Catalytic asymmetric synthesis of β-sultams as precursors for taurine derivatives

Article abstract of DOI:10.1002/chem.200900496

β-Sultams, biologically interesting sulfonyl analogues of β-lactams, have been prepared by an organocata-lytic asymmetric formal [2+ 2]-cycloaddition approach of non-nucleophilic imines with alkyl sulfonyl chlorides. In the case of very electron poor N-to

Full text of DOI:10.1002/chem.200900496

DOI: 10.1002/chem.200900496
Catalytic Asymmetric Synthesis of b-Sultams as Precursors for Taurine
Derivatives
Marian Zajac[b] and Renꢀ Peters*[a]
Abstract: b-Sultams, biologically inter-
esting sulfonyl analogues of b-lactams,
have been prepared by an organocata-
lytic asymmetric formal [2+2]-cycload-
dition approach of non-nucleophilic
imines with alkyl sulfonyl chlorides. In
the case of very electron poor N-tosyl
imines derived from chloral or ethyl-
glyoxylate, this reaction type was cata-
lyzed by cinchona alkaloids providing
the heterocycles in high yield, with
good diastereoselectivity and up to
94% ee. Mechanistic investigations sug-
gested that the product formation pro-
ceeded via a zwitterionic imine–catalyst
adduct. The scope was significantly ex-
tended by 2-pyridylsulfonyl imines de-
rived from non-activated aromatic al-
dehydes employing Yb(OTf)3 as Lewis
AHCTUNGTRENNUNG
acid cocatalyst. The synthetic value of
the strained enantioenriched b-sultams
was demonstrated by smooth nucleo-
philic ring opening reactions with O-,
N- and C-nucleophiles yielding a varie-
ty of acyclic b-aminosulfonyl (taurine)
derivatives (sulfonates, sulfonamides,
sulfones) without racemization or epi-
merization.
Keywords: asymmetric catalysis
·
cycloaddition · imines · sultams ·
ytterbium
Introduction
Sulfonyl groups constitute an important module in medicinal
chemistry. They improve water solubility and are capable to
form H-bonds while their strong inductive effect can be uti-
lized to tune pKa values of adjacent or remote amino
groups.[1] On the other hand the structural and electronic
properties might mimic transition states to tetrahedral inter-
mediates.[2]
1,2-Thiazetidine-1,1-dioxides (1), commonly known as b-
sultams, are highly reactive sulfonyl analogues of b-lactams
2. They are of biological and medicinal interest as a result of
their notable physiological activity.
arthritis with the active site serine being sulfonylated via a
[3]
À
S N bond fission. b-Sultams can also serve as both b-lacta-
mase[4] and d,d-peptidase inhibitors[5] and are consequently
appealing for the development of new antibiotics. Moreover,
they can be regarded as cyclic sulfonamide derivatives of
the ubiquitous b-aminosulfonic acid taurine 3.
Since the first reported preparation of b-sultams 1 in
1960,[6] their chemistry has been widely investigated not
only because of the interesting biological properties, but
also due to the usefulness of 1 as versatile reactive synthetic
building blocks.[7] As four membered ring systems, b-sultams
are highly strained species (CSN angle: ca. 818; for acyclic
sulfonamides: ca. 1138).[8] As a result of the structural distor-
tion in combination with a smaller resonance stabilization
than in their b-lactam analogues,[9] b-sultams are at least two
orders of magnitude more reactive towards nucleophilic ring
opening reactions than b-lactams, although acyl transfer re-
actions normally proceed about 102- to 104-fold faster com-
pared with sulfonyl transfer reactions.[8] b-Sultams show rate
enhancements of at least 107- and 109-fold, respectively, as
Specifically, b-sultams 1 can act as irreversible active site
directed inhibitors of elastases like the human neutrophil
elastase (HNE) which is implicated in the development of
diseases such as emphysema, cystic fibrosis and rheumatoid
[a] Prof. Dr. R. Peters
Institut fꢀr Organische Chemie, Universitꢁt Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
Fax : (+49)711-685-64321
E-mail: rene.peters@oc.uni-stuttgart.de
[b] Dr. M. Zajac
ETH Zꢀrich, Hçnggerberg, Laboratory of Organic Chemistry, Wolf-
gang-Pauli-Str. 10
8093 Zꢀrich, (Switzerland)
À
compared to the base- and acid-catalyzed hydrolytic S N
bond cleavage of the corresponding acyclic sulfonamides.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900496.
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FULL PAPER
Depending on the reaction conditions, the ring-opening pro-
cesses can occur by heterolytic cleavage of each of the three
[7]
À
À
À
hetero s-bonds, the C S bond, S N bond or N C bond.
Reactions of b-sultams with O- and N-nucleophiles proceed
À
in most cases via a regioselective S N bond fission and lead
to taurine derivatives, namely b-aminosulfonates and -sul-
A
ACHTUNGTRENNUNGamides.
the tissues of mammals. High concentrations of taurine are,
for example, found in the heart. It protects from excessive
or inadequate intracellular Ca2+ and ischemic damage
acting as a membrane stabilizer and protecting from injury
and oxidative stress.[10] Supplement of taurine is also able to
prevent hypertension through osmoregulation.[11] Taurine
decreases cholesterol levels due to increased bile acid conju-
gation and antioxidant effects and reduces the development
of atherosclerosis in animals.[10a,12] Taurine plays an essential
role in both brain development and regeneration, promotes
the survival and proliferation of neurons,[13] increases brain
levels of acetylcholine, while decreased levels of taurine
have been found in Alzheimer patients.[10a] Taurine also
holds promise in the prevention of epilepsy as an inhibitory
neurotransmitter[13,14] and protects various organs against
toxins.[15]
A number of taurine derived structures have been identi-
fied to be of high medicinal interest. For instance, flavo
ACHTUNGTRNEcNUNG rist-
ACHTUNGTRENNUNGamide A (4) is a naturally occurring sulfonolipid which effi-
ciently inhibits the enzyme DNA polymerase A.[16] Pharma-
cia has developed a-amino-b-sulfone hydroxamates 5, which
are potent and selective MMP-13 inhibitors (treatment of
arthritis).[17] Abbott reported N-formylhydroxylamines 6 as
potent and selective MMP-2 and -9 inhibitors (treatment of
cancer).[18] Canfosfamide (7, Telik) exerts high antitumor ac-
tivity and has recently reached phase-III studies.[19] In addi-
tion, the very potent and highly selective memapsin 2 inhibi-
tor 8 was recently developed by Ghosh et al.[20] Memapsin 2
(b-secretase) is a leading target for the therapeutic interven-
tion of Alzheimerꢃs disease.
additions of enantiopure hydrazine nucleophiles to a,b-unsa-
turated sulfonates,[21] 1,2-additions to enantiomerically pure
a-sulfanyl hydrazones,[22] or sulfonyl-analogous Mannich
type reactions with enantiopure N-sulfinyl imines.[23]
The high reactivity of b-sultams towards nucleophiles
allows for a direct access to taurine derivatives. Despite of
this high reactivity, most b-sultams are bench-stable com-
pounds, but only few can be purified by chromatography
without considerable loss of material as a result of hydroly-
sis. The substituents on the b-sultam ring display a large in-
fluence on the overall stability.[7] Most notably, N-unsubsti-
tuted b-sultams rapidly hydrolyze or polymerize.
Scheme 1. Concepts for the formation of b-sultams 1.
To synthesize chiral b-sultams, a number of methods has
been developed (Scheme 1),[7] most notably: A) cyclization
of 2-aminosulfonyl halides 9; B) cyclization of activated b-
hydroxysulfonamides 10; C) cyclization of a-(halomethylsul-
fonamido)ketones, -esters or -nitriles 11; D) [2+2]-cycload-
dition reactions of sulfonylamines 12 with particularly elec-
tron-rich olefins 13; and E) [2+2] cycloaddition reactions of
sulfenes 14 with nucleophilic imines 15.
Highly enantioenriched O-sulfonylated b-hydroxysulfona-
mides 10 (R2 =ortho-substituted aryl groups, method B)
were prepared from enantiomerically pure planar chiral tri-
carbonyl-(h6-arene)chromium complexes.[24] For methods
C)[25] and D)[26] efficient asymmetric versions are unknown.
Method E), the [2+2]-cycloaddition of nucleophilic
imines 15 and an in situ generated sulfene 14 (from a sulfo-
nyl chloride), provides a straightforward access to b-sul-
tams.[27] A diastereoselective approach using an optically
pure benzaldehyde derived imine bearing an N-((S)-1-tert-
Asymmetric synthesis by method A depends on the asym-
metric preparation of b-aminosulfonyl derivatives 9, which
was recently accomplished by diastereoselective aza-Michael
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R. Peters and M. Zajac
butylethyl) substituent was reported by Kataoka et al.[28]
However, high stereocontrol was reported only for a single
derivative, while the issue of cleavage of the chiral N-resi-
due was not addressed.
Table 1. Catalyst screening in the model reaction of sulfonyl chloride
16a and imine 21.
Although chiral enantioenriched b-sultams have thus
been prepared by various methods, no catalytic asymmetric
procedure has been reported prior to our studies.[29] Herein,
we describe the development of a catalytic asymmetric
methodology to form highly enantioenriched b-sultams
which were further investigated for nucleophilic ring open-
ing reactions to provide taurine derivatives.
Results and Discussion
In analogy to our catalytic asymmetric synthesis of b-sul-
tones,[30] it was anticipated that a zwitterionic nucleophilic
intermediate 18, generated by addition of an enantiomeri-
cally pure nucleophile 17 to the sulfene S-atom, might be ca-
pable of initiating an asymmetric [2+2] cycloaddition with
electron-poor imines 19 to provide the title compounds 20
enantioselectively (Scheme 2).[31,32] Although sulfenes,[33] the
sulfonyl analogues to ketenes, are far less stable than ke-
tenes[34] the catalytic asymmetric formation of b-sultones
could be accomplished via reactive sulfene intermediates. In
the case of b-sultam formation it was expected that the
imines 19 would have to be non-nucleophilic to avoid a non-
enantioselective competitive reaction as a result of direct
nucleophilic addition of the imine to sulfene 14 without in-
volvement of the enantiopure nucleophile 17. In contrast, all
previously reported [2+2]-cycloadditions of sulfenes and
imines relied on the use of nucleophilic imines.[7,27,28]
Catalyst
Yield[a] [%]
d.r.[b]
ee[c] [%]
1
2
3
4
5
6
7
8
quinuclidine
quinine (Q)
cinchonidine (Cd)
quinidine (Qd)
cinchonine (C)
De-Me-Q
De-OH-Q
MeQ
BnQ
TMSQ
b-ICD
AHCTUNGTRENNUNG
88
82
78
68
70
51
71
78
88
62
82
73
60
18:1
20:1
19:1
28:1
16:1
15:1
12:1
24:1
26:1
14:1
25:1
13:1
13:1
–
79
81
À79
À70
86
49
48
60
39
29
1
9
10
11
12
13
21
[a] Yield determined by 1H NMR using nitromethane as internal stan-
dard. [b] Determined by 1H NMR. [c] ee of the cis-diastereomer deter-
mined by HPLC; negative values indicate that the (S,S)-enantiomer is
preferentially formed.
Scheme 2. Initial proposal for the catalytic asymmetric formation of b-
sultams 20.
(Table 1). High stereoselectivities were obtained with the
cinchona alkaloids quinine (Q) and cinchonidine (Cd) with
unprotected hydroxyl moieties (entries 2–3). The pseudo-
To determine whether the formation of b-sultams cata-
lyzed by a nucleophile would at all be feasible, a catalytic
amount of quinuclidine was employed as simple achiral
model catalyst (Table 1, entry 1). Propanesulfonylchloride
(16a) and the highly electrophilic chloral derived N-tosyl
AHCTUNGTREGeNNNU nantiomeric catalysts quinidine (Qd) and cinchonine (C)
provided the enantiomeric product with similar enantiose-
lectivity (entries 4–5). The quinine derivative De-Me-Q pos-
sessing two free hydroxyl groups provided the product with
the highest ee (entry 6), but the yield obtained was only
moderate. The hydroxy substituted stereocenter at C-9 is es-
sential for high enantioselectivity, since both the absence
(entry 7) and the protection of the hydroxy moiety (en-
tries 8–13) result in only poor to moderate ee values.
The elaborated conditions using Q or Cd as catalyst were
useful regarding yields and ee values for sulfonylchlorides 16
having RꢀEt (Table 2, ee=79–94%, d.r. 11:1–21:1), where-
imine 21 reacted in dichloro
meth
U
presence of an excess of iPr2NEt (DIPEA, Hꢀnigꢃs base) as
non-nucleophilic stoichiometric base, giving the product 22a
in high yield and with high cis-diastereoselectivity, while the
targeted product was not obtained in the absence of the nu-
cleophilic catalyst under otherwise identical reaction condi-
tions. After proof of concept, various cinchona alkaloid de-
rivatives were investigated as chiral enantiopure catalysts
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Taurine Derivatives
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as the best result for ethanesulfonylchloride (16 f) was real-
ized with Q2PYR (entry 9). While Cd was found to be
slightly superior in the reaction with propanesulfonyl chlo-
ride 16a (entry 2) as compared to Q (entry 1), with butane-
sulfonyl chloride 16b (entries 3–4) and especially with 3-
chloropropanesulfonyl chloride 16c (entries 5–6), the yields
were significantly lower than with Q. Therefore quinine can
be considered to be the most general catalyst of those inves-
tigated.
cooled to À808C prior to the addition of DIPEA and sulfo-
nylchloride 16, the ee was reproducibly high. However, addi-
tion of a quinine solution to an imine solution at À808C, re-
sulted in almost racemic products. This indicated that the
imine reacts with quinine at room temperature to form a
more selective catalyst species. Most probably the free OH
group attacks the imine to form N,O-acetal 23 which is the
catalytically active species. Attempts to isolate this com-
pound were not successful since it decomposed after evapo-
ration of solvent. If a solution of imine 21 and Q (1:1 ratio
in CH2Cl2) was evaporated and
Table 2. Enantioselective reaction of imine 21 with sulfonyl chlorides 16
using quinine (Q) or cinchonidine (Cd) as chiral nucleophilic catalyst.
the resulting solid was em-
ployed as catalyst, again only
racemic product was obtained.
The structure of 23 was af-
1
firmed by H NMR titration ex-
periments
and
ESI-HRMS
R
Product Catalyst Yield[a] d.r.[b] ee[c]
spectrometry in solution (calcd
[%]
[%]
for [M+H]+: 624.1252, found:
1
2
3
4
5
6
7
8
9
Et
Et
nPr
nPr
ACHTUNGTRENNUNG
22a
22a
22b
22b
22c
22c
22d
Q
Cd
Q
Cd
Q
Cd
Q
82
78
81
70
78
36
94
95
80
20:1
19:1
18:1
18:1
11:1
10:1
21:1
13:1
17:1
79
81
91
91
94
93
94
87
À80
624.1255).
The initially assumed base induced dehydrohalogenation
of sulfonylchlorides 16 to form sulfene intermediates 14 was
examined by deuteration experiments under the standard
cycloaddition conditions, but in the presence of H3COD in-
stead of 21 (Scheme 3). Compounds 16a and 16 f were
T
T
Q
Q2PYR
[a] Yield determined by 1H NMR using nitromethane as internal stan-
dard. [b] Determined by 1H NMR. [c] ee of the cis-diastereomer deter-
mined by HPLC; negative values indicate that the (S,S)-enantiomer is
preferentially formed.
Scheme 3. Deuteration experiments to investigate the presence of sulfene
intermediates.
The (R,R)-configuration of 22b was established by X-ray
crystal structure analysis (Figure 1).[36,37] In contrast to litera-
ture known b-sultam structures, the cis-configured ring
mainly recovered unchanged and only traces of methylesters
were formed with no a-deuterated products observed thus
demonstrating that a sulfene is most likely not generated in
significant amounts.[41] In contrast, for the case of the cata-
lytic asymmetric formation of b-sultones, we have unambig-
uously demonstrated the generation of sulfenes at À158C by
similar deuteration experiments.[30]
According to the fact that almost no sulfene is generated
at À808C, a mechanism involving the intermediate forma-
tion of an adduct 24 of the nucleophilic catalyst with the
highly electrophilic imine 21 is likely (Scheme 4). Similar
zwitterionic adducts of N-trifluoromethylsulfonyl imines
with a nucleophilic chiral pyridine derivative have been pre-
viously reported by Fu et al. for the catalytic asymmetric
synthesis of b-lactams.[31n] We assume that the negatively
charged N atom of the zwitterionic aminal intermediate 24
subsequently attacks the sulfonylchloride without prior sul-
fene formation. The sulfonimide 25 thus generated would be
deprotonated at the acidic a-CH2-position to the SO2 group
to form a zwitterionic carbanion 26 which subsequently un-
dergoes an intramolecular nucleophilic substitution reaction
to release the catalyst for the next turnover.
Figure 1. X-ray crystal structure of b-sultam 22b. H atoms are omitted
for clarity.
system within 22b is only slightly puckered (dihedral angle:
6.58, typical values in literature:[38] ca. 12–248). The C-S-N
angle of 79.58 partly explains the high reactivity towards nu-
cleophiles which is shown below.[39] The N-atom is slightly
pyramidalized[40] and the tosyl group adopts a trans-orienta-
tion to the bulky CCl3.
The setup of the reaction is crucial to achieve high enan-
tioselectivity. If quinine was prestirred with imine 21 at
room temperature and this solution was subsequently
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R. Peters and M. Zajac
formed into the dichloromethyl-substituted 30. Reduction to
the monochloromethyl species 31 required addition of a rad-
ical initiator such as AIBN.
The trichloromethyl moiety on b-sultam 22a can also be
efficiently reduced under similar conditions, as applied to
the acyclic sulfonamides 28 and 29, without destruction of
the four-membered ring (Scheme 6). By variation of the
amount of nBu3SnH and AIBN, the reaction temperature
and time, the chlorination degree can be adjusted permitting
selective access to dichloromethyl derivative 32, chlorometh-
yl substituted b-sultam 33a and fully dechlorinated product
34.[42] Like before, also during this procedure no epimeriz-
ation was observed.
Scheme 4. Proposed mechanism for the nucleophile catalyzed asymmetric
formation of b-sultams 22 from chloral derived N-tosyl imine 21.
The synthetic utility of the strained target compounds 22a
was demonstrated by ring-opening reactions with N- and O-
nucleophiles (Scheme 5). Diastereomerically pure starting
Scheme 6. Selective dehalogenation of b-sultam 22a.
Since as mentioned above a number of drugs or drug can-
didates contain a b-aminosulfone moiety, a nucleophilic ring
opening with C-nucleophiles would be very attractive to get
rapid access to this compound class. Smooth ring opening
reactions of b-sultams possessing acidic H atoms at C-4 with
C-nucleophiles have previously not been achieved, due to a
predominant elimination pathway, although similar reactions
with b-sultones are known.[30,43]
Scheme 5. Ring opening reactions of b-sultam 22a and subsequent partial
dehalogenations.
Ring-opening attempts of 22a with alkyl, aryl, or alkynyl
llithium, magnesium, cerium, zincate or alanate reagents all
failed and either starting material was recovered unchanged
or complex product mixtures were obtained, but in most
cases the a,b-unsaturated sulfonimide 35 was formed as
major or only product (Scheme 7). Formation of this prod-
uct can be explained by an initial nucleophilic attack of the
base on the trichloromethyl group.
In contrast, treating 3-(chloromethyl)-b-sultam 33a with
PhMgBr in Et2O at RT resulted in a smooth ring-opening
reaction giving b-amino sulfone 38 in 85% yield
(Scheme 8).
Recently, the highly active and selective sulfonyl thiirane
based MMP-2/-9 inhibitor 39 has been reported by Mobash-
ery et al. (Scheme 9).[44] Sulfone-derived MMP (matrix met-
alloproteinase enzyme) inhibitors are promising novel drug
candidates, as elevated levels of MMPs are associated with
various pathologies such as osteoarthritis or rheumatoid ar-
thritis.[17] MMPs constitute a family of 26 closely related zinc
material 22a was obtained after a single recrystallization.
Using 2-phenylethanol, sulfonate 27 was formed in 85%
yield in diastereomerically pure form. This reaction was cat-
alyzed by Et3N as the ring opening with alcohols performed
only well in the presence of a nucleophilic tertiary amine
base. Benzylsulfonamide 28 and pyrrolidinesulfonamide 29
were formed in nearly quantitative yield as single diastereo-
mers using the corresponding primary or secondary amine.
No epimerizACHTUNGTRENNUNGation was observed during these transforma-
tions. Similar results were obtained if both the cycloaddition
step and the nucleophilic ring opening experiments with al-
cohols or amines were performed in the same pot without
isolation of 22a.
The synthetically versatile trichloromethyl group can un-
dergo a partial reduction with Bu3SnH (Scheme 5). Depend-
ing upon the reaction conditions, either the di- or the mono-
chloro derivatives 30 or 31 were selectively obtained. By
Bu3SnH in refluxing THF, sulfonamide 29 could be trans-
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Taurine Derivatives
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Scheme 10. Retrosynthetic analysis for the formation of
a potential
MMP-2/-9 inhibitor 41.
centers at this carbon (very often cysteine is used as starting
material).
Scheme 7. Explanation for the preferred formation of a,b-unsaturated
sulfonimide 35 by treatment of b-sultam 22a with nucleophilic organome-
tallic reagents.
To showcase the feasibility of this synthetic approach, sul-
fonylaziridine 41a was synthesized from b-sultam 33a
(Scheme 11) which smoothly underwent a ring-opening reac-
tion with (4-phenoxyphenyl)magnesium bromide in Et2O at
RT, providing sulfone 42 in 83% yield. The aziridine ring
was formed by an intramolecular nucleophilic substitution
promoted by AgNO3 and DIPEA. The target product 41a
was obtained in 94% yield and with ee values identical with
the starting b-sultam.
Scheme 8. b-Aminosulfone formation by ring opening of 33a with a
Grignard reagent.
Scheme 9. Rationalization of the mode of action of MMP-2/-9 inhibitor
39.
Scheme 11. Synthetic route to the potential MMP-2/-9 inhibitor 41a.
dependent enzymes, responsible for the remodeling and deg-
radation of all components of the extracelular matrix. One
class of possible targets are gelatinases A and B (MMP-2
and -9), which degrade type IV collagen, the main compo-
nent of basement membrane and which are implicated in
cancer metastasis.
The b-sultam methodology was extended to a-iminoester
43. Using the conditions optimized for the formation of 3-
trichloromethyl-b-sultams 22, the targeted product was pro-
duced in poor yield as the imine polymerized when pre-
mixed with the nucleophilic catalyst in solution at room
temperature. However, dropwise addition of the imine solu-
tion over 10 h to a solution of catalyst, base and sulfonyl-
chloride 16 at À808C resulted in improved yields. The inves-
tigated 3-ethylcarboxy-b-sultams were oils and could not be
recrystallized. Moreover, they are also not stable on silica
gel or alox and could not be purified by flash chromatogra-
phy. For that reason a tandem one-pot cycloaddition/nucleo-
philic ring opening sequence with n-octylamine was used to
provide stable products 44 (Table 3), which were readily pu-
rified by chromatography.
The authors proposed the following enzymatic mechanism
of action: the biphenyl moiety (which is a common motif for
MMP-inhibitors) fits in the deep hydrophobic pocket in the
active sites of gelatinases. Additionally, the inhibitor inter-
acts with the active-site zinc ion through coordination of the
thiirane moiety, as shown in structure 40. This interaction
activates the thiirane for nucleophilic attack by the active
site glutamate, resulting in irreversible suicide inhibition.
Based on these results and owing to the azaphilicity of
Zn2+, we targeted the formation of the related aziridines 41
from 3-(chloromethyl)-b-sultams 33 (Scheme 10). This ap-
proach would allow for the formation of b-sulfonylaziridines
with varying alkyl substituents on the C-2 position. The fact
that most sulfonyl drug candidates do not have a substituent
a- to the SO2 moiety is at least in part due to a lack of effi-
cient synthetic methodologies to selectively construct stereo-
The absolute configuration of the cycloaddition products
and the derived acyclic products 44 could not be determined
by X-ray single crystal structure analysis, and synthetic cor-
1
relation were also not successful. H NMR NOE studies on
the sultam stage revealed that the major diastereomer has
the trans-configuration (see Supporting Information) in con-
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R. Peters and M. Zajac
Table 3. One-pot cycloaddition/nucleophilic ring opening using N-tosyl
a-iminoester 43.
tively deprotect the tosylated amino moieties prior or after
ring-opening reactions with 22. To address the issues of the
imine substrate scope and a removable protecting group,
various electron-withdrawing N-substituents were examined.
While most of them resulted either in no or poor conversion
with chiral (Boc, Cbz, MeOC(O), F3CC(O), 4-O2N-
H4C6S(O)2, 2-O2N-H4C6S(O)2) or even achiral catalysts
(P(O)OEt2, P(O)Ph2 PhOC(O)), others resulted in product
decomposition during ring opening reactions with amines
(Troc, F5C6S(O)2) or provided low to moderate ee and d.r.
values (F3CS(O)2, F9C4S(O)2, 2,4-O2N-H4C6S(O)2) despite
extensive catalyst screenings.
R
Product
Yield[a] [%]
d.r.[b]
ee[c] [%]
1
2
3
Et
nPr
CH2Ph
44a
44b
44d
55
51
40
11:1
11:1
17:1
80
86
78
[a] Isolated yield after column chromatography. [b] Determined by
1H NMR. [c] ee of the major anti-diastereomer of 44 determined by
HPLC.
In 2-pyridylsulfonyl imines 49,[46] the sulfonyl residue is
not as electron-withdrawing as for 2,4-dinitrobenzenesulfon-
yl imines, but it offers the possibility for additional activa-
tion by bidentate coordination to a Lewis acid cocatalyst.
The model reaction of benzaldehyde derived imine 49A
with propanesulfonyl chloride 16a, catalyzed by quinucli-
dine in the absence of a Lewis acid cocatalyst, provided the
racemic b-sultam 50aA in an excellent yield of 92% and
with a high d.r. of 26:1 (Table 4, entry 1). As expected, this
imine was not reactive enough when Q or MeQ were used
as catalysts. Consequently, triflate salts of a variety of metals
were screened as Lewis acid cocatalysts in combination with
MeQ. While most of them resulted in no or traces of prod-
uct formation [LiI, MgII, CuII, ZnII, SnII, LaIII, NdIII, SmIII,
EuIII], the 3-Ph-substituted sultam 50aA was obtained in
low yield employing stoichiometric amounts of the main
trast to the cycloaddition products of chloral derived imine
21.[45]
By reduction with LiAlH4, ester 44b was transformed to
alcohol 45 in 82% yield (Scheme 12). A ring closure to azir-
idine 46 occurred under Mitsunobu conditions (74% yield).
The corresponding five-membered ring product implying the
octylamide nitrogen was not observed.
group metal salts In
pseudolanthanide salts Sc
and the late lanthanide salts Er
G
ACHTUNGTRENNUNG
E
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
tries 6–7) uncovering the latter as the best cocatalyst regard-
ing yield and diastereoselectivity.[47] MeQ was initially used
as catalyst instead of Q to exclude possible disturbing effects
of the free OH group in combination with the Lewis acid
like irreversible coordination to the catalyst.
Scheme 12. Formation of aziridine 46 from a-amino ester 44b.
Ring opening with a Grignard reagent is also readily ac-
complished. The crude product of 47a gave sulfone 48 in
75% yield (Scheme 13). Remarkably, the ester function re-
mained unchanged in this process.
To enable precomplexation of the imine 49A to the metal
cocatalyst, the suspension in CH2Cl2 was prestirred for
25 min at RT prior to cooling to À808C. In contrast, when
the mixture of 49A and YbACTHNUTRGNE(NUG OTf)3 (1.0 equiv) was formed at
À808C, no product 50aA was obtained (entry 8). On the
other hand, when the suspension was stirred for 60 min at
RT, the product yield strongly decreased due to side reac-
tions of the activated imine (entry 9). With substoichiomet-
ric YbACTHUNTGRNE(NUG OTf)3 loadings (0.5 equiv), the yield of product 50aA
increased to 59% (entry 10).
A number of cinchona alkaloid derivatives was subse-
Scheme 13. Formation of b-amino sulfone 48 by chemoselective ring
opening with a Grignard reagent.
quently examined in combination with Yb
In this screening, the best results were attained using TMSQ
in combination with 0.5 equiv of Yb(OTf)3 (entry 11). b-
ACHTUNGRTEN(NUNG OTf)3 (Table 5).
AHCTUNGTRENNUNG
Sultam 50aA was isolated in 71% yield, with 73% ee and a
d.r. of 15:1. In contrast, the reaction did not work well with
cinchona alkaloids possessing a free OH group under similar
conditions (entries 1–3, 9). Extending the reaction time from
20 to 40 h using TMSQ, 50aA was isolated in significantly
lower yield and a mixture of byproducts was found in the
Alternative N-tosyl imines derived from slightly less elec-
tron deficient aldehydes such as 2,2-dichloroalkylaldehydes
or 4-trifluoromethylbenzaldehyde were less useful for b-
sultam formation, and only the non-enantioselective method
using quinuclidine as catalyst provided the products in mod-
erate to good yields. Moreover, all attempts failed to reduc-
crude product (entry 12). Similarly, with smaller YbACHTUNGTRENNUNG(OTf)3
8210
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Chem. Eur. J. 2009, 15, 8204 – 8222

Taurine Derivatives
FULL PAPER
Table 4. Optimization of the model reaction of sulfonyl chloride 16a and benzaldehyde-derived imine 49A
bearing a 2-pyridylsulfonyl N-protecting group.
preventing the permanent com-
plexation of product or quinine.
Interestingly, ethyl glyme or tri-
glyme did not show the same
effect (entries 8–9).
The best setting found uti-
lizes 0.5 equiv Yb
1.0 equiv diglyme at c
0.167m (entry 10).
ACHTUNGTRENNUNG
Catalyst
Lewis Acid
–
x
Yield[a] [%]
d.r.[b]
ee[c] [%]
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
quinuclidine
MeQ
MeQ
MeQ
MeQ
MeQ
MeQ
MeQ
MeQ
–
92
21
37
25
11
29
39
0
26:1
3:1
5:1
4:1
5:1
4:1
15:1
–
–
n.d.
43
n.d.
n.d.
62
58
–
n.d.
61
57
A
In
T
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
1.5
concentration resulted in better
yields, but enantioselectivity de-
creased (entries 11–12). Lower
diglyme amounts resulted in de-
creased yield and ee (entry 13).
For all sulfonylchloride/imine
combinations listed in Table 7,
the two best performing chiral
catalysts Q (in the presence of
diglyme) and TMSQ were ex-
amined in combination with
Bi
Sc
ACHTUNGTRENNUNG
A
YACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Yb
Yb
Yb
Yb
Yb
N
8[d]
9[e]
10
11
19
59
42
10:1
8:1
8:1
MeQ
MeQ
[a] Determined by 1H NMR of the crude product using DMSO as internal standard. [b] Determined by
1H NMR. [c] ee of the major diastereomer, determined by HPLC from the corresponding octylsulfonamide
after ring opening with n-octylamine. [d] The mixture of imine 49A and Lewis acid was formed at À808C.
[e] The mixture of imine 49A and Lewis acid was stirred at RT for 60 min.
YbACHTNURTGNE(UNG OTf)3 (0.5 equiv), while
Table 5. Catalyst screening in the model reaction of sulfonyl chloride
16a and imine 49A.
Table 6. Investigation of various ether additives for the formation of b-
sultam 50aA.
Catalyst
Additive
x
Yield[a] [%]
d.r.[b]
ee[c] [%]
Catalyst
x
Yield[a] [%]
d.r.[b]
ee[c] [%]
1
2
3
4
5
6
7
8
TMSQ
TMSQ
TMSQ
TMSQ
Q
Q
Q
Q
Q
Q
Q
Q
Q
THF
Et2O
10.0
10.0
10.0
10.0
10.0
5.0
1.0
1.0
1.0
1.0
15
0
0
41
59
58
65
0
7:1
–
–
36
–
–
1
2
3
4
5
6
7
8
Q
Cd
Qd
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.5
0.5
0.5
0.2
10
7
10:1
5.6:1
10:1
15:1
9:1
24:1
14:1
17:1
5.6:1
8:1
n.d.
n.d.
n.d.
58
70
74
n.d.
62
n.d.
61
73
72
ethyl glyme
diglyme
diglyme
diglyme
diglyme
ethyl glyme
triglyme
diglyme
diglyme
diglyme
diglyme
12
39
48
44
10
23
12
59
71
20
56
56:1
26:1
25:1
24:1
–
n.d.
28:1
26:1
23:1
21:1
51
67
68
76
–
n.d.
80
76
69
69
MeQ
BnQ
TMSQ
b-ICD
Q2PYR
Q
MeQ
TMSQ
TMSQ
TMSQ
9
9
9
10[d]
11[e]
12[f]
13[g]
82
83
87
59
10
11
12[d]
13
1.0
1.0
0.5
15:1
13:1
26:1
66
[a] Determined by 1H NMR of the crude product using DMSO as inter-
[a] Determined by 1H NMR of the crude product using DMSO as inter-
nal standard. [b] Determined by 1H NMR. [c] ee of the major trans-dia-
stereomer. [d] Reaction time 40 h.
nal standard. [b] Determined by 1H NMR. [c] ee of the major trans-dia-
stereomer determined by HPLC. [d] c
[f] c(49A)=0.33m. [g] c(49A)=0.10m.
ACHUTNGTRENNUG(49A)=0.167m. [e] cACHTUNGTRENN(UGN 49A)=0.2m.
N
ACHTUNGTRENNUNG
loadings, both yield and enantioselectivity decreased
(entry 13).
achiral quinuclidine was used in a non-enantioselective ver-
sion in the absence of Yb(OTf)3. In most cases only the re-
AHCTUNGTRENNUNG
A number of achiral additives were explored to further
improve the process (Table 6). Coordinating cosolvent like
Et2O, THF, ethyl glyme or diglyme in combination with
TMSQ resulted in a decrease in yield and ee or no product
formation at all (entries 1–4). In contrast, it was found that
the presence of diglyme considerably improved the product
formation, when quinine is used as a catalyst (entries 5–7).
Diglyme is most likely able to reversibly bind to YbIII, thus
sults for the better of the two chiral catalyst systems are
given.
While for nPrSO2Cl (16a) and nBuSO2Cl (16b), higher
enantioselectivity is attained with Q (compare entries 2, 3, 5,
6), for PhACTHNUGTRNEUNG(CH2)2SO2Cl (16d), TMSQ was more useful
(entry 8). If not mentioned otherwise the reactions were per-
formed at c=0.1m, however, different concentration optima
might exist for every substrate combination.
Chem. Eur. J. 2009, 15, 8204 – 8222
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8211

R. Peters and M. Zajac
Table 7. Investigation of different sulfonyl chlorides 16 and aromatic imines 49 bearing a 2-pyridylsulfonyl N-
protecting group.
52. Since lanthanide ions such
as YbIII offer a large number of
coordination sites, the complex-
ation of the sulfonyl chloride
substrate as in 53 is likely and
would facilitate the N-sulfony-
lation step. Coordination of the
sulfonyl moiety in 54 would
also promote the formation of
carbanion 55. Due to the elec-
tron withdrawing nature of
16
R
49
X
50
Catalyst
Yield [%][a]
d.r.[b]
ee [%][c]
both
the
2-pyridylsulfonyl
moiety coordinated to the
Lewis acid and the positively
charged aminal moiety, the gen-
erated carbanion 55 is expected
to be configurationally rather
stable at the low reaction tem-
1
2
3
4
5
6
7
8
a
a
a
b
b
b
d
d
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
Et
Et
Et
A
A[d]
A
A
A
A
A
A
B
B
C
C
D
D
E
E
F
H
H
H
H
H
H
H
H
p-Cl
p-Cl
m-Cl
m-Cl
p-Br
p-Br
m-Br
m-Br
p-F
aA
aA
aA
bA
bA
bA
dA
dA
bB
bB
bC
bC
bD
bD
bE
bE
bF
quin.
Q
TMSQ
quin.
Q
TMSQ
quin.
TMSQ
quin.
Q
quin.
TMSQ
quin.
Q
quin.
TMSQ
quin.
Q
quin.
Q
quin.
TMSQ
quin.
TMSQ
quin.
TMSQ
92
82[d]
71
73
71
59
83
52
72
70
92
72
37
46
93
59
84
73
91
76
89
61
88
67
43
54
26:1
28:1
15:1
21:1
43:1
19:1
>99:1
42:1
21:1
39:1
41:1
21:1
25:1
41:1
21:1
51:1
24:1
30:1
22:1
36:1
17:1
21:1
23:1
25:1
30:1
32:1
–
80
73
–
85
80
–
76
–
83
–
77
–
82
–
73
–
88
–
nPr
nPr
nPr
CH2Ph
CH2Ph
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
perature.[48]
Both
sulfonyl
9
oxygen atoms from the former
sulfonylchloride should be ar-
ranged gauche to the lone pair
in the a-C as a result of a stabi-
lizing nC–s*SN interaction lead-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
À
ing to hindered Ca S rotation.
This would be in analogy to
(nC–s*SR
)
interactions which
F
p-F
bF
G
G
H
H
I
I
K
K
m-F
m-F
p-MeO2C
p-MeO2C
p-F3C
p-F3C
p-Me
p-Me
bG
bG
bH
bH
bI
bI
bK
bK
are known to stabilize sulfone
carbanions[49] and might indi-
cate that deprotonation of 54
should be a diastereoselective
step thus determining the abso-
lute configuration of 50. The
templating effect of the Lewis
acid reduces the conformational
77
–
78
–
80
–
77
quin.=quinuclidine; [a] Determined by 1H NMR using DMSO as internal standard. [b] Determined by
1H NMR. [c] ee of the major diastereomer determined by HPLC. [d] Concentration of imine 49A c=0.167m.
A variety of aryl aldimines 49 bearing a phenyl moiety
substituted with a s-acceptor (Cl, Br, F, CF3), s-donor
(CH3), p-acceptor (CO2Me) or p-donor (OMe) moiety was
investigated furnishing in most cases good yields, d.r. and ee
values. For 4-halide substituted aryl imines 49B,D,F, the qui-
nine/diglyme system is superior (entries 10, 14, 18), while for
3-halide substituted aryl imines 49C,E as well as for imines
49H,I with larger acceptors in 4-position, TMSQ provides a
better outcome (entries 12, 16, 22, 24). In contrast the reac-
tion with the corresponding 2-chlorophenyl imine was not
successful. Similarly, no product was isolated applying the
corresponding imine with a 4-methoxy p-donor group. The
relatively low yields using p-bromophenyl imine 49D are
caused by its low solubility in CH2Cl2 at low temperatures
(entries 13–14).
Since YbACHTUNGTRENNUNG(OTf)3 is required for a sufficient reactivity of
the imine, it is likely, that 49 is activated by a bidentate co-
ordination forming a five-membered chelate ring in 51
(Scheme 14). This complex should be sufficiently active for
the nucleophilic addition of the alkaloid catalyst to generate
Scheme 14. Proposed mechanism for the nucleophile catalyzed and YbIII
promoted asymmetric formation of b-sultams 50 from aromatic 2-pyridyl-
sulfonyl protected imines 49.
-
8212
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Chem. Eur. J. 2009, 15, 8204 – 8222

Taurine Derivatives
FULL PAPER
flexibility resulting in enhanced stereoselectivity, but since
we have no structural or spectroscopic data about the short-
living species 52–55, it would be highly speculative to pro-
vide a working model at this point in order to explain the
origin of the (3S,4S)-configuration of 50 (for the determina-
tion of the configuration see below).
b-Sultams 50 prepared from aromatic N-pyridylsulfonyl
imines 49 were also useful for ring-opening reactions with
O-, N- and C-nucleophiles as showcased for 50bA
(Scheme 15). Using 2-phenylethanol/Et3N, sulfonate 56 was
formed in 76% yield. With benzylamine and pyrrolidine the
secondary sulfonamide 57 and the tertiary sulfonamide 58
were prepared in 83 and 91% yield, respectively. Treatment
with PhMgBr furnished phenylsulfone 59 in 86% yield.
During these transformations, no change of ee or d.r. was
detected.[50]
b-sultams 50. With sodium amalgam in MeOH, both the pyr-
idylsulfonyl and phenylsulfonyl groups can be removed in
one step to give the 1-phenylpentane amine (62) in a non-
optimized yield of 43% (Scheme 17). By comparison to lit-
erature reported optical rotation data,[52] the (R)-configura-
tion was assigned to this product. 1H NMR NOE experi-
1
ments and the H NMR J-coupling constants of the ring pro-
tons (ca. 9 Hz for cis-b-sultams, ca. 5 Hz for trans-b-sultams)
revealed a trans configuration on the sultam stage (see the
Supporting Information). The absolute configuration of
50bA could thus be assigned to as (3S,4S).
Scheme 17. Determination of the absolute configuration of b-sultam
50bA via b-amino sulfone 59 by complete reductive desulfonylation
forming the literature-known chiral primary amine 62.
Conclusion
In conclusion, we have developed an organocatalytic cyclo-
addition method which allows for a rapid asymmetric access
to enantioenriched b-sultams starting from sulfonylchlorides
and highly reactive non-nucleophilic imines derived from
chloral or ethylglyoxylate. Our studies suggest that a zwitter-
ionic aminal is formed as reactive intermediate and that no
sulfene formation is involved. The limitation to exceptional-
ly electrophilic imines was overcome by 2-pyridylsulfonyl
imines derived from non-activated aromatic aldehydes in
combination with YbACTHNUTRGNEUNG(OTf)3 as Lewis acid cocatalyst. The b-
sultams are valuable precursors for the formation of enan-
tioenriched b-aminosulfonyl derivatives possessing two vici-
nal stereocenters. Smooth nucleophilic ring opening reac-
tions were accomplished with O-, N- and C-nucleophiles
yielding acyclic b-aminosulfonates, -sulfonamides, or -sul-
fones without racemization or epimerization. Both the cy-
cloaddition products and the acyclic taurine derivatives are
of potential biological interest.
Scheme 15. Nucleophilic ring opening of pyridylsulfonyl protected b-
sultam 50bA with an alcohol, a primary and a secondary amine, and a
Grignard reagent.
Cleavage of the N-2-pyridylsulfonyl group from the acy-
clic products was achieved under reductive conditions
(Scheme 16). The deprotected b-aminosulfonamides 60 and
61 could be isolated in 76 and 73% yield, respectively, after
treatment with Mg/MeOH.[51]
Experimental Section
General information, additional procedures, NMR spectra and HPLC
chromatograms are given in the Supporting Information.
À
The lability of the S C bonds in sulfone 59 was finally uti-
General procedure for the formation of N-tosyl-4-alkyl-3-trichlorometh-
yl-b-sultams (GP 1): A Schlenk tube was charged with imine 21 (50 mg,
0.166 mmol, 1.0 equiv) and the corresponding cinchona alkaloid deriva-
tive (0.017 mmol, 0.1 equiv), evacuated and filled with nitrogen. A solu-
tion was prepared by addition of dry CH2Cl2 (1 mL) which was stirred
for 5 min at room temperature and which was subsequently cooled to
À808C. After 10 min, DIPEA (diisopropylethylamine, 72 mL,
0.414 mmol, 2.5 equiv) was added dropwise, followed after additional
5 min by the indicated sulfonyl chloride 16 [0.332 mmol, 2.0 equiv, neat
or as a solution in CH2Cl2 (0.5 mL, for sulfonylchlorides 16d and 16e)].
The reaction mixture was stirred at À808C for 20 h. After this time, the
lized for the determination of the absolute configuration of
Scheme 16. Deprotection of the acyclic derivatives 57 and 58.
Chem. Eur. J. 2009, 15, 8204 – 8222
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www.chemeurj.org
8213

R. Peters and M. Zajac
reaction was quenched with 0.1m aqueous HCl (1 mL) and the mixture
was warmed up to room temperature, diluted with ethyl acetate (10 mL)
and washed with 0.1m HCl (10 mL) and brine (10 mL). The organic
ACHTUNGTRENNUNG
phase was dried over Na2SO4, filtered and evaporated in vacuo to give
1
the crude product. Yields were determined by H NMR using nitro
N
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
dine-1,1-dioxide (22a): According to GP 1, using cinchonidine (Cd, 6 mg,
0.017 mmol, 0.1 equiv) as the catalyst and n-propanesulfonyl chloride 16a
(37 mL, 0.332 mmol, 2.0 equiv). The product was obtained as slightly
yellow solid (0.129 mmol, 78% yield, 19:1 d.r., 81% ee). The ee values
were determined by HPLC (Chiralcel OD-H, n-hexane/iPrOH 80:20,
1.0 mLminÀ1). An analytical sample was obtained by recrystallization
from cyclohexane/ethyl acetate 1:1. C12H14Cl3NO4S2, MW
=
406.72 gmolÀ1; m.p. 184.9–185.68C; [a]D24:6 (c=1.485, CHCl3) = +56.3Æ
0.3 (sample with ee 82% after recrystallization from ethyl acetate/cyclo-
hexane 1:1); 1H NMR (400 MHz, CDCl3, 228C): d=7.92 (d, J=8.4 Hz,
2H, CHPh), 7.37 (d, J=8.4 Hz, 2H, CHPh), 4.77 (d, J=9.1 Hz, 1H, CH-
N), 4.68 (ddd, J=12.4, 9.1, 3.6 Hz, 1H, CH-CH2), 2.63–2.51 (m, 1H,
CH2), 2.47 (s, 3H, CH3-Ph), 2.31–2.21 (m, 1H, CH2), 1.17 ppm (t, J=
7.3 Hz, 3H, CH3-CH2); 13C NMR (100 MHz, CDCl3, 228C): d=145.8,
134.5, 129.8, 128.6, 95.3, 80.8, 65.3, 21.8, 18.6, 13.3 ppm; IR (ATR, neat):
793 cmÀ1
; HRMS (ESI): m/z: calcd for: 489.9479; found: 489.9486
[M+Na]+; elemental analysis calcd (%) for C17H16Cl3NO4S2: C 43.55, H
3.44, N 2.99; found: C 43.54, H 3.52, N 2.96.
AHCTUNGTERG(NNUN 3R,4R)-4-(2-(4-Methoxyphenoxy)-ethyl)-2-(p-toluenesulfonyl)-3-(tri-
chloromethyl)-1,2-thiazetidine-1,1-dioxide (22e): According to GP 1,
using quinine (Q, 6 mg, 0.017 mmol, 0.1 equiv) as catalyst and 2-(4-me-
thoxyphenoxy)propanesulfonyl chloride 16e (88 mg, 0.332 mmol,
2.0 equiv) as solution in CH2Cl2 (0.5 mL). The product was obtained as
slightly yellow solid (0.158 mmol, 95% yield, 13:1 d.r., 87% ee). The ee
values were determined by HPLC (Chiralcel OD-H, n-hexane/EtOH
65:35, 1.0 mLminÀ1). An analytical sample was obtained by recrystalliza-
n˜ =2955, 2936, 1372, 1362, 1199, 1176, 1157, 1085, 1015, 932, 802 cmÀ1
;
HRMS (EI): m/z (%): calcd for: 288.0359; found: 288.0356 (18.7)
[MÀCCl3]+; elemental analysis calcd (%) for C12H14Cl3NO4S2: C 35.44, H
3.47, N 3.44; found: C 35.57, H 3.57, N 3.41.
ACHTUNGTRENNUNG(3R,4R)-4-Propyl-2-(p-toluenesulfonyl)-3-(trichloromethyl)-1,2-thiazeti-
dine-1,1-dioxide (22b): According to GP 1, using quinine (Q, 6 mg,
0.017 mmol, 0.1 equiv) as catalyst and n-butanesulfonyl chloride 16b
(43 mL, 0.332 mmol, 2.0 equiv). The product was obtained as slightly
yellow solid (0.134 mmol, 81% yield, 18:1 d.r., 91% ee). The ee values
were determined by HPLC (Chiralcel OD-H, n-hexane/iPrOH 97:3,
1.0 mLminÀ1). An analytical sample was obtained by recrystallization
tion from cyclohexane/ethyl acetate 1:1. C19H20Cl3NO6S2, MW
=
528.86 gmolÀ1; m.p. 199.0–199.48C; [a]D24:7 (c=0.970, CHCl3) = À48.1Æ
0.9 (sample with ee 90% after recrystallization from ethyl acetate/cyclo-
hexane 1:1); 1H NMR (400 MHz, CDCl3, 228C): d=7.94 (d, J=8.4 Hz,
2H, CHPh), 7.37 (d, J=8.4 Hz, 2H, CHPh), 6.86–6.80 (m, 4H, CHPh), 5.02
(ddd, J=11.8, 9.2, 2.6 Hz, 1H, CH-CH2), 4.81 (d, J=9.2 Hz, 1H, CH-N),
4.10–4.05 (m, 1H, CHH-O), 4.01–3.96 (m, 1H, CHH-O), 3.76 (s, 3H,
CH3-O), 3.05–2.96 (m, 1H, CHH-CH), 2.81–2.73 (m, 1H, CHH-CH),
2.47 ppm (s, 3H, CH3-Ph); 13C NMR (100 MHz, CDCl3, 228C): d=154.5,
152.1, 145.8, 134.5, 129.9, 128.6, 115.6, 114.7, 95.4, 76.3, 65.6, 64.8, 55.7,
25.1, 21.8 ppm; IR (ATR, neat): n˜ =2950, 2935, 1509, 1376, 1365, 1230,
1193, 1169, 1053, 1030, 936, 810 cmÀ1; HRMS (ESI) m/z: calcd for:
549.9690; found: 549.9701 [M+Na]+.
from cyclohexane/ethyl acetate 1:1. C13H16Cl3NO4S2, MW
=
420.76 gmolÀ1; m.p. 162.0–162.58C; [a]D23:9 (c=1.015, CHCl3) = +89.0Æ
0.2 (sample with ee 99% after recrystallization from ethyl acetate/cyclo-
hexane 1:1); 1H NMR (400 MHz, CDCl3, 228C): d=7.92 (d, J=8.4 Hz,
2H, CHPh), 7.37 (d, J=8.4 Hz, 2H, CHPh), 4.79–4.70 (m, 2H, CH-CH2,
CH-N), 2.56–2.46 (m, 1H, CHH-CH), 2.47 (s, 3H, CH3-Ph), 2.22–2.13
(m, 1H, CHH-CH), 1.65–1.54 (m, 1H, CHH-CH2), 1.52–1.39 (m, 1H,
CHH-CH2), 1.01 ppm (t, J=7.3 Hz, 3H, CH3-CH2); 13C NMR (100 MHz,
CDCl3, 228C): d=145.8, 134.6, 129.8, 128.6, 95.3, 79.0, 65.2, 26.6, 22.3,
21.8, 13.3 ppm; IR (ATR, neat): n˜ =2990, 2971, 1465, 1357, 1342, 1194,
1169, 1158, 1086, 1035, 950, 803 cmÀ1; HRMS (EI): m/z (%): calcd for:
302.0515; found: 302.0514 (19.9) [MÀCCl3]+; elemental analysis calcd
(%) for C13H16Cl3NO4S2: C 37.14, H 3.83, N 3.33; found: C 37.32, H 4.01,
N 3.24.
AHCTUNGTRENGN(UN 3S,4S)-4-Methyl-2-(p-toluenesulfonyl)-3-(trichloromethyl)-1,2-thiazeti-
dine-1,1-dioxide (22 f): According to GP 1, using Q2PYR (15 mg,
0.017 mmol, 0.1 equiv) as catalyst and ethanesulfonyl chloride 16 f
(29 mL, 0.332 mmol, 2.0 equiv). The product was obtained as colorless
solid (0.133 mmol, 80% yield, 17:1 d.r., 80% ee). The ee values were de-
termined by HPLC (Chiralcel OD-H, n-hexane/EtOH 80:20,
1.0 mLminÀ1). An analytical sample was obtained by recrystallization
ACHTUNGTRENNUNG(3R,4R)-4-(2-Chloroethyl)-2-(p-toluenesulfonyl)-3-(trichloromethyl)-1,2-
thiazetidine-1,1-dioxide (22c): According to GP 1, using quinine (Q,
6 mg, 0.017 mmol, 0.1 equiv) as catalyst and 3-chloropropanesulfonyl
chloride 16c (40 mL, 0.332 mmol, 2.0 equiv). The product was obtained as
slightly yellow solid (0.129 mmol, 78% yield, 11:1 d.r., 94% ee). The ee
values were determined by HPLC (Chiralcel OD-H, n-hexane/EtOH
85:15, 1.0 mLminÀ1). An analytical sample was obtained by recrystalliz-
from cyclohexane/ethyl acetate 1:1. C11H12Cl3NO4S2, MW
=
392.71 gmolÀ1; m.p. 178.5–179.38C (racemic); [a]D23:4 (c=0.450, CHCl3)=
À48.3Æ0.7 (sample with ee 98% after recrystallization from ethyl ace-
1
tate/cyclohexane 1:1); H NMR (400 MHz, CDCl3, 228C): d=7.93 (d, J=
8.4 Hz, 2H, CHPh), 7.37 (d, J=8.4 Hz, 2H, CHPh), 4.87 (qd, J=9.1,
7.4 Hz, 1H, CH-CH3), 4.78 (d, J=9.1 Hz, 1H, CH-N), 2.47 (s, 3H, CH3-
Ph), 1.87 ppm (d, J=7.4 Hz, 3H, CH3-CH); 13C NMR (100 MHz, CDCl3,
228C): d=145.9, 134.4, 129.8, 128.7, 95.2, 73.0, 64.8, 21.8, 9.7 ppm; IR
(ATR, neat): n˜ =2963, 1364, 1204, 1178, 1163, 1039, 1001, 926, 828, 805,
785 cmÀ1; HRMS (EI): m/z (%): calcd for: 274.0202; found: 274.0201
(18.8) [MÀCCl3]+; elemental analysis calcd (%) for C11H12Cl3NO4S2: C
33.64, H 3.08, N 3.57; found: C 33.46, H 3.03, N 3.55.
ACHTUNGTRENNUNGation from cyclohexane/ethyl acetate 1:1. C12H13Cl4NO4S2, MW =
441.18 gmolÀ1; m.p. 178.0–178.48C; [a]D24:4 (c=0.610, CHCl3) = +97.3Æ
0.3 (sample with ee 99% after recrystallization from ethyl acetate/cyclo-
hexane 1:1); 1H NMR (400 MHz, CDCl3, 228C): d=7.93 (d, J=8.4 Hz,
2H, CHPh), 7.39 (d, J=8.4 Hz, 2H, CHPh), 5.05 (ddd, J=11.4, 9.1, 3.0 Hz,
1H, CH-CH2), 4.82 (d, J=9.1 Hz, 1H, CH-N), 3.81–3.76 (m, 1H, CHH-
Cl), 3.61–3.55 (m, 1H, CHH-Cl), 3.08–2.99 (m, 1H, CHH-CH), 2.78–2.69
(m, 1H, CHH-CH), 2.48 ppm (s, 3H, CH3-Ph); 13C NMR (100 MHz,
CDCl3, 228C): d=146.1, 134.1, 129.9, 128.7, 95.0, 74.9, 64.7, 41.9, 27.9,
21.8 ppm; IR (ATR, neat): n˜ =2933, 1367, 1357, 1348, 1181, 1192, 1163,
1084, 1025, 930, 829, 813, 799 cmÀ1; HRMS (EI): m/z (%): calcd for:
438.9035; found: 438.9038 (0.3) [M]+; elemental analysis calcd (%) for
C12H13Cl4NO4S2: C 32.67, H 2.97, N 3.17; found: C 32.90, H 3.01, N 3.15.
AHCTUNGTERG(NNUN 2R,3R)-1,1,1-Trichloro-2-(p-toluenesulfonylamino)pentane-3-sulfonic
acid phenethyl ester (27): To a stirred solution of b-sultam 22a (50 mg,
0.123 mmol, 1.0 equiv, recrystallized from ethyl acetate/cyclohexane 1:1,
> 100:1 d.r., 83% ee) in CH2Cl2 (0.5 mL) at room temperature, 2-phenyl-
ethanol (29 mL, 0.246 mmol, 2.0 equiv) and triethylamine (17 mL,
0.246 mmol, 1.0 equiv) were added as a solution in CH2Cl2 (0.5 mL) and
the mixture was stirred for 14 h. After this time, the mixture was diluted
8214
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ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 8204 – 8222

Taurine Derivatives
FULL PAPER
with ethyl acetate (10 mL) and washed with 0.1m aqueous HCl (10 mL)
and brine (10 mL). The organic phase was dried over Na2SO4, filtered
and evaporated in vacuo. The crude product was purified by flash chro-
matography on silica gel (ethyl acetate/cyclohexane 1:4) to furnish the
pure product 27 as colorless solid (55 mg, 0.105 mmol, 85% yield,
>100:1 d.r., 83% ee). The ee values were determined by HPLC (Chiral-
of PhMgBr (3m in Et2O, 59 mL, 0.178 mmol, 2.0 equiv) was slowly added,
the mixture was stirred at À58C for 15 min, allowed to warm to RT and
stirred for additional 15 h. The reaction was quenched by addition of sat.
aq. NH4Cl (2 mL), the mixture was diluted with brine (10 mL) and ex-
tracted with ethyl acetate (2ꢄ10 mL). The combined organic layers were
dried over Na2SO4 and evaporated in vacuo. The crude product was puri-
fied by flash chromatography on silica gel (ethyl acetate/cyclohexane 1:3)
to furnish the pure product 38 as colorless oil which solidified upon
standing (31 mg, 0.076 mmol, 85% yield, > 100:1 d.r., 82% ee). The ee
values were determined by HPLC (Chiralcel OD-H, n-hexane/iPrOH
90:10, 1.0 mLminÀ1). C18H22ClNO4S2, MW = 415.95 gmolÀ1; [a]D29:1 (c=
0.75, CHCl3)=À7.5Æ0.6 (sample with ee 82%); 1H NMR (300 MHz,
CDCl3, 228C): d=7.81 (d, J=8.4 Hz, 2H, CHTs), 7.74 (d, J=7.2 Hz, 2H,
CHPh), 7.68 (t, J=7.5 Hz, 1H, CHPh), 7.55 (t, J=7.5 Hz, 2H, CHPh), 7.33
(d, J=8.4 Hz, 2H, CHTs), 5.84 (d, J=8.1 Hz, 1H, NH), 3.97 (m, 2H, CH-
CH2, CHHCl), 3.73 (dd, J=10.3, 3.1 Hz, 1H, CHHCl), 3.35 (m, 1H, CH-
NH), 2.45 (s, 3H, CH3-Ph), 1.73 (m, 2H, CH2-CH3), 0.91 ppm (t, J=
7.5 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3, 228C): d = 143.9, 137.8,
136.8, 134.2, 129.6, 129.3, 128.3, 127.5, 67.6, 55.1, 43.2, 21.5, 19.5,
11.8 ppm; IR (ATR, neat): n˜ =3310, 1447, 1332, 1301, 1282, 1157, 1140,
1088, 1071, 817, 729 cmÀ1; HRMS (ESI): m/z: calcd for: 438.0571; found:
438.0566 [M+Na]+.
cel AD-H, n-hexane/EtOH 93:7, 1.0 mLminÀ1). C20H24Cl3NO5S2, MW
=
528.90 gmolÀ1; m.p. 145.3–145.78C; [a]D26:1 (c=0.285, CHCl3) = +19.3Æ
1.0 (sample with ee 90% after recrystallization from ethyl acetate/cyclo-
hexane 1:1); 1H NMR (300 MHz, CDCl3, 228C): d=7.81 (d, J=8.4 Hz,
2H, CHPh), 7.35–7.22 (m, 7H, CHPh), 5.32 (d, J=10.6 Hz, 1H, NH), 5.16
(dd, J=10.6, 1.2 Hz, 1H, CH-NH), 4.49 (t, J=7.2 Hz, 2H, CH2-O), 3.64
(m, 1H, CH-CH2), 3.09 (t, J=7.2 Hz, 2H, CH2-Ph), 2.42 (s, 3H, CH3-Ph),
1.92–1.80 (m, 2H, CH2-CH), 1.09 ppm (t, J=7.5 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3, 228C): d=143.8, 137.7, 136.0, 129.4, 128.9, 128.6, 127.2,
127.0, 101.2, 70.3, 66.8, 63.8, 35.8, 21.7, 21.2, 12.8 ppm; IR (ATR, neat):
n˜ =3291, 2972, 2926, 1456, 1340, 1318, 1233, 1151, 1140, 1094, 951, 928,
902, 853 cmÀ1
; HRMS (MALDI) m/z: calcd for: 550.0054; found:
550.0053 [M+Na]+; elemental analysis calcd (%) for C20H24Cl3NO5S2: C
45.42, H 4.57, N 2.65; found: C 45.70, H 4.75, N 2.57.
ACHTUNGTRENNUNG(1R,2R)-N-[2-Benzylsulfamoyl-1-(trichloromethyl)-butyl]-p-toluenesulfo-
namide (28): To a stirred solution of b-sultam 22a (50 mg, 0.123 mmol,
1.0 equiv, ethyl acetate/cyclohexane 1:1, > 100:1 d.r., 83% ee) in CH2Cl2
(0.5 mL) at room temperature, benzylamine (13 mL, 0.123 mmol,
1.0 equiv) was added as a solution in CH2Cl2 (0.5 mL) and the solution
was stirred for 14 h. The solvent was then evaporated in vacuo to furnish
the pure product 28 as colorless solid (61 mg, 0.118 mmol, 96% yield,
>100:1 d.r., 83% ee). The ee values were determined by HPLC (Chiral-
(S)-2-((R)-1-(4-Phenoxyphenylsulfonyl)propyl)-1-tosylaziridine (41a): In
a glove-box under nitrogen, a reaction flask was charged with finely
ground AgNO3 (15 mg, 0.087 mmol, 1.1 equiv). A solution containing sul-
fone 42a (40 mg, 0.079 mmol, 1.0 equiv, > 100:1 d.r., 82% ee) in DMF
(3 mL) was added followed by DIPEA (15 mL, 0.087 mmol, 1.1 equiv)
and the mixture was stirred at RT for 15 h. After this time, the mixture
was poured onto water (10 mL) and extracted with ethyl acetate (2ꢄ
10 mL). The combined organic layers were washed with brine, dried over
Na2SO4 and evaporated in vacuo. The crude product was purified by
flash chromatography on silica gel (ethyl acetate/cyclohexane 1:3) to fur-
nish the pure aziridine 41a as colorless oil (35 mg, 0.075 mmol, 95%
yield, > 100:1 d.r., 82% ee). The ee values were determined by HPLC
(Chiralcel OD-H, n-hexane/iPrOH 90:10, 1.0 mLminÀ1). C24H25ClNO5S2,
MW = 471.59 gmolÀ1; [a]D28:5 (c=0.45, CHCl3)=À39.8Æ0.3 (sample with
cel AD-H, n-hexane/EtOH 93:7, 1.0 mLminÀ1). C19H23Cl3N2O4S2, MW
=
513.89 gmolÀ1; m.p. 171.0–171.38C; [a]D25:9 (c=0.595, CHCl3)=À26.7Æ0.6
(sample with ee 80%); 1H NMR (300 MHz, CDCl3, 228C): d=7.78 (d,
J=8.4 Hz, 2H, CHPh), 7.43–7.25 (m, 7H, CHPh), 5.52 (dd, J=6.8, 5.0 Hz,
1H, NH-CH2), 5.32 (d, J=10.6 Hz, 1H, NH-Ts), 5.10 (d, J=10.0 Hz, 1H,
CH-NH), 4.56 (dd, J=14.3, 7.2 Hz, 1H, CHH-Ph), 4.40 (dd, J=14.3,
4.7 Hz, 1H, CHH-Ph), 3.70 (m, 1H, CH-CH2), 2.42 (s, 3H, CH3-Ph),
2.05–1.93 (m, 2H, CH2-CH), 1.27 ppm (t, J=7.5, 3H, CH3-CH2);
13C NMR (75 MHz, CDCl3, 228C): d=144.2, 137.4, 136.8, 129.5, 128.7,
127.8, 127.4, 101.0, 67.7, 66.3, 48.1, 21.7, 20.9, 13.3 ppm; IR (ATR, neat):
ee 82%); 1H NMR (300 MHz, CDCl3, 228C): d=7.79 (m, 4H, CHPh
,
CHTs), 7.44 (t, J=8.4 Hz, 2H, CHPh), 7.34 (d, J=8.1 Hz, 2H, CHTs), 7.26
(t, J=7. Hz 2, 1H, CHPh), 7.09 (m, 4H, CHPh), 2.83 (m, 1H, CH-CH2),
2.54 (d, J=10.9 Hz, 1H, CHH-N), 2.49 (m, 1H, CH-N), 2.45 (s, 3H,
CH3-Ph), 2.02 (m, 1H, CHH-CH3), 1.94 (d, J=4.0 Hz, 1H, CHH-N), 1.72
(m, 1H, CHH-CH3), 1.04 ppm (t, J=7.5 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3, 228C): d=163.1, 154.6, 145.2, 134.2, 131.1, 130.9, 130.4,
129.9, 128.2, 125.4, 120.6, 117.6, 68.4, 37.9, 33.5, 21.9, 21.7, 11.1 ppm; IR
(ATR, neat): n˜ =1580, 1486, 1319, 1293, 1242, 1158, 1140, 1084, 901, 868,
711 cmÀ1; HRMS (EI): m/z (%): calcd for: 407.1550; found: 407.1547
(17.8) [MÀSO2]+.
n˜ =3299, 3239, 2963, 2923, 1454, 1322, 1159, 1132, 1089, 1073, 923 cmÀ1
;
HRMS (MALDI) m/z: calcd for: 535.0057; found: 535.0056 [M+Na]+;
elemental analysis calcd (%) for C19H23Cl3N2O4S2: C 44.41, H 4.51, N
5.45; found: C 44.27, H 4.60, N 5.38.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
0.246 mmol, 1.0 equiv, recrystallized from ethyl acetate/cyclohexane 1:1,
> 100:1 d.r., 83% ee) in CH2Cl2 (1 mL) at room temperature, pyrrolidine
(21 mL, 0.246 mmol, 1.0 equiv) was added as
a solution in CH2Cl2
N-((2R,3R)-1-Chloro-3-(4-phenoxyphenylsulfonyl)pentan-2-yl)-4-methyl-
benzene-sulfonamide (42): A reaction flask was charged with b-sultam
33a (40 mg, 0.118 mmol, 1.0 equiv, > 100:1 d.r., 82% ee), evacuated and
filled with nitrogen. A suspension was prepared by addition of Et2O
(5 mL) and was subsequently cooled to À58C in an ice bath. After 5 min,
a solution of 4-(phenoxyphenyl)magnesium bromide (prepared from 1-
bromo-4-phenoxybenzene and Mg, 2m in Et2O, 118 mL, 0.237 mmol,
2.0 equiv) was slowly added, the mixture was stirred at À58C for 15 min,
allowed to warm to RT and stirred for additional 16 h. The reaction was
quenched by addition of sat. aq. NH4Cl (3 mL), the mixture was diluted
with brine (10 mL) and extracted with ethyl acetate (2ꢄ10 mL). The
combined organic layers were dried over Na2SO4 and evaporated in
vacuo. The crude product was purified by flash chromatography on silica
gel (ethyl acetate/cyclohexane 1:2) to furnish the pure sulfone 42a as col-
orless oil (50 mg, 0.098 mmol, 83% yield, > 100:1 d.r., 82% ee). The ee
values were determined by HPLC (Chiralcel OD-H, n-hexane/iPrOH
90:10, 1.0 mLminÀ1). C24H26ClNO5S2, MW = 508.05 gmolÀ1; [a]D25:6 (c=
0.78, CHCl3) = À0.6Æ0.2 (sample with ee 82%); 1H NMR (300 MHz,
CDCl3, 228C): d=7.81 (d, J=8.4 Hz, 2H, CHTs), 7.64 (d, J=9.0 Hz, 2H,
CHPh), 7.44 (t, J=8.1 Hz, 2H, CHPh), 7.32 (d, J=8.4 Hz, 2H, CHTs), 7.26
(t, J=7.2 Hz, 1H, CHPh), 7.08 (d, J=7.5 Hz, 2H, CHPh), 7.02 (d, J=
9.0 Hz, 2H, CHPh), 5.85 (d, J=8.1 Hz, 1H, NH), 3.95 (m, 2H, CH-CH2,
(0.5 mL) and the solution was stirred for 14 h. The solvent was then
evaporated in vacuo to furnish the pure product 29 as colorless solid
(114 mg, 0.239 mmol, 97% yield, > 100:1 d.r., 85% ee). The ee values
were determined by HPLC (Chiralcel AD-H, n-hexane/EtOH 93:7,
1.0 mLminÀ1). C16H23Cl3N2O4S2, MW
= ; m.p. 170.5–
477.85 gmolÀ1
171.18C; [a]2D5:6 (c=1.510, CHCl3) = +37.1Æ0.2 (sample with ee 80%);
1H NMR (300 MHz, CDCl3, 228C): d=7.85 (d, J=8.1 Hz, 2H, CHPh),
7.28 (d, J=8.1 Hz, 2H, CHPh), 5.37 (d, J=10.3, 1H, NH), 5.06 (dd, J=
10.3, 0.9, 1H, CH-NH), 3.57–3.43 (m, 5H, CH-CH2, 2ꢄCH2-N), 2.42 (s,
3H, CH3-Ph), 1.99–1.88 (m, 4H, 2ꢄCH2CH2-N), 1.86–1.76 (m, 2H, CH2-
CH), 1.14 ppm (t, J=7.5 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3,
228C): d=143.9, 138.4, 129.6, 127.5, 102.2, 66.9, 64.3, 48.8, 26.2, 21.8,
20.5, 13.5 ppm; IR (ATR, neat): n˜ =3258, 2972, 2883, 1459, 1325, 1314,
1159, 1133, 1091, 1013, 984, 915 cmÀ1; HRMS (MALDI): m/z: calcd for:
499.0057; found: 499.0052 [M+Na]+; elemental analysis calcd (%) for
C16H23Cl3N2O4S2: C 40.22, H 4.85, N 5.86; found: C 40.49, H 4.91 N, 5.88.
N-((2R,3R)-1-Chloro-3-(phenylsulfonyl)pentan-2-yl)-4-methylbenzenesul-
fonamide (38): A reaction flask was charged with b-sultam 33a (30 mg,
0.089 mmol, 1.0 equiv, > 100:1 d.r., 82% ee), evacuated and filled with
nitrogen. A suspension was prepared by addition of Et2O (3 mL) and
was subsequently cooled to À58C in an ice bath. After 5 min, a solution
Chem. Eur. J. 2009, 15, 8204 – 8222
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8215

R. Peters and M. Zajac
CHHCl), 3.72 (dd, J=10.9, 4.0 Hz, 1H, CHHCl), 3.31 (m, 1H, CH-NH),
2.41 (s, 3H, CH3-Ph), 1.73 (m, 2H, CH2-CH3), 0.95 ppm (t, J=7.5 Hz,
3H, CH3); 13C NMR (75 MHz, CDCl3, 228C): d=162.7, 154.2, 143.7,
136.7, 130.7, 130.5, 130.1, 129.5, 127.3, 125.2, 120.4, 117.3, 76.9, 55.3, 43.4,
21.8, 19.8, 12.3 ppm; IR (ATR, neat): n˜ =3289, 1580, 1486, 1289, 1242,
1158, 1133, 1085, 1070, 869, 728 cmÀ1; HRMS (ESI): m/z: calcd for:
530.0833; found: 530.0834 [M+Na]+.
The product was obtained as colorless solid (43 mg, 0.078 mmol, 40%
yield, 17:1 d.r., 78% ee). The ee values were determined by HPLC (Chir-
alcel AD-H 25 cm, n-hexane/EtOH 90:10, 1.0 mLminÀ1). C27H40NO6S2,
MW = 552.76 gmolÀ1; m.p. 98.6–99.58C; [a]D26:9 (c = 0.585, CHCl3) =
+31.9Æ0.5 (sample with ee 78%); 1H NMR (300 MHz, CDCl3, 228C):
d=7.70 (d, J=8.1 Hz, 2H, CHPh), 7.38–7.25 (m, 7H, CHPh), 5.67 (d, J=
9.3 Hz, 1H, NH-CH), 4.19 (dd, J=9.3, 2.5 Hz, 1H, CH-NH), 4.05–3.88
(m, 3H, CH2-O, NH-CH2), 3.72 (m, 1H, CH-CH2), 3.29 (dd, J=14.3,
6.2 Hz, 1H, CHH-Ph), 3.17 (dd, J=14.3, 8.1 Hz, 1H, CHH-Ph), 3.06–2.94
(m, 1H, CHH-NH), 2.87–2.76 (m, 1H, CHH-NH), 2.41 (s, 3H, CH3-Ph),
1.43–1.29 (m, 2H, CH2-CH2NH), 1.24 (brs, 10H, (CH2)5), 1.07 (t, J=
6.8 Hz, 3H, CH3-CH2O), 0.88 ppm (t, J=6.8 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3, 228C): d=169.2, 144.0, 136.9, 136.8, 129.8, 129.4, 129.2,
127.6, 65.3, 62.8, 55.6, 43.7, 33.3, 31.9, 30.3, 29.3, 26.6, 22.8, 21.7, 14.3,
13.9 ppm; IR (ATR, neat): n˜ =3336, 2925, 2854, 1721, 1715, 1443, 1408,
1328, 1278, 1165, 1149, 1092, 1028 cmÀ1; HRMS (ESI): m/z: calcd for:
575.2220; found: 575.2219 [M+Na]+; elemental analysis calcd (%) for
C27H40NO6S2: C 58.67, H 7.29, N 5.07; found: C 58.38, H 7.22, N 4.95.
General procedure for the formation of N-tosyl-4-alkyl-3-ethylcarboxyl-
b-sultams (GP 2): In a Schlenk tube, a solution of quinine (Q, 6 mg,
0.020 mmol, 0.1 equiv) in dry CH2Cl2 (0.5 mL) was cooled to À808C.
After 10 min, DIPEA (diisopropylethylamine, 85 mL, 0.490 mmol,
2.5 equiv) was added dropwise, followed after additional 5 min by the
requisite sulfonyl chloride 16 (0.392 mmol, 2.0 equiv, neat or as a solution
in CH2Cl2 (0.25 mL) in the case of sulfonyl chloride 16d). To this mix-
ture, imine 43 (50 mg, 0.196 mmol, 1.0 equiv) was added as a solution in
CH2Cl2 (0.5 mL) over a period of 10 h using a syringe pump. After com-
plete addition the reaction mixture was stirred at À808C for additional
10 h and finally n-octylamine (65 mL, 0.392 mmol, 2.0 equiv) was added at
the same temperature. The mixture was allowed to warm to room tem-
perature and was stirred for additional 1 h. It was subsequently diluted
with ethyl acetate (10 mL) and washed successively with 0.1m aqueous
HCl (10 mL) and brine (10 mL). The organic phase was dried over
Na2SO4, filtered and evaporated in vacuo. The crude product was puri-
fied by flash chromatography on silica gel (cyclohexane/ethyl acetate
6:1).
N-1-Hydroxy-3-(N-octylsulfamoyl)hexan-2-yl)-4-methylbenzenesulfon
ACHTUNGTRENNUNGam-
AHCTUNGTREiGNUNN de (45): A reaction flask was charged with LiAlH4 (2 mg, 0.06 mmol,
2.0 equiv), evacuated and filled with nitrogen. A suspension was formed
by addition of THF (0.5 mL) and was subsequently cooled to 08C. To
this mixture, sulfonamide 44b (16 mg, 0.03 mmol, 1.0 equiv, > 50:1 d.r.,
racemic) was added slowly as a solution in THF (0.5 mL). The resulting
mixture was allowed to warm to RT and was stirred for additional 15 h.
The reaction was quenched by addition of 0.1m aqueous HCl (10 mL)
and the mixture was extracted with ethyl acetate (3ꢄ5mL). The com-
bined organic layers were dried over Na2SO4, filtered and evaporated in
vacuo. The crude product was purified by flash chromatography on silica
gel (ethyl acetate/cyclohexane 1:3) to furnish the pure sulfonamide 45 as
3-Octylsulfamoyl-2-(p-toluenesulfonylamino)pentanoic acid ethyl ester
(44a): According to GP 2, using n-propanesulfonyl chloride 16a (44 mL,
0.392 mmol, 2.0 equiv). The product was obtained as colorless solid
(53 mg, 0.108 mmol, 55% yield, 11:1 d.r., 80% ee). The ee values were
determined by HPLC (Chiralcel OD-H 25+15 cm, n-hexane/EtOH 98:2,
0.7 mLminÀ1). C22H38N2O6S2, MW = 490.69 gmolÀ1; m.p. 124.8–125.38C;
[a]2D6:4 (c=0.865, CHCl3) = +10.4Æ0.7 (sample with ee 80%); 1H NMR
(300 MHz, CDCl3, 228C): d=7.73 (d, J=8.4 Hz, 2H, CHPh), 7.28 (d, J=
8.4 Hz, 2H, CHPh), 5.74 (d, J=9.6 Hz, 1H, NH-CH), 4.39 (t, J=5.9 Hz,
1H, NH-CH2), 4.27 (dd, J=9.6, 2.8 Hz, 1H, CH-NH), 4.08–3.86 (m, 2H,
CH2-O), 3.55–3.48 (m, 1H, CH-CH2), 3.04 (q, J=6.8 Hz, 2H, CH2-NH),
2.41 (s, 3H, CH3-Ph), 2.06–1.82 (m, 2H, CH2-CH), 1.59–1.44 (m, 2H,
CH2-CH2NH), 1.26 (brs, 10H, (CH2)5), 1.09 (m, 6H, 2ꢄCH3), 0.87 ppm
(t, J=7.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3, 228C): d=169.6,
144.0, 137.0, 129.8, 127.5, 66.0, 62.7, 54.6, 43.9, 31.9, 30.6, 29.3, 26.7, 22.8,
21.7, 20.1, 14.2, 13.9, 11.6 ppm; IR (ATR, neat): n˜ =3308, 2928, 2855,
1749, 1716, 1460, 1437, 1336, 1318, 1290, 1166, 1132, 1093, 1081, 1032,
colorless oil (12 mg, 0.026 mmol, 82% yield,
> 50:1 d.r., racemic).
C21H38N2O5S2, MW = 462.68 gmolÀ1 1H NMR (300 MHz, CDCl3, 228C):
;
d=7.88 (d, J=8.1 Hz, 2H, CHPh), 7.31 (d, J=8.1 Hz, 2H, CHPh), 5.66 (d,
J=8.1 Hz, 1H, NH-CH), 4.65 (t, J=5.9 Hz, 1H, NH-CH2), 3.77 (m, 2H,
CH2-OH), 3.64 (q, J=6.8 Hz, 1H, CH-SO2), 3.24 (m, 1H, CH-NH), 3.09
(q, J=6.8 Hz, 1H, CH2-N), 2.51 (t, J=6.5 Hz, 1H, OH), 2.43 (s, 3H,
CH3-Ph), 1.68 (m, 2H, CH2-CHSO2), 1.54 (m, 2H, CH2-CH3), 1.27 (m,
12H, (CH2)6), 0.88 (t, J=6.8 Hz, 3H, CH3), 0.82 (t, J=7.5 Hz, 3H, CH3);
13C NMR (75 MHz, CDCl3, 228C): d=144.0, 137.8, 130.0, 127.2, 63.3,
62.2, 54.1, 43.9, 31.9, 30.6, 29.3 (2C), 28.9, 26.7, 22.8, 21.7, 20.5, 14.2,
13.9 ppm; IR (ATR, neat): n˜ =3287, 2957, 2926, 2856, 1456, 1424, 1316,
1305, 1157, 1087, 1046, 814 cmÀ1; HRMS (ESI): m/z: calcd for: 485.2114;
found: 485.2114 [M+Na]+.
912, 811 cmÀ1
; HRMS (MALDI): m/z: calcd for: 491.2244; found:
491.2243 [M+H]+.
N-Octyl-1-(1-tosylaziridin-2-yl)butane-1-sulfonamide (46):
A reaction
flask was charged with PPh3 (13 mg, 0.048 mmol, 1.1 equiv), evacuated
and filled with nitrogen. Sulfonamide 45 (20 mg, 0.043 mmol, 1.0 equiv,
>50:1 d.r., racemic) was added as a solution in THF (0.5 mL) at RT fol-
lowed by DIAD (9.4 mL, 0.048 mmol, 1.1 equiv) as a solution in THF
(0.3 mL). The resulting mixture was stirred at RT for further 14 h. After
this time, the solvent was removed in vacuo and the residue was purified
by flash chromatography on silica gel (ethyl acetate/cyclohexane 1:4) to
furnish the pure aziridine 46 as colorless oil (14 mg, 0.032 mmol, 74%
3-Octylsulfamoyl-2-(p-toluenesulfonylamino)hexanoic acid ethyl ester
(44b): According to GP 2, using n-butanesulfonyl chloride 16b (52 mL,
0.392 mmol, 2.0 equiv). The product was obtained as colorless solid
(50 mg, 0.100 mmol, 51% yield, 11:1 d.r., 86% ee). The ee values were
determined by HPLC (Chiralcel OD-H 25+15 cm, n-hexane/EtOH 95:5,
0.7 mLminÀ1). C23H40N2O6S2, MW = 504.70 gmolÀ1; m.p. 130.1–130.88C;
[a]2D6:7 (c=0.860, CHCl3)=+9.3Æ0.4 (sample with ee 86%); 1H NMR
(300 MHz, CDCl3, 228C): d=7.73 (d, J=8.4 Hz, 2H, CHPh), 7.29 (d, J=
8.4 Hz, 2H, CHPh), 5.73 (d, J=9.6 Hz, 1H, NH-CH), 4.28 (t, J=5.9 Hz,
1H, NH-CH2), 4.23 (dd, J=9.6, 2.8 Hz, 1H, CH-NH), 4.10–3.90 (m, 2H,
CH2-O), 3.64–3.58 (m, 1H, CH-CH2), 3.05 (q, J=6.8 Hz, 2H, CH2-NH),
2.42 (s, 3H, CH3-Ph), 1.90–1.80 (m, 2H, CH2-CH), 1.60–1.44 (m, 2H,
CH2-CH2NH), 1.46–1.32 (m, 2H, CH2-CH3), 1.27 (m, 10H, (CH2)5), 1.10
(t, J=7.2 Hz, 3H, CH3-CH2O), 0.93 (t, J=7.2 Hz, 3H, CH3), 0.87 ppm (t,
J=6.8 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3, 228C): d=169.4, 143.7,
136.7, 129.5, 127.2, 63.8, 62.4, 54.7, 43.6, 31.7, 30.3, 29.0, 28.3, 26.4, 22.5,
21.4, 19.9, 14.0, 13.6, 13.5 ppm; IR (ATR, neat): n˜ =3305, 2925, 2855,
yield,
> 50:1 d.r., racemic). C21H36N2O4S2, MW = ;
444.66 gmolÀ1
1H NMR (300 MHz, CDCl3, 228C): d=7.77 (d, J=8.4 Hz, 2H, CHPh),
7.39 (d, J=8.1 Hz, 2H, CHPh), 5.60 (dd, J=8.1, 4.4 Hz, 1H, NH-CH2),
3.05 (m, 2H, CH2-NH), 2.90 (m, 1H, CH-SO2), 2.55 (dt, J=9.3, 4.7 Hz,
1H, CH-N), 2.47 (s, 3H, CH3-Ph), 2.45 (m, 1H, CHH-N), 2.12 (d, J=
4.4 Hz, 1H, CHH-N), 2.06 (m, 1H, CHH-CHSO2), 1.78 (m, 1H, CHH-
CHSO2), 1.62 (m, 1H, CHH-CH3), 1.49 (m, 1H, CHH-CH3), 1.29 (brs,
12H, (CH2)6), 0.92 (t, J=7.5 Hz, 3H, CH3-Oct), 0.88 ppm (t, J=6.8 Hz,
3H, CH3); 13C NMR (75 MHz, CDCl3, 228C): d=145.9, 131.7, 130.3,
128.9, 60.7, 43.7, 37.9, 32.0, 31.8, 30.2, 29.5, 29.4 (2C), 26.9, 22.8, 21.9,
20.4, 14.3, 14.2 ppm; HRMS (ESI): m/z: calcd for: 467.2009; found:
467.2010 [M+Na]+.
1749, 1716, 1440, 1327, 1306, 1286, 1165, 1135, 1092, 1032, 811 cmÀ1
;
HRMS (MALDI): m/z: calcd for: 527.2220; found: 527.2215 [M+H]+; el-
emental analysis calcd (%) for C23H40N2O6S2: C 54.73, H 7.99, N 5.55;
found: C 54.99, H 7.87, N 5.57.
Ethyl 2-(4-methylphenylsulfonamido)-3-(phenylsulfonyl)pentanoate (48):
A reaction flask was charged with b-sultam 47a (30 mg, 0.083 mmol,
1.0 equiv, 11:1 d.r., 80% ee, prepared according to GP 2, excess of sulfo-
nylchloride was removed under high vacuum at 608C overnight), evacu-
3-Octylsulfamoyl-4-phenyl-2-(p-toluenesulfonylamino)butyric acid ethyl
ester (44d): According to GP 2, using 2-phenylethanesulfonyl chloride
16d (81 mg, 0.392 mmol, 2.0 equiv) as a solution in CH2Cl2 (0.25 mL).
8216
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 8204 – 8222

Taurine Derivatives
FULL PAPER
ated and filled with nitrogen. A solution was prepared by addition of
Et2O (3 mL) and was subsequently cooled to À58C in an ice bath. After
5 min, a solution of PhMgBr (3m in Et2O, 83 mL, 0.249 mmol, 3.0 equiv)
was slowly added, the mixture was stirred at À58C for 15 min, allowed to
warm to RT and stirred for additional 15 h. The reaction was quenched
by addition of sat. aq. NH4Cl (2 mL), the mixture was diluted with brine
(10 mL) and extracted with ethyl acetate (2ꢄ10 mL). The combined or-
ganic layers were dried over Na2SO4, filtered and evaporated in vacuo.
The crude product was purified by flash chromatography on silica gel
(ethyl acetate/cyclohexane 1:3) to furnish the pure product 48 as colorless
solid (27 mg, 0.062 mmol, 75% yield, > 50:1 d.r., 82% ee). The ee values
were determined by HPLC (Chiralcel AS-H, n-hexane/iPrOH 80:20,
1.0 mLminÀ1). C20H25NO6S2, MW = 439.55 gmolÀ1; m.p. 176.1–177.28C;
[a]2D6:3 (c=0.70, CHCl3) = +31.5Æ0.6 (sample with ee 82%); 1H NMR
(300 MHz, CDCl3, 228C): d=7.84 (d, J=8.1 Hz, 2H, CHPh), 7.73 (d, J=
8.1 Hz, 2H, CHPh), 7.65 (d, J=6.8 Hz, 1H, CHPh), 7.56 (t, J=7.8 Hz, 2H,
CHPh), 7.29 (d, J=8.1 Hz, 2H, CHPh), 5.68 (d, J=9.6 Hz, 1H, NH-CH),
4.39 (dd, J=9.6, 2.8 Hz, 1H, CH-NH), 4.03 (m, 1H, CHH-O), 3.91 (m,
1H, CHH-O), 3.70 (m, 1H, CH-CH2), 2.43 (s, 3H, CH3-Ph), 1.85 (m, 2H,
CH2-CH3), 1.11 (t, J=7.2 Hz, 3H, CH3-CH2O), 0.97 ppm (t, J=7.2 Hz,
3H, CH3-CH2CH); 13C NMR (100 MHz, CDCl3, 228C): d=169.1, 143.7,
138.8, 137.1, 134.1, 129.6, 129.3, 128.6, 127.3, 68.4, 62.5, 54.2, 21.5, 19.6,
13.7, 11.3 ppm; IR (ATR, neat): n˜ =3272, 2939, 1749, 1716, 1447, 1333,
1304, 1292, 1166, 1142, 1093, 1073, 1031, 915, 813, 725 cmÀ1; HRMS (EI):
m/z (%): calcd for: 366.0828; found: 366.0824 (98.2) [MÀC3H5O2]+.
ACHTUNGTRENNUNG
from cyclohexane/ethyl acetate 1:1. C16H18N2O4S2, MW = 366.46 gmolÀ1
;
m.p. 119.8–120.28C; [a]2D5:6 (c=1.11, CHCl3)=À86.6Æ0.3 (sample with
ee=85%); 1H NMR (300 MHz, CDCl3, 228C): d=8.70 (d, J=4.0, 1H,
CHPyr), 7.98 (d, J=8.1, 1H, CHPyr), 7.89 (dt, J=7.5, 1.6, 1H, CHPyr), 7.55
(ddd, J=7.5, 4.7, 1.2, 1H, CHPyr), 7.47 (m, 2H, CHPh), 7.35 (m, 3H,
CHPh), 5.08 (d, J=5.6, 1H, CH-N), 4.26 (dt, J=9.0, 5.9, 1H, CH-CH2),
2.01 (m, 1H, CHH-CH), 1.88 (m, 1H, CHH-CH), 1.40 (m, 2H, CH2-
CH3), 0.89 ppm (t, J=7.2, 3H, CH3); 13C NMR (75 MHz, CDCl3, 228C):
d=156.2, 149.7, 138.2, 135.4, 129.3, 129.0, 127.7, 126.6, 123.4, 81.8, 59.3,
30.4, 20.3, 13.6 ppm; IR (ATR, neat): n˜ =2964, 1460, 1426, 1358, 1345,
1188, 1151, 1110, 1048, 1010, 988, 925, 831, 769 cmÀ1; HRMS (EI) m/z
(%): 301.1006; found: 301.1005 (4.5) [MÀHSO2]+.
AHCTUNGTRENGN(UN 3S,4S)-4-Benzyl-2-(2-pyridylsulfonyl)-3-phenyl-1,2-thiazetidine-1,1-diox-
ide (50dA): According to GP 3, using the imine 49 A (25 mg,
0.102 mmol, 1.0 equiv), no diglyme, TMSQ (4 mg, 0.01 mmol, 0.1 equiv),
2-phenylethanesulfonyl chloride 16d (42 mg, 0.203 mmol, 2.0 equiv, solu-
tion in 0.5 mL CH2Cl2) and CH2Cl2 (1 mL). The product was obtained as
slightly yellow oil (0.052 mmol, 52% yield, 42:1 d.r., 76% ee). The ee
values were determined by HPLC (Chiralcel OD-H, n-hexane/iPrOH
85:15, 1.0 mLminÀ1). The product was characterized as the corresponding
n-octylsulfonamide, purified by flash chromatography on silica gel (ethyl
acetate/cyclohexane 1:2).
General procedure for the formation of N-(2-pyridyl)sulfonyl-3-aryl-b-
sultams (GP 3): In a glove-box under nitrogen, a Schlenk tube was
charged with YbACHTUNGTRENNUNG(OTf)3 (32 mg, 0.051 mmol, 0.5 equiv). The respective
imine 49 (0.102 mmol, 1.0 equiv) was added as a solution in dry CH2Cl2
(1 mL), diethyleneglycol dimethyl ether (diglyme, 15 mL, 0.102 mmol,
1.0 equiv, if applicable) was added and the suspension was stirred at RT
for 25 min prior to cooling to À808C. After 5 min, the specified cinchona
alkaloid derived catalyst (0.01 mmol, 0.1 equiv) was added as a solution
in CH2Cl2 (0.1 mL), followed by DIPEA (diisopropylethylamine, 44 mL,
0.254 mmol, 2.5 equiv) and by the indicated sulfonyl chloride 16
(0.203 mmol, 2.0 equiv, neat or as a solution in CH2Cl2 (0.5 mL, for sulfo-
nylchloride 16d)). The reaction mixture was stirred at À808C for 20 h.
After this time, the mixture was diluted with ethyl acetate (10 mL) and
washed successively with 0.1m HCl (10 mL) and brine (10 mL). The or-
ganic phase was dried over Na2SO4, filtered and evaporated in vacuo to
give the corresponding crude product. The yields were determined by
1H NMR using DMSO as internal standard. In cases, where the produced
b-sultam is an oil and thus cannot be purified by recrystallization, the
product was characterized as the corresponding n-octylsulfonamide,
which was obtained by addition of n-octylamine (34 mL, 0.203 mmol,
2.0 equiv) after complete cycloaddition at À808C and subsequent stirring
at RT for 1 h prior to standard work-up. The crude product was purified
by flash chromatography on silica gel (ethyl acetate/cyclohexane 1:2).
N-((1S,2S)-2-(N-Octylsulfamoyl)-1,3-diphenylpropyl)pyridine-2-sulfon
ACHTUNGTRENNUNGam-
A
=
543.74 gmolÀ1 [a]D25:7 (c=0.375, CHCl3)=
;
+28.7Æ0.5 (sample with ee=76%); 1H NMR (300 MHz, CDCl3, 228C):
d=8.54 (d, J=4.7, 1H, CHPyr), 7.70 (m, 2H, CHPyr), 7.37–7.25 (m, 6H,
CHPyr, CHPh), 7.13 (m, 3H, CHPh), 7.03 (m, 2H, CHPh), 6.74 (d, J=7.1,
1H, NHSO2Pyr), 5.04 (brs, 1H, NH-CH2), 3.65 (dt, J=8.5, 4.7, 1H, CH-
CH2), 3.38 (dd, J=14.3, 4.9, 1H, CHH-Ph), 3.26 (dd, J=14.3, 8.5, 1H,
CHH-Ph), 3.17 (dd, J=6.6, 5.2, 1H, CH-NH), 2.68 (m, 1H, CHH-NH),
2.36 (m, 1H, CHH-NH), 1.30–0.97 (m, 12H, (CH2)6), 0.87 ppm (t, J=6.9,
3H, CH3); 13C NMR (75 MHz, CDCl3, 228C): d=157.3, 149.8, 137.8,
137.6, 137.4, 129.0, 128.9, 128.5, 127.9, 129.1, 126.5, 126.4, 121.9, 67.6,
56.4, 43.3, 32.7, 31.6, 29.4, 28.9, 28.8, 26.2, 22.5, 14.0 ppm; IR (ATR,
neat): n˜ =3293, 2925, 2855, 1454, 1426, 1327, 1175, 1141, 1120, 1084, 917,
738 cmÀ1
[M+Na]+.
(3S,4S)-3-(4-Chlorophenyl)-4-propyl-2-(2-pyridylsulfonyl)-1,2-thiazeti-
; HRMS (ESI) m/z: calcd for: 566.2118; found: 566.2120
AHCTUNGTRENNUNG
dine-1,1-dioxide (50bB) According to GP 3, using imine 49B (29 mg,
0.102 mmol, 1.0 equiv), diglyme (15 mL, 0.102 mmol, 1.0 equiv), quinine
(3 mg, 0.01 mmol, 0.1 equiv), butanesulfonyl chloride 16b (27 mL,
0.203 mmol, 2.0 equiv) and CH2Cl2 (1 mL). The product was obtained as
slightly yellow oil (0.071 mmol, 70% yield, 39:1 d.r., 83% ee). The ee
values were determined by HPLC (Chiralcel OD-H, n-hexane/iPrOH
85:15, 1.0 mLminÀ1). The product was characterized as the corresponding
n-octylsulfonamide, purified by flash chromatography on silica gel (ethyl
acetate/cyclohexane 1:2).
ACHTUNGTRENNUNG(3S,4S)-4-Ethyl-2-(2-pyridylsulfonyl)-3-phenyl-1,2-thiazetidine-1,1-dioxide
(50aA): According to GP 3, using the imine 49A (25 mg, 0.102 mmol,
1.0 equiv), diglyme (15 mL, 0.102 mmol, 1.0 equiv), quinine (3 mg,
0.01 mmol, 0.1 equiv), propanesulfonyl chloride 16a (23 mL, 0.203 mmol,
2.0 equiv) and CH2Cl2 (0.6 mL). The product was obtained as colorless
solid (0.084 mmol, 82% yield, 28:1 d.r., 80% ee). The ee values were de-
termined by HPLC (Chiralcel OD-H, n-hexane/iPrOH 85:15,
1.0 mLminÀ1). An analytical sample was obtained by recrystallization
N-((1S,2S)-1-(4-Chlorophenyl)-2-(N-octylsulfamoyl)pentyl)pyridine-2-sul-
fonamide: C24H36ClN3O4S2, MW
from cyclohexane/ethyl acetate 1:1. C15H16N2O4S2, MW = 264.28 gmolÀ1
;
=
530.14 gmolÀ1
;
[a]2D7:6 (c=0.655,
m.p. 185.2–186.48C; [a]2D5:3 (c=0.51, CHCl3)=À74.2Æ0.6 (sample with ee
83%); 1H NMR (300 MHz, CDCl3, 228C): d=8.70 (d, J=4.0 Hz, 1H,
CHPyr), 8.00 (d, J=8.1 Hz, 1H, CHPyr), 7.91 (dt, J=7.5, 1.6 Hz, 1H,
CHPyr), 7.55 (ddd, J=7.5, 4.7, 0.9 Hz, 1H, CHPyr), 7.48 (m, 2H, CHPh),
7.36 (m, 3H, CHPh), 5.11 (d, J=5.6 Hz, 1H, CH-N), 4.26 (dt, J=9.3,
5.9 Hz, 1H, CH-CH2), 2.05 (m, 1H, CHH-CH), 1.96 (m, 1H, CHH-CH),
1.03 ppm (t, J=7.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3, 228C): d=
156.6, 149.9, 138.3, 135.7, 129.4, 129.2, 127.8, 126.7, 123.6, 83.5, 59.2, 22.2,
11.5 ppm; IR (ATR, neat): n˜ =2975, 1455, 1357, 1341, 1193, 1176, 1154,
1112, 1053, 1031, 1007, 975, 888, 845, 767, 712 cmÀ1; HRMS (EI): m/z
(%): calcd for: 353.0624; found: 353.0622 (0.1) [M+H]+.
1
CHCl3)=À3.1Æ0.4 (sample with ee=83%); H NMR (300 MHz, CDCl3,
228C): d=8.54 (d, J=4.7, 1H, CHPyr), 7.77 (m, 2H, CHPyr), 7.39 (m, 1H,
CHPyr), 7.16 (m, 4H, CHPh), 6.72 (d, J=8.7, NHSO2Pyr), 5.04 (dd, J=8.4,
5.6, CH-NH), 3.66 (dd, J=7.5, 4.7, 1H, NH-CH2), 3.29 (dt, J=7.5, 5.0,
1H, CH-CH2), 2.92 (m, 1H, CHH-NH), 2.56 (m, 1H, CHH-NH), 1.86
(m, 2H, CH2-CH), 1.50 (m, 2H, CH2-CH3), 1.29–1.10 (m, 12H, (CH2)6),
0.87 ppm (m, 6H, 2ꢄCH3); 13C NMR (75 MHz, CDCl3, 228C): d=157.6,
149.9, 137.9, 137.3, 133.9, 128.8, 128.0, 126.6, 121.9, 65.7, 56.6, 43.5, 31.7,
29.9, 29.3, 29.1 (2C), 26.5, 22.6, 20.3, 14.1, 13.8 ppm; IR (ATR, neat): n˜ =
3222, 2925, 1454, 1342, 1294, 1179, 1117, 1088, 1070, 901, 832, 773 cmÀ1
;
HRMS (ESI) m/z: calcd for: 552.1728; found: 552.1734 [M+Na]+.
Chem. Eur. J. 2009, 15, 8204 – 8222
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8217

R. Peters and M. Zajac
A
0.203 mmol, 2.0 equiv) and CH2Cl2 (1 mL). The product was obtained as
slightly yellow oil (0.074 mmol, 73% yield, 30:1 d.r., 88% ee). The ee
values were determined by HPLC (Chiralcel OD-H, n-hexane/iPrOH
85:15, 1.0 mLminÀ1). The product was characterized as the corresponding
n-octylsulfonamide, purified by flash chromatography on silica gel (ethyl
acetate/cyclohexane 1:2).
dine-1,1-dioxide (50bC): According to GP 3, using imine 49C (29 mg,
0.102 mmol, 1.0 equiv), no diglyme, TMSQ (4 mg, 0.01 mmol, 0.1 equiv),
butanesulfonyl chloride 16b (27 mL, 0.203 mmol, 2.0 equiv) and CH2Cl2
(1 mL). The product was obtained as slightly yellow solid (0.073 mmol,
72% yield, 21:1 d.r., 77% ee). The ee values were determined by HPLC
(Chiralcel OD-H, n-hexane/iPrOH 85:15, 1.0 mLminÀ1). An analytical
sample was obtained by recrystallization from cyclohexane/ethyl acetate
N-((1S,2S)-1-(4-Fluorophenyl)-2-(N-octylsulfamoyl)pentyl)pyridine-2-sul-
fonamide: C24H36FN3O4S2, MW
=
513.69 gmolÀ1
;
[a]2D8:1 (c=0.795,
1
1:1. C16H17ClN2O4S2, MW
CHCl3)=+0.6Æ0.2 (sample with ee=88%); H NMR (300 MHz, CDCl3,
228C): d=8.55 (d, J=4.4, 1H, CHPyr), 7.77 (m, 2H, CHPyr), 7.39 (m, 1H,
CHPyr), 7.18 (dd, J=8.5, 4.9, 2H, CHPh), 6.89 (t, J=8.5, 2H, CHPh), 6.69
(d, J=9.1, NHSO2Pyr), 5.04 (dd, J=9.1, 5.5, CH-NH), 3.57 (dd, J=7.4,
4.7, 1H, NH-CH2), 3.27 (dt, J=7.8, 5.0, 1H, CH-CH2), 2.92 (m, 1H,
CHH-NH), 2.53 (m, 1H, CHH-NH), 1.86 (m, 2H, CH2-CH), 1.49 (m,
2H, CH2-CH3), 1.31–1.10 (m, 12H, (CH2)6), 0.86 ppm (m, 6H, 2ꢄCH3);
13C NMR (100 MHz, CDCl3, 228C): d=161.1 (d, J=248.5), 156.7, 148.8,
136.8, 133.5, 127.3 (d, J=8.0), 125.5, 120.8, 114.6 (d, J=21), 64.9, 55.9,
42.5, 30.7, 29.0, 28.7, 28.0 (2C), 25.4, 21.6, 19.3, 13.0, 12.7 ppm; 19F NMR
(282 MHz, CDCl3, 228C): d=À112.8 ppm; IR (ATR, neat): n˜ =3288,
2957, 2927, 2856, 1737, 1605, 1510, 1454, 1427, 1325, 1288, 1175, 1140,
(c=0.79, CHCl3)=À91.4Æ0.6 (sample with ee=80%); 1H NMR
(300 MHz, CDCl3, 228C): d=8.70 (d, J=4.0, 1H, CHPyr), 8.02 (d, J=8.1,
1H, CHPyr), 7.93 (dt, J=7.8, 1.6, 1H, CHPyr), 7.58 (ddd, J=7.8, 4.7, 1.2,
1H, CHPyr), 7.41 (m, 2H, CHPh), 7.32 (m, 2H, CHPh), 5.09 (d, J=5.6, 1H,
CHN), 4.22 (dt, J=9.0, 5.9, 1H, CH-CH2), 2.01 (m, 1H, CHH-CH), 1.88
(m, 1H, CHH-CH), 1.41 (m, 2H, CH2-CH3), 0.91 ppm (t, J=7.5, 3H,
CH3); 13C NMR (75 MHz, CDCl3, 228C): d=156.1, 149.6, 138.1, 137.5,
134.9, 130.3, 129.4, 127.8, 126.6, 124.7, 123.4, 81.9, 58.5, 30.6, 20.5,
13.7 ppm; IR (ATR, neat): n˜ =2970, 145, 1428, 1372, 1343, 1180, 1152,
1114, 1043, 990, 927, 891, 853, 792, 774, 754, 733, 714 cmÀ1; HRMS (EI)
m/z (%): calcd for: 335.0616; found: 335.0612 (2.9) [MÀHSO4]+.
(3S,4S)-3-(4-Bromophenyl)-4-propyl-2-(2-pyridylsulfonyl)-1,2-thiazeti-
1119, 1084, 912, 836, 775, 737 cmÀ1
; HRMS (ESI) m/z: calcd for:
dine-1,1-dioxide (50bD): According to GP 3, using imine 49D (33 mg,
0.102 mmol, 1.0 equiv), diglyme (15 mL, 0.102 mmol, 1.0 equiv), quinine
(3 mg, 0.01 mmol, 0.1 equiv), butanesulfonyl chloride 16b (27 mL,
0.203 mmol, 2.0 equiv) and CH2Cl2 (1 mL). The product was obtained as
slightly yellow oil (0.071 mmol, 46% yield, 41:1 d.r., 82% ee). The ee
values were determined by HPLC (Chiralcel OD-H, n-hexane/iPrOH
85:15, 1.0 mLminÀ1). The product was characterized as the corresponding
n-octylsulfonamide, purified by flash chromatography on silica gel (ethyl
acetate/cyclohexane 1:2).
536.2023; found: 536.2028 [M+Na]+.
AHCTUNGTERG(NNUN 3S,4S)-3-(3-Fluorophenyl)-4-propyl-2-(2-pyridylsulfonyl)-1,2-thiazeti-
dine-1,1-dioxide (50bG): According to GP 3, using imine 49G (27 mg,
0.102 mmol, 1.0 equiv), diglyme (15 mL, 0.102 mmol, 1.0 equiv), quinine
(3 mg, 0.01 mmol, 0.1 equiv), butanesulfonyl chloride 16b (27 mL,
0.203 mmol, 2.0 equiv) and CH2Cl2 (1 mL). The product was obtained as
slightly yellow solid (0.078 mmol, 76% yield, 36:1 d.r., 77% ee). The ee
values were determined by HPLC (Chiralcel OD-H, n-hexane/iPrOH
85:15, 1.0 mLminÀ1). An analytical sample was obtained by recrystalliza-
N-((1S,2S)-1-(4-Bromophenyl)-2-(N-octylsulfamoyl)pentyl)pyridine-2-sul-
tion from cyclohexane/ethyl acetate 1:1. C16H17FN2O4S2, MW
=
fonamide: C24H36BrN3O4S2, MW
=
574.59 gmolÀ1
;
[a]2D8:8 (c=0.42,
384.45 gmolÀ1; m.p. 138.3–138.58C; [a]D26:3 (c=1.21, CHCl3)=À67.5Æ0.4
(sample with ee=79%); 1H NMR (300 MHz, CDCl3, 228C): d=8.72 (d,
J=5.3, 1H, CHPyr), 8.04 (d, J=8.1, 1H, CHPyr), 7.95 (dt, J=7.5, 1.6, 1H,
CHPyr), 7.58 (ddd, J=7.8, 4.7, 1.2, 1H, CHPyr), 7.40–7.26 (m, 2H, CHPh),
7.21 (dt, J=9.3, 1.9, 1H, CHPh), 7.06 (dt, J=8.4, 2.5, 1H, CHPh), 5.12 (d,
J=5.6, 1H, CH-N), 4.22 (dt, J=8.7, 6.2, 1H, CH-CH2), 2.00 (m, 1H,
CHH-CH), 1.89 (m, 1H, CHH-CH), 1.42 (m, 2H, CH2-CH3), 0.90 ppm
(t, J=7.5, 3H, CH3); 13C NMR (100 MHz, CDCl3, 228C): d=163.1 (d,
J=248.5), 156.6, 149.8, 138.4, 138.3 (d, J=9.1), 130.9 (d, J=9.1), 127.9,
123.6, 122.4, 116.5 (d, J=21.1), 113.7 (d, J=21.1), 81.9, 58.6, 30.4, 20.3,
13.5 ppm; 19F NMR (282 MHz, CDCl3, 228C): d=À110.6 ppm; IR (ATR,
neat): n˜ =1969, 1457, 1426, 1370, 1345, 1265, 1194, 1181, 1139, 1115, 1056,
990, 927, 881, 783, 750, 732 cmÀ1; HRMS (ESI) m/z (%): calcd for:
319.0911; found: 319.0911 (2.2) [MÀHSO2]+.
1
CHCl3)=À4.7Æ0.6 (sample with ee=82%); H NMR (300 MHz, CDCl3,
228C): d=8.55 (d, J=4.7, 1H, CHPyr), 7.78 (m, 2H, CHPyr), 7.40 (m, 1H,
CHPyr), 7.33 (d, J=8.4, 2H, CHPh), 7.09 (d, J=8.4, 2H, CHPh), 6.65 (d,
J=8.7, NHSO2Pyr), 5.04 (dd, J=8.1, 5.3, CH-NH), 3.48 (dd, J=7.5, 4.7,
1H, NHCH2), 3.27 (dt, J=7.8, 5.0, 1H, CHCH2), 2.90 (m, 1H, CHHNH),
2.53 (m, 1H, CHH-NH), 1.88 (m, 2H, CH2-CH), 1.49 (m, 2H, CH2-CH3),
1.31–1.10 (m, 12H, (CH2)6), 0.88 ppm (m, 6H, 2ꢄCH3); 13C NMR
(75 MHz, CDCl3, 228C): d=157.3, 149.6, 137.7, 137.6, 131.5, 128.0, 126.4,
121.7, 121.6, 65.6, 56.7, 43.6, 31.9, 30.0, 29.4, 29.2 (2C), 26.6, 22.8, 20.5,
14.3, 14.0 ppm; IR (ATR, neat): n˜ =3290, 2926, 2855, 1738, 1579, 1454,
1427, 1324, 1175, 1140, 1119, 1073, 1009, 737 cmÀ1; HRMS (ESI) m/z:
calcd for: 596.1223; found: 596.1223 [M+Na]+.
ACHTUNGTRENNUNG(3S,4S)-3-(3-Bromophenyl)-4-propyl-2-(2-pyridylsulfonyl)-1,2-thiazeti-
dine-1,1-dioxide (50bE): According to GP 3, using the imine 49E (33 mg,
0.102 mmol, 1.0 equiv), no diglyme, TMSQ (4 mg, 0.01 mmol, 0.1 equiv),
butanesulfonyl chloride 16b (27 mL, 0.203 mmol, 2.0 equiv) and CH2Cl2
(1 mL). The product was obtained as slightly yellow oil (0.060 mmol,
59% yield, 51:1 d.r., 73% ee). The ee values were determined by HPLC
(Chiralcel OD-H, n-hexane/iPrOH 85:15, 1.0 mLminÀ1). An analytical
sample was obtained by recrystallization from cyclohexane/ethyl acetate
ACHTUNGTNER(NUNG 3S,4S)-3-(4-Methylcarboxylphenyl)-4-propyl-2-(2-pyridylsulfonyl)-1,2-
thiazetidine-1,1-dioxide (50bH): According to GP 3, using the imine 49H
(31 mg, 0.102 mmol, 1.0 equiv), no diglyme, TMSQ (4 mg, 0.01 mmol,
0.1 equiv), butanesulfonyl chloride 16b (27 mL, 0.203 mmol, 2.0 equiv)
and CH2Cl2 (1 mL). The product was obtained as slightly yellow oil
(0.062 mmol, 61% yield, 21:1 d.r., 78% ee). The ee values were deter-
mined by HPLC (Chiralcel OD-H, n-hexane/iPrOH 85:15, 1.0 mLminÀ1).
An analytical sample was obtained by recrystallization from cyclohexane/
1:1. C16H17BrN2O4S2, MW
=
264.28 gmolÀ1; m.p. 149.1–149.98C; [a]2D7:2
(c=0.92, CHCl3)=À74.1Æ0.8 (sample with ee=75%); 1H NMR
(300 MHz, CDCl3, 228C): d=8.71 (d, J=4.7, 1H, CHPyr), 8.01 (d, J=8.1,
1H, CHPyr), 7.93 (dt, J=7.5, 1.6, 1H, CHPyr), 7.57 (m, 2H, CHPyr, CHPh),
7.47 (t, J=8.4, 2H, CHPh), 7.26 (t, J=7.8, 1H, CHPh), 5.07 (d, J=5.6, 1H,
CH-N), 4.22 (dt, J=9.3, 5.9, 1H, CH-CH2), 2.01 (m, 1H, CHH-CH), 1.89
(m, 1H, CHH-CH), 1.42 (m, 2H, CH2-CH3), 0.91 ppm (t, J=7.5, 3H,
CH3); 13C NMR (75 MHz, CDCl3, 228C): d=156.1, 149.6, 138.1, 137.7,
132.4, 130.5, 129.4, 127.8, 125.2, 123.4, 123.0, 81.9, 58.4, 30.6, 20.5,
13.7 ppm; IR (ATR, neat): n˜ =2969, 1427, 1372, 1343, 1193, 1180, 1151,
1114, 1043, 990, 926, 846, 775, 754, 732 cmÀ1; HRMS (EI) m/z (%): calcd
for: 379.0111; found: 379.0110 (1.3) [MÀHSO2]+.
ethyl acetate 1:1. C18H20N2O6S2, MW = ; m.p. 142.3–
424.49 gmolÀ1
143.38C; [a]2D9:4 (c=0.15, CHCl3)=À111.0Æ1.1 (sample with ee=82%);
1H NMR (300 MHz, CDCl3, 228C): d=8.70 (d, J=4.7, 1H, CHPyr), 8.05
(d, J=8.4, 2H, CHPh), 8.04 (m, 1H, CHPyr), 7.94 (dt, J=7.5, 1.6, 1H,
CHPyr), 7.59 (d, J=8.4, 2H, CHPh), 7.58 (m, 1H, CHPyr), 5.20 (d, J=5.6,
1H, CH-N), 4.24 (dt, J=8.4, 5.6, 1H, CH-CH2), 3.94 (s, 3H, CH3-O),
2.01 (m, 1H, CHH-CH), 1.89 (m, 1H, CHH-CH), 1.42 (m, 2H, CH2-
CH3), 0.90 ppm (t, J=7.5, 3H, CH3); 13C NMR (75 MHz, CDCl3, 228C):
d=166.1, 156.3, 149.7, 140.5, 138.3, 131.0, 130.3, 127.9, 126.6, 123.5, 81.8,
58.7, 52.4, 30.5, 20.3, 13.6 ppm; IR (ATR, neat): n˜ =2952, 1711, 1430,
1366, 1278, 1177, 1150, 1111, 989, 911 cmÀ1; HRMS (ESI) m/z (%): calcd
for: 393.0574; found: 393.0574 (3.0) [MÀCH3O]+.
ACHTUNGTRENNUNG(3S,4S)-3-(4-Fluorophenyl)-4-propyl-2-(2-pyridylsulfonyl)-1,2-thiazeti-
dine-1,1-dioxide (50bF): According to GP 3, using the imine 49F (27 mg,
0.102 mmol, 1.0 equiv), diglyme (15 mL, 0.102 mmol, 1.0 equiv), quinine
(3 mg, 0.01 mmol, 0.1 equiv), butanesulfonyl chloride 16b (27 mL,
ACHTUNGTNER(NUNG 3S,4S)-4-Propyl-2-(2-pyridylsulfonyl)-3-(4-trifluoromethylphenyl)-1,2-
thiazetidine-1,1-dioxide (50bI): According to GP 3, using the imine 49I
(32 mg, 0.102 mmol, 1.0 equiv), no diglyme, TMSQ (4 mg, 0.01 mmol,
8218
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 8204 – 8222

Taurine Derivatives
FULL PAPER
0.1 equiv), butanesulfonyl chloride 16b (27 mL, 0.203 mmol, 2.0 equiv)
and CH2Cl2 (1 mL). The product was obtained as slightly yellow oil
(0.068 mmol, 67% yield, 25:1 d.r., 80% ee). The ee values were deter-
mined by HPLC (Chiralcel OD-H, n-hexane/iPrOH 85:15, 1.0 mLminÀ1).
The product was characterized as the corresponding n-octylsulfonamide,
purified by flash chromatography on silica gel (ethyl acetate/cyclohexane
1:2).
13C NMR (75 MHz, CDCl3, 228C): d=157.3, 149.7, 137.4, 137.1, 135.7,
128.8, 128.5, 128.0 (2C), 127.6, 126.9 (2C), 126.7, 126.3, 121.7, 69.8, 66.0,
56.8, 35.2, 29.0, 20.2, 13.8 ppm; IR (ATR, neat): n˜ =3029, 2964, 2874,
1738, 1454, 1427, 1338, 1175, 1164, 1119, 953, 914, 896, 750, 738 cmÀ1
;
HRMS (ESI) m/z: calcd for: 511.1332; found: 511.1331 [M+Na]+.
N-((1S,2S)-2-(N-Benzylsulfamoyl)-1-phenylpentyl)pyridine-2-sulfonamide
(57): To stirred solution of b-sultam 50bA (20 mg, 0.055 mmol,
a
N-((1S,2S)-2-(N-Octylsulfamoyl)-1-(4-(trifluoromethyl)phenyl)pentyl)pyr-
idine-2-sulfonamide: C25H36F3N3O4S2, MW
1.0 equiv, recrystallized from ethyl acetate/cyclohexane 1:1, >100:1 d.r.,
85% ee) in CH2Cl2 (0.25 mL) at room temperature, benzylamine (12 mL,
0.109 mmol, 2.0 equiv) was added as a solution in CH2Cl2 (0.25 mL) and
the mixture was stirred for 14 h. After this time, the mixture was diluted
with ethyl acetate (10 mL) and washed successively with 0.1m aqueous
HCl (10 mL) and brine (10 mL). The organic phase was dried over
Na2SO4, filtered and evaporated in vacuo. The crude product was puri-
fied by flash chromatography on silica gel (ethyl acetate/cyclohexane 1:2)
=
563.70 gmolÀ1; [a]2D8:6 (c=
0.635, CHCl3)=À1.1Æ0.5 (sample with ee=80%); 1H NMR (300 MHz,
CDCl3, 228C): d=8.52 (d, J=4.7, 1H, CHPyr), 7.76 (m, 2H, CHPyr), 7.47
(d, J=8.1, 2H, CHPh), 7.37 (m, 1H, CHPyr), 7.35 (d, J=8.1, 2H, CHPh),
6.76 (d, J=8.7, NHSO2Pyr), 5.14 (dd, J=8.4, 5.3, CH-NH), 3.60 (dd, J=
6.8, 5.0, 1H, NH-CH2), 3.27 (dt, J=8.1, 5.0, 1H, CH-CH2), 2.91 (m, 1H,
CHH-NH), 2.54 (m, 1H, CHH-NH), 1.88 (m, 2H, CH2-CH), 1.51 (m,
2H, CH2-CH3), 1.31–1.10 (m, 12H, (CH2)6), 0.87 ppm (m, 6H, 2ꢄCH3);
13C NMR (75 MHz, CDCl3, 228C): d=157.4, 149.8, 142.3, 137.8, 130.1 (d,
J=33.0), 127.0, 126.6, 125.4 (d, J=4.2), 123.6 (q, J=271.6), 121.7, 65.6,
56.7, 43.3, 31.6, 29.8, 29.2, 28.9 (2C), 26.3, 22.5, 20.2, 13.9, 13.6 ppm;
19F NMR (282 MHz, CDCl3, 228C): d=À62.5 ppm; IR (ATR, neat): n˜ =
3231, 2928, 2857, 1458, 1340, 1322, 1298, 1176, 1163, 1117, 1067, 901,
to furnish the pure sulfonamide 57 as
a colorless solid (21 mg,
0.046 mmol, 83% yield, >100:1 d.r., 84% ee). The ee values were deter-
mined by HPLC (Chiralcel OD-H, n-hexane/EtOH 85:15, 1.0 mLminÀ1).
C23H27N3O4S2, MW = 473.61 gmolÀ1. M.p. 168.2–170.08C [a]2D8:1 (c=0.87,
1
CHCl3)=+9.7Æ0.2 (sample with ee=84%); H NMR (300 MHz, CDCl3,
228C): d=8.45 (d, J=4.0, 1H, CHPyr), 7.77 (d, J=7.8, 1H, CHPyr), 7.70
(dt, J=7.5, 1.6, 1H, CHPyr), 7.35–7.26 (m, 4H, 3ꢄCHPh, CHPyr), 7.20–7.05
(m, 7H, CHPh), 6.46 (d, J=9.3, NHSO2Pyr), 5.01 (dd, J=9.3, 5.9, CH-
NH), 4.12–4.01 (m, 2H, NH-CH2, CHH-Ph), 3.70 (dd, J=12.8, 4.0, 1H,
CHH-Ph), 3.19 (dt, J=7.5, 5.3, 1H, CH-CH2), 1.86 (m, 2H, CH2-CH),
1.46 (m, 2H, CH2-CH3), 0.85 ppm (t, J=7.5, 3H, CH3); 13C NMR
(75 MHz, CDCl3, 228C): d=157.3, 149.5, 138.2, 137.5, 136.0, 128.6 (2C),
128.5, 127.9 (2C), 127.8, 126.3, 126.1 (2C), 121.7, 66.7, 57.2, 47.5, 29.4,
20.4, 13.9 ppm; IR (ATR, neat): n˜ =3218, 2961, 1581, 1454, 1425, 1332,
1311, 1173, 1135, 1097, 1069, 992, 829, 739 cmÀ1; HRMS (ESI) m/z: calcd
for: 496.1335; found: 496.1330 [M+Na]+.
773 cmÀ1
[M+Na]+.
(3S,4S)-3-(4-Methylphenyl)-4-propyl-2-(2-pyridylsulfonyl)-1,2-thiazeti-
; HRMS (ESI) m/z: calcd for: 586.1992; found: 586.1997
ACHTUNGTRENNUNG
dine-1,1-dioxide (50bK) According to GP 3, using the imine 49K (27 mg,
0.102 mmol, 1.0 equiv), no diglyme, TMSQ (4 mg, 0.01 mmol, 0.1 equiv),
butanesulfonyl chloride 16b (27 mL, 0.203 mmol, 2.0 equiv) and CH2Cl2
(1 mL). The product was obtained as slightly yellow oil (0.055 mmol,
54% yield, 32:1 d.r., 77% ee). The ee values were determined by HPLC
(Chiralcel OD-H, n-hexane/iPrOH 85:15, 1.0 mLminÀ1). The product was
characterized as the corresponding n-octylsulfonamide, purified by flash
chromatography on silica gel (ethyl acetate/cyclohexane 1:2).
N-((1S,2S)-1-Phenyl-2-(pyrrolidin-1-ylsulfonyl)pentyl)pyridine-2-sulfon-
ACHUTNGRENUaNG mACHUTGNTRENiNUGN de (58): To a stirred solution of b-sultam 50bA (20 mg, 0.055 mmol,
N-((1S,2S)-2-(N-Octylsulfamoyl)-1-p-tolylpentyl)pyridine-2-sulfonamide:
C25H39N3O4S2, MW = 509.72 gmolÀ1; [a]D27:9 (c=0.46, CHCl3)=+1.1Æ0.2
(sample with ee=77%); 1H NMR (300 MHz, CDCl3, 228C): d=8.55 (d,
J=4.0, 1H, CHPyr), 7.79 (d, J=7.8, 1H, CHPyr), 7.72 (dt, J=7.4, 1.9, 1H,
CHPyr), 7.36 (dd, J=7.4, 5.9, 1.2, 1H, CHPyr), 7.09 (d, J=8.1, 2H, CHPh),
7.02 (d, J=8.1, 2H, CHPh), 6.66 (d, J=9.6, NHSO2Pyr), 5.14 (dd, J=9.6,
4.7, CH-N), 3.27 (dt, J=8.4, 4.7, 1H, CH-CH2), 3.05 (dd, J=8.4, 3.4, 1H,
NH-CH2), 2.83 (m, 1H, CHH-NH), 2.29 (m, 1H, CHH-NH), 2.27 (s, 3H,
CH3-Ph), 1.91 (m, 2H, CH2-CH), 1.59 (m, 1H, CHH-CH3), 1.46 (m, 1H,
CHH-CH3), 1.30–1.00 (m, 12H, (CH2)6), 0.88 ppm (m, 6H, 2ꢄCH3);
13C NMR (75 MHz, CDCl3, 228C): d=157.6, 149.7, 137.7, 137.6, 135.6,
129.3, 126.3, 125.9, 121.6, 65.2, 56.5, 43.5, 31.8, 29.6, 29.1 (2C), 29.0, 26.5,
22.7, 21.0, 20.4, 14.2, 13.9 ppm; IR (ATR, neat): n˜ =3288, 2926, 2856,
1.0 equiv, recrystallized from ethyl acetate/cyclohexane 1:1, >100:1 d.r.,
85% ee) in CH2Cl2 (0.25 mL) at room temperature, pyrrolidine (9 mL,
0.109 mmol, 2.0 equiv) was added as a solution in CH2Cl2 (0.25 mL) and
the mixture was stirred for 14 h. After this time, the mixture was diluted
with ethyl acetate (10 mL) and washed successively with 0.1m aqueous
HCl (10 mL) and brine (10 mL). The organic phase was dried over
Na2SO4, filtered and evaporated in vacuo. The crude product was puri-
fied by flash chromatography on silica gel (ethyl acetate/cyclohexane 1:2)
to furnish the pure sulfonamide 58 as a colorless oil (22 mg, 0.050 mmol,
91% yield, >100:1 d.r., 84% ee). The ee values were determined by
HPLC (Chiralcel OD-H, n-hexane/EtOH 90:10, 1.0 mLminÀ1).
C20H27N3O4S2, MW = 437.58 gmolÀ1; [a]D28:2 (c=0.71, CHCl3)=À11.7Æ0.3
(sample with ee=84%); 1H NMR (300 MHz, CDCl3, 228C): d=8.57 (d,
J=4.4, 1H, CHPyr), 7.70 (m, 2H, CHPyr), 7.34 (ddd, J=6.5, 2.2, 1.9, 1H,
CHPyr), 7.13 (m, 5H, CHPh), 6.77 (d, J=8.1, NHSO2Pyr), 5.04 (dd, J=8.1,
4.7, CH-NH), 3.38 (dt, J=8.1, 4.7, 1H, CH-CH2), 3.01 (m, 4H, 2ꢄCH2-
N), 1.95–1.72 (m, 2H, CH2-CH), 1.60 (m, 4H, 2ꢄCH2-CH2N), 1.58–1.36
(m, 2H, CH2-CH), 0.87 ppm (t, J=7.5, 3H, CH3); 13C NMR (75 MHz,
CDCl3, 228C): d=157.4, 149.5, 138.1, 137.3, 127.8, 127.1, 126.4, 126.1,
121.6, 66.3, 57.1, 47.2, 29.3, 25.7, 20.7, 14.0 ppm; IR (ATR, neat): n˜ =
3253, 2962, 2927, 2874, 1738, 1454, 1427, 1334, 1313, 1174, 1119, 1085,
1068, 1015, 760, 738, 700 cmÀ1; HRMS (ESI) m/z: calcd for: 460.1335;
found: 460.1333 [M+Na]+.
1738, 1454, 1427, 1325, 1175, 1142, 1119, 1084, 1047, 913, 775, 736 cmÀ1
;
HRMS (ESI) m/z: calcd for: 532.2274; found: 532.2280 [M+Na]+.
ACHTUNGTRENNUNG(1S,2S)-Phenethyl 1-phenyl-1-(pyridine-2-sulfonamido)pentane-2-sulfo-
nate (56): To a stirred solution of b-sultam 50bA (20 mg, 0.055 mmol,
1.0 equiv, recrystallized from ethyl acetate/cyclohexane 1:1, >100:1 d.r.,
85% ee) in CH2Cl2 (0.25 mL) at room temperature, 2-phenylethanol
(13 mL, 0.109 mmol, 2.0 equiv) and triethylamine (8 mL, 0.055 mmol,
1.0 equiv) were added as a solution in CH2Cl2 (0.25 mL) and the mixture
was stirred for 14 h. After this time, the mixture was diluted with ethyl
acetate (10 mL) and washed successively with 0.1m aqueous HCl (10 mL)
and brine (10 mL). The organic phase was dried over Na2SO4, filtered
and evaporated in vacuo. The crude product was purified by flash chro-
matography on silica gel (ethyl acetate/cyclohexane 1:2) to furnish the
pure sulfonate 56 as a colorless oil (20 mg, 0.042 mmol, 76% yield,
>100:1 d.r., 85% ee). The ee values were determined by HPLC (Chiral-
N-((1S,2S)-1-Phenyl-2-(phenylsulfonyl)pentyl)pyridine-2-sulfonamide
(59):
A reaction flask was charged with b-sultam 50bA (100 mg,
0.273 mmol, 1.0 equiv, recrystallized from ethyl acetate/cyclohexane 1:1,
>100:1 d.r., 85% ee), evacuated and filled with nitrogen. A suspension
was prepared by addition of Et2O (6 mL) and was subsequently cooled to
À58C in an ice bath. After 5 min, a solution of PhMgBr (3m in Et2O,
182 mL, 0.546 mmol, 2.0 equiv) was slowly added, the mixture was stirred
at À58C for 15 min, allowed to warm to RT and stirred for additional
15 h. The reaction was quenched by addition of sat. aq. NH4Cl (3 mL),
the mixture was diluted with brine (15 mL) and extracted with ethyl ace-
tate (2ꢄ15 mL). The combined organic layers were dried over Na2SO4
and evaporated in vacuo. The crude product was purified by flash chro-
cel OD-H, n-hexane/EtOH 85:15, 1.0 mLminÀ1). C24H28N2O5S2, MW
=
488.62 gmolÀ1; [a]D27:8 (c=0.78, CHCl3)=À0.3Æ0.15 (sample with ee=
85%); 1H NMR (300 MHz, CDCl3, 228C): d=8.51 (d, J=4.7, 1H,
CHPyr), 7.67 (m, 2H, CHPyr), 7.32–7.22 (m, 4H, 3ꢄCHPh, CHPyr), 7.15–
7.03 (m, 7H, CHPh), 6.38 (d, J=9.0, 1H, NHSO2Pyr), 5.09 (dd, J=9.0,
4.7, 1H, CH-NH), 4.06 (m, 1H, CHH-O), 3.91 (m, 1H, CHH-O), 3.44
(dt, J=7.2, 5.3, 1H, CH-CH2), 2.61 (m, 2H, CH2-Ph), 1.90 (m, 2H, CH2-
CH), 1.64–1.40 (m, 2H, CH2-CH3), 0.90 ppm (t, J=7.5, 3H, CH3);
Chem. Eur. J. 2009, 15, 8204 – 8222
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8219

R. Peters and M. Zajac
matography on silica gel (ethyl acetate/cyclohexane 1:1.5) to furnish the
pure sulfone 59 as colorless solid (104 mg, 0.235 mmol, 86% yield,
>100:1 d.r., 85% ee). The ee values were determined by HPLC (Chiral-
flash chromatography on silica gel (200:9:1 CHCl3/MeOH/conc. NH4OH)
to furnish the pure amine 62 as light yellow oil (4.0 mg, 0.024 mmol, 43%
yield). C11H17N, MW = 163.26 gmolÀ1; [a]D26:1 (c=0.20, CHCl3)=+15.2Æ
0.4 (sample with ee 85%); 1H NMR (300 MHz, CDCl3, 228C): d=7.05–
7.32 (m, 5H, CHPh), 3.90 (t, J=6.3, 1H, CH-NH2), 2.88 (brs, 2H, NH2),
1.58–1.78 (m, 2H, CH2-CH), 1.15–1.28 (m, 4H, CH2), 0.85 ppm (t, J=7.2,
3H, CH3). The other analytical data are in accordance with literature
precedence.[52]
cel OD-H, n-hexane/iPrOH 85:15, 1.0 mLminÀ1). C22H24N2O4S2, MW
=
444.57 gmolÀ1; [a]D27:1 (c=1.42, CHCl3)=+9.3Æ0.2 (sample with ee=
85%); 1H NMR (300 MHz, CDCl3, 228C): d=8.55 (d, J=4.7, 1H,
CHPyr), 7.66 (m, 2H, CHPyr), 7.58 (m, 2H, CHPh), 7.51 (t, J=7.5, 1H,
CHPh), 7.37 (t, J=7.8, 2H, CHPh), 7.32 (m, 1H, CHPyr), 6.97 (m, 5H,
CHPh), 6.71 (d, J=8.1, NHSO2Pyr), 5.02 (dd, J=7.8, 5.6, CH-NH), 3.38
(dt, J=7.5, 5.3, 1H, CH-CH2), 1.94–1.67 (m, 2H, CH2-CH), 1.46–1.22 (m,
2H, CH2-CH3), 0.77 ppm (t, J=7.5, 3H, CH3); 13C NMR (75 MHz,
CDCl3, 228C): d=157.7, 149.8, 139.2, 137.6, 136.8, 133.5, 129.0 (2C),
128.2, 128.1, 127.7, 127.2 (2C), 126.3, 121.8, 68.9, 57.4, 28.6, 20.6,
13.6 ppm; IR (ATR, neat): n˜ =3362, 2962, 1581, 1448, 1427, 1335, 1298,
1287, 1175, 1136, 1120, 1079, 992, 756, 740, 725, 701 cmÀ1; HRMS (ESI)
m/z: calcd for: 467.1070; found: 467.1070 [M+Na]+.
Acknowledgements
This work was financially supported by the Roche Research Foundation,
F. Hoffmann-La Roche, ETH research grant TH-01 07-1, the Swiss Na-
tional Science Foundation and the Universitꢁt Stuttgart. We thank Paul
Seiler (ETHZ) for X-ray crystal structure determination.
ACHTUNGTRENNUNG(1S,2S)-1-Amino-N-benzyl-1-phenylpentane-2-sulfonamide (60): A reac-
tion flask was charged with Mg turnings (5 mg, 0.211 mmol, 5.0 equiv),
evacuated and filled with nitrogen. Sulfonamide 57 (20 mg, 0.042 mmol,
1.0 equiv, >100:1 d.r., 84% ee) was added as a solution in dry MeOH
(1 mL) and the mixture was stirred for 2 h at RT. After this time, the
mixture was diluted with sat. aq. NaHCO3 (5 mL) and brine (5 mL) and
extracted with ethyl acetate (2ꢄ10 mL). The combined organic layers
were dried over Na2SO4, filtered and evaporated in vacuo. The crude
product was purified by flash chromatography on silica gel (CHCl3/
MeOH/conc. NH4OH 200:9:1) to furnish the pure deprotected amine 60
as light yellow oil (11 mg, 0.032 mmol, 76% yield, >100:1 d.r.).
C18H24N2O2S, MW = 332.46 gmolÀ1; [a]D27:4 (c=0.25, CHCl3)=À52.2Æ1.0
(sample with ee=84%); 1H NMR (300 MHz, CDCl3, 228C): d=7.40 (m,
5H, CHPh), 7.29 (m, 3H, CHPh), 7.02 (dd, J=8.1, 1.9, 2H, CHPh), 4.33
(dd, J=19.6, 14.0, 2H, CH2-NH), 4.09 (d, J=10.3, 1H, CH-NH2), 2.89
(m, 1H, CH-CH2), 1.64 (m, 3H, NH2, NH), 1.43 (m, 2H, CH2-CH), 1.28
(m, 2H, CH2-CH3), 0.67 ppm (t, J=7.5, 3H, CH3); 13C NMR (100 MHz,
CDCl3, 228C): d=142.4, 136.6, 128.1, 127.9, 127.6, 127.3, 126.9, 125.4,
65.8, 56.0, 46.7, 28.7, 19.0, 12.9 ppm; IR (ATR, neat): n˜ =2958, 2870,
1455, 1293, 1140, 1072, 986, 832, 742 cmÀ1; HRMS (ESI) m/z: calcd for:
333.1631; found: 333.1633 [M+H]+.
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ACHTUNGTRENNUNG(1S,2S)-1-Phenyl-2-(pyrrolidin-1-ylsulfonyl)pentan-1-amine (61): A reac-
tion flask was charged with Mg turnings (5 mg, 0.229 mmol, 5.0 equiv),
evacuated and filled with nitrogen. Sulfonamide 58 (20 mg, 0.046 mmol,
1.0 equiv, >100:1 d.r., 84% ee) was added as a solution in dry MeOH
(1 mL) and the mixture was stirred for 2 h at RT. After this time, the
mixture was diluted with sat. aq. NaHCO3 (5 mL) and brine (5 mL) and
extracted with ethyl acetate (2ꢄ10 mL). The combined organic layers
were dried over Na2SO4, filtered and evaporated in vacuo. The crude
product was purified by flash chromatography on silica gel (CHCl3/
MeOH/conc. NH4OH 200:9:1) to furnish the pure deprotected amine 61
as light yellow oil (9 mg, 0.034 mmol, 73% yield, >100:1 d.r.).
C15H24N2O2S, MW = 269.43 gmolÀ1; [a]D29:5 (c=0.215, CHCl3)=À26.6Æ
1
2.2 (sample with ee=84%); H NMR (300 MHz, CDCl3, 228C): d=7.40–
7.25 (m, 5H, CHPh), 4.38 (d, J=8.1, 1H, CH-NH2), 3.36 (m, 4H, 2ꢄCH2-
N), 3.24 (m, 1H, CH-CH2), 1.86 (m, 6H, 2ꢄCH2CH2N, NH2), 1.64 (m,
1H, CHH-CH), 1.49 (m, 1H, CHH-CH), 1.16 (m, 2H, CH2-CH3),
0.69 ppm (t, J=7.2, 3H, CH3); 13C NMR (75 MHz, CDCl3, 228C): d=
142.7, 128.4, 127.7, 127.5, 68.6, 56.2, 47.8, 30.0, 25.9, 20.7, 13.9 ppm; IR
(ATR, neat): n˜ =2960, 2872, 1454, 1311, 1197, 1135, 1071, 1009, 760,
702 cmÀ1; HRMS (EI) m/z (%): calcd for: 296.1553; found: 296.1545
(0.1) [M]+.
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(R)-1-Phenylpentan-1-amine (62): In a glove-box unter nitrogen, a reac-
tion flask was charged with finely ground sodium amalgam (5% Na,
201 mg, 0.437 mmol, 8.0 equiv) and finely ground anhydrous Na2HPO4
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8220
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 8204 – 8222

Taurine Derivatives
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[37] Since the same reaction setup and catalysts are used for the forma-
tion of sultams 22a–e, all configurations were assigned to be
(3R,4R) assuming a uniform reaction pathways. For b-sultam 22 f,
for which Q2PYR was used as catalyst, the (3S,4S)-configuration
was assigned by comparison of the CD spectra (22 f shows a maxi-
mum elipticity at 209 nm/+4.7 mdeg and minimum at 229 nm/
À0.7 mdeg, while 22a has a minimum at 211 nm/À5.0 mdeg and
maximum at 228 nm/+1.0 mdeg). It is therefore very likely that 22 f
possesses a (3S,4S)-configuration. This is confirmed by the formation
of the opposite enantiomer with (3R,4R)-configuration using quinine
as catalyst (same conditions as in Table 2: yield 87%, d.r. 23:1, ee=
34%). The syn-configuration of 22 f was confirmed by 1H NMR
NOE experiments.
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[41] In contrast, methanesulfonic acid methyl ester was obtained in 43%
yield with a monodeuteration level of 70% (use of 3 equiv MeOD,
1.0 equiv DIPEA, CH2Cl2, À808C, 1h) has determined by 1H NMR
and MS analyses. The deuteration level is lower than 100% due to a
competing H/D exchange involving MeOD and the ammonium salt
of DIPEA, formed by deprotonation of sulfonyl chloride during the
sulfene generation, thus yielding non-deuterated MeOH. The ab-
sence of the bisdeuterated methyl ester product provides strong evi-
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Chem. Eur. J. 2009, 15, 8204 – 8222
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www.chemeurj.org
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merically pure starting material (>100:1 dr, 85% ee).
[45] In our preliminary communication (ref. [29]), the absolute configu-
ration of 44 was unfortunately misassigned as (R,R) assuming an
identical mechanistic pathway for the chloral derived imine 29 and
the ethyl glyoxylate derived imine 43. In addition to the NOE stud-
ies, the trans-configuration was confirmed by the 1H NMR coupling
constants J of the ring protons. For cis isomers like b-sultams 22,
they are typically about 9 Hz, while the trans-isomers have coupling
constants about 5 Hz. Moreover, we have prepared the syn diaste-
reomer of 46 starting from b-sultam 22b by nucleophilic ring open-
ing with n-octylamine, double dechlorination, and intramolecular
nucleophilic substititution. (R)-N-Octyl-1-((S)-1-tosylaziridin-2-yl)-
butane-1-sulfonamide: 1H NMR (300 MHz, CDCl3, 228C): d=7.81
(d, J=8.1, 2H, CHPh), 7.37 (d, J=8.1, 2H, CHPh), 4.45 (m, 1H, NH-
CH2), 3.11 (m, 2H, CH2-NH), 3.00 (m, 1H, CH-SO2), 2.70 (m, 1H,
CH-N), 2.66 (d, J=6.8, 1H, CHH-N), 2.46 (s, 3H, CH3-Ph), 2.36 (d,
J=4.4, 1H, CHH-N), 1.90–1.77 (m, 1H, CHH-CHSO2), 1.60–1.48
(m, 1H, CHH-CHSO2), 1.48–1.37 (m, 2H, CH2-CH3), 1.27 (brs,
12H, (CH2)6), 0.88 (t, J=6.8, 3H, CH3), 0.81 ppm (t, J=7.2, 3H,
CH3); 13C NMR (75 MHz, CDCl3, 228C): d=145.1, 133.4, 129.8,
128.3, 63.2, 44.0, 38.1, 32.6, 31.8, 30.8, 29.9, 29.8, 29.2, 26.6, 22.7,
21.8, 20.2, 14.2, 14.0 ppm; HRMS (ESI): m/z: calcd for: 467.2009;
found: 467.2009 [M+Na]+.
[46] For recent use of N-(heteroarylsulfonyl) imines in addition and cy-
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Received: February 23, 2009
Published online: July 16, 2009
8222
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Chem. Eur. J. 2009, 15, 8204 – 8222