Hydrogenation condition for sequential processes to (+)-trifluoromethyl monomorine

Article abstract of DOI:10.1016/j.tetlet.2004.11.094

(+)-Trifluoromethyl monomorine has been synthesized under mild hydrogenation condition by initiating reductive cleavage of the oxazoline ring followed by deprotection and intramolecular reductive amination reaction. The precursors could be prepared concis

Full text of DOI:10.1016/j.tetlet.2004.11.094

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 423–425
Hydrogenation condition for sequential processes to
(+)-trifluoromethyl monomorine
Guncheol Kim* and Nakjeong Kim
Department of Chemistry, College of Natural Science, Chungnam National University, Taejon 305-764, Korea
Received 6 November 2004; revised 15 November 2004; accepted 18 November 2004
Available online 2 December 2004
Abstract—(+)-Trifluoromethyl monomorine has been synthesized under mild hydrogenation condition by initiating reductive cleav-
age of the oxazoline ring followed by deprotection and intramolecular reductive amination reaction. The precursors could be pre-
pared concisely by condensation and palladium-catalyzed coupling reaction.
Ó 2004 Elsevier Ltd. All rights reserved.
Since isolation of the indolizidine alkaloid monomorine,
a trail pheromone of the PharaohÕs ant, from Monomo-
rium pharaonis L. by Ritter,1 many synthetic ways have
been developed for the skeleton with the correct
arrangement of chiral centers adjacent to the nitrogen
atom.2
lished by endo facial hydrogenation of 3, controls the
stereochemistry at C2 of 2 when it is reduced, and the
following reductive amination of the deprotected piper-
idine intermediate would afford the expected product 1
(Eq. 1).
Intermediate 5 was prepared by condensation of 6 with
(S)-(+)-phenylglycinol, and was transformed to triflate 4
by reaction with N-(5-chloro-2-pyridinyl)triflimide using
the known procedure.4 Coupling of 4 with 1-heptyne-3-
ol 7 using PdCl2(PPh3)2, and CuI as catalysts afforded 3
in 65% yield as an inseparable ca. 1:1 mixture. Hydroge-
nation of 3 over hydrogen (50 psi) using PtO2 as a cata-
lyst afforded a mixture of 8, which could be separated to
yield epimers 8a and 8b in 33% and 35% yields, respec-
tively (Scheme 1).
H
N
Bu
CH3
(+)-Monomorine
Recently, we have published intramolecular reductive
amination approaches for the indolizidine skeleton.3
As an extension of the sequential strategy, we hoped
to synthesize a trifluoromethyl-substituted monomorine
derivative and find new biological properties.
In order to prepare the required precursor 2, the mixture
8 was oxidized using Dess–Martin periodinane. The
yield was 91% and the enantiomeric purity was proved
to be >98% by chiral HPLC. For the desired transfor-
mation of 2, hydrogenation under 1 atm of H2 for 1 h
The previous results for the construction of the 2,6-
disubstituted piperidine derivatives by reductive condi-
tions have indicated that proper arrangement of the
functional groups would secure the synthesis of the
new derivative in one pot under the similar condition.2c,4
Stereochemistry at C6 of 2, which is believed to be estab-
at room temperature was enough to afford 62% of (+)-
23
D
CHCl3), as a sole product after purification (Scheme 2).
trifluoromethyl monomorine 1, ½aꢀ 12:5ꢁ (c 0.75,
As the synthesis of the new monomorine derivative 1
could not be confirmed by comparison with authentic
sample, although spectra (1H and 13C NMR, IR,
HRMS) supported it, we decided to synthesize 1 via a
different route and match them. Instead of reductive
amination reaction for the last transformation, we con-
sidered that SN2 type reaction of 9a would afford the
Keywords: (+)-Trifluoromethyl monomorine; Reductive amination;
Hydrogenation.
*
Corresponding author. Tel.: +42 821 5475; fax: +42 823 1360; e-mail:
guncheol@cnu.ac.kr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.094

424
G. Kim, N. Kim / Tetrahedron Letters 46 (2005) 423–425
CF3
H
N
CF3
2
O
O
Hydrogenation
condition
N
N
6
O
Ph
Bu
Ph
CF3
Bu
1
2
HO
Bu
O
(+)-Trifluoromethyl monomorine
ð1Þ
3
Cl
CF3
CF3
N
O
O
N
N(Tf)2
Pd-catalyzed
O
N
coupling
F3C
OH
Ph
Ph
OTf
O
6
4
5
CF3
N
CF3
CF3
H
N
O
O
CF3
O
O
a
a
b
N
N
b
OH
Bu
OMs
Bu
a
N
Ph
Ph
OH
Bu
Ph
Bu
CF3
Ph
OH
8a
9a
HO
Bu
1
8a, b
7
3
CF3
CF3
N
H
O
O
Scheme 1. Reagents and conditions: (a) 4, PdCl2(PPh3)2, CuI, THF–(i-
Pr)2NH, rt, 65%; (b) H2 (50 psi), Pt2O, toluene, 33% and 35%,
respectively.
b
N
NH
OH
Bu
OMs
Bu
Bu
Ph
Ph
CF3
8b
10
9b
CF3
N
CF3
N
H
N
O
Scheme 3. Reagents and conditions: (a) (i) MsCl, Et3N, CH2Cl2, rt,
89% for 9a and 94% for 9b; (b) H2, Pd(OH)2, EtOH, rt, 58% for 1 and
53% for 9.
O
b
a
OH
Bu
O
Ph
Ph
Bu
CF3
Bu
8a, b
1
2
hydrogenation, and made the synthetic process possible
with minimum functional group protection. Search for
new biological activities of the new derivative is under
study.
Scheme 2. Reagents and conditions: (a) Dess–Martin periodinane,
CH2Cl2, 91%; (b) H2, Pd(OH)2, EtOH, rt, 62%.
same products 1, on the other hand 9b might afford the
epimeric compound.5,6 For this verification, the sepa-
rated isomers 8a and 8b were mesylated to 9a and 9b
in 89% and 94% yields, respectively. When compound
9a was subjected to the same hydrogenation condition,
compound 1 was obtained in 58% yield, and therefore
Acknowledgements
This work was supported by the Korea Research Foun-
dation Grant (KRF-2003-041-C00179), and we appreci-
ate Center for Research Facilities, CNU for the
permission to NMR.
the synthesis could be confirmed.7 However, 9b afforded
23
D
unanticipated piperidine 10 ½aꢀ 16:1ꢁ (c 1.00, CHCl3) in
53% yield under the hydrogenation condition (Scheme
3).8
References and notes
1. Ritter, F. J.; Rotgans, I. E. M.; Talman, E.; Verwiel, P. E.
J.; Stein, F. Experiencia 1973, 29, 530.
In conclusion, we have described the concise hydrogena-
tion-condition sequential route to a new derivative, (+)-
trifluoromethyl monomorine. The precursors 2 and 3,
have been prepared by condensation of 6 and (+)-phen-
ylglycinol followed by palladium coupling reactions. It
is noteworthy in this approach (+)-phenylglycinol group
of 2 has served as a chiral template for the selective
2. (a) Jefford, C. W.; Tang, Q.; Zaslona, A. J. Am. Chem. Soc.
1991, 113, 3513; (b) Shawe, T. T.; Sheils, C. J.; Gray, S. M.;
Conard, J. L. J. Org. Chem. 1994, 59, 5841; (c) Munchhob,
M. J.; Meyers, A. I. J. Am. Chem. Soc. 1995, 117, 5399; (d)
Berry, M. B.; Craig, D.; Jones, P. S.; Ronlands, G. J. J.
Chem. Soc., Chem. Commun. 1997, 2141; (e) Mori, M.;

G. Kim, N. Kim / Tetrahedron Letters 46 (2005) 423–425
425
Hori, M.; Sato, Y. J. Org. Chem. 1998, 63, 4832; (f)
Riesinger, S. W.; Lofstedt, J.; Petterson-Fasth, H.; Ba¨ckv-
all, J.-E. Eur. J. Org. Chem. 1999, 12, 3277; (g) KelÕin, A.
V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001,
123, 20746, and references therein.
2.73–2.80 (m, 2H); 13C NMR (125 MHz, CDCl3) 14.06,
22.71, 23.61, 26.53, 29.15, 29.65, 29.98, 30.25, 37.79, 61.75,
64.10, 64.30, 67.30. EIMS 249 (M+, 7), 192 (M+–butyl,
100), HRMS calcd for C13H22NF3 found 249.1704, found
249.1729.
3. (a) Kim, G.; Jung, S.-d.; Kim, W. J. Org. Lett. 2001, 3,
2985; (b) Kim, G.; Jung, S.-d.; Lee, E.-j.; Kim, N. J. Org.
Chem. 2003, 68, 5395.
4. Jiang, J.; DeVita, R. J.; Doss, G. A.; Goulet, M. T.;
Wyvratt, M. J. J. Am. Chem. Soc. 1999, 121, 593.
5. Watanabe, Y.; Iida, H.; Kibayashi, C. J. Org. Chem. 1989,
54, 4088.
6. The stereochemistry of the side chain of 8a, 8b, 9a, and 9b
was assumed retrospectively by the comparison result.
7. Compound 1: 1H NMR (500 MHz, CDCl3) 0.88 (t, 3H),
1.16–1.18 (m, 2H), 1.76–1.90 (m, 4H), 2.19–2.22 (m, 1H),
8. Compound 10: 1H NMR (500 MHz, CDCl3) 0.88 (t, 3H),
1.02–1.09 (m, 1H), 1.67 (d, 1H, J = 12.1 Hz), 1.80–1.90 (m,
2H), 2.47–2.53 (m, 1H), 3.11–3.16 (m, 1H); 13C NMR
(125 MHz, CDCl3) 14.07, 22.63, 23.30, 24.84, 25.76, 29.20,
29.69, 31.56, 31.78, 37.08, 56.48, 58.44, 58.66. EIMS 251
(M+, 3), 152 (M+–heptyl, 100), HRMS calcd for
C13H24NF3 found 251.1861, found 251.1880. The forma-
tion of 10 was assumed to proceed via elimination followed
by hydrogenation of the side chain before SN2 cyclization,
however, the explanation why cyclization was slowed down
or inhibited is still under investigation.