A Flexible Asymmetric Synthesis of anti-1,2-Sulfanyl Amines

Article abstract of DOI:10.1002/ejoc.200300249

An efficient and flexible asymmetric synthesis of various protected anti-1,2-sulfanyl amines bearing two adjacent stereogenic centres is described. Key steps are the diastereoselective α-alkylation of α-sulfanylated acetaldehyde-SAMP-hydrazones with various electrophiles and subsequent nucleophilic 1,2-addition of organocerium reagents to the hydrazone CN double bond. The resulting hydrazines were converted into the title compounds with excellent diastereomeric and enantiomeric excesses (de and ee values ≥ 96%) by reductive N,N bond cleavage to remove the chiral auxiliaries and protection of the amino functions. The relative and absolute configurations were determined by NOE experiments and X-ray structure analysis. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300249

FULL PAPER
A Flexible Asymmetric Synthesis of anti-1,2-Sulfanyl Amines
Dieter Enders,*[a] Alexander Moll,[a] Annette Schaadt,[a] Gerhard Raabe,[a] and
Jan Runsink[a]
Dedicated to Professor Reinhard W. Hoffmann on the occasion of his 70th birthday
Keywords: Alkylations / β-Amino sulfides / Asymmetric synthesis / Hydrazones / Nucleophilic addition
An efficient and flexible asymmetric synthesis of various pro-
tected anti-1,2-sulfanyl amines bearing two adjacent ste-
reogenic centres is described. Key steps are the diastereose-
lective α-alkylation of α-sulfanylated acetaldehyde-SAMP-
hydrazones with various electrophiles and subsequent
nucleophilic 1,2-addition of organocerium reagents to the hy-
drazone CN double bond. The resulting hydrazines were
converted into the title compounds with excellent diastereo-
meric and enantiomeric excesses (de and ee values Ն 96%)
by reductive N,N bond cleavage to remove the chiral auxili-
aries and protection of the amino functions. The relative and
absolute configurations were determined by NOE experi-
ments and X-ray structure analysis.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
stituents is restricted. One possibility is to synthesise them
from natural α-amino acids in an ex-chiral-pool synthesis.[6]
Chiral 1,2-sulfanyl amines (β-amino sulfides, vic-thio- Van Leeuwen et al., for example, synthesised two different
ether amines) and 1,2-amino thiols of high diastereomeric ligands derived from cysteine and pseudo-ephedrine and
and enantiomeric purity are of great interest in synthetic used them in iridium()-catalysed asymmetric hydrogenation
organic chemistry. In recent years they have gained particu- reactions.[7] Some diastereoselective syntheses[8] for this
lar attention as N,S-ligands in asymmetric catalysis. N,N- class of compounds have been reported, but to the best of
and N,O-ligands have already been employed in numerous our knowledge there is only one asymmetric synthesis.[9]
instances in catalytic asymmetric synthesis and have been One of the simplest routes is probably through treatment of
used with great success.[1] vic-Sulfanyl amines offer ad- thiols with aziridines in a regio- and stereoselective ring-
ditional possibilities over N,N- and N,O-ligands, since, for opening reaction.[10] Kellogg et al., for example, have pre-
example, the sulfur atom becomes a stereocentre when pared these aziridines through a Mitsunobu reaction start-
coordinated to a metal.[2]
ing from ephedrine.[11] An alternative approach for the syn-
The lack of simple and flexible synthetic routes to suit- thesis of vic-sulfanyl amines was developed by Ishibashi et
able derivatives of the title compounds has been a major al., who used a mixture of 2-oxazolidinone and thiols in the
barrier in investigation of their use in asymmetric catalysis. presence of alkoxides to afford the desired products.[12]
Heterobidentate N,S-ligands have proved to be very effec-
The 1,2-sulfanyl amine unit has also been found in a
tive in enantioselective palladium-catalysed allylic substi-
number of important biologically active compounds. It is a
tution reactions.[3] 1,2-Sulfanyl amines, 1,2-amino thiols,
characteristic structural feature found in ecteinascidine
and their corresponding disulfides have also been shown
family marine alkaloids that serve as an important class of
to be particularly effective catalysts for the enantioselective
anticancer agents.[13]
addition of dialkylzinc reagents to prochiral carbonyl com-
pounds.[4] Furthermore, they are also used in the enantiose-
lective conjugate addition of organometallic reagents to
α,β-unsaturated carbonyl compounds.[5]
Our synthetic strategy, which employs the SAMP/
RAMP-hydrazone methodology,[14] should provide an ef-
ficient and flexible route to the desired 1,2-sulfanyl amines
and permit access to both anti-configured enantiomers. The
concept of α-alkylation and 1,2-addition to SAMP/RAMP-
hydrazones and subsequent N,N bond cleavage has already
been demonstrated by our group in various applications.[15]
We now wish to report an important extension of our pre-
vious procedure on the asymmetric synthesis of anti-1,2-
tert-butylsulfanyl amines, as reported in our short com-
Several methods for the synthesis of vic-sulfanyl amines
have been described in the literature, but the choice of sub-
[a]
Institut für Organische Chemie, Rheinisch-Westfälische
Technische Hochschule,
Professor-Pirlet-Str.1, 52074 Aachen, Germany
Fax: (internat.) ϩ49-(0)241-8092127
E-mail: enders@rwth-aachen.de
Eur. J. Org. Chem. 2003, 3923Ϫ3938
DOI: 10.1002/ejoc.200300249
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3923

D. Enders, A. Moll, A. Schaadt, G. Raabe, J. Runsink
FULL PAPER
munication,[16] to anti-1,2-benzylsulfanyl amines and to
describe this new technique in detail.
Results and Discussion
As shown in Scheme 1, acetaldehyde SAMP hydrazones
(S)-3 were obtained by a literature procedure[17] on a multi-
gram scale from commercially available 2-(bromomethyl)-
1,3-dioxolane (1a) or bromoacetaldehyde diethyl acetal
(1b), which were treated with two different lithium thiolates.
Nucleophilic displacement of bromide gave the acetals 2 in
very good yields (83Ϫ99%, Table 1). Acidic hydrolysis of
the acetal group afforded the α-sulfanylated acetaldehydes,
which were directly converted in high yields (71Ϫ89%) into
their corresponding SAMP hydrazones (S)-3 by the stand-
ard procedure[18](Table 2).
Scheme 2. Synthesis of β-amino sulfides (S,R)-5: a) 1. LDA, THF,
0 °C, 5 h; 2. R1X, Ϫ100 °C to room temp.; b) 1. R2Li/CeCl3, THF,
Ϫ100 °C to room temp.; 2. BH3·THF, THF, reflux, 4 h; (3. CbzCl,
K2CO3, CH2Cl2/H2O reflux)
purified by flash column chromatography to give the de-
sired hydrazones in good yields (74Ϫ92%) and with high
diastereomeric excesses (de ϭ 87 to Ն 96%). The results of
the α-alkylation are summarised in Table 3. The configura-
tion of the newly generated stereogenic centre has already
been investigated[17,19] and was found to be in agreement
with the proposed mechanism for the alkylation of metal-
lated SAMP hydrazones.[14]
Table 3. Diastereoselective α-alkylation of hydrazone (S)-3a with
various electrophiles
Scheme 1. a) 1. R2SH, nBuLi, THF, 0 °C; 2. 1, THF, reflux, 4 h;
b) 1. 6  HCl, Et2O, reflux, 7 h; 2. SAMP, MgSO4, CH2Cl2,
room temp.
Product
R1
Yield [%]
de[a] [%][a]
(S,S)-4a
(S,S)-4b
(S,S)-4c
(S,S)-4d
(S,S)-4e
iPr
iBu
92
82
85
74
74
88
Ն 96
87
87
Ն 96
Bn(CH2)
p-(BrBn)
naphthyl(CH2)
Table 1. Synthesis of acetals 2
Product
R1
R2
Yield [%]
Determined by H and 13C NMR spectroscopy.
[a]
1
2a
2b
2c
ϪCH2CH2Ϫ
ϪCH2CH2Ϫ
Et
tBu
Bn
Bn
83
96
99
For the subsequent nucleophilic 1,2-addition to the CN
double bond, organocerium reagents were used. Initial at-
tempts with the use of commercially available organoli-
thium compounds turned out to present difficulties in ob-
taining the desired hydrazines. Because of their high ba-
sicity, elimination of the sulfur substituent was mainly ob-
served. Thanks to the lower basicity and the higher
nucleophilicity of Imamoto reagents, however, this problem
could be circumvented simply and without any limitation
in the choice of the electrophiles used in the previous
step.[20] The cerium reagents were freshly prepared from the
corresponding organolithium compound and dehydrated
CeCl3 in a lithium cerium transmetallation reaction. Be-
cause of the incomplete asymmetric induction in the α-alky-
lation step for (S,S)-4a, (S,S)-4c, and (S,S)-4d, the 1,2-ad-
dition products were expected to be mixtures of dia-
Table 2. Synthesis of α-sulfanylated acetaldehyde-SAMP-hydra-
zones (S)-3
Starting material
Product
R2
Yield [%]
2a
2b
2c
(S)-3a
(S)-3b
(S)-3b
tBu
Bn
Bn
89
70
71
Synthesis of anti-1,2-tert-Butylsulfanyl Amines
As depicted in Scheme 2, the hydrazone (S)-3a was met- stereomers. However, the NMR spectra of the crude hydra-
allated with lithium diisopropylamide (LDA) in THF at 0 zines showed exclusively one set of signals (de Ն 96%). Our
°C for 5 hours. For that purpose, the hydrazone was dis- conclusion was that the minor diastereomers did not react
solved in THF and slowly added dropwise to the solution in the 1,2-addition step.
of LDA. The intermediate azaenolates were trapped with
Many procedures to yield free amines from their corre-
various alkyl halides at Ϫ100 °C to form the α-sulfanylated sponding hydrazines by cleavage of the N,N bond have been
hydrazones (S,S)-4, which, after aqueous workup, were reported.[21] We decided to use the reductive cleavage with
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A Flexible Asymmetric Synthesis of anti-1,2-Sulfanyl Amines
FULL PAPER
a high concentration of base might not only produce the
desired azaenolate but could also deprotonate the benzylic
protons, finally resulting in the decomposition of the sub-
strate, so a reversed addition of the LDA solution to the
dissolved benzylsulfanyl hydrazone (S)-3b was carried out.
This procedure allowed us to be sure that the concentration
of the base was low at all times, so that it was possible to
deprotonate only the α-position of the hydrazone moiety
chemoselectively. The alkylated hydrazones (S,S)-6 were ob-
tained by this procedure in good yields (70Ϫ92%) and with
very good diastereomeric excesses (de ϭ 83 to Ն 96%)
Table 4. Synthesis of anti-1,2-tert-butylsulfanyl amines (S,R)-5 by
1,2-addition, N,N bond cleavage and protection of the amino group
Product R1
R2 R3 Yield [%] de[a] [%][a] ee[b] [%]
(S,R)-5a iPr
Me Cbz 28
tBu Cbz 61
tBu Cbz 54
nBu H 41
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
(S,R)-5b iBu
(S,R)-5c Bn(CH2)
(S,R)-5d p-(BrBn)
(S,R)-5e naphthyl(CH2) nBu H 32
[a] Determined by 1H and 13C NMR spectroscopy. [b] In correlation
with the de value of the corresponding hydrazines determined by
1H and 13C NMR spectroscopy. The subsequent steps are racemis- (Scheme 3). The results of the α-alkylation are summarised
ation-free
in Table 5.
excess BH3·THF complex as a very mild method not requir-
ing activation of the N,N bond. The hydrazine was dis-
solved in THF and heated to reflux with a large excess of
BH3·THF complex, the corresponding amines being ob-
tained after methanolysis. These were either purified by
flash column chromatography to give (S,R)-5d or (S,R)-5e,
or were directly protected as benzyl carbamates to yield
(S,R)-5a؊c. The results are summarised in Table 4.
The hydrazines were shown to be diastereomerically pure
1
by H and 13C NMR spectroscopy. Because the reductive
N,N bond cleavage and the protection of the amino group
proceeded without epimerisation the synthesised β-amino
sulfides (S,R)-5 were not only diastereomerically but also
enantiomerically pure within the limits of detection.
The relative configurations of the title compounds were
determined to be anti by NOE measurements on (S,R)-5a
(Figure 1). The known S configuration of the stereogenic
centre generated by the α-alkylation[22] allowed the determi-
nation of the absolute configurations of the β-amino sulf-
ides, which were assigned as (S,R).
Scheme 3. Synthesis of 1,2-sulfanyl amines (S,R)-8: a) 1. LDA,
THF, Ϫ20 °C, 2 h, 2. R1X, Ϫ100 °C to room temp.; b) 1. R2Li/
CeCl3, THF, Ϫ100 °C to room temp.; c) 1. BH3·THF, THF, reflux,
4 h; 2. MocCl, K2CO3, CH2Cl2, reflux, 3 d
Table 5. Diastereoselective α-alkylation of hydrazone (S)-3b with
various electrophiles to afford the α-thiolated hydrazones (S,S)-6
Product
R1
Yield [%]
de[a] D [%][a]
(S,S)-6a
(S,S)-6b
(S,S)-6c
(S,S)-6d
(S,S)-6e
(S,S)-6f
(S,S)-6g
(S,S)-6h
iPr
iBu
92
70
73
92
90
81
83
74
83
Ն 96
94
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Figure 1. NOE measurements on (S,R)-5a
o-xylyl
naphthyl(CH2)
Bn
BnCH2
allyl
Synthesis of anti-1,2-Benzylsulfanyl Amines
p-(tBuBn)
The α-alkylation of the benzylsulfanyl hydrazones (S)-3b
was initially carried out under the same conditions as used
for the alkylation of the tert-butylsulfanyl hydrazones (S)-
3a, but the desired products could not be obtained. At-
tempts to optimise the reaction conditions by variation of
[a]
1
Determined by H and 13C NMR spectroscopy.
The nucleophilic 1,2-addition to the CN double bond
metallation time, temperature, and equivalents of LDA re- was carried out under the same conditions as described
sulted either in the isolation of only small amounts of the above. Unlike the tert-butylsulfanyl hydrazines, which were
desired products or in decomposition. It was assumed that used directly for the NϪN bond cleavage, the benzylsul-
Eur. J. Org. Chem. 2003, 3923Ϫ3938
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3925

D. Enders, A. Moll, A. Schaadt, G. Raabe, J. Runsink
FULL PAPER
fanyl hydrazines (S,R,S)-7 were isolated and fully character-
ised. The results of the 1,2-addition to the hydrazones (S,S)-
6 are summarised in Table 6.
Table 6. 1,2-Addition of organocerium reagents to the α-sulfanyl-
ated aldehyde SAMP-hydrazones (S,S)-6 to afford the hydrazines
(S,R,S)-7
Product
R1
R2
Yield [%]
de[a] [%][a]
(S,R,S)-7a
(S,R,S)-7b
(S,R,S)-7c
(S,R,S)-7d
(S,R,S)-7e
(S,R,S)-7f
(S,R,S)-7g
(S,R,S)-7h
(S,R,S)-7i
iPr
iBu
nBu
nBu
nBu
nBu
nBu
nBu
nHex
Me
85
98
99
81
80
87
79
65
70
93
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
o-xylyl
naphthyl(CH2)
Bn
Bn(CH2)
Bn
Bn
p-(tBuBn)
nBu
[a]
1
Determined by H and 13C NMR spectroscopy.
Figure 2. Crystal structure of the 1,2-benzylsulfanyl amine (S,R)-8e
The corresponding amines were obtained by reductive
cleavage of the N,N bond with an excess of BH3·THF. It
was observed that the use of 1  HCl instead of methanol,
combined with washing with saturated aqueous NaHCO3
solutions, gave significant improvements in the yields. The
crude amines obtained were either purified by flash column
chromatography or protected directly. The results of the re-
ductive cleavage and the protection are summarised in
T7able 7.
Table 7. Synthesis of the 1,2-benzylsulfanyl amines (S,R)-8 by re-
ductive cleavage of the N,N bond and protection of the amino
group
Figure 3. Proposed transition state for the asymmetric 1,2-addition
Product R1
R2
R3 Yield [%] de[a] [%][a] ee[b] [%]
methoxy group) and even tridentate (plus thioether group)
ligands, resulting in the steric hindrance of the si-face. The
second organocerium equivalent would then attack the re-
face of the CN double bond. The observed relative topicity
is also in agreement with the FelkinϪAnh model.
(S,R)-8a iPr
(S,R)-8b iBu
(S,R)-8c o-xylyl
(S,R)-8d naphthyl(CH2) nBu Moc 55
(S,R)-8e Bn
(S,R)-8f Bn(CH2)
(S,R)-8g Bn
(S,R)-8h Bn
nBu
nBu
nBu
H
H
H
80
39
81
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
nBu Moc 92
nBu Moc 68
nHex Moc 57
Me Moc 71
Conclusion
In summary, we have developed an efficient method for
the α-alkylation of α-sulfanylated acetaldehyde SAMP-hy-
drazones and subsequent nucleophilic 1,2 addition to the
CN double bond to afford α-sulfanylated hydrazines, which
were easily converted into the title N-protected anti-1,2-sul-
fanyl amines with high diastereomeric and enantiomeric ex-
cesses (de and ee Ն 96%). Deprotection of the 1,2-benzyl-
sulfanyl amines to afford their corresponding 1,2-amino thi-
ols should open a facile route to novel N,S-ligands for
asymmetric catalysis and to useful precursors of oligopepti-
dosulfonamides.[24]
[a] Determined by 1H and 13C NMR spectroscopy. [b] In correlation
with the de value of the corresponding hydrazines (S,R,S)-7 deter-
mined by 1H and 13C NMR spectroscopy. The subsequent steps
are racemisation-free.
The relative and absolute configurations of the 1,2-
benzylsulfanyl amine (S,R)-8e were determined by X-ray
crystallography as depicted in Figure 2.
The obtained relative and absolute configurations of the
anti-1,2-sulfanyl amines (S,R)-5 and (S,R)-8 are in full
agreement with our previous results on nucleophilic 1,2-ad-
ditions of organolithium, Grignard and organocerium re-
agents to aldehyde-SAMP-hydrazones.[23] To explain the
fact that at least two equivalents of the nucleophile are
necessary in order for 1,2-addition to be observed, we as-
sume a precoordination of the first equivalent of the
organocerium reagent. As shown in Figure 3, the hydrazone
Experimental Section
General Remarks: All reagents were purchased from common com-
mercial suppliers and used from freshly opened containers. Solvents
substrates can act as bidentate (pyrrolidino nitrogen and for chromatography and for workup were dried and purified by
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Eur. J. Org. Chem. 2003, 3923Ϫ3938

A Flexible Asymmetric Synthesis of anti-1,2-Sulfanyl Amines
conventional methods prior to use. Tetrahydrofuran was freshly (SCH2), 36.6 (CH3), 65.2 (OCH2CH2O), 104.4 (CH), 127.0, 128.5,
FULL PAPER
distilled from sodium/lead and benzophenone under argon. nBuLi
(1.6  in hexane) was purchased from Merck, Darmstadt. Diiso-
propylamine was distilled from CaH2 and stored over molecular
sieves. Preparative flash column chromatography was carried out
with Merck silica gel 60, particle size 0.040Ϫ0.063 mm. Optical
rotation values were measured with a PerkinϪElmer P 241 polari-
meter, solvents used were of Merck UVASOL quality. IR spectra:
PerkinϪElmer FT/IR 1750 and PerkinϪElmer FT/IR 1720 X.
NMR spectra: Varian VXR 300, Varian Gemini 300 and Varian
Inova 400, TMS as internal standard. MS: Varian MAT 212 (EI,
70 eV, 1 mA) and Finnigan MAT SSQ 7000 (CI, 100 eV). Microan-
alyses were obtained with a Heraeus, CHN-O-Rapid instrument.
High-resolution MS: Finningan MAT, MAT 95. Merck TLC plates
silica gel 60 F254 were used for TLC analyses and the products were
viewed by UV detection or by use of phosphormolybdic acid (5
wt.-% in EtOH). The diastereomeric excesses were determined by
NMR spectroscopy. The chiral auxiliary SAMP [(S)-1-amino-2-
(methoxymethyl)pyrrolidine] was prepared from (S)-proline by lit-
erature procedures.[25]
129.1 (Ar-C), 138.2 (Ar-Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ 210
(6) [Mϩ], 148 (16), 91 (26), 73 (100), 45 (23). C11H14O2S (210.29):
calcd. C 62.83, H 6.71; found C 62.41, H 6.80.
[(2,2-Diethoxyethyl)sulfanylmethyl]benzene
(2c):
Benzylthiol
(6.2 mL, 50.0 mmol) was treated with bromoacetaldehyde diethyl
acetal (1b, 7.7 mL, 51.0 mmol) as described in GP 1 to yield 2c as
a colourless oil after reduced pressure distillation (113 °C, 3 mbar).
Yield: 11.90 g (99%). Rt ϭ 9.63 min (CP-Sil-8, 100Ϫ10Ϫ300). The
spectroscopic data were in accordance with those reported in the
literature.[17]
General Procedure for the Synthesis of the α-Sulfonylated Acetalde-
hyde SAMP-Hydrazones (GP 2): HCl (6 , 3.0 mL/mmol) was ad-
ded to a solution of acetal 2 in Et2O (7.0 mL/mmol). The mixture
was heated at reflux for 7 h. After the mixture had cooled to room
temperature, a pH 7 buffer solution was added and the aqueous
layer was extracted three times with Et2O. The combined organic
phases were washed with brine, dried with MgSO4 and concen-
trated in vacuo. The crude 2-sulfanylated acetaldehyde was dis-
solved in CH2Cl2 and treated with (S)-1-amino-2-(methoxymeth-
yl)pyrrolidine (SAMP) in the presence of MgSO4 to afford the cor-
responding crude SAMP hydrazones (S)-3, which were purified by
flash column chromatography.
General Procedure for the Synthesis of the Acetals 2 (GP 1): The
thiol (1.0 equiv.) was dissolved in dry THF (1 mL/mmol) under
argon atmosphere and cooled to 0 °C. nBuLi (1.0 equiv.) was slowly
added dropwise, and the solution was stirred at this temperature
for 1 h. The reaction mixture was allowed to warm up to room
temperature, and acetal 1 (1.1Ϫ1.2 equiv.) was then slowly added.
The solution was heated at reflux for 4 h and after cooling to room
temperature it was quenched with pH 7 buffer solution and ex-
tracted three times with Et2O. The combined organic phases were
dried with MgSO4 and concentrated in vacuo. The crude product
was distilled under reduced pressure.
(2S)-(؊)-[2-(tert-Butylsulfanyl)ethylidene][2-(methoxymethyl)pyr
rolidin-1-yl]amine [(S)-3a]: Dioxolane 2a (3.0 g, 17.1 mmol) and
SAMP (2.34 g, 18.0 mmol) were converted as described in GP 2
into the SAMP hydrazone (S)-3a, which could be obtained as a
colourless oil after flash column chromatography (SiO2, pentane/
Et2O, 15:1, 1% NEt3). Yield: 3.72 g (89%). Rt ϭ 8.52 min (OV-17,
100Ϫ10Ϫ260). Rf ϭ 0.55 (pentane/Et2O, 3:1). [α]2D5 ϭ Ϫ278.9 (c ϭ
1.13, CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 1.34 [s, 9 H,
2-(tert-Butylsulfanylmethyl)-1,3-dioxolane (2a): tert-Butyl thioalco-
hol (5.6 mL, 50.0 mmol) was treated with 2-(bromomethyl)-1,3-di-
oxane (1a, 6.2 mL, 60.0 mmol) as described in GP 1, and 2a was
obtained as a colourless oil after reduced pressure distillation.
Yield: 7.30 g (83%). Rt ϭ 6. 37 min (OV-17, 60Ϫ10Ϫ260). Rf ϭ
0.42 (pentane/Et2O, 10:1). b.p. 81 °C (7 mbar). IR (film): ν˜ ϭ 3521
(w), 2962 (s), 2928 (s), 2888 (s), 2746 (w), 2649 (w), 2603 (w), 2384
(w), 2177 (w), 1999 (w), 1473 (m), 1469 (s), 1424 (m), 1390 (m),
1365 (s), 1212 (m), 1133 (s), 1040 (s), 971 (s), 945 (s), 617 (m), 772
(w), 709 (w), 657 (w), 592 (w), 469 (w) cmϪ1. 1H NMR (400 MHz,
CDCl3): δ ϭ 1.34 [s, 9 H, C(CH3)3], 2.78 (d, J ϭ 4.7 Hz, 2 H,
SCH2), 3.90 (m, 2 H, OCH2), 4.02 (m, 2 H, OCH2), 5.04 (t, J ϭ
4.7 Hz, 1 H, CH) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 30.9
(CH3), 32.3 (SCH2), 42.1 [C(CH3)3], 65.2 (OCH2CH2O), 103.6
(CH) ppm. MS (EI, 70 eV): m/z (%) ϭ 176 (12) [Mϩ], 73 (100), 57
(9). C8H16O2S (176.09): calcd. C 54.51, H 9.15; found C 54.01,
H 9.17.
C(CH3)3], 1.80 (m,
1 H, NCH2CH2CHH), 1.93 (m, 3 H,
NCH2CH2, NCH2CH2CHH), 2.79 (m, 1 H, NCHH), 3.36 (m, 2
H, CHHO, NCHH), 3.37 (s, 3 H, OCH3), 3.46 (m, 1 H, OCH2CH),
3.54 (dd, J ϭ 8.5, 3.6 Hz 1 H, CHHO), 6.51 (t, J ϭ 6.0 Hz, 1 H,
NϭCH), ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 22.2 (NCH2CH2),
26.7 (NCH2CH2CH2), 31.5 (CH3), 31.9 (SCH2), 42.8 [C(CH3)),
49.8 (NCH2), 59.2 (OCH3), 63.1 (NCH), 74.7 (CH2OCH3), 133.2
(CϭN) ppm. The spectroscopic data were in accordance with those
reported in the literature.[26]
(2S)-(؊)-[2-(Benzylsulfanyl)ethylidene][2-(methoxymethyl)pyr-
rolidin-1-yl]amine [(S)-3b]: Acetal 2c (4.80 g, 20.0 mmol) and
SAMP (2.60 g, 20.0 mmol) were converted as described in GP 2
into the SAMP hydrazone (S)-3b, which could be obtained as a
colourless oil after flash column chromatography (SiO2, pentane/
Et2O, 6:1, 1% NEt3). Yield: 3.95 g (71%). Rt ϭ 16.85 min (CP-Sil-
8, 80Ϫ10Ϫ300). Rf ϭ 0.11 (pentane/Et2O, 6:1). [α]2D5 ϭ Ϫ158.1 (c ϭ
1.8, CHCl3). IR (CHCl3): ν˜ ϭ 3393 (w), 3083 (w), 3060 (m), 3027
2-(Benzylsulfanylmethyl)-1,3-dioxolane (2b): Benzyl thioalcohol
(7.7 mL, 65.0 mmol) was treated with 2-(bromomethyl)-1,3-dioxane (m), 2974 (s), 2919 (s), 2877 (s), 2825 (s), 1590 (m), 1494 (s), 1453
(1a, 8.0 mL, 78.0 mmol) as described in GP 1, and 2b was obtained
as a colourless oil after reduced pressure distillation. Yield: 13.15 g
(s), 1414 (m), 1382 (m), 1342 (s), 1323 (m), 1304 (m), 1284 (m),
1197 (s), 1120 (s), 1073 (s), 1029 (m), 1002 (m), 973 (m), 923 (m),
(96%). Rt ϭ 11.58 min (CP-Sil-8, 80Ϫ10Ϫ300). Rf ϭ 0.31 (pentane/ 907 (m), 865 (m), 771 (m), 701 (s), 565 (m), 474 (m) cmϪ1. 1H NMR
Et2O, 10:1). b.p. 125 °C (1 mbar). IR (film): ν˜ ϭ 3390 (w), 3084 (400 MHz, CDCl3): δ ϭ 1.73Ϫ2.02 (m, 4 H, NCH2CH2CH2), 2.74
(m), 3061 (m), 3028 (m), 2958 (m), 2919 (m), 2885 (s), 2747 (w),
2701 (w), 1602 (w), 1494 (m), 1474 (m), 1454 (s), 1407 (m), 1387
(m, 1 H, NCHH), 3.21 (d, J ϭ 6.0 Hz, 2 H, CH2CϭN), 3.28Ϫ3.63
(m, 4 H, NCHCH2OCH3, NCHH), 3.38 (s, 3 H, OCH3), 3.68 (s, 2
(m), 1322 (w), 1231 (m), 1133 (s), 1072 (m), 1038 (s), 978 (s), 945 H, SCH2Ph), 6.44 (t, J ϭ 6.0 Hz, 1 H, NϭCH), 7.18Ϫ7.36 (m, 5
(s), 918 (m), 875 (w), 806 (w), 752 (m), 703 (s), 565 (m), 472 (m)
H, CHarom.) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 22.1
cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 2.61 (d, J ϭ 4.4 Hz, 2 H, (NCH2CH2), 26.6 (NCH2CH2CH2), 33.6 (SCH2), 34.9 (ArCH2),
SCH2), 3.82 (s, 2 H, CH2Ph), 3.88 (m, 2 H, OCH2), 4.00 (m, 2 H, 49.6 (NCH2), 59.2 (OCH3), 63.2 (NCH), 74.5 CH2OCH3), 126.6,
OCH2), 5.04 (t, J ϭ 4.4 Hz, 1 H, CH), 7.24 (m, 1 H, CHarom.), 7.32 128.2, 128.9 (Ar-C), 131.9 (CϭN), 138.5 (Ar-Cq) ppm. MS (EI,
(m, 4 H, CHarom.) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 34.1 70 eV): m/z (%) ϭ 278 (15) [Mϩ], 235 (6), 234 (17), 233 (100), 187
Eur. J. Org. Chem. 2003, 3923Ϫ3938
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3927

D. Enders, A. Moll, A. Schaadt, G. Raabe, J. Runsink
mer): δ ϭ 22.2 (NCH2CH2), 22.3, 22.9 [CH(CH3)2], 25.8
FULL PAPER
(16), 156 (12), 155 (28), 109 (8), 91 (62), 82 (6), 71 (12), 70 (7), 68
(5), 55 (10), 45 (17). C15H22N2OS (278.41): calcd. C 64.71, H 7.97, [CH(CH3)2], 27.1 (NCH2CH2CH2), 32.0 [C(CH3)3], 43.4 [C(CH3)3],
N 10.06; found C 64.57, H 8.19, N 10.16.
43.6 (CHCH2), 44.7 (SCH), 49.4 (NCH2), 58.8 (OCH3), 63.4
(NCH), 75.5 (CH2OCH3), 139.1 (CϭN) ppm. MS (EI, 70 eV): m/
z (%) ϭ 300 (3) [Mϩ], 255 (7), 212 (15), 211 (100), 199 (6), 114 (9),
112 (6), 71 (7), 70 (11), 57 (10), 55 (6), 45 (7). C16H32N2OS (300.50):
calcd. C 63.95, H 10.73, N 9.32; found C 63.94, H 10.65, N 9.55.
General Procedure for the α-Alkylation of α-Sulfanylated Acetalde-
hyde-SAMP-Hydrazone (S)-3a (GP 3): Compound (S)-3a (1 equiv.)
was added dropwise at 0 °C to a solution of LDA (1.05 equiv.),
freshly prepared from nBuLi and diisopropylamine, in dry THF
(2.0 mL/mmol). After the mixture had been stirred at this tempera-
ture for 5 h, alkyl halide (1.1 equiv.) was added at Ϫ100 °C. This
solution was allowed to warm up to room temperature over 15 h.
The reaction mixture was quenched with brine and the aqueous
layer was extracted with Et2O. The combined organic layers were
washed with brine and dried with MgSO4. The solvent was re-
moved in a rotary evaporator and the crude product was purified
by flash column chromatography (SiO2, pentane/Et2O, 15:1, 1%
NEt3).
(2S,2S)-(؉)-[2-(tert-Butylsulfanyl)-4-phenylbutylidene][2-(methoxy-
methyl)pyrrolidin-1-yl]amine (S,S)-4c: Hydrazone (S)-3a (1.22 g,
5.0 mmol) was alkylated with (2-iodoethyl)benzene (0.9 mL,
6.5 mmol) as described in GP 3. Compound (S,S)-4c was obtained
as a colourless oil after purification by flash column chromatogra-
phy (SiO2, pentane/Et2O, 15:1, 1% NEt3). Yield: 1.51 g (85%); de ϭ
87%. Rt ϭ 11.33, 11.49 min (OV-17, 140Ϫ10Ϫ260). Rf ϭ 0.30 (pen-
tane/Et2O, 5:1). [α]2D5 ϭ ϩ44.0 (c ϭ 1.2, CHCl3). IR (film): ν˜ ϭ
3083 (m), 3062 (m), 3026 (s), 2958 (s), 2923 (s), 2896 (s), 2825 (s),
2742 (w), 1944 (w), 1872 (w), 1804 (w), 1719 (w), 1602 (m), 1496
(m), 1473 (m), 1456 (s), 1389 (m), 1364 (s), 1342 (m), 1324 (m),
1302 (m), 1282 (m), 1197 (s), 1162 (s),1122 (s), 1076 (m), 1030 (m),
1002 (m), 973 (m), 934 (m), 903 (m), 882 (m), 843 (w), 813 (w), 749
(2S,2S)-(؉)-[2-(tert-Butylsulfanyl)-3-methylbutylidene][2-(methoxy-
methyl)pyrrolidin-1-yl]amine [(S,S)-4a]: Hydrazone (S)-3a (1.43 g,
5.9 mmol) was alkylated with 2-iodopropane (0.9 mL, 6.5 mmol) as
described in GP 3. Compound (S,S)-4a was obtained as a colour-
less oil after purification by flash column chromatography (SiO2,
pentane/Et2O, 15:1, 1% NEt3). Yield: 1.55 g (92%); de ϭ 88%. Rt ϭ
7.04 min (OV-17, 120Ϫ10Ϫ260). Rf ϭ 0.35 (pentane/Et2O, 5:1).
[α]2D5 ϭ ϩ105.0 (c ϭ 1.0, CHCl3). IR (film): ν˜ ϭ 2959 (s), 2925 (s),
2873 (s), 2825 (m), 1592 (m), 1460 (s), 1384 (m), 1365 (s), 1341 (m),
1303 (m), 1282 (w), 1249 (w), 1197 (m), 1162 (s), 1122 (s), 1074
(m), 700 (s), 671 (w), 597 (w), 554 (w), 504 (w) cmϪ1 1H NMR
.
(400 MHz, C6D6), (Z isomer): δ ϭ 1.28 [s, 9 H, C(CH3)3], 1.60 (m,
1 H, NCHCHH), 1.75 (m, 2 H, NCH2CH2), 1.87 (m, 2 H,
SCHCHH, NCHCHH), 2.04 (m, 1 H, SCHCHH), 2.69 (m, 1 H,
NCHH), 2.82 (m, 2 H, PhCH2), 2.94 (m, 1 H, NCHH), 3.16 (s, 3
H, OCH3), 3.25 (m, 1 H, CHHO), 3.40 (m, 1 H, OCH2CH), 3.47
(m, 1 H, CHHO), 4.09 (m, 1 H, SCH), 6.36 (m, 1 H, NϭCH),
7.06Ϫ7.22 (m, 5 H, CHarom.) ppm. 13C NMR (100 MHz, C6D6),
(Z isomer): δ ϭ 23.1 (NCH2CH2), 27.1 (NCH2CH2CH2), 31.7
[C(CH3)3], 32.4 (ArCH2), 33.7 (ArCH2CH2), 40.5 (SCH), 43.5
[C(CH3)3], 49.2 (NCH2), 58.7 (OCH3), 67.3 (NCH), 75.3
(CH2OCH3), 126.0, 128.3, 128.8 (Ar-C), 141.5 (Ar-Cq), 158.5 (Cϭ
N) ppm. MS (EI, 70 eV): m/z (%) ϭ 348 (3) [Mϩ], 303 (12), 260
(15), 259 (100), 161 (5), 144 (5), 129 (12), 123 (10), 117 (19), 114
(12), 112 (6), 91 (15), 82 (7), 71 (7), 70 (15), 57 (15), 55 (6), 45 (9).
C20H32N2OS (348.55): calcd. C 68.92, H 9.25, N 8.04; found C
68.76, H 9.62, N 8.47.
(m), 1026 (w), 997 (w), 973 (m), 927 (w), 893 (m) cmϪ1. H NMR
1
(400 MHz, C6D6), (Z isomer): δ ϭ 1.02 (d, J ϭ 6.7 Hz, 3 H,
SCHCH3), 1.13 (d, J ϭ 6.7 Hz, 3 H, SCHCH3), 1.32 [s, 6 H,
C(CH3)3], 1.55Ϫ1.75 (m, 3 H, NCHCHH, NCH2CH2), 1.91 (m, 1
H, NCHCHH), 2.19 [m, 1 H, (CH3)2CH], 2.89 (m, 1 H, NCHH),
3.14 (s, 3 H, OCH3), 3.16 (m, 1 H, NCHH), 3.25 (dd, J ϭ 8.8,
6.6 Hz, CHH2), 3.44 (m, 1 H, NCH), 3.50 (dd, J ϭ 8.8, 4.9 Hz, 1
H, CHHO), 4.19 (dd, J ϭ 8.2, 4.1 Hz, 1 H, SCH), 7.26 (d, J ϭ
8.2 Hz, 1 H, NϭCH) ppm. 13C NMR (100 MHz, C6D6), (Z iso-
mer):
δ ϭ 19.0, 20.4 [CH(CH3)2], 23.2 (NCH2CH2), 27.2
(NCH2CH2CH2), 31.1 [CH(CH3)2], 31.7 [C(CH3)3], 42.9 [C(CH3)3],
47.1 (SCH), 55.1 (NCH2), 58.7 (OCH3), 67.7 (NCH), 75.6
(CH2OCH3), 159.0 (CϭN) ppm. MS (EI, 70 eV): m/z (%) ϭ 286
(5) [Mϩ], 241 (9), 198 (13), 197 (100), 185 (7), 116 (11), 114 (13),
82 (6), 70 (18), 57 (10). C15H30N2OS (286.48): calcd. C 62.89, H
10.56, N 9.78; found C 62.59, H 10.64, N 10.16.
(2S,2S)-(؊)-[3-(4-Bromophenyl)-2-(tert-butylsulfanyl)propylidene][2-
(methoxymethyl)pyrrolidin-1-yl]amine [(S,S)-4d]: Hydrazone (S)-3a
(1.22 g, 5.0 mmol) was alkylated with 4-bromobenzyl bromide
(1.38 g, 5.5 mmol) as described in GP 3. Compound (S,S)-4d was
obtained as a colourless oil after purification by flash column chro-
(2S,2S)-(؊)-[2-(tert-Butylsulfanyl)-4-methylpentylidene][2-(meth- matography (SiO2, pentane/Et2O, 15:1, 1% NEt3). Yield: 1.62 g
oxymethyl)pyrrolidin-1-yl]amine [(S,S)-4b)]: Hydrazone (S)-3a
(1.43 g, 5.9 mmol) was alkylated with sec-butyl iodide (0.8 mL,
6.5 mmol) as described in GP 3. Compound (S,S)-4b was obtained
as a colourless oil after purification by flash column chromatogra-
(74%); de ϭ 87%. Rt ϭ 16.24 min (CP-Sil-8, 120Ϫ10Ϫ300). Rf ϭ
0.54 (pentane/Et2O, 5:1). [α]2D5 ϭ Ϫ62.1 (c ϭ 0.9, CHCl3). IR
(CHCl3): ν˜ ϭ 2960 (s), 2923 (s), 2894 (s), 2826 (s), 1592 (m), 1488
(s), 1473 (s), 1459 (s), 1403 (m), 1390 (m), 1364 (s), 1342 (m), 1324
phy (SiO2, pentane/Et2O, 15:1, 1% NEt3). Yield: 1.43 g (81%); de (m), 1303 (m), 1283 (m), 1197 (s), 1161 (s), 1122 (s), 1073 (s), 1012
Ն 96%. Rt ϭ 7.55 min (OV-17, 120Ϫ10Ϫ260). Rf ϭ 0.50 (pentane/ (s), 972 (m), 929 (m), 902 (m), 872 (m), 839 (m), 801 (s), 757 (s),
Et2O, 5:1). [α]2D5 ϭ Ϫ146.7 (c ϭ 1.0, CHCl3). IR (CHCl3): ν˜ ϭ 3373 713 (w), 666 (w), 641 (w), 592 (w), 525 (m) cmϪ1 1H NMR
(w), 3190 (w), 2956 (s), 2925 (s), 2898 (s), 2870 (s), 2826 (s), 2718 (400 MHz, C6D6), (E isomer): δ ϭ 1.30 [s, 9 H, SC(CH3)3], 1.44
(w), 1722 (w), 1595 (m), 1460 (s), 1384 (m), 1364 (s), 1341 (m), (m, H, NCH2CH2CHH), 1.67 (m, H, NCH2CH2,
1303 (m), 1282 (m), 1197 (s), 1163 (s), 1122 (s), 1072 (m), 1024 (m), NCH2CH2CHH), 2.44 (m, 1 H, NCHH), 2.82 (dd, J ϭ 7.2,
1003 (m), 973 (m), 899 (m), 856 (m), 758 (m), 651 (w), 596 (w) 13.8 Hz, 1 H, ArCHH), 2.92 (dd, J ϭ 7.7, 13.8 Hz, 1 H, ArCHH),
cmϪ1 1H NMR (400 MHz, C6D6), (E isomer): δ ϭ 0.92 (d, J ϭ 3.00 (m, 1 H, NCHH), 3.13 (s, 3 H, OCH3), 3.35 (dd, J ϭ 6.9,
6.6 Hz, 6 H, CH(CH3)2] 1.42 [s, 9 H, SC(CH3)3], 1.50 (m, 1 H, 9.1 Hz, 1 H, CHHO), 3.43 (m, 1 H, CHCH2O), 3.57 (dd, J ϭ 3.6,
NCH2CHH), 1.58Ϫ1.77 (m, 5 H, NCH2CHH, NCH2CH2CH2, 9.1 Hz, 1 H, CHHO), 3.86 (dt, J ϭ 7.4, 14.8 Hz, 1 H, SCH), 6.32
.
1
3
.
SCHCH2), 1.92 [m, 1 H, CH(CH3)3], 2.52 (m, 1 H, NCHH), 3.08
(d, J ϭ 7.4 Hz, 1 H, NϭCH), 6.83 (m, 2 H, CHarom.), 7.22 (m, 2
(m, 1 H, NCHH), 3.16 (s, 3 H, OCH3), 3.39 (dd, J ϭ 7.4, 9.1 Hz, H, CHarom.) ppm. 13C NMR (100 MHz, C6D6), (E isomer): δ ϭ
1 H, CHHO), 3.53 (m, 1 H, OCH2CH), 3.66 (dd, J ϭ 3.6, 9.1 Hz, 22.3 (NCH2CH2), 27.1 (NCH2CH2CH2), 31.7 [C(CH3)3], 40.4
1 H, CHHO), 3.91 (dt, J ϭ 8.0, 15.8 Hz, 1 H, SCH), 6.35 (d, J ϭ
(ArCH2), 43.7 [C(CH3)3], 47.5 (SCH), 49.3 (NCH2), 58.8 (OCH3),
63.2 (NCH), 75.4 (CH2OCH3), 120.3 (Ar-Cq), 131.2, 131.6 (Ar-C),
8.0 Hz, 1 H, NϭCH) ppm. 13C NMR (100 MHz, C6D6), (E iso-
3928
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3923Ϫ3938

A Flexible Asymmetric Synthesis of anti-1,2-Sulfanyl Amines
FULL PAPER
137.0 (CϭN), 138.2 (Ar-Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ 413 times with CH2Cl2, and the combined organic layers were washed
(6) [Mϩ], 412 (7), 369 (24), 367 (24), 326 (16), 325 (98), 324 (21), with brine, dried with MgSO4 and concentrated in vacuo. The resi-
323 (100), 313 (9), 279 (14), 277 (16), 244 (24), 243 (43), 199 (35),
due was purified by flash column chromatography (SiO2, pen-
187 (32), 169 (5), 155 (31), 143 (27), 141 (13), 131 (6), 130 (8), 129 tane/Et2O).
(6), 115 (6), 114 (19), 112 (13), 109 (17), 102 (6), 82 (14), 71 (27), 70
Benzyl (2S,1R)-[2-(tert-Butylsulfanyl)-1,3-dimethylbutyl]carbamate
(42), 69 (6), 68 (12), 57 (55), 56 (8), 55 (15), 45 (40). C19H29BrN2OS
(413.42): calcd. C 55.20, H 7.07, N 6.78; found C 54.98, H 7.18,
N 6.94.
[(S,R)-5a]: Compound (S,S)-4a (0.20 g, 1.4 mmol) and CeCl3/MeLi
(3.0 equiv.) were treated as described in GP 4 to afford the corre-
sponding hydrazine, which was directly used in the next step. N,N
bond cleavage with BH3·THF (12.0 equiv.) afforded the crude am-
ine, which was dissolved in CH2Cl2 and treated with K2CO3
(3.8 mmol, 0.52 g) and CbzCl (3.5 mmol, 0.58 g). The carbamic es-
ter was obtained as a colourless solid after flash column chroma-
tography (SiO2, pentane/Et2O, 15:1). Yield: 0.06 g (28% over three
steps). de, ee Ն 96%. Rt ϭ 9.90 min (OV-17, 140Ϫ10Ϫ260). Rf ϭ
0.60 (pentane/Et2O, 3:1). [α]2D5 ϭ Ϫ1.2 (c ϭ 1.0, CHCl3). IR (KBr):
ν˜ ϭ 3854 (w), 3842 (w), 3676 (w), 3650 (w), 3630 (w), 3334 (s),
3033 (m), 2957 (s), 2865 (m), 2175 (w), 1682 (s), 1529 (s), 1457 (s),
1383 (m), 1365 (s), 1344 (m), 1324 (m), 1249 (s), 1161 (s), 1095 (s),
1028 (s), 970 (m), 930 (m), 912 (m), 863 (w), 848 (w), 784 (m), 756
(m), 732 (m), 698 (s), 629 (m), 596 (w), 583 (w), 539 (w), 508 (w),
486 (w) cmϪ1. 1H NMR (500 MHz, C6D6): δ ϭ 0.90 [d, J ϭ 6.7 Hz,
3 H, CH(CH3)2], 0.94 (d, J ϭ 6.7 Hz, 3 H, NCHCH3), 1.07 [d, J ϭ
6.7 Hz, 3 H, CH(CH3)2], 1.13 [s, 9 H, C(CH3)3], 1.55 [m, 1 H,
CH(CH3)2], 2.45 (dd, J ϭ 4.0, 8.9 Hz, 1 H, SCH), 4.27 (m, 1H
CHNH), 5.03 (d, J ϭ 9.0 Hz, 1 H, NH), 5.12 (d, J ϭ 12.5 Hz,
PhCH2), 7.07 (m, 1 H, CHarom.), 7.13 (m, 2 H, CHarom.), 7.35 (m,
2 H, CHarom.) ppm. 13C NMR (100 MHz, C6D6): δ ϭ 20.7 (CH3),
22.1, 16.4 [CH(CH3)2], 32.2 [C(CH3)3], 32.4 [CH(CH3)2], 42.7
[C(CH3)3], 47.5 (SCH), 56.0 (CHNH), 66.4 (ArCH2), 127.9, 128.2,
128.4, (Ar-C), 137.4 (Ar-Cq), 155.1 (CϭO) ppm. MS (EI, 70 eV):
m/z (%) ϭ 323 (4) [Mϩ], 178 (13), 172 (14), 146 (21), 145 (13), 144
(17), 134 (24), 92 (9), 91 (100), 89 (39), 57 (23). C18H29NO2S
(323.500): calcd. C 66.83, H 9.04, N 4.33; found C 66.44, H 9.38,
N 4.13.
(2S,2S)-(؊)-[2-(tert-Butylsulfanyl)-3-(naphthalen-2-yl)propylidene]-
[2-(methoxymethyl)pyrrolidin-1-yl]amine [(S,S)-4e]: Hydrazone (S)-
3a (1.22 g, 5.0 mmol) was alkylated with 2-(bromomethyl)naphtha-
lene (1.22 g, 5.5 mmol) as described in GP 3. Compound (S,S)-4e
was obtained as a colourless oil after purification by flash column
chromatography (SiO2, pentane/Et2O, 15:1, 1% NEt3). Yield: 1.42 g
(74%); de Ն 96%. Rt ϭ 14.05, 14.21 min (CP-Sil-8, 160Ϫ10Ϫ300).
Rf ϭ 0.29 (pentane/Et2O, 5:1). [α]2D5 ϭ Ϫ44.2 (c ϭ 1.3, CHCl3). IR
(CHCl3): ν˜ ϭ 3578 (w), 3052 (m), 2960 (vs), 2923 (s), 2893 (s), 2873
(s), 2827 (s), 2727 (w), 1914 (w), 1719 (m), 1631 (m), 1600 (m),
1509 (m), 1471 (m), 1459 (s), 1388 (m), 1364 (s), 1342 (m), 1303
(m), 1271 (m), 1197 (s), 1161 (w), 1123 (s), 1019 (m), 969 (m), 899
(m), 854 (m), 818 (s), 785 (m), 747 (s), 639 (w), 622 (w), 594 (w),
547 (w), 477 (m) cmϪ1 1H NMR (400 MHz, C6D6), (Z isomer):
.
δ ϭ 1.33 [s, 9 H, C(CH3)3] 1.40 (m, 1 H, NCH2CH2CHH), 1.62
(m, 3 H, NCH2CH2, NCH2CH2CHH), 2.46 (m, 1 H, NCHH), 3.02
(m, 1 H, NCHH), 3.12 (s, 3 H, OCH3), 3.16Ϫ3.39 (m, 4 H, CHHO,
OCH2CH, SCHCH2), 3.57 (m, 1 H, CHHO), 4.12 (m, 1 H, SCH),
6.45 (d, J ϭ 7.7 Hz, 1 H, NϭCH) 7.16Ϫ7.69 (m, 7 H, CHarom.
)
ppm. 13C NMR (100 MHz, C6D6), (Z isomer):
δ
ϭ
22.2
(NCH2CH2), 27.0 (NCH2CH2CH2), 31.7 [C(CH3)3], 40.4 (ArCH2),
43.7 [C(CH3)3], 47.7 (SCH), 49.3 (NCH2), 55.3 (OCH3), 63.2
(NCH), 75.3 (CH2OCH3), 128.3, 128.3, 127.7, 127.7, 125.8, 125.3
(Ar-C), 136.7, 133.8, 132.6 (Ar-Cq), 137.7 (CϭN) ppm. MS (EI,
70 eV): m/z (%) ϭ 384 (5) [Mϩ], 339 (16), 396 (21), 295 (100), 244
(6), 243 (37), 187 (22), 182 (10), 180 (14), 154 (5), 153 (7), 141 (16),
115 (5), 114 (8), 70 (11), 57 (11), 45 (8). C23H32N2OS (384.224):
calcd. C 71.83, H 8.39, N 7.28; found C 71.79, H 8.70, N 7.60.
Benzyl (3S,2R)-(؊)-[3-(tert-Butylsulfanyl)-1,1,5-trimethylhex-2-yl]-
carbamate [(S,R)-5b]: Compound (S,S)-4b (0.30 g, 1.0 mmol) and
CeCl3/tBuLi (3.0 equiv.) were treated as described in GP 4 to afford
the corresponding hydrazine, which was directly used in the next
General Procedure for 1,2-Addition, N,N Cleavage and the Protec-
tion of the Amino Groups of tert-Butylsulfanyl Hydrazones (S,S)-4 step. N,N bond cleavage with BH3·THF (12.0 equiv.) afforded the
(GP 4): CeCl3·7H2O (3.0 equiv.) was dehydrated for 2 h at 130 °C crude amine, which was dissolved in CH2Cl2 and treated with
in vacuo (0.1 Torr) and then suspended in dry THF (3.0 mL/mmol)
with sonification. The suspension was stirred overnight at room
temperature. After the mixture had been cooled to Ϫ78 °C, organ-
K2CO3 (2.7 mmol, 0.37 g) and CbzCl (2.5 mmol, 0.43 g). The car-
bamic ester was obtained as a colourless oil after flash column
chromatography (SiO2, pentane/Et2O, 15:1). Yield: 0.23 g (61%
olithium reagent (3.0 equiv.) was added, and the mixture was stirred over
3 steps); de, ee Ն 96%. Rt ϭ 12.37 min (CP-Sil-8,
for 2 h at this temperature. Hydrazone (S,S)-4 (1.0 equiv.), dis-
solved in dry THF (4.0 mL/mmol), was added to the resulting yel-
low suspension at Ϫ100 °C. The solution was allowed to warm up
to room temperature over 15 h. The reaction mixture was quenched
with saturated aqueous NaHCO3 solution and the aqueous portion
140Ϫ10Ϫ300). Rf ϭ 0.70 (pentane/Et2O, 3:1). [α]2D5 ϭ Ϫ47.8 (c ϭ
1.3, CHCl3). IR (CHCl3): ν˜ ϭ 3458 (w), 3277 (m), 3149 (w), 3090
(w), 3065 (w), 3033 (w), 2956 (s), 2899 (m), 2867 (s), 2716 (w), 1949
(w), 1707 (s), 1608 (w), 1598 (w), 1508 (s), 1469 (w), 1458 (w), 1405
(m), 1365 (s), 1341 (s), 1218 (s), 1163 (m), 1114 (m), 1054 (s), 1029
was extracted with CH2Cl2. The combined organic layers were (m), 1009 (m), 917 (w), 895 (w), 875 (w), 753 (m), 697 (m), 666 (w),
dried with Na2SO4 and concentrated in vacuo. The crude hydra-
607 (w), 571 (w), 527 (w), 491 (w) cmϪ1 1H NMR (300 MHz,
zines were used directly in the N,N cleavage. For that purpose, the C6D6): δ ϭ 0.87 [d, J ϭ 6.6 Hz, 6 H, CH(CH3)2], 0.92 [s, 9 H,
crude hydrazines (1.0 equiv.) were dissolved in dry THF (10 mL/ CHC(CH3)3], 1.14 (m, 2 H, SCHCH2), 1.32 [s, 9 H, SC(CH3)3],
mmol), BH3·THF (12 equiv.) was then added, and the solution was 2.10 [m, 1 H, CH(CH3)2], 3.05 (m, 1 H, SCH), 4.31 (dd, J ϭ 10.7,
.
heated at reflux for 4 h. The reaction mixture was hydrolysed with
methanol and concentrated in vacuo. The residue was dissolved in
methanol (10.0 mL/mmol) and heated at reflux for another 2 h.
The mixture was concentrated in vacuo and the crude amine was
either purified by flash column chromatography on silica gel or
subsequently converted into the benzylcarbamate. For that purpose
the crude amine was dissolved in CH2Cl2 (10.0 mL/mmol), K2CO3
(2.7 equiv.), and CbzCl (2.5 equiv.) were added, and the system was
heated at reflux for 3 days. The aqueous layer was extracted three
1.8 Hz, 1 H, CHNH), 4.75 (m, d, J ϭ 10.7 Hz, 1 H, NH), 5.17 (d,
J ϭ 12.4 Hz, 2 H, CH2Ar), 7.10 (m, 3 H, CHarom.), 7.28 (m, 2 H,
CHarom.) ppm. 13C NMR (75 MHz, C6D6): δ ϭ 23.0 [CH(CH3)2],
24.8, 20.8 [CH(CH3)2], 27.4 [C(CH3)3], 30.9 [SC(CH3)3], 35.8
[C(CH3)3], 39.4 (CH2CH(CH3)2], 41.8 (SCH), 42.0 [C(CH3)3], 63.7
(CHNH), 65.8 (ArCH2), 127.6, 127.5, 127.0 (Ar-C), 136.7 (Ar-Cq),
156.1 (CϭO) ppm. MS (EI, 70 eV): m/z (%) ϭ 379 (2) [Mϩ], 221
(7), 220 (53), 177 (10), 176 (71), 158 (10), 103 (8), 92 (8), 91 (100),
57 (17). HRMS: C22H37NO2S: calcd. 379.2545; found 379.2546.
Eur. J. Org. Chem. 2003, 3923Ϫ3938
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3929

D. Enders, A. Moll, A. Schaadt, G. Raabe, J. Runsink
FULL PAPER
Benzyl
(3S,2R)-(؊)-[3-(tert-Butylsulfanyl)-1,1-dimethyl-5-phe-
next step. N,N bond cleavage with BH3·THF (10.9 mmol, 12.0
nylpent-2-yl]carbamate [(S,R)-5c]: Compound (S,S)-4c (0.20 g, equiv.) afforded the crude amine, which was obtained as a colour-
0.56 mmol) and CeCl3/tBuLi (1.68 mmol, 3.0 equiv.) were treated
as described in GP 4 to afford the corresponding hydrazine, which
was directly used in the next step. N,N bond cleavage with
less oil after flash column chromatography (SiO2, pentane/Et2O,
1:1). Yield: 0.10 g (32% over 2 steps); de, ee Ն 96%. Rt ϭ 9.59 min
(CP.Sil-8, 180Ϫ10Ϫ300) Rf ϭ 0.28 (pentane/EtOAc ϭ 3:1). [α]2D5
ϭ
BH3·THF (6.70 mmol, 12.0 equiv.) afforded the crude amine, which ϩ19.7 (c ϭ 1.2, CHCl3). IR (CHCl3): ν˜ ϭ 3259 (m), 3224 (m), 3137
was dissolved in CH2Cl2 and treated with K2CO3 (1.5 mmol, (w), 3053 (m), 3007 (m), 2958 (s), 2931 (s), 2862 (s), 2369 (s), 2323
0.21 g) and CbzCl (1.40 mmol, 0.24 g). The carbamic ester was ob-
tained as a colourless oil after flash column chromatography (SiO2,
(s), 2277 (m), 1765 (w), 1705 (s), 1632 (w), 1601 (m), 1578 (s), 1509
(m), 1460 (s), 1393 (m), 1366 (s), 1302 (m), 1271 (m), 1215 (m),
pentane/Et2O, 15:1). Yield: 0.13 g (54% over 3 steps); de, ee Ն 96%. 1171 (s), 1137 (m), 1083 (w), 1046 (m), 1018 (m), 983 (w), 961 (m),
Rt ϭ 16.80 min (CP-Sil-8, 140Ϫ10Ϫ300). Rf ϭ 0.60 (pentane/Et2O, 932 (w), 896 (m), 855 (m), 817 (s), 757 (s), 667 (m), 642 (w), 623
3:1) [α]2D5 ϭ Ϫ12.9 (c ϭ 0.8, CHCl3). IR (CHCl3): ν˜ ϭ 3425 (m),
(w), 598 (w), 477 (m) cmϪ1.1H NMR (400 MHz, C6D6): δ ϭ 0.91
3278 (m), 3149 (m), 3086 (m), 3063 (m), 3028 (m), 2960 (s), 2865 (t, J ϭ 7.4 Hz, 3 H, CH2CH3), 1.05 [s, 9 H, [C(CH3)3], 1.28 (m, 6
(m), 1949 (w), 1873 (w), 1807 (w), 1705 (s), 1604 (m), 1586 (w), H, CH3CH2CH2CH2), 2.93 (m, 2 H, CHNH2, SCH), 3.03 (m, 2 H,
1510 (s), 1472 (s), 1455 (s), 1405 (m), 1365 (s), 1342 (s), 1218 (s), ArCH2), 7.26 (m, 2 H, CHarom.), 7.36 (m, 1 H, CHarom.), 7.67 (m,
1163 (m), 1130 (m), 1083 (m), 1058 (s), 1030 (m), 1016 (m), 930
4 H, CHarom.) ppm. 13C NMR (100 MHz, C6D6): δ ϭ 14.4
(w), 909 (w), 754 (s), 699 (s), 667 (m), 609 (m), 566 (m), 526 (w), (CH2CH3), 23.2 (CH2CH3), 29.5 (CH2CH2CH3), 31.6 [SC(CH3)3],
494 (m) cmϪ1 1H NMR (400 MHz, C6D6): δ ϭ 0.82 [s, 9 H, 33.9 (CH2CH2CH2CH3), 39.9 (ArCH2), 43.0 [SC(CH3)3], 53.7
SC(CH3)3], 1.32 [s, H, NCHC(CH3)3], 1.38 (m, H, (SCH), 55.3 (H2NCH), 125.7 126.2, 127.3, 127.7, 127.8, 127.9,
.
9
1
PhCH2CHH), 1.68 (m, 1 H, PhCH2CHH), 2.58 (m, 1 H, PhCHH), 128.5 (Ar-C), 132.8, 133.8, 135.8 (Ar-Cq) ppm. MS (EI, 70 eV): m/
2.90 (m, 1 H, SCH), 3.05 (m, 1 H, PhCHH), 4.29 (dd, J ϭ 1.6, z (%) ϭ 330 (5) [Mϩ], 244 (16), 141 (14), 87 (5), 86 (100), 57 (8).
11.0 Hz, 1 H, CHNH), 4.66 (d, J ϭ 11.0 Hz, 1 H, NH), 5.15 (d,
J ϭ 12.4 Hz, 2 H, OCH2Ph), 7.12 (m, 10 H, CHarom.) ppm. 13C
NMR (100 MHz, C6D6): δ ϭ 27.2 [SC(CH3)3], 30.9 [C(CH3)3], 33.0
(ArCH2CH2), 33.5 (ArCH2), 35.7 [SC(CH3)3], 42.2 [C(CH3)3], 43.4
(SCH), 63.6 (HNCH), 65.8 (ArCH2O), 127.7, 127.6, 127.5, 125.3
(Ar-C), 141.2, 136.7 (Ar-Cq), 156.1 (CϭO) ppm. MS (EI, 70 eV):
m/z (%) ϭ 428 (1) [Mϩ], 221 (7), 220 (50), 208 (19), 177 (10), 176
(73), 117 (13), 92 (8), 91 (100), 57 (16). HRMS: C26H37NO2S: calcd.
427.2545; found 427.2546.
HRMS: C21H31NS: calcd. 329.2177; found 329.2178.
General Procedure for the α-Alkylation of α-Sulfanylated Acetalde-
hyde-SAMP-Hydrazone (S)-3b (GP 5): Compound (S)-3b (1 equiv.)
was dissolved in dry THF (2.0 mL/mmol) and the system was co-
oled to Ϫ20 °C under argon. LDA (1.0 equiv.), freshly prepared
from nBuLi (1.0 equiv.) and diisopropylamine (1.05 equiv.), was
added to this solution. After the system had been stirred at this
temperature for 2 to 3 h, alkyl halide (1.2 equiv.) was added at
Ϫ100 °C. This solution was allowed to warm up to room tempera-
(2S,1R)-(؉)-1-[2-(4-Bromophenyl)-1-(tert-butylsulfanyl)ethyl]- ture over 15 h. The reaction mixture was quenched with brine and
pentylamine [(S,R)-5d]: Compound (S,S)-4d (0.20 g, 0.48 mmol) the aqueous portion was extracted three times with Et2O. The com-
and CeCl3/MeLi (1.44 mmol 3.0 equiv.) were treated as described bined organic layers were washed with brine and dried with
in GP 4 to afford the corresponding hydrazine, which was directly
used in the next step. N,N bond cleavage with BH3·THF (5.8 mmol,
12.0 equiv.) afforded the crude amine, which was obtained as a
colourless oil after flash column chromatography (SiO2, pentane/
Et2O, 1:1). Yield: 0.03 g (41% over 2 steps); de, ee Ն 96%. Rt ϭ
7.52 min (CP.Sil-8, 180Ϫ10Ϫ300). Rf ϭ 0.29 (pentane/Et2O, 1:1).
[α]2D5 ϭ ϩ33.4 (c ϭ 0.8, CHCl3). IR (CHCl3): ν˜ ϭ 3257 (m), 3136
(w), 3023 (w), 2958 (s), 2930 (s), 2862 (s), 2368 (s), 2323 (s), 2276
(m), 1579 (s), 1489 (s), 1460 (s), 1404 (m), 1393 (m), 1382 (m), 1365
(s), 1303 (m), 1274 (m), 1166 (s), 1137 (m), 1106 (m), 1073 (s), 1045
(m), 1012 (s), 957 (m), 928 (w), 895 (w), 834 (m), 798 (m), 757 (m),
MgSO4. The solvent was removed in a rotary evaporator and the
crude product was purified by flash column chromatography (SiO2,
pentane/Et2O, 1% NEt3).
(2S,2S)-(؊)-(2-Benzylsulfanyl-3-methylbutylidene)[2-(methoxy-
methyl)pyrrolidin-1-yl]amine [(S,S)-6a]: Hydrazone (S)-3b (0.64 g,
2.3 mmol) was alkylated with 2-iodopropane (0.47 g, 2.8 mmol) as
described in GP 5. Compound (S,S)-6a was obtained as a yellow oil
after purification by flash column chromatography (SiO2, pentane/
Et2O, 6:1, 1% NEt3). Yield: 0.68 g (92%); de ϭ 83%. Rf ϭ 0.22
(pentane/Et2O, 6:1). [α]2D5 ϭ Ϫ248.9 (c ϭ 1.0, CHCl3). IR (CHCl3):
ν˜ ϭ 3083 (w), 3060 (m), 3027 (m), 2960 (vs), 2924 (vs), 2874 (vs),
2825 (s), 1587 (m), 1493 (m), 1455 (s), 1418 (w), 1384 (m), 1367
(m), 1342 (m), 1304 (w), 1240 (m), 1197 (s), 1121 (vs), 1071 (s),
1029 (m), 972 (m), 887 (m), 768 (m), 702 (vs), 565 (w), 470 (w)
733 (m), 628 (w), 596 (w), 527 (w), 473 (w) cmϪ1 1H NMR
.
(400 MHz, C6D6): δ ϭ 0.91 (t, J ϭ 6.9 Hz, 3 H, CH3), 1.02 [s, 9
H, C(CH3)3], 1.17Ϫ1.33 (m, 4 H, CH3CH2CH2), 1.41 [m, 2 H,
CH(N)CH2], 2.61 (m, 2 H, ArCHH, SCH), 2.69 (dd, J ϭ 3.3,
10.4 Hz, 1 H, ArCHH), 2.80 (m, 1 H, CHN), 6.85 (m, 2 H,
CHarom.), 7.29 (m, 2 H, CHarom.), ppm. 13C NMR (100 MHz,
C6D6): δ ϭ 14.4 (CH2CH3), 23.2 (CH2CH3), 29.5 (CH2CH2CH3),
31.5 [C(CH3)3], 34.0 (CH2CH2CH2CH3), 38.4 (ArCH2), 42.8
[C(CH3)3], 53.2 (SCH), 55.5 (H2NCH), 120.3 (CBr), 131.4, 131.8
(Ar-C), 139.9 (Ar-Cq), ppm. MS (CI, isobutane): m/z (%) ϭ 417
(3) [Mϩ ϩ59], 415 (3) [Mϩ ϩ57], 398 (5) [Mϩ ϩ40], 396 (5) [Mϩ
ϩ38], 361 (20) [Mϩ ϩ3], 360 (100) [Mϩ ϩ2], 359 (20) [Mϩ ϩ1],
358 (95) [Mϩ], 280 (14), 86 (36). C17H28BrNS (358.386): calcd. C
56.97, H 7.88, N 3.91; found C 57.07, H 8.25, N 4.19.
1
cmϪ1. H NMR (400 MHz, CDCl3), (E isomer): δ ϭ 0.97 [d, J ϭ
6.9 Hz, 3 H, CH(CH3)2], 0.98 [d, J ϭ 6.9 Hz, 3 H, CH(CH3)2],
1.79Ϫ2.02 [m, 5 H, NCH2CH2CH2, CH(CH3)2], 2.79 (dt, J ϭ 8.2,
8.2 Hz, 1 H, NCHH), 3.15 (dd, J ϭ 6.9, 8.5 Hz, 2 H, SCH),
3.35Ϫ3.71 (m, 6 H, NCHCH2OCH3, NCHH, SCH2Ph), 3.38 (s, 3
H, OCH3), 6.45 (d, J ϭ 8.2 Hz, NϭCH), 7.19Ϫ7.37 (m, 5 H,
CHarom.) ppm. 13C NMR (100 MHz, CDCl3), (E isomer): δ ϭ 20.3,
20.6 (CH3), 22.1 (NCH2CH2), 26.6 (NCH2CH2CH2), 31.2
[CH(CH3)2], 34.6 (SCH2), 50.1 (NCH2), 54.2 (SCH), 59.2 (OCH3),
63.1 (NCH), 74.6 (CH2OCH3), 126.4, 128.1, 128.9 (Ar-C), 136.5
(Ar-Cq), 139.0 (CϭN) ppm. MS (EI, 70 eV): m/z (%) ϭ 320 (6)
(2S,1R)-1-[1-(tert-Butylsulfanyl)-2-naphthalen-2-ylethyl]pentylamine [Mϩ], 275 (18) [Mϩ Ϫ CH2OCH3], 198 (17), 197 (100) [Mϩ
Ϫ
[(S,R)-5e]: Compound (S,S)-4e (0.35 g, 0.91 mmol) and CeCl3/
nBuLi (2.73 mmol, 3.0 equiv.) were treated as described in GP 4 to
afford the corresponding hydrazine, which was directly used in the
SC7H7], 114 (6), 91 (22) [C7H7], 70 (12), 45 (10) [CH2OCH3].
C18H28N2OS (320.49): calcd. C 67.46, H 8.81, N 8.74; found C
67.17, H 9.12, N 8.41.
3930
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3923Ϫ3938

A Flexible Asymmetric Synthesis of anti-1,2-Sulfanyl Amines
FULL PAPER
(2S,2S)-(؊)-(2-Benzylsulfanyl-4-methylpentylidene)[2-(methoxy-
methyl)pyrrolidin-1-yl]amine [(S,S)-6b]: Hydrazone (S)-3b (1.40 g,
5.0 mmol) was alkylated with isobutyl iodide (1.10 g, 6.0 mmol) as
described in GP 5. Compound (S,S)-6b was obtained as a colour-
less oil after purification by flash column chromatography (SiO2,
(c ϭ 1.00, CHCl3). IR (film): ν˜ ϭ 3399 (w), 3056 (s), 3026 (s), 2921
(vs), 1947 (w), 1712 (m), 1631 (m), 1599 (s), 1509 (m), 1495 (m),
1453 (s), 1383 (m), 1365 (m), 1343 (m), 1304 (w), 1272 (m), 1240
(m), 1198 (s), 1121 (vs), 1072 (s), 1021 (w), 970 (m), 902 (m), 855
1
(s), 818 (s), 745 (s), 703 (vs), 621 (w), 565 (w), 477 (vs) cmϪ1. H
pentane/Et2O, 6:1, 1% NEt3). Yield: 1.17 g (87%); de Ն 96%. Rf ϭ NMR (400 MHz, CDCl3), (E isomer): δ ϭ 1.74Ϫ1.96 (m, 4 H,
0.38 (pentane/Et2O, 6:1). [α]2D5 ϭ Ϫ232.5 (c ϭ 0.8, CHCl3). IR
(film): ν˜ ϭ 3084 (w), 3061 (m), 3028 (m), 2955 (vs), 2725 (w), 1713
NCH2CH2CH2), 2.67 (dt, J ϭ 8.2, 7.7 Hz, 1 H, NCHH), 3.08 (dd,
J ϭ 14.3, 6.9 Hz, 1 H, ArCHH), 3.17 (dd, J ϭ 14.0, 8.0 Hz, 1
(m), 1588 (m), 1494 (m), 1454 (s), 1419 (w), 1384 (m), 1367 (m), H, ArCHH), 3.23Ϫ3.78 (m, 7 H, NCHCH2OCH3, SCH, NCHH,
1341 (m), 1304 (w), 1236 (m), 1197 (s), 1120 (vs), 1072 (m), 1028 SCH2Ph), 3.34 (s, 3 H, OCH3), 6.41 (d, J ϭ 7.7 Hz, 1 H, NϭCH),
1
(w), 973 (s), 899 (m), 768 (m), 702 (s), 566 (m), 475 (w) cmϪ1. H 7.20Ϫ7.81 (m, 12 H, CHarom.) ppm. 13C NMR (100 MHz, CDCl3),
NMR (400 MHz, CDCl3), (E isomer): δ ϭ 0.81 [d, J ϭ 6.6 Hz, 3
H, CH(CH3)2], 0.84 [d, J ϭ 6.6 Hz, 3 H, CH(CH3)2], 1.50 [m, 2 (SCH2), 39.3 (Ar-CH2), 47.9 (SCH), 49.6 (NCH2), 59.1 (OCH3),
H, CH2CH(CH3)2], 1.72 [m, 1 H, CH(CH3)2], 1.79Ϫ2.02 (m, 4 H, 62.9 (NCH), 74.4 (CH2OCH3), 125.1, 125.6, 126.5, 127.4, 127.5,
(E isomer): δ ϭ 22.0 (NCH2CH2), 26.5 (NCH2CH2CH2), 34.9
NCH2CH2CH2), 2.76 (dt, J ϭ 8.2/8.2 Hz, 1 H, NCHH), 3.34Ϫ3.52 127.5, 127.6, 128.2, 128.9 (Ar-C), 132.0, 133.2 (Ar-Cq), 135.8 (Cϭ
(m, 7 H, NCHCH2OCH3, SCH, NCHH), 3.34 (s, 3 H, OCH3), N), 135.9, 138.7 (Ar-Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ 306 (7),
3.63 (d, J ϭ 13.5 Hz, 1 H, SCHHPh), 3.71 (d, J ϭ 13.5 Hz, 1 H, 278 (10), 251 (10), 249 (11), 235 (5), 234 (16), 233 (100), 199 (9),
SCHHPh), 6.45 (d, J ϭ 8.5 Hz, NϭCH), 7.19Ϫ7.37 (m, 5 H,
187 (11), 184 (8), 180 (7), 156 (8), 155 (26), 142 (6), 141 (42), 111
CHarom.) ppm. 13C NMR (100 MHz, CDCl3), (E isomer): δ ϭ 22.1 (5), 109 (6), 92 (5), 91 (62, C7H7), 71 (8), 70 (9), 45 (6) [CH2OCH3].
(NCH2CH2), 22.3, 22.5 (CH3), 25.8 [CH(CH3)2], 26.5 C26H30N2OS (418.60): calcd. C 74.60, H 7.22, N 6.69; found C
(NCH2CH2CH2), 34.5 (SCH2), 41.5 [CH2CH(CH3)2], 45.3 (SCH), 74.24, H 7.03, N 6.77.
49.8 (NCH2), 59.2 (OCH3), 63.1 (NCH), 74.5 (CH2OCH3), 126.4,
(2S,2S)-(؊)-(2-Benzylsulfanyl-3-phenylpropylidene)[2-(methoxy-
methyl)pyrrolidin-1-yl]amine [(S,S)-6e]: Hydrazone (S)-3b (0.42 g,
1.5 mmol) was alkylated with benzyl bromide (0.31 g, 1.8 mmol) as
described in GP 5. Compound (S,S)-6e was obtained as a yellow oil
after purification by flash column chromatography (SiO2, pentane/
Et2O, 6:1, 1% NEt3). Yield: 0.50 g (90%); de Ն 96%. Rf ϭ 0.23
(pentane/Et2O, 6:1). Rt ϭ 15.86 min (CP-Sil-8, 140Ϫ10Ϫ300).
[α]2D5 ϭ Ϫ184.8 (c ϭ 1.0, CHCl3). IR (CHCl3): ν˜ ϭ 3083 (m), 3061
(m), 3027 (s), 2972 (vs), 2921 (vs), 2876 (vs), 2826 (m), 1586 (m),
1495 (s), 1453 (s), 1341 (m), 1303 (m), 1283 (w), 1197 (s), 1120 (vs),
128.1, 128.9 (Ar-C), 137.6 (CϭN), 139.1 (Ar-Cq) ppm. MS (EI,
70 eV): m/z (%) ϭ 334 (4) [Mϩ], 289 (12) [Mϩ Ϫ CH2OCH3], 212
(16), 211 (100) [Mϩ Ϫ SC7H7], 123 (6) [SC7H7], 91 (15) [C7H7], 70
(6), 45 (7) [CH2OCH3]. C19H30N2OS (334.52): calcd. C 68.22, H
9.04, N 8.37; found C 68.31, H 8.98, N 8.41.
(2S,2S)-(؊)-(2-Benzylsulfanyl-3-o-tolylpropylidene)[2-(methoxy-
methyl)pyrrolidin-1-yl]amine [(S,S)-6c]: Hydrazone (S)-3b (0.56 g,
2.0 mmol) was alkylated with 1-bromomethyl-2-methylbenzene
(0.48 g, 2.6 mmol) as described in GP 5. Compound (S,S)-6c was
obtained as a yellow oil after purification by flash column chroma-
tography (SiO2, pentane/Et2O, 6:1, 1% NEt3). Yield: 0.56 g (73%);
de ϭ 94%. Rf ϭ 0.18 (pentane/Et2O, 6:1). Rt ϭ 14.34 min (CP-Sil-
8, 160Ϫ10Ϫ300). [α]2D5 ϭ Ϫ180.2 (c ϭ 1.1, CHCl3). IR (CHCl3):
1072 (s), 1030 (m), 973 (m), 899 (w), 752 (s), 700 (vs), 568 (w) cmϪ1
.
1H NMR (400 MHz, CDCl3), (E isomer): δ ϭ 1.74Ϫ1.98 (m, 4 H,
NCH2CH2CH2), 2.67 (dt, J ϭ 8.5, 7.7 Hz, 1 H, NCHH), 2.92 (dd,
J ϭ 14.0, 7.1 Hz, 1 H, ArCHH), 3.01 (dd, J ϭ 14.0, 8.0 Hz, 1 H,
ν˜ ϭ 3374 (w), 3060 (m), 3025 (s), 2921 (vs), 2876 (vs), 2825 (vs), ArCHH), 3.28Ϫ3.63 (m, 5 H, NCHCH2OCH3, SCH, NCHH),
2733 (w), 1711 (w), 1587 (s), 1493 (vs), 1453 (vs), 1342 (m), 1303
(m), 1284 (w), 1197 (vs), 1156 (s), 1119 (vs), 1072 (s), 1029 (m), 973
3.35 (s, 3 H, OCH3), 3.63 (d, J ϭ 14.0 Hz, 1 H, SCHHPh), 3.70
(d, J ϭ 13.5 Hz, 1 H, SCHHPh), 6.37 (d, J ϭ 7.4 Hz, 1 H, Nϭ
(m), 901 (m), 868 (m), 769 (m), 746 (vs), 703 (vs), 597 (w), 565 CH), 7.12Ϫ7.32 (m, 10 H, CHarom.) ppm. 13C NMR (100 MHz,
1
(w), 465 (m) cmϪ1. H NMR (400 MHz, CDCl3), (E isomer): δ ϭ
CDCl3), (E isomer): δ ϭ 22.0 (NCH2CH2), 26.5 (NCH2CH2CH2),
1.74Ϫ1.98 (m, 4 H, NCH2CH2CH2), 2.22 (s, 3 H, ArCH3), 2.66 34.8 (SCH2), 39.1 (ArCH2), 48.0 (SCH), 49.6 (NCH2), 59.1
(dt, J ϭ 8.2, 8.0 Hz, 1 H, NCHH), 2.94 (m, 2 H, ArCH2) 3.27Ϫ3.62 (OCH3), 62.9 (NCH), 74.4 (CH2OCH3), 126.1, 126.5, 127.9, 128.2,
(m, 5 H, SCH, CHCH2OCH3, NCHH), 3.35 (s, 3 H, OCH3), 3.63 128.8, 129.1 (Ar-C), 136.0 (CϭN), 138.3, 138.7 (Ar-Cq) ppm. MS
(d, J ϭ 13.5 Hz, 1 H, SCHHPh), 3.71 (d, J ϭ 13.5 Hz, 1 H,
(EI, 70 eV): m/z (%) ϭ 368 (9) [Mϩ], 324 (6), 323 (29) [Mϩ
Ϫ
SCHHPh), 6.40 (d, J ϭ 7.4 Hz, NϭCH), 7.05Ϫ7.32 (m, 9 H, CH2OCH3], 277 (20) [Mϩ Ϫ C7H7], 246 (19), 245 (100) [Mϩ
Ϫ
CHarom.) ppm. 13C NMR (100 MHz, CDCl3), (E isomer): δ ϭ 19.6 SC7H7], 199 (11), 91 (29) [C7H7], 70 (8), 45 (11) [CH2OCH3].
(CH3), 22.0 (NCH2CH2), 26.5 (NCH2CH2CH2), 34.9 (ArCH2), C22H28N2OS (368.54): calcd. C 71.70, H 7.66, N 7.60; found C
36.4 (SCH2), 46.9 (SCH), 49.6 (NCH2), 59.1 (OCH3), 62.9 (NCH), 71.84, H 7.99, N 7.88.
74.4 (CH2OCH3), 125.4, 126.2, 126.5, 128.1, 128.9, 129.7, 130.0
(2-Benzylsulfanyl-4-phenylbutylidene)[2-(methoxymethyl)pyrrolidin-
(Ar-C), 136.2 (CϭN), 136.1, 136.7, 138.7 (Ar-Cq) ppm. MS (EI,
70 eV): m/z (%) ϭ 382 (7) [Mϩ], 338 (6), 337 (24) [Mϩ
Ϫ
1-yl]amine [(S,S)-6f]: Hydrazone (S)-3b (0.84 g, 3.0 mmol) was al-
kylated with benzyl bromide (0.91 g, 3.9 mmol) as described in GP
5. Compound (S,S)-6f was obtained as a yellow oil after purifi-
cation by flash column chromatography (SiO2, pentane/Et2O, 6:1,
1% NEt3). Yield: 0.93 g (81%); de Ն 96%. Rf ϭ 0.25 (pentane/Et2O,
6:1) (Rt ϭ 8.80 min (CP-Sil-8, 160Ϫ10Ϫ300). [α]2D5 ϭ Ϫ232.2 (c ϭ
0.9, CHCl3). IR (CHCl3): ν˜ ϭ 3084 (m), 3060 (m), 3026 (s), 2973
CH2OCH3], 278 (7), 277 (39) [Mϩ Ϫ C8H9], 260 (21), 259 (100)
[Mϩ Ϫ SC7H7], 141 (6), 105 (7) [C8H9], 91 (27) [C7H7], 70 (8), 45
(11) [CH2OCH3]. C23H30N2OS (382.56): calcd. C 72.21, H 7.90, N
7.32; found C 71.74, H 8.26, N 7.67.
(2S,2S)-(؊)-[2-Benzylsulfanyl-3-(naphthalen-2-yl)propylidine][2-
(methoxymethyl)pyrrolidin-1-yl]amine [(S,S)-6d]: Hydrazone (S)-3b (vs), 2922 (vs), 2876 (vs), 2825 (s), 1601 (m), 1586 (m), 1495 (s),
(0.56 g, 2.0 mmol) was alkylated with 2-(bromomethyl)naphthalene
(0.58 g, 2.6 mmol) as described in GP 5. Compound (S,S)-6d was
obtained as a colourless oil after purification by flash column chro-
matography (SiO2, pentane/Et2O, 6:1, 1% NEt3). Yield: 0.76 g
(90%); de Ն 96%. Rf ϭ 0.14 (pentane/Et2O, 6:1). [α]2D5 ϭ Ϫ144.62
1454 (s), 1418 (w), 1341 (m), 1303 (w), 1283 (w), 1197 (s), 1120
(vs), 1072 (m), 1030 (m), 973 (m), 902 (w), 879 (m), 752 (s), 769
1
(m), 751 (m), 700 (vs), 564 (m), 504 (w), 474 (w) cmϪ1. H NMR
(300 MHz, CDCl3), (E isomer):
δ ϭ 1.76Ϫ2.04 (m, 6 H,
NCH2CH2CH2, PhCH2CH2), 2.67 (m, 3 H, NCHH, PhCH2CH2),
Eur. J. Org. Chem. 2003, 3923Ϫ3938
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3931

D. Enders, A. Moll, A. Schaadt, G. Raabe, J. Runsink
FULL PAPER
3.29Ϫ3.60 (m, 5 H, NCHCH2OCH3, SCH, NCHH), 3.37 (s, 3 H,
(NCH2CH2CH2), 31.3 (CH3), 34.3 [C(CH3)2], 34.8 (SCH2), 38.6
OCH3), 3.64 (d, J ϭ 13.6 Hz, 1 H, SCHHPh), 3.71 (d, J ϭ 13.6 Hz, (ArCH2), 48.0 (SCH), 49.7 (NCH2), 59.2 (OCH3), 63.0 (NCH),
1 H, SCHHPh), 6.34 (d, J ϭ 7.7 Hz, 1 H, NϭCH), 7.04Ϫ7.37 (m,
74.4 (CH2OCH3), 124.9, 126.5, 128.1, 128.8, 128.9 (Ar-C), 136.3
10 H, CHarom.) ppm. 13C NMR (75 MHz, CDCl3), (E isomer): δ ϭ (CϭN), 135.2, 138.8 (Ar-Cq), 148.8 (Ar-Cq) ppm. MS (EI, 70 eV):
22.5 (NCH2CH2), 27.0 (NCH2CH2CH2), 33.9, 35.0, 35.0 (SCH2, m/z (%) ϭ 424 (3) [Mϩ], 380 (5), 379 (20) [Mϩ Ϫ CH2OCH3], 333
ArCH2, ArCH2CH2), 47.0 (SCH), 50.1 (NCH2), 59.7 (OCH3), 63.5
(NCH), 75.0 (CH2OCH3), 126.1, 126.9, 128.6, 128.6, 128.7, 129.3 (46), 141 (6), 132 (6), 91 (15) [C7H7], 70 (5), 45 (5) [CH2OCH3].
(3) [Mϩ Ϫ C7H7], 302 (24), 301 (100) [Mϩ Ϫ SC7H7], 278 (8), 277
(Ar-C), 137.1 (CϭN), 139.4, 141.8 (Ar-Cq) ppm. MS (EI, 70 eV):
C26H36N2OS (424.64): calcd. C 73.54, H 8.54, N 6.60; found C
m/z (%) ϭ 382 (4) [Mϩ], 338 (5), 337 (20) [Mϩ Ϫ CH2OCH3], 260 73.43, H 8.84, N 6.89.
(20), 259 (100) [Mϩ Ϫ SC7H7], 213 (17), 144 (7), 129 (7), 123 (10),
117 (11), 114 (7), 91 (34) [C7H7], 70 (7), 45 (5) [CH2OCH3].
C23H30N2OS (382.56) calcd. C 72.21, H 7.90, N 7.32; found C
72.03, H 7.93, N 7.66.
General Procedure for the 1,2-Addition to α-Sulfanylated SAMP-
Hydrazones (S,S)-6 (GP 6): CeCl3·7H2O (3.0 equiv.) was dehy-
drated in vacuo (0.1 Torr) for 2 h at 130 °C and then suspended
in dry THF (3.0 mL/mmol) with sonification. The suspension was
stirred overnight at room temperature. After the system had been
cooled toϪ78 °C, lithiumorganyl (3.0 equiv.) was added and the
mixture was stirred at this temperature for 2 h. Hydrazone (S,S)-6
(1.0 equiv.), dissolved in dry THF (4.0 mL/mmol), was then added
at Ϫ100 °C to the resulting canary yellow suspension. The solution
was allowed to warm up to room temperature over 15 h. The reac-
tion mixture was quenched with saturated aqueous NaHCO3 solu-
tion and the aqueous portion was extracted with CH2Cl2. The com-
bined organic layers were dried with Na2SO4 and concentrated in
vacuo. The crude hydrazines were purified by flash column chro-
matography (SiO2, pentane/Et2O).
(2S,2S)-(؊)-[2-(Benzylsulfanyl)pent-4-enylidene][2-(methoxy-
methyl)pyrrolidin-1-yl]amine [(S,S)-6g]: Hydrazone (S)-3b (0.70 g,
2.5 mmol) was alkylated with allyl bromide (0.55 g, 3.3 mmol) as
described in GP 5. Compound (S,S)-6g was obtained as a yellow oil
after purification by flash column chromatography (SiO2, pentane/
Et2O, 6:1, 1% NEt3). Yield: 0.66 g (83%); de Ն 96%. Rf ϭ 0.40
(pentane/Et2O, 6:1). Rt ϭ 11.87 min (E isomer), 11.75 (Z isomer)
(CP-Sil-8, 160Ϫ10Ϫ300). [α]2D5 ϭ Ϫ269.2 (c ϭ 1.1, CHCl3). IR
(film): ν˜ ϭ 3062 (m), 3027 (m), 2975 (vs), 2922 (vs), 2877 (vs), 2826
(vs), 1714 (w), 1640 (m), 1587 (s), 1495 (s), 1453 (vs), 1417 (m),
1342 (m), 1304 (m), 1283 (w), 1197 (vs), 1120 (vs), 1072 (s), 1029
(m), 992 (m), 973 (m), 915 (vs), 867 (m), 770 (m), 703 (vs), 618 (w),
(2S,1R,2S)-(؊)-[1-(1-Benzylsulfanyl-2-methylpropyl)pentyl][2-
(methoxymethyl)pyrrolidin-1-yl]amine [(S,R,S)-7a]: This compound
was prepared as described in GP 6, by 1,2-addition of CeCl3/nBuLi
(1.5 mmol) to hydrazone (S,S)-6a (0.16 g, 0.5 mmol). Compound
(S,R,S)-7a was obtained as a colourless oil after purification by
flash column chromatography (SiO2, pentane/Et2O, 6:1). Yield:
1
565 (m), 472 (m) cmϪ1. H NMR (400 MHz, CDCl3), (E isomer):
δ ϭ 1.80Ϫ2.03 (m, 4 H, NCH2CH2CH2), 2.42 (m, 2 H, CH2ϭ
CHCH2), 2.76 (dt, J ϭ 8.5, 8.2 Hz, 1 H, NCHH), 3.33Ϫ3.80 (m,
7 H, CH2OCH3, SCH, SCH2Ph, CHCH2OCH3, NCHH), 3.38 (s,
3 H, OCH3), 5.06 (m, 2 H, H2CϭCH), 5.77 (m, 1 H, H2CϭCH),
6.35 (d, J ϭ 8.0 Hz, 1 H, NϭCH), 7.21Ϫ7.37 (m, 5 H, CHarom.
)
0.16 g (85%); de ϭ 93%. Rf ϭ 0.50 (pentane/Et2O, 6:1). Rt
ϭ
ppm. 13C NMR (100 MHz, CDCl3), (E isomer): δ ϭ 22.1
(NCH2CH2), 26.5 (NCH2CH2CH2), 34.6 (SCH2), 37.3 (CH2CH),
46.4 (SCH), 49.7 (NCH2), 59.2 (OCH3), 63.0 (NCH), 74.4
(CH2OCH3), 116.9 (H2CϭCH), 126.5, 128.2, 128.9 (Ar-C), 134.8
(H2CϭCH), 136.3 (CϭN), 138.9 (Ar-Cq) ppm. MS (EI, 70 eV): m/
z (%) ϭ 318 (2) [Mϩ], 273 (19) [Mϩ Ϫ CH2OCH3], 196 (11), 195
(67) [Mϩ Ϫ SC7H7], 177 (7), 173 (12), 149 (13), 141 (6), 124 (5),
123 (31) [SC7H7], 115 (9), 114 (7), 99 (6), 92 (8), 91 (100) [C7H7],
89 (5), 88 (5), 87 (5), 85 (5), 82 (5), 73 (40), 71 (9), 70 (16), 65 (8),
55 (9), 45 (54) [CH2OCH3]. C18H26N2OS (318.48): calcd. C 67.88,
H 8.23, N 8.80; found C 67.72, H 8.34 N 9.22.
13.18 min (CP-Sil-8, 140Ϫ10Ϫ300). [α]2D5 ϭ Ϫ108.7 (c ϭ 2.3,
CHCl3). IR (film): ν˜ ϭ 3062 (w), 3027 (m), 2956 (vs), 2871 (vs),
1726 (w), 1602 (w), 1493 (m), 1456 (s), 1382 (m), 1364 (m), 1196
(m), 1126 (s), 1070 (m), 1027 (w), 918 (m), 766 (w), 701 (s), 564
1
(w), 471 (w) cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 0.88 (t, J ϭ
7.4 Hz, 3 H, CH2CH3), 0.95 [d, J ϭ 6.6 Hz, 3 H, CH(CH3)2], 1.03
[d,
J ϭ 6.6 Hz, 3 H, CH(CH3)2], 1.13Ϫ1.50 [m, 6 H,
CH(NH)CH2CH2CH2), 1.60 (m, 1 H, NCH2CH2CHH), 1.70 (m,
2 H, NCH2CH2), 1.87 (m, 1 H, NCH2CH2CHH), 1.99 [m, 1 H,
CH(CH3)2], 2.11 (m, 1 H, NCHH), 2.57 (m, 1 H, NCHCH2OCH3),
2.68 (dd, J ϭ 3.6, 5.5 Hz, 1 H, SCH), 2.90 (m, 1 H, CHNH), 3.19
(m, 1 H, NCHH), 3.32 (m, 1 H, CHHOCH3), 3.35 (s, 3 H, OCH3),
3.53 (dd, J ϭ 3.9, 9.3 Hz, 1 H, CHHOCH3), 3.70 (d, J ϭ 12.9 Hz,
1 H, SCHHPh), 3.74 (d, J ϭ 12.6 Hz, 1 H, SCHHPh), 7.19Ϫ7.33
(m, 5 H, CHarom.) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 14.2
(CH2CH3), 20.8, 22.0 (CH3), 21.1 (NCH2CH2), 23.0 (CH2CH3),
26.0 (NCH2CH2CH2), 28.8 (CH2CH2CH3), 29.6 [CH(CH3)2], 30.5
(CH2CH2CH2CH3), 37.23 (SCH2), 56.3 (SCH), 57.0 (NCH2), 59.0
(OCH3), 60.8 (CHNH), 66.5 (NCH), 74.8 (CH2OCH3), 126.8,
128.2, 128.9 (Ar-C), 138.5 (Ar-Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ
378 (13) [Mϩ], 200 (13), 199 (100), 129 (5), 114 (9), 91 (14) [C7H7],
70 (13), 45 (6) [CH2OCH3]. HRMS: calcd. 378.2705; found
378.2705.
(2S,2S)-(؊)-[2-Benzylsulfanyl-3-(4-tert-butylphenyl)propylidene][2-
(methoxymethyl)pyrrolidin-1-yl]amine (S,S)-6h: Hydrazone (S)-3b
(0.64 g, 2.3 mmol) was alkylated with 4-tert-butylbenzyl bromide
(0.63 g, 2.8 mmol) as described in GP 5. Compound (S,S)-6h was
obtained as a yellow oil after purification by flash column chroma-
tography (SiO2, pentane/Et2O, 6:1, 1% NEt3). Yield: 0.72 g (74%);
de Ն 96%. Rf ϭ 0.20 (pentane/Et2O, 6:1). [α]2D5 ϭ Ϫ147.7 (c ϭ 0.9,
CHCl3). IR (CHCl3): ν˜ ϭ 3084 (w), 3059 (m), 3026 (m), 2962 (vs),
2873 (vs), 2826 (s), 1712 (w), 1587 (m), 1515 (m), 1495 (m), 1455
(s), 1413 (w), 1364 (m), 1342 (m), 1269 (m), 1217 (m), 1198 (m),
1118 (s), 1072 (m), 1023 (m), 973 (w), 901 (w), 836 (m), 812 (m),
757 (vs), 702 (s), 666 (m), 565 (m), 472 (w) cmϪ1
.
1H NMR
(400 MHz, CDCl3), (E isomer): δ ϭ 1.29 [s, 9 H, C(CH3)2],
(2S,1R,2S)-(؊)-(2-Benzylsulfanyl-1-butyl-4-methylpentyl)[2-(meth-
1.76Ϫ1.99 (m, 4 H, NCH2CH2CH2), 2.68 (dt, J ϭ 8.8/8.0 Hz, 1 H, oxymethyl)pyrrolidin-1-yl]amine [(S,R,S)-7b]: This compound was
NCHH), 2.89 (dd, J ϭ 14.0, 6.9 Hz, 1 H, ArCHH), 2.99 (dd, J ϭ prepared as described in GP 6, by 1,2-addition of CeCl3/nBuLi
14.0, 8.0 Hz, 1 H, ArCHH), 3.28Ϫ3.64 (m, 5 H, NCHCH2, SCH,
NCHH), 3.35 (s, 3 H, OCH3), 3.63 (d, J ϭ 13.5 Hz, 1 H, (S,R,S)-7b was obtained as a colourless oil after purification by
SCHHPh), 3.70 (d, J ϭ 13.5 Hz, 1 H, SCHHPh), 6.39 (d, J ϭ flash column chromatography (SiO2, pentane/Et2O, 6:1). Yield:
7.4 Hz, 1 H, NϭCH), 7.05Ϫ7.32 (m, 9 H, CHarom.) ppm. 13C NMR 0.48 g (98%); de Ն 96%. Rf ϭ 0.60 (pentane/Et2O, 5:1). Rt
(100 MHz, CDCl3), (E isomer): δ ϭ 22.1 (NCH2CH2), 26.5 11.38 min (CP-Sil-8, 160Ϫ10Ϫ300). [α]2D5 ϭ Ϫ176.3 (c ϭ 0.7,
(3.0 mmol) to hydrazone (S,S)-6b (0.33 g, 1.0 mmol). Compound
ϭ
3932
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3923Ϫ3938

A Flexible Asymmetric Synthesis of anti-1,2-Sulfanyl Amines
FULL PAPER
CHCl3). IR (CHCl3): ν˜ ϭ 3084 (w), 3063 (w), 3028 (m), 2955 (vs),
2929 (vs), 2870 (vs), 2730 (w), 1725 (w), 1601 (w), 1494 (m), 1466
(m), 1454 (m), 1384 (m), 1368 (m), 1343 (w), 1236 (w), 1217 (m),
Yield: 0.81 g (81%); de Ն 96%. Rf ϭ 0.23 (pentane/Et2O, 6:1). Rt ϭ
19.66 min (CP-Sil-8, 180Ϫ10Ϫ300). [α]2D5 ϭ Ϫ15.1 (c ϭ 1.4,
CHCl3). IR (CHCl3): ν˜ ϭ 3056 (m), 3026 (m), 2928 (vs), 2871 (vs),
1199 (m), 1113 (m), 1071 (m), 1029 (w), 918 (m), 897 (w), 757 (vs), 1725 (w), 1701 (w), 1632 (w), 1601 (w), 1508 (m), 1494 (m), 1454
701 (s), 667 (m), 565 (w), 471 (w) cmϪ1 1H NMR (400 MHz, (s), 1377 (m), 1238 (w), 1197 (m), 1125 (s), 1100 (s), 1071 (m), 1028
CDCl3): δ ϭ 0.68 [d, J ϭ 6.6 Hz, 3 H, CH(CH3)2], 0.86 [d, J ϭ (w), 950 (m), 918 (m), 892 (m), 854 (m), 817 (s), 752 (s), 701 (s),
.
6.6 Hz, 3 H, CH(CH3)2], 0.87 (t, J ϭ 6.9 Hz, 3 H, CH2CH3), 477 (s) cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 0.89 (t, J ϭ 6.9 Hz,
1.03Ϫ1.78 [m, 12 H, CH(NH)CH2CH2CH2, CH2CH(CH3)2, 3 H, CH2CH3), 1.29 (m, 4 H, CH2CH2CH3), 1.50 [m, 3 H,
NCH2CH2CH2], 1.89 [m, 1 H, CH(CH3)2], 2.18 (m, 1 H, NCHH), NCH2CH2CHH, CH(NH)CH2], 1.65 (m, 2 H, NCH2CH2), 1.85
2.57 (m, 2 H, SCH, NCHCH2OCH3), 2.82 (m, 1 H, CHNH), 3.24 (m, 1 H, NCH2CH2CHH), 2.15 (m, 1 H, NCHH), 2.54 (m, 1 H,
(m, 1 H, NCHH), 3.32 (m, 1 H, CHHOCH3), 3.35 (s, 3 H, OCH3), NCHCH2OCH3), 2.88 (m, 2 H, ArCHH, CHNH), 3.05Ϫ3.20 (m,
3.52 (dd, J ϭ 3.6, 9.1 Hz, 1 H, CHHOCH3), 3.67 (d, J ϭ 13.5 Hz,
2 H, NCHH, ArCHH), 3.18 (s, 3 H, OCH3), 3.23Ϫ3.42 (m, 5 H,
1 H, SCHHPh), 3.72 (d, J ϭ 13.5 Hz, 1 H, SCHHPh), 7.20Ϫ7.33 SCH, CH2OCH3), 3.46 (m, 2 H, SCH2Ph), 7.10 (m, 2 H, CHarom.),
(m, 5 H, CHarom.) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 14.1 7.17 (m, 2 H, CHarom.), 7.30 (m, 2 H, CHarom.), 7.44 (m, 2 H,
(CH2CH3), 21.0 (NCH2CH2), 21.5, 23.3 (CH3), 23.0 (CH2CH3),
CHarom.), 7.60 (m, 2 H, CHarom.), 7.78 (m, 2 H, CHarom.) ppm. 13C
25.6 [CH(CH3)2], 26.1 (NCH2CH2CH2), 28.6 (CH2CH2CH3), 30.2 NMR (100 MHz, CDCl3): δ ϭ 14.1 (CH3), 21.1 (NCH2CH2), 23.0
(CH2CH2CH2CH3), 35.7 (SCH2), 38.1 [CH2CH(CH3)2], 45.1 (CH2CH3), 26.2 (NCH2CH2CH2), 28.9 (CH2CH2CH3), 29.9
(SCH), 56.6 (NCH2), 59.0 (CH2OCH3), 60.0 (CHNH), 66.0 (CH2CH2CH2CH3), 36.3 (SCH2), 37.8 (ArCH2), 49.5 (SCH), 57.1
(NCH), 74.7 (CH2OCH3), 126.8, 128.2, 128.9 (Ar-C), 138.4 (Ar- (NCH2), 58.8 (OCH3), 61.1 (CHNH), 66.5 (NCH), 74.8
Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ 392 (3) [Mϩ], 213 (5), 200
(CH2OCH3), 125.1, 125.7, 126.7, 127.35, 127.38, 127.41, 127.6,
(8), 199 (60), 195 (7), 194 (8), 193 (11), 183 (5), 156 (7), 137 (18), 128.1, 128.3, 128.8 (Ar-C), 131.9, 133.3, 137.5, 138.0 (Ar-Cq) ppm.
123 (87), 114 (7), 113 (5), 103 (11), 102 (6), 92 (11), 91 (100, C7H7), MS (EI, 70 eV): m/z (%) ϭ 476 (12) [Mϩ], 353 (6) [Mϩ Ϫ SBn],
73 (13), 70 (12), 69 (15), 65 (6), 60 (10), 57 (10), 55 (10).
200 (12), 199 (100), 167 (6), 153 (5), 141 (10), 129 (6), 114 (10), 91
C23H40N2OS (392.64): calcd. C 70.36 H 10.27 N 7.13; found C (13) [C7H7], 70 (13).HRMS: calcd. 476.2861; found 476.2864.
70.60 H 10.60, N 7.17.
(2S,1R,2S)-(؊)-[1-(1-Benzylsulfanyl-2-phenylethyl)pentyl][2-(meth-
(2S,1R,2S)-(؊)-{1-[1-Benzylsulfanyl-2-(o-tolyl)ethyl]pentyl}- oxymethyl)pyrrolidin-1-yl]amine [(S,R,S)-7e]: This compound was
[2-(methoxymethyl)pyrrolidin-1-yl]amine [(S,R,S)-7c]: This com-
prepared as described in GP 6, by 1,2-addition of CeCl3/nBuLi
pound was prepared as described in GP 6, by 1,2-addition of (0.9 mmol) to hydrazone (S,S)-6e (0.10 g, 0.3 mmol). Compound
CeCl3/nBuLi (2.7 mmol) to hydrazone (S,S)-6d (0.21 g, 0.9 mmol).
Compound (S,R,S)-7d was obtained as a colourless oil after purifi-
(S,R,S)-7e was obtained as a colourless oil after purification by
flash column chromatography (SiO2, pentane/Et2O, 4:1). Yield:
cation by flash column chromatography (SiO2, pentane/Et2O, 6:1). 0.10 g (87%); de Ն 96%. Rf ϭ 0.29 (pentane/Et2O, 3:1). Rt
ϭ
Yield: 0.44 g (99%); de Ն 96%. Rf ϭ 0.19 (pentane/Et2O, 6:1). Rt ϭ
14.78 min (CP-Sil-8, 160Ϫ10Ϫ300). [α]2D5 ϭ Ϫ12.1 (c ϭ 2.2,
CHCl3). IR (film): ν˜ ϭ 3084 (m), 3062 (m), 3027 (s), 2929 (vs),
15.47 min (CP-Sil-8, 160Ϫ10Ϫ300). [α]2D5 ϭ Ϫ37.2 (c ϭ 0.8,
CHCl3). IR (film): ν˜ ϭ 3061 (m), 3025 (m), 2928 (vs), 2871 (vs), 2872 (vs), 1946 (w), 1695 (m), 1602 (m), 1536 (w), 1495 (m), 1453
1602 (w), 1492 (s), 1455 (vs), 1378 (m), 1346 (w), 1238 (w), 1192 (s), 1378 (m), 1345 (w), 1239 (w), 1197 (m), 1123 (s), 1073 (m),
(m), 1126 (vs), 1071 (m), 1030 (w), 917 (m), 764 (m), 744 (s), 702 1030 (m), 967 (w), 918 (m), 753 (m), 701 (vs), 564 (w), 508 (w), 474
1
(s), 564 (w), 518 (w), 460 (w) cmϪ1. 1H NMR (400 MHz, CDCl3,): (m) cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 0.88 (t, J ϭ 7.1 Hz,
δ ϭ 0.87 (t, J ϭ 6.9 Hz, 3 H, CH2CH3), 1.15 (m, 2 H,
3 H, CH2CH3), 1.19 (m, 2 H, CH2CH2CH3), 1.29 (m, 2 H,
H, CH(NH)CH2], 1.55 (m, H,
CH2CH2CH3), 1.28 (m, H, CH2CH3), 1.43 [m, H, CH2CH3), 1.43 [m,
2
2
2
1
CH(NH)CH2], 1.55 (m, 1 H, NCH2CH2CHH), 1.64 (m, 2 H, NCH2CH2CHH), 1.64 (m, 2 H, NCH2CH2), 1.85 (m, 1 H,
NCH2CH2), 1.86 (m, 1 H, NCH2CH2CHH), 2.11 (dt, J ϭ 8.8, NCH2CH2CHH), 2.11 (dt, J ϭ 8.5, 8.8 Hz, 1 H, NCHH), 2.58 (m,
8.5 Hz, 1 H, NCHH), 2.28 (s, 3 H, ArCH3), 2.55 (m, 1 H, 1 H, NCHCH2OCH3), 2.71 (dd, J ϭ 14.3, 5.0 Hz, 1 H, ArCHH),
NCHCH2OCH3), 2.79 (dd, J ϭ 14.3, 9.7 Hz, 1 H, ArCHH), 2.82
2.84 (m, 1 H, CHNH), 2.96 (dd, J ϭ 14.3, 5.5 Hz, 1 H, ArCHH),
(m, 1 H, CHNH), 2.95 (dd, J ϭ 14.3, 5.5 Hz, 1 H, ArCHH), 3.02 3.04 (m, 1 H, NCHH), 3.12Ϫ3.46 (m, 5 H, SCH, CH2OCH3,
(m, 1 H, NCHH), 3.20 (m, 1 H, SCH), 3.27 (s, 3 H, OCH3), SCH2Ph), 3.27 (s, 3 H, OCH3), 7.12Ϫ7.31 (m, 10 H, CHarom.) ppm.
3.32Ϫ3.47 (m, 4 H, CH2OCH3, SCH2Ph), 7.09Ϫ7.25 (m, 9 H, 13C NMR (100 MHz, CDCl3): δ ϭ 14.1 (CH3), 21.1 (NCH2CH2),
CHarom.) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 14.1 (CH2CH3), 22.9 (CH2CH3), 26.1 (NCH2CH2CH2), 28.9 (CH2CH2CH3), 29.8
19.7 (CH3), 21.1 (NCH2CH2), 23.0 (CH2CH3), 26.2 (CH2CH2CH2CH3), 36.2 (SCH2), 37.9 (ArCH2), 49.9 (SCH), 57.1
(NCH2CH2CH2), 29.0 (CH2CH2CH3), 29.9 (CH2CH2CH2CH3), (NCH2), 58.9 (OCH3), 61.2 (CHNH), 66.5 (NCH), 74.8
35.4 (ArCH2), 36.3 (SCH2), 48.5 (SCH), 57.1 (NCH), 58.9 (OCH3),
61.8 (CHNH), 66.4 (NCH), 75.0 (CH2OCH3), 125.5, 126.1, 126.7,
(CH2OCH3), 126.0, 126.7, 128.0, 128.8, 128.9, 129.1 (Ar-C), 138.1,
140.1 (Ar-Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ 426 (14) [Mϩ], 213
128.1, 128.9, 130.0, 130.1 (Ar-C), 136.2, 138.2 (Ar-Cq) ppm. MS (6), 200 (13), 199 (100), 183 (8), 129 (6), 114 (6), 91 (25, C7H7), 70
(EI, 70 eV): m/z (%) ϭ 440 (16) [Mϩ], 200 (13), 199 (100), 129
(11), 45 (5) [CH2OCH3]. C26H38N2OS (426.66): calcd. C 73.19, H
(5), 114 (7), 105 (5), 91 (14, C7H7), 70 (11), 45 (5) [CH2OCH3]. 8.98, N 6.57; found C 73.54, H 8.97, N 6.43.
C27H40N2OS (440.69): calcd. C 73.59, H 9.15, N 6.36; found C
(2S,1R,2S)-(؊)-[1-Benzylsulfanyl-3-(phenylpropyl)pentyl][2-(meth-
73.30, H 9.30, N 6.84.
oxymethyl)pyrrolidin-1-yl]amine [(S,R,S)-7f]: This compound was
prepared as described in GP 6, by 1,2-addition of CeCl3/nBuLi
(0.9 mmol) to hydrazone (S,S)-6f (0.12 g, 0.3 mmol). Compound
(2S,1R,2S)-(؊)-{1-[1-Benzylsulfanyl-2-(naphthalen-2-yl)ethyl]-
pentyl}[2-(methoxymethyl)pyrrolidin-1-yl]amine [(S,R,S)-7d]: This
compound was prepared as described in GP 6, by 1,2-addition of (S,R,S)-7f was obtained as a colourless oil after purification by
CeCl3/nBuLi (7.5 mmol) to hydrazone (S,S)-6e (0.88 g, 2.1 mmol).
Compound (S,R,S)-7e was obtained as a colourless oil after purifi-
cation by flash column chromatography (SiO2, pentane/Et2O, 6:1).
flash column chromatography (SiO2, pentane/Et2O, 6:1). Yield:
115 mg (87%); de Ն 96%. Rf ϭ 0.20 (pentane/Et2O, 6:1). Rt ϭ
13.69 min (CP-Sil-8, 180Ϫ10Ϫ300). [α]2D5 ϭ Ϫ149.43, (c ϭ 0.87,
Eur. J. Org. Chem. 2003, 3923Ϫ3938
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3933

D. Enders, A. Moll, A. Schaadt, G. Raabe, J. Runsink
FULL PAPER
CHCl3). IR (CHCl3): ν˜ ϭ 3084 (m), 3061 (m), 3027 (s), 2929 (vs), 1692 (m), 1602 (m), 1495 (s), 1453 (vs), 1373 (m), 1328 (w), 1238
2871 (vs), 1602 (m), 1495 (m), 1454 (vs), 1378 (m), 1340 (w), 1284 (m), 1197 (m), 1117 (vs), 1030 (m), 918 (m), 804 (w), 755 (vs), 701
(w), 1238 (w), 1188 (m), 1127 (vs), 1100 (s), 1071 (m), 1029 (m),
(vs), 511 (w), 475 (w) cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 1.04
917 (m), 752 (vs), 701 (vs), 667 (w), 567 (w), 473 (w) cmϪ1
.
1H (d, J ϭ 6.6 Hz, 3 H, CH3), 1.52 (m, 1 H, NCH2CH2CHH), 1.65
NMR (300 MHz, CDCl3): δ ϭ 0.80 (t, J ϭ 7.2 Hz, 3 H, CH2CH3), (m, 2 H, NCH2CH2), 1.85 (m, 1 H, NCH2CH2CHH), 2.15 (dt, J ϭ
0.90 (m, 1 H, CHHCH2CH3), 1.20 (m, 4 H, CHHCH2CH3, 8.5, 8.8 Hz, 1 H, NCHH), 2.55 (m, 1 H, NCHCH2OCH3), 2.74
ArCH2CHH), 1.40Ϫ1.80 (m, 5 H, NCH2CH2, CH2CH2CH2CH3, (dd, J ϭ 14.3, 5.5 Hz, 1 H, ArCHH), 2.93 (dd, J ϭ 14.3, 6.04 Hz,
ArCH2CHH) 1.85 (m, 2 H, NCH2CH2CH2), 2.16 (dt, J ϭ 8.4,
2 H, ArCHH) 3.05 (m, 3 H, SCH, CHNH, NCHH), 3.23 (dd, J ϭ
8.7 Hz, 1 H, NCHH), 2.54 (m, 2 H, NCHCH2OCH3, ArCHH), 9.1, 6.0 Hz, 1H CHHOCH3) 3.27 (s, 3 H, OCH3), 3.34 (dd, J ϭ
2.74Ϫ2.88 (m, 3 H, SCH, ArCHH, CHNH), 3.13 (m, 1 H, 9.1, 4.4 Hz, 1H CHHOCH3), 3.48 (d, J ϭ 12.6 Hz, 1 H, SCHHPh),
NCHH), 3.30 (m, 1H CHHOCH3), 3.34 (s, 3 H, OCH3), 3.51 (dd, 3.54 (d, J ϭ 12.9 Hz, 1 H, SCHHPh), 7.15Ϫ7.30 (m, 10 H,
J. ϭ 9.2, 3.5 Hz, 1H CHHOCH3), 3.64 (d, J ϭ 13.4 Hz, 1 H, CHarom.) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 16.0 (CH3), 21.0
SCHHPh) 3.72 (d, J ϭ 13.4 Hz, 1 H, SCHHPh), 7.05Ϫ7.31 (m, 10 (NCH2CH2), 26.1 (NCH2CH2CH2), 36.2 (SCH2), 38.4 (ArCH2),
H, CHarom.
(CH2CH3),
(NCH2CH2CH2),
)
ppm. 13C NMR (75 MHz, CDCl3):
20.9 (NCH2CH2), 23.0 (CH2CH3),
28.5 (CH2 CH2CH3), 30.1,
δ
ϭ 14.1
51.2 (SCH), 56.0 (CHNH), 57.0 (NCH2), 58.9 (OCH3), 66.2
26.0 (NCH), 75.1 (CH2OCH3), 126.0, 126.7, 128.1, 128.2, 128.8, 129.0
31.5, (Ar-C), 138.2, 139.9 (Ar-Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ 384
(CH2CH2CH2CH3, ArCH2CH2), 33.6 (ArCH2), 35.7 (SCH2), 46.2 (3) [Mϩ], 261 (6), 259 (12), 193 (5), 158 (6), 157 (100), 153 (6), 147
(SCH), 56.6 (NCH2), 58.9 (OCH3), 60.4 (CHNH), 66.1 (NCH), (5), 131 (6), 129 (9), 125 (8), 114 (9), 92 (5), 91 (60, C7H7), 70 (15),
74.5 (CH2OCH3), 125.5, 126.7, 128.0, 128.2, 128.4, 128.8 (Ar-C),
138.4, 141.7 (Ar-Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ 440, (14)
[Mϩ], 200 (13), 199 (100), 126 (6), 117 (9), 114 (8), 91 (25) [C7H7],
70 (11), 45 (5) [CH2OCH3]. C27H40N2OS (440.70): calcd. C 73.59,
H 9.15, N 6.36; found C 73.42, H 9.42, N 6.22.
65 (6), 55 (6), 51 (5), 45 (15, CH2OCH3). HRMS: (C23H32N2OS)
calcd. 384.2235; found 384.2236.
(2S,1R,2S)-(؊)-{1-[1-Benzylsulfanyl-2-(4-tert-butylphenyl)ethyl]-
pentyl}[2-(methoxymethyl)pyrrolidin-1-yl]amine [(S,R,S)-7i]: This
compound was prepared as described in GP 6, by 1,2-addition of
(2S,1R,2S)-(؊)-[1-(1-Benzylsulfanyl-2-phenylethyl)heptyl][2-(meth- CeCl3/nBuLi (1.5 mmol) to hydrazone (S,S)-6h (0.21 g, 0.5 mmol).
oxymethyl)pyrrolidin-1-yl]amine (S,R,S)-7g: This compound was
prepared as described in GP 6, by 1,2-addition of CeCl3/n-HexLi
(0.9 mmol) to hydrazone (S,S)-6e (0.10 g, 0.3 mmol). Compound
(S,R,S)-7g was obtained as a colourless oil after purification by
flash column chromatography (SiO2, pentane/Et2O, 9:1). Yield:
Compound (S,R,S)-7i was obtained as a colourless oil after purifi-
cation by flash column chromatography (SiO2, pentane/Et2O, 6:1).
Yield: 0.17 g (70%); de Ն 96%. Rf ϭ 0.43 (pentane/Et2O, 5:1).
[α]2D5 ϭ Ϫ22.7 (c ϭ 0.8, CHCl3). IR spectrum (CHCl3): ν˜ ϭ 3058
(w), 3024 (m), 2958 (vs), 2870 (vs), 1702 (s), 1602 (s), 1513 (m),
1494 (m), 1456 (m), 1393 (w), 1364 (m), 1268 (m), 1238 (w), 1217
115 mg (84%); de Ն 96%. Rf ϭ 0.27 (pentane/Et2O, 6:1). [α]2D5
ϭ
Ϫ37.2, (c ϭ 1.1, CHCl3). IR (CHCl3): ν˜ ϭ 3061 (m), 3027 (s), 2926 (m), 1200 (m), 1110 (s), 1022 (w), 918 (m), 834 (m), 815 (w), 757
(vs), 2856 (vs), 1602 (m), 1494 (w), 1454 (s), 1376 (w), 1239 (w), (vs), 701 (m), 666 (w), 565 (m) cmϪ1. 1H NMR (400 MHz, CDCl3):
1191 (m), 1124 (s), 1030 (w), 917 (m), 751 (m), 701 (vs), 625 (w),
565 (w), 514 (w), 472 (w) cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ CH2CH2CH3), 1.32 [s. 9 H, C(CH3)3] 1.42 [m, 2 H, CH(NH)CH2],
0.88 (t, J ϭ 7.1 Hz, 3 H, CH2CH3), 1.22Ϫ1.33 (m, 4 H, 1.55 (m, 1 H, NCH2CH2CHH), 1.64 (m, 2 H, NCH2CH2), 1.85
δ ϭ 0.88 (t, J ϭ 7.1 Hz, 3 H, CH2CH3), 1.15Ϫ1.36 (m, 4 H,
CH2CH2CH3), 1.43 [m, 2 H, CH(NH)CH2], 1.55 (m, 1 H, (m, 1 H, NCH2CH2CHH), 2.11 (dt, J ϭ 8.8, 8.5 Hz, 1 H, NCHH),
NCH2CH2CHH), 1.64 (m, 2 H, NCH2CH2), 1.85 (m, 1 H, 2.53 (m, 1 H, NCHCH2OCH3), 2.69 (dd, J ϭ 14.3, 9.1 Hz, 1 H,
NCH2CH2CHH), 2.11 (m,
NCHCH2OCH3), 2.71 (dd, J ϭ 14.3, 9.4 Hz, 1 H, ArCHH), 2.84 ArCHH), 3.03 (m, 1 H, NCHH), 3.13Ϫ3.46 (m, 5 H, SCH,
(m, 1 H, CHNH), 2.96 (dd, J ϭ 14.3, 5.5 Hz, 1 H, ArCHH), 3.04 CH2OCH3, SCH2Ph), 3.27 (s, 3 H, OCH3), 7.09Ϫ7.32 (m, 9 H,
1
H, NCHH), 2.55 (m,
1
H,
ArCHH), 2.84 (m, 1 H, CHNH), 2.93 (dd, J ϭ 14.3, 5.8 Hz, 1 H,
(m, 1 H, NCHH), 3.12Ϫ3.46 (m, 5 H, SCH, CH2OCH3, SCH2Ph), CHarom.) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 14.1 (CH2CH3),
3.27 (s, 3 H, OCH3), 7.12Ϫ7.31 (m, 10 H, CHarom.) ppm. 13C NMR 21.0 (NCH2CH2), 23.0 (CH2CH3), 26.1 (NCH2CH2CH2), 28.9
(100 MHz, CDCl3): δ ϭ 14.1 (CH2CH3), 21.0 (NCH2CH2), 22.6 (CH2CH2CH3), 29.8 (CH2CH2CH2CH3), 31.4 [C(CH3)3], 34.4
(CH2CH3), 26.1 (NCH2CH2CH2), 26.6, 29.5, 30.1, 31.8 [C(CH3)3], 36.3 (SCH2), 37.4 (ArCH2), 50.0 (SCH), 57.2 (NCH2),
(CH2CH2CH2CH2CH2CH3), 36.3 (SCH2), 37.9 (ArCH2), 49.9 58.9 (OCH3), 61.3 (CHNH), 66.5 (NCH), 74.8 (CH2OCH3), 124.9
(SCH), 57.1 (NCH2), 58.9 (OCH3), 61.2 (CHNH), 66.4 (NCH), 126.7, 128.1, 128.7, 128.9 (Ar-C), 137.0, 138.2, 148.8 (Ar-Cq) ppm.
74.8 (CH2OCH3), 126.0, 126.7, 128.0, 128.1, 128.9, 129.1 (Ar-C),
MS (EI, 70 eV): m/z (%) ϭ 483 (6) [Mϩ], 482 (19), 359 (6), 200
(13), 199 (100), 195 (8), 183 (6), 129 (7), 114 (6), 91 (18), 70 (11),
138.1, 140.1 (Ar-Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ 454 (2) [Mϩ],
247 (11), 228 (12), 227 (100), 223 (7), 211 (5), 181 (5), 149 (6), 131 57 (8), 45 (7). C30H46N2OS (482.77): calcd. C 74.64, H 9.60, N
(7), 129 (11), 117 (6), 114 (20), 113 (5), 105 (5), 97 (6), 91 (40)
[C7H7], 85 (7), 84 (6), 83 (5), 82 (5), 71 (8), 70 (18), 69 (9), 59 (5),
57 (8), 55 (8), 51 (8), 45 (8) [CH2OCH3]. C28H42N2OS (454.71)
calcd. C 73.96, H 9.31, N 6.16, found C 73.52, H 9.42, N 6.22.
5.80; found C 74.36, H 9.53, N 6.26.
General Procedure for the N,N Bond Cleavage and Protection of the
Amino Groups of the Hydrazines (S,R,S)-7 (GP 7): The hydrazines
(S,R,S)-7 (1.0 equiv.) were dissolved in dry THF (10.0 mL/mmol),
BH3·THF (12 equiv.) was then added, and the solution was heated
at reflux for 4 h. The reaction mixture was cooled to 0 °C and
hydrolysed with 1  HCl. The solvent was removed under reduced
pressure and the residue was dissolved in saturated aqueous
NaHCO3 solution. The crude amine was extracted with CH2Cl2
and either purified by flash column chromatography or directly
used in the next step. For that purpose, the solution of the crude
(2S,1R,2S)-(؊)-[2-Benzylsulfanyl-1-methyl-3-phenylpropyl][2-(meth-
oxymethyl)pyrrolidin-1-yl]amine [(S,R,S)-7h]: This compound was
prepared as described in GP 6, by 1,2-addition of CeCl3/MeLi
(3.0 mmol) to hydrazone (S,S)-6e (0.37 g, 1.0 mmol). Compound
(S,R,S)-7h was obtained as a colourless oil after purification by
flash column chromatography (SiO2, pentane/Et2O, 6:1). Yield:
0.25 g (65%); de Ն 96% Rf ϭ 0.20 (pentane/Et2O, 6:1). [α]2D5
ϭ
Ϫ40.8, (c ϭ 1.1, CHCl3), IR (film): ν˜ ϭ 3382 (w), 3084 (m), 3061 amine, dissolved in CH2Cl2, was treated with K2CO3 (5.0 equiv.)
(m), 3027 (s), 2970 (vs), 2925 (vs), 2826 (s), 1721 (m), 1692 (m), and MocCl (5.0 equiv.) and heated at reflux for 2 days. After that,
3934
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3923Ϫ3938

A Flexible Asymmetric Synthesis of anti-1,2-Sulfanyl Amines
FULL PAPER
the reaction mixture was quenched with water and the aqueous
portion was extracted three times with CH2Cl2. The combined or-
2955 (vs), 2927 (vs), 2857 (vs), 1946 (w), 1804 (w), 1729 (w), 1602
(m), 1493 (s), 1454 (s), 1380 (m), 1290 (w), 1262 (w), 1238 (m),
ganic layers were dried with Na2SO4 and the solvent was removed 1197 (w), 1159 (w), 1125 (m), 1071 (m), 1052 (m),1029 (m), 945
in a rotary evaporator. The residue was purified by flash column
chromatography (SiO2, pentane/Et2O).
(w), 916 (w), 851 (w), 821 (w), 765 (m), 744 (vs), 703 (vs), 620 (w),
1
565 (w), 465 (w) cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 0.90 (t,
J
ϭ 7.1 Hz, 3 H, CH2CH2CH3), 1.17Ϫ1.55 (m, 6 H,
(2S,1R)-(؉)-1-(1-Benzylsulfanyl-2-methylpropyl)pentylamine [(S,R)-
8a]: This compound was prepared as described in GP 7; NN bond
cleavage of hydrazine (S,R,S)-7a (70 mg, 0.18 mmol) with
BH3·THF (2.2 mL, 12.0 equiv.) afforded amine (S,R)-8a as a
colourless oil after flash column chromatography (SiO2, pentane/
Et2O, 1:1). Yield: 0.04 g (80%); de, ee Ն 96%. Rf ϭ 0.11 (pentane/
Et2O, 1:1). Rt ϭ 10.34 min (CP-Sil-8, 120Ϫ10Ϫ300). [α]2D5 ϭ ϩ12.3
(c ϭ 0.6, CHCl3). IR (film): ν˜ ϭ 3375 (w), 3083 (w), 3061 (m),
3027 (m), 2956 (vs), 2927 (vs), 2868 (s), 1602 (w), 1494 (m), 1456
(s), 1381 (m), 1364 (m), 1323 (w), 1237 (w), 1070 (w), 1028 (w), 827
CH2CH2CH2CH3), 2.25 (s, 3 H, CH3), 2.76 (m, 1 H, SCH),
2.82Ϫ2.96 (m, 2 H, ArCH2, H2NCH), 3.27 (d, J ϭ 13.5 Hz, 1 H,
SCHHPh), 3.45 (d, J ϭ 13.5 Hz, 1 H, SCHHPh), 7.05Ϫ7.26 (m, 9
H, CHarom.
) δ ϭ 14.1
ppm. 13C NMR (100 MHz, CDCl3):
(CH2CH3), 19.6 (CH3), 22.7 (CH2CH3), 29.0 (C-CH2CH2CH3),
33.2 (CH2CH2CH2CH3), 35.1 (ArCH2), 36.5 (SCH2), 53.3 (SCH),
54.2 (H2NCH), 125.5, 126.2, 126.7, 128.1, 128.7, 130.1, 130.2 (Ar-
C), 136.1, 137.6, 138.1 (Ar-Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ
245 (5), 236 (5) [Mϩ Ϫ C7H7], 127 (5), 126 (23), 105 (12), 91 (25)
[C7H7], 86 (100) [H2NCH(CH2)3CH3], 70 (5). HRMS: calcd.
327.2021; found 327.2019.
1
(m), 767 (w), 700 (s), 564 (w), 474 (w) cmϪ1. H NMR (400 MHz,
CDCl3): δ ϭ 0.89 (t, J ϭ 7.1 Hz, 3 H, CH2CH2CH3), 0.92 [d, J ϭ
6.6 Hz, 3 H, CH(CH3)2], 1.03 [d, J ϭ 6.6 Hz, 3 H, CH(CH3)2],
1.09Ϫ1.40 (m, 6 H, CH2CH2CH2CH3), 1.95 [m, 1 H, CH(CH3)2],
2.23 (dd, J ϭ 5.2, 6.9 Hz, 1 H, SCH), 2.84 (m, 1 H, H2NCH), 3.70
(d, J ϭ 12.9 Hz, 1 H, SCHHPh), 3.76 (d, J ϭ 12.9 Hz, 1 H,
Methyl (2S,1R)-(؉)-{1-[1-Benzylsulfanyl-2-(naphthalen-2-yl)ethyl]-
pentyl}carbamate [(S,R)-8d]: This compound was prepared as de-
scribed in GP 7; NN bond cleavage of hydrazine (S,R,S)-7d (0.47 g,
1.0 mmol) with BH3·THF (12.0 mL, 12.0 equiv.) afforded the crude
amine, which was directly converted into the carbamic acid methyl
ester (S,R)-8d by treatment with K2CO3 (0.69 g, 5.0 mmol) and
MocCl (0.38 mL, 5.0 mmol). The product was obtained as a
colourless oil after flash column chromatography (SiO2, pentane/
Et2O, 9:1). Yield: 0.23 g (55% over 2 steps); de, ee Ն 96%. Rf ϭ
0.34 (pentane/Et2O, 3:1) Rt ϭ 13.49 min (CP-Sil-8, 180Ϫ10Ϫ300).
[α]2D5 ϭ ϩ135.4 (c ϭ 0.7, CHCl3). IR (CHCl3): ν˜ ϭ 3406 (m), 3336
(m), 3056 (m), 3025 (m), 2954 (s), 2858 (m), 1721 (vs), 1632 (w),
1601 (m), 1508 (vs), 1454 (s), 1354 (m), 1292 (w), 1239 (s), 1193
(m), 1117 (m), 1075 (m), 1016 (m), 939 (w), 916 (w), 890 (w), 855
SCHHPh), 7.20Ϫ7.31 (m,
5 H, CHarom.)
ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 14.1 (CH2CH3), 20.3, 21.4 (CH3), 22.8
(CH2CH3), 28.9 (CH2CH2CH3), 30.5 [CH(CH3)2], 33.0
(CH2CH2CH2CH3), 38.7 (SCH2), 53.0 (H2NCH), 61.7 (SCH),
126.8, 128.3, 129.0 (Ar-C), 138.7 (Ar-Cq) ppm. MS (EI, 70 eV): m/
z (%) ϭ 265 (2) [Mϩ], 208 (1) [Mϩ Ϫ C4H9], 180 (2), 112 (2), 91
(15) [C7H7], 86 (100) [H2NCH(CH2)3CH3], 85 (3), 69 (3), 65 (2),
56 (2), 55 (2). HRMS: calcd. 265.1864; found 265.1865.
(2S,1R)-(؊)-(2-Benzylsulfanyl-1-butyl-4-methylpentyl)amine [(S,R)-
8b]: This compound was prepared as described in GP 7; NN bond
cleavage of hydrazine (S,R,S)-7b (0.43 g, 1.09 mmol) with
BH3·THF (13.0 mL, 12.0 equiv.) afforded amine (S,R)-8b as a
colourless oil after flash column chromatography (SiO2, pentane/
Et2O, 1:4). Yield: 0.12 g (39%); de, ee Ն 96%. Rf ϭ 0.10 (pentane/
Et2O, 1:4). Rt ϭ 8.81 min (CP-Sil-8, 140Ϫ10Ϫ300). [α]2D5 ϭ Ϫ86.9
(c ϭ 0.9, CHCl3). IR (film): ν˜ ϭ 3372 (w), 3084 (w), 3062 (m),
3028 (m), 2955 (vs), 2928 (vs), 2867 (vs), 1729 (w), 1602 (m), 1494
(m), 1455 (s), 1382 (m), 1368 (m), 1267 (w), 1238 (w), 1168 (w),
1125 (w), 1071 (m), 1030 (w), 915 (w), 838 (m), 815 (m), 767 (m),
(m), 818 (m), 754 (s), 703 (s), 563 (w), 477 (m) cmϪ1 1H NMR
.
(400 MHz, CDCl3): δ ϭ 0.88 (t, J ϭ 6.6 Hz, 3 H, CH2CH2CH3),
1.18Ϫ1.60 (m, 6 H, CH2CH2CH2CH3), 2.90Ϫ3.00 (m, 3 H,
ArCH2, SCH), 3.08 (m, 1 H, SCHHPh), 3.34 (d, J ϭ 13.2 Hz, 1
H, SCHHPh), 3.57 (s, 3 H, OCH3), 3.80 (m, 1 H, CHN), 4.84 (d,
J ϭ 9.6 Hz, 1 H, NH), 7.00Ϫ7.80 (m, 12 H, CHarom.) ppm. 13C
NMR (100 MHz, CDCl3): δ ϭ 14.3 (CH3), 22.8 (CH2CH3), 28.6
(CH2CH2CH3), 30.1 (CH2CH2CH2CH3), 37.4 (SCH2), 41.2
(ArCH2), 52.3 (OCH3), 53.3 (SCH), 54.3 (H2NCH), 125.8, 126.3,
127.2, 127.9, 128.0, 128.3, 128.7, 128.9, 129.2 (Ar-C), 132.6, 133.8,
136.8, 138.3 (Ar-Cq), 156.9 (CϭO) ppm. MS (EI, 70 eV): m/z (%) ϭ
421 (1) [Mϩ], 298 (15), 297 (75), 280 (6), 278 (13), 255 (10), 240
(20), 186 (5), 185 (10), 165 (5), 145 (8), 144 (100), 141 (23), 91 (28)
[C7H7], 88 (17). HRMS: calcd. 421.2076; found 421.2075.
702 (s), 622 (w), 566 (w), 472 (w) cmϪ1 1H NMR (400 MHz,
.
CDCl3): δ ϭ 0.68 [d, J ϭ 6.6 Hz, 3 H, CH(CH3)2], 0.86 [d, J ϭ
6.6 Hz, 3 H, CH(CH3)2], 0.89 (t, J ϭ 7.1 Hz, 3 H, CH2CH2CH3),
1.18Ϫ1.40 [m, 8 H, (CH3)2CHCH2, CH2CH2CH2CH3], 1.75 [m, 1
H, CH(CH3)2], 2.56 (dt, J ϭ 2.8, 10.2 Hz, 1 H, SCH), 2.86 (dt, J ϭ
2.8, 6.3 Hz, 1 H, H2NCH), 3.68 (d, J ϭ 13.5 Hz, 1 H, SCHHPh),
Methyl (2S,1R)-(؉)-[1-(1-Benzylsulfanyl-2-phenylethyl)pentyl]car-
bamate [(S,R)-8e]: This compound was prepared as described in GP
7; NN bond cleavage of hydrazine (S,R,S)-7e (2.13 g, 5.0 mmol)
with 60.0 mL (12.0 equiv.) BH3·THF afforded the crude amine,
which was directly converted into the carbamic acid methyl ester
(S,R)-8e by treatment with K2CO3 (3.46 g, 25.0 mmol) and MocCl
(1.93 mL, 25.0 mmol). The product was obtained as a colourless
solid after flash column chromatography (SiO2, pentane/Et2O, 6:1);
m.p. 47.5 °C. Yield: 1.71 g (92% over 2 steps); de, ee Ն 96%. Rf ϭ
3.73 (d, J ϭ 13.5 Hz, 1 H, SCHHPh), 7.20Ϫ7.33 (m, 5 H, CHarom.
)
ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 14.1 (CH2CH3), 21.4, 23.5
(CH3), 22.7 (CH2CH3), 25.3 [CH(CH3)2], 29.0 (CH2CH2CH3), 33.5
(CH2CH2CH2CH3), 35.9 (SCH2), 38.1 [CH2CH(CH3)], 49.7
(SCH), 53.3 (H2NCH), 126.8, 128.2, 128.8, 138.5 (Ar-C) ppm. MS
(EI, 70 eV): m/z (%) ϭ 128 (4), 114 (3), 91 (14, C7H7), 87 (6), 86
(100), 85 (3), 69 (4), 65 (2), 57 (2), 56 (4), 55 (2). C17H29NS (279.48):
calcd. C ϭ 73.06, H 10.46, N 5.01; found C 72.60, H 10.37, N 5.36.
(2S,1R)-(؉)-{1-[1-Benzylsulfanyl-2-(o-tolyl)ethyl]pentyl}amine 0.13 (pentane/Et2O, 9:1). [α]2D5 ϭ ϩ108.9 (c ϭ 1.0, CHCl3) IR
[(S,R)-8c]: This compound was prepared as described in GP 7; NN
bond cleavage of hydrazine (S,R,S)-7c (0.12 g, 0.27 mmol) with
BH3·THF (3.3 mL, 12.0 equiv.) afforded amine (S,R)-8c as a
(CHCl3): ν˜ ϭ 3405 (m), 3336 (m), 3084 (w), 3061 (m), 3027 (m),
2954 (vs), 2859 (m), 1723 (vs), 1602 (w), 1507 (vs), 1454 (s), 1352
(m), 1291 (m), 1241 (s), 1194 (m), 1156 (w), 1115 (w), 1074 (m),
colourless oil after flash column chromatography (SiO2, pentane/ 1031 (m), 938 (w), 916 (w), 756 (m), 701 (vs), 506 (w), 470 (w)
1
Et2O, 1:4). Yield: 0.07 g (81%); de, ee Ն 96%. Rf ϭ 0.10 (pentane/
Et2O, 1:4). Rt ϭ 13.48 min (CP-Sil-8, 140Ϫ10Ϫ300). [α]2D5 ϭ ϩ43.2
(c ϭ 0.7, CHCl3). IR (film): ν˜ ϭ 3369 (w), 3061 (m), 3025 (m),
cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 0.87 (t, J ϭ 6.9 Hz, 3 H,
CH2CH2CH3), 1.18Ϫ1.60 (m, 6 H, CH2CH2CH2CH3), 2.75Ϫ2.98
(m, 3 H, ArCH2, SCH), 3.10 (d, J ϭ 13.2 Hz, 1 H, SCHHPh), 3.38
Eur. J. Org. Chem. 2003, 3923Ϫ3938
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3935

D. Enders, A. Moll, A. Schaadt, G. Raabe, J. Runsink
FULL PAPER
(d, J ϭ 12.9 Hz, 1 H, SCHHPh), 3.56 (s, 3 H, OCH3), 3.74 (m, 1
(CHNH), 126.6, 126.9, 128.4, 128.7, 128.9, 129.4 (Ar-C), 138.1,
H, CHN), 4.83 (d, J ϭ 9.6 Hz, 1 H, NH), 7.04Ϫ7.33 (m, 10 H, 139.0 (Ar-Cq), 156.5 (CϭO) ppm. MS (EI, 70 eV): m/z (%) ϭ 324
CHarom.) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 14.0 (CH3), 22.5
(10), 308 (8), 276 (7), 275 (30), 233 (9), 228 (11), 226 (5), 173 (12),
(CH2CH3), 28.3 (CH2CH2CH3), 29.7 (CH2CH2CH2CH3), 36.9 172 (100), 135 (8), 92 (5), 91 (58), 88 (34), 76 (5), 59 (7), 55 (12),
(SCH2), 40.8 (ArCH2), 51.9 (OCH3), 53.1 (SCH), 53.7 (CHNH), 45 (7). C24H33NO2S (399.60): calcd. C 72.14, H 8.32, N 3.51; found
126.6, 126.9, 128.4, 128.9, 129.0 129.4 (Ar-C), 138.1, 139.0 (Ar-Cq),
156.5 (CϭO) ppm. MS (EI, 70 eV): m/z (%) ϭ 371 (1) [Mϩ], 296
(10), 280 (7), 248 (5), 247 (27), 228 (11), 205 (8), 145 (8), 144 (100),
143 (5), 91 (10), 88 (17). C22H29NO2S (371.55): calcd. C 71.12, H
7.87, N 3.77; found C 70.71, H 7.86, N 4.14. After column flash
chromatography the compound was recrystallised from n-heptane
in order to provide crystals for X-ray structure analysis.
C 72.15, H 8.34, N 3.99.
Methyl (2S,1R)-(؉)-(2-Benzylsulfanyl-1-methyl-3-phenylpropyl)car-
bamate [(S,R)-8h]: This compound was prepared as described in
GP 7; NN bond cleavage of hydrazine (S,R,S)-7h (0.48 g,
1.2 mmol) with BH3·THF (15.0 mL, 12.0 equiv.) afforded the crude
amine, which was directly converted into the carbamic acid methyl
ester (S,R)-8h by treatment with K2CO3 (0.86 g, 6.2 mmol) and
MocCl (0.48 mL, 6.2 mmol). The product was obtained as a
Methyl (2S,1R)-(؉)-[1-(1-Benzylsulfanyl-3-phenylpropyl)pentyl]car-
bamate [(S,R)-8f]: This compound was prepared as described in GP colourless oil after flash column chromatography (SiO2, pentane/
7; NN bond cleavage of hydrazine (S,R,S)-7f (0.47 g, 1.1 mmol) Et2O, 6:1). Yield: 0.29 g (71% over 2 steps); de, ee Ն 96%. Rf ϭ
with BH3·THF (14.0 mL, 12.0 equiv.) afforded the crude amine,
which was directly converted into the carbamic acid methyl ester (CHCl3): ν˜ ϭ 3408 (m), 3336 (m), 3083 (m), 3061 (m), 3026 (m),
0.12 (pentane/Et2O, 6:1). [α]2D5 ϭ ϩ113.4 (c ϭ 1.1, CHCl3). IR
(S,R)-8f by treatment with K2CO3 (0.74 g, 5.4 mmol) and MocCl
(0.41 mL, 5.4 mmol). The product was obtained after flash column
chromatography (SiO2, pentane/Et2O, 9:1) as a colourless solid;
m.p. 48.5 °C. Yield: 0.28 g (68% over 2 steps); de, ee Ն 96%. Rf ϭ
0.18 (pentane/Et2O, 9:1). [α]2D5 ϭ ϩ22.9 (c ϭ 1.0, CHCl3). IR (KBr):
ν˜ ϭ 3363 (s), 3085 (w), 3059 (m), 3029 (m), 2940 (s), 2855 (m),
2973 (m), 2948 (m), 2845 (s), 1804 (w), 1720 (vs), 1602 (m), 1505
(vs), 1453 (vs), 1380 (m), 1351 (m), 1240 (s), 1194 (m), 1115 (m),
1070 (s), 1031 (m), 966 (w), 936 (w), 843 (w), 804 (w), 757 (vs), 702
(vs), 668 (w) 505 (w) cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 1.11
(d, J ϭ 6.6 Hz, 3 H, CH3), 2.78 (m, 1 H, CHHPh), 2.89 (m, 2 H,
CHHPh, SCH), 3.16 (d, J ϭ 13.2 Hz, 1 H, SCHHPh), 3.41 (d, J ϭ
1699 (vs), 1602 (w), 1525 (vs), 1496 (m), 1454 (m), 1351 (m), 1287 13.2 Hz, 1 H, SCHHPh), 3.56 (s, 3 H, OCH3), 3.87 (m, 1 H,
(m), 1243 (s), 1187 (m), 1120 (m), 1088 (m), 1074 (m), 1004 (m), CHNH), 4.97 (d, J ϭ 8.5 Hz, 1 H, NH), 7.06Ϫ7.33 (m, 10 H,
923 (w), 779 (w), 766 (w), 740 (m), 699 (s), 639 (w), 565 (w), 494
CHarom.) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 15.8 (CH3), 36.8
1
(w) cm؊1. H NMR (400 MHz, CDCl3): δ ϭ 0.85 (t, J ϭ 6.9 Hz, (SCH2), 41.0 (ArCH2), 48.9 (CHNH), 51.8 (OCH3), 52.9 (SCH),
3
H, CH2CH2CH3), 1.15Ϫ1.92 (m, H, CH2CH2CH2CH3, 126.4, 126.8, 128.25, 128.28, 128.7, 129.1 (Ar-C), 137.9, 138.7 (Ar-
8
PhCH2), 2.52 (m, 1 H, PhCH2CHH), 2.65 (m, 1 H, SCH), 2.80 (m, Cq), 155.7 (CϭO) ppm, MS (EI, 70 eV): m/z (%) ϭ 254 (7), 228
1 H, PhCH2CHH), 3.63 (s, 3 H, OCH3), 3.66 (d, J ϭ 12.91 Hz, 1 (5), 227 (6), 205 (22), 193 (10), 163 (8), 149 (12), 135 (11), 130 (6),
H, SCHHPh), 3.74 (d, J ϭ 13.5 Hz, 1 H, SCHHPh), 3.81 (m, 1 H,
104 (5), 103 (5), 102 (59), 92 (9), 91 (100) [C7H7], 70 (5), 65 (12),
CHNH), 4.77 (d, J ϭ 9.89 Hz, 1 H, NH), 7.10Ϫ7.32 (m, 10 H, 59 (7), 58 (11), 57 (9), 56 (5), 55 (6), 45 (17). HRMS: calcd.
CHarom.) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 14.0 (CH3), 22.5 297.1187 (Mϩ Ϫ CH4O); found 297.1187.
(CH2CH3), 28.3 (CH2CH2CH3), 30.1, 33.5, 35.1 (ArCH2CH2,
X-ray Crystallographic Study: X-ray Crystallographic Study of
(S,R)-8e. Suitable crystals were obtained by crystallisation from n-
heptane. The compound (C22H29NO2S; Mr ϭ 371.55) crystallises
in orthorhombic space group P21212 (no.18) with cell dimensions
CH2CH2CH2CH3), 37.1 (SCH2), 50.8 (SCH), 52.0 (OCH3), 53.7
(CHNH), 126.0, 127.1, 128.4, 128.5, 128.6, 129.0 (Ar-C), 138.5,
141.6 (Ar-Cq), 156.7 (CϭO). ppm. MS (EI, 70 eV): m/z (%) ϭ 385
(6) [Mϩ], 310 (11), 294 (10), 243 (5), 242 (29), 145 (8), 144 (100),
117 (16), 91 (26) [C7H7], 88 (16). C23H31NO2S (385.57): calcd. C
71.65, H 8.10, N 3.63; found C 71.49, H 8.34, N 3.51.
˚
a ϭ 17.715(3), b ϭ 21.850(1), and c ϭ 5.3278(4) A. With Z ϭ 4
3
˚
the cell volume V ϭ 2062.2(4) A results in a calculated density of
d
calcd. ϭ 1.197 g·cmϪ3. 4797 reflections were collected at T ϭ 150 K
Methyl (2S,1R)-(؉)-[1-(1-Benzylsulfanyl-2-phenylethyl)heptyl]car-
on an ENRAF-NONIUS CAD4 diffractometer by use of graphite-
˚
bamate [(S,R)-8g]: This compound was prepared as described in monochromated Cu-Kα-radiation (λ ϭ 1.54179 A) in the ω)/2Θ
GP 7; NN bond cleavage of hydrazine (S,R,S)-7g (0.72 g, mode. Data collection covered the range Ϫ6 Յ h Յ 6, Ϫ21 Յ k Յ
1.6 mmol) with BH3·THF (19.0 mL, 12.0 equiv.) afforded the crude 21, and Ϫ25 Յ l Յ 27 up to Θmax ϭ 72.7°. Lorentz and polarisation
amine, which was directly converted into the carbamic acid methyl
ester (S,R)-8g by treatment with K2CO3 (1.10 g, 8.0 mmol) and
MocCl (0.61 mL, 8.0 mmol). The product was obtained as a
colourless oil after flash column chromatography (SiO2, pentane/
correction were applied to the diffraction data but no absorption
correction (µ ϭ 1.503 mmϪ1) was made. The structure was solved
by direct methods as implemented in the Xtal3.7 suite of crystallo-
graphic routines[27] by employment of GENSIN to generate the
Et2O, 9:1). Yield: 0.36 g (57% over 2 steps); de, ee Ն 96%. Rf ϭ structure-invariant relationships and GENTAN for the general tan-
0.20 (pentane/Et2O, 9:1). [α]2D5 ϭ ϩ104.2 (c ϭ 1.6, CHCl3). IR gent phasing procedure. 4015 observed reflections [I Ͼ 2σ(I)] were
(CHCl3): ν˜ ϭ 3334 (m), 3083 (w), 3061 (m), 3027 (s), 2927 (vs), included in the final full-matrix, least-squares refinement on F in-
2856 (s), 1722 (vs), 1602 (m), 1507 (m), 1454 (vs), 1355 (m), 1240
volving 347 parameters and converging at R(Rw) ϭ 0.061(0.065,
(s), 1193 (m), 1118 (m), 1073 (m), 1031 (m), 937 (w), 916 (w), 756 w ϭ l/[20σ(F)Ϫ2]), a final shift/error Ͻ0.0002, S ϭ 1.075, and a
(m), 701 (vs), 505 (w), 470 (w) cm؊1. 1H NMR (300 MHz, CDCl3): residual electron density of Ϫ1.68/1.00 e·AϪ3. Xabsϭ Ϫ0.014(45)[28]
˚
δ ϭ 0.87 (t, J ϭ 6.4 Hz, 3 H, CH3), 1.17Ϫ1.62 [m, 10 H, for the structure shown in Figure 2. All hydrogen positions except
(CH2)5CH3], 2.75Ϫ2.98 (m, 3 H, CH2Ph, SCH), 3.10 (d, J ϭ H6 could be located in a difference Fourier map and were refined
13.1 Hz, 1 H, SCHHPh), 3.38 (d, J ϭ 13.1 Hz, 1 H, SCHHPh),
3.56 (s, 3 H, OCH3), 3.74 (m, 1 H, CHNH), 4.81 (d, J ϭ 9.7 Hz, graphic data for structure (S,R)-8e. These data can be obtained free
1 H, NH), 7.05Ϫ7.35 (m, 10 H, CHarom.) ppm. 13C NMR (75 MHz,
of charge at www.ccdc.cam.ac.uk./conts/retrieving.html [or from
isotropically. CCDC 207541 contains the supplementary crystallo-
CDCl3): δ ϭ 14.1 (CH3), 22.6 (CH2CH3), 26.1 [CH2(CH2)3CH3], the Cambridge Crystallographic Data Centre, 12, Union Road,
29.1 [CH2(CH2)2CH3], 30.0 (CH2CH2CH3), 31.7 [CH2(CH2)4CH3], Cambridge CB2 1 EZ, UK; fax: (internat.) ϩ44Ϫ1223/336-033;
37.0 (SCH2), 40.8 (ArCH2), 51.9 (OCH3), 53.1 (SCH), 53.7
E-mail: deposit@ccdc.cam.ac.uk].
3936
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3923Ϫ3938

A Flexible Asymmetric Synthesis of anti-1,2-Sulfanyl Amines
FULL PAPER
G. I. Petra, P. C. J. Kamer, A. L. Spek, H. E. Schoemaker, P.
[7]
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www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3937

D. Enders, A. Moll, A. Schaadt, G. Raabe, J. Runsink
FULL PAPER
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Received April 23, 2003
3938
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3923Ϫ3938