Improved synthesis of trans-4-alkylcyclohexane carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2004.06.117

Several stereomerically pure amino acid derivatives containing the N-terminal trans-4-alkylcyclohexanoyl fragment were obtained. Hydrogenation of 4-alkylbenzoic acids in the presence of a special Ru-Ni/C catalytic system and isomerization of the resulting mixture of trans- and cis-isomers of 4-alkylcyclohexanecarboxylic acids were used as the key steps. The stereomeric configuration of all compounds was confirmed by ¹H NMR spectroscopy. The compounds obtained possess a broad biological activity potential and are useful intermediates in the synthesis of stereomerically pure modified peptides.

Full text of DOI:10.1016/j.tetlet.2004.06.117

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6669–6672
Improved synthesis of trans-4-alkylcyclohexane carboxylic acids
Alexey A. Bazurin, Sergey V. Krasnikov,* Tatiana A. Obuchova, Angelina S. Danilova
and Konstantin V. Balakin
Department of Organic Chemistry, Yaroslavl State Technical University, Moskovskii Prospect 88, Yaroslavl 150023, Russia
Received 19 January 2004; revised 11 June 2004; accepted 25 June 2004
Abstract—Several stereomerically pure amino acid derivatives containing the N-terminal trans-4-alkylcyclohexanoyl fragment were
obtained. Hydrogenation of 4-alkylbenzoic acids in the presence of a special Ru–Ni/C catalytic system and isomerization of the
resulting mixture of trans- and cis-isomers of 4-alkylcyclohexanecarboxylic acids were used as the key steps. The stereomeric con-
figuration of all compounds was confirmed by 1H NMR spectroscopy. The compounds obtained possess a broad biological activity
potential and are useful intermediates in the synthesis of stereomerically pure modified peptides.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
stereoselective reactions where chemists aim to synthe-
size compounds with their stereogenic centers of correct
configuration, rather than as mixtures of stereoisomers
that must be separated later.1
In recent years, stereochemically pure drugs have
increasingly dominated the global pharmaceutical
industry. A better understanding of the central role that
chirality plays in biological processes has led to pharma-
ceuticals being developed as single stereoisomers. This
need for single isomers has fueled the development of
Due to the fact that the physiological activity of amino
acids and peptides strongly depends on the configura-
tion of their stereogenic centers, stereomerically pure
peptides and peptidomimetics have been the subject of
considerable interest. Many synthetic peptidomimetics
have been described as potent and selective ligands to
therapeutically significant protein biotargets.2 From this
point of view, there is considerable interest in synthesiz-
ing modified amino acids bearing N- or C-terminal stereo-
merically pure non-natural fragments. Such fragments
can improve the pharmacological profile of potential
therapeutic agents. In particular, synthetic peptidomi-
metics containing the N-terminal 4-alkylcyclohexanoyl
fragment were reported as physiologically active agents.
Probably the best known compound is the antidiabetic
drug Nateglinide 1, which represents a final generation
of orally active modulators of insulin secretion with im-
proved pharmacokinetics and reduced toxicity.3 Both
the pharmacokinetics and pharmacodynamics of Nate-
glinide strongly depend on the stereoconfiguration of
the cyclohexane ring: only the trans-isomer possesses
pharmacological activity. Among other physiologically
active peptidomimetics containing the N-terminal 4-alkyl-
cyclohexanoyl moiety, compound 24 was described
as a potential oncolytic, and compound 35 was reported
as an agent for the treatment of osteoporosis. A series
of 4-alkylcyclohexanoyl acids and their amino acid
O
OH
N
H
O
1
O
OH
O
O
H
O
N
OH
N
H
N
H
O
O
2
NH2
O
OH
O
O
H
N
N
H
O
3
*
Corresponding author. Fax: +7-0852-44-8793; e-mail: krasnikovsv@
ystu.yar.ru
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.117

6670
A. A. Bazurin et al. / Tetrahedron Letters 45 (2004) 6669–6672
derivatives has been synthesized, and their biological
activity and toxicity were studied.6
solution of NaOH in water in the presence of RNC-5
catalyst (Scheme 1). For all the acids 1–7 studied, mix-
tures of trans- and cis-isomers of the corresponding
4-alkylcyclohexanecarboxylic acids were formed in an
approximate ratio of 2:3. Probably, the observed ratio
of stereoisomers is due to the nonequilibrium state of
the reaction mixture.13 However, thermodynamic calcu-
lations indicate that the ratio of trans- and cis-isomers in
an equilibrium state at a temperature of 513–573K is
equal to ꢀ3:1.13 In order to achieve the equilibrium state
and increase the content of trans-isomer in the mixture,
the catalyst was removed and the reaction mixture was
kept at 260–280°C and a pressure of 3.0–4.0MPa for
2h. The trans-isomer was isolated by crystallization
from hexane. After isolation of the trans-isomer, the
remaining mixture was subjected to repeated isomeriza-
tion. After 3–4 cycles of isomerization–crystallization,
up to 90% yields of individual trans-isomers of 4-alkyl-
cyclohexanecarboxylic acids 8–14 were achieved
(Scheme 1, Table 1).
In this work, we have developed a novel synthetic
approach to structures containing trans-4-alkylcyclohex-
ane and a-amino acid fragments. The approach is based
on an efficient hydrogenation of 4-alkylbenzoic acids in
the presence of a heterogeneous ruthenium–nickel cata-
lyst followed by alkali-mediated isomerization of the
mixture of trans- and cis-isomers of 4-alkylcyclohexane-
carboxylic acids. It permits the convenient synthesis and
separation of trans-4-alkylcyclohexanecarboxylic acids,
which represent useful intermediates for introduction
of the trans-4-alkylcyclohexane moiety into synthetic
and natural molecules.
2. Results and discussion
Hydrogenation of arylcarboxylic acid derivatives using
traditional heterogeneous catalysts based on platinum7
or nickel,8 is a well-documented process. For example,
4-trans-isopropylcyclohexanecarboxylic acid used for
the synthesis of Nateglinide 1 has been obtained in
66% yield using PtO2-catalyzed hydrogenation of 4-iso-
propylbenzoic acid followed by sodium hydride-medi-
ated isomerization.9 However, the reactions are carried
out under severe conditions and are usually not selec-
tive, particularly in the case of alkylbenzoic acids with
alkyl chains more than three carbon atoms in length.
As a result, the yields of the desired products are often
decreased. An alternative method of hydrogenation with
the use of a sodium metal catalyst gives the desired
product, albeit in low yields.10
The ratio of trans- to cis-isomers in the hydrogenated
mixtures were analyzed by 1H NMR spectroscopy using
the relative intensity of the signals due to the a-protons
1
of the cyclohexane fragment. Thus the H NMR spec-
trum of pure trans-4-methylcyclohexanecarboxylic acid
8 showed a triplet of triplets, centering around d 2.00,
1
corresponding to the a-proton. The H NMR spectrum
of the reaction mixture in the equilibrium state also con-
tained signals from the same a-proton in the cis-isomer,
which appeared as a triplet around d 2.35 corresponding
to averaged signals from the, a,e- and, e,a-conformers.
When the methyl group was replaced with higher homo-
logs, the degree of isomerization and 1H NMR sig-
nals follows a pattern very similar to that shown by
4-methylcyclohexanecarboxylic acid. These characteristic
1H NMR signals allowed us to analyse effectively the
ratio of trans- to cis-isomers in the resulting products.
It was reported that ruthenium-containing catalysts are
more active in the hydrogenation of aromatic rings than
platinum- or palladium-based catalytic systems.11 Re-
cently, we developed and applied in a pilot factory, an
efficient carbon-supported ruthenium–nickel catalyst,
RNC-5 (5% Ru–Ni/C, Ru:Ni=9:1).12 In this work, we
demonstrated the usefulness of this catalytic system for
the convenient synthesis of several different stereomeri-
cally pure trans-4-alkylcyclohexanecarboxylic acids. 4-
Alkylbenzoic acids 1–7 were hydrogenated in a 10%
Upon treatment with thionyl chloride, acids 8–14 were
quantitatively converted into the corresponding chlo-
rides, which were used in the next step without purifica-
tion. The target amino acid derivatives 15–24 were then
obtained in 60–80% yields as pure (S)-stereoisomers
using the Schotten–Baumann reaction between the acid
R
H
O
O
O
c
a
H
R
R
OH
OH
+
OH
H
H
H
trans- 8-14
cis- 8-14
1-7
trans/cis ~ 2/3
trans/cis ~ 3/1
H
b
OH
R1
O
O
O
d, e
c
R
R
OH
N
H
H
R2
trans- 8-14,
80-90% from 1-7
15-24, 60-80%
Scheme 1. Reagents and conditions: (a) H2, 10% NaOH, H2O, RNC-5, 140–150°C, 3.0–4.0MPa; (b) 10% NaOH, H2O, 260–280°C, 3.0–4.0MPa;
(c) crystallization, hexane, ꢁ10°C; (d) SOCl2, C6H6; (e) amino acid, 2N NaOH, H2O/1,4-dioxane.

A. A. Bazurin et al. / Tetrahedron Letters 45 (2004) 6669–6672
6671
Table 1. trans-4-Alkylcyclohexanecarboxylic acids synthesized in this
work (Scheme 1)
heated under an atmosphere of hydrogen at 140–
150°C and 3.0–4.0MPa for 1h. The catalyst was re-
moved and the reaction mixture was heated at 260–
280°C and 3.0–4.0MPa for an additional 2h. The mix-
ture was cooled to room temperature and acidified with
conc. HCl until pH2. The precipitate formed was fil-
tered off and dried to afford a mixture, which contained
ꢀ75% of the trans-isomer. Pure trans-isomer was sepa-
rated by recrystallization from hexane at ꢁ10°C. The
mother liquor was evaporated to dryness, and the resi-
due was dissolved in 10% aqueous NaOH and subjected
to isomerization. The repeated isomerization–crystalli-
zation cycles afforded trans-4-n-alkylcyclohexanecarb-
oxylic acids 8–14 as white crystals in 80–90% yields.
Compound
R
Yield (%)
8
CH3
90
85
82
88
85
9
C3H7
C4H9
C5H11
C6H13
10
11
12
C3H7
C5H11
13
14
80
80
chlorides and amino acids (Scheme 1, Table 2) as previ-
ously reported.14 All the compounds synthesized were
successfully identified and characterized using 1H
NMR, elemental, and mass-spectral analysis.15
References and notes
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In summary, we have described a convenient synthetic
approach to the amino acid derivatives of trans-4-alkyl-
cyclohexanecarboxylic acids, featuring a convenient
RNC-5-catalyzed hydrogenation of 4-alkylbenzoic acids
as the key step. Even in the case of bulky and long-chain
4-alkyl groups, the ruthenium–nickel-catalyzed hydro-
genation followed by alkali-mediated isomerization
provides high yields of pure trans-4-alkylcyclohexane-
carboxylic acids as compared to alternative methods.
Considering the ease of preparation of the initial reac-
tants, convenient synthesis and isolation of products,
and the overall good chemical yields of the described
transformations, this route provides a new valuable
entry to novel stereomerically pure peptidomimetics,
which are of significant interest as promising physiolog-
ically active agents.
8. (a) London, D. T. J. Org. Chem. 1963, 28, 1770–1773; (b)
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3. Experimental protocol for the hydrogenation of
4-alkylbenzoic acids
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2550–2555.
4-Alkylbenzoic acids 1–5 were purchased from Aldrich.
4-(trans-4-Alkylcyclohexyl)benzoic acids 6, 7 were syn-
thesized as reported.16
4-Alkylbenzoic acid (20g), RNC-5 (3g) and 10% aque-
ous NaOH (100mL) were placed in an autoclave
equipped with a high-speed mixer. The mixture was
11. (a) Gurskii, R. N.; Istratova, R. V.; Kirova, A. V.;
Kotlyar, S. A.; Ivanov, O. V.; LukÕyanenko, N. G. J. Org.
Table 2. Amino acid derivatives synthesized in this work (Scheme 1)
Compound
R
R1
R2
Yield from 8–14 (%)
15
16
CH3
CH3
(CH3)2CH
(CH3)2CHCH2
H
H
80
60
17
CH3
62
18
19
20
21
22
C3H7
C4H9
C5H11
C6H13
C6H13
(CH3)2CH
(CH3)2CH
(CH3)2CH
(CH3)2CH
CH3S(CH2)2
H
H
H
H
H
65
66
77
60
68
C3H7
23
(CH3)2CH
H
65
C5H11
24
(CH3)2CH
H
68

6672
A. A. Bazurin et al. / Tetrahedron Letters 45 (2004) 6669–6672
Chem. USSR ðEngl. Transl.Þ 1988, 24, 543–547; (b) Litvin,
E. F. Zhurn. Org. Khim. USSR 1974, 10, 1475–1478.
cyclohexylcarboxamido)butanoic acid (15): mp 184–
186°C; 1H NMR [DMSO-d6+CCl4 (1:3), 500MHz]:
d=12.35 (s, 1H), 7.70 (d, 1H, J=5.3 Hz), 4.15 (dd, 1H,
J=6.9, 5.3Hz), 2.23 (m, 1H), 2.05 (m, 1H), 1.70 (m, 4H),
12. (a) Obuchova, T. A.; Betnev, A. F.; Budanov, N. A.;
Danilova, A. S.; Obuchov, M. V. Zhurn. Org. Khim. 1998,
34, 99–102; (b) Obuchova, T. A.; Betnev, A. F.; Budanov,
N. A.; Kolpashchikova, I. S.; Betnev, S. A. Zhurn. Org.
Khim. 1999, 35, 546–548.
13. Obuchova, T. A.; Betnev, A. F.; Kuznetsov, M. M.;
Bazurin, A. A.; Yasinskii, O. A. Izv. Vuzov. Khim. Techn.
2002, 45, 47–49.
1.35 (m, 3H), 0.90 (m, 11H); EIMS: m/z 241 [M]+, m/z (Irel
,
%)=196 (36), 142 (54), 125 (45), 97 (100), 72 (95), 55 (93)
(93,5). Anal. Calcd for C13H23NO3: C, 64.7; H, 9.6; N, 5.8;
O, 19.9. Found: C, 64.8; H, 9.7; N, 5.7; O, 19.8. 3-Methyl-
2S-[trans-4-(trans-4-propylcyclohexyl)-cyclohexylcarboxami-
do]butanoic acid (23): mp 202–204°C; 1H NMR [DMSO-d6,
500MHz]: d=7.52 (s, 1H), 4.05 (m, 1H), 2.17 (t, 1H, J=
12.5Hz), 2.03 (m, 1H), 1.70 (m, 8H), 1.30 (m,
4H), 1.12 (m, 3H), 0.95 (m, 6H), 0.83 (m, 11H);
EIMS: m/z 351 [M]+, m/z (Irel, %)=306 (30), 235 (42),
169 (100). Anal. Calcd for C21H37NO3 : C, 71.8; H,
10.5; N, 4.0; O, 13.7. Found C, 71.6; H, 10.6; N, 4.0; O,
13.8.
14. Steiger, R. J. Org. Chem. 1944, 92, 396.
15. Satisfactory analytical data (1H NMR, mass spectra) were
obtained for all new compounds. For example: trans-4-
methylcyclohexanecarboxylic acid (8): white crystals, mp
110–112°C; 1H NMR [DMSO-d6+CCl4 (1:3), 500MHz]:
d=10.00 (s, 1H), 2.02 (tt, 1H, J=15.6, 3.8Hz), 1.80 (m,
2H), 1.72 (m, 2H), 1.33 (dq, 2H, J=12.0, 3.4Hz), 1.30 (m,
1H), 0.92 (dq, 2H, J=12.0, 4.3Hz), 0.88 (d, 3, J=7.2Hz).
Anal. Calcd for C8H14O2: C, 67.6; H, 9.9; O, 22.5. Found:
C, 67.5; H, 10.0; O, 22.5. 3-Methyl-(2S)-(trans-4-methyl-
16. Betnev, A. F.; Karamisheva, L. A.; Geyvandova, T. A.;
Torgova, S. I.; Kovshev, E. I.; Obuchova, T. A. Zhurn.
Prikl. Khim. USSR 1986, 59, 1565–1570.