Asymmetric synthesis of chiral, nonracemic trifluoromethyl-substituted piperidines and decahydroquinolines

Full text of DOI:10.1021/ja983389n

J. Am. Chem. Soc. 1999, 121, 593-594
Asymmetric Synthesis of Chiral, Nonracemic
593
Trifluoromethyl-Substituted Piperidines and
Decahydroquinolines
Jinlong Jiang,*,‡ Robert J. DeVita,‡ George A. Doss,†
Mark T. Goulet,‡ and Matthew J. Wyvratt‡
Figure 1.
Department of Medicinal Chemistry
Department of Drug Metabolism
Merck Research Laboratories, Rahway, New Jersey 07065
Scheme 1
ReceiVed September 23, 1998
The synthesis of trifluoromethyl-substituted heterocycles has
become an important area of pharmaceutical research owing to
the unique physical and biological properties imparted by the
trifluoromethyl group.1 In many systems, the substitution of a
methyl by a trifluoromethyl group results in added metabolic
stability and lipophilicity (πCF ) 1.07 vs πCH ) 0.5)2, which
3
3
may improve pharmacokinetic properties of drug candidates.
Although trifluoromethyl derivatives of aromatic nitrogen het-
erocycles are well documented, saturated analogues are much less
known.3 The synthesis of structurally complex trifluoromethyl-
substituted saturated heterocycles in either racemic or enantio-
merically pure forms creates significant challenges for the
synthetic chemist. In this communication, we describe an efficient
preparation of chiral, nonracemic trifluoromethyl-substituted
piperidines and decahydroquinolines from the chiral trifluoro-
methyl lactam 2 via palladium-catalyzed reactions of the R-(tri-
fluoromethanesulfonyloxy)enamine 3 (enamine triflate) and
R-(diphenylphosphoryloxy)enamine 4 (enamine phosphate), as
well as highly regioselective and facially selective Diels-Alder
reactions of the novel, nonracemic trifluoromethyl-substituted
diene 16 (Scheme 3).
Chiral lactams of type 1 (Figure 1) have been extensively
studied as templates in asymmetric syntheses mainly based on
the initial alkylation of the methylene group adjacent to the
carbonyl group either by treatment with a base followed by
reaction with an alkyl halide4a-c or by thio-Claisen rearrangement
of the corresponding thiolactams.5 Synthetic methods for the
introduction of an alkyl group at the position where the lactam
carbonyl group is situated (the 2-position of the six-membered
ring) seldom have been reported.6,7 We now report a cyclic
enamine triflate or phospate route to functionalize the carbonyl
group of the lactam 2.
derived triflates invariably had a stabilizing carbonyl or sulfonyl
group on the lactam-nitrogen atom. Cyclic enamine triflates
without a carbonyl or sulfonyl group on the nitrogen atom and
cyclic enamine phosphates were not previously reported. We now
disclose the preparation of chiral, nonracemic trifluoromethyl-
substituted enamine triflate 3 and enamine phosphate 4 from the
lactam 2, and the preliminary results of their Pd-catalyzed
coupling reactions. The synthetic utility of the intermediates 3
and 4 is illustrated by the first asymmetric synthesis of an
enantiomerically pure 2-trifluoromethyl-6-alkylpiperidine 15, ox-
azoline-protected piperidines 12-14 (Scheme 2), and 2-trifluo-
romethyldecahydroquinolines 20 and 22 (Scheme 3).
Lactam 2 was prepared by condensation of acid 53 with (S)-
(+)-phenylglycinol 6 in the presence of p-toluenesulfonic acid
with a Dean-Stark trap. Purification by column chromatography
afforded a single diastereomer 2 in 70% yield (Scheme 1).
Treatment of the lactam 2 with potassium bis(trimethylsilyl)amide
(KHMDS) at -78 °C followed by reaction with N-(5-chloro-2-
pyridinyl)triflimide (7) gave triflate 3 in 91% yield. Triflate 3 is
stable under basic conditions and was purified by filtration through
a basic aluminum oxide pad, but it was readily hydrolyzed under
acidic conditions. The new triflate 3 was subjected to the typical
organometallic coupling reactions as previously reported for
R-(trifluoromethanesulfonyloxy)encarbamates.8a,b Reaction of the
triflate 3 with methyl cuprate and palladium-catalyzed coupling
reactions with propargyl alcohol, phenylzinc chloride, and carbon
monoxide/methanol gave enamines 8-11 in good to excellent
yield.
Palladium-catalyzed coupling reactions of the lactam-derived
triflates,8a-c and lactone-derived cyclic ketene acetal phosphates9
were reported only recently. All previously reported lactam-
‡ Department of Medicinal Chemistry.
† Department of Drug Metabolism.
(1) (a) Welch, J. T. Tetrahedron, 1987, 43, 3123-3197. (b) Welch, J. T.;
Eswarakrishnan S. Fluorine in Bioorganic Chemistry; John Wiley & Son:
New York, 1991. (c) McAtee, J. J.; Schinazi, R. F.; Liotta, D. C. J. Org.
Chem. 1998, 63, 2161-2167 and references therein.
(2) Arnone, A.; Bernardi, R.; Blasco, F.; Cardillo, R.; Resnati, G.; Gerus,
I. I.; Kukhar, V. P. Tetrahedron 1998, 54, 2809-2818.
(3) Okano, T.; Sakaida, T.; Eguchi, S. J. Org. Chem. 1996, 61, 8826-
8830 and references therein.
(4) (a) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503-9569. (b)
Meyers, A. I.; Seefeld, M. A.; Lefker, B. A. J. Org. Chem. 1996, 61, 5712-
5713. (c) Meyers, A. I.; Seefeld, M. A.; Lefker, B. A.; Blake, J. F.; Williard,
P. G. J. Am. Chem. Soc. 1998, 120, 7429-7438.
(5) Devine, P.; Meyers, A. I. J. Am. Chem. Soc. 1994, 116, 2633-2634.
(6) Meyers et al.7 recently reported the synthesis of chiral, nonracemic
piperidines from the chiral lactam 1 (n ) 2) via Eschenmoser sulfide
contraction followed by hydrogenation of the ester. Our attempts to use this
method for the synthesis of chiral 2-trifluoromethyl-6-alkylpiperidines were,
however, unsuccessful. Treatment of the CF3 version of chiral thiolactam
derived from 2 with an excess of methyl R-bromoacetate led exclusively to
the recovery of lactam 2 propbably via hydrolysis of a labile thioiminium
intermediate.
Cleavage of the oxazoline ring of oxazoline-protected piper-
idines such as 12 (Scheme 2) by hydrogenation to generate cis-
(8) (a) Foti, C. J.; Comins, D. L. J. Org. Chem. 1995, 60, 2656-2657. (b)
Luker, T.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997, 62, 8131-
8140. (c) Luker, T.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997, 62,
3592-3596.
(9) Nicolaou, K. C.; Shi, G.-Q.; Ga¨rtner, G. P.; Yang, Z. J. Am. Chem.
Soc. 1997, 119, 5467-5468.
(7) Munchhof, M. J.; Meyers, A. I. J. Am. Chem. Soc. 1995, 117, 5399-
5400.
10.1021/ja983389n CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/06/1999

594 J. Am. Chem. Soc., Vol. 121, No. 3, 1999
Communications to the Editor
Scheme 2
of lactone-derived ketene acetal phosphates (Scheme 3). Thus,
treating lactam 2 with KHMDS, HMPA, and diphenyl chloro-
phosphate gave the cyclic enamine phosphate 4, which was stable
under neutral and basic conditions, but partially hydrolyzed to
the lactam 2 on silica gel column chromatography. In practice,
phosphate 4 was used without purification.
Reaction of the phosphate 4 with tributyl(vinyl)tin in the
presence of catalytic Pd(PPh3)4 and anhydrous LiCl in refluxing
THF for 2 h gave diene 16, which was trapped in situ by ethyl
acrylate or methyl fumarate to give adducts 19. The initially
formed adducts 19 were partially isomerized to adducts 17 and
18 during workup and column chromatography on silica gel, and
complete isomerization was accomplished by stirring with silica
gel for 1 h. Both adducts 17 and 18 were obtained as single
isomers in 65-71% yield (overall isolated yields based on the
lactam 2). The exclusive endo facial selectivity from the R-face
can be accounted for by the Diels-Alder transition state model
of diene 16 in which the bulky phenyl and trifluoromethyl groups
block the endo entry of dienophiles from the â-face. The exo
Scheme 3
1
compounds were not detected by H NMR.
The asymmetric Diels-Alder reaction is a very powerful tool
to build complex molecules with absolute stereocontrol. However,
as previously noted,13 there are few examples of the use of
enantiomerically pure dienes for Diels-Alder reactions. The
present diene 1614 represents a novel example of the chiral,
nonracemic trifluoromethyl-substituted dienes. The chiral auxiliary
oxazoline is readily cleaved by hydrogenation. Thus, adduct 17
was transformed in high yield by hydrogenation over Pd(OH)2
catalyst7 into the decahydroquinoline 20 with (S)-configuration
at the 2-position. The oxazoline ring appears to be reduced prior
to the CdC bond during the H2/Pd(OH)2 process (via a chiral,
nonracemic imine intermediate). Compound 22 with (R)-config-
uration at the 2-position was obtained by a two-step hydrogenation
from compound 18 in which the CdC bond was reduced prior to
cleavage of the oxazoline ring.
In summary, we have developed an efficient method to
functionalize the carbonyl group of lactam 2 via the palladium-
catalyzed coupling reaction of the cyclic enamine triflate 3 and
phosphate 4. Reactions of triflate 3 with a variety of organome-
tallic reagents afforded chiral, nonracemic trifluoromethyl-
substituted piperidine derivatives.15 Conversion of phosphate 4
to the chiral, nonracemic diene 16, followed by highly facially
selective Diels-Alder reactions and hydrogenation, gave chiral,
nonracemic trifluoromethyl-substituted decahydroquinolines.15
Other reactions and applications of triflate 3 and phosphate 4 are
currently under investigation.
2,6-disubstituted piperidines is well documented.10 The mechanism
involves cleavage of the PhCH-N bond, formation of an imine
intermediate, and reduction of the CdN bond. Therefore, forma-
tion of the enantiomerically pure piperidines by hydrogenation
of compounds 8 and 9 requires the enamine CdC bond to be
reduced prior to the oxazoline ring. We found that the enamine
double bond of compounds 8 and 9 was selectively reduced by
hydrogen (45 psi) over PtO2 in toluene to give the oxazoline-
protected piperidine 12 and CF3-pipecolic ester 13, respectively.
Hydrogenation of 12 over Pd(OH)2 in ethanol gave piperidine
15 in 86% yield. One-step hydrogenation of compound 8 over
Pd(OH)2 in ethanol gave the piperidine 15 with lower optical
rotation indicating a portion of 15 was generated via an achiral
imine intermediate (formed by initial cleavage of the PhCH-N
bond). The oxazoline ring of compounds 12 and 13 can be
visualized as a NH protecting group during side chain transforma-
tions such as that needed to convert the alcohol 12 to olefin 1411
or to make further transformations of the CdC bond of the olefin
14 before the oxazoline ring was cleaved.12
Acknowledgment. We thank Ms. Amy Bernick and Dr. Ziqiang Guan
for assistance with mass spectrometry.
Supporting Information Available: Experimental procedures and
characterization data for compounds 2, 3, 8-18, and 20-22 and their
1
1H NMR (including H NMR spectrum of the crude phosphate 4) and
13C NMR spectra (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JA983389N
(13) Kozmin S. A.; Rawal, V. H. J. Am. Chem. Soc. 1997, 119, 7165-
7166.
(14) The Diels-Alder reactions of racemic 2-(N-acylamino)-1,3-diene (23)
and 2-(N-tosylamino)-1,3-diene (24) were recently reported by Cha et al. (Ha,
J. D.; Kang, C. H.; Belmore, K. A.; Cha, J. K. J. Org. Chem. 1998, 63, 3810-
3811) and by Speckamp et al.,8b respectively.
The cyclic enamine phosphate 4 was prepared from the lactam
2 by using the procedure of Nicolaou et al.9 for the preparation
(10) (a) Bonin, M.; Royer, J.; Grierson, D. S.; Husson, H.-P. Tetrahedron
Lett. 1986, 27, 1569. (b) Zhu, J.; Quirion, J.-C.; Husson, H.-P. J. Org. Chem.
1993, 58, 6451.
(11) Hart, D. J.; Kanai, K.-I. J. Am. Chem. Soc. 1983, 105, 1255-1263.
(12) For example, we prepared 2-trifluoromethyl-6-(2-hydroxyethyl)-
piperidine in high yield by ozolysis of the olefin 14 followed by hydrogenation
over Pd(OH)2.
(15) [a]20
: 2, +144.3° (CHCl3, c 0.6); 3, +122.3° (CHCl3, c 2.3); 8,
D
+184.9° (CHCl3, c 0.35); 9, +151.0° (CHCl3, c 0.9); 10, +161.3° (CHCl3, c
0.7); 11, +204.0° (CHCl3, c 1.5); 12, +89.2° (CHCl3, c 0.9); 13, +62.5°
(CHCl3, c 0.5); 14, +89.7° (CHCl3, c 0.9); 15, +19.7° (CHCl3, c 1.7); 17,
+147.8° (CHCl3, c 0.8); 18, +92.0° (CHCl3, c 1.1); 20, -6.0° (CHCl3, c
1.0); 21, +153.5° (CHCl3, c 1.3); 22, +4.2° (CHCl3, c 1.0).