Enantioselective synthesis of some tetrahydroisoquinoline and tetrahydro-β-carboline alkaloids

Article abstract of DOI:10.1016/j.tetasy.2007.01.014

Four alkaloids: (R)-(+)-cryspine A 5, (R)-(+)-octahydroindolo[2,3-a]quinolizidine 8, (R)-(+)-harmicine 19 and (R)-(+)-desbromoarborescidine 22 were prepared via the asymmetric transfer hydrogenation reaction of a prochiral enamine (iminium salt). The enan

Full text of DOI:10.1016/j.tetasy.2007.01.014

Tetrahedron: Asymmetry 18 (2007) 406–413
Enantioselective synthesis of some tetrahydroisoquinoline
and tetrahydro-b-carboline alkaloids
a
a
a
a
Joanna Szawkało, Stefan J. Czarnocki, Anna Zawadzka, Krystyna Wojtasiewicz,
a
b,c
a,
d,
*
*
Andrzej Leniewski, Jan K. Maurin, Zbigniew Czarnocki and J o´ zef Drabowicz
a
Faculty of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
b
National Medicines Institute, Chełmska 30/34, 00-750 Warsaw, Poland
c
´
Institute of Atomic Energy, 05-400 Otwock-Swierk, Poland
d
Centre of Molecular and Macromolecular Studies, Department of Heteroorganic Chemistry,
Polish Academy of Sciences, Sienkiewicza 112, 90-363 Ł o´ d z´ , Poland
Received 22 December 2006; accepted 8 January 2007
Available online 21 February 2007
Abstract—Four alkaloids: (R)-(+)-cryspine A 5, (R)-(+)-octahydroindolo[2,3-a]quinolizidine 8, (R)-(+)-harmicine 19 and (R)-(+)-des-
bromoarborescidine 22 were prepared via the asymmetric transfer hydrogenation reaction of a prochiral enamine (iminium salt). The
1
enantiomeric excesses of the isolated alkaloids were determined from their H NMR spectra measured in the presence of (+)-(R)-tert-
butylphenylphosphinothio(seleno)ic acids as chiral solvating agents. The absolute configurations at the newly created stereogenic carbon
atoms were confirmed, in all cases, by X-ray crystallography.
ꢀ
2007 Elsevier Ltd. All rights reserved.
1. Introduction
The asymmetric transfer hydrogenation (ATH) has
become, over the last decade, a highly powerful, versatile
and practical tool for the stereoselective synthesis of non-
racemic secondary alcohols and amines from prochiral
Ru
Ru
O2S
Cl
H
H
Cl
H
H
TsN
Ph
N
N
N
Ph
1
–4
Ph
Ph
ketones or imines (iminium salts).
(
R,R)-1
(R,R)-2
Due to the use of 2-propanol or formic acid (usually in the
presence of triethylamine) as a hydrogen source, dangerous
manipulation with molecular hydrogen can be avoided in
this reaction. Several effective ligands have already been
introduced, including a variety of b-amino alcohols and
Figure 1. Selected chiral catalysts for ATH.
In the mid 1990s, Noyori reported that Ru(II) complexes of
monotosylosulfonated 1,2-diamines, such as N-tosyl-
1R,2R)-diphenylethylenediamine (TsDPEN) or its enan-
tiomer, were able to effectively stabilize the transition state
through hydrogen bonding, which allowed an efficient chi-
rality transfer as a result of the apparent simultaneous pro-
tonation by the NH group and hydride ion attack from the
Ru–H onto the imine. Since that time several modifications
of the original procedure have been proposed, including
5
–12
1
,2-diamino compounds.
These ligands, when reacted
6
with a ruthenium pre-catalyst, such as [RuCl (g -mesityl-
2
(
ene)] , form chiral, coordinatively saturated 18-electron
2
Ru(II) complexes [such as (R,R)-1 (Fig. 1)] that serve as pro-
motors for a stereoselective reduction of prochiral ketones.
In comparison with ketones, imines are far less popular sub-
strates and a limited number of successful examples of effec-
2
,4,13–26
tive chirality transfer have been published so far.
2
7
variations of the central atom from Ru(II) to Rh(III),
*
Corresponding authors. Tel.: +48 22 822 02 11; fax: +48 22 822 59 96
Z.C.); tel.: +48 42 680 3 234; fax: +48 42 684 71 26 (J.D.); e-mail
addresses: czarnoz@chem.uw.edu.pl; draj@bilbo.cbmm.lodz.pl
and the nature of the ligands. The most effective and prom-
ising seems to be the ‘tethered’ Ru(II) catalyst (R,R)-2
(
1
4,28
introduced by Wills et al.
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.01.014

J. Szawkało et al. / Tetrahedron: Asymmetry 18 (2007) 406–413
407
We have recently communicated that the asymmetric
hydrogen transfer protocol is very effective in the enantio-
selective synthesis of various fatty acid 1-substituted-
2
9
tetrahydro-b-carbolines, the antihelminitic drug Prazi-
3
0
31
quantel and the isoquinoline alkaloid crispine A. Here-
in, we report our recent results, which show the synthetic
utility of the ATH methodology for the preparation of
analogous heterocyclic systems and present structural
assignments performed for the alkaloids products, includ-
ing the determination of their absolute configurations.
2
. Results and discussion
2
.1. Enantioselective synthesis of (+)-crispine A 5
Figure 2. The absolute stereochemistry of the picrate salt of (R)-(+)-5.
The title alkaloid has been isolated from Carduus crispus
Linn. (welted thistle), the plant intensively studied for its
3
2,33
promising pharmacological activity.
Our approach
In recent years, considerable efforts have been devoted to
the stereoselective construction of emetine alkaloids and
for its preparation in its enantiomerically pure form
3
1
3
8
(
already described in our preliminary communication ) is
based on the ATH procedure applied to iminium salt 3
Scheme 1). This allows the chirality induction in the last
step of the synthetic sequence, which maximizes the atom
their synthetic congeners. Having been encouraged by
the positive results of our catalytic approach to crispine
A, we considered a similar reaction sequence for the enan-
tioselective synthesis of benzo[a]quinolizidine ring system.
Thus, simple condensation of 3,4-dimethoxyphenylethyl-
amine with d-valerolactone in boiling toluene afforded,
after crystallization, N-homoveratryl-x-hydroxyvaler-
(
3
4
economy.
Tos
N
39
amide in 92% yield. Its subsequent treatment with POCl3
in toluene gave, after a careful basification, the iminium
Ru
39
salt 6 in 93% yield.
Cl
N
H2
It is interesting to note that the isolation of the hydroxy-
amide intermediate was not necessary and when the whole
process was performed as a one-pot sequential operation,
only a slight loss in the chemical yield of 6 (69%) was
observed (Scheme 2).
(
S,S)-4
CH O
CH O
3
3
(
S,S)-4
Et3N/HCOOH
1%, 92% ee
N
N
CH O
CH O
3
3
H
9
3
(R)-(+)-5
Scheme 1. The synthesis of (R)-(+)-5.
CH O
CH O
3
3
NH2
HN
O
CH3O
CH3O
toluene
reflux, 92%
The wanted, desired crispine A (R)-(+)-5 was isolated in
6% yield and 92% ee. Even better results (90% chemical
+
O
9
O
yield, ee >99%) were obtained when the enamine corre-
sponding to 3 was subjected to the reduction. The (R)-
absolute configuration at the newly created stereogenic
carbon atom in (+)-5 was finally confirmed on the basis
of the X-ray analysis of its picrate salt (Fig. 2).
OH
POCl3
reflux, 93%
CH3O
N
Cl
2.2. Enantioselective synthesis of benzo[a]quinolizidine ring
system
CH3O
6
(S,S)-4
CH3O
CH3O
The title heterocyclic moiety is abundant in several types of
isoquinoline alkaloids, including emetine-related bases,
known as Ipecac alkaloids. The medicinal value of the ex-
tracts derived from Cephaelis ipecacuanha (Brot.) A. Rich-
ard and Cephaelis accuminata Carsten (Rubiaceae) rests
OH-
N
H
CH3O
CH3O
(S,S)-4
(
R)-(+)-8
N
3
5
mainly on emetine and cephaeline, but is not limited to
their emetic and expectorant properties, and includes also
7
3
6
37
their antiamoebic and anti-tumour activity.
Scheme 2. Chemical transformations leading to (R)-(+)-8.

408
J. Szawkało et al. / Tetrahedron: Asymmetry 18 (2007) 406–413
The iminium salt 6 was then subjected to a series of hydro-
gen transfer reductions (Scheme 2) with ruthenium cata-
lysts modified with various ligands 9–12 (Fig. 3),
according to the protocol optimized for the synthesis of
scattering analysis proved the (R)-absolute configuration
at the stereogenic carbon atom in the trans-N-oxide 15.
This means also that in the parent amine, the stereogenic
carbon atom has the (R) absolute configuration (Fig. 5).
3
1
crispine A.
Tos
NH
CH3
CH3O
O
H3C
N
H
N
CH3O
H
NH2
OH
(S,S)-9
10
(
(
R)-15
R)-16
N
N
O
O
CH3
Tos
NH
H3C
N
Figure 5. The structure of N-oxides 15 and 16 and the absolute
configuration at the stereogenic carbon in (R)-(ꢀ)-15.
H
OH
NH2
1
1
(R,R)-12
The cis-stereochemistry of the quinolizidine moiety in (R)-
16 was fully supported by the NMR data. Interestingly,
Figure 3. The structure of chiral ligands.
phosphinothioic acid 13 was also found to behave as a
1
good chiral solvating agent in H NMR experiments with
In all cases, the reduction proceeded smoothly, giving good
to excellent yields of benzo[a]quinolizidine 8. The enantio-
meric excesses for the isolated samples of the product were
determined based on the NMR measurements described
N-oxide 15. It probably results from the presence of a basic
oxygen atom in this compound (Fig. 6).
3
1
already
with (+)-(R)-tert-butylphenylphosphinothioic
acid 13 (Fig. 4) as a chiral solvating agent.
O
P
Se
Ph
Ph
P
SH
OH
(
H3C)3C
(H C) C
3
3
(+)-(R)-13
(+)-(R)-14
Figure 4. Chiral solvating agents.
In sharp contrast to the previous findings, there was no
temperature influence on asymmetric induction and the
‘
classical’ Noyori ligand (S,S)-9 was again the most effec-
tive, albeit only 87% ee was achieved, even after optimiza-
tion efforts. Moreover, the experiments realized on the
corresponding enamine 7 did not afford a product with
higher enantiomeric excess (Table 1).
6
.650 6.600 6.550 6.500 6.450
6.650 6.600 6.550 6.500 6.450
ppm (t1)
Table 1. Enantioselective synthesis of benzo[a]quinolizidine 8
ppm (t1)
Entry Substrate Ligand
T
Yield Configuration ee (%)
1
(
ꢁC) (%)
Figure 6. H NMR spectra of 15 (aromatic region) (a) racemic; (b)
2
3
enantiopure (R)-(ꢀ)-15 ½aꢁ ¼ ꢀ14:3 (c 1, CHCl
3
) {both measured in the
D
1
2
3
4
5
6
7
6
6
6
6
6
7
7
9
9
22
0
97
83
97
65
82
80
89
(R)-(+)-
(R)-(+)-
(R)-(+)-
(R)-(+)-
(S)-(ꢀ)-
(R)-(+)-
(R)-(+)-
87.0
85.8
1.0
presence of (+)-(R)-13}.
10
11
12
9
22
22
22
22
0
5.2
2
.3. Enantioselective synthesis of (R)-(+)-harmicine 19
84.3
68.7
82.7
A basic fraction of an ethanolic extract from the leaves of
Malaysian plant Kopsia griffithii exhibits a profound anti-
leishmania activity. Among several nitrogen bases found
in this extract, (R)-(+)-harmicine (+)-19 is suspected to be
responsible for a pharmacological profile of the plant. An
elegant synthesis of the racemic harmicine has recently
9
4
0
Our attempts to obtain good quality crystals for enantio-
mers of 8 (or their salts) were unsuccessful. Therefore, in
order to establish the absolute configuration, we trans-
formed the dextrorotary enantiomer of 8 into the diastereo-
meric mixture of its N-oxides 15 and 16 (MCPBA, 78%
chemical yield, 15:16 = 6:1, Fig. 5). An anomalous X-ray
4
1
been published. Also, (S)-(ꢀ)-harmicine (ꢀ)-19 was pre-
pared using optically active 1-allyl-1,2,3,4-tetrahydro-b-
4
2
carboline as a substrate.

J. Szawkało et al. / Tetrahedron: Asymmetry 18 (2007) 406–413
409
From a synthetic point of view, the preparation of optically
active harmicine should be possible by an analogous route
2.4. Enantioselective synthesis of (+)-desbromoarborescidine
A 22
3
1
applied for the synthesis of crispine A, (R)-(+)-5. Thus,
the condensation of c-butyrolactone with tryptamine affor-
The indolo[2,3-a]quinolizine heterocyclic ring system, pres-
ent also in (+)-desbromoarborescidine A 22, is of parti-
cular interest for the pharmacological chemistry of
tryptophan-derived alkaloids, since it is a common struc-
tural motif in many highly bioactive secondary metabo-
lites, including Rauwolfia family bases (ajmaline,
4
3
ded hydroxyamide 17 in 78% yield. Its subsequent treat-
ment with POCl was found to be most effective when the
3
reaction was carried out without the solvent. We were not
able to obtain good analytical data for the prepared
iminium salt 18 (except acceptable MS spectrum) due to
its strong tendency to decomposition. A similar behav-
iour of analogous compounds was observed by other
4
9
ajmalicine, reserpine) along with newly characterized bro-
minated b-carbolines from marine tunicate Pseudodistoma
4
4–48
50
authors.
The asymmetric transfer hydrogenation car-
arborescens or desbromoarborescidine 22, isolated from
4
2,51
ried out on the crude samples of 18 under standard condi-
tions using (S,S)-4 as the catalyst gave (+)-harmicine (+)-
the bark of Dracontomelum mangiferum.
1
9 in 81% chemical yield (Scheme 3).
Our attempts to enantioselectively synthesize desbromo-
arborescidine A 22 were based on the reaction sequence
already discussed in this paper. Again, the condensation of
tryptamine with d-valerolactone in refluxing toluene gave
4
7
known hydroxyamide 20 in 87% yield. It should be noted
NH2
N
O
4
7
here that the use of tetralin as a solvent caused further
transformation of 20 into the lactam derivative and low-
ered the yield. Its subsequent Bischler–Napieralski cycliza-
HN
H
toluene
reflux, 78%
N
H
+
tion in neat POCl gave, after a short work-up, unstable
3
44,45,47
O
O
17
HO
iminium salt 21.
Its immediate reduction under stan-
dard conditions using (S,S)-4 afforded (+)-desbromoarbo-
rescidine A (+)-22 in 84% chemical yield (Scheme 4).
POCl3
reflux
Cl
N
NH2
O
N
H
N
H
HN
toluene
reflux, 87%
N
H
(
S,S)-4
+
18
O
O
81%
20
N
OH
N
H
H
POCl3
reflux
(
R)-(+)-19
Scheme 3. The synthesis of (R)-(+)-19.
Cl
N
N
H
The highest enantiomeric excess (determined on the basis
of H NMR experiments with phosphinothioic acid 13)
(
S,S)-4
1
2
1
was only 79% despite our optimization efforts. Fortunately,
after a single crystallization, an almost enantiopure alka-
loid could be obtained. Again, the absolute configuration
at the stereogenic carbon was established by the X-ray crys-
tallographic analysis (Fig. 7) thus concluding the discus-
8
4%
N
N
H
H
(R)-(+)-22
4
2
sion on this subject.
Scheme 4. Synthesis of (R)-(+)-22.
2
3
Comparison of the specific rotation ð½aꢁ ¼ þ74:4Þ, of the
D
4
2
isolated product with the reported value indicated that it
had an enantiomeric excess of 90.5%. Again, a single crys-
tallization afforded almost enantiopure material. In con-
trast to the determination of the enantiomeric excesses
1
discussed above, the H NMR differentiation using phos-
phinothioic acid 13 was unsuccessful for (+)-22. However,
using its selenium analogue, (R)-(+)-14, we were able to
observe a very good separation of the signals of the formed
dynamic diastereomeric associates (Fig. 8).
Figure 7. The absolute stereochemistry of (R)-(+)-19.

410
J. Szawkało et al. / Tetrahedron: Asymmetry 18 (2007) 406–413
1
3
1
1
25 MHz for C NMR or at 200 MHz for H NMR and
1
3
at 50 MHz for C NMR. The spectra were measured in
CDCl or CD OD and are given as d values (in ppm)
3
3
elative to TMS. Mass spectra were collected on Quatro
LC Micromass and LCT Micromass TOF HiRes appara-
tus. Optical rotations were measured on a Perkin–Elmer
247MC polarimeter. TLC analyses were performed on sil-
ica 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 mixtures of chloroform/
methanol as eluents. Melting points were determined on
a Boetius hot-plate microscope and were uncorrected. All
solvents used in the reactions were anhydrous. The single
crystal X-ray measurements were carried out on either
Oxford Diffraction Xcalibur R j-axis diffractometer with
CCD Ruby detector (crystals of 15, 19 and 22) or on Enraf
Nonius TurboCAD4 j-axis diffractometer with a point
scintillation counter (crystal of 5). In all cases, Cu Ka char-
acteristic radiation was applied. After the initial corrections
and data reduction, intensities of reflections were used to
9
.00 8.90 8.80 8.70
9.00 8.90 8.80 8.70
ppm (t1)
ppm (t1)
1
53
Figure 8. H NMR spectra of 22 (indole N–H region): (a) racemic
solve and consecutively refine the structures. SHELXS97
2
D
3
5
4
mixture; (b) sample (R)-(+)-22 ½aꢁ ¼ þ74:4 (c 1, CH
3
OH) {both
and SHELXL97 programs were used for these tasks. The
absolute structures were estimated by applying Flack para-
measured in the presence of (+)-(R)-14}.
5
5
meter values calculated using Friedel pair reflections for
each structure.
Crystallization of the enantiopure (+)-22 gave a monocrys-
tal that was used for X-ray analysis (Fig. 9), which indi-
cated the (R) absolute configuration at the stereogenic
carbon atom. This is in accordance with the data collected
4.1. General procedure for the synthesis of x-hydroxyamides
5
2
To a stirred solution of homoveratrylamine or tryptamine
for an analogous heterocyclic system.
(
(
20.0 mmol) in toluene (30 mL), an appropriate lactone
22.0 mmol) and a catalytic quantity of p-toluenesulfonic
acid were added. The mixture was refluxed for 7 h under
argon. The solvent was evaporated, and the residue was
crystallized from AcOEt to afford x-hydroxyamides as
white solids.
Data for N-[2-(3,4-dimethoxyphenyl)ethyl]-5-hydroxypen-
tanamide (Scheme 2): yield 92%; mp 65–65.5 ꢁC; ESMS
+
1
(
positive ion mode) m/z 282.2 [M+H] ; H NMR
(
3
200 MHz, CDCl ): d 6.69–6.83 (m, 3H), 6.03 (br s, 1H),
.86 (s, 3H), 3.85 (s, 3H), 3.60 (t, 2H, J = 6 Hz), 3.48 (q,
3
Figure 9. The absolute stereochemistry of (R)-(+)-22.
2
H, J = 7 Hz, J = 6 Hz), 3.02 (br s, 1H), 2.75 (t, 2H,
1
2
1
3
3. Conclusion
J = 7 Hz), 2.18 (t, 2H, J = 7 Hz), 1.45–1.77 (m, 4H);
C
NMR (50 MHz, CDCl ): d 173.19, 148.87, 147.53,
131.28, 120.52, 111.81, 111.23, 61.78, 55.79, 55.75, 40.58,
35.92, 35.10, 31.81, 21.65.
3
In conclusion, we used asymmetric transfer hydrogenation
for the enantioselective synthesis of four alkaloids: (R)-(+)-
cryspine A 5, (R)-(+)-octahydroindolo[2,3-a]quinolizidine
8
, (R)-(+)-harmicine 19 and (R)-(+)-desbromoarboresci-
Data for compound 17: yield 78%; mp 71–73 ꢁC; ESMS
+
1
dine 22. The enantiomeric excesses of the alkaloids pre-
pared were determined from their H NMR spectra
(negative ion mode) m/z 245.2 [MꢀH] ; H NMR
1
(200 MHz, CD OD): d 1.77 (quintet, 2H, J = 6.8 Hz),
3
measured in the presence of (+)-(R)-tert-butylphenylphos-
phinothio(seleno)ic acids as chiral solvating agents. The
absolute configurations at the newly created stereogenic
carbon atoms were established in all cases by the X-ray
analysis.
2.22 (t, 2H, J = 7.4 Hz), 2.93 (t, 2H, J = 7.4 Hz), 3.43–
5.56 (m, 4H), 6.95–7.12 (m, 3H), 7.31 (d, 1H, J =
1
3
8.3 Hz), 7.53 (d, 1H, J = 7.5 Hz); C NMR (50 MHz,
CD OD): d 26.27, 29.82, 33.71, 41.43, 62.29, 112.23,
3
113.26, 119.28, 119.58, 122.29, 123.39, 128.79, 138.15,
175.85.
1
4
. Experimental
Data for compound 20: yield 87%; mp 75–77 ꢁC; H NMR
200 MHz, CD OD): d 1.44–1.67 (m, 4H), 2.16 (t, 2H,
(
3
The NMR spectra were recorded on a Varian Unity Plus
spectrometer operating at 500 MHz for H NMR and at
J = 7.2 Hz), 2.93 (t, 2H, J = 6.8 Hz), 3.43–5.55 (m, 4H),
6.95–7.12 (m, 3H), 7.32 (d, 1H, J = 8.2 Hz), 7.55 (d, 1H,
1

J. Szawkało et al. / Tetrahedron: Asymmetry 18 (2007) 406–413
411
1
3
J = 7.6 Hz); C NMR (50 MHz, CD OD): d 23.38, 26.27,
3
in 4 mL CH CN was introduced at 0 ꢁC to a stirred solu-
3
3
3.01, 36.81, 41.36, 62.49, 112.21, 113.23, 119.23, 119.56,
tion of iminium salts 3, 6, 18 or 21 in CH CN (10 mL) con-
3
1
22.29, 123.39, 128.78, 138.12, 176.00.
taining also a 5:2 formic acid–triethylamine mixture
(
2.5 mL). Stirring was continued for 10 h at 0 ꢁC and then
the reaction mixture was made basic by the addition of
aqueous Na CO (or NH in the case of 19 and 22)
4
.2. Preparation of iminium salt 6
2
3
3aq
To a stirred solution of N-[2-(3,4-dimethoxyphenyl)ethyl]-
-hydroxypentanamide (5.0 g, 17.8 mmol) in toluene
50 mL), POCl (16 mL, 175.3 mmol) was added and the
and extracted with diethyl ether (or chloroform). The or-
5
(
ganic phase was dried over MgSO and concentrated under
4
reduced pressure. The residue was purified by flash chro-
matography using chloroform/methanol as a solvent
system to afford amines 5, 8, 19 or 22.
3
reaction mixture refluxed for 2 h. Next it was poured onto
crushed ice and the mixture was made basic with NH3aq
.
The aqueous layer was subsequently extracted with chloro-
form (3 · 30 mL) and the combined organic layers were
Data for compound (R)-(+)-5: 79.3 mg (96% yield); all the
3
1
dried over MgSO and concentrated under reduced pres-
spectral data were the same as already described. The pic-
rate salt was obtained by mixing hot solutions of equimolar
amounts of amine 5 and picric acid in ethanol.
4
sure. The residue was crystallized from ethanol/ether to
give 4.7 g (93%) of compound 6 as white needles. Mp
1
62–165 ꢁC; ESMS (positive ion mode) m/z 246.1
+ 1
[
M ꢀCl]; H NMR (500 MHz, CDCl ): d 7.25 (s, 1H),
Crystallographic data: C H N O , M = 462.42, T =
3
20 22
4
9
r
6
.89 (s, 1H), 4.03 (s, 3H), 3.97 (s, 3H), 3.89 (t, 2H,
293(2) K, monoclinic crystals, P21 space group with
˚
J = 7 Hz), 3.67 (t, 2H, J = 6 Hz), 3.35 (t, 2H, J = 7 Hz),
a = 9.2228(5), b = 10.5363(7) and c = 11.3660(7) A, b =
1
3
3
˚
3
.07 (t, 2H, J = 8 Hz), 1.99–2.04 (m, 4H); C NMR
105.724(8)ꢁ, V = 1063.15(11) A , Z = 2, F(000) = 484,
3
ꢀ1
(
125 MHz, CDCl ): d 176.85, 156.55, 149.07, 133.67,
q = 1.445 Mg/m , l(Cu Ka) = 0.986 mm , R1 = 0.0534
and wR2 = 0.1195 for 2122 reflections with I P 2r(I).
Absolute structure parameter x = ꢀ0.2(4). In the crystal
3
1
3
17.01, 111.29, 111.26, 56.76, 56.67, 44.34, 40.77, 31.38,
1.27, 25.83, 25.50.
0
structure, strong N(4)–H(4)ꢂ ꢂ ꢂO(1 ) hydrogen bonds be-
4
1
.3. General procedure for the preparation of iminium salts
8 and 21
tween crispine cation and picric acid anion were observed.
The detailed structural parameters have been deposited
with the Cambridge Crystallographic Data Centre under
the number CCDC 630264.
The solution of x-hydroxyamides 17 or 20 (6.0 mmol) and
freshly distilled POCl (15 mL) was refluxed for 3 h under
3
argon. The excess of POCl was removed in vacuo and
Data for compound (R)-(+)-8: yields 83–97% depending on
3
5
6
the residue was dissolved in CH Cl (20 mL). The solution
the temperature of the reduction; mp 57–59 ꢁC [lit. 58–
2
2
23
was washed with 25% NH3aq, saturated solution of NaH-
60 ꢁC]; ½aꢁ ¼ þ94:0 (c 1.0, CHCl ) (87% ee); ESMS (posi-
D
3
+
1
CO and brine, and finally evaporated (after drying over
tive ion mode) m/z 248.1 [M+H] ; H NMR (500 MHz,
3
MgSO ). The crude salts were reduced in the presence of
CDCl ): d 6.69 (s, 1H), 6.56 (s, 1H), 3.84 (2s, 6H), 3.04–
4
3
catalyst (S,S)-4 as described below.
3.14 (m, 2H), 2.91–2.99 (m, 2H), 2.58–2.62 (m, 1H),
2
.47–2.52 (m, 1H), 2.24–2.33 (m, 2H), 1.90–1.93 (m, 1H),
1
3
Data for compound 18: ESMS (positive ion mode) m/z
1.70–1.75 (m, 2H), 1.38–1.53 (m, 2H);
C NMR
+
1
2
47.1 [M+H] ; H NMR (200 MHz, CDCl ): d 2.34 (quin-
(125 MHz, CDCl ): d 147.38, 147.14, 130.51, 126.83,
3
3
tet, 2H, J = 7.3 Hz), 3.17 (t, 2H, J = 8.5 Hz), 3.35–3.59 (m,
H), 3.91 (t, 2H, J = 8.5 Hz), 7.16 (t, 1H, J = 7.5 Hz), 7.39
t, 1H, J = 7.5 Hz), 7.58 (d, 1H, J = 8.5 Hz), 7.71 (d, 1H,
J = 8.5 Hz), 12.73 (br s, 1H); C NMR (50 MHz, CDCl3):
d 19.46, 30.42, 31.16, 42.10, 43.99, 114.28, 121.25, 121.94,
111.52, 108.22, 63.28, 56.94, 56.00, 55.85, 52.93, 31.58,
29.17, 25.52, 25.15.
4
(
1
3
Data for compound (R)-(+)-19: 81% yield; mp 171–172 ꢁC
5
7
23
D
[lit. 164–167 ꢁC]; ½aꢁ ¼ þ94:0 (c 1, CHCl ) (79% ee)
3
4
0
23
D
1
24.14, 125.55, 129.15, 142.20, 169.22.
[lit. ½aꢁ ¼ þ119 (c 0.086, CHCl )]; after recrystallization
3
2
3
from ethanol: mp 171–172 ꢁC; ½aꢁ ¼ þ109:5 (c 0.99,
+ 1
D
+
Å
Data for compound 21: MS m/z (%) 224 (M , 91), 223
CHCl ) (92% ee); ESMS (negative ion mode) m/z 211.2
3
1
(
100), 209 (26), 195 (19), 167 (21), 154 (7), 104 (11); H
[MꢀH] ; H NMR (500 MHz, CDCl ): d 1.81–1.95 (m,
3
NMR (200 MHz, CDCl ): d 1.85–2.09 (m, 4H), 3.23 (t,
3H), 2.23–2.32 (m, 1H), 2.62–2.67 (m, 1H), 2.84–2.99 (m,
3H), 3.05–3.11 (m, 1H), 3.31–3.35 (m, 1H), 4.22–4.24
(m, 1H), 7.08–7.15 (m, 2H), 7.29 (d, 1H, J = 8 Hz), 7.49
3
2
H, J = 8.3 Hz), 3.47–3.64 (m, 4H), 3.99 (t, 2H,
J = 8.3 Hz), 7.19 (t, 1H, J = 7.3 Hz), 7.43 (t, 1H, J =
1
3
7
1
2
1
.3 Hz), 7.62 (d, 1H, J = 8 Hz), 7.73 (d, 1H, J = 8 Hz),
(d, 1H, J = 7.5 Hz), 7.86 (br s, 1H);
C NMR
1
3
2.29 (br s, 1H); C NMR (50 MHz, CDCl ): d 19.76,
(125 MHz, CDCl ): d 17.78, 23.44, 29.43, 45.93, 49.26,
3
3
6.06, 31.95, 32.20, 42.37, 44.53, 107.17, 114.37, 121.54,
22.18, 124.38, 125.65, 129.39, 142.20, 170.24.
56.91, 107.77, 110.70, 118.09, 119.93, 121.36, 127.32,
135.44, 135.95.
4
.4. General procedure for the asymmetric transfer
hydrogenation
Crystallographic data: C H N , M = 212.29, T =
1
4
16
2
r
293(2) K, orthorhombic, P2 2 2 space group, a =
1 1 1
˚
7.3217(6),
b = 9.1999(9),
c = 17.495(4) A,
1178.4(3) A , Z = 4, q = 1.197 Mg/m , F(000) = 456,
l(Cu Ka) = 0.548 mm , R1 = 0.0367 and wR2 = 0.1000
for 2066 independent reflections with I P 2r(I). Absolute
V =
3
3
˚
The catalyst (S,S)-4 formed independently from
ꢀ
1
[
RuCl (C H )] (6 mg, 24 lmol) and (1S,2S)-1,2-diphenyl-
2
6
6 2
N-(p-toluoylsulfonyl)ethylenediamine 9 (7.3 mg, 20 lmol)

412
J. Szawkało et al. / Tetrahedron: Asymmetry 18 (2007) 406–413
structure parameter x = ꢀ0.2(5). In the crystal structure,
strong N(11)–H(11)ꢂ ꢂ ꢂN(4) hydrogen bonds between adja-
cent symmetry related molecules were observed. The
detailed structural parameters have been deposited with
Cambridge Crystallographic Data Centre under the num-
ber CCDC 630266.
Crystallographic data: C H NO ÆH O, M = 281.34,
15 21 3 2 r
T = 173(2) K, orthorhombic, P2 2 2 , a = 9.987(6),
1
1 1
3
˚
˚
b = 14.074(11), c = 20.786(8) A, V = 2922(3) A , Z = 8,
3
q = 1.279 Mg/m ,
F(000) = 1216,
l(Cu Ka) = 0.754
ꢀ
1
mm , R1 = 0.0308, wR2 = 0.0671 for 4361 independent
reflections with I P 2r(I). Absolute structure parameter
x = 0.05(13). The crystal structure of 15 is a hydrate
structure where compound molecules are linked together
via strong intermolecular water–compound and water–
water O–Hꢂ ꢂ ꢂO hydrogen bonds. Two molecules of 15,
slightly differing in geometry, and two water molecules
form independent part of the unit cell. The detailed struc-
tural parameters have been deposited with Cambridge
Crystallographic Data Centre under the number CCDC
630265.
Data for compound (R)-(+)-22: 84% yield; mp 148–149 ꢁC
4
2
23
D
[
lit. 149–152 ꢁC]; ½aꢁ ¼ þ74:4 (c 1, MeOH) (90.5% ee);
after recrystallization from propanol/H O mp 148–
2
23
1
49 ꢁC; ½aꢁ ¼ þ82:7 (c 0.96, MeOH); MS m/z (%) 226
D
+
Å
(
M , 68), 225 (100), 197 (27), 169 (30), 156 (9), 115 (7);
1
H NMR (500 MHz, CDCl ): d 1.43–1.63 (m, 2H), 1.71–
3
1
.82 (m, 2H), 1.90 (d, 1H, J = 12.5 Hz), 2.06 (dd, 1H,
J = 12.5, 2.5 Hz), 2.39 (td, 1H, J = 11.3, 3.4 Hz), 2.61–
2
1
.72 (m, 2H), 2.98–3.09 (m, 3H), 3.23 (d, 1H, J =
0.5 Hz), 7.07–7.14 (m, 2H), 7.29 (d, 1H, J = 8 Hz), 7.47
2
D
3
Data for compound 16: colourless oil; ½aꢁ ¼ þ9:1 (c 1,
1
3
+
(
d, 1H, J = 8 Hz), 7.78 (br s, 1H); C NMR (125 MHz,
CHCl ); ESMS (positive ion mode) m/z 264.1 [M+H] ;
H NMR (500 MHz, CDCl , 27 ꢁC): d 6.65 (s, 1H), 6.58
(s, 1H), 4.61 (br s, 1H), 4.34 (d, 1H, J = 9.8, J =
2.8 Hz), 3.86 (s, 3H), 3.84 (s, 3H), 3.78–3.95 (m, 8H),
.70 (m, 1H), 3.60 (m, 1H), 3.49 (m, 1H), 3.37 (m, 1H),
2.89 (br d, 1H, J = 16.6 Hz) 2.39 (m, 1H), 2.06 (m, 1H),
3
1
CDCl ): d 21.58, 24.31, 25.73, 29.98, 53.55, 55.74, 60.22,
3
3
1
1
08.09, 110.68, 118.08, 119.31, 121.22, 127.46, 135.10,
35.89.
1
2
3
Crystallographic data: C H N Æ1/2H O, M = 235.32,
T = 293(2) K, monoclinic, C2, a = 19.297(4), b =
1
5
18
2
2
r
1
3
1.65–1.85 (m, 4H:2H after exchange with D O);
C
2
˚
6
.5192(13),
c = 10.423(2) A,
b = 91.71(3)ꢁ,
V =
NMR (125 MHz, CDCl , 27 ꢁC): d 148.63, 148.29,
125.88, 122.32, 111.45, 109.91, 77.43, 73.78, 56.32, 56.11,
29.69, 25.03, 22.63, 21.52, 19.00.
3
3
3
˚
1
310.7(5) A , Z = 4, q = 1.193 Mg/m , F(000) = 508,
ꢀ
1
l(Cu Ka) = 0.567 mm , R1 = 0.0386 and wR2 = 0.0956
for 2003 independent reflections with I P 2r(I). Absolute
structure parameter x = ꢀ0.2(4). The crystal structure is
a hydrate structure with water molecules occupying special
positions on twofold axes. Strong hydrogen bonds N(12)–
H(12)ꢂ ꢂ ꢂO(1S) and O(1S)–H(1S)ꢂ ꢂ ꢂN(5) between 22 and
water molecules are observed. The detailed structural
parameters have been deposited with Cambridge Crystallo-
graphic Data Centre under the number CCDC 630267.
Acknowledgement
Financial support from Grants PBZ-KBN-126/T09/2004/
3, KBN-3/T09A/073/28 and 288/FNiTP/624/2005 is
1
gratefully acknowledged.
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.5. Preparation of N-oxides 15 and 16
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