418
J . Org. Chem. 1998, 63, 418-419
Sch em e 1
A Dia ster eosp ecific Syn th esis of
2-Meth yl-5â-p h en yl-5r-ca r beth oxy-2-
a za bicyclo[2.2.1]h ep ta n e: A Rin g-Con str a in ed
An a logu e of Mep er id in e
Stephen M. Husbands, Richard H. Kline,
Andrew C. Allen,† and Amy Hauck Newman*
Psychobiology Section, National Institute on Drug
Abuse-Intramural Research Program, National Institutes of
Health, 5500 Nathan Shock Drive, Baltimore, Maryland 21224
Received September 29, 1997
Meperidine (1) is an atypical µ-opioid agonist that displays
psychostimulant effects1 that suggest it might also share
some pharmacological characteristics with cocaine. Indeed
it has recently been shown that, under certain conditions,
meperidine will fully substitute for cocaine in squirrel
monkeys, in a drug discrimination model of drug abuse.2 One
hypothesis that has been proposed is that this effect may
be due to meperidine interacting at a high affinity binding
domain on the dopamine transporter (DAT).2,3 The psycho-
stimulant effects of cocaine are also believed to result from
its blockade of dopamine uptake. However, in contrast to
meperidine, cocaine appears to bind to both high and low
affinity sites.4 Although the meperidine structure has been
studied in relation to its µ-opioid activity,5 no work has been
carried out to identify the conformation adopted on binding
to the DAT.
the original synthesis, satisfactorally. Specifically, the
detosylation of the 4a , 4b mixture to 5a , 5b could not be
performed using the originally reported procedure nor a
number of alternative reagents and conditions. This original
synthesis also required the separation of the two diastere-
omers by column chromatography and recrystallization,
whereas we now report the diastereospecific synthesis of one
of the desired diastereomers using a procedure that is readily
reproducible.
trans-L-Hydroxyproline methyl ester (6) is readily made
from commercially available trans-L-hydroxyproline7 which
could be converted into 3a in five steps (Scheme 1). Forma-
tion of the ethyl carbamate (7) was achieved by treating 6
with ethyl chloroformate and triethylamine in CHCl3. This
was followed by reduction with lithium aluminum hydride
(2 equiv) to give the NMe, diol 8. Tosylation using 2.4
equivalents of TsCl in pyridine (4 °C) gave 9 in 18% yield
(over the three steps). Alkylation with phenylacetonitrile
anion was attempted with three different bases. It was
found that best results were obtained with LDA or NaNH2
in THF, a multicomponent mixture being formed with NaH
in DMSO. Thus treatment of 9 with phenylacetonitrile (1.2
equiv) and LDA (2.7 equiv) in THF yielded 10 (48%).
Utilization of NaNH2 in THF led to a 37% yield of 10.
Interestingly, these successful alkylations resulted in only
one diastereoisomer being formed.8 This is in contrast to
alkylation utilizing the bulkier N-tosyl analogue of 9, where
both isomers are formed (4a , 4b).7 This is an unusual
finding, in that the smaller group resulted in greater
stereoselectivity and may be explained by consideration of
the likely transition states 11a and 11b (Figure 1). Clearly
the phenyl group has a much greater steric bulk than the
nitrile, and thus transition state 11a should be favored over
11b, leading to formation of the exo-phenyl product. How-
ever, in the case of the NTs intermediate, edge to face
interactions between the two phenyl groups can be envi-
sioned, thus stabilizing the more hindered transition state.
Meperidine is a 4-phenylpiperidine that has significant
structural flexibility and can exist in both chair and boat
conformations. To gain a better understanding of the
conformation adopted on binding to the DAT, we were
interested in studying ring constrained analogues in which
the important pharmacophores are held rigidly with respect
to one another. Analogues of the chair conformation of
meperidine have been prepared and include the tropanes
(2a , 2b).6 In contrast, no compounds are commercially
available that mimic the boat conformation of meperidine.
Analogues 3a and 3b have been prepared previously, to
study binding to the µ-opioid receptor and appeared ideal
for our own studies.5 However, we were unable to repeat
* Corresponding author. Ph 410-550-1455. FAX 410-550-1648. email:
anewman@irp.nida.nih.gov
† Current address: Smith Kline Beecham, Research and Development,
King of Prussia, PA 19406.
(1) Himmelsbach, C. K. J . Pharmacol. Exp. Ther. 1942, 75, 64.
(2) Izenwasser, S.; Newman, A. H.; Cox, B. M.; Katz, J . L. Eur. J .
Pharmacol. 1996, 297, 9.
(3) Katz, J . L.; Newman, A. H.; Izenwasser, S. Pharmacol. Biochem.
Behav. 1997, 57, 1.
(4) Madras, B. K.; Fahey, M. A.; Bergman, J .; Canfield, D. R.; Spealman,
R. D. J . Pharmacol. Exp. Ther. 1989, 251, 131.
(5) Portoghese, P. S.; Mikhail, A. A.; Kupferberg, H. J . J . Med. Chem.
1968, 11, 219.
(6) Daum, S. J .; Martini, C. M.; Kullnig, R. K.; Clarke, R. L. J . Med.
Chem. 1975, 18, 196.
(7) Remuzon, P. Tetrahedron 1996, 52, 13803.
(8) The configuration at C-5 was determined by NOE experiments.
Irradiation of the H-6 exo, but not the H-6 endo, proton caused an
enhancement of the signal for the phenyl ring.
(9) See the Supporting Information. Newman, A. H.; Kline, R. H.; Allen,
A. C.; Izenwasser, S.; George, C.; Katz, J . L. J . Med. Chem. 1995, 38, 3933.
S0022-3263(97)01791-X This article not subject to U.S. Copyright. Published 1998 by the American Chemical Society
Published on Web 01/14/1998
Husbands
