p-TsCl, displacement of the tosylates in neat allylamine,
followed by protection of the secondary amines either with
a t-Boc or with a trifluoroacetate (TFA) group.
The conventional ring-closing reaction conditions12 were
applied using Cl2Ru(dCHPh)(Pcy3)2 catalyst (10 mol %) in
a solvent upon heating, and the results are summarized in
Table 1 below. We noticed that the protecting groups at the
improved reaction results were obtained this time: ethyl
diene (3b) in 88% yield in 21 h and the phenyl diene (3c) in
81% in 24 h. However, slow reaction occurred in the
cyclization of the diene (3d). Higher temperatures and longer
times were needed to convert the diene to the product in
order to get a reasonable yield (60% of the product and 25%
of the recovered starting diene).
With the (3S)-t-Boc-amino 4-substituted 1,2,3,6-tetrahy-
dropyridines (4a-d) synthesized, our next step was to
examine stereocontrolled reduction of the carbon-carbon
double bond under hydrogenation conditions. We anticipated
that the stereochemistry outcome in reduction of the allyl-
amines would be influenced by neighboring group participa-
tion, in which the 3-t-Boc amino group might interact with
the catalyst surface and the hydrogen may be delivered from
the same side of the amino group.15 Therefore, the trans
isomers would be obtained as the predominant products. The
double-bond reduction of 4a was initially carried out under
hydrogenation conditions (5% Pd/C in EtOH at 1 atm of H2
pressure) to afford two isomers, 5a and 6a, which were
separated by flash chromatography (see Table 2). We found
Table 1. Protecting Group Influence on Ring-Closing
Metathesis Reaction
Table 2. Reduction of Carbon-Carbon Double Bond under
Hydrogenation Conditions
a After flash chromatography. b Recovered yield.
secondary amine played a significant role in effecting the
reaction rate of the ring-closing metathesis. In the case of
the methyl diene (3a), the cyclization proceeded smoothly
in refluxing CH2Cl2 in 4 h to give 4-methyl-tetrahydropip-
eridine 4a in 87% yield after purification, whereas under
the same conditions the cyclization of the ethyl diene (3b)
in 45 h resulted in 4-ethyl product 4b in an unacceptable
low yield (23%) and with the starting diene recovered. Even
worse was the cyclization of the phenyl diene (3c), in which
only 5% cyclized product was isolated. In both cases,
unidentified byproducts were observed as major components
when more catalyst was used in an extended reaction time
in refluxing benzene or toluene. However, another commonly
used amino protecting group, trifluoroacetyl (TFA),13 ap-
peared to us to be another alternative for our RCM reaction,
possibly because of less steric effect on cyclization by
altering either the diene precursor conformation or the
product conformation.14 TFA-protected 3b-d were prepared
and subjected to the RCM reaction conditions. Much
a Based on flash chromatography separation. b Combined yield.
that the catalyst loading impacted the diastereomer distribu-
tion in reduction: loading of 0.1 equiv of the catalyst by
weight gave an isomer ratio of 3.5:1 in 24 h, whereas loading
of 0.5 and 1.0 equiv of the catalyst gave diastereomer ratios
of 2:1 in 12 h and 1:1 in 1 hour, respectively. The
stereochemistry of the trans and cis isomers was unambigu-
ously assigned by NOE NMR analysis on the basis of
deprotected piperidines 7a and 8a (Figure 2), indicating that
the major stereoisomer was trans piperidine 7a. In addition,
a large coupling constant (Jtrans ) 11.6 MHz) between C(3)H
(9) Unpublished results.
(10) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361.
(11) (a) Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.;
Zurbano, M. Tetrahedron: Asymmetry 2000, 11, 2195. (b) Koskinen, A.
M. P.; Hassila, H.; Myllymaki, V. T.; Rissanen, K. Synlett 1998, 389.
(12) Rutjes, F. P. J. T.; Schoemaker, H. E. Tetrahedron Lett. 1997, 38,
677.
(13) Phillip, A. J.; Abell, A. D. Aldrichimica Acta 1999, 32, 75 and
references cited therein.
(14) The effect of the TFA protecting group on the ring-closing metathesis
reaction is not completely understood, and one may argue that a possible
electronic effect could play a role in this reaction.
(15) (a) Costa, B. R. D.; Bowen, W. D.; Hellewell, S. B.; George, C.;
Rothman, R. B.; Reid, A. A.; Walker, J. M.; Jacobson, A. E.; Rice, K. C.
J. Med. Chem. 1989, 32, 1996. (b) Costa, B. R. D.; Radesca, L. Heterocycles
1990, 31, 1837. (c) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV.
1993, 93, 1307. (d) Thompson, H. W.; Wong, J. K. J. Org. Chem. 1985,
50, 4270.
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