Synthesis of hindered chiral guanidine bases starting from (S)-(N,N-dialkyl-aminomethyl)pyrrolidines and BrCN

Article abstract of DOI:10.1016/j.tetasy.2006.02.009

An efficient method for the preparation of hindered chiral guanidines using cyanogen bromide is described. The reaction between BrCN and vicinal diamines derived from (S)-2-(N,N-dialkyl-aminomethyl)-pyrrolidines provides chiral substituted cyanamides. The cyanamide derivatives reacted with secondary amines in hexafluoroisopropanol at reflux to form chiral hindered guanidines, which were isolated in good to excellent yields (70-96%). The chiral guanidines were prepared in an effort to design sophisticated chiral guanidine catalysts for asymmetric synthesis.

Full text of DOI:10.1016/j.tetasy.2006.02.009

Tetrahedron: Asymmetry 17 (2006) 811–818
Synthesis of hindered chiral guanidine bases starting from
(S)-(N,N-dialkyl-aminomethyl)pyrrolidines and BrCN
Uwe Ko¨hn,a Maurice Klopfleisch,a Helmar Go¨rlsb and Ernst Andersa,*
aInstitut fu¨r Organische Chemie und Makromolekulare Chemie der Friedrich-Schiller-Universita¨t,
Humboldtstrasse 10, D-07743 Jena, Germany
bInstitut fu¨r Anorganische und Analytische Chemie der Friedrich-Schiller-Universita¨t, Lessingstrasse 8, D-07743 Jena, Germany
Received 19 January 2006; accepted 13 February 2006
Available online 24 March 2006
Abstract—An efficient method for the preparation of hindered chiral guanidines using cyanogen bromide is described. The reaction
between BrCN and vicinal diamines derived from (S)-2-(N,N-dialkyl-aminomethyl)-pyrrolidines provides chiral substituted cyan-
amides. The cyanamide derivatives reacted with secondary amines in hexafluoroisopropanol at reflux to form chiral hindered gua-
nidines, which were isolated in good to excellent yields (70–96%). The chiral guanidines were prepared in an effort to design
sophisticated chiral guanidine catalysts for asymmetric synthesis.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
to give higher substituted guanidine.9 Additionally, the
nucleophilic reaction of an amine to a reagent of the
type R2N(Z)C@NR leads to a displacement of a leaving
group Z, where Z can be the benzotriazole group of
benzotriazole-1-carboxamidinium tosylate or di(benzo-
triazol-1-yl)methanimine, the pyrazole moiety of 1H-
pyrazole-1-carboxamidine, or of its N,N0-diprotected
derivatives.10
The guanidine functional group is an important com-
pound in many biological, chemical and medicinal
applications.1 For instance,2 guanidines received
increasing interest as medicinal agents with antitumour,
anti-hypertensive, anti-glaucoma and cardiotonic activi-
ties, as well as H2 antagonism/agonism.
In some cases, due to their strongly basic character,
guanidines can be as considered superbases that readily
undergo protonation to generate resonance-stabilized
guanidinium cations.3 The wide range of biological
activities and chemical applications found for guani-
dines has motivated the development of many reagents
for their synthesis. Various methods achieve guanylation
by the addition of a nucleophilic amine to a cyanamide,4
or a carbodiimide.5 Further guanylating methods
involve the reaction between primary or secondary
amines with heavy metals or carbodiimide promoted
Chiral guanidines have potential as chiral auxiliaries in
asymmetric synthesis, but obviously there is a lack of
convenient preparation methods.11 Previously, we
reported the simple preparation of chiral guanidines as
potential chiral superbases. These procedures have
allowed the synthesis of enantiopure guanidines starting
from N,N0-di-isopropylcarbodiimide and (S)-2-(N,N-
dialkylamino-methyl)pyrrolidine.5b However, we could
show that the diisopropyl groups are limited to the use
of these guanidines in asymmetric synthesis.12 For this
reason, we have used an efficient synthesis, which allows
access to sterically hindered chiral guanidine bases.
N,N-dialkylthioureas,6
N-protected-S-alkylisothio-
ureas,7 or aminoiminosulfonic-acids.8 Further methods,
which would expand the range of substrates that could
be converted into guanidine products, are based on the
reaction of an electrophile with a nucleophilic guanidine
Herein, we report the preparation of sterically hindered
ambitious chiral guanidines by a convenient method
using chiral 1,2-diamines and cyanogen bromide. To
the best of our knowledge, no attempt to synthesize chi-
ral guanidines starting from (S)-2-(N,N-dialkylamino-
methyl)pyrrolidines and cyanogen bromide has so far
been published.
*
Corresponding author. Tel.: +49 (0)3641 948210; fax: +49 (0)3641
948212; e-mail: Ernst.Anders@uni-jena.de
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.02.009

812
U. Ko¨hn et al. / Tetrahedron: Asymmetry 17 (2006) 811–818
Table 1. Results for the preparation of 2a–c
Cyanamide
R1 Yielda (%)
2a 1-Pyrrolidinyl
2. Results and discussion
rt
½aꢁD
The starting chiral vicinal diamines 1a–c were prepared,
using a known three step procedure13 in good to excel-
lent yields by reaction in the first step of (S)-2-pyrrolid-
inone-5-carboxylic acid with anhydrous chloral to afford
a diastereomerically pure oxazolidinone derivate precur-
sor. This compound could be readily transformed into
amides by nucleophilic ring opening with the corres-
ponding amines. Finally, the amides were reduced with
LiAlH4 to the desired chiral vicinal diamines 1a–c. Fur-
thermore, the procedure could be extended to larger
scales as described in the literature.12
64.0
80.0
77.6
ꢀ50.2
ꢀ40.5
ꢀ50.8
2b
2c
4-Morpholinyl
1-Piperidinyl
a Isolated yields.
Chiral guanidines 3–6 were prepared following a modi-
fied procedure of Snider et al.14 Treatment of 1 equiv
of cyanamide 2a–c with 1 equiv of secondary amine in
hexafluoroisopropanol (HFIP) for 16 h, yielded the
corresponding chiral guanidines 3–5 (Scheme 1). After
simple purification of guanidines 3–5 by dissolution
in aqueous citric acid (pH = 7) in order to extract the
impurities, the aqueous solution was basified with 50%
KOH solution and the guanidines extracted with
CH2Cl2 to afforded the desired products in good to
excellent yields (Table 2). As expected, the reaction of
2a–c with the chiral 1,2-diamines 1a–c as secondary
amine led to comparable results and produced only
the single diastereomer. Guanidines 6a–c were easily
purified by the above-mentioned procedure to give
good yields in a purity of over 90% by 1H NMR
spectroscopy.
Based on literature procedure for the formation of
hindered guanidines,14 we decided to prepare the
cyanamides from the chiral N,N-(dialkylaminomethyl)-
pyrrolidine derivates 1a–c, and in a second step, we
transformed the substituted cyanamide derivates with
the corresponding amines into the desired guanidines.
The reaction of 1a–c with a small excess of cyanogen
bromide and 1.3 equiv of triethylamines in THF afford-
ed, after stirring at room temperature, the substituted
crude cyanamides 2a–c in quantitative yields (Scheme 1).
The purification of 2a–c with bulb to bulb distillation
gave yields in the range of 60–80% (isolated yields, Table
1). The molecular structures of compounds 2a–c were
established from their NMR (1H, 13C, DEPT 135,
HMQC, HMBC) spectroscopic data. The 13C NMR
spectra of 2a–c exhibited the requisite number of signals
in small appearance, whereas the resonance signal of the
significant cyano group was assigned to d 117 ppm. In
To elucidate the structures of 3–6, 2D NMR experi-
ments (HMQC, HMBC, COSY) were carried out at
1
room temperature in addition to H, 13C and DEPT
135. In general, the NMR measurements of 3–6 were
recorded in dichloromethane and benzene due to the
strong basic character of these guanidines.5b As ex-
pected, the 13C NMR spectra showed the requisite num-
ber of signals and the significant guanidine carbon atom
1
the H NMR spectra, the methylene protons of 2a–c
1
appeared in the range of 161–165 ppm. In the H NMR
are diastereotopic and appeared as complex multiplets
in the range of d 1.5–4.0 ppm. Furthermore, the IR spec-
tra showed a strong band of the CN group at
spectra of 3–6, the methylene protons were observed as
complex multiplets in the region of d 1.1–4.5 ppm and
the methine proton appeared as multiplet in the range
2200 cmꢀ1
.
R1
N
H
1a-c
BrCN
R1
N
2a-c
CN
Pyrrolidine
Morpholine
Piperidine
1a-c
R1
R1
R1
R1
N
N
N
N
N
HN
HN
N
HN
N
HN
N
O
R1
4a-c
3a-c
5a-c
6a-c
Scheme 1. Synthesis of chiral cyanamides 2a–c and guanidines 3–6; R1 see Table 1.

U. Ko¨hn et al. / Tetrahedron: Asymmetry 17 (2006) 811–818
813
guanidine hydrochloride complex5b of 6a were crystal-
lized and investigated by X-ray crystallography. The
X-ray analysis of 4aÆ(ZnCl2) showed the expected (S)-
configuration at C2-carbon (Fig. 2 and Table 3).
Table 2. Prepared hindered guanidines 3–6
Guanidines R1
Sec. amine
rt
Yielda (%) ½aꢁD
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
1-Pyrrolidinyl Pyrrolidine 98.5
4-Morpholinyl Pyrrolidine 97.4
ꢀ22.2
ꢀ18.9
ꢀ21.5
27.7
26.2
23.1
54.2
51.7
34.3
1-Piperidinyl
Pyrrolidine 79.4
1-Pyrrolidinyl Morpholine 71.9
4-Morpholinyl Morpholine 75.1
1-Piperidinyl
Morpholine 76.9
1-Pyrrolidinyl Piperidine
4-Morpholinyl Piperidine
90.7
96.7
90.6
75.1
98.6
75.1
1-Piperidinyl
Piperidine
1-Pyrrolidinyl 1a
4-Morpholinyl 1b
ꢀ40.8
ꢀ49.3
ꢀ40.4
1-Piperidinyl
1c
a Isolated yields.
of d 3.7–4.5 ppm. The NH guanidine proton revealed as
broad singlet at d 4.9–6.1 ppm, but in some cases, no
identification was possible. Positive EI mass spectrome-
try was used to confirm that all products had the ex-
pected molecular formulas.
Figure 2. Crystal structure of 4aÆ(ZnCl2).
Choosing 4a as a representative for guanidines 3–6,
1H NMR investigations of 4a were carried out in the
presence of the shift reagent (S)-(+)-2,2,2-trifluoro-1-
(9-anthryl)ethanol in order to assess the enantiomeric
purity.15 Additionally, the reliability of the shift reagent
was tested with the racemate of 4a. Figure 1 shows the
1H NMR spectra of the racemic and enantiopure (S)-
form of 4a.
˚
Table 3. Selected bond lengths (A) and bond angles (ꢁ) for the zinc(II)
complex 4aÆ(ZnCl2)
Bond lengths
Bond angles
N(1)–C(7)
N(3)–C(7)
N(4)–C(10)
N(2)–Zn
N(4)–Zn
Zn–Cl(1)
Zn–Cl(2)
1.349(4)
1.386(4)
1.310(4)
2.096(3)
2.000(3)
2.2487(8)
2.2487(8)
N(1)–C(7)–N(3)
N(3)–C(7)–N(4)
N(1)–C(7)–N(4)
N(2)–Zn–N(4)
N(2)–Zn–Cl(1)
N(2)–Zn–Cl(2)
N(4)–Zn–C(10)
115.4(2)
123.9(3)
120.7(3)
103.87(11)
109.05(7)
110.68(7)
138.1(2)
For the hydrochloride complex 6aÆ(HCl)16 of the dia-
stereomer 6a, the absolute configuration for both
stereogenic centres (C2, C3) was determined to be S
(Fig. 3 and Table 4).
Figure 1. 1H-spectra (400 MHz) of 4a after addition of the chiral shift
reagent (S)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol.
When the chiral shift agent was added to a solution of
racemic 4a in THF-d8 and immediately after that the
1H NMR spectrum was measured at room temperature,
one of the C3 methylene protons split into two multi-
plets of roughly equal intensity (Fig. 1B). In the case
of the enantiomerically pure guanidine 4a, no racemiza-
tion was observed within the NMR accuracy (Fig. 1A).
Thus, the enantiomeric purity of the isolated compound
4a is higher than 95%.5b
Figure 3. Crystal structure of diastereomeric hydrochloride complex
6aÆ(HCl), chlorides are omitted for clarity.
˚
Table 4. Selected bond lengths (A) and bond angles (ꢁ) for the hydro-
chloride complex 6aÆ(HCl)
Bond lengths
Bond angles
N(1)–C(1)
N(3)–C(1)
N(2)–C(1)
N(1)–C(2)
N(2)–C(3)
1.337(6)
1.325(6)
1.358(6)
1.483(6)
1.487(6)
N(1)–C(1)–N(3)
N(3)–C(1)–N(2)
N(1)–C(1)–N(2)
C(1)–N(2)–C(3)
C(1)–N(1)–C(2)
122.7(4)
120.4(4)
116.8(4)
121.7(4)
123.8(4)
To confirm the correct absolute configuration of chiral
guanidines 3–6, a zinc chloride complex5a of 4a and a

814
U. Ko¨hn et al. / Tetrahedron: Asymmetry 17 (2006) 811–818
1
Finally, in preliminary tests we found that the new gua-
nidines 3–6 possess strong basicity. The Henry reaction
between 2-methylpropanal and nitromethane in CD3CN
promoted by 6a provided the corresponding nitro-
alcohol. This experiment demonstrates that 6a has a
pKa value of at least 28 in MeCN, since the pKa value
of nitromethane in MeCN is approximately 28.17 Poten-
tiometric titrations are currently in progress and will be
reported in due course.
requires 155.1548. H NMR (CDCl3): d 3.17 (m, 1H,
CH), 2.91/2.76 (m, 2H, CH2), 2.53/2.46 (m, 4H,
2 · CH2), 2.49/2.32 (m, 2H, CH2), 2.06 (s, 1H, NH),
1.86/1.32 (m, 2H, CH2), 1.73 (m, 6H, 3 · CH2). 13C
NMR (CDCl3):
d 62.6 (CH2), 57.8 (CH), 54.9
(2 · CH2), 46.5 (CH2), 30.6 (CH2), 25.5 (CH2), 23.8
(2 · CH2). IR (ATR, m/cmꢀ1): 3277 (mNH), 2959–2783
20
D
(mCH). EI-MS m/z 155 (M+H)+. ½aꢁ ¼ þ10:8 (c 2.59,
EtOH).
4.2.2. (S)-2-(Morpholin-4-ylmethyl)-pyrrolidine 1b.12
Yield 55.5%. HRMS m/z 171.1490 (M+1)+.
C9H19N2O requires 171.1497. 1H NMR (CDCl3): d
3.66 (m, 4H, 2 · CH2), 3.23 (m, 1H, CH), 2.95/2.81
(m, 2H, CH2), 2.51/2.38 (m, 4H, 2 · CH2) 2.26 (m,
2H, CH2), 2.00 (s, 1H, NH), 1.84/1.29 (m, 2H, CH2),
1.71 (m, 2H, CH2). 13C NMR (CDCl3): d 67.4
(2 · CH2), 64.9 (CH2), 55.3 (CH), 54.8 (2 · CH2), 46.7
(CH2), 30.9 (CH2), 25.4 (CH2). IR (ATR, m/cmꢀ1):
3. Conclusion
An efficient method for the preparation of sterically hin-
dered chiral guanidines 3–6 derived from (S)-2-(N,N-
dialkylamino-methyl)pyrrolidines 1a–c using cyanogen
bromide has been reported. In the first step, the reaction
of 1,2-diamines with BrCN produced substituted cyan-
amides 2a–c, which were subsequently reacted with
secondary amines in the presence of hexafluoroiso-
propanol to afford hindered chiral guanidines 3–6. This
protocol provides an alternative method for the prepa-
ration of chiral guanidines. An attractive feature of this
methodology is that only a few byproducts are gener-
ated and at the end of the reaction, simple aqueous
work-up gives high yields of the desired products.
3313 (mNH), 2954–2705 (mCH). EI-MS m/z 171 (M+1)+.
20
½aꢁD ¼ þ11:3 (c 2.40, EtOH).
4.2.3.
(S)-2-(Piperidin-1-ylmethyl)-pyrrolidine
1c.13
Yield 36.2%. HRMS m/z 169.1705 (M+1)+. C10H21N2
1
requires 169.1705. H NMR (CDCl3): d 3.24 (m, 1H,
CH), 2.97/2.81 (m, 2H, CH2), 2.45/2.32 (m, 4H,
2 · CH2), 2.24 (m, 2H, CH2), 1.84/1.30 (m, 2H, CH2),
1.72 (m, 2H, CH2), 1.55 (m, 4H, 2 · CH2), 1.42 (m,
2H, CH2), NH at room temperature not detected. 13C
NMR (CDCl3): d 65.3 (CH2), 56.0 (2 · CH2), 55.5
(CH), 46.4 (CH2), 30.5 (CH2), 26.6 (2 · CH2), 25.4
(CH2), 24.9 (CH2). IR (ATR, m/cmꢀ1): 3313 (mNH),
We are currently seeking to extend the guanidine chemis-
try to investigate its application in asymmetric synthe-
ses, for example, Henry reaction or Michael addition
as chiral bases. Further work is currently in progress
in order to determine the basicity of this new class of
guanidines.
2954–2705 (mCH). EI-MS m/z 169 (M+H)+.
20
½aꢁD ¼ þ15:2 (c 10.0, EtOH).
4. Experimental
4.1. General
4.3. General procedure for preparation of chiral
cyanamide derivates 2
To a solution of 1a–c (6.5 mmol) and triethylamine
(8.5 mmol) in 30 mL dry THF, 7.5 mmol of cyanogen
bromide dissolved in 5 mL, THF was added while stir-
ring. The reaction mixture was magnetically stirred for
30 min at room temperature. The white precipitate
formed was filtered off and washed with THF. The sol-
vent was evaporated under reduced pressure and the
resulting yellow oily residue dissolved in 40 mL of water.
The aqueous solution was adjusted with aqueous citric
acid to pH 7. After extraction with ether (3 · 20 mL),
the pH value of the aqueous solution was raised with
concentrated KOH solution (50%) to pH 10. Following
an extraction with CH2Cl2 (3 · 20 mL), the combined
organic phases were dried over anhydrous sodium sul-
fate. The solvent was evaporated under reduced pressure
and the resulting oily crude product purified by bulb to
bulb distillation.
NMR spectra were recorded on a Bruker AC 250 MHz
and AC 400 MHz using the residual solvent resonance
as an internal standard. CD2Cl2 (H d = 5.32, C
d = 53.8) and C6D6 (H d = 7.15, C d = 128.0) were used
as solvents. The geminal protons are described as X/X.
Optical rotations were recorded on a Polartronic E and
rt
are reported as ½aꢁD (c in g/100 ml, solvent). Elemental
analyses were conducted by the microanalytical service
of our department. IR spectra were recorded on an
ATR–BIORAD FTS-25. MS spectra were recorded on
a Finnigan MAT SAQ 710 (EI) and on a Finnigan
MAT SSQ (ESI). All compounds were fully characterized.
The elemental compositions were determined by micro-
analytical data ( 0.4%) or HRMS. Hexafluoro-isoprop-
anol, (S)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol and
cyanogen bromide were commercially available and used
without further purification. Chiral 1,2-diamines 1a–c are
described in the literature.13 Tetrahydrofuran (THF) was
distilled under argon from sodium/benzophenone.
4.3.1. (S)-2-(Pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbo-
nitrile 2a. Yield 64.0%. (Found: C, 67.27; H, 9.45; N,
23.27. C10H17N3 requires C, 67.00; H, 9.56; N, 23.44.)
1H NMR (CDCl3): d 3.63 (m, 1H, CH), 3.35 (m, 2H,
CH2), 2.66/2.43 (m, 2H, CH2), 2.50 (m, 4H, 2 · CH2),
1.96/1.67 (m, 2H, CH2), 1.83 (m, 2H, 2 · CH2), 1.70
(m, 2H, CH2). 13C NMR (CDCl3): d 117.3 (CN), 61.0
4.2. Chiral diamines 1a–c
4.2.1. (S)-2-(Pyrrolidin-1-ylmethyl)-pyrrolidine 1a.13
Yield 90.1%. HRMS m/z 155.1550 (M+1)+. C9H19N2

U. Ko¨hn et al. / Tetrahedron: Asymmetry 17 (2006) 811–818
815
(CH), 59.6 (CH2), 54.6 (2 · CH2), 50.9 (CH2), 30.0
(CH2), 24.5 (CH2), 23.5 (2 · CH2). IR (ATR, m/cmꢀ1):
4.4.2.
C-(2-(Morpholin-4-ylmethyl)-pyrrolidin-1-yl)-C-
pyrrolidin-1-yl-methylenamine 3b. Yield 97.4%. HRMS
m/z 267.2186 (M+1)+. C14H27N4O requires 267.2185.
1H NMR (C6D6): d 5.00 (s, 1H, NH), 4.33 (m, 1H,
CH), 3.60 (m, 4H, 2 · CH2), 3.04/2.97 (m, 2H, CH2),
3.01 (m, 4H, 2 · CH2), 2.71/2.09 (m, 2H, CH2), 2.43/
2.32 (m, 4H, 2 · CH2), 1.99/1.55 (m, 2H, CH2), 1.50/
1.36 (m, 4H, 2 · CH2), 1.50 (m, 2H, CH2). 13C NMR
(C6D6): d 161.2 (CN3), 67.1 (2 · CH2), 63.2 (CH2),
56.2 (CH), 54.8 (2 · CH2), 50.2 (CH2), 48.1 (2 · CH2),
31.1 (CH2), 25.3 (2 · CH2), 24.8 (CH2). IR (ATR,
2959–2787 (mCH), 2203 (mCN). EI-MS, m/z 179 (M+).
20
½aꢁD ¼ ꢀ50:2 (c 2.95, CHCl3).
4.3.2. (S)-2-(Morpholin-4-ylmethyl)-pyrrolidine-1-carbo-
nitrile 2b. Yield 80.0%. (Found: C, 61.26; H, 8.81; N,
21.01 C10H17N3O requires C, 61.51; H, 8.78; N,
21.52.) 1H NMR (CDCl3): d 3.68 (m, 4H, 2 · CH2),
3.68 (m, 1H, CH), 3.41 (m, 2H, CH2), 2.49/2.39 (m,
2H, CH2), 2.45 (m, 4H, 2 · CH2), 1.98/1.66 (m, 2H,
CH2), 1.87 (m, 2H, CH2). 13C NMR (CDCl3): d 117.3
(CN), 66.9 (2 · CH2), 62.3 (CH2), 59.1 (CH), 54.3
(2 · CH2), 51.1 (CH2), 29.8 (CH2), 24.7 (CH2). IR
m/cmꢀ1): 2956–2867 (mCH), 1567 (mC@N), 1115 (mCOC).
20
EI-MS m/z 266 (M+). ½aꢁD ¼ ꢀ18:9 (c 3.49, CH2Cl2).
(ATR, m/cmꢀ1): 2953–2806 (mCH), 2202 (mCN). EI-MS,
4.4.3.
C-(2-(Piperidin-1-ylmethyl)-pyrrolidin-1-yl)-C-
20
m/z 195 (M+). ½aꢁD ¼ ꢀ40:5 (c 2.37, CHCl3).
pyrrolidin-1-yl-methylenamine 3c. Yield 79.4%. HRMS
m/z 265.2394 (M+1)+. C15H29N4 requires 265.2392. H
1
4.3.3. (S)-2-(Piperidin-1-ylmethyl)-pyrrolidine-1-carbo-
nitrile 2c. Yield 77.6%. (Found: C, 68.16; H, 9.72; N,
21.62. C11H19N3 requires C, 68.35; H, 9.91; N, 21.74.)
1H NMR (CDCl3): d 3.66 (m, 1H, CH), 3.36 (m, 2H,
CH2), 2.44/2.26 (m, 2H, CH2), 2.37 (m, 4H, 2 · CH2),
1.97/1.65 (m, 2H, CH2), 1.84 (m, 2H, CH2), 1.52 (m,
4H, 2 · CH2), 1.36 (m, 2H, CH2). 13C NMR (CDCl3):
d 117.4 (CN), 62.5 (CH2), 59.6 (CH), 55.1 (2 · CH2),
51.0 (CH2), 30.0 (CH2), 25.9 (2 · CH2), 24.4 (CH2),
NMR (C6D6): d 5.17 (s, 1H, NH), 4.25 (m, 1H, CH),
3.05 (m, 6H, 3 · CH2), 2.76/2.17 (m, 2H, CH2), 2.49/
2.33 (m, 4H, 2 · CH2), 2.05/1.64 (m, 2H, CH2), 1.62–
1.40 (m, 12H, 6 · CH2). 13C NMR (C6D6): d 161.7
(CN3), 63.9 (CH2), 56.9 (CH), 55.3 (2 · CH2), 50.4
(2 · CH2), 48.3 (CH2), 31.6 (CH2), 26.6 (2 · CH2), 25.5
(2 · CH2), 25.0 (CH2), 24.9 (CH2). IR (ATR, m/cmꢀ1):
2931–2866 (mCH), 1573 (mC@N). EI-MS m/z 264 (M+).
20
½aꢁD ¼ ꢀ21:5 (c 3.08, CH2Cl2).
24.2 (CH2). IR (ATR, m/cmꢀ1): 2933–2776 (mCH), 2204
20
(mCN). EI-MS, m/z 193 (M+). ½aꢁ ¼ ꢀ50:8 (c 2.71,
D
CH2Cl2).
4.4.4.
C-Morpholin-4-yl-C-(2-(pyrrolidin-1-ylmethyl)-
4a. Yield 71.9%.
pyrrolidin-1-yl)-methylenamine
HRMS m/z 267.2182 (M+1)+. C14H27N4O requires
267.2185. 1H NMR (CD2Cl2): d 3.86 (m, 1H, CH),
3.64 (m, 4H, 2 · CH2), 3.35/3.23 (m, 2H, CH2), 3.06/
2.96 (m, 4H, 2 · CH2), 2.59/2.34 (m, 2H, CH2), 2.50
(m, 4H, 2 · CH2), 2.10/1.76 (m, 2H, CH2), 1.80 (m,
2H, CH2), 1.72 (m, 4H, 2 · CH2), NH not detected
at room temperature. 13C NMR (CD2Cl2): d 164.3
(CN3), 67.1 (2 · CH2), 59.6 (CH2), 57.7 (CH), 55.0
(2 · CH2), 49.4 (CH2), 49.2 (2 · CH2), 31.0 (CH2), 24.6
4.4. General procedure for preparation of chiral guanidine
derivates 3–6
To a solution of 2 (3 mmol) in hexafluoroisopropanol
(3 mL) was added the corresponding secondary amine
(3 mmol, pyrrolidine, morpholine, piperidine or 1a–c).
The reaction mixture was refluxed for 16 h. Under vigor-
ous stirring, the brown solution was then diluted with
water (40 mL) and adjusted with aqueous citric acid to
pH 7. After extraction of the impurities with ether
(3 · 20 mL), the aqueous solution was alkalinized with
concentrated KOH solution (50%) to pH 14 and the
guanidines 3–6 were extracted with CH2Cl2 (3 ·
20 mL). The combined organic layers were dried over
anhydrous sodium sulfate and the solvent removed
under reduced pressure. Guanidines 3–6 are over 90%
pure by 1H NMR spectroscopy. Additionally, the result-
ing oily crude product can be purified by bulb to bulb
distillation.
(CH2), 23.9 (2 · CH2). IR (ATR, m/cmꢀ1): 2957–2766
20
D
(mCH), 1587 (mC@N). EI-MS m/z 266 (M+). ½aꢁ
þ27:7 (c 2.60, CH2Cl2).
¼
4.4.5.
pyrrolidin-1-yl)-methylenamine
C-Morpholin-4-yl-C-(2-(morpholin-4-ylmethyl)-
75.1%.
4b. Yield
(Found: C, 59.23; H, 9.58; N, 19.44. C14H26N4O2
requires C, 59.55; H, 9.28; N, 19.44.) 1H NMR (CD2Cl2):
d 4.90 (s, 1H, NH), 3.93 (m, 1H, CH), 3.65 (m, 8H,
4 · CH2), 3.34/3.24 (m, 2H, CH2), 3.09/2.97 (m, 4H,
2 · CH2), 2.46 (m, 4H, 2 · CH2), 2.41/2.19 (m, 2H,
CH2), 2.13/1.69 (m, 2H, CH2), 1.77 (m, 2H, CH2). 13C
NMR (CD2Cl2): d 164.3 (CN3), 67.3 (2 · CH2), 67.1
(2 · CH2), 62.3 (CH2), 56.3 (CH), 54.8 (2 · CH2), 49.4
(CH2), 49.2 (2 · CH2), 31.0 (CH2), 24.5 (CH2). IR
4.4.1.
pyrrolidin-1-yl)-methylenamine
C-Pyrrolidin-1-yl-C-(2-(pyrrolidin-1-ylmethyl)-
3a. Yield
98.5%.
HRMS m/z 251.2235 (M+1)+. C14H27N4 requires
1
251.2236. H NMR (C6D6): d 6.06 (s, 1H, NH), 4.39
(m, 1H, CH), 3.18/3.05 (m, 2H, CH2), 3.05 (m, 4H,
2 · CH2), 2.84/2.42 (m, 2H, CH2), 2.51 (m, 4H,
2 · CH2), 2.06/1.68 (m, 2H, CH2), 1.59 (m, 2H, CH2),
1.55–1.27 (m, 6H, 3 · CH2). 13C NMR (C6D6): d 160.7
(CN3), 60.0 (CH2), 57.9 (CH), 54.8 (2 · CH2), 50.2
(2 · CH2), 48.3 (CH2), 30.9 (CH2), 25.3 (CH2), 24.8
(2 · CH2), 23.8 (2 · CH2). IR (ATR, m/cmꢀ1): 2961–
(ATR, m/cmꢀ1): 2955–2848 (mCH), 1586 (mC@N), 1113
20
(mCOC). EI-MS m/z 282 (M+). ½aꢁ ¼ þ26:2 (c 2.60,
D
CH2Cl2).
4.4.6.
pyrrolidin-1-yl)-methylenamine
C-Morpholin-4-yl-C-(2-(piperidin-1-ylmethyl)-
4c. Yield 76.0%.
2781 (mCH), 1570 (mC@N). EI-MS m/z 250 (M+).
(Found: C, 64.16; H, 10.14; N, 19.70. C15H28N4O
20
1
½aꢁD ¼ ꢀ22:2 (c 2.47, CH2Cl2).
requires C, 64.25; H, 10.06; N, 19.98.) H NMR (C6D6):

816
U. Ko¨hn et al. / Tetrahedron: Asymmetry 17 (2006) 811–818
d 4.08 (m, 1H, CH), 3.60 (m, 4H, 2 · CH2), 3.23/3.04
(m, 2H, CH2), 3.04/2.93 (m, 4H, 2 · CH2), 2.66/2.18
(m, 2H, CH2), 2.54/2.40 (m, 4H, 2 · CH2), 1.98/1.74
(m, 2H, CH2), 1.61/1.54 (m, 2H, CH2), 1.61 (m, 4H,
2 · CH2), 1.40 (m, 2H, CH2), NH not detected at room
temperature. 13C NMR (C6D6): d 163.6 (CN3), 66.6
(2 · CH2), 62.5 (CH2), 56.3 (CH), 55.6 (2 · CH2), 48.9
(3 · CH2), 30.8 (CH2), 26.4 (2 · CH2), 24.6 (CH2), 24.2
31.3 (2 · CH2), 24.8 (2 · CH2), 24.0 (4 · CH2). IR
(ATR, m/cmꢀ1): 2959, 2871, 2781 (mCH), 1577 (mC@N).
20
EI-MS m/z 333 (M+). ½aꢁD ¼ ꢀ40:8 (c 3.19, CH2Cl2).
4.4.11.
C-[Bis-(2-(morpholin-4-ylmethyl)-pyrrolidin-1-
yl)]-methylenamine 6b. Yield 98.6%. HRMS m/z
1
366.2872 (M+1)+. C19H36N5O2 requires 366.2869. H
NMR (C6D6): d 5.21 (s, 1H, NH), 4.24 (m, 2H,
2 · CH), 3.71 (m, 8H, 4 · CH2), 3.14 (m, 4H,
2 · CH2), 2.74/2.16 (m, 4H, 2 · CH2), 2.50/2.43 (m,
8H, 4 · CH2), 2.06/1.66 (m, 4H, 2 · CH2), 1.62 (m,
4H, 2 · CH2). 13C NMR (C6D6): d 160.9 (CN3), 67.2
(4 · CH2), 63.1 (2 · CH2), 56.1 (2 · CH), 54.9 (4 ·
CH2), 50.0 (2 · CH2), 31.3 (2 · CH2), 24.8 (2 · CH2).
(CH2). IR (ATR, m/cmꢀ1): 2930–2848 (mCH), 1588
20
D
(mC@N), 1116 (mCOC). EI-MS m/z 280 (M+). ½aꢁ
þ23:1 (c 2.60, CH2Cl2).
¼
4.4.7. C-Piperidin-1-yl-C-(2-(pyrrolidin-1-ylmethyl)-pyr-
rolidin-1-yl)-methylenamine 5a. Yield 90.7%. HRMS
m/z 265.2391 (M+1)+. C15H29N4 requires 265.2392.
1H NMR (C6D6): d 4.25 (m, 1H, CH), 3.33/3.16 (m,
2H, CH2), 3.03 (m, 4H, 2 · CH2), 2.87/2.54 (m, 2H,
CH2), 2.61 (m, 4H, 2 · CH2), 2.03/1.90 (m, 2H, CH2),
1.76 (m, 12H, 6 · CH2) NH not detected at room tem-
perature. 13C NMR (C6D6): d 164.6 (CN3), 59.6
(CH2), 57.5 (CH), 54.9 (2 · CH2), 49.5 (2 · CH2), 49.2
(CH2), 30.7 (CH2), 26.2 (2 · CH2), 25.2 (CH2), 24.4
IR (ATR, m/cmꢀ1): 2954, 2851, 2804 (mCH), 1573 (mC@N),
20
1115 (mCOC). EI-MS m/z 365 (M+). ½aꢁ ¼ ꢀ49:3 (c 2.23,
D
CH2Cl2).
4.4.12. C-[Bis-(2-(piperidin-1-ylmethyl)-pyrrolidin-1-yl)]-
methylenamine 6c. Yield 75.1%. HRMS m/z 362.3290
(M+1)+. C21H40N5 requires 362.3283. 1H NMR
(CD2Cl2): d 3.98 (m, 1H, 2 · CH), 3.29 (m, 4H,
2 · CH2), 2.51/2.15 (m, 4H, 2 · CH2), 2.41 (m, 8H, 4 ·
CH2), 2.09/1.70 (m, 4H, 2 · CH2), 1.82 (m, 4H,
2 · CH2), 1.53 (m, 8H, 2 · CH2), 1.41 (m, 4H,
2 · CH2), NH not detected at room temperature. 13C
NMR (CD2Cl2): d 160.4 (CN3), 63.6 (2 · CH2), 58.0
(2 · CH), 55.5 (4 · CH2), 50.1 (2 · CH2), 31.6 (2 ·
CH2), 26.6 (4 · CH2), 25.0 (2 · CH2), 24.6 (2 · CH2).
(CH2) 24.0 (2 · CH2). IR (ATR, m/cmꢀ1): 2930–2790
20
D
(mCH), 1584 (mC@N). EI-MS m/z 264 (M+). ½aꢁ
þ54:2 (c 2.40, CH2Cl2).
¼
4.4.8.
C-(2-(Morpholin-4-ylmethyl)-pyrrolidin-1-yl)-C-
piperidin-1-yl-methylenamine 5b. Yield 96.7%. HRMS
m/z 281.2348 (M+1)+. C15H29N4O requires 281.2341.
1H NMR (C6D6): d 4.91 (m, 1H, NH), 4.24 (m, 1H,
CH), 3.71 (m, 4H, 2 · CH2), 3.30/3.13 (m, 2H, CH2),
3.00/2.93 (m, 4H, 2 · CH2), 2.70/2.18 (m, 2H, CH2),
2.52/2.41 (m, 4H, 2 · CH2), 1.91/1.71 (m, 2H, CH2),
1.67–1.34 (m, 8H, 4 · CH2). 13C NMR (C6D6): d 164.5
(CN3), 67.3 (2 · CH2), 62.5 (CH2), 55.8 (CH), 55.0
(2 · CH2), 49.4 (2 · CH2), 49.3 (CH2), 30.8 (CH2), 26.1
(2 · CH2), 25.1 (CH2), 24.4 (CH2). IR (ATR, m/cmꢀ1):
IR (ATR, m/cmꢀ1): 2930, 2852, 2779 (mCH), 1577 (mC@N).
20
EI-MS m/z 361 (M+). ½aꢁD ¼ ꢀ40:4 (c 3.66, CH2Cl2).
4.5. Synthesis of zinc guanidine complex 4aÆ(ZnCl2)
A solution of 4a (1.4 mmol) in 5 mL dry acetonitrile was
added to a suspension of dehydrated ZnCl2 (1.5 mmol)
in 5 mL dry acetonitrile under argon. The resulting mix-
ture was stirred for 20 min, filtered warm through Celite
and concentrated to a volume of approximately 1 mL.
The zinc complex 4aÆ(ZnCl2) was precipitated upon
addition of dry diethyl ether (5 mL). The suspension
was filtered, washed with absolute diethyl ether
(10 mL) and dried in vacuum to afford the solid. Single
crystals suitable for X-ray analysis were obtained from
pyridine by concentration and cooling.
2929–2804 (mCH), 1582 (mC@N). EI-MS m/z 280 (M+).
20
½aꢁD ¼ þ51:7 (c 2.32, CH2Cl2).
4.4.9. C-Piperidin-1-yl-C-(2-(piperidin-1-ylmethyl)-pyr-
rolidin-1-yl)-methylenamine 5c. Yield 90.6%. HRMS
m/z 279.2553 (M+1)+. C16H31N4 requires 279.2549.
1H NMR (C6D6): d 5.24 (s, 1H, NH), 4.10 (m, 1H,
CH), 3.19/3.03 (m, 2H, CH2), 2.91/2.86 (m, 4H,
2 · CH2), 2.61/2.10 (m, 2H, CH2), 2.46/2.30 (m, 4H,
2 · CH2), 1.87/1.69 (m, 2H, CH2), 1.55–1.23 (m, 14H,
7 · CH2). 13C NMR (C6D6): d 164.3 (CN3), 62.5
(CH2), 56.2 (CH), 55.6 (2 · CH2), 49.3 (2 · CH2), 49.0
(CH2), 30.8 (CH2), 26.5, 26.0, 25.0, 24.7, 24.2
4.6. X-ray crystallography
The intensity data for the compounds were collected on
a Nonius Kappa CCD diffractometer, using graphite-
monochromated Mo-Ka radiation. Data were corrected
for Lorentz and polarization effects, but not for absorp-
tion.18,19 The structures were solved by direct methods
(SHELXS20) and refined by full-matrix least squares tech-
niques against Fo2 (SHELXL-9721). The hydrogen atoms
for the imino-group and for the pyridine molecule were
located by difference Fourier synthesis and refined iso-
tropically. All other hydrogen atoms were included at
calculated positions with fixed thermal parameters. All
non-hydrogen atoms were refined anisotropically.21 XP
(SIEMENS Analytical X-ray Instruments, Inc.) was
used for structure representations.
(6 · CH2), 24.2 (CH2). IR (ATR, m/cmꢀ1): 3427 (mNH
)
2923, 2852 (mCH), 1589 (mC@N). EI-MS m/z 278 (M+).
20
½aꢁD ¼ þ34:3 (c 3.45, CH2Cl2).
4.4.10.
C-[Bis-(2-(pyrrolidin-1-ylmethyl)-pyrrolidin-1-
yl)]-methylenamine 6a. Yield 75.1%. HRMS m/z
334.2967 (M+1)+. C19H36N5 requires 344.2971. 1H
NMR (C6D6): d 5.30 (s, 1H, NH) 4.31 (m, 2H,
2 · CH), 3.19 (m, 4H, 2 · CH2), 2.94/2.49 (m, 4H,
2 · CH2), 2.60 (m, 8H, 4 · CH2), 2.13/1.80 (m, 4H,
2 · CH2), 1.70 (m, 8H, 4 · CH2), 1.61 (m, 4H, 2 ·
CH2). 13C NMR (C6D6): d 160.8 (CN3), 60.1 (2 ·
CH2), 57.7 (2 · CH), 54.9 (4 · CH2), 50.1 (2 · CH2),

U. Ko¨hn et al. / Tetrahedron: Asymmetry 17 (2006) 811–818
817
4.6.1. Crystal data for 4aÆ(ZnCl2).22 C14H26Cl2N4OZnÆ
C5H5N, Mr = 481.76 g molꢀ1, colourless prism, size
0.04 · 0.04 · 0.04 mm3, orthorhombic, space group
Pepper, E. S.; White, G. R. J. Med. Chem. 1985, 28, 1414–
1422; (e) Corelli, F.; Dei, D.; Delle Monache, G.; Botta,
B.; De Luca, C.; Carmignani, M.; Volpe, A. R.; Botta, M.
Bioorg. Med. Chem. Lett. 1996, 6, 653–658.
P212121, a = 8.0709(2), b = 10.4601(3), c = 26.4511(8)
3. (a) Ishikawa, T.; Isobe, T. Chem. Eur. J. 2002, 8, 552–557;
(b) Costa, M.; Chiusoli, G. P.; Taffurelli, D.; Dalmonego,
G. J. Chem. Soc., Perkin Trans. 1 1998, 9, 1541–1546.
4. (a) Herrera, A.; Martinez-Alvarez, R.; Chioua, R.;
Benabdelouahab, F.; Chioua, M. Tetrahedron 2004, 60,
5475–5479; (b) Rogister, F.; Laeckmann, D.; Plasman, P.-
O.; Van Eylen, F.; Ghyoot, M.; Maggetto, C.; Sokolow,
S.; Liegeois, J.-F.; Geczy, J.; Masereel, B.; Delarge, J.;
Herchuelz, A. Eur. J. Med. Chem. 2001, 36, 597–614; (c)
Snider, B. B.; Ahn, Y.; O’Hare, S. M. Org. Lett. 2001, 3,
4217–4220; (d) Rowley, G. L.; Greenleaf, A. L.; Kenyon,
G. L. J. Am. Chem. Soc. 1971, 93, 5542–5551.
3
˚
˚
A, V = 2233.07(11) A , T = ꢀ90 ꢁC, Z = 4, qcalcd
=
1.433 g cmꢀ3, l (Mo-Ka) = 13.59 cmꢀ1, F(000) = 1008,
13,448 reflections in h(ꢀ8/10), k(ꢀ11/13), l(ꢀ34/34),
measured in the range 2.64ꢁ 6 H 6 27.46ꢁ, completeness
H
max = 98.6%, 4988 independent reflections, Rint =
0.053, 3840 reflections with Fo > 4r(Fo), 276 parameters,
0
restraints, R1obs = 0.038, wR2obsd ¼ 0:073, R1all
=
0.066, wR2all ¼ 0:082, GOOF = 0.960, Flack-parameter
ꢀ0.004(12), largest difference peak and hole: 0.325/
ꢀ3
˚
ꢀ0.409 e A
.
5. (a) Ko¨hn, U.; Schulz, M.; Go¨rls, H.; Anders, E. Tetrahe-
dron: Asymmetry 2005, 16, 2125–2131; (b) Ko¨hn, U.;
4.6.2. Crystal data for 6Æ(HCl).22 [C19H38Cl4N5]3+
3ClꢀÆHCl, Mr = 479.35 g molꢀ1
colourless prism,
size 0.05 · 0.05 · 0.04 mm3, orthorhombic, space group
P212121, a = 22.3618(9), b = 9.0905(3), c =
12.1901(5) A, V = 2478.00(16) A , T = ꢀ90 ꢁC, Z = 4,
calcd = 1.285 g cmꢀ3 (Mo-Ka) = 4.93 cmꢀ1
,
,
Gunther, W.; Go¨rls, H.; Anders, E. Tetrahedron: Asym-
¨
metry 2004, 15, 1419–1426; (c) Molina, P.; Alajarin, M.;
Sanchez-Andrada, P.; Sanz-Aparicio, J.; Martinez-Ripoll,
M. J. Org. Chem. 1998, 63, 2922–2927; (d) Williams, A.;
Ibrahim, I. T. Chem. Rev. 1981, 81, 589–636; (e) Khorana,
H. G. Chem. Rev. 1953, 53, 145–166.
3
˚
˚
q
,
l
F(000) = 1024, 15,865 reflections in h(ꢀ28/28), k(ꢀ11/
11), l(ꢀ14/15), measured in the range 1.82ꢁ 6 H 6
27.45ꢁ, completeness Hmax = 99.3%, 5602 independent
reflections, Rint = 0.086, 4653 reflections with Fo >
4r(Fo), 258 parameters, 0 restraints, R1obsd = 0.080,
wR2obsd ¼ 0:206, R1all = 0.099, wRa2ll ¼ 0:219, GOOF =
1.090, Flack-parameter 0.04(12), largest difference peak
6. Hg promoted: (a) Yu, Y.; Ostresh, J. M.; Houghten, R. A.
J. Org. Chem. 2002, 67, 3138–3141; (b) Zhang, J.; Shi, Y.;
Stein, P.; Atwal, K.; Li, C. Tetrahedron Lett. 2001, 43, 57–
59; (c) Cunha, S.; Costa, M. B.; Napolitano, H. B.;
Lariucci, C.; Vencato, I. Tetrahedron 2001, 57, 1671–1675;
(d) Levallet, C.; Lerpiniere, J.; Ko, S. Y. Tetrahedron 1997,
53, 5291–5304; (e) Kim, K. S.; Qian, L. Tetrahedron Lett.
1993, 34, 7677–7680; Carbodiimide promoted: (f) Linton,
B. R.; Carr, A. J.; Orner, B. P.; Hamilton, A. D. J. Org.
Chem. 2000, 65, 1566–1568; (g) Poss, M. A.; Iwanowicz,
E.; Reid, J. A.; Lin, J.; Gu, Z. Tetrahedron Lett. 1992, 33,
5933–5936.
7. (a) Moroni, M.; Koksch, B.; Osipov, S. N.; Crucianelli,
M.; Frigerio, M.; Bravo, P.; Burger, K. J. Org. Chem.
2001, 66, 130–133; (b) Guo, Z.-X.; Cammidge, A. N.;
Horwell, D. C. Synth. Commun. 2000, 30, 2933–2943; (c)
Elliott, A. J.; Morris, P. E., Jr.; Petty, S. L.; Williams, C.
H. J. Org. Chem. 1997, 62, 8071–8075; (d) Kent, D. R.;
Cody, W. L.; Doherty, A. M. Tetrahedron Lett. 1996, 37,
8711–8714.
ꢀ3
˚
and hole: 1.076/ꢀ0.515 e A
.
4.7. Chiral shift investigations
Compound 4a (0.01 g, 0.038 mmol) was dissolved in THF-
d8 (ca. 0.5 mL) and examined by 1H NMR spectroscopy.
(S)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol (0.01 g, 0.038
mmol) was added to the NMR tube, and the solution
was reexamined. Additional shift reagent (3 equiv total)
was added, and the solution was reexamined.
8. (a) Jursic, B. S.; Neumann, D.; McPherson, A. Synthesis
2000, 1656–1658; (b) Maryanoff, C. A.; Stanzione, R. C.;
Plampin, J. N.; Mills, J. E. J. Org. Chem. 1986, 51, 1882–
1884; (c) Miller, A. E.; Bischoff, J. J. Synth. 1986, 777–
779.
9. (a) Vaidyanathan, G.; Zalutsky, M. R. J. Org. Chem.
1997, 62, 4867–4869; (b) Ko, S. Y.; Lerpiniere, J.;
Christofi, A. M. Synlett 1995, 815–816.
10. (a) Katritzky, A. R.; Rogovoy, B. V.; Chassaing, C.;
Vvedensky, V. J. Org. Chem. 2000, 65, 8080–8082; (b)
Katritzky, A. R.; Parris, R. L.; Allin, S. M.; Steel, P. J.
Synth. Commun. 1995, 25, 1173–1186; (c) Bernatowicz, M.
S.; Wu, Y.; Matsueda, G. R. Tetrahedron Lett. 1993, 34,
3389–3392; (d) Bernatowicz, M. S.; Wu, Y.; Matsueda, G.
R. J. Org. Chem. 1992, 57, 2497–2502.
11. (a) Chinchilla, R.; Najera, C.; Sanchez-Agullo, P. Tetra-
hedron: Asymmetry 1994, 5, 1393–1402; (b) Corey, E. J.;
Grogan, M. J. Org. Lett. 1999, 1, 157–160; (c) Iyer, M. S.;
Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am. Chem.
Soc. 1996, 118, 4910–4911; (d) Ma, D.; Cheng, K.
Tetrahedron: Asymmetry 1999, 10, 713–719; (e) Ishikawa,
T.; Araki, Y.; Kumamoto, T.; Isobe, T.; Seki, H.; Fukuda,
K. Chem. Commun. 2001, 3, 245–246; (f) Isobe, T.;
Fukuda, K.; Araki, Y.; Ishikawa, T. Chem. Commun.
2001, 3, 243–244.
Acknowledgements
Financial Support from the Deutsche Forschungs-
gemeinschaft (Sonderforschungsbereich 436, University
of Jena, Germany), the Thuringer Ministerium fur Wis-
¨
¨
senschaft, Forschung und Kultur (Erfurt, Germany)
and the Fonds der Chemischen Industrie (Germany) is
gratefully acknowledged.
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16. Compound 6a was dissolved in diethylether and HCl gas
was bubbled through the solution. After removing the
solvent, the crystallization from acetonitrile provided
single-crystals suitable for X-ray analysis.
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22. CCDC 278298 [4aÆ(ZnCl2)] and 280198 [6aÆ(HCl)] contains
the supplementary crystallographic data for this paper.
These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/re-trieving.html (or from the
Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223 336
033; or deposit@ccdc.cam.ac.uk).
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