First asymmetrie synthesis of frans-3,4-dimethyl-4-arylpiperidines

Article abstract of DOI:10.1021/ol0713988

The first asymmetric synthesis of the trans-3,4-dimethyl-4-arylpiperidine opioid antagonist scaffold is reported. C-3 stereochemistry was established via CBS reduction and stereoselective anti-S_N2′ cuprate displacement of the derived allylic phosphonate. The resultant vinyl bromide was then elaborated to the target compound by Suzuki coupling and frans-selective 4-methylation. Extension of this methodology should allow general enantioselective access to highly substituted piperidine ring systems.

Full text of DOI:10.1021/ol0713988

ORGANIC
LETTERS
2007
Vol. 9, No. 19
3769-3771
First Asymmetric Synthesis of
trans-3,4-Dimethyl-4-arylpiperidines
Daniel P. Furkert* and Stephen M. Husbands
Department of Pharmacy & Pharmacology, UniVersity of Bath, ClaVerton Down,
Bath, BA2 7AY, U.K.
df218@bath.ac.uk
Received June 13, 2007
ABSTRACT
The first asymmetric synthesis of the trans-3,4-dimethyl-4-arylpiperidine opioid antagonist scaffold is reported. C-3 stereochemistry was
established via CBS reduction and stereoselective anti-SN2 cuprate displacement of the derived allylic phosphonate. The resultant vinyl
′
bromide was then elaborated to the target compound by Suzuki coupling and trans-selective 4-methylation. Extension of this methodology
should allow general enantioselective access to highly substituted piperidine ring systems.
trans-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidines are an
important class of non-morphinoid compounds that exhibit
pure antagonist activity at opioid receptors.1 Since their initial
discovery in 1978, extensive study of ligands derived from
the basic piperidine scaffold (1, Figure 1) has delivered
To date, only racemic syntheses of 1 have been reported,
and consequently, enantiomeric resolution of chiral salts is
required to deliver optically pure material.4 Although this
approach is convenient for large-scale production, an asym-
metric synthesis would avoid the loss of material represented
by the unwanted stereoisomer and potentially allow access
to novel chemical entities for pharmacological study.
From a retrosynthetic point of view, metalation and
alkylation of 4-arylpiperidines such as 4 (Figure 2) is known
to afford exclusively the trans-3,4-dimethyl product 1 after
reduction of the initially obtained enamine.5 We expected
that enantiopure 4 should in turn be available from 5 via
Pd-catalyzed coupling with an arylboronic acid and appropri-
ate protecting group manipulation.
Unsaturated piperidines such as 5 are not well-known in
the literature,6 but we anticipated that their assembly might
(2) Thomas, J. B.; Atkinson, R. N.; Rothman, R. B.; Fix, S. E.;
Mascarella, S. W.; Vinson, N. A.; Xu, H.; Dersch, C. M.; Lu, Y.-F.; Cantrell,
B. E.; Zimmerman, D. M.; Carroll, F. I. J. Med. Chem. 2001, 44, 2687.
(3) Neary, P.; Delaney, C. P. Expert Opin. InVest. Drugs 2005, 14 (4),
479.
(4) (a) Mitch, C. H.; Zimmerman, D. M.; Snoddy, J. D.; Reel, J. K.;
Cantrell, B. E. J. Org. Chem. 1991, 56, 1660. (b) Werner, J. A.; Cerbone,
L. R.; Frank, S. A.; Ward, J. A.; Labib, P.; Tharp-Taylor, R. W.; Ryan, C.
W. J. Org. Chem. 1996, 61, 587. (c) Oueslati, F.; Perrio, C.; Dupas, G.;
Barre, L. Org. Lett. 2007, 9, 153.
Figure 1. Selective opioid antagonists based on the 3,4-trans-
dimethyl-4-(3-hydroxyphenyl)piperidine scaffold.
several promising drug candidates including JDTic (2)2 for
treatment of drug abuse and Alvimopan (3)3 for prevention
of gastrointestinal side effects of opioid analgesia.
(1) Zimmerman, D. M.; Nickander, R.; Horng, J. S.; Wong, D. T. Nature
1978, 275, 332.
(5) Barnett, C. J.; Copley-Merriman, C. R.; Maki, J. J. Org. Chem. 1989,
54, 4795.
10.1021/ol0713988 CCC: $37.00
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bromination-elimination gave R-bromoenone 10 which was
conveniently purified by recrystallization from methanol.
Luche reduction of 10 proceeded quantitatively to give rac-
11, and we were pleased to find that CBS reduction of 10
using the catalyst derived from (R)-(+)-diphenylprolinol and
methylboronic acid8 provided (+)-11 in high yield with
excellent enantioselectivity (96% ee by chiral HPLC).
To effect the SN2′ displacement, 11 was transformed into
the corresponding diethylphosphonate 12.11 Treatment of 12
with dialkyl cuprates (Scheme 2, entries 1 and 2) proved
Figure 2. Retrosynthetic analysis of 1.
be accomplished by an approach beginning with aza-
Achmatowicz reaction of R-furfuryl amine 7 (Scheme 1) to
Scheme 2
Scheme 1
a 12 (1 equiv) added to preformed organocuprate (2 equiv) in
THF. bEquivalents of RM relative to the copper source. cComplex
d
e
mixture. No reaction. Plus 30% recovered starting material.
disappointing, however. Starting material was rapidly con-
sumed at low temperature to provide an inseparable mixture
of many products, possibly containing 13, in addition to
compounds obtained via other reaction pathways. Use of the
organozinc-derived copper reagent (entry 3) did not result
in any reaction even after prolonged reaction times. We were
finally pleased to discover that use of the monoalkyl cuprate
derived from methyllithium and CuCN‚2LiCl (entry 4) led
to the slow formation of the desired product 13 in reasonable
yield, the remainder of the mass balance being unreacted
starting material which could be recovered and reused.
establish the 3-piperidinone ring system.7 The cyclohexyl
analogue of 11 has previously been prepared enantioselec-
tively via CBS reduction of the corresponding ketone,8 and
although stereoselective SN2′ displacements involving deriva-
tives of 11 are unreported, we had reason to believe that the
reaction might be successful based on the reports of the
Knochel group involving vinyl iodides and zinc cuprate
nucleophiles.9
Upon treatment with slightly more than 2 equiv of
m-CPBA, protected R-furfuryl amine 7 was smoothly
converted to intermediate hydroxyaminal 8 with concomitant
oxidation of the sulfinamide (Scheme 1). In our hands
however, 8 proved particularly unstable and resisted all
attempts at purification or isolation. Combining the two steps
into a one-pot operation10 was unsuccessful, but further
investigation revealed that basic aqueous workup without
remoVal of solVent allowed the subsequent reduction to
proceed to afford 3-piperidinone 9 in good yield. One-pot
Further investigation of the nucleophilic component (en-
tries 5 and 6) revealed that the combination of methyl
Grignard and the copper bromide-dimethyl sulfide complex
was most effective, leading to rapid and complete consump-
tion of starting material. To confirm the exact mechanism
of the displacement, d-12 was prepared by Luche reduction
of 10 with NaBD4 and submitted to the optimized reaction
conditions (Scheme 3).
2
Examination of the deuterium D NMR spectra of the
product mixtures revealed that at -10 °C the displacement
proceeded with SN2′:SN2 selectivity of only ca. 3.5:1, as
determined by the ratio of products 13b/13c.12 Lowering the
(6) Buffat, M. G. P. Tetrahedron 2004, 60, 1701.
(7) Zhou, W.-S.; Lu, Z.-H.; Xu, Y.-M.; Liao, L.-X.; Wang, Z.-M.
Tetrahedron 1999, 55, 11959.
(8) Holub, N.; Neidho¨fer, J.; Blechert, S. Org. Lett. 2005, 7, 1227.
(9) Soorukram, D.; Knochel, P. Org. Lett. 2004, 6 (14), 2409.
(10) Matzanke, N.; Gregg, R. J.; Weinreb, S. M. J. Org. Chem. 1997,
62, 1920.
(11) Yanagisawa, A.; Noritake, Y.; Nomura, N.; Yamamoto, H. Synlett
1991, 251.
3770
Org. Lett., Vol. 9, No. 19, 2007

was then transformed into the required N-methyl alkylation
substrate 15 by quantitative removal of the N-tert-butylsul-
fonamide group with triflic acid in the presence of anisole
as a cation scavenger13 and reductive amination of the free
amine.
Scheme 3*
Metalation of 15 with butyllithium at -15 °C according
to a literature procedure4b followed by quenching of the
resultant stabilized anion with dimethylsulfate at -50 °C led
to 4-alkylation exclusively trans to the 3-methyl substituent.
Reduction of the crude enamine product 16 with sodium
borohydride in methanol gave amine 17 in 71% yield over
the two steps.
* Ratio 13b/13c determined by deuterium 2D NMR. a Complete
in 30 min. Complete in 4 h.
We were pleased to find that NMR analysis of 17 with
the chiral complexing agent (S)-(+)-1-(9-anthryl)-2,2,2-
trifluoroethanol4a,14 indicated the presence of only one
enantiomer to the limits of NMR detection. Comparison of
the measured optical rotation ([R]D +69.3, c 0.021, MeOH)
b
temperature to -35 °C extended the reaction time to 4 h
and resulted in almost exclusive preference for the SN2′
pathway.
Compound 13 exhibited an optical rotation of [R]D -9.0
(c 0.062, CHCl3), but to assess the enantiomeric excess
obtained, it proved necessary to carry this material forward
through the synthesis for comparison with previously re-
ported data.
i
with the literature value for the Pr ether analogue ([R]D
+76.2, c 1.01, MeOH)4b suggested that the key SN2′
displacement had indeed occurred stereoselectively anti to
the phoshonate in 12 to eventually afford the desired
enantiomer (+)-17.
Finally, deprotection of the N- and O-methyl groups was
achieved in two operations under standard conditions to give
the target 4-(3-hydroxyphenyl)-3,4-trans-dimethylpiperidine
(+)-1 in excellent yield. Chiral HPLC analysis in comparison
with a racemic sample confirmed an enantiomeric excess of
91.1%.
In conclusion, the first asymmetric synthesis of the
pharmaceutically important 4-aryl-3,4-dialkylpiperidine opi-
oid antagonist scaffold is reported via the unprecedented
stereoselective displacement of an enantiopure R-bromo
allylic phosphonate. Due to the variety of reactions possible
starting from 4-brominated unsaturated piperidines such as
10 or 11, we hope this chemistry will prove useful for
enantioselective synthesis of natural products and pharma-
ceutical target compounds containing highly substituted
piperidine ring systems.
Our attention now turned to preparation of the complete
3,4-trans-dimethyl-4-arylpiperidine system (Scheme 4). Su-
Scheme 4
Acknowledgment. This work was funded under grant
DA007315 from the National Institute on Drug Abuse
(NIDA/NIH).
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0713988
(12) Determined by the relative integrals of the signals due to deuterium
in the vinylic (13b) and allylic (13c) positions (δ 6.00 and 2.59 ppm,
respectively).
(13) Sun, P.; Weinreb, S. M.; Shang, M. J. Org. Chem. 1997, 62, 8604.
Significant migration of the double bond was observed in the absence of
anisole.
zuki coupling of 13 with 3-methoxybenzeneboronic acid
afforded 14 in high yield, contaminated by a small amount
(<5%) of inseparable homocoupling product, which could
be readily separated at the next step. The coupling product
(14) Doubling of signals due to the three methyl groups was observed
with a racemic sample.
Org. Lett., Vol. 9, No. 19, 2007
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