Chemoenzymatic preparation of optically active trans- and cis-cyclohex-4-ene-1,2-diamine and trans-6-aminocyclohex-3-enol derivatives

Article abstract of DOI:10.1016/j.tet.2012.05.087

Lipase from Burkholderia cepacia (PSL-C) effectively catalyzed the kinetic resolution of both racemic trans-N,N-diallylcyclohex-4-ene-1,2-diamine (±)-6 and its precursor trans-6-(diallylamino)cyclohex-3-enol (±)-5. The resulting optically active vicinal diamine and β-amino alcohol were converted into a precursor of oseltamivir and a cis-cyclohex-4-ene-1,2-diamine derivative, respectively.

Full text of DOI:10.1016/j.tet.2012.05.087

Tetrahedron 68 (2012) 7670e7674
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Tetrahedron
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Chemoenzymatic preparation of optically active trans- and cis-cyclohex-4-ene-
1,2-diamine and trans-6-aminocyclohex-3-enol derivatives
*
*
F. Javier Quijada, Francisca Rebolledo , Vicente Gotor
ꢀ
ꢀ
Departamento de Química Organica e Inorganica, Universidad de Oviedo, 33071 Oviedo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Lipase from Burkholderia cepacia (PSL-C) effectively catalyzed the kinetic resolution of both racemic
trans-N,N-diallylcyclohex-4-ene-1,2-diamine (ꢀ)-6 and its precursor trans-6-(diallylamino)cyclohex-3-
Received 29 February 2012
Received in revised form 25 April 2012
Accepted 22 May 2012
enol (ꢀ)-5. The resulting optically active vicinal diamine and
b-amino alcohol were converted into
a precursor of oseltamivir and a cis-cyclohex-4-ene-1,2-diamine derivative, respectively.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 28 May 2012
Keywords:
Vicinal diamines
Aminolysis
Vicinal amino alcohols
Transesterification
Lipase
1. Introduction
have carried out the enzymatic resolution of b-amino alcohol 5, as
well as its subsequent conversion into an optically active cis-cyclo-
Oseltamivir phosphate (1, Tamiflu), a carbocyclic analogue of
sialic acid, is the most widely used antiviral drug for the treatment
and prevention of influenzas. This compound acts by blocking the
active site of neuraminidase, a glycoprotein expressed by both
influenza A and B viruses.1 Between the variety of synthetic
approaches to oseltamivir,2 those described by Shibasaki and Kanai
et al. start from epoxide 4, which is converted into the optically
active diamine derivative 23 or into another non-symmetrical
diprotected trans-cyclohex-4-ene-1,2-diamine.4 In both cases,
eight steps were necessary to access to the corresponding (1S,2S)-
diamine derivative, the key step being the catalytic asymmetric
ring-opening of the meso-N-3,5-dinitrobenzoylaziridine 3 with
TMSN3 (Fig. 1).
On the other hand, we have developed in the last years an in-
teresting chemoenzymatic method to obtain enantioenriched trans-
cycloalkane-1,2-diamines starting from the corresponding epox-
ide.5 The good results attained, in both optical and chemical yields,
encouraged us to apply this methodology to the synthesis of opti-
cally active trans-cyclohex-4-ene-1,2-diamine derivatives. Thus, we
report herein an alternative chemoenzymatic preparation of the
diamine precursor of oseltamivir. Moreover, taking into account the
hex-4-ene-1,2-diamine derivative.
2. Results and discussion
2.1. Chemoenzymatic preparation of optically active
trans-cyclohex-4-ene-1,2-diamine derivatives
Epoxide 4 was obtained from 1,4-cyclohexadiene as described
by Albeck et al.8 Ring-opening of 4 with diallylamine yielded ra-
cemic trans-6-(diallylamino)cyclohex-3-enol (ꢀ)-5, which was
one-pot converted into the trans-diamine (ꢀ)-6 by the successive
treatment with mesyl chloride and aqueous ammonia. In this
process an aziridinium intermediate is formed as a consequence of
the SN2 intramolecular displacement of the mesylate group by the
vicinal tertiary amine. The subsequent attack of ammonia to the
wide interest of b-amino alcohols and vicinal diamines in different
chemical areas (medicinal, synthetic or supramolecular),6,7 we also
* Corresponding authors. Tel./fax: þ34 985103448; e-mail addresses: frv@unio-
vi.es (F. Rebolledo), vgs@uniovi.es, vgs@fq.uniovi.es (V. Gotor).
Fig. 1. Diamine derivative 2 as a precursor in the synthesis of oseltamivir (Ref. 3).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.087

F.J. Quijada et al. / Tetrahedron 68 (2012) 7670e7674
7671
meso-aziridinium cation ensures the trans configuration of the
resulting diamine 6 (Scheme 1).
Scheme 2. Transformation of (1S,2S)-6 into (1S,2S)-2.
of (1S,2S)-6 with di-tert-butyl pyrocarbonate yielded carbamate
(1S,2S)-8, which was submitted to reaction with N,N0-dime-
thylbarbituric acid (NDMBA) as the allyl group scavenger and Pd(0)
as catalyst.13 In these conditions, removal of both allyl groups took
place. The resulting crude mono-Boc diamine derivative was next
treated with di-tert-butyl pyrocarbonate to give (1S,2S)-2 in very
high yield (92%, calculated from 6). The sign of the optical rotation
of the thus obtained di-carbamate 2 matched the described value
for (1S,2S)-2 (see Experimental section).
Scheme 1. Synthesis of racemic trans-diamine (ꢀ)-6.
Resolution of (ꢀ)-6 was accomplished by enzymatic aminolysis
using ethyl acetate as the acyl donor and the solvent. At first, we
tried the resolution of (ꢀ)-6 using lipase B from Candida antarctica
(CAL-B) as catalyst. This lipase had shown both great activity and
high enantioselectivity in the resolution of racemic trans-N,N-dia-
2.2. Enzymatic resolution of b-amino alcohol ( )-5. Synthesis
of an optically active cis-cyclohexen-4-ene-1,2-diamine
derivative
llylcyclohexane-1,2-diamine,
a
saturated analogue of (ꢀ)-6.5c
However, its reaction with (ꢀ)-6 was very slow (Table 1, entry 1),
the acetylation of the diamine taking place with a very low enan-
tioselectivity (E¼3).9 Other combinations of acylating agent and
solvent were assayed, but in no case was the reaction of practical
utility (entries 2e4), the best result being obtained with (ꢀ)-1-
phenylethyl acetate and tert-butyl methyl ether (TBME).10 Fortu-
nately, a remarkable improvement was achieved when CAL-B was
replaced by the lipase from Burkholderia cepacia (PSL-C).11 This li-
pase transformed the substrate with total enantioselectivity, the
remaining diamine (1S,2S)-6 and the produced acetamide (1R,2R)-
7 being obtained in enantiopure form after 48 h of reaction (Table 1,
entry 5). In this process, both compounds were isolated in very high
yields. The absolute configuration (1S,2S) of the remaining sub-
strate 6 was established after its transformation into (1S,2S)-2 (see
Scheme 2). This means that the enzyme shows preference for the
enantiomer (1R,2R) of the amine, thus following the Kazlauskas’
rule.12
Enzymatic resolution of racemic trans-6-(diallylamino)cyclo-
hex-3-enol (ꢀ)-5 was carried out by transesterification reaction
using PSL-C as catalyst,14 vinyl acetate as the acyl donor and TBME
as the solvent (Scheme 3). Similarly to the preceding aminolysis
process, the enzyme showed a great efficacy, catalyzing the acet-
ylation of the (1R,6R) enantiomer of the amino alcohol 5. Thus, after
48 h of reaction (28 ꢁC), the remaining substrate (1S,6S)-5 and the
produced acetate (1R,6R)-9 were obtained with very high enan-
tiomeric excesses and yields.
The (1R,6R) enantiopreference of the lipase was demonstrated
by the chemical correlation of the remaining substrate (1S,6S)-5
with the configurationally known derivative (1S,2S)-12 (Scheme 4).
At first, allyl groups were removed as indicated in Scheme 2. The
resulting free (1S,6S)-6-aminocyclohex-3-enol [(1S,6S)-10] was
converted into the tert-butyl carbamate (1S,6S)-11. Catalytic hy-
drogenation of 11 yielded the tert-butyl carbamate 12. Comparison
of the sign of the optical rotation of 12 with that published for
a 20
(1S,2S)-12 (½ ꢂD þ19.19; c 0.50, MeOH)15 establishes the (1S,2S)
Since the allyl groups on the tertiary nitrogen can be easily and
selectively removed in the presence of other protecting groups, the
method developed here could be applied to the synthesis of a va-
riety of trans-cyclohex-4-ene-1,2-diamine derivatives in the two
enantiomeric forms. As a proof, (1S,2S)-6 was converted into
(1S,2S)-2, precursor of the oseltamivir (Scheme 2). Thus, treatment
configuration for the remaining substrate of the enzymatic
transesterification.
Moreover, in order to show the synthetic utility of the enzy-
matically prepared compounds, the optically active cis-diamine
derivative (1S,2R)-15 was prepared from the tert-butyl carbamate
Table 1
Lipase-catalyzed resolution of diamine (ꢀ)-6
Entry
Enzyme
Acyl donor (AcOR)
Solvent
Time (days)
Remaining substrate (1S,2S)-6, eeS (%)
Product (1R,2R)-7 eeP (%)
c
a (%)
Eb
1
2
3
4
5
CAL-B
CAL-B
CAL-B
CAL-B
PSL-C
AcOEt
AcOEt
TBME
TBME
THF
5
7
5
7
2
11
4
12
41
85
93
21
4
11
7
3
12
31
11
AcOEtc
d
AcOCH(Ph)CH3
AcOCH(Ph)CH3
AcOEt
d
6
83
AcOEt
>99e
>99e
50
>200
a
Conversion degree: c¼eeS/(eeSþeeP).
b
c
Determined from eeS and eeP as in Ref. 9.
A molar ratio ester/diamine of 6:1 was used.
A molar ratio ester/diamine of 3:1 was used.
d
e
Isolated yields after flash chromatography were 42% and 47% for (1S,2S)-6 and (1R,2R)-7, respectively.

7672
F.J. Quijada et al. / Tetrahedron 68 (2012) 7670e7674
samples in open capillary tubes and are uncorrected. 1H NMR and
proton-decoupled 13C NMR spectra (CDCl3 solutions) were
obtained using AC-300 or DPX-300 (1H, 300.13 MHz and 13C,
75.5 MHz) and AV-400 MHz (1H, 400.13 MHz and 13C, 100.63 MHz)
spectrometers using the
d scale (parts per million) for chemical
shifts; calibration was made on the CDCl3
(
13C; 76.95 ppm) or the
residual CHCl3 (1H; 7.26 ppm) signals.
Scheme 3. Enzymatic resolution of (ꢀ)-5.
4.2. Procedures and characterization of products
4.2.1. (ꢀ)-trans-6-(Diallylamino)cyclohex-3-en-1-ol [(ꢀ)-5].
Diallylamine (10.3 mL, 84.0 mmol) was added to a solution of
epoxide 4 (3.80 g, 40.0 mmol) in deoxygenated ethanol (80 mL).
After refluxing under a nitrogen atmosphere for 48 h, the solvent
and the excess amine were evaporated in vacuo to give the crude
product, which was purified by distillation to reduced pressure to
give the title compound (ꢀ)-5 (bp¼54 ꢁC, 0.01 Torr; 5.00 g, 66%) as
a colourless oil; [found: C, 74.8; H, 10.2; N 7.5. C12H19NO requires C,
74.57; H, 9.91; N, 7.25%]; Rf (hexane/AcOEt 10:1) 0.21; nmax(CH2Cl2)
Scheme 4. Assignment of the absolute configuration of the enzymatically prepared 5
and its transformation into the cis-diamine (1S,2R)-15.
3412, 1630, 1527, 1120 cmꢃ1
; dH (400 MHz CDC13) 5.80 (dddd, 2H,
3JC,A 4.4 Hz, 3JC,B 8.0 Hz, 3JC,D 10.2 Hz, 3JC,E 14.9 Hz, HC), 5.63e5.50 (m,
2H, H-3 and H-4), 5.22e5.08 (m, 4H, HD and HE), 3.69 (ddd,1H, 3J 6.1,
2
9.5,10.8 Hz, H-1), 3.33 (ddt, 2H, 4JA,D¼4JA,E¼1.7 Hz, 3JA,C 4.4 Hz, j JA,B
j
(1S,6S)-11. Thus, treatment of 11 with mesyl chloride gave the
mesylate derivative, which was subsequently treated with sodium
azide in DMF at 70 ꢁC. In this reaction, beside the cis-azido carba-
mate (1S,6R)-13, the oxazolidinone 14 was also isolated as a minor
product (see experimental section). This bicyclic compound is the
result of an intramolecular SN2 displacement of the mesylate group
by the carbonyl oxygen of the Boc group.16 To minimize the for-
mation of 14, the reaction with sodium azide was also tried at
a lower temperature (50 ꢁC) but under these reaction conditions,
compound 13 was not formed. Finally, the Staudinger reduction of
the azide function of (1S,6R)-13 yielded the cis-amino carbamate
(1S,2R)-15. In all the synthetic approaches no racemization took
place as confirmed by chiral-HPLC analysis of 15.
14.2 Hz, HA), 2.95 (dd, 2H, 3JB,C 8.0 Hz, j JB,Aj 14.2 Hz, HB), 2.83 (dt,1H,
3J 5.6 (d), 10.8 (t) Hz, H-6), 2.58e2.50 (m, 1H), 2.21e2.12 (m, 1H),
2.09e1.97 (m, 2H); dC (75.5 MHz CDC13) 136.3 (CH]CH2), 125.1(C-3
or C-4),124.5 (C-4 or C-3),117.3 (CH]CH2), 65.7 (CH), 61.1 (CH), 52.4
(NeCH2), 33.8 (CH2), 22.7 (CH2); m/z (ESIþ) 194 (100, MHþ).
2
4.2.2. (ꢀ)-trans-N,N-Diallylcyclohex-4-ene-1,2-diamine [(ꢀ)-6]. To
a cooled (0 ꢁC) solution of (ꢀ)-5 (1.50 g, 7.70 mmol) in anhydrous
diethyl ether (17 mL), triethylamine (1.7 mL, 12.4 mmol) and mesyl
chloride (0.720 mL, 9.30 mmol) were added. The stirred mixture
was allowed to warm to room temperature and, after 30 min,
triethylamine (2.2 mL, 15.5 mmol) and concentrated aqueous NH3
(20 mL) were added. The resulting two-phase reaction mixture was
vigorously stirred for 12 h. The layers were separated, and the
aqueous layer was extracted with diethyl ether (420 mL). All the
organic layers were combined and successively washed with
aqueous 3 M NaOH (20 mL) and brine (20 mL). After removal of the
organic solvents under reduced pressure, the obtained crude
product was purified by flash chromatography (a gradient of AcOEt
to AcOEt/methanol 4:1 was used as eluent) to give the title com-
pound (ꢀ)-6 (78%) as a colourless oil; [found: C, 74.8; H, 10.7; N
14.3. C12H20N2 requires C, 74.95; H, 10.48; N, 14.57%]; Rf (hexane/
3. Conclusions
Efficient chemoenzymatic approaches to optically active trans-
cycohex-4-ene-1,2-diamine and trans-6-aminocyclohex-3-enol
derivatives have been developed, in both cases the key step being
the kinetic resolution of the corresponding racemic compound
catalyzed by PSL-C. Moreover, the preparation of a precursor of
oseltamivir as well as an optically active cis-cyclohex-4-ene-1,2-
diamine derivative have also been carried out.
AcOEt 1:1) 0.17; nmax(CH2Cl2) 3420, 3347, 2980, 1634 cmꢃ1
; dH
4. Experimental section
4.1. General
(300 MHz CDC13) 5.81 (dddd, 2H, 3J 4.5, 7.8, 10.2, 14.7 Hz, CH]CH2),
5.67e5.57 (m, 2H, CH]CH), 5.22e5.03 (m, 4H, CH]CH2),
3.34e3.20 (m, 2H, NeCHH), 2.99e2.85 (m, 3H, NeCHHþH-1), 2.64
[dt, 1H, 3J 5.4 (d), 10.8 (t) Hz, H-2], 2.50e2.38 (m, 1H), 2.20e2.08 (m,
1H), 2.19e1.77 [mþs, 4H. Singlet corresponds to NH2 (1.80 ppm)];
dC (75.5 MHz CDC13) 136.8 (CH]CH2), 125.2 (CH]CH), 124.5 (CH]
CH), 115.9 (CH]CH2), 60.8 (CH), 52.0 (NeCH2), 47.6 (CH), 35.0
(CH2), 22.3 (CH2); m/z (ESIþ) 193 (100, MHþ).
Lipase B from C. antarctica (Novozyme 435, available immobi-
lized on polyacrylamide, 7300 PLU/g) was gifted by Novo Nordisk
Co. Immobilized lipase from Burkholderia cepacia (PSL-C, 783 U/g)
was purchased from Amano Pharmaceutical Co. For the enzymatic
reactions, ethyl acetate of spectrophotometric grade (stored with
ꢁ
4 A molecular sieves), anhydrous TBME or THF and (ꢀ)-1-
4.2.3. Enzymatic kinetic resolution of amino alcohol (ꢀ)-5. To
ꢁ
phenylethyl acetate were used. Melting points were taken on
a mixture of (ꢀ)-5 (1.00 g, 5.10 mmol), PSL-C (520 mg) and 4 A

F.J. Quijada et al. / Tetrahedron 68 (2012) 7670e7674
7673
molecular sieves (50 mg), under a nitrogen atmosphere, anhydrous
tert-butyl methyl ether (30 mL) and vinyl acetate (1.40 mL,
15.6 mmol) were added. The mixture was stirred for 48 h at 28 ꢁC
and 200 rpm. After this time, the enzyme was filtered through a pad
of CeliteÒ and the solid was washed with methanol. The solutionwas
concentrated to reduced pressure and the resulting crude, which
was formed by the optically active (1S,6S)-5 and the ester (1R,6R)-9,
was submitted to flash chromatography (hexane/AcOEt 30:1).
CH]CH2), 3.57e3.43 (m, 1H, H-1), 3.32e3.18 (m, 2H, NeCHH),
2.91e2.76 (m, 4H, NeCHHþH-2þCHH), 2.26e2.12 (m, 1H, CHH),
t
2.08e1.83 (m, 2H, 2ꢅ CHH), 1.44 (s, 9H, Bu); dC (75.5 MHz CDC13)
156.0 (C]O), 136.6 (CH]CH2), 124.9 (CH]CH), 124.8 (CH]CH),
116.6 (CH]CH2), 78.5 (C), 57.6 (CH), 52.0 (NeCH2), 48.3 (CH), 33.8
(CH2), 28.3 (CH3), 23.0 (CH2), m/z (ESIþ) 293 (50, MHþ), 237 (100);
HRMS (ESIþ): MHþ, found 293.2230. C17H29N2O2 requires 293.2224.
4.2.6. (1S,2S)-N,N0-Di(tert-butoxycarbonyl)cyclohex-4-ene-1,2-
diamine [(1S,2S)-2]. Obtained from (1S,2S)-8 (0.58 mmol). The allyl
groups were removed following the method described by an
analogous N,N-diallylcyclopentane-1,2-diamine.17 The resulting
crude mono-Boc diamine was subsequently dissolved in methanol
(4 mL) and treated with di-tert-butyl pyrocarbonate (0.140 g,
0.64 mmol). After 5 h of reaction at room temperature, solvents
were eliminated and the residue was subjected to flash chroma-
tography (hexane/Et2O 7:3 as eluent) to yield the title compound
(1S,2S)-2 (94%). Spectroscopic data are in good agreement with
4.2.3.1. (1S,6S)-6-(Diallylamino)cyclohex-3-en-1-ol
[(1S,6S)-
5]. Yield 49%; ½a D20
þ43.5 (c 1.0, CHCl3), ee 95%.
ꢂ
4.2.3.2. (1R,6R)-6-(Diallylamino)cyclohex-3-enyl acetate [(1R,6R)-
9]. Colourless oil; yield 45%; [found: C, 71.7; H, 8.7; N 6.2. C14H21NO2
requires C, 71.46; H, 8.99; N, 5.95%]; Rf (hexane/AcOEt 10:1) 0.42;
½
a 2D0
1210 cmꢃ1
ꢂ
ꢃ2.6 (c 1.0, CHCl3), ee >99%; nmax(CH2Cl2) 1728, 1634, 1503,
;
dH (300 MHz CDC13) 5.72 (dddd, 2H, 3J 5.4, 6.9, 10.3,
12.0 Hz, CH]CH2), 5.61e5.55 (m, 1H, CH]CH), 5.47e5.42 (m, 1H,
CH]CH), 5.15 [dq, 2H, J 1.7 (q),12.0 (d) Hz, CH]CHH], 5.20e5.00 (m,
1H, H-1), 5.05 [dq, 2H, J 1.7 (q), 10.3 (d) Hz, CH]CHH], 3.22 (ddt, 2H,
those previously reported.3
½
a 2D0
ꢂ
ꢃ30.1 (c 1.0, CHCl3). Ref. 3: ½a D21
ꢂ
ꢃ34.5 (c 1.100, CHCl3), ee 99%.
2
4J 1.4 (t) Hz, 3J 5.0 Hz, j Jj 14.4 Hz, NeCHH), 3.10e2.94 (m, 3H,
NeCHHþH-6), 2.52e2.42 (m, 1H), 2.24e2.02 [mþs, 6H. Singlet
corresponds to CH3 (2.07 ppm)]; dC (75.5 MHz CDC13) 170.2 (C]O),
137.4 (CH]CH2), 125.8 (CH]CH), 123.4 (CH]CH), 115.9 (CH]CH2),
69.8 (CH), 57.6 (CH), 52.8 (NeCH2), 31.9 (CH2), 25.8 (CH2), 21.2 (CH3);
m/z (EIþ): 235 (15, Mꢄþ), 194 [18 (MꢃCH2eCH]CH2)þ], 149 (100).
4.2.7. (1S,6S)-6-Aminocyclohex-3-en-1-ol
[(1S,6S)-10]. It
was
obtained from (1S,6S)-5 (0.400 g, 2.07 mmol) following the method
described for the removal of allyl groups.17 White solid; yield 82%;
mp 106e107 ꢁC; Rf (methanol) 0.18; ½a 2D0
ꢂ
þ141.9 (c 1.0, CHCl3), ee
95%; nmax(CH2Cl2) 3410, 3368, 3320, 1693, 1535 cmꢃ1
;
dH (400 MHz
CDC13) 5.58e5.48 (m, 2H, CH]CH), 3.47 (dt, 1H, J 5.9 (d), 9.6 (t) Hz,
H-1), 2.77 (q, 1H, 3J 9.6 Hz, H-6), 2.43e2.18 (m, 5H, 2ꢅ
CHHþOHþNH2), 2.09e1.97 (m, 1H, CHH), 1.93e1.81 (m, 1H, CHH);
dC (100 MHz CDC13) 125.0 (CH]CH), 71.9 (CH), 53.0 (CH), 34.9
(CH2), 33.6 (CH2); m/z (ESIþ) 114 (100, MHþ); HRMS (ESIþ): MHþ,
found 114.0919. C6H12NO requires 114.0913.
4.2.4. Enzymatic kinetic resolution of diamine (ꢀ)-6. Ethyl acetate
(24 mL) was added to a mixture of racemic diamine (ꢀ)-6 (0.750 g,
3.90 mmol) and PSL-C (0.390 g) under a nitrogen atmosphere. The
new mixture was stirred at 28 ꢁC and 200 rpm during 48 h. Then,
the reaction mixture was filtered through a pad of CeliteÒ and the
solid was washed with methanol. Organic solvents were evapo-
rated under reduced pressure and the resulting crude, which con-
sisted of a mixture of diamine (1S,2S)-6 and monoamide (1R,2R)-7,
was subjected to flash chromatogarphy (a gradient of hexane/
AcOEt 1:1 to AcOEt/methanol 4:1 was used as eluent).
4.2.8. tert-Butyl (1S,6S)-N-[6-(hydroxy)cyclohex-3-enyl]carbamate
[(1S,6S)-11]. Prepared by tert-butoxycarbonylation of (1S,6S)-10
following the method described for (1S,2S)-8. The title compound
was isolated as a white solid (99%); mp 95e96 ꢁC; Rf (hexane/AcOEt
3:1) 0.28; ½a 2D0
ꢂ
þ30.5 (c 1.0, CHCl3), ee 95%; nmax(CH2Cl2) 3428,
4.2.4.1. (1S,2S)-N,N-Diallylcyclohex-4-ene-1,2-diamine [(1S,2S)-
2980, 1693, 1503, 1171 cmꢃ1
; dH (300 MHz CDC13) 5.62e5.50 (m,
6]. Yield 42%; ½a D20
ꢂ
þ67.3 (c 1.0, CHCl3), ee >99%.
2H, CH]CH), 4.66 (br s, 1H, NH), 3.78e3.58 (m, 2H, H-1þH-6), 2.92
(br s, 1H, OH), 2.57e2.43 (m, 2H), 2.18e2.00 (m, 1H), 2.00e1.90 (m,
1H),1.45 (s, 9H, tBu); dC (75.5 MHz CDC13) 156.7 (C]O),124.6 (CH]
CH), 124.2 (CH]CH), 79.7 (C), 70.1 (CH), 52.1 (CH), 33.5 (CH2), 31.3
(CH2), 28.2 (CH3); m/z (ESIþ) 236 (100, MNaþ); HRMS (ESIþ): MNaþ,
found 236.1266. C11H19NNaO3 requires 236.1257.
4.2.4.2. (1R,2R)-N-Acetyl-N0,N0-diallylcyclohex-4-ene-1,2-
diamine [(1R,2R)-7]. Yield 47%; mp 98e100 ꢁC; [found: C, 71.9; H,
9.6; N 12.2. C14H22N2O requires C, 71.76; H, 9.46; N, 11.95%]; Rf
(hexane/AcOEt 5:1) 0.41; ½a D20
ꢂ
ꢃ5.4 (c 1.0, CHCl3), ee >99%;
nmax(CH2Cl2) 3261, 3095,1634,1579 cmꢃ1
;
dH (300 MHz CDC13) 6.39
(br s, 1H, NH), 5.72 (dddd, 2H, 3J 4.6, 8.0, 10.2, 12.6 Hz, CH]CH2),
5.64e5.48 (m, 2H, CH]CH), 5.21e5.05 (m, 4H, CH]CH2), 3.79e3.65
(m, 1H, H-1), 3.31e3.19 (m, 2H, NeCHH), 3.02e2.80 (m, 4H,
NeCHHþH-2þCHH), 2.28e2.12 (m, 1H, CHH), 2.12e1.77 [mþs, 5H.
Singlet corresponds to CH3 (1.95 ppm)]; dC (75.5 MHz CDC13) 170.4
(C]O), 136.5 (CH]CH2), 125.1 (CH]CH), 124.9 (CH]CH), 116.8
(CH]CH2), 57.5 (CH), 52.0 (NeCH2), 47.8 (CH), 33.3 (CH2), 23.4 (CH3),
23.0 (CH2); m/z (EIþ): 193 [70, (MꢃCH2eCH]CH2)þ], 162 (100).
4.2.9. tert-Butyl (1S,2S)-N-(2-hydroxycyclohexyl)carbamate [(1S,2S)-
12]. To a mixture of (1S,6S)-11 (27 mg, 0.13 mmol) and 10% PdeC
(13 mg) under a hydrogen atmosphere, methanol (1.0 mL) was
added. The mixture was stirred under the hydrogen atmosphere at
room temperature for 10 h. After this time, the catalyst was filtered
through a pad of CeliteÒ and washed with methanol. The filtrate
was concentrated to reduced pressure to give pure the title com-
pound (1S,2S)-12 (99%). Spectroscopic data are in good agreement
with those previously reported.15
½
a 2D0
ꢂ
þ22.6 (c 0.50, MeOH), ee
4.2.5. (1S,2S)-N-(tert-Butoxycarbonyl)-N0,N0-diallylcyclohex-4-ene-
1,2-diamine [(1S,2S)-8]. Di-tert-butyl pyrocarbonate (0.419 g,
1.90 mmol) was added to a solution of (1S,2S)-6 (0.336 g,
1.75 mmol) in methanol (10 mL). After 1 h of reaction at room
temperature, solvents were evaporated and the residue was puri-
fied by flash chromatography (hexane/AcOEt 15:1 as eluant) to
yield the title compound (1S,2S)-8 (98%) as a white solid; mp
95%. Ref. 15: ½a 2D0
ꢂ
þ19.19 (c 0.50, MeOH), enantiopure.
4.2.10. tert-Butyl
(1S,6R)-N-[6-(azido)cyclohex-3-enyl]carbamate
[(1S,6R)-13]. It was obtained by previous mesylation of (1S,6S)-11
(0.115 g, 0.54 mmol) with mesyl chloride following the procedure
described.18 Then, the crude mesyl derivative was dissolved in
anhydrous N,N-dimethylformamide (1.0 mL) and sodium azide
(0.105 g, 1.62 mmol) was added. After heating the mixture at 70 ꢁC
during 24 h, ethyl acetate (5 mL) was added and the organic solu-
tion was repeatedly washed with water. The organic phase was
dried with Na2SO4, and evaporated to reduce pressure to give
45e46 ꢁC; Rf (hexane/AcOEt 5:1) 0.52; ½a 2D0
ꢂ
þ49.7 (c 1.0, CHCl3), ee
98%; nmax(CH2Cl2) 3381, 2977, 1715, 1648 cmꢃ1
;
dH (300 MHz
CDC13) 5.77 (dddd, 2H, 3J 4.8, 8.0, 10.2, 12.7 Hz, CH]CH2),
5.62e5.50 (m, 2H, CH]CH), 5.42 (br s, 1H, NH), 5.20e5.04 (m, 4H,

7674
F.J. Quijada et al. / Tetrahedron 68 (2012) 7670e7674
a residue, which was subjected to flash chromatography (hexane/
AcOEt 30:1; hexane/AcOEt 20:1; dichloromethane were succes-
sively used as eluent).19 The title compound (1S,6R)-13 was
obtained as a white solid (63%); mp 72e73 ꢁC; Rf (hexane/AcOEt
Amino carbamate (ꢀ)-8: hexane/ethanol 98:2, 0.8 mL/min,
30 ꢁC; tR¼5.6 (1R,2R) and 6.8 (1S,2S) min; RS¼3.3.
Amido carbamate derived from (ꢀ)-15: hexane/propan-2-ol
90:10, 0.8 mL/min, 30 ꢁC; tR¼17.3 (1S,2R) and 20.4 (1R,2S) min;
RS¼2.6.
3:1) 0.51; ½a 2D0
ꢂ
ꢃ60.1 (c 1.0, CHCl3), ee¼95%; nmax(CH2Cl2) 2980,
2130, 1634, 1340, 1160 cmꢃ1
;
dH (300 MHz CDC13) 5.70e5.50 (m,
2H, CH]CH); 4.72 (br s, 1H, NH), 4.00e3.82 (m, 2H, H-1þH-6),
2.58e2.40 (m, 1H), 2.38e2.29 (m, 2H), 2.11e2.01 (m, 1H), 1.44 (s,
Acknowledgements
t
9H, Bu); dC (75.5 MHz CDC13) 155.1 (C]O), 125.1 (CH]CH), 122.6
(CH]CH), 79.6 (C), 59.1 (CH), 48.1 (CH), 29.0 (CH2), 28.3
(CH3þCH2); m/z (ESIþ) 261 (100, MNaþ); HRMS (ESIþ): MNaþ,
found 261.1318. C11H18N4NaO2 requires 261.1322.
Financial support from the Spanish MICINN (CTQ2007-61126) is
gratefully acknowledged. F.J.Q. thanks the Spanish MICINN for
a predoctoral fellowship.
4.2.11. (3aS,7aR)-3a,4,7,7a-Tetrahydrobenzo[d]oxazol-2(3H)-one
[(3aS,7aR)-14]. It was isolated after the flash chromatography of
the residue obtained in the previous reaction with 27% yield. White
References and notes
solid; mp 53e55 ꢁC; Rf (AcOEt) 0.37; ½a 2D0
ꢂ
þ49.7 (c 1.0, CHCl3), ee
1. Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.; Swaminathan, S.;
Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y.; Laver, W. G.; Stevens, R. C.
J. Am. Chem. Soc. 1997, 119, 681e690.
2. (a) For a review, see: Magano, J. Chem. Rev. 2009, 109, 4398e4438; (b) Werner,
L.; Machara, A.; Sullivan, B.; Carrera, I.; Moser, M.; Adams, D. R.; Hudlicky, T.;
Andraos, J. J. Org. Chem. 2011, 76, 10050e10067 and references therein cited; (c)
Kim, H.-K.; Park, K.-J. J. Tetrahedron Lett. 2012, 53, 1561e1563.
3. Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006,
128, 6312e6313.
95%; nmax(CH2Cl2) 2973, 1684, 1634, 1167 cmꢃ1
;
dH (300 MHz
CDC13) 6.12 (br s, 1H, NH), 5.91 (br s, 2H, CH]CH), 4.98e4.84 (m,
1H, OeCH), 4.16e4.04 (m, 1H, NeCH), 2.58e2.44 (m, 1H, CHH),
2.24e2.02 (m, 3H, CH2þCHH); dC (75.5 MHz CDC13) 160.1 (C]O),
126.6 (CH]CH), 125.9 (CH]CH), 75.3 (CH), 50.4 (CH), 28.4 (CH2),
27.6 (CH2); m/z (ESIþ) 162 (100, MNaþ), 140 (60, MHþ); HRMS
(ESIþ): MHþ, found 140.0706. C7H10NO2 requires 140.0704.
4. Mita, T.; Fukuda, N.; Roca, F. X.; Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9,
259e262.
ꢀ
5. (a) Gonzalez-Sabín, J.; Gotor, V.; Rebolledo, F. Chem.dEur. J. 2004, 10,
4.2.12. (1S,2R)-N-(tert-Butoxycarbonyl)cyclohex-4-ene-1,2-diamine
[(1S,2R)-15]. It was prepared by Staudinger reduction of azido-
carbamate (1S,6R)-13 following a previously described procedure.18
Flash chromatography (AcOEt/methanol 10:1 as eluent) of the
crude of the reaction yielded compound (1S,6R)-15 (68%) as a col-
ꢀ
5788e5794; (b) Gonzalez-Sabín, J.; Gotor, V.; Rebolledo, F. J. Org. Chem. 2007,
ꢀ
72, 1309e1314; (c) Quijada, F. J.; Gonzalez-Sabín, J.; Rebolledo, F.; Gotor, V.
Tetrahedron 2009, 65, 8028e8034.
6. For some reviews about vicinal amino alcohols, see: (a) Bergmeier, S. C.
Tetrahedron 2000, 56, 2561e2576; (b) Lee, H.-S.; Kang, S. H. Synlett 2004,
1673e1685; (c) Della Sala, G.; Russo, A.; Lattanzi, A. Curr. Org. Chem. 2011, 15,
2147e2183.
7. For some reviews about vicinal diamines, see: (a) Bennani, Y. L.; Hanessian, S.
Chem. Rev. 1997, 97, 3161e3196; (b) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew.
Chem., Int. Ed. 1998, 37, 2580e2627; (c) Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem.
Biol. Drug Des. 2006, 67, 101e114; (d) Gonzalez-Sabín, J.; Rebolledo, F.; Gotor, V.
Chem. Soc. Rev. 2009, 38, 1916e1925; (e) Alfonso, I. Curr. Org. Synth. 2010, 7,
1e23.
ourless oil; Rf (AcOEt/MeOH 20:1) 0.17; ½a D20
ꢂ
ꢃ14.7 (c 1.0, CHCl3), ee
95%; nmax(CH2Cl2) 3355, 3281, 2976, 1692, 1535, 1167 cmꢃ1
;
dH
(300 MHz CDC13) 5.52 (s, 2H, CH]CH), 5.00 (br s, 1H, NH), 3.75 (br
s, 1H, H-1), 3.10e3.01 (m, 1H, H-2), 2.47e2.25 (m, 2H), 2.06e1.82
ꢀ
t
(m, 2H), 1.62e1.38 [br sþs, 11H; NH2 (br s, 1.53 ppm) and Bu (s,
1.42 ppm)]; dC (75.5 MHz CDC13) 155.8 (C]O),124.4 (CH]CH), 79.1
(C), 49.4 (CH), 48.2 (CH), 33.0 (CH2), 29.1 (CH2), 28.3 (CH3); m/z
(ESIþ) 213 (100, MHþ); HRMS (ESIþ): MHþ, found 213.1592.
C11H21N2O2 requires 213.1598.
8. Perlman, N.; Albeck, A. Synth. Commun. 2000, 30, 4443e4449.
9. (a) Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. Am. Chem. Soc. 1982, 104,
7294e7299; (b) Program ‘Selectivity’ http://borgc185.kfunigraz.ac.at/sites/re-
search/model.htm.
10. This combination of acyl donor and solvent had a beneficial effect in the CAL-B-
ꢀ
catalyzed resolution of some racemic amines: Gonzalez-Sabín, J.; Gotor, V.;
Rebolledo, F. Tetrahedron: Asymmetry 2004, 15, 481e488.
11. For some examples using PSL-C as catalyst in the resolution and desymme-
4.3. HPLC determination of the enantiomeric excesses
ꢀ
tryzation of amines, see: (a) Torre, O.; Busto, E.; Gotor-Fernandez, V.; Gotor, V.
The ee for each compound obtained in the enzymatic resolu-
tions as well as for the cis-diamine derivative 15 was determined by
chiral HPLC using Chiralpack-IA column. Compounds 5 and 7 were
analyzed directly. Amino ester 9 was previously converted into the
amino alcohol 5 by hydrolysis with a 0.50 M methanolic solution of
NaOH. trans-Diamine 6 was transformed into its tert-butyl carba-
mate derivative 8. The chemoenzymatically prepared cis-amino
carbamate 15 was treated with acetic anhydride and the resulting
amido carbamate analysed. Results obtained in the analysis of ra-
cemic samples are as follows:
Adv. Synth. Catal. 2007, 349, 1481e1488; (b) Ríos-Lombardía, N.; Busto, E.;
Gotor-Fernandez, V.; Gotor, V. J. Org. Chem. 2011, 76, 5709e5718.
12. Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org. Chem.
ꢀ
1991, 56, 2656e2665.
13. Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993, 58, 6109e6613.
ꢀ
14. Thus far, lipase from Burkholderia cepacia (before classified as Pseudomonas
cepacia) has proven to be the most effective catalyst for the resolution of
secondary alcohols. See for example: Bornscheuer, U. T.; Kazlauskas, R. J.
Hydrolases in Organic Synthesis Regio- and Stereoselective Biotransformations,
2nd ed.; Wiley-VCH: Weinheim, 2006, Chapter 5.
15. Okano, M.; Mito, J.; Maruyama, Y.; Masuda, H.; Niwa, T.; Nakagawa, S.-i.;
Nakamura, Y.; Matsuura, A. Bioorg. Med. Chem. 2009, 17, 119e132.
16. Benedetti, F.; Norbedo, S. Tetrahedron Lett. 2000, 41, 10071e10074.
Amino alcohol (ꢀ)-5: hexane/ethanol 98:2, 0.8 mL/min, 30 ꢁC;
tR¼8.9 (1R,6R) and 11.6 (1S,6S) min; RS¼4.3.
~
ꢀ
17. Pena, C.; Gonzalez-Sabín, J.; Rebolledo, F.; Gotor, V. Tetrahedron: Asymmetry
2008, 19, 751e755.
18. Quijada, F. J.; Gotor, V.; Rebolledo, F. Org. Lett. 2010, 12, 3602e3605.
19. Beside the compound (1S,6R)-13, the bicyclic oxazolidinone 14 was also
isolated in this reaction. Characterization of 14 is given in section 4.2.10.
Amino amide (ꢀ)-7: hexane/ethanol 95:5, 0.8 mL/min, 30 ꢁC;
tR¼10.4 (1R,2R) and 14.4 (1S,2S) min; RS¼6.0.