Synthesis of enantiopure cis- and trans-2-aminocyclohexane-1-carboxylic acids from octahydroquinazolin-4-ones

Article abstract of DOI:10.1016/j.tetasy.2004.08.032

The chemoselective and diastereoselective hydrogenation of 2,3-dihydro-3-[(S)-α-methylbenzyl]-4-quinazolinone 2 affords octahydroquinazolinones cis-3 and cis-4. Epimerization of cis-3 and cis-4 using t-BuO^-K⁺ produces trans-5 and tra

Full text of DOI:10.1016/j.tetasy.2004.08.032

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3545–3549
Synthesis of enantiopure cis- and
trans-2-aminocyclohexane-1-carboxylic acids from
octahydroquinazolin-4-ones
Jaime Priego, Patricia Flores, Claudia Ortiz-Nava and Jaime Escalante*
´
´
Centro de Investigaciones Quımicas, Universidad Autonoma del Estado de Morelos. Av. Universidad No. 1001,
Col. Chamilpa, C.P. 62210 Cuernavaca-Mor., Mexico
Received 2 August 2004;accepted 30 August 2004
Abstract—The chemoselective and diastereoselective hydrogenation of 2,3-dihydro-3-[(S)-a-methylbenzyl]-4-quinazolinone 2 affords
octahydroquinazolinones cis-3 and cis-4. Epimerization of cis-3 and cis-4 using t-BuOꢀK+ produces trans-5 and trans-6, respec-
tively. Hydrolysis with HCl of these octahydroquinazolinones leads to the free, enantiomerically pure, cis- and trans-2-aminocyclo-
hexane-1-carboxylic acids 7–10.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
as the chiral block for assembly of quinazolinone 2. It is
intended to complement methods already reported.
Enantiomerically pure cyclic b-amino acids have been of
considerable interest owing to their potential use as thera-
peutic agents and for their role as structure-forming
elements in b-peptides, which possess an ability to adopt
stable secondary structures such as oligomers.1 For
example, trans-aminocyclohexanecarboxylic acid has re-
cently been shown by Gellman et al. to form 14- and 12
helices that are generally more rigid and stable than
those comprised of linear a- and b-amino acids.2–7 Fur-
thermore, modification of the carbocyclic ring of these
monomeric units to include additional functional groups
has led to foldamers with enhanced solubility in aqueous
media.8,9
Herein, we report a versatile method for the enantiomer-
ically pure preparation of the cis- and trans-2-amino-
cyclohexane-1-carboxylic acids 7–10, from 2,3-dihydro-
3-[(S)-a-methylbenzyl]-4-quinazolinone 2. The key to
our strategy is the diastereoselective synthesis of octa-
hydroquinazolinones cis-3 and 4, which can also be epi-
merized under basic conditions to produce stereoisomers
trans-5 and 6, respectively (Fig. 1).
2. Results and discussion
2.1. Synthesis of 3,4-dihydro-3-[(S)-a-methylbenzyl]-4-
quinazolinone 2
Given the significance of cyclic b-amino acids, it is not
surprising that their synthesis has become an important
and challenging endeavour for organic chemists. Numer-
ous methodologies have appeared in the literature, with
the subject being extensively reviewed.10 The most widely
used techniques employ diastereo- and enantioselective
syntheses,11 chemoselective resolution12 and enzymatic
separations.13 Therefore, the goal herein is to provide a
new synthesis of all four isomers of 2-amino cyclohexane-
carboxylic acid, through the use of 2-aminobenzamide 1
The 2-aminobenzamide 1 was obtained through treat-
ment of isatoic anhydride with (S)-a-methylbenzylamine
(Scheme 1).14 Subsequently, the cyclocondensation with
triethyl orthoformate and p-TsOH in toluene yielded
quinazolinone 2 in 93% overall yield.
2.2. Synthesis of octahydroquinazolinones cis-3, cis-4 and
trans-5
Hydrogenation of 2 with PtO2 catalyst at 60lb for
30min in AcOH and catalytic H2SO4 gave the target
compounds 3–5. Spectroscopic analysis by 1H NMR
*
Corresponding author. Tel./fax: +52 777
jaime@ciq.uaem.mx
3 29 79 97;e-mail:
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.08.032

3546
J. Priego et al. / Tetrahedron: Asymmetry 15 (2004) 3545–3549
O
CH3
Ph
O
O
CH3
Ph
N
O
N
H
N
N
H
O
NH2
2
1
O
CH3
Ph
O
N
OH
N
H
3 - 6
NH2
7 - 10
Figure 1. Retrosynthetic analysis.
O
O
N
O
CH3
Ph
AcOEt, 40 oC
97%
CH3
CH3
N
H
N
O
Ph
Ph
H2N
HC(OC2H5)3
Toluene
p-TsOH
96%
NH2
N
H
O
1
2
Scheme 1.
showed a mixture of diastereoisomers cis-3, cis-4 and
trans-5 in a ratio of 60:30:10, respectively (Scheme 2).
The hydrogenation reaction was chemoselective: no
reduction of the phenyl group in the chiral auxiliary at
N-3 was observed.
The stereochemistry of each compound was confirmed
by X-ray. The major stereoisomer was identified as cis-
3 (Fig. 2) with the second product corresponding to
cis-4. Finally, it is important to point out that in this
hydrogenation reaction we observed another stereo-
isomer with low yield, which has been assigned as
trans-5 by X-ray (vide infra).
With these intermediates in hand, we investigated the
epimerization reaction of the cis-diastereoisomers in
the formation of the trans-octahydroquinazolinones 5
and 6, (Scheme 3). From the crystal structure of the
product derived from the epimerization of cis-3, the
stereochemistry is deduced as trans-5 (Fig. 3).
O
O
O
O
CH3
Ph
CH3
CH3
CH3
H
H
H
H
H
N
N
Ph
N
N
Ph
Ph
H2 - PtO2
AcOH - H2SO4
60 lbs / 30 min
+
+
N
H
cis-3
N
H
N
H
N
H
2
cis-4
trans-5
10%
60%
30%
Scheme 2.
Figure 2. X-ray structures of cis-3 and cis-4.

J. Priego et al. / Tetrahedron: Asymmetry 15 (2004) 3545–3549
3547
acids 7–10 were purified by chromatography on an
ion-exchange column (Dowexꢂ 50WX8-200);the yields
were ca. 75%.
O
O
H
H
H
R*
R*
R*
N
N
N
t-BuOK
THF,
N
H
cis-3
N
H
80%
H
1
The specific rotations, melting points and the H and
13C NMR spectra of compounds 7–10 were found to
be essentially identical with those values already present
in the literature.
trans-5
O
H
O
H
R*
t-BuOK
THF -Toluene
80%
N
3. Conclusions
N
H
N
H
H
H
trans-6
cis-4
We have reported a method for the preparation of both
cis- and trans-2-aminocyclohexane-1-carboxylic acids in
enantiomerically pure form from octahydroquinazol-
inones. This method would be suitable for preparing a
variety of structural analogues.
R* = (S)-α-methylbenzyl
Scheme 3.
4. Experimental
4.1. General
For a description of the general experimental data, see
Ref. 15. Microanalyses were performed in Elementar
Vario EL III. Optical rotations: 10cm, 1mL cell,
Perkin–Elmer-341 polarimeter.
Figure 3. X-ray structure of octahydroquinazolinone trans-5.
This result, with the specific rotation, permits the assign-
ment of the relative configuration of the product, which
was obtained in lower quantity in the hydrogenation
reaction, as trans-5. The stereochemistry of trans-6
was determined by chemical correlation with the free
b-amino acid.
4.1.1. 2-Amino-N-[(S)-a-methylbenzyl]-benzamide 1.
1.1equiv of the (S)-a-methylbenzylamine (0.9mL,
7.0mmol) was added to a suspension of isatoic anhy-
dride (1equiv, 1.0g, 6.2mmol) in ethyl acetate (15mL,
0.62M). The reaction mixture was warmed to 35–40ꢁC
for 40min. The solution was then concentrated under
reduced pressure. The crude product was purified by
FC (hexane–ethyl acetate, 70:30 ! 50:50) to afford
2.3. Hydrolysis of the octahydroquinazolinones 3–6 to
produce the cis- and trans-2-aminocyclohexane-1-
carboxylic acids 7–10
1.44g (97% yield) of 1, as a white solid: mp 136–
24
138ꢁC; ½aŠ ¼ þ110:9 (c 1.0, CHCl3); 1H NMR
D
(400MHz, CDCl3) d 1.59 (3H, d, J = 7.0Hz), 5.28
(1H, dq, J1 = J2 = 7.0Hz), 6.29 (1H, d, J = 6.2Hz),
The final step of the overall conversion of isatoic anhy-
drides to b-amino acids, the hydrolysis of quinazol-
inones 3–6, was achieved by heating to 115–120ꢁC with
6M HCl in a sealed tube (Scheme 4). The free amino
6.62 (1H, d, Jortho = 7.3Hz), 6.66 (1H, t, Jortho
8.4Hz), 7.20 (1H, td, Jmeta = 1.5Hz, Jortho = 7.7Hz),
=
7.26–7.40 (6H, m); 13C NMR (100MHz, CDCl3) d
cis-7
(S)
(R)
CO2H
NH2
HCl 6M
[α]D22 = + 22.3 (c = 0.25, H2O)
Lit.13b [α]D25 = +20.0 (c = 0.25, H2O)
cis-3
cis-4
110-115 oC
6 hr
(R)
(S)
cis-8
CO2H
NH2
HCl 6M
110-115 oC
6 hr
[α]D22 = - 23.0 (c = 0.25, H2O)
Lit.13b [α]D25 = - 19.6 (c = 0.25, H2O)
(R)
(R)
CO2H
NH2
trans-9
HCl 6M
[α]D22 = - 57.8 (c = 0.5, H2O)
Lit.11a [α]D25 = - 52.0 (c = 0.5, H2O)
trans-5
trans-6
110-115 oC
6 hr
trans-10
(S)
(S)
CO2H
NH2
HCl 6M
110-115 oC
6 hr
[α]D22 = + 42.0 (c = 0.5, H2O) (HCl salt)
Lit.11c,11i [α]D25 = + 47.4 (c = 1.14, H2O) (HCl salt)
Scheme 4.

3548
J. Priego et al. / Tetrahedron: Asymmetry 15 (2004) 3545–3549
22.0, 48.9, 116.6, 116.6, 117.4, 126.1, 127.1, 127.4, 128.8,
132.2, 143.4, 148.8, 168.4. Anal. Calcd for C15H16N2O:
C, 74.22;H, 6.78;N, 11.32. Found: C, 74.97;H, 6.71;
N, 11.66.
d, J = 12.0Hz), 4.12 (1H, d, J = 12.0Hz), 6.06 (1H,
c, J = 7.2Hz), 7.20–7.40 (5H, m); 13C NMR (50MHz,
CDCl3) d 16.0, 22.3, 24.4, 26.1, 29.9, 43.3, 48.8, 51.6,
56.8, 127.2, 127.5, 128.6, 140.1, 171.1. Anal. Calcd for
C16H22N2O: C, 74.42;H, 8.53;N, 10.85. Found: C,
73.86;H, 8.56;N, 10.77. X-ray crystallographic struc-
ture in Figure 2.16
4.1.2.
3,4-Dihydro-3-[(S)-a-methylbenzyl]-4-quinazol-
inone 2. A solution of the aminobenzamide 1 (1equiv,
1.0g, 4.16mmol) in toluene (20mL) was treated with tri-
ethyl orthoformate (1.1equiv, 0.7mL, 4.58mmol), p-tolu-
enesulfonic acid monohydrate (0.1g) and the reaction
mixture heated to 40ꢁC for 2h. The organic layer was
concentrated under reduced pressure. The crude product
was purified by FC (hexane–ethyl acetate 70:30 !
4.2.3. (4aR,8aR)-3-[(S)-a-Methylbenzyl]-1,2,4a,5,6,7,8,
8a-octahydroquinazolin-4-one 5. 0.093g (10% yield) as
24
D
a white crystals, mp 107–109 ꢁC; ½aŠ ¼ ꢀ83:7 (c 1.0,
1
MeOH); H NMR (200MHz CDCl3) d 1.09–1.33 (5H,
m), 1.52 (3H, d, J = 7.2Hz), 1.79–1.88 (3H, m), 1.93–
1.96 (1H, m), 2.46–2.49 (1H, m), 2.57 (1H, ddd,
J = 3.6Hz, J = J = 11.2Hz), 3.87 (1H, d, J = 11.2Hz),
4.25 (1H, d, J = 11.6Hz), 6.07 (1H, q, J = 7.6Hz),
7.23–7.36 (5H, m); 13C NMR (50MHz, CDCl3) d 16.0,
25.5, 26.3, 26.5, 33.9, 49.0, 49.3, 57.5, 56.7, 127.3,
127.4, 128.4, 140.7, 170.1. Anal. Calcd for C16H22N2O:
C, 74.42;H, 8.53;N, 10.85. Found: C, 74.00;H, 8.60;
N, 10.54. X-ray crystallographic structure in Figure 3.16
50:50) to produce 1.01g (96% yield) of 2, as an oil:
24
½aŠ ¼ ꢀ277:0 (c 0.50, MeOH), 1H NMR (200MHz,
D
CDCl3) d 1.85 (3H, d, J = 7.0Hz), 6.38 (1H, q, J =
6.8Hz), 7.38 (5H, m), 7.48 (1H, dd, Jmeta = 1.8Hz,
Jortho = 7.6Hz), 7.65–7.80 (2H, m), 7.94 (1H, s), 8.36
(1H, dd, Jmeta = 1.6Hz, Jortho = 8.0Hz); 13C NMR
(50MHz, CDCl3) d 19.3, 51.9, 122.0, 127.2, 127.4,
127.5, 127.5, 128.5, 129.2, 134.4, 139.6, 144.6, 147.7,
161.0. Anal. Calcd for C16H14N2O: C, 76.78;H, 5.64;
N, 11.19. Found: C, 76.45;H, 5.70;N, 10.97.
4.3. General procedure for epimerization of cis-
octahydroquinazolinones
4.2. General procedure for the hydrogenation of quinaz-
olinone 2
A
solution of cis-octahydroquinazolinone (0.2g,
0.78mmol) in 10mL anhydrous THF was treated with
t-BuOK (0.087g, 0.78mmol) and heated at reflux for
6h. The mixture was then evaporated to afford the crude
product. The residue was purified by FC (hexane/ethyl
acetate/isopropyl alcohol 6:3.6:0.4).
Quinazolinone 2 (1.0g, 4.0mmol), 10mL of acetic acid,
two drops of sulfuric acid, 0.02g of PtO2 catalyst and
activated charcoal (0.8g) were combined, and the mix-
ture shaken at room temperature in a Parr hydrogenator
for 30min under 60psi of hydrogen. The catalyst was fil-
tered through Celite and the filtrate neutralized with
NaOH 30% aq until it reached pH10–12. The resulting
cloudy, aqueous solution, was extracted with CH2Cl2
(3 · 15mL). The combined organic layers were dried
over MgSO4 and the solvent removed to obtain a pale
yellow oil. Octahydroquinazolinones 3–5 were purified
by FC [hexane/ethyl acetate/isopropyl alcohol
(6:3.6:0.4)].
4.3.1. (4aR,8aR)-3-[(S)-a-Methylbenzyl]-1,2,4a,5,6,7,8,
8a-octahydroquinazolin-4-one 5. 0.16g (80% yield) as
white crystals. The spectroscopy data were found to be
identical with those already presented.
4.3.2. (4aS,8aS)-3-[(S)-a-Methylbenzyl]-1,2,4a,5,6,7,8,
8a-octahydroquinazolin-4-one 6. 0.16g (80% yield) as
24
D
white crystals, mp 128–130ꢁC; ½aŠ ¼ ꢀ87:0 (c 1.0,
1
MeOH); H NMR (200MHz, CDCl3) d 1.10–1.29 (4H,
m), 1.52 (3H, d, J = 7.2Hz), 1.77–1.92 (4H, m), 1.77–
1.92 (1H, m), 2.42–2.49(1H, m), 2.42–2.49 (1H, m),
3.78 (1H, d, J = 12.0Hz), 4.10 (1H, d, J = 12.0Hz),
6.03 (1H, q, J = 7.2Hz), 7.24–7.35 (5H, m); 13C NMR
(50MHz, CDCl3) d 16.0, 25.4, 26.1, 26.6, 34.1, 49.0,
49.0, 57.0, 57.7, 127.4, 127.4, 128.6, 140.1, 170.1. Anal.
Calcd for C16H22N2O: C, 74.42;H, 8.53;N, 10.85.
Found: C, 74.23;H, 8.56;N, 10.76.
4.2.1. (4aS,8aR)-3-[(S)-a-Methylbenzyl]-1,2,4a,5,6,7,8,8a-
octahydroquinazolin-4-one 3. 0.558g (60% yield) as a
24
D
white crystals, mp 113–115ꢁC; ½aŠ ¼ ꢀ112:8 (c
1
1.0, MeOH), H NMR (200MHz, CDCl3) d 1.32–1.40
(2H, m), 1.51 (3H, d, J = 7.6Hz), 1.54–1.77 (6H, m),
1.90–1.97 (1H, m), 2.44 (1H, dt, J = J = 4.4Hz,
J = 14.8Hz), 3.17 (1H, dd, J = J = 4.4Hz), 3.83 (1H, d,
J = 11.6Hz), 4.17 (1H, d, J = 12.0Hz), 6.06 (1H, q,
J = 7.2Hz), 7.25–7.37 (5H, m); 13C NMR (50MHz,
CDCl3) d 15.8, 21.6, 24.7, 26.3, 30.3, 43.1, 48.4, 51.7,
56.9, 127.3, 127.5, 128.7, 140.7, 171.6. Anal. Calcd for
C16H22N2O: C, 74.42;H, 8.53;N, 10.85. Found: C,
74.51;H, 8.64;N, 10.71. X-ray crystallographic struc-
ture in Figure 2.16
4.4. General procedure of the hydrolysis of the cis- and
trans-octahydroquinazolinones
A suspension of 0.1g (0.39mmol) of the adduct in 10mL
of 6M HCl was heated in a sealed ampoule to 110–
115ꢁC for 6h. The solution was then allowed to cool
to ambient temperature. The residue was evaporated
at reduced pressure, and treated with a 10% solution
of NaOH (pH P10). The aqueous phase was extracted
with three 10mL portions of CH2Cl2. The combined ex-
tracts were dried over MgSO4, filtered and evaporated
to give the crude chiral auxiliary [(S)-a-methylbenzyl-
amine]. The aqueous phase was then treated with a
4.2.2. (4aR,8aS)-3-[(S)-a-Methylbenzyl]-1,2,4a,5,6,7,8,-
8a-octahydroquinazolin-4-one 4. 0.279g (30% yield) as
24
D
a white crystals, mp 128–130ꢁC; ½aŠ ¼ ꢀ126:0 (c 1.0,
1
MeOH), H NMR (200MHz, CDCl3) d 1.44–1.48 (2H,
m), 1.53 (3H, d, J = 7.2Hz), 1.61–1.64 (6H, m),
1.82–1.86 (1H, m), 2.46 (1H, dt, J = J = 4.8Hz,
J = 13.6Hz), 3.09 (1H, dd, J = J = 4.4Hz), 3.75 (1H,

J. Priego et al. / Tetrahedron: Asymmetry 15 (2004) 3545–3549
3549
10% solution of HCl until reaching pH 62. The solution
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24
D
217–220ꢁC (lit.11h 220–223ꢁC); ½aŠ ¼ þ22:0 (c 0.25,
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D
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D
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D
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24
D
mp 234–235ꢁC (lit.12b 239–240ꢁC); ½aŠ ¼ ꢀ57:8 (c 0.5,
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D
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Jpn. 1970, 43, 2230;(b) Armarego, W. L. F.;Kobayashi,
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Watanabe, K.;Misao, K. Chem. Lett. 1976, 4, 299.
˘
4.4.4. (1S,2S)-(+)-trans-2-Aminocyclohexane-1-carboxy-
lic acid hydrochloride 10. The solid obtained according
to general procedure, was treated with a solution of
MeOH and HCl gas (10mL) for 30min. The residue ob-
tained upon evaporation of the solvent was recrystal-
lized (acetone:water) to yield a colourless solid (0.05g,
24
D
69%): mp 202–204ꢁC (lit.11c 202–206ꢁC); ½aŠ ¼ þ42:0
´
´
13. (a) Kanerva, L. T.;Csomo s, P.;Sundholm, O.;Berna th,
G.;Fu¨lo¨p, F. Tetrahedron: Asymmetry 1996, 7, 1705;(b)
25
(c 0.5, H2O) (HCl salt) lit.11c,i ½aŠ ¼ þ47:4 (c 1.14,
D
´
Kaman, J.;Forro , E.;Fu lo¨p, F. Tetrahedron: Asymmetry
2000, 11, 1593;(c) Forro , E.;Fu lo¨p, F. Org. Lett. 2003, 5,
´
´
¨
H2O) (HCl salt).
´
¨
1209.
14. Juaristi, E.;Leo n-Romo, J. L.;Ramı rez-Quiros, Y. J. Org.
´
Chem. 1999, 64, 2914.
15. For general experimental procedures, see: Escalante, J.;
´
´
Acknowledgements
´
We are grateful to Vanesa Domınguez V. for technical
´
Hernandez, A.;Juaristi, E. Rev. Soc. Quim. de Mex. 2001,
45, 177.
´
support, to the CONACYT for financial support (Pro-
ject No. 38187-E), to J.P., P.F. and C.O. for a scholar-
ship, and to Dr. David Hook for many important
observations.
16. Crystallographic data are deposited at Cambridge Crys-
tallographic Data Center (CCDC: 241089, 241090 and
241091).