Synthesis of new mono-N-tosylated diamine ligands based on (R)-(+)-limonene and their application in asymmetric transfer hydrogenation of ketones and imines

Article abstract of DOI:10.1016/j.tetasy.2013.04.010

A synthetic procedure leading to the preparation of a new family of enantiopure mono-N-tosylated-1,2-diamines derived from (R)-(+)-limonene is described. (+)-Limonene was transformed into the appropriate N-tosyl derivative using N-tosylaziridination based on chloramine-T trihydrate. Subsequent ring opening by sodium azide afforded the corresponding isomeric azides. Finally, reduction of the azide function gave enantiomerically pure mono-N-tosylated-1,2- diamines. The ligands obtained proved to be effective in the asymmetric transfer hydrogenation protocol on aromatic ketones and imines.

Full text of DOI:10.1016/j.tetasy.2013.04.010

Tetrahedron: Asymmetry 24 (2013) 643–650
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of new mono-N-tosylated diamine ligands based on
(R)-(+)-limonene and their application in asymmetric transfer
hydrogenation of ketones and imines
Piotr Roszkowski a, , Jan K. Maurin b,c, Zbigniew Czarnocki a
⇑
a Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
b National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland
c
´
National Centre for Nuclear Research, 05-400 Otwock-Swierk, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 March 2013
Accepted 17 April 2013
A synthetic procedure leading to the preparation of a new family of enantiopure mono-N-tosylated-1,2-
diamines derived from (R)-(+)-limonene is described. (+)-Limonene was transformed into the appropriate
N-tosyl derivative using N-tosylaziridination based on chloramine-T trihydrate. Subsequent ring opening
by sodium azide afforded the corresponding isomeric azides. Finally, reduction of the azide function gave
enantiomerically pure mono-N-tosylated-1,2-diamines. The ligands obtained proved to be effective in the
asymmetric transfer hydrogenation protocol on aromatic ketones and imines.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
proposed by Rosa et al. allowed a one-pot preparation of secondary
and tertiary amines from (R)-(+)-limonene.7 Limonene oxides were
Naturally occurring monoterpenes, such as (+)-3-carene, (ꢀ)-
a
-
also starting materials for the preparation of diastereomeric aziri-
dines.8 The selective addition of nitrosyl chloride to limonene
afforded the formation of the corresponding dimeric nitrosochlo-
ride, which was then trapped by a reactive diamine to afford chiral
ligands for binuclear complexes with PdCl2.2f The highly selective
formation of limonene aziridines9 allowed their further transfor-
mation into bifunctionalized limonenes as reported by Voronkov
et al.10
Considering that chiral vicinal diamines are valuable synthetic
auxiliaries, such as their application as chiral ligands for various
catalytic asymmetric transformations,2e,11,12 we recently reported
a simple method for the transformation of limonene into trans-
1,2-diamine derivatives.13 In particular, the appropriate mono-
N-tosylated compounds were applied as ligands in asymmetric
hydrogen transfer reaction.
pinene, (ꢀ)-b-pinene and (+)-limonene, are readily available chiral
substrates used widely in organic synthesis. They have served as
inexpensive starting materials from renewable sources for the con-
struction of complex chiral molecules.1 The monoterpenes have
also been incorporated in the structure of chiral adjuvants and aux-
iliaries used as ligands in a variety of stereoselective catalytic
transformations.2 Limonene itself (both enantiomers and dipen-
tene) as well as its oxygenated derivatives are valuable compo-
nents in food additives, cosmetics, pharmaceuticals and
agrochemicals.3 From a chemical point of view, limonene enantio-
mers are very attractive and simple starting materials. However,
despite the relatively simple chemical structure, limonene has
quite a complex chemistry and a fully selective functionalization
of this molecule creates a considerable challenge. For example,
due to the presence of two olefinic bonds, both enantiomers of lim-
onene form eight epoxides that are difficult to isolate in a pure
form.4 Other addition reactions usually also give a mixture of prod-
ucts.5 Recently, several effective and selective procedures for limo-
nene functionalization have been proposed. Basing on the
commercially available 47:53 mixture of cis- and trans-epoxides
(limonene epoxides), Palmieri et al. developed a convenient syn-
Herein we report our studies on the synthesis of mono-N-tosy-
lated-1,2-diamines from limonene and on the evaluation of their
catalytic utility in the asymmetric transfer hydrogenation of aro-
matic ketones and imines.
2. Results and discussion
thesis of new diamines, aminoalcohols and aminophosphines.6
A
The application of direct N-tosylaziridination reactions on
limonene is very attractive starting point for the synthesis of
blabblaba chiral diamine derivatives.14 Thus, the reaction of
(R)-(+)-limonene 1 with Chloramine-T trihydrate in the presence
of phenyltrimethylammonium tribromide (PTAB) gave a mixture
tandem
hydroformylation/reductive
amination
procedure
⇑
Corresponding author. Tel.: +48 22 822 02 11; fax: +48 22 822 59 96.
E-mail address: roszkowski@chem.uw.edu.pl (P. Roszkowski).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.04.010

644
P. Roszkowski et al. / Tetrahedron: Asymmetry 24 (2013) 643–650
of (1S,4R,6R)- and (1R,4R,6S)-aziridinolimonene in 62% yield, in
which the main product was the diastereoizomer 2a (Scheme 1).
Aziridines 2a,b were isolated by column chromatography on silica
gel using hexane/ethyl acetate as the eluent (from 0% to 5% of ethyl
acetate). The ratio of both isomers formed was approximately
75–25%, based on the 1H NMR spectrum of the crude reaction mix-
ture. The generation of aziridine (1S,4R,6R)-2a as the predominant
product can be explained by considering the analogous mechanism
azide substituent is present in the isopropylidene part of the limo-
nene molecule.
Finally, regioisomers 3–5 were transformed into the corre-
sponding diamines by the reduction of azide function. Thus com-
pounds 3–5 were individually hydrogenated over 10% Pd/C to
afford the desired monotosylated diamines 6, 8 and 10 almost
quantitatively. Alternatively, only the azide substituent was re-
duced in derivatives 3–5. Diamine 7 was obtained from 3 in 51%
yield under typical Staudinger reduction conditions.15 However,
the reduction of azides 4 and 5 under the same conditions failed
and only the presence of a cyclic aziridine such as 2 was detected
by MS analysis. For the reduction of compounds 4 and 5, a simple
procedure presented by Lin was applied.16 In the reaction of azides
4 and 5 with zinc and ammonium chloride as the reducing agent,
of aziridination of
D
3-carene.14 The first step of this Sharpless pro-
cedure was the formation of the bromonium ion, which occurs
selectively in a trans-fashion due to the steric interaction caused
by the substituents at the cyclohexene moiety. Subsequent open-
ing of the bromonium ion by Chloramine-T proceeds from the
a-face of the molecule and the whole process ends up with the for-
mation of an aziridine with a cis-disposition of the heterocyclic
ring versus the isopropylidene moiety of carene. In the case of
(R)-(+)-limonene, an analogous mechanism seems to operate, giv-
ing rise to the predominant formation of aziridine 2a. The forma-
tion of 2b is thus less likely due to the energetically unfavorable
structure of the trans-bromonium ion. The nucleophilic ring open-
ing of N-tosylaziridines 2b by the azide anion is regio- and diaste-
reoselective, as was described for analogous epoxides.6,10
Therefore, the reaction of (1R,4R,6S)-2b with NaN3 occurs at the
more sterically hindered tertiary carbon atom, forming the azido
amine 5 (27% yield) with the inversion of configuration at this ste-
reogenic centre. Instead, nucleophilic attack on (1S,4R,6R)-2a is
diastereoselective but not regioselective. The main product, amino
azide 3 (51% yield), was formed by the nucleophilic attack of NaN3
on aziridine 2a at the less sterically hindered secondary carbon
atom. However, in the case of the second isomer 4 (isolated in
12% yield), nucleophilic attack of the azide anion on derivative
2a occurred at the more sterically hindered C-1 position giving iso-
mer 4 with an inversion of configuration at the C-1 position. Iso-
mers 3–5 were isolated from the reaction mixture by gradient
elution column chromatography on silica gel using hexane/ethyl
acetate, 0–10% of ethyl acetate, as the eluent system. When DMF
(rt, 12 h) was used as the solvent in the aziridination reaction, iso-
mer 4 was formed with only 5% yield while the yield of regioisomer
3 was increased to 57%.
diamines
respectively.
9 and 11 were obtained in 56% and 64% yield,
The absolute configurations of compounds 6–10 were deter-
mined on the basis of an X-ray analysis, as shown in Figures 1–5.
The detailed stereo structures of these amines can be helpful in
the better understanding of the activity of catalysts 12–18 which
were formed in the reaction with ruthenium–arene complexes.
In order to evaluate amines 6–11 as potential ligands, we chose
to use the Ru-catalysed asymmetric hydrogen transfer (ATH) pro-
tocol on a series of ketones. The catalysts were prepared in situ
by mixing [RuCl2(benzene)]2 or [RuCl2(p-cymene)]2 with mono-
tosylated diamines 6–11 and triethylamine (Ru/Amine/Et3N molar
ratio = 1:2.5:2) in acetonitrile (Fig. 6). After 20 min of stirring at
room temperature, the solution of the catalyst and the formic
acid/triethylamine azeotrope was added to a ketone. The reduction
of aromatic ketones (Scheme 2) was carried out at room tempera-
ture and the reaction progress was monitored by TLC. The products
were isolated by a short-path column chromatography on SiO2 and
the enantiomeric excess was determined by GC analysis on a chiral
stationary phase. Recently, we presented our preliminary data for
the asymmetric reduction of aromatic ketones using catalysts 12,
14 and 16.13 Tables 1 and 2 summarize the results for complexes
13, 15, 17 and 18.
As shown in Tables 1 and 2, the rate and enantioselectivity of
the reaction are highly influenced by the structure of the ligands
In our preliminary study we reported on the presence of five
isomers formed in the reaction of 2 with the azide ion. Further
studies showed that the two unidentified peaks on the HPLC
chromatogram corresponded to the regioisomers in which the
6–11 and the g
6–arene part of the complex. The catalytic activity
of complex 1213 and 13 exhibited low activity and low asymmetric
induction. In both cases, the reaction was carried out at room tem-
perature and was not completed even after 20 days, still giving
Chloramine-T·3H2O,
PTAB,CH3CN,rt
+
N
Tos
N
Tos
2a:2b = 75:25
62%
2a
2b
1
2-propanol:H2O, 1:1
NaN3, rt
Tos
NH
90%
N3
N3
+
+
NH
NH
N3
3
4
5
Tos
Tos
(51%)
(12%)
(27%)
A. H2, Pd/C, EtOH (95%) for 6, 8 and 10
B. Ph3P for 7; Zn, NH4Cl for 9, 11
Tos
NH
NH2
NH2
NH
Tos
NH
NH
NH2
8
6
10
NH2
NH2
Tos
Tos
NH
NH
NH2
7
11
Tos
Tos
9
Scheme 1. Synthetic pathway for monotosylated diamines 6–11.

P. Roszkowski et al. / Tetrahedron: Asymmetry 24 (2013) 643–650
645
Figure 1. The ORTEP diagram for the X-ray analysis of compound 6.
Figure 4. The ORTEP diagram for the X-ray analysis of compound 9 picrate. For the
sake of clarity, the second molecule of compound and picrate anion, as well as the
solvent molecules are omitted.
Figure 2. The ORTEP diagram for the X-ray analysis of compound 7. Only one
molecule from the independent part is shown for clarity.
Figure 5. The ORTEP diagram for the X-ray analysis of compound 10 picrate. Only
one molecule of compound and one picrate anion are shown.
enantioselectivity in comparison to catalysts 14–15. In this case,
catalyst 15 which contained a C@C bond, afforded alcohols with
the same or slightly better enantioselectivity. The exception was
the reduction of the ortho-substituted acetophenones where prob-
ably due to unfavorable steric interactions, significant decrease in
stereoselectivity was observed (Table 2).
Complexes 17 and 18 unexpectedly showed lower values for
the asymmetric induction than catalysts 14–15 (Table 2). The
change in efficacy of complexes 17–18 was connected with the re-
versed configuration at the carbon atoms bearing amine functions
from (R,R) in 14–15 to (S,S) in 17–18.
Figure 3. The ORTEP diagram for the X-ray analysis of compound 8.
unsatisfactory ee values (1–36%) of the products. The presence of
the C@C double bond in the structure of catalyst 13 gave a signif-
icant increase in the enantioselectivity of ketone reduction (Ta-
ble 1). Generally, the reduction of aromatic ketones using
catalysts 1413 and 15 possessing a tertiary amine group gave prod-
ucts with high chemical yield and good enantiomeric excess. The
introduction of a p-cymene ligand in the structure of catalyst
1613 gave 1-phenylethanol with a lower yield and with lower
On the basis of these promising results in the enantioselective
reduction of various aromatic ketones, complexes 12–18 were then
applied to the asymmetric hydrogenation of endocyclic imines. Ini-

646
P. Roszkowski et al. / Tetrahedron: Asymmetry 24 (2013) 643–650
Tos
Ru
Tos
Ru
N
N
N
H
N
H
Cl
Cl
13
12
H
N
H
N
H
N
Ru
Ru
Ru
N
N
N
Cl
Tos
Cl
Tos
Cl
Tos
16
15
14
H
N
H
N
Ru
Ru
N
N
Cl
Tos
Cl
Tos
18
17
Figure 6. The structure of catalysts 12–18.
Table 2
O
OH
The ATH reduction of ketones with catalysts 15, 17 and 18a
complexes 13, 15, 17 and 18
Y
Y
HCOOH, Et3N, rt
*
ee (%)b,c
½ ꢁ
a 2D3
d
X
Entry
Cat.
X
Y
Time (h)
Conv. (%)
X
1
2
3
4
5
6
7
8
15
17
18
15
17
18
15
17
18
15
17
18
15
17
18
15
15
17
18
15
15
17
18
15
17
18
15
17
18
15
17
18
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
42
96
96
72
96
96
18
96
96
18
96
96
18
96
96
52
52
96
96
52
18
96
96
18
96
96
18
96
96
72
96
96
100
10
21
66
12
36
100
41
37
100
52
34
100
82
67
83
100
24
41
92
100
81
62
95
60
96
100
83
70
82
16
8
93 (R)
60 (S)
37 (S)
90 (R)
52 (S)
34 (S)
14 (R)
32 (S)
31 (S)
82 (R)
56 (S)
50 (S)
81 (R)
74 (S)
52 (S)
26 (R)
86 (R)
62 (S)
51 (S)
91 (R)
16 (R)
15 (S)
20 (S)
82 (R)
81 (S)
62 (S)
87 (R)
67 (S)
47 (S)
88 (R)
7 (S)
+50.7
ꢀ33.0
ꢀ20.5
+48.0
ꢀ27.5
ꢀ18.0
+7.1
Scheme 2. Asymmetric transfer hydrogenation of aromatic ketones with catalysts
13, 15, 17 and 18.
Table 1
o-Br
o-Br
o-Br
m-Br
m-Br
m-Br
p- Br
p- Br
p- Br
o-CH3
m-CH3
m-CH3
m-CH3
p-CH3
o-Cl
o-Cl
o-Cl
m-Cl
m-Cl
m-Cl
p-Cl
p-Cl
p-Cl
p-OCH3
p-OCH3
p-OCH3
The ATH reduction of ketones with catalyst 13a
ꢀ16.7
ꢀ15.9
+26.3
ꢀ18.0
ꢀ16.1
+30.3
ꢀ28.0
ꢀ19.3
+22.2
+49.2
ꢀ35.3
ꢀ29.4
+53.4
+11.0
ꢀ10.2
ꢀ14.2
+32.9
ꢀ32.8
ꢀ25.0
+41.2e
ꢀ32.3e
ꢀ22.4e
+44.5
ꢀ3.5
ee (%)b,c
½ ꢁ
a 2D3
d
9
Entry
Cat.
X
Y
Time (days)
Conv. (%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
1
2
3
4
5
13
13
13
13
13
H
H
o-Br
m-Br
p-Br
H
CH3
H
H
H
20
20
20
20
20
44
15
63
45
36
17 (R)
36 (R)
15 (R)
15 (R)
8 (R)
+9.2
+19.3
+7.6
+4.9
+3.2
a
The reaction was carried out at room temperature using a ketone (2.40 mmol)
in CH3CN (1 mL) and a formic acid–triethylamine mixture (5:2, 1 mL) with S/
C = 100.
b
Determined by GC analysis using a Supelco cyclodextrin-DEX 120 capillary
column (20 m ꢂ 0.25 mm I.D. and 0.25
lm film thickness).
Determined by the sign of specific rotation of the isolated product.
c
d
c 1, CHCl3.
tially, the ATH process was applied to the reduction of 1-methyl-
3,4-dihydro-b-carboline (Scheme 3). As might be expected, the
best results were obtained using catalysts 14–15. Complex 15,
which possessed a C@C bond gave amine 7 with excellent results,
100% yield and 98% ee (Table 3). A similar decrease in activity of
compounds 17–18 versus 14–15 was observed as in the case of ke-
tones. The change of configuration caused unfavorable steric inter-
actions, which led to a significant loss of asymmetric induction.
Additionally, the change of configuration from (1R,2R) in catalysts
14–15 to (1S,2S) in complexes 17–18 led to a change of course of
the imine reduction and gave amine 20 with opposite configura-
tion. Complexes 12–13 gave amine 7 with an enantioselectivity
comparable to derivatives 17–18.
13 (S)
ꢀ6.5
a
The reaction was carried out at room temperature using a ketone (2.40 mmol)
in CH3CN (1 mL) and a formic acid–triethylamine mixture (5:2, 1 mL) with S/
C = 100.
b
Determined by GC analysis using a Supelco cyclodextrin-DEX 120 capillary
lm film thickness).
Determined by the sign of specific rotation of the isolated product.
c 1, CHCl3.
c 1, Et2O.
column (20 m ꢂ 0.25 mm I.D. and 0.25
c
d
e
The results obtained for 1-methyl-3,4-dihydro-b-carboline 19
prompted us to apply our catalytic platform to a variety of imines
and iminium salts (Fig. 7). The asymmetric reduction of imine 21,
possessing a less accessible C@N double bond using complexes
14–15 gave the appropriate amine with a slightly lower enantiose-
lectivity than the Noyori-type catalyst (Ru-TsCYDN).17 The more
sterically demanding complex 16 was not able to effectively reduce
the iminium double bond and gave a racemic product. We ob-
served a lack of activity for derivatives 17–18. In the case of imine
22, the results of the asymmetric hydrogenation for all complexes
complexes 12-18
HCOOH, Et3N, rt
NH
N
*
N
H
N
H
20
19
Scheme 3. Asymmetric transfer hydrogenation of imine 19 with catalysts 12–18.
12–18 were comparable and provided the product with low enan-
tiomeric purity (24–34% ee). The reduction of iminium chloride 23

P. Roszkowski et al. / Tetrahedron: Asymmetry 24 (2013) 643–650
647
Table 3
The ATH reduction of imines/iminium salts with catalysts 12–18
3. Conclusion
½ ꢁ
a 2D3
d
Entry
Cat.
Imine
Time (h)
Conv. (%)
ee (%)a,b
In conclusion, we have presented a simple synthesis of a new
class of monotosylated diamine 6–11 starting from an inexpen-
sive enantiomerically pure natural product (R)-(+)-limonene. The
N-tosylaziridination procedure followed by sodium azide treat-
ment and reduction afforded compounds 3 in 51%, 4 in 12%
and 5 in 27% yield. The asymmetric hydrogen transfer protocol
using 6–11 as ligands gave good to excellent results for the
reduction of aromatic ketones as well as for selected endocyclic
imines.
1
2
3
4
5
6
7
8
12
13
14
15
17
18
12
13
14
15
16
17
18
12
13
14
15
16
17
18
12
13
14
15
16
17
18
12
13
14
15
16
17
18
19
19
19
19
19
19
21
21
21
21
21
21
21
22
22
22
22
22
22
22
23
23
23
23
23
23
23
24
24
24
24
24
24
24
20
20
20
20
20
20
19
19
19
19
19
19
19
4
100
100
100
100
100
100
14
17
55
70
0
59 (S)c
50 (S)c
95 (S)c
98 (S)c
54 (R)c
48 (R)c
19 (S)
22 (S)
47 (R)
48 (R)
rac
ꢀ36.6e
ꢀ31.3e
ꢀ60.6e
ꢀ61.3e
+33.6e
+30.2e
ꢀ8.1
ꢀ9.4
+19.8
+20.1
0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
32
47
rac
rac
0
0
4. Experimental
4.1. General
100
100
100
100
0
100
100
77
76
72
74
70
72
81
94
90
90
89
87
89
27 (R)
24 (R)
33 (R)
25 (R)
rac
34 (S)
33 (S)
rac
+23.0
+20.2
+28.1
+21.0
0
ꢀ28.6
ꢀ27.8
0
4
1.5
1.5
5
4
4
16
16
5
5
16
8
The NMR spectra were recorded on a Varian Unity Plus spec-
trometer operating at 500 MHz for 1H NMR and at 125 MHz for
13C NMR. The spectra were measured in CDCl3 and are given as d
values (in ppm) relative to TMS. Mass spectra were collected on
Quatro LC Micromass and LCT Micromass TOF HiRes apparatuses.
Optical rotations were measured on a Perkin–Elmer 247 MC
polarimeter. TLC analyses were performed on silica gel plates
(Merck Kiesegel GF254) and visualized using UV light or iodine
vapour. Column chromatography was carried out at atmospheric
pressure using Silica Gel 60 (230–400 mesh, Merck) using mix-
tures of chloroform/methanol and hexane/ethyl acetate as elu-
ents. The enantiomeric purity was determined by HPLC
analysis using Chiralcel OD-H column or by GC analysis using
a b-DEX 120 capillary column. Melting points were determined
on a Boetius hot-plate microscope and are uncorrected. All sol-
vents used in the reactions were anhydrous. The single crystal
X-ray measurements were carried out on an Oxford Diffraction
rac
0
84 (S)
53 (S)
1 (S)
16 (S)
10 (S)
6 (S)
ꢀ84.0
ꢀ53.4
ꢀ1.0
ꢀ16.2
ꢀ10.2
ꢀ6.9
0
ꢀ52.1
ꢀ60.5
ꢀ3.0
ꢀ34.0
ꢀ38.6
8
16
16
5
5
16
8
rac
48 (S)
56 (S)
3 (S)
31 (S)
35 (S)
8
90
a
Determined by the sign and value of the specific rotation of the isolated
product.
Determined by the sign and value of the specific rotation of the isolated
product.
b
Excalibur
R CCD j-axis diffractometer using monochromatic
CuK radiation. After initial corrections and data reduction,
a
c
Determined by HPLC analysis using Daicel OD-H column.
c 1, CHCl3.
c 1, EtOH.
intensities of reflections were used to solve and consecutively re-
d
e
fine structures using SHELXS97 and SHELXL97 programs.18
4.2. (1S,2S,5R)-N-(2-Azido-5-isopropenyl-2-methyl-cyclohexyl)-
4-methyl-benzenesulfonamide 5
N
N
N
To
a stirred solution of aziridines 2a,b mixture (15.40 g,
O
N
50.42 mmol) in isopropanol (80 mL), distilled water (80 ml) and
sodium azide (12.50 g, 201.70 mmol) were added. The resulting
suspension was stirred at room temperature for 72 h. After evap-
oration of the solvents to the residue, diethyl ether (250 mL) and
water (125 mL) were added. The layers were separated and the
water layer was extracted twice with diethyl ether (200 mL).
The combined organic layers were washed with brine (100 mL),
dried over MgSO4 and the solvent was evaporated in vacuo.
Compound 5 was isolated by column chromatography on silica
gel using hexane/ethyl acetate (3–6% of ethyl acetate) as eluent
system to afford 4.74 g (27%) of compound 5 as a colourless
O
N
22
21
O
O
O
O
O
Cl-
Cl-
N+
N+
O
24
23
Figure 7. The structure of imines/iminium salts for ATH.
oil; ½a 2D3
¼ þ3:9ðc1:0; CHCl3Þ. The enantiomeric purity was deter-
ꢁ
mined by HPLC [Chiracel OD-H, hexane/i-PrOH (90:10), 1 mL/
min]; the (1S,2S,4R)-isomer eluted at 7.6 min. 1H NMR (CDCl3,
500 MHz): d 1.19–1.24 (m, 1H), 1.27 (s, 3H), 1.43–1.55 (m,
3H), 1.57 (s, 3H), 1.66–1.72 (m, 2H), 1.86–1.90 (m, 1H), 2.43
(s, 3H), 3.23–3.26 (m, 1H), 4.60 (s, 1H), 4.67 (t, 1H, J = 1.5 Hz),
5.08 (d, 1H, J = 10.0 Hz), 7.31 (d, 2H, J = 8.0 Hz), 7.77 (d, 2H,
J = 8.0 Hz); 13C NMR (CDCl3, 125 MHz): d 20.8, 21.6, 23.1, 25.7,
31.6, 31.8, 37.6, 55.7, 62.8, 109.7, 127.1, 129.8, 137.6, 143.8,
147.8. HRMS: m/z calcd for C17H24N4O2NaS [M+Na]+: 371.1518;
found: 371.1524.
using complex 14 gave (S)-crispine A with good enantiomeric pur-
ity (84% ee). Lower asymmetric induction (53% ee) was obtained
when catalyst 15 was used. Catalysts 12–13 gave racemic crispine
A, and for 17–18 a very low level of asymmetric induction was
observed.
Similar results were collected for the hydrogenation of iminium
salt 24, but the enantiomeric excess of obtained product did not
exceed 56% for complex 15. Obviously the enantioselectivity of
the reduction strongly depends both on the structure of the cata-
lyst and the structure of the substrate.

648
P. Roszkowski et al. / Tetrahedron: Asymmetry 24 (2013) 643–650
4.2.1. (1S,2S,4R)-N-(2-Amino-4-isopropyl-1-methyl-cyclohexyl)-
4-methyl-benzenesulfonamide 6
4.2.4. N-(1R,2R,5R)-N-(2-Amino-5-isopropenyl-2-methyl-
cyclohexyl)-4-methyl-benzenesulfonamide 9
Amine 6 was synthesized from azide 3 according to the litera-
ture.13 Monocrystals of 6 suitable for crystallographic measure-
ments were obtained from a diethyl ether solution by slow
evaporation. The absolute structure of the studied crystal, and
hence the absolute configuration of the compound was determined
based on the value of the Flack parameter.19 Since its value for the
structure shown in Figure 1 was approximately 0, the molecular
structure has the depicted configuration. The data were deposited
with Cambridge Crystallographic Data Centre under the number
CCDC 923755.
To a stirred suspension of azide 4 (0.5 g, 1.44 mmol) in a mix-
ture of ethanol (10 mL) and distilled water (3 mL) were added
ammonium chloride (175 mg, 3.30 mmol) and then zinc powder
(122 mg, 1.86 mmol) and the resulting mixture was stirred vigor-
ously at 70 °C for 2 h. After completion of the reaction, ethyl ace-
tate (50 mL), concentrated aqueous ammonia (2 mL) and distilled
water (5 mL) were added. The layers were separated and the or-
ganic layer was extracted with water (10 mL). The combined or-
ganic layers were dried over Na2SO4 and the solvent was
evaporated in vacuo. The oily residue was purified by column chro-
matography on silica gel using chloroform/methanol, 0–8% of
methanol as eluent system to afford 0.26 g (56%) of compound 9
4.2.2. (1S,2S,4R)-N-(2-Amino-4-isopropenyl-1-methyl-cyclo-
hexyl)-4-methyl-benzenesulfonamide 7
as a colourless oil; ½a D23
¼ ꢀ40:0ðc1:0; CHCl3Þ. The enantiomeric
ꢁ
To a stirred solution of azide 3 (1.0 g, 2.87 mmol) in THF
(50 mL), triphenylphosphine (829 mg, 3.16 mmol) and distilled
water (5 mL) were added and the resulting mixture was stirred
at room temperature for 1 h and then at 60 °C for 3 h. The solvents
were evaporated in vacuo, and to the residue 50 mL of CH2Cl2 and
15 mL of water were added and the mixture was basified with solid
K2CO3. The layers were separated and the water layer was ex-
tracted twice with CH2Cl2 (25 mL). The combined organic layers
were washed with brine (25 mL), dried over MgSO4 and the solvent
was evaporated in vacuo. The residual oil was purified by column
chromatography on silica gel using chloroform/methanol, 0–3% of
methanol as eluent system to afford 0.48 g (51%) of compound 7
purity was determined by HPLC [Chiracel OD-H, hexane/i-PrOH
(90:10), 1 mL/min]; the (1R,2R,4R)-isomer eluted at 16.5 min. 1H
NMR (CDCl3, 500 MHz):
d
0.99 (s, 3H), 1.13 (q, 1H,
J = 12.5 Hz),1.21–1.34 (m, 2H), 1.56–1.64 (m, 5H), 1.72–1.76 (m,
1H), 1.81–1.86 (m, 1H), 2.42 (s, 3H), 2.89 (dd, 1H, J = 12.0,
4.0 Hz), 4.58 (s, 1H), 4.64 (t, 1H, J = 1.5 Hz), 7.31 (d, 2H,
J = 8.0 Hz), 7.78 (d, 2H, J = 8.0 Hz); 13C NMR (CDCl3, 125 MHz): d
19.8, 20.9, 21.5, 27.7, 35.0, 40.6, 44.3, 52.0, 62.7, 109.1, 127.1,
129.7, 137.6, 143.5, 148.1. HRMS: m/z calcd for C17H26N2O2SNa
[M+Na]+: 345.1613; found: 345.1620.
Monocrystals of 9 picrate suitable for crystallographic measure-
ments were obtained from an ethanol solution by slow evaporation.
Compound crystallizes in non-centrosymmetric orthorhombic
space group P212121 with two independent molecules of the same
enantiomer, two picrate anions and solvent molecules in the asym-
metric part of the unit cell. The absolute structure of the studied
crystal, and hence the absolute configuration of the compound
was determined based on the value of the Flack parameter.19 Since
its value for the structure shown in Figure 4 was approximately 0,
the molecular structure has the depicted configuration. The data
were deposited with Cambridge Crystallographic Data Centre under
the number CCDC 923758.
as a colourless solid; ½a D23
¼ þ10:1ðc1:0; CHCl3Þ; mp = 141–142 °C.
ꢁ
The enantiomeric purity was determined by HPLC [Chiracel OD-
H, hexane/i-PrOH (90:10), 1 mL/min]; the (1S,2S,4R)-isomer eluted
at 19.2 min. 1H NMR (CDCl3, 500 MHz): d 1.61 (s, 3H), 1.41–1.50
(m, 3H), 1.65 (s, 3H), 1.66–1.81 (m, 3H), 2.18–2.22 (m, 1H), 2.41
(s, 3H), 3.06 (t, 1H, J = 3.0 Hz), 4.63 (s, 1H), 4.72 (s, 1H), 4.94 (bs,
1H), 7.27 (d, 2H, J = 8.0 Hz), 7.77 (d, 2H, J = 8.0 Hz); 13C NMR (CDCl3,
125 MHz): d 21.3, 21.5, 22.1, 25.5, 32.3, 34.1, 37.2, 53.2, 59.8, 109.6,
126.9, 129.5, 140.7, 142.8, 148.1. HRMS: m/z calcd for
C
17H26N2O2SNa [M+Na]+: 345.1613; found: 345.1608.
Monocrystals of 7 suitable for crystallographic measurements
were obtained from a diethyl ether solution by slow evaporation.
Compound crystallizes in non-centrosymmetric monoclinic space
group P21 with two independent molecules of the same enantio-
mer in the asymmetric part of the unit cell. The absolute structure
of the studied crystal, and hence the absolute configuration of the
compound was determined based on the value of the Flack param-
eter.19 Since its value for the structure shown in Figure 2 was
approximately 0, the molecular structure has the depicted config-
uration. The data were deposited with Cambridge Crystallographic
Data Centre under the number CCDC 923757.
4.2.5. (1S,2S,5R)-N-(2-Amino-5-isopropyl-2-methyl-cyclohexyl)-
4-methyl-benzenesulfonamide 10
To a stirred solution of azide 5 (0.55 g, 1.58 mmol) in anhydrous
ethanol (20 mL) was added palladium on carbon-10% (90 mg) and
the resulting suspension was stirred at room temperature in an
atmosphere of hydrogen at room temperature for 17 h. The etha-
nolic solution was filtered and the solvent was evaporated in va-
cuo. The oily residue was purified by column chromatography on
silica gel using chloroform/methanol, 0–7% of methanol as an elu-
ent system to afford 0.42 g (82%) of compound 10 as a colourless
oil; ½a 2D3
¼ þ1:1ðc1:0; CHCl3Þ. The enantiomeric purity was deter-
ꢁ
4.2.3. (1R,2R,5R)-N-(2-Amino-5-isopropyl-2-methyl-cyclo-
hexyl)-4-methyl-benzenesulfonamide 8
mined by HPLC [Chiracel OD-H, hexane/i-PrOH (90:10), 1 mL/
min]; the (1R,2R,4R)-isomer eluted at 14.6 min. 1H NMR (CDCl3,
500 MHz): d 0.62 (d, 3H, J = 7.0 Hz), 0.76 (d, 3H, J = 7.5 Hz), 1.02
(s, 3H), 1.03–1.09 (m, 1H), 1.19–1.50 (m, 7H), 2.41 (s, 3H), 3.03
(bs, 1H), 4.70 (bs, 1H), 7.29 (d, 2H, J = 7.5 Hz), 7.76 (d, 2H,
J = 8.5 Hz); 13C NMR (CDCl3, 125 MHz): d 20.0, 20.2, 21.5, 24.1,
30.5, 35.3, 38.3, 51.3, 58.9, 127.2, 129.7, 137.9, 143.3. HRMS: m/z
calcd for C17H29N2O2S [M+H]+: 325.1950; found: 325.1957.
Amine 8 was synthesized from azide 4 according to the litera-
ture.13 Monocrystals of 8 suitable for crystallographic measure-
ments were obtained from a diethyl ether solution by slow
evaporation. Compound crystallizes in non-centrosymmetric
monoclinic space group P21 with one molecule in the asymmetric
part of the unit cell. The absolute structure of the studied crystal,
and hence the absolute configuration of the compound was deter-
mined based on the value of the Flack parameter.19 Since its value
for the structure shown in Fig. 3 was approximately 0, the molec-
ular structure has the depicted configuration. The data were depos-
ited with Cambridge Crystallographic Data Centre under the
number CCDC 923756.
Monocrystals of 10 picrate suitable for crystallographic mea-
surements were obtained from an ethanol solution by slow evapo-
ration. Compound crystallizes in non-centrosymmetric monoclinic
space group C2 with two independent molecules of the same enan-
tiomer and two picrate anions in the asymmetric part of the unit
cell. The absolute structure of the studied crystal, and hence the

P. Roszkowski et al. / Tetrahedron: Asymmetry 24 (2013) 643–650
649
absolute configuration of the compound was determined based on
the value of the Flack parameter.19 Since its value for the structure
shown in Figure 5 was approximately 0, the molecular structure
has the depicted configuration. The data were deposited with Cam-
bridge Crystallographic Data Centre under the number CCDC
923759.
(6 lmol in 0.5 mL of CH3CN) and formic acid/triethylamine azeo-
tropic mixture (1.2 mL) were added. The mixture was then stirred
at room temperature and the progress of the reaction was moni-
tored by TLC until the specified conversion was achieved. After
evaporation of the solvents, 4 mL of CH2Cl2 and 2 mL of water were
added and the mixture was basified with solid K2CO3. The layers
were separated and the water layer was extracted twice with
3 mL CH2Cl2. The combined organic layers were dried over Na2SO4
and the solvent was evaporated in vacuo. The crude product 20
was purified by column chromatography on aluminium oxide
using chloroform/methanol, (0–5% of methanol) as the eluent sys-
tem. The enantiomeric excess of compound 20 was determined by
HPLC analysis using a Chiracel OD-H column, hexane/i-PrOH/dieth-
ylamine (90:10:0.1), 1 mL/min. The products of the reduction of
imines 21 and 22 were purified by column chromatography on sil-
ica gel using chloroform. The products of the reduction of imines
23 and 24 were purified by column chromatography on aluminium
oxide using chloroform. The enantiomeric excess and the configu-
ration of the products of the reduction of compound 21–24 were
determined by comparison of the values and sign of specific rota-
tion. The results of the reduction are summarized in Table 3.
4.2.6. N-(1S,2S,5R)-N-(2-Amino-5-isopropenyl-2-methyl-cyclo-
hexyl)-4-methyl-benzenesulfonamide 11
To a stirred suspension of azide 5 (0.45 g, 1.29 mmol) in ethanol
(10 mL) and distilled water (3 mL) were added ammonium chlo-
ride (157 mg, 2.97 mmol) and then zinc powder (110 mg,
1.68 mmol) and the resulting mixture was stirred vigorously at
70 °C for 3 h. After completion of the reaction, ethyl acetate
(50 mL), concentrated aqueous ammonia (2 mL) and distilled
water (5 mL) were added. The layers were separated and the or-
ganic layer was extracted with water (10 mL). The combined or-
ganic layers were dried over Na2SO4 and the solvent was
evaporated in vacuo. The oily residue was purified by column chro-
matography on silica gel using chloroform/methanol, 0–5% of
methanol as eluent system to afford 0.26 g (64%) of compound
11 as a colourless oil; ½a D23
¼ þ12:5ðc1:0; CHCl3Þ. The enantiomeric
ꢁ
purity was determined by HPLC [Chiracel OD-H, hexane/i-PrOH
(90:10), 1 mL/min]; the (1R,2R,4R)-isomer eluted at 17.2 min. 1H
NMR (CDCl3, 500 MHz): d 1.01 (s, 3H), 1.37–1.48 (m, 3H), 1.53–
1.56 (m, 5H), 1.71–1.77 (m, 1H), 2.02 (bs, 1H), 2.42 (s, 3H), 3.07
(br s, 1H), 4.57 (s, 1H), 4.70 (d, 1H, J = 1.0 Hz), 4.94 (br s, 1H),
7.31 (d, 2H, J = 8.0 Hz), 7.78 (d, 2H, J = 8.0 Hz); 13C NMR (CDCl3,
125 MHz): d 21.4, 21.5, 25.3, 31.7, 35.5, 38.2, 51.3, 58.8, 109.9,
127.2, 129.7, 137.8, 143.4, 147.3. HRMS: m/z calcd for
Acknowledgements
We acknowledge the financial support from the Polish Ministry
of Science and Higher Education in the form of Grant no. N204
117939. We cordially thank Dr. Dariusz Błachut (Internal Security
Agency) for the determination of ee values by GC.
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C
17H26N2O2SNa [M+Na]+: 345.1613; found: 345.11603.
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18
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separated and the water layer was extracted twice with 2 mL of
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the solvent was evaporated in vacuo. The oily residue was purified
by column chromatography on silica gel using chloroform (dried
over CaCl2) as eluent to afford the appropriate ketone. The enantio-
meric excess was determined by GC analysis using a Supelco cyclo-
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To a suspension of imine/iminium salt (0.3 mmol) in 1 mL of
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650
P. Roszkowski et al. / Tetrahedron: Asymmetry 24 (2013) 643–650
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