A rapid and practical entry into cis-1,4-aminocyclohexanols

Article abstract of DOI:10.1016/j.tetlet.2010.01.029

A selective and practical approach for the formation of cis-1,4-aminocyclohexanol was developed. The key transformation involves a one-pot imine formation/ Lewis acid-directed imine reduction and results in a highly selective attack of the reducing agent. This simple and practical method is easily amenable to large-scale synthesis.

Full text of DOI:10.1016/j.tetlet.2010.01.029

Tetrahedron Letters 51 (2010) 1419–1422
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A rapid and practical entry into cis-1,4-aminocyclohexanols
b
b
a
a
Fabrice Gallou a, , Bo Han , Jiang Lu , Manuela Seeger-Weibel , Anne-Florence Stoessel ,
*
Simon Allmendinger a
a Novartis Pharma AG, Chemical and Analytical Development, CH-4002 Basel, Switzerland
b Suzhou Novartis Pharma Technology Co., Ltd.;18 Tonglian Road, Riverside Industrial Park, Changshu Economic Development Zone, Changshu/Jiangsu Province 215537, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A selective and practical approach for the formation of cis-1,4-aminocyclohexanol was developed. The
key transformation involves a one-pot imine formation/ Lewis acid-directed imine reduction and results
in a highly selective attack of the reducing agent. This simple and practical method is easily amenable to
large-scale synthesis.
Received 23 November 2009
Revised 21 December 2009
Accepted 8 January 2010
Available online 14 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cis-1,4-aminocyclohexanol
Reductive amination
Selectivity
1. Introduction
specific problem and tried to design a system that could provide a
selective entry into variously substituted cis-1,4-aminocyclohexa-
The good understanding of the cyclohexane ring conformation
and its easy amenability to Structure Activity Relationship has
made this ring system an attractive scaffold for medicinal chemists
for various applications such as, for example, antihelmintic
agents,1a anti-inflammatory agents,1b Melanin-Concentrating Hor-
mone Receptor antagonists,1c phosphodiesterase inhibitors,1d
presynaptic silent antagonists,1e dopamine receptor antago-
nists,1f–h modulator of chemokine receptor activity,1i antibacterial
nols in a practical, robust, and economical manner.
The numerous available methods of reductive amination
prompted us to focus on this approach.4 We were hoping that upon
imine formation mediated by a suitable dehydrating agent, the lat-
ter could also serve as a Lewis acid to chelate the free hydroxyl
group and the imine in a boat-like conformation, thus inducing
the entry of the hydride from the opposite face (Scheme 1).5
Titanium-based reagents first appeared as suitable candidates
to promote both the dehydration-imine formation and the chela-
tion that would shield one face of the ring. An initial feasibility
study showed that the reaction proceeded well with the mild Lewis
acidic titanium tetraalkoxide (ethoxide or isopropoxide).3d We
tested this reaction with compound 1.6 Encouraged by these re-
sults, we evaluated various entering amine group. An optimal ca
9:1 ratio of cis/trans isomer was obtained with benzylamine (Table
1).7
A subsequent screening of reducing agents showed that sodium
borohydride was superior to other more complex boron or other
hydride reagents or all other more expensive reagents (see Table
2, entries 1–5). The more reactive aluminum-based reducing agent
was not assessed to guarantee high chemoselectivity and a larger
compatibility with functional groups. No major counter-ion effect
could be observed (entries 1 and 3). The aluminum-based hydride
reagents especially led to much lower overall efficiency for both
the yield and the selectivity. Solvent evaluation revealed that the
selectivity was similar in various solvents and showed that alco-
hols were optimal (entries 6–8). We rationalize the marginal
difference observed as a consequence of the addition of solid
agents,1j N-methyl- -aspartate receptor antagonists,1k hyperten-
D
sive agents,1l and chemokine receptor antagonists.1m The 1-substi-
tuted-4-aminocyclohexanol framework especially has in the last
few years been extensively used by research chemists. It is gener-
ally synthesized in a non-stereoselective manner to give rise to
both the cis and trans isomers. For the cis aminoalcohol isomer,
the commonly used approach consists of an iminonitroso Diels–Al-
der sequence which upon reduction of the N–O bond gives rise to
the desired aminocyclohexanol with a syn relationship of the
amine and alcohol functionality.2 An alternative often encountered
is a non-stereoselective reductive amination of the corresponding
cyclohexanone system, which induces at best a modest selectivity,
and requires subsequent purification by column chromatography.3
Both strategies suffer from poor practicality and ease of operations.
The iminonitroso Diels–Alder approach also presents further draw-
backs, for example, the cost inherent in the formation of the diene
precursor and the safety limitations. We became interested in this
* Corresponding author. Tel.: +41 61 696 3491; fax: +41 61 6962711.
E-mail address: fabrice.gallou@novartis.com (F. Gallou).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.029

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F. Gallou et al. / Tetrahedron Letters 51 (2010) 1419–1422
H
O
LA
R
R'
N
OH
HO
H
N
OH
R
R
R'
via
R
R'
N
H
Hydride
O
Scheme 1. Working hypothesis for the selective formation of cis-1,4-aminocyclohexanol.
Table 1
sodium borohydride which reacted rapidly with the imine without
complexing the solvent. A final step of our optimization consisted
in the identification of a practical and optimal temperature range.
We herein found that selectivities >97:3 could be obtained at a
temperature of ca. À15 °C which allowed a highly practical and
economically attractive non-cryogenic process (entries 8–10).
Interestingly, when the sodium borohydride was added directly
to a solution of the imine preformed in the absence of a dehydrat-
ing agent but by azeotropic distillation, a ca 83:17 ratio of isomers
was obtained (entry 12). The extent of the effectiveness of the che-
lation in a polar protic solvent as demonstrated, for example, by
comparison of entries 10 and 12, is remarkable here.
We finally aimed at further enrichment of the isomeric ratio by
salt formation. A rapid screening allowed us to identify methane-
sulfonic acid or the enantiopure mandelic acid as optimal acid
partners for such systems that resulted, respectively, in excesses
of 96:4 and 99:1 after crystallization from ethyl acetate at room
temperature.
Optimization of reaction conditions for the synthesis of 2a
BnNH2
HO
HO
COOEt
HO
COOEt
COOEt
Ti(OiPr)4
+
reducing agent
NHBn
O
NHBn
3a
solvent
1
2a
temperature
Entry
Reducing agent
Solvent
Temperature
Yield
2a/3a(*)
1
2
3
4
5
6
7
8
9
NaBH4
NaBH3CN
LiBH4
THF
THF
THF
THF
À10 °C
À10 °C
À10 °C
À10 °C
À10 °C
À10 °C
À10 °C
À15 °C
À60 °C
À15 °C
0–5 °C
À15 °C
66%
70%
69%
63%
Messy
81%
76%
82%
56%
75%
75%
80%
90:10
80:20
90:10
92:8
—
95:5
95:5
95:5
96:4
97:3
89:11
83:17
NaBH(OAc)3
NaBH(s-Bu)3
NaBH4
THF
CH2Cl2
EtOH
iPrOH
EtOH
EtOH
EtOH
EtOH
NaBH4
NaBH4
NaBH4
NaBH4
With an optimized process in hand, we turned our attention to
the scope of the methodology (Table 2). Not surprisingly, ratio
>97:3 could be observed for all substrates that displayed a confor-
mational preference for an axial hydroxyl group (entries 2 to 4,
R = iso-propyl, allyl, phenyl). In these cases, the ratio of isomers
could be further enriched to >99:1 via salt formation as described
10
11
12
NaBH4
NaBH4
**
*
Ratio determined by HPLC area% at 210 nm.
From the imine generated under dehydrative conditions without Ti(OiPr)4.
**
Table 2
Substrate scope
Entry
Ketone
Product Major isomer
Yield
57%
Cis/trans Isomeric ratio(*)
OH
OH
1
70/30
(4a)
(5a)
O
NHBn
HO
HO
2
3
76%
79%
98/2
97/3
(4b)
(5b)
O
NHBn
NHBn
HO
HO
HO
(5c)
(4c)
O
HO
4
5
87%
98/2
(5d)
(4d)
NHBn
OTBS
O
OTBS
>85%
80/20
(4e)
(5e)
O
NHBn

F. Gallou et al. / Tetrahedron Letters 51 (2010) 1419–1422
1421
Table 2 (continued)
Entry
Ketone
Product Major isomer
Yield
>95%
Cis/trans Isomeric ratio(*)
6
25/75
(5f)
(4f)
O
NHBn
HO
HO
COOEt
COOEt
7
8
94%
95/5
(2a)
(1)
NHBn
NH2
O
NH2
>95%
73/27
(5g)
(4g)
O
NHBn
Reaction conditions: BnNH2, Ti(OiPr)4, EtOH, rt, 1 h then NaBH4, À15 °C, 1 h.
*
Ratio determined by HPLC area % at 210 nm.
above. Control experiments also showed the importance of the hy-
droxyl group to induce the hydride reduction from the opposite
face. Protection of the latter by a non-coordinating group (OTBS en-
try 5) indeed showed a ca. 10% change in the selectivity. When the
hydroxyl group was removed, the reductive amination even led to
the formation of the trans isomer preferentially in a 75/25 ratio
(entry 6).4b We finally showed that an amino group displayed the
same directing effect as the hydroxyl group and confirmed the al-
ready described lack of selectivity (73/27 cis/trans isomeric ratio,
entry 8).3a,c
In conclusion, we have designed practical and general reac-
tion conditions that allow the selective formation of cis-1,4-
aminocyclohexanols via a controlled reductive amination. The
process is simple and directly amenable to large-scale synthesis.
We are currently investigating extension to other well-defined
ring systems and their use for the formation of chiral
compounds.
(m, 3H), 1.95–1.30 (m, 8H), 1.28 (t, J = 7.7 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) d 172.8, 140.8, 129.0, 128.4, 126.8, 69.1, 60.6,
55.5, 50.9, 46.2, 35.8, 28.3, 14.2; HRMS calcd for C17H25NO3 [M+]
291.18344; found 291.18171.
References and notes
1. (a) Chassaing, C. P. A.; Schroeder, J.; Ilg, T. S.; Uphoff, M.; Meyer, T. WO2009/
077527.; (b) Ferrand, S.; Glickman, F.; Leblanc, C.; Ritchie, C.; Shaw, D.; Stiefl, N.
J.; Furet, P.; Imbach, P.; Stauffer, F.; Capraro, H.-G.; Gessier, F.; Gaul, C.; Albaugh,
P. A.; Chopiuk, G. WO2008/052734.; (c) Sekiguchi, Y.; Kanuma, K.; Omodera, K.;
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Bernardelli, P.; Lorthiois, E.; Pham, N.; Proust, E.; Oliveira, C.; Mafroud, A.-K.;
Ducrot, P.; Wrigglesworth, R.; Berlioz-Seux, F.; Coleon, F.; Chevalier, E.; Moreau,
F.; Idrissi, M.; Tertre, A.; Descours, A.; Berna, P.; Li, M. Bioorg. Med. Chem. Lett.
2004, 14, 4615–4621; (e) Mattson, R. J.; Catt, J. D.; Sloan, C. P.; Gao, Q.; Carter, R.
B.; Gentile, A.; Mahle, C. D.; Matos, F. F.; McGovern, R.; VanderMaelene, C. P.;
Yocca, F. D. Bioorg. Med. Chem. Lett. 2003, 13, 285–288; (f) Caprathe, B. W.; Jaen,
J. C.; Smith, S. J.; Wise, L. D. US4957921.; (g) Urban, F. J.; Anderson, B. G.; Stewart,
M. A.; Young, G. R. Org. Process Res. Dev. 1999, 3, 460–464; (h) Boy, K. M.; Dee,
M.; Yevich, J.; Torrente, J.; Gao, Q.; Iben, L.; Stark, A.; Mattson, R. J. Bioorg. Med.
Chem. Lett. 2004, 14, 4467–4470; (i) Xue, C.-B.; Metcalf, B.; Han, A. Q.; Robinson,
D. J.; Zheng, C.; Wang, A.; Zhang, Y. WO2005/060665.; (j) Axten, J. M.; Daines, R.
A.; Davies, D. T.; Gallagher, T. F.; Jones, G. E.; Miller, W. H.; Pearson, N. D.;
Pendrak, I. WO2004/002992.; (k) Kawai, M.; Nakamura, H.; Sakurada, I.;
Shimokawa, H.; Tanaka, H.; Matsumizu, M.; Ando, K.; Hattori, K.; Ohta, A.;
Nukui, S.; Omura, A.; Kawamura, M. Bioorg. Med. Chem. Lett. 2007, 17, 5533–
5536; (l) Xue, C.-B.; Zheng, C.; Cao, G.; Feng, H.; Xia, M.; Anand, R.; Glenn, J.;
Metcalf, B. W. US2005/125647.; (m) Hersperger, R.; Janser, P.; Miltz, W.
WO2008/101905.
2. (a) Yang, B.; Lin, W.; Krchnak, V.; Miller, M. J. Tetrahedron Lett. 2009, 50, 5879–
5883; (b) Adamo, M. F. A.; Bruschi, S. J. Org. Chem. 2007, 72, 2666–2669.
3. (a) Hutchins, R. O.; Su, W.-Y.; Sivakumar, R.; Cistone, F.; Stercho, Y. P. J. Org.
Chem. 1983, 48, 3412–3422; (b) Hutchins, R. O.; Su, W.-Y. Tetrahedron Lett. 1984,
25, 695–698; (c) Mattson, R. J.; Pham, K. M.; Leuck, D. J.; Cowen, K. A. J. Org.
Chem. 1990, 55, 2552–2554; (d) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849–3862.
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Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454–5459.
5. Reductive aminations of carbonyl compounds with borohydride and borane
reducing agents, Baxter, E. W.; Reitz, A. B. In Organic Reactions; John Wiley &
Sons: NewYork, 2002; pp 1–714.
2. Experimental section
General procedure: To a solution of ethyl 2-(1-hydroxy-4-oxo-
cyclohexyl)acetate 1 (2.4 g, 12 mmol, 1.0 equiv) in anhydrous eth-
anol (12 mL) at room temperature were added titanium
tetraisopropoxide (4.2 mL, 15 mmol, 1.25 equiv) and benzylamine
(1.4 mL, 12 mmol, 1.0 equiv). The resulting mixture was stirred
for 1 h, cooled to ca. À15 °C, and a freshly prepared solution of so-
dium borohydride (0.23 g, 6 mmol, 2 equiv) in anhydrous ethanol
(2 mL) was added dropwise at a rate such that the temperature re-
mained at ca. À15 °C. At completion, the mixture was quenched
with water (excess), and ethyl acetate was added. Filtration
through celite and extraction gave an organic extract that was
washed with water once, and concentrated to give the crude reac-
tion mixture.
Ethyl 2-((1S*, 4S*)-4-benzylamino)-1-hydroxycyclohexyl)ace-
tate 2a (major diastereoisomer) 1H NMR (400 MHz, CDCl3) d
7.40–7.10 (m, 5H), 4.22 (q, J = 7.7 Hz, 2H), 3.85 (s, 2H), 2.55–2.45
6. Both the cis and trans isomers were prepared via the sequence showed below,
purified as described, and the stereochemistry was unambiguously determined
by extensive NMR study and subsequent derivatization to a known compound.

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F. Gallou et al. / Tetrahedron Letters 51 (2010) 1419–1422
O
HO
OH
HO
COOEt
H
BnHN
. Cy2NH
O
hydrolysis then
Cy2NH
HO
COOEt
crystaline
NHBn
>30:1 cis:trans ratio
22% isolated yield
EtOAc
+
LHMDS
then acid
acetone
+
HO
COOEt
NHBn
NHBn
O
HO
OH
ca. 1:1 ratio
NHBn
NHBn
H
in mother liquor
ca. 1:4 cis:trans ratio
45% isolated yield
7. Only a marginal effect with an increase of the steric hindrance or additional
electronic interaction was observed, when going from benzylamine to
methylbenzylamine, to -phenylglycinol, and to its O-methyl derivative. We
formed in situ and the Lewis acid brought in coordination sphere of the metal in
a boat-like conformation with benzylamine. For all others, additional steric
hindrance or competitive chelation of electrons with the Lewis acid reduced the
extent of the selectivity.
a-
a
rationalize these observations by the optimal chelation between the imine
Amine
HO
COOEt
HO
COOEt
HO
COOEt
Ti(OiPr)4
+
NaBH4
O
NHR
NHR
THF
- 20 ºC
1
2a
3a
Entry
1
Amine
Yield
76%
2a/3a*
NH2
NH2
90/10
2
3
4
81%
77%
73%
80/20
88/12
80/20
NH2
OH
NH2
OH
NH2
5
6
86%
51%
89/11
90/10
OMe
NH3
* Ratio determined by HPLC area % at 210 nm.