Enantioselective synthesis of 3,4-disubstituted cis- and trans-1,2,5-thiadiazolidine-1,1-dioxides as precursors for chiral 1,2-diamines

Article abstract of DOI:10.1021/ol3034753

Both, cis- and trans-3,4-disubstituted thiadiazolidines 5 and 6 can enantioselectively be obtained from thiadiazoles 2 which, in turn, are efficiently prepared from the respective 1,2-diketone by an improved protocol. An asymmetric ruthenium-catalyzed transfer hydrogenation followed by a diastereoselective hydride addition furnishes exclusively the cis-isomers 5 which, under acidic conditions, undergo a novel isomerization into the trans-isomers 6. These cyclic sulfamides can be transformed into 1,2-diamines as well as 2,3-diamino acids.

Full text of DOI:10.1021/ol3034753

ORGANIC
LETTERS
2013
Vol. 15, No. 4
800–803
Enantioselective Synthesis
of 3,4-Disubstituted cis- and
trans-1,2,5-Thiadiazolidine-1,1-dioxides
as Precursors for Chiral 1,2-Diamines
†
Christian Schuttler, Zhen Li-Bohmer, Klaus Harms, and Paultheo von Zezschwitz*
†
€
€
€
Fachbereich Chemie, Philipps-Universitat Marburg, 35032 Marburg, Germany
zezschwitz@chemie.uni-marburg.de
Received December 19, 2012
ABSTRACT
Both, cis- and trans-3,4-disubstituted thiadiazolidines 5 and 6 can enantioselectively be obtained from thiadiazoles 2 which, in turn, are efficiently
prepared from the respective 1,2-diketone by an improved protocol. An asymmetric ruthenium-catalyzed transfer hydrogenation followed by a
diastereoselective hydride addition furnishes exclusively the cis-isomers 5 which, under acidic conditions, undergo a novel isomerization into the
trans-isomers 6. These cyclic sulfamides can be transformed into 1,2-diamines as well as 2,3-diamino acids.
The sulfamide moiety belongs to the most important
pharmacophores in medicinal chemistry and is found in
many pharmaceutical agents.1 Cyclic sulfamides are espe-
cially interesting due to their conformational rigidity, and
the 5-ring derivatives, i.e. 1,2,5-thiadiazolidine-1,1-dioxides,
can be modified to selectively interact with various biologi-
cal receptors. Among others this comprises inhibitors
of R-mannosidase,2a the TNF-R converting enzyme,2c
γ-secretase involved in Alzheimer’s disease,2d serine
proteases,2e and HIV protease,2f as well as antibiotics2b
and agonists at serotonin receptors.2g Moreover, 1,2,5-
thiadiazolidines are used as chiral auxiliaries,3 building
blocks in supramolecular chemistry,4 and intermediates
for the preparation of chiral 1,2-diamines.5
Their synthesis typically starts from acyclic 1,2-difunctio-
nalized precursors such as 1,2-diamines, 1,2-aminoalcohols,
or 2-chloroalkylamines, and enantioselective preparations
thus critically depend on the availability of the respective
† These authors contributed equally.
(1) Review: Winum, J.-Y.; Scozzafava, A.; Montero, J.-L.; Supuran,
C. T. Med. Res. Rev. 2006, 26, 767–792.
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(2) (a) Benltifa, M.; Garcıa Moreno, M. I.; Ortiz Mellet, C.; Garcıa
Dewynter, G. Tetrahedron: Asymmetry 2010, 21, 2361–2366. (b) Ahn,
K. H.; Yoo, D. J.; Kim, J. S. Tetrahedron Lett. 1992, 33, 6661–6664. (c)
Sartor, D.; Saffrich, J.; Helmchen, G.; Richards, C. J.; Lambert, H.
Tetrahedron Lett. 1991, 32, 639–642.
(4) (a) Hof, F.; Nuckolls, C.; Craig, S. L.; Martin, T.; Rebek, J., Jr. J.
Am. Chem. Soc. 2000, 122, 10991–10996. (b) Martin, T.; Obst, U.;
Rebek, J., Jr. Science 1998, 281, 1842–1845.
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Fernandez, J. M.; Wadouachi, A. Bioorg. Med. Chem. Lett. 2008, 18,
2805–2808. (b) Kim, S. J.; Park, H. B.; Lee, J. S.; Jo, N. H.; Yoo, K. H.;
Baek, D.; Kang, B.-w.; Cho, J.-H.; Oh, C.-H. Eur. J. Med. Chem. 2007,
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R.-Q.; Covington, M. B.; Duan, J. J.-W.; Decicco, C. P. Bioorg. Med.
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T.; Heath, F.; Madin, A.; Merchant, K. Synlett 2006, 833–836. (b) Kim,
I.-W.; Jung, S.-H. Arch. Pharm. Res. 2002, 25, 421–427. (c) Nicolaou,
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r
10.1021/ol3034753
Published on Web 01/24/2013
2013 American Chemical Society

enantiopure starting material.6 These traditional approaches
have been supplemented in recent years by inter- and intra-
molecular 1,2-diaminations of alkenes7 and oxidative cycli-
zations of allylic sulfamides.8 Being very promising due to
their atom efficiency, these methods, however, still suffer
from a limited substrate scope and only furnished racemic
1,2,5-thiadiazolidines so far.9
In contrast, the utilization of cyclic starting materials has
rarely been reported,10 including racemic syntheses from
thiadiazole-1,1-dioxides.10b,c These unsaturated analogs con-
taining two C,N-double bonds also have interesting biologi-
cal properties as histamine H2-receptor antagonists11a,b as
well as antihypertensive and vasodilating agents11c and are
often described in patent literature.12 Thiadiazole-1,1-diox-
ides with organic substituents at the C-atoms are obtained
from 1,2-diketones by condensation with sulfamide, SO2-
(NH2)2, and 3,4-diaryl substituted compounds can be
prepared under mild conditions using Et3N.10c However,
alkyl-substituted derivatives are so far only obtainable under
harsh conditions, i.e. refluxing with HCl in alcoholic
medium, which results in a limited functional group
tolerance.10c,13 Herein, we report on an improved protocol
for the preparation of 4-alkyl-3-aryl-1,2,5-thiadiazole-1,
1-dioxides and on their transformation into enantiopure
cis- and trans-thiadiazolidine-1,1-dioxides.
polar reagent which is readily prepared from SO2Cl2 and
NH(SiMe3)2.14 Stirring of 1,2-diketones 1 with an excess of
15
this reagent and stoichiometric amounts of BF3 OEt2
3
resulted in smooth formation of the desired condensa-
tion products in considerably increased yields of 70ꢀ90%
(Table 1). Thus, major improvements can be achieved espe-
cially in the case of more sensitive compounds (entries 2, 7). In
the case of longer n-alkyl chains at C4, the thiadiazoles 2 were
formed as mixtures with the respective 4-alkylidenethiadia-
zolines 3 in varying percentages. Similar observations have
been made before16 and might stem from reduced ecliptic
interactions when going from thiadiazoles 2 with a planar
ring to the tautomers 3.17
Table 1. Improved Synthesis of Thiadiazole-1,1-dioxides
entry
product
Ar
R
yield (%)a
1
2
3
4
5
6
7
8
2a
Ph
Ph
Ph
Ph
Me
Et
Et
iPr
Et
Et
Et
87 [58]c
78 [29]c
85 [56]c
90 [58]c
81 [65]c
72 [58]c
70 [30]c
75
2b
2cb
2db
2e
The inherent problem of the previous syntheses of
thiadiazole-1,1-dioxides is the poor solubility of SO2(NH2)2
in aprotic solvents, thus requiring the use of alcoholic media
and strong Brønsted acids. To overcome this limitation we
devised the use of N,N0-bis(trimethylsilyl)sulfamide as a less
p-MeOC6H4
p-MeOC6H4
p-ClC6H4
2fb
2gb
2hb
furan-2-yl
thiophen-3-yl
a Isolated yield. b Obtained as mixture with tautomer 3 in varying
percentages. c Numbers in brackets indicate isolated yield from prepara-
tion according to Wright and Ziegler et al. (refs 10c and 13) with
sulfamide and HCl.
ꢀ
€
(7) (a) Chavez, P.; Kirsch, J.; Hovelmann, C. H.; Streuff, J.; Martınez-
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The C,N-double bonds in thiadiazole-1,1-dioxides are quite
reactive toward nucleophilic additions,18 yet, asymmetric
reductions are unprecedented.19 A screening of various
protocols for such reactions20 including Ru(II)/binap-
€
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Gonzalez, Y.; Iglesias, A.; Zian, D.; Lishchynskyi, A.; Muniz, K.
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(18) For examples, see refs 10b and 17b as well as: (a) Luo, Y.;
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E. J. J. Phys. Org. Chem. 2007, 20, 1081–1087.
(19) For Rh(TsDPEN)-catalyzed hydrogenations of 3-aryl-1,2,5-
thiadiazoline-1,1-dioxides, see ref 10a. For Ru(TsDPEN)-catalyzed
hydrogenations of 1-arylpropan-1,2-diones, see: (a) Koike, T.; Murata,
K.; Ikariya, T. Org. Lett. 2000, 2, 3833–3836. For asymmetric hydro-
genations of other related compounds, see: (b) Lee, H.-K.; Kang, S.;
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(12) A SciFinder search revealed more than 45 patent documents
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Org. Lett., Vol. 15, No. 4, 2013
801

catalyzed hydrogenations revealed that the best results can be
achieved with the transfer hydrogenation catalyst RuCl-
(TsDPEN) A, introduced by Noyori et al. (Table 2).21 Under
these conditions, the C4,N5-double bond is substantially more
reactive than the C3,N2-double bond, enabling a selective
formation of thiadiazolines 4. While the Ph,Ph derivative 2a
only furnished racemic product 4a even when stopping the
reaction at low conversions (entry 1), the aryl,alkyl derivatives
underwent regio- and enantioselective reductions of the alkyl-
substituted C4,N5-double bonds. This behavior should be due
to the fact that the aryl rings in thiadiazoles 2 are twisted out
of plane to avoid ecliptic interactions.17c In thiadiazolines 4,
however, the aryl rings are almost coplanar with the C3,N2-
double bonds, thus stabilizing them against further reduc-
tion.17a Only in the case of prolonged reaction times, 2-fold
reduction was observed which, however, occurred with lower
stereoselectivity. Therefore, the reaction was stopped at the
stage of thiadiazolines 4, which were obtained in high yields
and excellent enantiopurities in most cases (Table 2). The
yield of the Ph,Me derivative 4b was moderate due to partial
dimerization of the starting material (entry 2),16 and trans-
formation of substrates 2c, 2d, and 2f revealed an electronic
effect: Better results were generally obtained in the case of
electron-rich aryl substituents. Thus, the electron-poor
p-ClC6H4-derivative 2f furnished a mixture of the desired 4f
and its regioisomer formed by reduction of the aryl-substitued
C3,N2-double bond.22 Notably, the reaction also tolerates
secondary alkyl groups at C4 (entry 5) as well as heteroaro-
matic substituents at C3 (entries 7,8), and complete conver-
sions were detected even when starting from mixtures of
tautomers 2 and 3 which points to a fast isomerization under
the reaction conditions.
Table 2. Asymmetric Transfer Hydrogenation
time
(h)
yield
(%)a
ee
entry
product
Ar
R
(%)b
1
2
3
4
5
6
7
8
4a
Ph
Ph
Ph
Ph
Me
Et
Et
iPr
Et
Et
Et
5
71
55
73
97
94
70d
85
72
0
4b
30
30
40
48
41
50e
55e
98
97
96
96
66
96
96
4cc
4dc
4e
p-MeOC6H4
p-MeOC6H4
p-ClC6H4
4fc
4gc
4hc
furan-2-yl
thiophen-3-yl
a Isolated yield. b Determined by HPLC on a chiral stationary phase.
c Prepared from a mixture of compounds 2 and 3. d Yield determined by
1H NMR from a mixture of 4f and a regioisomer. e Reaction performed
at ꢀ20 °C.
4d in THF led to no changes, and among various tested
boranes and borohydrides, LiBH4 arose as the reagent of
choice. Thus, all transformations occurred in almost
quantitative yields (Table 3), and only the Ph,Me deriva-
tive 5b still showed a slightly reduced ee (entry 1). All
sulfamides 5 are colorless solids, and an X-ray crystal-
lographic analysis of compound 5e allowed for the deter-
mination of its absolute configuration as (3R,4S).24
This transfer hydrogenation is not suitable for a selective
reduction of the second C,N-double bond, yet literature
precedence suggested NaBH4 for this purpose.10b The
corresponding reaction of thiadiazolines 4 in EtOH led
to diastereoselective formation of cis-thiadiazolidines 5,23
albeit it was accompanied by a serious drop in enantio-
purity. This partial racemization is caused by the alkaline,
protic reaction medium: stirring compound 4d in EtOH at
50 °C for 24 h led to a drop from 96% ee to 83% ee, and
complete racemization occurred upon stirring 4d with 1.2
equiv of DBU in EtOHat rt for 24 h. Incontrast, stirring of
Table 3. Diastereoselective Reduction with LiBH4
entry
product
Ar
R
yield (%)a
ee (%)b
1
2
3
4
5
6
5b
5c
5d
5e
5g
5h
Ph
Ph
Me
Et
91
93
93
95
97
96
92
95
96
95
95
94
p-MeOC6H4
p-MeOC6H4
furan-2-yl
Et
iPr
Et
(20) For reviews about asymmetric reduction of C,N-bonds, see: (a)
Fleur-Bregeot, N.; de la Fuente, V.; Castillon, S.; Claver, C. Chem-
CatChem 2010, 2, 1346–1371. (b) Spindler, F.; Blaser, H.-U. Enantio-
selective Hydrogenation of CdN Functions and Enamines. In The
Handbook of Homogeneous Hydrogenation; de Vries, J. G., Elsevier,
C. J., Eds.; Wiley-VCH: Weinheim, 2007; Vol. 3, pp 1193ꢀ1214. (c) Samec,
thiophen-3-yl
Et
a Isolated yield. b Determined by HPLC on a chiral stationary phase.
€
J. S. M.; Backvall, J.-E.; Andersson, P. G.; Brandt, P. Chem. Soc. Rev.
Having achieved an enantioselective synthesis of cis-
thiadiazolidines 5, cleavage of the sulfamide moiety was
intended to obtain anti-1,2-diamines. Accordingly, cis-
thiadiazolidine 5c was stirred in H2SO4,25 but instead of ring
opening, a smooth isomerization was observed to give the
corresponding trans-thiadiazolidine 6c under preservation of
the high ee (Table 4, entry 1). Examination of this novel
2006, 35, 237–248. (d) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35,
226–236.
(21) (a) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. Engl. 1997, 36, 285–288. (b) Noyori, R.; Hashiguchi,
S. Acc. Chem. Res. 1997, 30, 97–102. (c) Uematsu, N.; Fujii, A.; Hashiguchi,
S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916–4917.
(22) The reduced selectivity obviously stems from the increased
reactivity of starting material 2f. Similarly, the more reactive catalyst
Cp*RhCl(TsDPEN) generally leads to unselective reduction. These
results are consistent with those obtained by Ikariya et al. in the case
of 1-arylpropan-1,2-diones; cf. ref 19a.
(24) See Supporting Information for details.
(25) Newkome, G. R.; Pappalardo, S.; Gupta, V. K.; Fronczek, F. R.
J. Org. Chem. 1983, 48, 4848–4851.
(23) This high substrate-controlled diastereoselectivity should be
caused by a Cram-chelate type transition state.
802
Org. Lett., Vol. 15, No. 4, 2013

Table 4. Cis/Trans-Isomerization of 1,2,5-Thiadiazolidines
Scheme 1. Transformation into Chiral 2,3-Diamino Acids
yield
ee
entry product
Ar
R
acid
(%)a (%)b
1
2
3
4
6c
6d
6e
6h
Ph
Et
Et
H2SO4
96
93
94
94
96
96
95
94
p-MeOC6H4
p-MeOC6H4
CF3CO2H
iPr CF3CO2H
CF3CO2H
thiophen-3-yl Et
a Isolated yield. b Determined by HPLC on a chiral stationary phase.
reaction mode disclosed that, in the case of electron-rich aryl
groups, the isomerization already proceeded in the presence
of the milder trifluoroacetic acid (entries 2ꢀ4). Thus, the
isomerization presumably takes place through protonation
at the oxygen of the SO2 moiety.26 Subsequent scission of the
C3,N2-bond leads to a benzyl cation B which occurs more
readily in the case of the p-MeOC6H4-substituted com-
pounds.27 Recyclization then furnishes the trans-isomers 6
due to reduced torsional strain. Thus, each of the four stereo-
isomers of 3-aryl-4-alkyl-substituted thiadiazolidine-1,1-di-
oxides can efficiently be obtained from the respective 1,2-
diketone in 3ꢀ4 straightforward steps, and in a gram scale
process, 3.27 g of 6d with 96% ee were obtained from 1d in
75% overall yield.
Besides being interesting on their own, the prepared
thiadiazolidines 5 and 6 are precursors for chiral 1,2-
diamines, a substance class of utmost importance.28 More-
over, thearylsubstituent atC3 can be regardedasa masked
carboxy group, thus opening an access to 2,3-diamino
acids.29 For exemplification, both the cis- and the trans-
thiadiazolidines 5e and 6e were separately transformed
into the anti- and syn-diamino acids 11 and 12, respec-
tively; the latter has been reported as a substructure of
peptidomimetics (Scheme 1).30 The cleavage of sulfon-
amides and sulfamides is rather difficult, and harsh condi-
tions are frequently required. Preliminary experiments for
the ring opening of thiadiazolidines 5 by refluxing in pyr-
idine/water (95:5) according to Davis et al.31 or refluxing in
HBr with added phenol according to Pansare et al.5 led to
moderate yields (∼50%) of the free diamines, yet especially
the latter method is not compatible with sensitive substrates.
Better results were obtained when performing a nucleophilic
opening of the thiadiazolidine ring by refluxing in hydrazine
monohydrate, a rather cheap reagent. Thus, the free
diamines 7e and 8e were obtained in yields exceeding
90%. To avoid formation of zwitterionic free diamino
acids, these compounds were transformed into the bis-
trifluoroacetamides 9e and 10e prior to oxidative cleavage
of the aryl rings which was achieved using a protocol by
Boger et al.32 As can be seen from the ee’s of 9eꢀ11, the
synthesis of the 1,2-diamines and 2,3-diamino acids occurred
without any isomerization.
In conclusion, we have developed an improved method for
the preparation of thiadiazole-1,1-dioxides from enolizable
1,2-diketones. Moreover, the first enantioselective transfor-
mation of these compounds into both cis- and trans-thiadia-
zolidines was achieved, featuring an asymmetric transfer
hydrogenation, a diastereoselective hydride addition, and
an unprecedented cis/trans-isomerization under acidic con-
ditions. The possibility of using these cyclic sulfamides as
precursors for 1,2-diamines and 2,3-diamino acids and to
prepare all four stereoisomers of these compounds from a
common starting material adds to the synthetic value of this
approach. Work is now in progress to further enlarge the
utilization of thiadiazoles in organic synthesis especially
toward the formation of quaternary stereogenic centers.
(26) Computational data point to a slightly preferred protonation at
oxygen, not nitrogen; see ref 17a.
(27) No isomerization occurred in the case of the methyl,methyl
derivative; see Supporting Information for details.
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Drug Des. 2006, 67, 101–114. (b) Lucet, D.; Le Gall, T.; Mioskowski, C.
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(29) Viso, A.; Fernandez de la Pradilla, R.; Trotosa, M.; Garcıa, A.;
Flores, A. Chem. Rev. 2011, 111, PR1–PR42.
(30) (a) von Nussbaum, F.; Beck, H.; Brunner, N.; Endermann, R.;
Koebberling, J.; Ragot, J.; Telser, J.; Schuhmacher, J.; Anlauf, S.;
Cancho-Grande, Y.; Greschat, S.; Militzer, H.-C.; Schiffer, G.
(Aicuris GmbH & Co KG) US2009/203582 A1, 2009. (b) Viso, A.;
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra of all
compounds; ORTEP drawing and crystallographic data
of compound 5e. This material is available free of charge
via the Internet at http://pubs.acs.org.
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Fernandez de la Pradilla, R.; Flores, A.; Garcıa, A.; Tortosa, M.; Lopez-
Rodrıguez, M. L. J. Org. Chem. 2006, 71, 1442–1448. (c) Mohan, R.;
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The authors declare no competing financial interest.
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