standard conditions, affording the trisubstituted alkene 24
alongside trace amounts of the expected disubstituted alkene.
Following hydrogenation, the double reductive cleavage of
25 was investigated. It was found that when a large excess
of lithium (17 equiv) was used, cleavage of the benzylic bond
was observed, in addition to the desired double reductive
cleavage. Following N-tosylation, compound 26 was isolated
in 72% yield.
Scheme 5. Preparation of the Enantioenriched Double
Reduction Precursors syn-42 and anti-42
We reasoned that benzylic cleavage had occurred after the
desired double sulfonamide reduction. Therefore, both the
reaction period and the amount of reducing agent were
optimized. It was subsequently found that use of 5 equiv of
lithium completely reduced 25 after 5 min. 2-Phenyl-
pyrrolidine was isolated in 76% yield as its N-toluene-
sulfonamide 27.
Studies with the corresponding piperidinyl system, ac-
cessed from piperidin-2-one 28 via an identical sequence of
reactions, afforded precursor 33, which smoothly underwent
the desired double reduction, generating 2-phenylpiperidine
34 in 70% yield (Scheme 4).
separable by careful SiO2 flash column chromatography.
Nuclear Overhauser (NOE) NMR spectroscopic studies
indicated that the major isomer in this mixture possessed
the anti ring architecture, indicating preferential hydrogena-
tion from the same face as the substituent. Treatment of this
mixture with TBAF in THF afforded a similar diastereo-
isomeric mixture of alcohols 42 (in 31 and 59% yields,
respectively), which proved to be more readily separable by
SiO2 flash column chromatography.
Scheme 4. Synthesis of 2-Phenylpiperidine
Treatment of the major diastereomer anti-42 with Li (6
equiv) in liquid NH3 afforded the pyrrolidine product 43 of
the desired double reduction, which was further converted
to the sulfonamide anti-44 (Scheme 6). Similarly, the minor
Scheme 6. Preparation of syn- and anti-[5R/
S-Phenyl-1-(toluene-4-sulfonyl)pyrrolidin-2S-yl]methanol
The synthetic sequence described was adapted to prepare
the enantioenriched 2-phenylpyrrolidine architecture exhib-
ited by a series of natural and nonnatural aza sugars (Scheme
5).13 The TBDPS group was chosen to protect the enantiopure
primary alcohol 35,14 not only to withstand citric acid-
facilitated dehydration but also to present a bulky group on
one face of 39. On the basis of the previous results we had
obtained, the selective formation of 39 was expected.
However, it was produced alongside appreciable amounts
of 40 (single diastereomer on the basis of 1H NMR
spectroscopy), which proved to be inseparable by SiO2 flash
column chromatography. Somewhat surprisingly, reduction
of this mixture gave a diastereoisomeric mixture (anti:syn
) 3:1) of the saturated pyrrolidines 41, which were now
diastereomer syn-42 was converted into syn-44, whose
spectroscopic data were in accord with that reported previ-
ously for racemic syn-44.15 Additionally, X-ray crystal-
lographic studies16 demonstrated the syn-2,5-disubstituted
ring architecture, thereby corroborating the stereochemical
assignment made on the basis of the NOE studies indicated
in Scheme 5.
(9) For example, see: Bunnett, J. F.; Jenvey, J. J. Org. Chem. 1996, 61,
8069 and references therein.
(10) Harkin, S. A.; Singh, O.; Thomas, E. J. J. Chem. Soc., Perkin Trans.
1 1984, 1489.
(11) Neipp, C. E.; Humphrey, J. M.; Martin, S. F. J. Org. Chem. 2001,
66, 531.
In conclusion, we have described a novel method for the
efficient preparation of aryl-substituted cyclic amines via the
(12) Åhman, J.; Somfai, P. J. Chem. Soc., Perkin Trans. 1 1994, 1079.
(13) For example, see: Severino, E. A.; Costenaro, E. R.; Garcia, A. L.
L.; Correia, C. R. D. Org. Lett. 2003, 5, 305 and references therein.
(14) Cossy, J.; Cases, M.; Pardo, D. G. Tetrahedron 1999, 55, 6153.
(15) Gallagher, T.; Jones, S. W.; Mahon, M. F.; Molloy, K. C. J. Chem.
Soc., Perkin Trans. 1 1991, 2193.
(16) See Supporting Information for details.
Org. Lett., Vol. 7, No. 1, 2005
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