube at 100 °C, 48 h) to obtain a 94% yield
of the cinnamate 14. In this reaction, no trace of the Z-isomer
was observed in the NMR or GC. Reduction of 14 with 2
equiv of DIBAL at 0 °C gave the expected allylic alcohol
15 in 75% isolated yield (Scheme 2). Initial attempts to carry
Scheme 2 The Asymmetric Epoxidation Route
24
was accomplished by treatment with MgI2 in toluene at
-55 °C. The sensitive iodotosylate was not isolated, nor
purified; it was immediately reduced under mild catalytic
hydrogenation conditions in the presence of PtO2. The
resulting tosylate (18) was reduced with iron and HCl.25
(17) Plevyak, J. E.; Dickerson, J. E.; Heck, R. F. J. Org. Chem. 1979,
44, 4078-4080.
(18) Examples of Sharpless epoxidation of o-substituted cinnamyl alcohol
derivatives are rare; no examples of the especially valuable 2-nitrocinnamyl
alcohols have been reported previously. Yields and selectivities for these
reactions are generally low. See for example: (a) Medina, E.; Vidal-Ferran,
A.; Moyano, A.; Perica´s, M. A.; Riera, A. Tetrahedron: Asymmetry 1997,
8, 1581-1586. (b) Takahashi, K.; Ogata, M. J. Org. Chem. 1987, 52, 1877-
1880.
(19) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(20) Goument, B.; Duhamel, L.; Mauge, R. Tetrahedron 1994, 50, 171-
188.
(21) Wierenga, W. J. Am. Chem. Soc. 1981, 103, 5621-5623. See also:
(b) Fukuda, Y.; Itoh, Y.; Nakatani, K.; Terashima, S. Tetrahedron 1994,
50, 2793-2807. (c) This and the subsequent experiments were conducted
in the racemic series.
(22) Finan, J. M.; Kishi, Y. Tetrahedron Lett. 1982, 23, 2719-2722.
(23) Dai, L.; Lou, B.; Zhang, Y.; Guo, G. Tetrahedron Lett. 1986, 27,
4343-4346.
(24) Bonini, C.; Righi, G.; Sotgiu, G. J. Org. Chem. 1991, 56, 6206-
6209.
out the Sharpless asymmetric epoxidation using the catalytic
protocol (5 mol % of Ti(O-i-Pr)4 and L(+)-diethyl tartrate,
(15) Attempted conversion of 11a to the corresponding tosylate 11c led
mostly to an oxazoline.11
(16) Mesylation leads to a mixture of the mono- and di-N-mesyl
compounds. Also see ref 26. (b) To facilitate further transformations, the
N-Ac group could be exchanged for an N-BOC group (13) by the method
published by Burk et al. Burk, M. J.; Allen, J. G. J. Org. Chem. 1997, 62,
7054-7057.11
(25) (a) Rewcastle, G. W.; Baguley, B. C.; Cain, B. F. J. Med. Chem.
1982, 25, 1231-1235. (b) Verboom, W.; Orlemans, E. O. M.; Berga, H.
J.; Scheltinga, M. W.; Reinhoudt, D. N. Tetrahedron 1986, 42, 5053-5064.
(c) Le Corre, M..; Hercouet, A.; Le Stanc, Y.; Le Baron, H. Tetrahedron
1985, 41, 5313-5320.
Org. Lett., Vol. 3, No. 13, 2001
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