Highly diastereoselective lithiation and substitution of an (S)-prolinyl thiocarbamate via sterically homogeneous lithio(thiocarbamate): Synthesis of enantiomerically pure prolinethiols

Article abstract of DOI:10.1002/chem.200601853

Highly diastereoselective lithiation-substitution reactions of an (S)-proline derived S-alkyl thiocarbamate was accomplished. The configuration of the predominant alkyllithium species and the stereochemical course of the electrophilic substitution reactions are deduced by a combination of X-ray crystal structure analysis, NMR spectroscopic studies, deuteration/dedeuteration experiments, and quantum chemical calculations. The lithium intermediate (S,S)-9 was found to be kinetically and thermodynamically favoured, whereas (S,R)-9 rapidly epimerizes.

Full text of DOI:10.1002/chem.200601853

FULL PAPER
DOI: 10.1002/chem.200601853
Highly Diastereoselective Lithiation and Substitution of an (S)-Prolinyl
Thiocarbamate via Sterically Homogeneous Lithio(thiocarbamate):
Synthesis of Enantiomerically Pure Prolinethiols
Ravindra P. Sonawane, Christian Mück-Lichtenfeld, Roland Frçhlich,
Klaus Bergander, and Dieter Hoppe*[a]
Dedicated to Professor Hans J. Schäfer on the occasion of his 70th birthday
Abstract: Highly diastereoselective lithiation–substitution reactions of an (S)-pro-
line derived S-alkyl thiocarbamate was accomplished. The configuration of the
predominant alkyllithium species and the stereochemical course of the electrophil-
ic substitution reactions are deduced by a combination of X-ray crystal structure
analysis, NMR spectroscopic studies, deuteration/dedeuteration experiments, and
quantum chemical calculations. The lithium intermediate (S,S)-9 was found to be
kinetically and thermodynamically favoured, whereas (S,R)-9 rapidly epimerizes.
Keywords:
chiral auxiliaries
analysis · lithium
carbamates
·
·
configuration
Introduction
quisite for the successful employment of asymmetric depro-
tonation is the necessity of configurational stability of inter-
mediate lithium species under the reaction conditions. Al-
though many of the a-oxy and a-amino organolithium com-
pounds exhibit necessary levels of configurational stability,
their sulfur counterparts are known for their high configura-
tional instability and rapid epimerization even at low tem-
peratures.[3,4] In this situation, one has to rely on the post de-
protonation enantioenrichment (either thermodynamic reso-
lution or dynamic kinetic resolution) to obtain good selec-
tivity.[5] Evidences for a very different mechanism of racemi-
zation for a-thio substituted organolithium compounds were
put forth by the work of R. W. Hoffmann et al.[4] and H. J.
Reich et al.[6] who suggest that the bulky substituents and
branching at the carbanionic center renders some stability
to the organolithium species.
Asymmetric induction on prochiral methylene groups
through deprotonation followed by electrophilic substitution
À
is one of the basic asymmetric C C bond forming reac-
tions.[1] In this process, the chiral induction can occur either
in the deprotonation or in the post deprotonation step.[2]
Synthetic utility of these processes have been limited to the
a-heteroatom substituted organolithium compounds wherein
excellent enantio- and diastereoselectivities have been ach-
ieved. Especially, a-oxy[1a,b,d] and a-amino[1c] organolithium
compounds have proven highly valuable in synthetic organic
chemistry. The generation of these a-heteroatom substituted
organolithium compounds can often be controlled in a
manner that the chiral induction is achieved via an asym-
metric deprotonation pathway. The most important prere-
Indeed, tertiary thiobenzylic[7] and tertiary thioallylic[8]
lithiated carbanions investigated by our group showed re-
markably high configurational stability. However, there is
no report until date of an unbranched, configurationally
stable, highly enantioenriched alkylthio lithium compound[9]
(Scheme 1).
[a] Dr. R. P. Sonawane, Dr. C. Mück-Lichtenfeld,+ Dr. R. Frçhlich,#
Dr. K. Bergander,$ Prof. Dr. D. Hoppe
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstrasse 40, 48149 Münster (Germany)
Fax : (+49)251-833-9772
It is important to clarify the reaction pathways of un-
branched a-sulfenyl carbanions and develop highly enantio-
and diastereoselective reactions owing to the increasing im-
portance of a-chiral sulfides as chiral templates[10] or asym-
metric catalysts.[11] With this objective we synthesized and
investigated the deprotonation reactions of thiocarbamate 8
E-mail: dhoppe@uni-muenster.de
[+] Quantum chemical calculations
[#] X-ray crystal structure analysis
[$] NMR experiments
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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The above process was found to be generally applicable for
other silyl electrophiles as well as for alkylation, benzyla-
tion, allylation, and carbonyl additions (Scheme 4). Thus, de-
protonation of 8 under the above described conditions fol-
lowed by trapping the intermediate lithium species with var-
ious electrophiles (Scheme 4) afforded the corresponding
substitution products in excellent diastereoselectivity and in
good to excellent yields.
Thus, variously substituted benzylic halides and linear
chain alkyl halides react smoothly furnishing the benzylation
and alkylation products in good yields and with high diaste-
reoselectivity within 1–3 h at À788C. When the nature of
the electrophile is changed from primary alkyl halides to
open chain secondary or cyclic halides, the alkylation did
not occur. This can be attributed to the low reactivity of
these electrophiles with the lithium species due to steric rea-
sons.
Scheme 1. Configurationally stable a-thio-organolithium compounds.
derived from (S)-proline (Scheme 2).[12] Herein, we present
the detailed results of this investigation.
Results and Discussion
The synthesis of the starting material is depicted in
Scheme 2. N-Benzyl-(S)-prolinol (4)[13] was mesylated at
À788C followed by thioesterification with potassium thio-
acetate to obtain 6 in 77% yield[14] (Scheme 2). Reductive
cleavage of the thioester with lithium aluminium hydride
followed by carbamoylation with 2,2,4,4-tetramethyl-1,3-ox-
azolidinyl-3-carbonyl chloride (CbyCl) afforded the desired
thiocarbamate 8 in 76% yield.
An X-ray crystal structure (Figure 1) of silane 13 estab-
lished the configuration of the newly generated stereocenter
to be R. The absolute configuration of all silylated products
was assigned as R assuming that silylation by each electro-
phile takes the same stereochemical course as that of
TBDMSOTf.
Also, the absolute configura-
tions of alkylation and benzyla-
tion products were proven to
be S from the X-ray crystal
structure of (S)-20 and (S)-23
(Figures 2 and 3, respectively).
The absolute configurations
for the products obtained from
addition of lithiated 8 to benzo-
phenone, p-bromobenzaldehyde
Scheme 2. Preparation of starting material 8.
and pivaloyl chloride were as-
signed as R assuming the simi-
lar mode of the SE process as in
Thiocarbamate 8 was then subjected to extensive deproto-
the above proven cases.
nation reactions using different conditions. Thus, deprotona-
Thus, assuming a diastereomerically pure alkyllithium in-
termediate, silylation, alkylation, and benzylation occur
under similar stereochemical mode to furnish the substitu-
tion products. However, configurational stability and the
configuration of the lithium intermediate, at this point, were
less clear.
tion of
8
using 1.2 equivof
sBuLi and 1.2 equivof
N,N,N’,N’-tetramethylethylenediamine (TMEDA) at À788C
for 3 h proceeded smoothly in various solvents (Scheme 3).
Trapping the intermediate lithium species 9 with trime-
thylsilyl chloride afforded the corresponding silane 10 as a
single diastereomer in good to excellent yields (Scheme 3).
Thus, the high induction by the internal stereocenter is
evident from the high selectivities obtained for the silylation
product. As shown in Scheme 3, toluene is the best solvent.
Decarbamoylation of substituted thiocarbamates: There are
various methods reported by our group for the removal of
the carbamoyl moiety to generate the free hydroxy or thiol
group.[7b] Thus, treatment of the substituted thiocarbamate
with excess of DIBALH at 08C or room temperature under
argon atmosphere furnished free thiols in good yields
(Scheme 5, Table 1).
Configuration of alkyllithium compound 9 and stereochemi-
cal mode of electrophilic substitutions: Having explored this
highly diastereoselective reaction, it was important to under-
stand the stereochemical course of electrophilic substitution
as there are very few reports on the stereochemical behavior
Scheme 3. Deprotonation experiments of 8.
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Enantiomerically Pure Prolinethiols
FULL PAPER
with alkyllithium derivative
should clarify the stereochemi-
cal pathway. However, the al-
kyllithium species 9 was not
crystalline and hence indirect
methods had to be applied to
confirm its configuration. Fortu-
nately, a combination of NMR
and quantum chemical calcula-
tions provided the answer in
this case. It was observed that
the two diastereotopic protons
HR and HS of thiocarbamate 8
showed distinct chemical shifts
in 1H NMR spectrum at d=
3.03 and 3.53 ppm (Figure 4).
When
8 was deprotonated
followed by deuteration, the
downfield signal at 3.53 ppm
disappeared. As deuteration
occurs with stereoretention in
all known cases, assigning the
chemical shifts to pro-R and
pro-S protons would provide
the configuration of the alkyl-
lithium compound. Indeed, the
quantum chemical calculations
of the chemical shifts, details of
which are provided in the fol-
lowing
part,
conclusively
proved that the pro-S proton
has a downfield chemical shift
(d=3.53 ppm) compared with
Scheme 4. Results of lithiation and electrophilic substitution of 8 with different electrophiles.
the
pro-R
proton
(d=
3.03 ppm). Hence, the pro-S
proton was removed and (S,S)-
[D]-8 was formed via intermediate 9 (Scheme 6). Further,
from the configurations of silylated, alkylated and benzylat-
ed products, it is evident that these reactions occur under
stereoretention.
We generally found retention in the substitution reactions
of non-mesomerically stabilized sp3-hybridized O-lithioalkyl
carbamates.[1a,b,e] Noteworthy, the overall stereochemical
course of lithiation is opposite to the reaction of the corre-
sponding prolinol-O-carbamate.[15] The reasons for this are
presently unknown.
Details of quantum chemical calculations: The four lowest
energy conformers that resulted from a conformational
search with the MMX force field[16] were taken as starting
structures for geometry optimizations with the Turbomole[17]
program package using density functional theory. The B-
LYP functional[18] and
a triple zeta valence basis set
Figure 1. X-ray crystal structure of (R)-13.
(TZVP[19]) were used, together with the RI approxima-
tion.[20] We included an empirical dispersion correction term
(DFT-D[21]) that accounts for nonbonding van der Waals in-
teractions at intermediate interatomic distances (3–4 Š).
of a-thiocarbanions.[5a,e,7,8] As the configurations of most of
the substitution products were established, the correlation
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D. Hoppe et al.
discussed here. After optimiza-
tion, chemical shifts were calcu-
lated[22] on the same theoretical
level with respect to tetrame-
thylsilane as reference.
Both conformers differ in the
position of the benzyl group
À
around the C N bond. A pro-
nounced effect of this rotation
on the chemical shift is found
for Ha. The chemical shifts of
the methylene group at the
asymmetric center are changed
to a smaller extent. The torsion-
al angles between the pro-S/
pro-R protons and atom Ha
3
(and thus the expected J cou-
pling constants) are not influ-
enced by the rotation of the
benzyl group. We therefore
conclude that the proton with
the larger coupling constant
and the lower chemical shift
(high field signal) must be pro-
R.
Figure 2. X-ray crystal structure of triflate salt (S)-20.[12]
Configurational stability of in-
termediate alkyllithium deriva-
tive 9: As mentioned in the In-
troduction, there are various
pathways by which the highly
diastereoselective stereoinduc-
tion can occur. To know the
exact pathway operating in this
case, an in situ deprotonation
experiment was performed on
thiocarbamate
8 wherein the
Figure 3. X-ray crystal structure of (S)-23.
electrophile TBDMSOTf or
TMSCl is present at the time of
deprotonation (Scheme 7).
Scheme 5. Decarbamoylation of substituted thiocarbamates.
Table 1. Synthesis of free thiol.
Entry
R
Yield [%]
Product
1
2
3
Et
Ph-CH2
TBDMS
74
70
65
31
32
33
The two conformers lowest in energy (A and B) are shown
in Figure 5. Other conformations (Table 2) were found to be
at least 1.5 kcalmolÀ1 higher in energy than B and are not
Figure 4. Distinct chemical shifts of diastereotopic protons of thiocarba-
mate 8 (600 MHz, C6D6).
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Enantiomerically Pure Prolinethiols
FULL PAPER
Thus, the same diastereomer (R)-13 is obtained from the
in situ experiment, that is, formed by the standard deproto-
nation–substitution method. Similar results were obtained
for in situ experiment with TMSCl. This fact indicates that
the lithium species formed by in situ deprotonation is the
same which survives after 3 h of deprotonation. However,
the possibility that the alkyllithium species epimerizes
before the reaction with electrophile could not be complete-
ly excluded.[3d] Thus, from this experiment, question arises:
why no evidence was found for the existence of the epimeric
lithium compound epi-9? Is it due to rapid equilibration or
configurational stability of 9? To answer this question, we
decided to generate epi-9 by deprotonation of deuterated
(S,S)-[D]-8 (Scheme 8). (S,S)-[D]-8 was prepared by deuter-
Scheme 6. Deuteration experiment.
1
2
ation of 9 by MeOD. H and D NMR spectra revealed that
it is not contaminated by epi-[D]-8. Due to the high H/D-
isotope effect in the deprotonation reaction, which was
found for alkyl carbamates[23] and alkyl thiocarbamates,[24]
that should override the kinetic preference for the pro-S hy-
drogen. After deprotonation of [D]-8 under the usual condi-
tions, the reaction mixture was quenched with methanol.
The product obtained in 99% yield was subjected to a care-
1
2
ful H and H NMR analyses. It consisted of the undeuterat-
ed starting material 8 (78%), [D]-8 (3%) and epi-[D]-8
(19%). Hence, the removal of D from the preferred position
proceeded approximately four times faster than the former
pro-R position, overriding the H/D-isotope effect. Most im-
portantly, lithium compound epi-[D]-9 formed in 19% yield,
isomerizes to the thermodynamically favored epimer [D]-9
before being trapped by protonation.
The above conclusion are supported by the NMR data as
follows: The GHSQC NMR spectrum of the mixture of 8,
[D]-8 and epi-[D]-8, as obtained above, clearly showed the
presence of a methylene (CH2) of 8 and a methyne group
(CH) of epi-[D]-8 correlating to the carbon signals at d 34.6
2
(singlet) and 34.3 ppm (triplet, due to H, 13C coupling) (cf.
Figure 5. DFT-D optimized conformers A and B of the thiocarbamate 8.
Supporting Information). In addition, it was clearly visible
that in [D]-8 and epi-[D]-8, the protons on the D-bearing
carbon atom show different chemical shifts for example, in
former; the proton in discussion was observed at d 3.03,
while in latter case at 3.53 ppm. This is possible only if the
intermediate lithium compound epi-[D]-9 had undergone
epimerization before adding the proton from the opposite
face.
We attempted to trap the unfavored lithium species epi-
[D]-9 (formed in 22% yield) by TMSCl. For this purpose,
[D]-8 was deprotonated in presence of 10 equivalents of
TMSCl and the product obtained was subjected to careful
NMR analysis. The analyses showed the presence of a single
diastereomer of silane, indicating that the barrier of inver-
sion for epi-[D]-9 is lower than
Table 2. Relative energies for conformers A and B, chemical shifts (vs
TMS) of hydrogen atoms HR/S and Ha, and dihedral angles of HR/S with
Ha.
A
B
Found
Erel (DFT-D) [kcalmolÀ1
scalcd (HS) [ppm]
]
+1.2
3.58
2.28
0.0
3.59
2.07
–
3.53
3.03
scalcd (HR) [ppm]
scalcd (Ha) [ppm]
2.68
3.03
2.85
scalcd (PhCH2) [ppm]
V (HS-C-C-Ha) [8]
V (HR-C-C-Ha) [8]
3.16, 4.71
69.1
À169.7
3.84, 4.38
68.5
À170.5
3.11, 4.12
–
–
the barrier for its reaction with
TMSCl (Scheme 9).
From these experiments, it
must be concluded: Lithium
compound
9 (which also is
Scheme 7. In situ deprotonation–silylation experiments with 8.
formed more rapidly from 8) is
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D. Hoppe et al.
Experimental Section
General remarks: All solvents were
dried and purified prior to use. Diethyl
ether and toluene were distilled over
sodium/benzophenone, THF over po-
tassium/benzophenone, and CH2Cl2
was distilled over CaH2. N,N,N’,N’-Tet-
ramethylethylenediamine (TMEDA).
TMSCl and NEt3 were distilled from
powdered CaH2 and stored under
argon. EA refers to ethyl acetate, CH:
cyclohexane, E: Et2O, P: pentane. All
reactions were performed under argon
atmosphere in flame-dried glassware
using septum and syringe techniques.
Flash column chromatography (FCC)
was performed on Merck 60 silica gel,
0.040–0.063 mm using an argon pres-
sure of 1.2–1.4 bar, and monitored by
thin-layer chromatography (TLC) on
Merck 60 F254 silica gel. Gas chroma-
tography was performed on Agilent
6890 plus, Agilent, Bçblingen. HP-5
was used as an achiral column (30 m
long, 0.32 mm diameter, 0.25 mm thick
Scheme 8. Dedeuteration/deprotonation–protonation of 8.
stationary phase, N2 as the mobile
phase, 106 kPa pressure, 2908C injec-
tion temperature, 3008C detector tem-
perature, program: 508C start temperature, 108CminÀ1 heating rate,
3008C final temperature for 15 min). Melting points were measured on
an SMP3 melting point apparatus purchased from Stuart Scientific, UK
(uncorrected values). The optical rotations were measured in a 10 cm
cuvette on a polarimeter 341 purchased from Perkin-Elmer. Unless oth-
erwise stated, H and 13C NMR data were recorded on Bruker ARX 300,
1
Scheme 9. In situ dedeuteration/deprotonation–silylation of [D]-9.
AM 360, AMX 400 or Varian Associated Unity Plus 600; spectra were
obtained from solutions in CDCl3 (dC =77.0 ppm) and were calibrated
relative to residual content of CHCl3 (dH =7.24 ppm) or SiMe4 (dH =
0.0 ppm). Elemental analyses were performed at the Microanalytical Sec-
tion of the Organisch-Chemisches Institut, WWU Münster, on a Vario El
III, purchased from Elementar Analysen Systeme, Hanau (Germany).
Mass spectrometric data were obtained on Finnigan MAT 8230 (EI); Mi-
cromass Quattro LCZ (ESI), Micromass MAT 8200 (GC-TOF/HRMS).
thermodynamically more stable than epi-9. Assuming the
ratio 10/epi-10 is in the magnitude 98:2 or higher (according
to the level of detection), DDGꢀ amounts to at least
1.5 kcalmolÀ1 estimated from the equation DG = ÀRTlnK.
Synthesis of starting material 8
(S)-S-[(1-Benzylpyrrolidin-2-yl)methyl] ethanethioate (6):[12] Anhydrous
triethylamine (3.90 g, 39.1 mmol, 1.5 equiv) was added to a solution of N-
benzyl prolinol[11] (5.0 g, 26.1 mmol, 1.0 equiv) in dichloromethane
(40 mL). This solution was stirred at room temperature for 10 min then
cooled to À788C and a solution of methanesulfonyl chloride (3.5 g,
30.7 mmol, 1.2 equiv) in anhydrous dichloromethane (10 mL) was added.
This mixture was stirred for 1 h. Afterwards, the solvent was removed
under vacuum to obtain a pale yellow semisolid. A solution of potassium
thioacetate (5 g, 43.8 mmol, 1.6 equiv) in water (50 mL) was added and
the resulting solution was stirred at room temperature for 2 h. After-
wards, the reaction mixture was poured into dichloromethane (100 mL),
the layers were separated and the aqueous layer was washed with di-
chloromethane (3”25 mL). The combined organic layer was dried with
anhydrous magnesium sulfate and evaporated under reduced pressure.
The residue was purified by column chromatography (EA/CH 1:6) to
Conclusion
In summary, a new class of unbranched, non-mesomerically
stabilized, lithiated a-thiocarbanions has been discovered.
Its (S,S)-diastereomer 9 is formed with high, kinetically and
thermodynamically controlled, substrate-induced diastereo-
selectivity. Alkyllithium species 9 formed after deprotona-
tion is persistent under the reaction conditions, due to its
high thermodynamic stability in comparison with epi-9. The
alkyllithium 9 undergoes substitution reactions with various
classes of electrophiles with retention of configuration to
furnish the products in good to excellent yields and high dia-
stereoselectivity. The pathway of diastereoselectivity and the
stereochemical course of electrophilic substitution reactions
were elucidated using a combination of X-ray crystal struc-
ture analysis, NMR studies, deuteration and dedeuteration
experiments, and quantum chemical calculations. Facile de-
carbamoylation of so obtained products gives access to a-
branched chiral amino thiols.
afford the desired thioester as an yellow oil (5.0 g, 20 mmol, 77%). Rf
=
0.60 (EA/CH 1:1); [a]2D0 =À111.0 (c=1.25, CHCl3); 1H NMR (400 MHz):
d = 1.42–1.80 (m, 3H, CH2-pyrro-3, CH2-pyrro-2a), 1.85 (m, 1H, CH2-pyrro-2b),
2.12 (ddd, 1H, CH2-pyrro-4a), 2.28 (s, 3H, CH3), 2.67 (m, 1H, CHpyrro-1), 2.92
(m, 2H, CH2-pyrro-4b, CH2-pyrro-5a), 3.29(dd, 3J=3.0 Hz, 2H), 4.05 (d, 2J=
13.3 Hz,1H, CH2-Ph), 7.24 ppm (m, 5H, Ph); 13C NMR (100 MHz):d =
22.3, 29.9, 30.5, 33.1, 54.23, 58.4, 62.5, 126.8, 128.5, 128.7, 139.7 (Ph),
195.8 ppm (C=O); elemental analysis calcd (%) for C14H19NOS (249.1):
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Enantiomerically Pure Prolinethiols
FULL PAPER
C 67.43, H 7.68, N 5.92; found C 67.52, H 7.72, N 6.04; MS (ESI): m/z:
250.1279 [M+H]+.
[(1R),1(2S)]-S-[(1-Benzylpyrrolidin-2-yl)-1-(methyldiphenylsilyl)methyl]
2,2,4,4-tetramethyl-oxazolidine-3-carbothioate (11): Colorless oil; yield:
65%; Rf = 0.62 (E/P 1:2); tR = 26.2 min (HP-5); [a]2D0 =À46.2 (c=0.58,
(S)-S-[(1-Benzylpyrrolidin-2-yl)methyl] 2,2,4,4-tetramethyl-oxazolidine-3-
carbothioate (8): A solution of thioester 6, obtained as above, (5.0 g,
20 mmol, 1.0 equiv) in Et2O (40 mL) was added in a dropwise manner at
08C to a well stirred suspension of LiAlH4 (1.1 g, 30 mmol, 1.5 equiv) in
Et2O (50 mL). The resulting solution was stirred at 08C for 30 min and at
room temperature for an additional hour. Afterwards, the reaction flask
was cooled to 08C and the reaction was quenched by careful addition of
water (10 mL). After filtration of the aluminum salts followed by evapo-
ration of solvent from filtrate, the crude thiol was obtained as a colorless
liquid. The thiol was used in the subsequent step without further purifica-
tion.
1
CH2Cl2); H NMR (400 MHz, CDCl3): d=1.15 (s, 3H, Si-CH3), 1.70–1.98
(m, 13H, 4”CH3-Cby, CHpyrro-4a), 2.15 (m, 1H, CHpyrro-4b), 2.40 (m, 1H,
CHpyrro-3a), 3.15 (m, 3H, CHpyrro-3b, CH2-pyrro-5), 3.22 (m, 1H, CHpyrro-2), 3.35
2
3
(d, J=13.8 Hz, 1H, CH2-Ph), 3.95 (s, 2H, Cby-CH2), 4.35 (d, J=4.6 Hz,
2
1H, Ph2MeSi-CH), 4.50 (d, J=13.8 Hz, 1H; CH2-Ph), 7.30–7.55 ppm (m,
15H, Ph); 13C NMR (100 MHz): d=À1.23 (Si-CH3), 23.1, 24.4, 25.6, 30.7,
32.3, 53.8, 59.4, 67.5, 76.7, 126.6, 127.8, 128.6, 129.0, 129.7, 133.9, 134.7,
135.0, 136.5, 137.1 (Ph), 164.0 ppm (C=O); IR (film): n˜ = 3064, 3030 (m,
C-Haro), 2962, 2942, 2865 (s, C-Hali), 1630 (s, C=O), 1490 (s), 1368 (s),
1333 (s), 1309 (s), 1247 (s), 1203 (s), 1081 (s), 920 (s), 824 (s), 791 cmÀ1
(s); elemental analysis calcd (%) for C33H42N2O2SSi (558.8): C 70.92, H
7.58, N 5.01; found: C 70.69, H 7.58, N 4.88; MS (ESI): m/z: 559.2859
[M+H]+, 581.2643 [M+Na]+.
A solution of crude thiol in anhydrous THF (20 mL) was added to a
stirred suspension of NaH (60% in mineral oil, 1.2 g, 30 mmol, 1.5 equiv)
in anhydrous THF (40 mL). The resulting solution was stirred at room
temperature for 15 min and then a solution of CbyCl (5.74 g, 30 mmol,
1.5 equiv) in anhydrous THF (25 mL) was added. This mixture was
stirred at room temperature for 24 h. Afterwards, the reaction flask was
cooled to 08C and water (10 mL) was slowly injected into the flask. The
layers were separated and the aqueous layer was extracted with Et2O
(3”25 mL). The collective organic phase along with washing was dried
over anhydrous MgSO4, filtered through glass wool, and concentrated
under reduced pressure to get the crude thiocarbamate which was sub-
jected to column chromatography (E/P 1:4) to furnish the desired thio-
carbamate 8 as a colorless, viscous oil (5.5 g, 15.2 mmol, 76% based on
[(1R),1(2S)]-S-[(1-Benzylpyrrolidin-2-yl)-1-(triisopropylsilyl)methyl]
2,2,4,4-tetramethyl-oxazolidine-3-carbothioate (12): Colorless oil; yield:
90%; Rf = 0.62 (E/P 1:1), tR = 23.7 min (HP-5); [a]2D0 =À66.1 (c=1.23,
CH2Cl2); 1H NMR (300 MHz, CDCl3): d=0.98–1.32 (m, 21H, Si(CH-
ACHTRE(UNG CH3)2)3), 1.50–1.80 (m, 15H, 4”CH3-Cby, CHpyrro-3a, CH2-pyrro-4), 1.87–
2.17 (m, 2H, CHpyrro-3b, CHpyrro-5a), 2.88 (m, 2H, CHpyrro-2, CH2-pyrro-5b), 3.33
(d, 2J=13.2 Hz, 1H, CH2-Ph), 3.55 (d, 3J=5.1 Hz, 1H, iPr3Si-CH), 3.68
(s, 2H, Cby-CH2), 4.20 (d, 2J=13.2 Hz, 1H, CH2-Ph), 7.00–7.45 ppm (m,
5H, Ph); 13C NMR (75 MHz): d=12.7 (Si(CH
ACHTREUNG
AHCTREUNG
0.58 (E/P 1:1); [a]D20 =À78.9 (c=1.1, CHCl3); 1H NMR
126.6, 128.2, 128.9, 140.7 (Ph), 164.3 (C=O); IR (film): n˜ = 3064, 3030
(m, C-Haro), 2962, 2942, 2865 (s, C-Hali), 1630 (s, C=O), 1490 (s), 1368 (s),
1333 (s), 1309 (s), 1247 (s), 1203 (s), 1081 (s), 920 (s), 824 (s), 791 cmÀ1
(s); elemental analysis calcd (%) for C29H50N2O2SSi (518.8): 67.13, H
9.71, N 5.40; found: C 67.02, H 10.08, N 4.99; MS (ESI): m/z: 519.3418
[M+H]+.
6). Rf
=
(500 MHz, C6D6): d=1.37 (s, 6H, 2”CH3-Cby), 1.47–1.86 (m, 10H, 2”
CH3-Cby, CH2-pyrro-3, CH2-pyrro-4), 1.95 (m, 1H, CHpyrro-5), 2.67 (m, 1H,
CHpyrro-5), 2.84 (tt, 3J=1.8, 3J=8.2 Hz, 1H, CHpyrro-2), 3.03 (dd, 3J=7.6,
2J=13.1 Hz 1H, S-CH2-pro-HR), 3.12 (d, 2J=13.4 Hz, 1H, CH2-Ph), 3.36
(s, 2H, Cby-CH2), 3.53 (dd, 3J=3.2, 2J=13.1 Hz, 1H, S-CH2-pro-HS),
7.05–7.23 ppm (m, 5H, Ph); 13C NMR (100 MHz): d=22.4, 24.7, 25.7,
30.0, 34.2, 54.0, 54.1, 58.8, 62.9, 77.2, 96.0; 126.6, 128.1, 128.7, 139.4 (Ph),
163.8 (C=O); elemental analysis calcd (%) for C20H30N2O2S (362.2): C
66.26, H 8.34, N 7.73; found C 66.11, H 8.37, N 7.62; MS (ESI): m/z:
363.2064 [M+H]+, 385.1870 [M+Na]+.
[(1R),1(2S)]-S-[(1-Benzylpyrrolidin-2-yl)-1-(tert-butyldimethylsilyl)meth-
yl] 2,2,4,4-tetramethyloxazolidine-3-carbothioate (13): Colorless solid;
yield: 65%; Rf = 0.62 (E/P 1:2); tR = 23.7 min (HP-5); [a]2D0 =À88.0 (c=
0.96, CH2Cl2); 1H NMR (300 MHz, CDCl3): d=0.00 (s, 3H, Si-CH3a),
0.12 (s, 3H, Si-CH3b), 0.08 (s, 9H, Si-CACHTER(UNG CH3)3), 1.40–1.60 (m, 15H, 4”
CH3-Cby, CHpyrro-3a, CH2-pyrro-4), 1.95 (m, 2H, CHpyrro-3b, CHpyrro-5a), 2.53
(m, 1H, , CH2-pyrro-5b), 2.75 (m, 1H, CHpyrro-2), 3.0 (d, 2J=13.2 Hz, 1H,
CH2-Ph), 3.45 (d, 3J=4.2 Hz, 1H, TBDMS-CH), 3.58 (s, 2H, Cby-CH2),
4.20 (d, 1H, 2J=13.2 Hz, 1H, CH2-Ph), 7.00–7.35 ppm (m, 5H, Ph);
13C NMR (75 MHz): d = À3.4 (Si-CH3a), À3.1 (Si-CH3b), 18.1 (Si-C-
General procedure for the deprotonation and electrophilic substitution:
Thiocarbamate 8 (100 mg, 0.27 mmol, 1.0 equiv) was dissolved in toluene
(5 mL). TMEDA (37 mg, 0.32 mmol, 1.2 equiv) was added and the reac-
tion flask was cooled to À788C. Afterwards, sBuLi (1.36m, 0.23 mL,
0.32 mmol, 1.2 equiv) was injected in a dropwise manner and the reaction
mixture was stirred at À788C for 3 h. Then appropriate electrophile
(0.81 mmol, 3.0 equiv) injected and the reaction mixture stirred for 1–
12 h until no more of the starting material could be detected by TLC.
The reaction was quenched with water (2 mL). The layers were separated
and the aqueous layer was extracted with Et2O (3”10 mL). The collec-
tive organic phase was dried over anhydrous MgSO4, filtered through
glass wool, and concentrated under reduced pressure to get the crude
product. The crude product was subjected to column chromatography
(Et2O/pentane or ethyl acetate/cyclohexane) to obtain the pure substitu-
tion product.
AHCTRE(UNG CH3)3), 22.6, 25.3, 26.2, 27.4, 30.6, 30.6, 54.0, 54.4, 59.6, 70.2, 77.2, 98.0,
126.7, 128.3, 129.0, 140.7 (Ph), 164.5 ppm (C=O); IR (film): n˜ = 3064,
3030 (m, C-Haro), 2952, 2935, 2796 (s, C-Hali), 1626 (s, C=O), 1457 (s),
1362 (s), 1332 (s), 1308 (s), 1244 (s), 1200 (s), 1153 (s), 916 (s), 837 (s),
828 cmÀ1 (s); elemental analysis calcd (%) for C26H44N2O2SSi (476.2): C
65.50, H 9.30, N 5.88; found: C 65.19, H 9.56, N 5.51; MS (ESI): m/z:
477.2933 [M+H]+, 499.2747 [M+Na]+.
[(1R),1(2S)]-S-[(1-Benzylpyrrolidin-2-yl)-1-(triphenylsilyl)methyl]
2,2,4,4-tetramethyl-oxazolidine-3-carbothioate (14): Colorless oil; yield:
41%; Rf = 0.87 (E/P 1:1); tR = 30.2 min (HP-5); [a]2D0 =À17.1 (c=1.1,
CHCl3); 1H NMR (300 MHz, CDCl3): d=1.10–1.90 (m, 15H, 4”CH3-
Cby, CHpyrro-3a, CH2-pyrro-4), 2.05 (m, 1H, CHpyrro-3b), 2.15 (m, 1H, CHpyrro-5a),
2.69 (m, 1H, CHpyrro-5b), 3.10 (d, 2J=13.2 Hz, 1H, CH2-Ph), 3.60 (s, 2H,
Cby-CH2), 3.85 (d, 2J=13.2 Hz, 1H, CH2-Ph), 4.25 (d, 3J=4.2 Hz, 1H,
Ph3Si-CH), 6.80–7.85 ppm (m, 20H, Ph); 13C NMR (75 MHz): d = 23.9,
24.9, 25.4, 32.1, 33.7, 53.8, 54.0, 60.1, 67.4, 77.2, 96.0, 126.6, 127.9, 128.0,
129.1, 129.6, 135.2, 136.8, 140.2 (Ph), 164.4 ppm (C=O); IR (film): n˜ =
3064, 3030 (m, C-Haro), 2962, 2942, 2865 (s, C-Hali), 1630 (s, C=O), 1490
(s), 1368 (s), 1333 (s), 1309 (s), 1247 (s), 1203 (s), 1081 (s), 920 (s), 824
(s), 791 cmÀ1 (s); HR MS (ESI): m/z: calcd for C38H44N2O2SSi: 621.2971;
found: 621.2973 [M+H]+.
[(1R),1(2S)]-S-[(1-Benzylpyrrolidin-2-yl)-1-(trimethylsilyl)methyl]
2,2,4,4-tetramethyl-oxazolidine-3-carbothioate (10): Colorless oil; yield:
83%; Rf = 0.55 (EA/CH 1:4); tR = 20.4 min (HP-5); [a]2D0 =À81.5 (c=
1.15, CHCl3); 1H NMR (400 MHz, CDCl3): d = 0.18 (s, 9H, Si
ACHTREUNG
1.60–1.80 (m, 15H, 4”CH3-Cby, CHpyrro-3a
,
CHpyrro-3b), 2.07 (m, 1H, CHpyrro-5a), 2.83 (m, 1H, CHpyrro-5b), 2.89 (m, 1H,
CHpyrro-2), 3.23 (d, 1H, 2JH,H =13.2 Hz, Ph-CH2), 3.35 (d, 3J=4.2 Hz, 1H,
2
CH-SiMe3), 3.75 (s, 2H, Cby-CH2), 4.30 (d, JH,H =13.2 Hz, 1H, Ph-CH2),
7.30–7.55 (m, 5H, Ph); 13C NMR (100 MHz): d = 0.01 (Si
ACHTRE(UNG CH3)3), 22.7,
24.7, 25.7, 30.2, 33.2, 54.0, 54.1, 58.8, 68.1, 77.2, 96.0, 126.6, 128.1, 128.7,
139.4, 164.3 ppm (C=O); IR (film): n˜ = 3064, 3030 (m, C-Haro), 2963,
2926, 2868 (s, C-Hali), 1630 (s, C=O), 1452 (s), 1368 (s), 1334 (s), 1310 (s),
1247 (s), 1202 (s), 1081 (s), 920 (s), 837 (s), 797 cmÀ1 (s); elemental analy-
sis calcd (%) for C23H38N2O2SSi (434.7): C 63.54, H 8.81, N 6.44; found:
C 63.43, H 8.88, N 6.22; MS (ESI): m/z: 434.2477 [M+H]+, 457.2335
[M+Na]+.
[(1S),1(2S)]-S-[(1-Benzylpyrrolidin-2-yl)ethyl] 2,2,4,4-tetramethyl-oxazo-
lidine-3-carbothioate (15): Colorless oil; yield: 83%; Rf = 0.45 (E/P 1:2);
3
1H NMR (300 MHz, CDCl3): d=1.25 (d, J=6.8 Hz, 3H, CH3), 1.29–1.80
(m, 16H, 4”CH3-Cby, CH2-pyrro-3, CH2-pyrro-4), 2.10 (m, 1H, CHpyrro-5a), 2.83
(m, 2H, CHpyrro-2, CHpyrro-5b), 3.23 (d, 2J=13.5 Hz, 1H, CH2Ph), 3.67 (s,
Chem. Eur. J. 2007, 13, 6419 – 6429
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6425

D. Hoppe et al.
2
2
3
2H, Cby-CH2), 3.90 (m, 1H, CH-SCby), 4.11 (d, 2J=13.5 Hz, 1H, CH2-
Ph), 7.10–7.45 ppm (m, 5H, Ph); 13C NMR (75 MHz): d=15.1, 23.7, 25.2,
26.1, 28.2, 41.8, 53.0, 54.7, 58.9, 67.0, 77.2, 94.0 (C-7), 124.4, 126.9, 128.7,
140.0 (Ph), 164.1 (C=O); elemental analysis calcd (%) for C21H32N2O2S
(376.2): C 66.98, H 8.57, N 7.44; found C 67.12 H 8.65, N 7.30; MS (ESI):
m/z: 377.2257 [M+H]+, 399.2046 [M+Na]+.
3.25 (d, J=13.5 Hz, 1H, CH2Ph), 3.45 (dd, J=14.5, J=2.9 Hz 1H, CH-
CH2aPh), 3.60 (s, 2H, Cby-CH2), 4.10 (dd, 2J=14.5, 3J=2.9 Hz, 1H, CH-
2
CH2bPh), 4.25 (d, J=13.5 Hz, 1H, CH2Ph), 7.07–7.41 ppm (m, 10H, Ph);
13C NMR (100 MHz): d=23.4, 24.8, 25.5, 29.5, 34.8, 49.0, 53.0, 54.4, 58.7,
66.9, 77.2, 94.0, 125.7, 126.5, 127.9, 128.0, 128.5, 129.1, 129.4, 139.9 (Ph),
163.0 ppm (C=O); elemental analysis calcd (%) for C27H36N2O2S (452.2):
C 71.64, H 8.02, N 6.19; found C 71.46, H 8.22, N 5.96; MS (ESI): m/z:
453.25 [M+H]+, 475.23 [M+Na]+.
[(1S),1(2S)]-S-[(1-Benzylpyrrolidin-2-yl)propyl] 2,2,4,4-tetramethyl-oxa-
1
zolidine-3-carbothioate (16): Colorless oil; Rf = 0.36 (E/P 1:2); H NMR
(300 MHz, CDCl3): d =1.27 (t, 3J=7.5 Hz 3H, CH3-CH2), 1.60–1.95 (m,
17H, 4”CH3-Cby, CH2CH3, CH2-pyrro-3a, CH2-pyrro-4), 2.10 (m, 1H, CH2-pyrro-3b),
2.41 (m, 1H, CH2-pyrro-5a), 3.14 (m, 2H, CH2-pyrro-5b, CHpyrro-2), 3.54 (d, 2J=
13.5 Hz, 1H, CH2Ph), 3.95 (m, 3H, Cby-CH2, CH-SCby), 4.45 (d, 2J=
13.5 Hz, 1H, CH2Ph), 7.30–7.55 ppm (m, 5H, Ph); 13C NMR (75 MHz):
d=12.7, 21.8, 23.8, 25.2, 26.2, 27.5, 50.0, 54.8, 59.1, 67.6, 77.2, 96.0; 126.9,
128.4, 129.0, 140.6 (Ph), 164.4 ppm (C=O); elemental analysis calcd (%)
for C22H34N2O2S (390.2): C 67.65, H 8.77, N 7.17; found C 67.70, H 8.82,
N 7.04; MS (ESI): m/z: 391 [M+H]+.
[(1S),1(2S)]-S-[(1-Benzylpyrrolidin-2-yl)-2-(naphthalen-1-yl)ethyl]
2,2,4,4-tetramethyloxazolidine-3-carbothioate (22): Colorless oil; yield:
55%; Rf = 0.50 (E/P 1:1); tR = 26.9 min (HP-5); [a]2D0 =+37.3 (c=1.12,
CH2Cl2); 1H NMR (300 MHz, CDCl3): d=1.25–1.70 (m, 12H, 4”CH3-
Cby), 1.55–1.90 (m, 4H, CH2-pyrro-3, CH2-pyrro-4), 2.18 (m, 1H, CH2-pyrro-5a),
2.71 (m, 1H, CH2-pyrro-5b), 2.96 (m, 1H, CHpyrro-2), 3.35 (d, 2J=13.5 Hz,
1H, CH2Ph), 3.50 (s, 2H, Cby-CH2), 3.60 (dd, 3J=2.9, 2J=14.5 Hz, 1H,
Nap-CH2a), 4.15 (dd, 3J=2.9, 2J=14.5 Hz, 1H, Nap-CH2b), 4.25 (d, 2J=
13.5 Hz, 1H, CH2Ph), 7.07–7.91 ppm (m, 12H, Ar); 13C NMR (75 MHz):
d=24.0, 24.9, 25.9, 27.8, 35.7, 49.5, 53.0, 55.0, 59.3, 67.5, 77.2, 94.0, 125.4,
126.0, 127.0, 127.8, 128.3, 128.6, 129.0, 132.5, 133.8, 138.0, 140.5 (Ar),
163.2 ppm (C=O); IR (film): n˜ = 3088, 3055 (s, C-Haro), 2979, 2866, 2790
(s, C-Hali), 1626 (s, C=O), 1599, 1514 (s), 1496 (s), 1454 (s), 1334 (s), 1309
(s), 1309 (s), 1264 (s), 1220 (s), 1058 (s), 917 (s), 826 (s), 784 cmÀ1 (s); ele-
mental analysis calcd (%) for C31H38N2O2S (502.2): C 74.06, H 7.62, N
5.57; found: C 74.04, H 7.88, N 5.25; MS (ESI): m/z: 503.2726 [M+H]+.
[(1S),1(2S)]-S-(1-Benzylpyrrolidin-2-yl)butyl] 2,2,4,4-tetramethyl-oxazoli-
dine-3-carbothioate (17): Colorless oil; yield: 90%; Rf = 0.38 (E/P 1:2);
tR
=
20.3 min (HP-5); [a]D20 =À77.4 (c=1.05, CHCl3); 1H NMR
(300 MHz, CDCl3): d
=
0.85 (t, 3J=7.0 Hz, 3H, CH3), 1.37–1.70 (m,
17H, 4”CH3-Cby, CH2CH2CH3, CH2-pyrro-4a), 1.81 (m, 2H, CH2-pyrro-3a
,
CH2-pyrro-4b), 2.01 (m, 2H, CH2-pyrro-3b, CH2-pyrro-5a), 2.84 (m, 2H, CH2-pyrro-5b
,
CHpyrro-2), 3.23 (d, 2J=13.5 Hz, 1H, CH2Ph), 3.65 (s, 2H, Cby-CH2), 3.75
2
(m, 1H, CH-SCby), 4.13 (d, J=13.5 Hz, 1H, CH2Ph), 7.05–7.36 ppm (m,
[(1S),1(2S)]-S-[(1-Benzylpyrrolidin-2-yl)-2-(anthracen-9-yl)ethyl] 2,2,4,4-
tetramethyl-oxazolidine-3-carbothioate (23): Yellow crystalline solid;
yield: 38%; Rf = 0.51 (E/P 1:1); m.p. 160.18C; tR = 31.6 min (HP-5);
[a]2D0 =+74.2 (c=1.01, CH2Cl2); 1H NMR (600 MHz, CDCl3): d=0.60–
1.25 (m, 12H, 4”CH3-Cby), 1.65–2.16 (m, 4H, CH2-pyrro-3, CH2-pyrro-4), 2.24
(m, 1H, CH2-pyrro-5a), 3.15(m, 2H, CH2-pyrro-5b, CHpyrro-2), 3.35 (s, 2H, Cby-
CH2), 3.48 (d, 2J=14.4 Hz, 1H, CH2-Ph), 3.75 (m, 1H, CH-SCby), 4.31
(dd, 3J=2.5 Hz, 2H, Anthra-CH2), 4.52 (d, 2J=14.4 Hz, 1H, CH2-Ph),
7.10–8.40 ppm (m, 14H, Ar); 13C NMR (150 MHz): d=24.2, 25.1, 25.3,
26.9, 48.7, 54.8, 55.0, 59.2, 64.2, 68.4, 76.9, 93.6, 124.2, 124.5, 124.8, 125.0,
125.2, 126.0, 126.5, 128.2, 128.3, 128.8, 130.6, 131.0, 131.3, 131.4, 132.1,
5H, Ph); 13C NMR (75 MHz): d = 14.5, 23.7, 25.2, 26.2, 27.3, 28.5, 30.4,
47.4, 53.0, 54.8, 59.0, 67.8, 77.2, 99.7, 126.9, 128.4, 129.0, 140.4 (Ph),
164.3 ppm (C=O); IR (film): n˜ = 3064, 3030 (m, C-Haro), 2968, 2919,
2863 (s, C-Hali), 1629 (s, C=O), 1454 (s), 1369 (s), 1335 (s), 1310 (s), 1268
(s), 1212 (s), 1082 (s), 918 (s), 837 (s), 791 cmÀ1 (s); elemental analysis
calcd (%) for C23H36N2O2S (404.5): C 68.27, H 8.97, N 6.92; found: C
68.30, H 9.15, N 7.09; MS (ESI): m/z: 405.5 [M+H]+.
[(1S),1(2S)]-S-[(1-Benzylpyrrolidin-2-yl)pentyl] 2,2,4,4-tetramethyloxazo-
lidine-3-carbothioate (18): Colorless oil; yield: 78%; Rf = 0.40 (E/P 1:2);
tR
=
20.8 min (HP-5); [a]D20 =À64.6 (c=1.05, CHCl3); 1H NMR
(400 MHz, CDCl3): d=0.81 (t, 3J=7.0 Hz, 3H, CH3), 1.15–1.70 (m, 20H,
4”CH3-Cby, CH2CH2CH2 CH2-pyrro-4), 1.80 (m, 1H, CH2-pyrro-3a), 2.10 (m,
2H, CH2-pyrro-3b, CH2-pyrro-5a), 2.82 (m, 2H, CH2-pyrro-5b, CH2-pyrro-2), 3.23 (d,
2J=13.5 Hz, 1H, CH2Ph), 3.62 (s, 2H, Cby-CH2), 3.79 (m, 1H, CH-
SCby), 4.15 (d, 2J=13.5 Hz, 1H, CH2Ph), 7.10–7.39 ppm (m, 5H, Ph);
13C NMR (100 MHz): d=14.0, 22.5, 23.1, 24.7, 25.7, 26.8, 27.5, 29.7, 47.2,
53.0, 54.3, 58.5, 67.2, 77.2, 96.7, 126.4, 127.8, 128.5, 140.1 (Ph), 163.8 ppm
(C=O); IR (film): n˜ = 3064, 3030 (m, C-Haro), 2968, 2919, 2863 (s, C-
Hali), 1629 (s, C=O), 1454 (s), 1369 (s), 1335 (s), 1310 (s), 1268 (s), 1212
(s), 1082 (s), 918 (s), 837 (s), 791 cmÀ1 (s); elemental analysis calcd (%)
for C24H38N2O2S (418.6): C 68.86, H 9.15, N 6.69; found: C 68.90, H 9.24,
N 6.54; MS (ESI): m/z: 419.2708 [M+H]+.
133.9 (Ar), 162.1 ppm (C=O); IR (KBr): n˜
= 3088, 3055 (s, C-Haro),
2979, 2866, 2790 (s, C-Hali), 1626 (s, C=O), 1599 (s), 1514 (s), 1496 (s),
1454 (s), 1334, 1309 (s), 1309 (s), 1264 (s), 1220 (s), 1058 (s), 917 (s), 826
(s), 784 cmÀ1 (s); elemental analysis calcd (%) for C35H40N2O2S (552.2): C
76.05, H 7.29, N 5.07; found C 75.83, H 7.19, N 4.70. MS (ESI): m/z:
553.2889 [M+H]+, 575.2704 [M+Na]+.
[(1S),1(2S)]-S-[(1-Benzylpyrrolidin-2-yl)-2-(3-bromo-5-fluorophenyl)eth-
yl] 2,2,4,4-tetramethyloxazolidine-3-carbothioate (24): Colorless oil;
yield: 80%; Rf = 0.55 (E/P 1:1); tR = 24.4 min (HP-5); [a]2D0 =+5.4 (c=
1.05, CH2Cl2); 1H NMR (300 MHz, CDCl3): d=1.47–1.89 (m, 14H, 4”
CH3-Cby, CH2-pyrro-4), 2.19 (m, 1H, CH2-pyrro-3a), 2.40 (m, 1H, CH2-pyrro-3b),
2.68 (m, 1H, CH2-pyrro-5a), 2.99 (m, 1H, CH2-pyrro-5b), 3.15 (m, 3H, CHpyrro-2
,
CbyS-CH-CH2a-Ph), 3.53 (d, 2J=13.3 Hz, 1H, CH2Ph), 3.60 (dd, 3J=3.6,
[(1S),1(2S)]-S-[(1-Benzylpyrrolidin-2-yl)but-3-enyl]
2,2,4,4-tetramethy-
0.54
2J=13.4 Hz, 1H, CbyS-CH-CH2b-Ph), 3.92 (s, 2H, Cby-CH2), 4.36 (d, J=
2
loxazolidine-3-carbothioate (19): Colorless oil; yield: 89%; Rf
=
13.4 Hz, 1H, CH2Ph), 7.29–7.60 ppm (m, 8H, Ph); 13C NMR (75 MHz):
d=24.7, 25.7, 27.0, 30.1, 34.2, 47.0, 54.0, 54.2, 58.6, 67.0, 77.2, 97.0, 126.6,
127.9, 128.0, 128.9, 129.1, 129.5, 131.1, 139.5, 139.7, 145.4 (Ar), 163.8 ppm
(C=O); 19F NMR (282.4 MHz): d=114.87 ppm; IR (film): n˜ =3029, 2964
(s, C-Haro), 2934, 2873, 2789 (s, C-Hali), 1625 (s, C=O), 1496 (s), 1454 (s),
1370 (s), 1336 (s), 1309 (s), 1260 (s), 1202 (s), 1058 (s), 917 (s), 826 (s),
784 cmÀ1 (s); elemental analysis calcd (%) for C27H34BrFN2O2S (550.1):
C 59.01, H 6.24, N 5.10; found: C 59.34, H 6.41, N 4.78. MS (ESI): m/z:
551.1575 [M+H]+, 573.1385 [M+Na]+.
(E/P 1:2); tR
=
20.0 min (HP-5); [a]2D0 =À31.9 (c=0.99, CHCl3);
1H NMR (300 MHz, CDCl3): d=1.25–1.70 (m, 15H, 4”CH3-Cby,
CH2-pyrro-3a, CH2-pyrro-4), 1.80 (m, 1H, CH2-pyrro-3b), 2.15 (m, 2H, CH2-pyrro-5),
2
2.83 (m, 3H, CHpyrro-2, CH2-CH=CH2), 3.23 (d, J=13.5 Hz, 1H, CH2Ph),
2
3.60 (s, 2H, Cby-CH2), 3.82 (m, 1H, CH-SCby), 4.15 (d, J=13.5 Hz, 1H,
3
3
CH2Ph), 5.00 (dd, Jcis =4.8, Jtrans =10.3 Hz, 2H, CH2-CH=CH2), 5.80 (m,
1H, CH2-CH=CH2), 7.05–7.41 ppm (m, 5H, Ph); 13C NMR (75 MHz):
d=23.8, 25.2, 26.2, 27.6, 33.5, 47.4, 53.0, 54.8, 59.1, 67.1, 77.2, 94.0, 116.5,
126.9, 128.4, 128.9, 137.1 (Ph), 140.4, 164.1 ppm (C=O); IR (film): n˜ =
3079, 2978 (m, C-Haro), 2931, 2869, 2782 (s, C-Hali), 1634 (s, C=O), 1449
(s), 1340 (s), 1311 (s), 1239 (s), 1268 (s), 1202 (s), 1079 (s), 920 (s), 826
(s), 793 cmÀ1 (s); elemental analysis calcd (%) for C23H34N2O2S (402): C
68.62, H 8.51, N 6.96; found C 68.68, H 8.53, N 6.72; MS (ESI): m/z:
403.5 [M+H]+.
[(1S),1(2S)]-S-[(1-Benzylpyrrolidin-2-yl)-2-(biphenyl-2-yl)ethyl] 2,2,4,4-
tetramethyloxazolidine-3-carbothioate (25): Colorless oil; yield: 88%; Rf
= 0.44 (E/P 1:1); tR = 26.9 min (HP-5); [a]2D0 =À11.6 (c=1.11, CH2Cl2);
1H NMR (300 MHz, CDCl3): d=1.25–1.70 (m, 15H, 4”CH3-Cby,
CH2-pyrro-4, CH2-pyrro-3a), 1.98 (m, 1H, CH2-pyrro-3a), 2.25 (m, 1H, CH2-pyrro-5a),
[(1S),1(2S)]-S-[(1-Benzylpyrrolidin-2-yl)-2-phenylethyl]
methyl-oxazolidine-3-carbothioate (21): Colorless oil; Rf
2,2,4,4-tetra-
0.50 (E/P
2.90 (dd, 3J=4.1, 2J=11.9 Hz, 1H, Ph-Ph-CH2a), 3.00 (m, 2H, CHpyrro-2
,
=
CH2-pyrro-5b), 3.24 (d, 2J=13.5 Hz, 1H, CH2-Ph), 3.65 (dd, 3J=4.1, 2J=
11.9 Hz, 1H, Ph-Ph-CH2b), 3.90 (s, 2H, Cby-CH2), 4.00 (d, 2J=13.5 Hz,
1H, CH2-Ph), 4.28 (m, 1H, CH-SCby), 7.25–7.60 ppm (m, 14H, Ph);
13C NMR (75 MHz): d=23.4, 25.2, 26.4, 27.8, 31.9, 48.5, 54.6, 58.8, 67.3,
1:2); [a]2D0 =À4.7 (c=1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d=1.25–
1.70 (m, 15H, 4”CH3-Cby, CH2-pyrro-3a, CH2-pyrro-4), 1.90 (m, 1H, CH2-pyrro-3b),
2.15 (m, 1H, CH2-pyrro-5a), 2.61 (m, 1H, CH2-pyrro-4b), 2.91 (m, 1H, CH2-pyrro-2),
6426
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 6419 – 6429

Enantiomerically Pure Prolinethiols
FULL PAPER
77.1, 126.1, 126.8, 127.1, 127.3, 128.3, 129.1, 129.8, 130.9, 137.6, 140.2,
142.3, 143.1 (Ph), 163.4 ppm (C=O); IR (film): n˜ = 3058, 2964 (s, C-
8.59, N 7.71; found: C 66.11, H 8.37, N 7.62; MS (ESI): m/z: 364.2170
[M+H]+.
H
aro), 2962, 2863, 2784 (s, C-Hali), 1632 (s, C=O), 1496 (s), 1478 (s), 1449
Dedeuteration experiment: According to the general experimental proce-
dure, the deprotonation was carried out with [D]-8 (100 mg, 0.27 mmol,
1.0 equiv) dissolved in toluene (5 mL). TMEDA (37 mg, 0.32 mmol,
1.2 equiv) was added and the reaction flask was cooled to À788C. After-
wards, sBuLi (1.36m, 0.23 mL, 0.32 mmol, 1.2 equiv) was injected in a
dropwise manner and the reaction mixture was stirred at À788C for 3 h.
Then MeOD (2.70 mmol, 10.0 equiv) was injected and the reaction mix-
ture stirred for 15 min. To the reaction mixture then anhydrous MgSO4
was added, the mixture filtered through glass wool and washed several
times with Et2O. The collective organic phase was concentrated under re-
duced pressure to get the crude product. The crude product was passed
through a short column (Et2O), concentrated, dried, and subjected to
analyses. From NMR and mass spectral analyses, it was found to be a
mixture of 8 (78%), [D]-8 (3%), and epi-[D]-8 (19%). Colorless oil;
yield: 98%; Rf = 0.42 (E/P 1:2); 1H NMR (600 MHz, C6D6): d=1.37 (s,
6H, 2”CH3-Cby), 1.51–185 (m, 10H, 2”CH3-Cby, CH2-pyrro-3, CH2-pyrro-4),
1.95 (m, 1H, CH2-pyrro-5a,), 2.68 (m, 1H, CH2-pyrro-5b), 2.84 (m, 1H, CHpyrro-2),
3.03 (dd, 3J=7.3, 2J=13.6 Hz; 1H), 3.12 (d, 2J=13.2 Hz, 2H, CH2Ph),
3.36 (s, 2H, Cby-CH2), 3.52 (dd, J=3.2, 13.6 Hz, 1H), 4.12 (d, 2J=
(s), 1370 (s), 1333 (s), 1309 (s), 1263 (s), 1199 (s), 1062 (s), 923 (s), 824
(s), 724 cmÀ1 (s); elemental analysis calcd (%) for C33H46N2O2S (528.7): C
74.96, H 7.63, N 5.30; found: C 74.76, H 7.71, N 5.16; MS (ESI): m/z:
529.5 [M+H]+, 551.5 [M+Na]+.
[(1S),1(2S)]-S-[(1-Benzylpyrrolidin-2-yl)-2-hydroxy-2,2-diphenylethyl]
2,2,4,4-tetramethyloxazolidine-3-carbothioate (26): Colorless oil; yield:
78%; Rf = 0.46 (E/P 1:1); tR = 26.9 min (HP-5); [a]2D0 =+18.5 (c=0.9,
CHCl3); 1H NMR (300 MHz, CDCl3): d=1.20–1.55 (m, 12H, 4”CH3-
Cby), 1.60–1.85 (m, 3H, CH2-pyrro-4, CH2-pyrro-3a), 2.05 (m, 1H, CH2-pyrro-3b),
2.55 (m, 1H, CH2-pyrro-5a), 2.81 (m, 1H, CH2-pyrro-5b), 2.91 (m, 1H, CHpyrro-2),
3.15 (d, J=13.5 Hz, 1H, CH2-Ph), 3.05 (d, J=13.5 Hz, 1H, CH2-Ph), 3.55
(s, 2H, Cby-CH2), 4.87 (d, 3J=3.5 Hz, 1H, CH-SCby), 7.0–7.80 (m, 15H,
Ph), 9.29 ppm (brs, 1H, OH); 13C NMR (75 MHz): d=23.3, 24.2, 25.2,
29.1, 51.3, 57.6, 60.5, 67.9, 77.2, 82.8, 98.0, 125.1, 125.8, 126.3, 126.9, 127.7,
127.9, 128.1, 128.9, 129.2, 138.6, 148.5, 148.1 (Ph), 164.6 ppm (C=O); IR
(film): n˜ = 3463 (b, OH), 3058, 3023, 2978 (s, C-Haro), 2939, 2867 (s,
C-Hali), 1621 (s, C=O), 1499 (s), 1453 (s), 1349 (s), 1315 (s), 1309 (s), 1265
(s), 1239 (s), 1204 (s), 1082 (s), 921 (s), 826 (s), 784 cmÀ1 (s); elemental
analysis calcd (%) for C23H40N2O3S (544.7): C 72.26, H 7.04, N 5.14;
found: C 72.32, H 7.41, N 4.68; MS (ESI): m/z: 545.2853 [M+H]+,
567.2654 [M+Na]+.
2
13.2 Hz, 1H), 7.07–7.21 ppm (m, 5H, Ph); H NMR [in C6H6 with a trace
of C6D6 for reference (600 MHz)]: d=3.03 (85%), 3.53 ppm (15%); MS
(ESI): m/z: 363.2101 [MÀD+H]+ (78%), 364.2170 [MD+H]
+A
CHTRE(UNG 22%).
In situ trapping with TMSCl-10 and [D]-10: According to the general ex-
perimental procedure, the deprotonation was carried out with [D]-8
(100 mg, 0.27 mmol, 1.0 equiv), dissolved in toluene (5 mL). TMEDA
(37 mg, 0.32 mmol, 1.2 equiv) and TMSCl (291 mg, 2.70 mmol, 10 equiv)
was added and the reaction flask was cooled to À788C. Afterwards,
sBuLi (1.36m, 0.23 mL, 0.32 mmol, 1.2 equiv) was injected in a dropwise
manner and the reaction mixture was stirred at À788C till no starting ma-
terial could be detected by TLC. Standard workup, followed by column
chromatography (E/P) afforded the product which was found to be a
67:33 mixture of 10 and [D]-10. (cf. Supporting Information).
ACHTREUNG
thioate (27 and epi-27 [mixture] dr 68:32): Colorless oil; yield: 76%; Rf
= 0.22 (E/P 1:1); tR = 20.5 and 22.5 min (HP-5); [a]2D0 =+29.05 (c=1.0,
CH2Cl2) of the above diastereomeric mixture; 1H NMR (300 MHz,
CDCl3): d=1.24–1.59 (m, 12H, 4”CH3-Cby), 2.00 (m, 2H, CH2-pyrro-4),
2.23 (m, 2H, CH2-pyrro-3), 2.38 (m, 1H, CH2-pyrro-5a), 3.11 (m, 1H, CH2-pyrro-5a),
3.46 (m, 2H, CHpyrro-2, CH-SCby), 3.79 (s, 2H, Cby-CH2), 4.51 (d, 2J=
12.8 Hz, 1H, CH2-Ph), 4.73 (d, 2J=12.8 Hz, 1H, CH2-Ph), 5.10 (d, 3J=
10.6 Hz, 1H, CH-OH), 7.36–7.63 (m, 9H, Ph), 8.62 ppm (brs, 1H, OH);
13C NMR (75 MHz): d=23.2, 24.8, 25.2, 26.4, 47.4, 53.5, 58.8, 65.6, 68.6,
75.5, 76.5, 127.3, 128.4, 128.9, 129.8, 130.5, 137.5, 141.3 (Ph), 160.5 ppm
(C=O); IR (film): n˜ = 3463 (b, OH), 3058, 3023, 2978 (s, C-Haro), 2939,
2867 (s, C-Hali), 1621 (s, C=O), 1499 (m), 1453 (s), 1349 (m), 1315 (s),
1309 (s), 1265 (s), 1239, 1204 (s), 1082 (s), 921 (s), 826 (s), 784 cmÀ1 (s);
elemental analysis calcd (%) for C27H35BrN2O3S (547.5): C 59.23, H 6.44,
N 5.12; found: C 59.28, H 6.40, N 4.94. MS (ESI): m/z: 549.1623 [M+H]+.
General experimental procedure for the decarbamoylation of substituted
thiocarbamates: Under argon atmosphere, appropriately substituted thio-
carbamate (1.0 equiv) was treated with diisobutylaluminium hydride
(DIBALH, 1m solution in hexanes, 20 equiv) at room temperature for 1–
3 h (TLC monitor). The reaction mixture was then cooled to 08C and
worked up according to the Fieser procedure[25] by adding calculated
amounts of water, 15% NaOH and water with several minutes of stirring
in between (for n g of metal hydride, successive addition of n mL of
water, n mL of 15% NaOH and 3n mL of water is required). The result-
ing aluminium salts were filtered through a short silica gel column under
vacuum and the solvent from the filtrate was evaporated to get the crude
thiol which was subjected to column chromatography.
[(1R),1(2S)]-S-[(1-Benzylpyrrolidin-2-yl)-3,3-dimethyl-2-oxobutyl]
2,2,4,4-tetramethyloxazolidine-3-carbothioate (28): Colorless oil; yield:
76%; Rf = 0.60 (E/P 1:2); tR = 14.2 min (HP-5); [a]2D0 =À1.4 (c=1.12,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=1.30 (s, 9H, C
ACHTRE(UNG CH3)3), 1.55–
1.70 (m, 15H, 4”CH3-Cby, CH2-pyrro-4, CH2-pyrro-3a), 1.90 (m, 1H, CH2-pyrro-3b),
2.31 (m, 1H, CH2-pyrro-4a), 2.91 (m, 1H, CHpyrro-2), 3.40 (m, 2H, CH2-pyrro-4b
,
(S)-1-[(S)-1-Benzylpyrrolidin-2-yl]propane-1-thiol (31): Colorless oil;
yield: 84%; Rf = 0.50 (E/P 1:1); [a]2D0 =À73.0 (c=2.0, CHCl3); 1H NMR
(300 MHz; CDCl3): d=0.92 (t, 3J=7.5 Hz, 3H, CH2-CH3), 1.55–1.68 (m,
5H, CH2-CH3, CH2-pyrro-3a, CH2-pyrro-4), 1.83 (m, 1H, CH2-pyrro-3b), 2.16 (m,
1H, CH2-pyrro-5a), 2.18 (dt, J=7.5 Hz, 1H, CH2-pyrro-5b), 2.64 (m, 1H,
CHpyrro-2), 2.71 (m, 1H, CH-SH), 3.28 (d, 2J=13.3 Hz, 1H, CH2-Ph), 3.92
(d, 2J=13.3 Hz, 1H, CH2-Ph), 7.14–7.26 ppm (m, 5H, Ph); 13C NMR
(75 MHz): d=12.6, 23.5, 26.0, 27.2, 46.6, 55.0, 59.9, 69.6, 126.7, 128.1,
128.3, 140.1 ppm (Ph); IR (film): n˜ = 3064, 3030 (w, C-Haro), 2962, 2929,
2873 (s, C-Hali), 1494 (s), 1453 (s), 1374 (s), 1215 (s), 1131 (s), 1072 (s),
918 (s), 847 (s), 751 (s), 698 cmÀ1 (s); HR MS (ESI): calcd for C14H21NS:
236.1467; found: 236.1459 [M+H]+.
CH2-Ph), 3.80 (s, 2H, Cby-CH2), 4.15 (d, 2J=12.9 Hz, 1H, CH2-Ph), 5.12
(d, 3J1,6 =7.0 Hz, 1H, CH-SCby), 7.14–7.51 ppm (m, 5H, Ph); 13C NMR
(100 MHz): d=25.2, 26.0, 26.8, 27.2, 31.6, 41.0, 49.3, 51.1, 55.2, 61.7, 66.1,
77.2, 98.0, 128.2, 129.5, 130.5, 140.1 (Ph), 163.0 (C=O), 214.9 ppm (O=C-
tBu); IR (film): n˜ = 3029, 2962 (s, C-Haro), 2928, 2864, 2793 (s, C-Hali),
1696, 1639 (s, C=O), 1493 (s), 1452 (s), 1339 (s), 1309 (s), 1267 (s), 1245
(s), 1200 (s), 1059 (s), 922 (s), 824 (s), 787 cmÀ1 (s); HR MS (ESI): m/z:
calcd for C25H38N2O3S: 447.2694; found: 447.2681 [M+H]+.
[(1S),1(2S)]-S-[(1-Benzylpyrrolidin-2-yl)-deuteriomethyl]
2,2,4,4-tetra-
methyl-oxazolidine-3-carbothioate ([D]-8): Colorless oil; yield: 99%; Rf
= 0.42 (E/P 1:2); tR = 20.39 min (HP-5); [a]2D0 =À69.5 (c=0.63, CHCl3);
1H NMR (400 MHz, CDCl3): d=1.40–1.80 (m, 15H, 4”CH3-Cby,
CH2-pyrro-3a, CH2-pyrro-4), 1.90 (m, 1H, CH2-pyrro-3b), 2.12 (m, 1H, CH2-pyrro-5a),
(S)-1-[(S)-1-Benzylpyrrolidin-2-yl]-2-phenylethanethiol (32): Colorless
oil; yield: 50%; Rf
=
0.37 (E/P 1:2); [a]2D0 =À67.5 (c=1.25, CHCl3);
3
1H NMR (400 MHz, CDCl3): d=1.64 (m, 2H, CH2-pyrro-4), 1.78 (m, 1H,
CH2-pyrro-3a), 1.88 (m, 1H, CH2-pyrro-3b), 2.16 (m, 1H, CH2-pyrro-5a), 2.22 (m,
1H, CH2-pyrro-5b), 2.84 (m, 1H, CHpyrro-2), 3.07 (m, 1H, CH-SH), 3.16 (d,
2J=13.3 Hz, 1H, N-CH2-Ph), 3.44 (m, 2H, HS-CH-CH2-Ph, N-CH2Ph),
3.99 (d, 2J=13.3 Hz, 1H, CH2-Ph), 7.03–7.38 ppm (m, 10H, Ph);
13C NMR (100 MHz): d=22.6, 25.9, 37.8, 44.6, 54.1, 58.7, 68.0; 125.1,
2.65 (m, 1H, CHpyrro-2), 2.85 (m, 1H, CH2-pyrro-5b), 3.03 (d, J=6.9 Hz, 1H,
CHD), 3.12 (d, 2J=13.2 Hz, 1H, CH2-Ph), 3.65 (s, 2H, Cby-CH2), 4.05
(d, 2J=13.2 Hz, 1H, CH2-Ph), 7.11–7.45 ppm (m, 5H, Ph); 13C NMR
(100 MHz): d=22.4, 24.7, 25.7, 30.0, 34.2, 54.0, 54.1, 58.8, 62.9, 77.2, 96.0,
126.6, 128.1, 128.7, 139.4 (Ph), 163.8 ppm (C=O); IR (film): n˜ = 3064,
3030 (m, C-Haro), 2974, 2926, 2869 (s, C-Hali), 1632 (s, C=O), 1690 (s),
1458 (s), 1364 (s), 1267 (s), 1241 (s), 1076 (s), 919 (s), 885 (s), 799 cmÀ1
(s); elemental analysis calcd (%) for C20H30DN2O2S (363.2): C 66.08, H
125.8, 127.1, 127.3, 127.5, 128.2, 139.0, 139.2 ppm (Ph); IR (film): n˜
=
3064, 3030 (w, C-Haro), 2962, 2929, 2873 (s, C-Hali), 2571 (w), 1494 (s),
Chem. Eur. J. 2007, 13, 6419 – 6429
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6427

D. Hoppe et al.
1453 (s), 1374 (s), 1215 (s), 1131 (s), 1072 (s), 918 (s), 847 (s), 751 (s),
698 cmÀ1 (s); HR MS (ESI): m/z: calcd for C19H23NS: 298.1624; found:
298.1614 [M+H]+.
112, 8994–8995; e) K. Brickmann, R. Brückner, Chem. Ber. 1993,
126, 1227–1239; f) F. Wang, J. Tang, L. Labaudiniere, I. Marek, J.-F.
Normant, Synlett 1995, 723–725.
[4] a) R. W. Hoffmann, T. Ruhl, J. Harbach, Liebigs Ann. Chem. 1992,
725–730; b) R. W. Hoffmann, M. Julius, F. Chemla, T. Ruhland, G.
Frenzen, Tetrahedron 1994, 50, 6049–6060; c) R. W. Hoffmann,
R. K. Dress, T. Ruhland, A. Wenzel, Chem. Ber. 1995, 128, 861–870;
d) T. Ruhland, R. Dress, R. W. Hoffmann, Angew. Chem. 1993, 105,
1487–1489; Angew. Chem. Int. Ed. Engl. 1993, 32, 1467–1469.
[5] a) R. Otte, R. Frçhlich, B. Wibbeling, D. Hoppe, Angew. Chem.
2005, 117, 5629–5632; Angew. Chem. Int. Ed. 2005, 44, 5492–5496;
b) S. Nakamura, Y. Ito, L. Wang, T. Toru, J. Org. Chem. 2004, 69,
1581–1589; c) S. Nakamura, A. Furutani, T. Toru, Eur. J. Org.
Chem. 2002, 1690–1695; d) S. Nakamura, R. Nagakawa, Y. Wata-
nabe, T. Toru, Angew. Chem. 2000, 112, 361–363; Angew. Chem. Int.
Ed. 2000, 39, 353–355; e) S. Nakamura, R. Nagakawa, Y. Watanabe,
T. Toru, J. Am. Chem. Soc. 2000, 122, 11340–11347.
(R)-[(S)-1-Benzylpyrrolidin-2-yl](tert-butyldimethylsilyl)-methanethiol
(33): Colorless oil; yield: 80%; Rf = 0.38 (E/P 1:2); [a]2D0 =À139.3 (c=
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d=0.10 (s, 3H, Si-CH3a), 0.10
(s, 3H, Si-CH3b), 0.90 (s, 9H, SiCCATHER(UGN CH3)3; 155–1.62 (m, 3H, CH2-pyrro-3a,
CH2-pyrro-4), 1.85 (m, 1H, CH2-pyrro-3b), 1.95 (m, 1H, CH2-pyrro-5a), 2.05 (m,
1H, CHpyrro-2), 2.24 (d, 3J=4.1 Hz, 1H, HS-CH-TBDMS), 2.74 (m, 2H,
CH2-pyrro-5b, SH), 3.10 (d, 2J=13.3 Hz, 1H, CH2Ph), 3.96 (d, 2J=13.3 Hz,
1H, CH2Ph), 7.10–7.26 ppm (m, 5H, Ph); 13C NMR (100 MHz): d
=
À5.3, À4.2, 17.5, 23.1, 25.7, 27.2, 31.2, 54.0, 60.4, 69.7; 126.7, 128.1, 128.5,
139.9 ppm (Ph); IR (film): n˜ = 3062, 3029 (w, C-Haro), 2962, 2929, 2873
(s, C-Hali), 2569 (w), 1494 (s), 1453 (s), 1374 (s), 1215 (s), 1131 (s), 1072
(s), 918 (s), 847 (s), 751 (s), 698 cmÀ1 (s); HR MS (ESI): calcd for
C18H31NSSi: 322.2019; found: 322.2019 [M+H]+.
Crystallographic data: Data sets were collected with a Nonius Kap-
paCCD diffractometer. Programs used: data collection COLLECT
(Nonius B.V., 1998), data reduction Denzo-SMN,[26], absorption correc-
tion Denzo,[27] structure solution SHELXS-97,[28] structure refinement
SHELXL-97,[29] graphics SCHAKAL.[30]
[6] a) H. J. Reich, R. Dykstra, J. Am. Chem. Soc. 1993, 115, 7041–7042;
b) H. J. Reich, R. Dykstra, Angew. Chem. 1993, 105, 1489–1491;
Angew. Chem. Int. Ed. Engl. 1993, 32, 1469–1471; c) H. J. Reich, K.
Kulicke, J. Am. Chem. Soc. 1995, 117, 6621–6622; d) H. J. Reich, K.
Kulicke, J. Am. Chem. Soc. 1996, 118, 273–274.
X-ray crystal structure analysis for (R)-13:[31] formula C26H44N2O2SSi,
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M=476.78, colorless crystal 0.35”0.15”0.05 mm, a=7.811(1), b=
17.453(1), c=21.319(1) Š, V=2906.3(4) Š3, 1calcd =1.090 gcmÀ3
, m=
1.55 mmÀ1, empirical absorption correction (0.613 % T % 0.927), Z=4,
orthorhombic, space group P212121 (No. 19), l=1.54178 Š, T=293 K, w
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and
f
scans, 9760 reflections collected (Æh, Æk, Æl), [(sinq)/l]=
0.60 ŠÀ1, 4636 independent (Rint =0.058) and 3666 observed reflections
[I ^ 2 s(I)], 289 refined parameters, R=0.070, wR2 =0.201, Flack pa-
rameter 0.05(4), max. residual electron density 0.32 (À0.22) eŠÀ3, hydro-
gen atoms calculated and refined as riding atoms.
X-ray
C35H40N2O2S·CHCl3, M=672.12, colorless crystal 0.20”0.10”0.10 mm,
a=11.331(1), b=14.506(1), c=21.213(1) Š, V=3486.7(4) Š3, 1calcd
1.280 gcmÀ3, m=3.20 mmÀ1, empirical absorption correction (0.567 % T
0.740), Z=4, orthorhombic, space group P212121 (No. 19), l=
crystal
structure
analysis
for
(S)-23:[31]
formula
=
%
1.54178 Š, T=293 K, w and f scans, 46664 reflections collected (Æh,
Æk, Æl), [(sinq)/l]=0.60 ŠÀ1, 6181 independent (Rint =0.075) and 4842
observed reflections [I
% 2 s(I)], 412 refined parameters, R=0.077,
wR2 =0.227, Flack parameter 0.02(3), max. residual electron density 0.28
(À0.63) e ŠÀ3, hydrogen atoms calculated and refined as riding atoms.
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This work was supported by Sonderforschungsbereich 424 and the Fonds
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NRW Graduate School of Chemistry, Münster (Germany), for doctoral
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www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 6419 – 6429

Enantiomerically Pure Prolinethiols
FULL PAPER
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Received: December 21, 2006
Published online: May 14, 2007
Chem. Eur. J. 2007, 13, 6419 – 6429
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6429