Enantioselective preparation of a novel chiral 1,2-diamine

Article abstract of DOI:10.1055/s-2001-13406

A short enantioselective preparation of (1S,2S)-trans-1,2-diamino-3-cyclohexene using a double [3,3]-sigmatropic rearrangement of an allylic bis(imidate) is described (Overman rearrangement). The starting chiral diol is conveniently obtained by enzymatic resolution.

Full text of DOI:10.1055/s-2001-13406

PAPER
863
Enantioselective Preparation of a Novel Chiral 1,2-Diamine
Stéphane Demay, Andras Kotschy, Paul Knochel*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstraße 5–13, Haus F, 81377 München, Germany
Fax +49(089)21807680; E-mail: Paul.Knochel@cup.uni-muenchen.de
Received 6 February 2001; revised 21 February 2001
1-one (5)6 as a key step for introducing the chirality. The
CBS-reduction7 of 5 (BH3·SMe2, Me-CBS (15 mol%),
THF, −10 °C, 1 hour) provided the chiral allylic alcohol
(R)-6 in 96% yield and 96–98% ee. The debromination of
6 with tert-BuLi8 (3.2 equivalents, −78 °C, 1 hour) and
epoxidation with m-chloroperbenzoic acid (m-CPBA; 1.4
equivalents) in CH2Cl2 at 20 °C for 6 hours furnished a
70:30 mixture of the two diastereoisomeric epoxides 7a
and 7b as already described in the literature.9
Abstract: A short enantioselective preparation of (1S,2S)-trans-
1,2-diamino-3-cyclohexene using a double [3,3]-sigmatropic rear-
rangement of an allylic bis(imidate) is described (Overman rear-
rangement). The starting chiral diol is conveniently obtained by
enzymatic resolution.
Key words: 1,2-diamines, enzymes, rearrangements, chiral resolu-
tion
Chiral diamines are an important class of ligands for
asymmetric catalysis.1,2 Their preparation is always a
challenge and only a few practical solutions have been re-
ported.3 Recently, we have developed a new method
based on a [2,3]-sigmatropic rearrangement starting from
allylic alcohols of type 1 and allowing the preparation of
a chiral phosphine of type 2 after reduction4 (Scheme 1).
This reaction proceeds with complete transfer of the
chirality from the alcohol to the phosphine.4 Herein, we
wish to report a related double Overman-rearrangement5
allowing the practical preparation of (1S,2S)-1,2-diami-
nocyclohex-3-ene (4) in 9% ee starting from (1R,2R)-1,2-
cyclohex-3-enediol (3) (Scheme 1).
O
OH
OTBDPS OTBDPS
Br
Br
b, c, d, e
a
+
O
O
5
6
96%
96–97% ee (R)
7b
7a:7b = 70:30
7a
7a is isolated in 50%
overall yield
OH
OTBDPS
OH
OTBDPS
O
OH
f
g
(1R,2R)-3
60%
8
7a
OH
99% ee
PPh2
Scheme 2 Reagents and conditions: (a) Me-CBS cat. (15 mol%),
BH3·SMe2 (60 mol%), THF, −10 °C, 1 h; (b) tert-BuLi (3.2 equiv),
pentane, Et2O, −78 °C, 1 h; (c) Sat. NaHCO3 solution, −78 °C to r.t.;
(d) TBDPS-Cl (1.1 equiv), imidazole (2.2 equiv), DMF, r.t., 12 h; (e)
m-CPBA (1.4 equiv), CH2Cl2, 0 °C to r.t., 6 h; (f) Et2NLi (3.5 equiv),
Et2O, hexane, reflux, 17 h; (g) TBAF (1.0 equiv), THF, r.t., 14 h
2
1
ClPPh2
PPh2
reduction
P(O)Ph2
O
[2,3]-sigmatropic shift
These two epoxides were readily separated by chromatog-
raphy (pentane-ether) and the major epoxide 7a was iso-
lated in 50% overall yield from the allylic alcohol 6. By
treatment with lithium diethylamide (3.5 equivalents) in a
mixture of ether and hexane at reflux for 17 hours, the ep-
oxide 7a underwent a smooth ring opening, affording the
selectively protected diol 8, which was directly used in the
next step. After desilylation with tetrabutylammonium
fluoride (TBAF) in THF and recrystallization in ethyl ac-
etate, the optically pure diol (1R,2R)-3 was obtained in
60% yield and 9% ee (Scheme 2).
NH2
NH2
OH
OH
3
4
Scheme 1
The starting 1,2-diol 3 can be prepared in optically pure
form using two methods. In the first approach, we have
used an asymmetric reduction of 2-bromo-2-cyclohexen-
Alternatively, diol 3 can be prepared using enzymatic res-
olution. The racemic diacetate 9 was obtained in three
steps from cyclohexadiene in 49% overall yield10
(Scheme 3). By using Pseudomonas Fluorescens Lipase
(PFL)11 in a buffered aqueous solution at pH 7, a selective
hydrolysis of the racemic diacetate 9 occurred leading to
Synthesis 2001, No. 6, 04 05 2001. Article Identifier:
1437-210X,E;2001,0,06,0863,0866,ftx,en;T01501SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

864
S. Demay et al.
PAPER
a mixture of the two (R,R)-monoacetate 10a and 10b
(45% yield, 94% ee) as well as unreacted (S,S)-diacetate 9
(43% yield; 97% ee). The monoacetates (R,R)-10 and the
unreacted (S,S)-9 were readily separated by chromatogra-
phy (using pentane-ether mixtures; see experimental sec-
tion). After saponification of 9 and 10 with sodium
methoxide in methanol and recrystallization in ethyl ace-
tate, the two chiral diols (1S,2S)-3 and (1R,2R)-3 were ob-
tained in > 9% ee (31% yield) and 98.6% ee (29% yield),
respectively as determined by HPLC analysis using a
Chiralsil-Dex CP column.
CCl3
NH
O
CCl3
NH
O
O
OH
OH
a
b
HN
O
HN
CCl3
CCl3
(S,S)-3
(S,S)-11
O
O
CCl3
NH
NH
NH2
c, d
2HCl
NH2
CCl3
a, b, c
(S,S)-4
(S,S)-12
65% yield
56% yield
OAc
(+/–)-9
Scheme 4 Reagents and conditions: (a) CCl3CN (2 equiv), NaH
(0.2 equiv), THF, 0°C; (b) xylene, reflux, 6 h; (c) 6 M NaOH, 85°C,
6 h; (d) 37 % HCl, EtOH
49%
OAc
d
OH
OAc
OAc
OAc
In summary, we have reported an enantioselective synthe-
sis to a new chiral diamine. The evaluation of (S,S)-4 or
simple derivatives of it as ligands for asymmetric metal
catalysis is currently underway in our laboratories.
+
+
OAc
OH
(R,R)-10a
(R,R)-10b
(S,S)-9
43%
97% ee
45%
94% ee
Mps were measured on a Büchi B-540 apparatus and are uncorrect-
ed. NMR spectra were recorded on a Bruker ARX 200 or ACX 300
instruments. IR spectra were recorded on a Nicolet 510 or a Perkin−
Elmer 281 spectrometer. Electron impact (EI) mass spectra were re-
corded on a Varian MAT CH 7A. All reagents were of commercial
quality. Pseudomonas Fluorescens Lipase was purchased from
FLUKA.
e, f
e, f
OH
OH
(S,S)-3
OH
OH
(R,R)-3
Optically Pure trans-1,2-Dihydroxy-3-cyclohexene (3)
29% (from 9)
98.6% ee
31% (from 9)
>99% ee
Method A: Enzymatic Resolution
Racemic trans-1,2-Diacetoxy-3-cyclohexene (9)10
Scheme 3 Reagents and conditions: (a) Br2, CHCl3, 0°C; (b) 2 M
KOH, H2O, r.t., 4 d; (c) Ac2O, pyridine; (d) Pseudomonas Fluore-
scens Lipase, pH 7, buffer; (e) NaOMe, MeOH, r.t., 1 h; (f) recryst.
from EtOAc
A solution of bromine (42 g, 14.5 mL) in CHCl3 (150 mL) was add-
ed dropwise to a solution of cyclohexadiene (27 mL, 280 mmol) in
CHCl3 (200 mL) at 0 °C. After evaporation of the solvent, the resi-
due was filtered through a short plug of silica with pentane. Follow-
ing the removal of pentane, the residual oil was treated with 2 N
KOH (400 mL) and vigorously stirred for 4 days. After neutraliza-
tion with concd HCl and solid NaHCO3 to set the pH to 7, all the
volatiles were removed in vacuum. The resulting solid was extract-
ed with CH2Cl2. After drying (MgSO4) and evaporation of the sol-
vent, crude 1,2-dihydroxy-3-cyclohexene 3 was obtained (20.6 g).
Without any further purification, the diol was dissolved in pyridine
(300 mL) and treated with acetic anhydride (51 mL, 540 mmol). Af-
ter stirring at r.t. over night, the solution was poured onto ice/water
(600 g), extracted with Et2O and dried (MgSO4). Removal of the
solvent and distillation at reduced pressure gave 25.4 g (49% yield)
of the racemic diacetate 9 as a colorless oil.
The reaction of (S,S)-3 with trichloroacetonitrile (2
equivalents) and NaH (0.2 equivalent) in THF at 0 °C for
4 hours furnished the intermediate (S,S)-trichloroimidate
derivative 11. This crude intermediate was heated at re-
flux in xylene for 6 hours leading by a double Overman-
rearrangement5 to the bis(trichloroacetamide) 12 in 56%
yield. The simplicity of the purification step is worth men-
tioning since the bis(trichloroacetamide) 12 precipitates
from the crude reaction mixture at 0°C, washing with pen-
tane and drying under vacuum was sufficient for obtaining
the bis(amide) 12 in an analytically pure form. Deprotec-
tion of the diamide with 6 M NaOH at 85 °C for 6 hours
provided the desired diamine (1S,2S)-4 isolated as its di-
hydrochloride in 65% yield and 9% ee.
Bp 126−129 °C (9 mbar).
1H NMR (300 MHz, CDCl3): δ = 5.90 (m, 1H, H-4), 5.58 (dd, 1H,
J = 9.9, 2.1 Hz, H-3), 5.38 (m, 1H), 5.03 (m, 1H), 2.22 (m, 2H, CH2),
2.08 (s, 6H, CH3), 1.99 (m, 1H, CH2), 1.83 (m, 1H, CH2).
13C NMR (75 MHz, CDCl3): δ = 170.9, 170.7, 131.7, 124.6, 71.8,
71.2, 25.8, 23.6, 21.5.
Synthesis 2001, No. 6, 863–866 ISSN 0039-7881 © Thieme Stuttgart · New York

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Enantioselective Preparation of a Novel Chiral 1,2-Diamine
865
(1S,2S)-1,2-Dihydroxy-3-cyclohexene (3)
13C NMR (50 MHz, CDCl3): δ = 135.1, 128.3, 72.3, 34.6, 30.4, 20.1
Racemic diacetate 9 (11.9 g, 60 mmol) and phosphate buffer pH 7
(2.4 L) were stirred in a 4 L round bottom flask. The enzyme
Pseudomonas Fluorescens Lipase (3601U/mg; 15 mg) was added
and the reaction mixture was warmed to 38 °C and was allowed to
react at this temperature until the ee of the diacetate reached at least
96% (40 h). The progress of the reaction was monitored by GC. Af-
ter cooling the mixture to r.t., solid NaCl was added until saturation.
The solution was then extracted with Et2O (4 × 800 mL) and the or-
ganic layer was dried (MgSO4). The solution was filtered and the
solvent was concentrated under vacuum. The resulting oil was puri-
fied by flash chromatography on flash silica gel. The (S,S)-diacetate
9 was first eluted with pentane-Et2O (4:1) yielding 9 as a colorless
oil (5.20 g, 43% yield, 97% ee). Then the (R,R)-monoacetates mix-
ture 10a and 10b was eluted with a mixture of pentane-Et2O-MeOH
(10:10:1) yielding 10a and 10b as a colorless oil (4.25 g, 45% yield,
94% ee).
MS (EI): m/z (%) = 176.0 (1) [M+], 97.0 (100) [M+ − Br], 79.0 (23),
41.0 (50).
Anal. Calcd for C6H9BrO (177.04): C, 40.70; H, 5.12. Found: C,
40.70; H, 5.31.
Enantiomeric excess was determined by HPLC with a Chiracel OJ
column. Flow rate: 0.7 mL min−1. Temp: 20°C. Eluent: n-heptane-
propan-2-ol (99.5:0.5). Retention times of (R)- and (S)- enantiomers
are 31.39 min and 36.94 min, respectively.
(1R,2R)-1,2-Dihydroxy-3-cyclohexene (3)
A
solution of tert-BuLi in pentane (1.2 M, 350 mL, 420.0 mmol,
3.2 equiv) was added dropwise to a solution of (R)-2-bromo-2-cy-
clohexen-1-ol (6, 23.0 g, 130 mmol) in Et2O (200 mL) at –78 °C.
After the addition, the mixture was stirred for further 10 min at
–78°C and slowly warmed up to –20 °C. Quenching was carefully
carried out by addition sat. NaHCO3 (50 mL) and warming up to r.t.
After drying the organic layer (MgSO4), the solvents were evaporat-
ed under vacuum. The crude 2-cyclohexenol (13.3 g) and imidazole
(19.5 g, 286 mmol, 2.2 equiv) were dissolved in DMF (100 mL) and
TBDPS-Cl (36.6 mL, 143 mmol, 1.1 equiv) was added dropwise at
r.t. After stirring overnight, the crude reaction mixture was poured
on water (200 mL) and extracted three times with Et2O (200 mL).
The organic layers were washed successively with 10% HCl, H2O,
and brine. After drying (MgSO4), the solvents were evaporated. The
crude protected 2-cyclohexenol was dissolved in CH2Cl2 (500 mL)
and cooled to 0 °C. Solid m -CPBA moistened with 30% H2O
(45 g, 180 mmol, 1.4 equiv) was added over 15 min. The reaction
mixture was allowed to warm up to r.t. and was stirred overnight.
After filtration of the white precipitate of m-CPBA, the organic lay-
er was washed successively with sat. Na2SO3, sat. NaHCO3, and
brine. After drying (MgSO4), the crude mixture of epoxides 7a and
7b (ratio 7:3) was purified by chromatography on silica gel (pen-
tane-Et2O, 99:1 to 95:5). The epoxide 7a (23.0 g, 50% yield from 6)
was isolated as a colorless oil, which was used without any further
purification in the following step.
The ee of the diacetate 9 was directly established using chiral GC
analysis. The ee of the monocetates mixture 10a and 10b was deter-
mined by chiral GC analysis after converting the monoacetates to
the diacetates with acetic anhydride in pyridine for 3 h.
Enantiomeric excess was obtained by chiral capillary GC analysis
of the corresponding diacetate using a Chiralsil-Dex CP column
(25.0 m × 250 µm × 0.25 µm). Carrier gas: H2. Internal pressure:
12.12 psi. H2 flow rate: 2.8 mL min−1. Oven temperature: 40 °C for
10 min, then warming up to 160 °C with a rate of 5 °C min−1 and
staying at 160 °C for 20 min. Retention times of the (R,R) and (S,S)
enantiomers are 27.45 min and 27.63 min respectively.
The (S,S)-diacetate 9 was then placed in MeOH (20 mL) with solid
sodium methoxide (2 equiv) and the reaction mixture was stirred at
r.t. for 1 h. Concd HCl was added until pH 5−6, then solid bicarbon-
ate was added. The mixture was concentrated under vacuum, the
crude residue was dissolved in EtOAc and the salts were filtered off.
The filtrate was concentrated under vacuum and the solid residue
was then recrystallized from EtOAc. (S,S)-Diol 3 was obtained as a
colorless crystalline solid (2.1 g, 99.5% ee, 31% overall yield from
9).
A solution of Et2NLi was prepared by adding BuLi (1.55 M in hex-
anes, 150 mL, 232 mmol) to a solution of Et2NH (28.0 mL, 275
mmol) in Et2O (100 mL) at 0 °C. This solution of Et2NLi was added
to a solution of epoxide 7a (23.0 g, 65.0 mmol) in Et2O (150 mL) at
r.t. and the reaction mixture was heated to reflux for 17 h. After
cooling to 0 °C, the reaction was carefully quenched with H2O
(30 mL). The organic phase was washed successively with 10%
HCl, sat. NaHCO3, and brine. After drying (MgSO4), the solvents
were evaporated. The crude monoprotected diol 8 was dissolved in
THF (30 mL) and TBAF (1 M solution in THF, 65 mL, 1 equiv) was
added at r.t. After stirring for 14 h, THF was evaporated and the
crude mixture was directly purified by chromatography on silica gel
(Et2O-MeOH, 100:0 to 96:4). After recrystallization from EtOAc,
the diol (1R,2R)-3 (4.45 g, 60% yield from 7a) was obtained in op-
tically pure form (> 9% ee) as a colorless crystalline solid.
The same procedure was applied for the hydrolysis of the (R,R)-
monoacetates mixture 10a and 10b using sodium methoxide
(1 equiv). The (R,R)-diol 3 was obtained as a colorless crystalline
solid (2.0 g, 98.6% ee, 29% overall yield from 9) (mp 72−73 °C).
Method B
(R)-2-Bromo-2-cyclohexen-1-ol (6)
2-Bromo-2-cyclohexen-1-one (5) was prepared according to the
method of Kowalski.6 The CBS-reduction of the enone 5 was per-
formed as follows: A solution of the enone 5 (25 g, 143 mmol) in
dry THF (150 mL) and a solution of BH3·SMe2 (8.6 mL, 86 mmol,
0.6 equiv) in dry THF (100 mL) were simultaneously added drop-
wise within 1 h to a solution of Me-CBS catalyst (6.0 g, 21 mmol,
0.15 equiv) in dry THF at –10 °C to −15 °C. After the addition, the
reaction mixture was stirred at –15 °C for 45 min and quenched
with MeOH (50 mL). After evaporating THF and MeOH under vac-
uum, the residue was dissolved in Et2O and washed with brine. The
organic layer was dried (MgSO4) and Et2O was evaporated. The
crude yellow oil obtained was purified by chromatography on silica
gel (Et2O-pentane, 1:1). (R)-2-Bromo-2-cyclohexen-1-ol (6) was
isolated as a colorless liquid (23.9 g, 95 % yield) with an optical pu-
rity of 96−98% ee.
Mp 72−73°C (racemic mixture recrystallized from EtOAc 76−
77°C).
IR (KBr): ν = 3306 cm−1.
[α]20 +22.4 (c 1.21, CHCl3) (99.5 % ee) for the (1S,2S) enanti-
D
omer.
1H NMR (300 MHz, CDCl3): δ = 5.75−5.70 (m, 1H, H-4), 5.50−
5.54 (m, 1H, H-3), 4.12−4.06 (m, 1H, H-2), 3.66−3.59 (m, 1H, H-
1), 2.52 (br s, 2H, OH), 2.21−2.14 (m, 2H), 1.99−1.91 (m, 1H),
1.71−1.61 (m, 1H).
13C NMR (75 MHz, CDCl3): δ = 128.6, 128.2, 73.3, 73.2, 28.5, 24.7.
MS (EI): m/z (%) = 114.1 (0.32) [M+], 96.2 (4.6), 70.3 (100), 69.2
IR (KBr): ν = 3371, 1641 cm−1.
[α] 20D +88 (c 1.8, CHCl3) (96.8 % ee).
1H NMR (200 MHz, CDCl3): δ = 6.23−6.10 (m, 1H, H-3), 4.25−
4.18 (m, 1H, H-1), 3.11 (br s, 1H, OH), 2.12−1.65 (m, 6H).
(23.4).
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S. Demay et al.
PAPER
Anal. Calcd for C6H10O2 (114.14): C, 63.14; H, 8.83. Found: C,
62.99; H, 8.84.
Anal. Calcd for C6H14N2Cl2 (185.09): C, 38.94; H, 7.62; N, 15.13.
Found: C, 38.48; H, 7.64; N, 14.83.
(1S,2S)-N,N′-Bis(trichloroacetyl)-trans-1,2-diamino-3-
cyclohexene (12)
Acknowledgement
NaH (200 mg, 60% dispersion in mineral oil) was added in portions
to a solution of (1S,2S)-1,2-dihydroxy-3-cyclohexene 3 (2.74 g,
24.0 mmol) in dry THF (20 mL) under Ar. The resulting mixture
was stirred for 1 h, then cooled in an ice/water bath and a solution
of trichloroacetonitrile (6.93 g, 4.8 mL, 48 mmol) in dry THF
(20 mL) was added dropwise within 30 min. The resulting brown
solution was stirred at r.t. for 3 h. After evaporation of the volatile
components in vacuum, the residue was extracted three times with
pentane (30 mL) and the combined extracts were evaporated in vac-
uum to give the colorless crystalline diimidate 11, which was then
dissolved in xylene (30 mL) and refluxed for 6 h. After cooling to 0
°C, the resulting white precipitate was filtered and washed with pen-
tane to give the optically pure bis(trichloroacetamide) 12 (5.40 g,
56% yield) as fine colorless needles.
We thank the Deutsche Forschungsgemeinschaft (Leibniz pro-
gram), the Institut de Recherches Servier (Suresnes, France), the
Humbolt Foundation for a fellowship to A. K. and PPG-SIPSY for
financial support. We also thank the BASF AG (Ludwigshafen),
Chemetall GmbH (Frankfurt) and Degussa-Hüls AG (Hanau) for
the generous gift of chemicals.
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Mp >290 °C (decomposition).
IR (KBr): ν = 3304, 1686.8, 1528.1 cm−1.
[α]20D +42.7 (c 0.52, MeOH).
1H NMR (300 MHz, DMSO-d6): δ = 9.09 (d, 1H, J = 8.47 Hz, NH),
8.93 (d, 1H, J = 8.52 Hz, NH), 5.87 (m, 1H, H-4), 5.47 (d, 1H,
J = 9.67 Hz, H-3), 4.73 (m, 1H, H-2), 4.16 (m, 1H, H-1), 2.23 (m,
2H), 2.02−1.88 (m, 2H).
13C NMR (75 MHz, DMSO-d6): δ = 160.9, 160.4, 128.1, 125.9,
92.3, 92.2, 51.2, 50.4, 26.5, 23.7.
MS (EI): m/z (%) = 367 (0.4) [M − Cl], 213 (96), 217 (29), 79 (100).
Anal. Calcd for C10H10N2O2Cl6 (402.92): C, 29.81; H, 2.50; N, 6.96.
Found: C, 29.55; H, 2.51; N, 6.74.
(1S,2S)-trans-1,2-Diamino-3-cyclohexene Dihydrochloride (4)
A slurry of bis(trichloroacetamide) 12 (1.72 g, 4.2 mmol) in 6 M
NaOH (10 mL) was stirred at 85 °C for 6 h leading to a yellow so-
lution. After cooling to r.t., the reaction mixture was extracted with
dioxane (3 × 30 mL) and the combined organic extracts were dried
(MgSO4). Evaporation of the solvent gave a yellow oil (550 mg),
which was dissolved in a MeOH-benzene mixture (1:1, 20 mL) and
treated with concd HCl (1 mL). Evaporation of the solvents and re-
peating the previous treatment gave a solid that was washed with
EtOH. After drying, the dihydrochloride 4 was obtained as a white
solid (510 mg, 65% yield).
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(11) (a) Laumen, K.; Breitgloff, D.; Seemayer, R.; Schneider, M.
P. J. Chem. Soc., Chem. Commun. 1989, 148. (b) Fang, C.;
Ogawa, T.; Suemune, H.; Sakai, K. Tetrahedron:
Asymmetry 1991, 2, 389.
Mp >310 °C (decomposition).
IR (KBr): 2912.5, 1604.9, 1524.0 cm–1.
[α]20D +66.7 (c 0.15, H2O).
1H NMR (300 MHz, D2O): δ = 6.25 (dd, 1H, J = 1.8, 10.1 Hz, H-4),
+
5.66 (dd, 1H, J = 1.8, 10.1 Hz, H-3), 4.69 (s, 6H, NH3 ), 4.07 (m,
1H, H-2), 3.75 (m, 1H, H-1), 2.29−1.98 (m, 4H).
13C NMR (75 MHz, D2O): δ = 135.6, 119.0, 48.9, 48.6, 22.8, 21.4.
Synthesis 2001, No. 6, 863–866 ISSN 0039-7881 © Thieme Stuttgart · New York