An entry into hexahydro-2H-thieno[2,3-c]pyrrole 1,1-dioxide derivatives

Article abstract of DOI:10.1021/jo200878t

Hexahydro-2H-thieno[2,3-c]pyrrole is proposed as a low molecular weight polar scaffold to construct compound libraries used in the search for new drugs. Practical syntheses of derivatives of this bicyclic scaffold were developed, based on [3 + 2] cycloadd

Full text of DOI:10.1021/jo200878t

ARTICLE
pubs.acs.org/joc
An Entry into Hexahydro-2H-thieno[2,3-c]pyrrole 1,1-Dioxide
Derivatives
Vladimir S. Yarmolchuk,†,‡ Ivan L. Mukan,†,‡ Oleksandr O. Grygorenko,*,†,‡ Andrey A. Tolmachev,†,‡
Svitlana V. Shishkina,§ Oleg V. Shishkin,§ and Igor V. Komarov†,‡
†Kyiv National Taras Shevchenko University, Volodymyrska Street 60, Kyiv 01601, Ukraine
‡Enamine Ltd., Alexandra Matrosova Street 23, Kyiv 01103, Ukraine
§STC “Institute for Single Crystals”, National Academy of Science of Ukraine, Lenina ave. 60, Kharkiv 61001, Ukraine
S Supporting Information
b
ABSTRACT: Hexahydro-2H-thieno[2,3-c]pyrrole is proposed as a
low molecular weight polar scaffold to construct compound libraries
used in the search for new drugs. Practical syntheses of derivatives of
this bicyclic scaffold were developed, based on [3 + 2] cycloaddition
of the ylide generated from N-benzyl-1-methoxy-N-((trimethylsilyl)-
methyl)methanamine and 4-substituted 2,3-dihydrothiophene
1,1-dioxides. All of the 3-substituted hexahydro-2H-thieno[2,3-c]
pyrrole 1,1-dioxide derivatives were obtained as single diastereo-
mers. Conformational properties of the hexahydro-2H-thieno[2,3-c]pyrrole 1,1-dioxide derivatives were explored using X-ray
diffraction studies. The potential of the scaffold to generate libraries of 3D-shaped molecules was demonstrated.
’ INTRODUCTION
Aromatic heterocyclic compounds have always been a major
source of building blocks used in drug design. There are at least
two reasons behind this: the heteroatoms and the aromatic
π-system ensure binding of heterocyclic molecules to biological
targets, whereas the ring systems provide conformationally
restricted templates, or scaffolds, for constructing the molecules
of potential drug candidates. A variety of synthetic methods have
been developed for the synthesis of numerous aromatic heterocycles
during the more than one-hundred year history of chemistry
of heterocyclic compounds. However, aromatic heterocycles are
flattened; therefore, libraries of their derivatives cannot be suffi-
ciently structurally diverse. Structural diversity is a very impor-
Figure 1. Fused pyrrolidine derivatives À marketed drugs.
tant requirement for the compounds used in the search for new
drugs;1,2 therefore, the latest tendencies in drug design demon-
turned our attention to bicyclic sulfones. The sulfone moiety, in
addition to the decrease of the lipophilicity, can be involved in the
interaction of the molecules with biological targets. We were
encouraged by the fact that several compounds possessing a cyclic
sulfone moiety have reached preclinical or clinical trials: antiglau-
coma agent Dorzolamide,8 antitrypanosomal drug Nifurtimox,9 and
compounds with antiviral10 or antipsychotic11 activity (Figure 2).
We would like to highlight the latter example (compound 1), which
is particularly relevant to the concept we pursue in this work:
the nonplanar, bicyclic saturated scaffold of 1 features the sulfone
moiety and the functional groups positioned properly in space
to interact with the biological target, metabotropic glutamate
receptors.
strated attempts to move away from this “flattened” part of chemi-
cal space by increasing saturation and introducing chirality
into the scaffolds.2 Implementation of these principles leads
to saturated heterocyclic compounds as preferred template
structures.
The simplest saturated heterocycles are rather flexible, whereas
conformational restriction is considered as one of the essential
properties of drug molecules.3 Bicyclic scaffolds are more bene-
ficial in this respect due to their inherent conformational restric-
tions. For example, bicyclic pyrrolidine derivatives were widely used
in drug design: antibacterials Moxifloxacin and Trovafloxacin,4
antipsychotic Asenapine,5 or antidiabetic Mitiglinide6 can be men-
tioned as examples (Figure 1). However, a drawback of the saturated
bicyclic scaffolds is their enhanced lipophilicity which imposes
serious limitations on further optimization of the potential drug
molecules.7 In a search for new saturated hydrophilic scaffolds, we
Received: April 30, 2011
Published: July 27, 2011
r
2011 American Chemical Society
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Scheme 3a
a Relative configurations are shown.
Scheme 4a
Figure 2. Biologically active cyclic sulfones.
Scheme 1. Retrosynthetic Analysis of Hexahydro-2H-
thieno[2,3-c]pyrrole 1,1-Dioxide Scaffold
Scheme 2a
a Relative configurations are shown.
N-(trimethylsilylmethyl)benzylamine 5 proceeded smoothly to
give the benzyl derivative 6 in 85% yield (Scheme 2). It should be
noted that using a 2-fold excess of 5 significantly improved the
yield of the reaction. Deprotection of 6 gave the parent bicyclic
compound, hexahydro-2H-thieno[2,3-c]pyrrole 1,1-dioxide 2,
which was isolated as the hydrochloride.
a Relative configurations are shown.
It would be of interest to obtain functionalized derivatives of 2
which could be used for constructing libraries of substituted
analogues. Such libraries are often used in the search for lead
compounds in medicinal chemistry and to fine-tune the biological
activity of a lead. Werefer heretoa relevantsuccessfulexample 7,19
taken randomly from the recent literature, where the authors
modified the substituents around a bicyclic diamine scaffold and
found a novel antagonist of a CC chemokine receptor CCR3 with
reduced human cytochrome P450 2D6 inhibitory activity.
In this work, we report on an approach to the synthesis
of the previously unknown saturated heterocyclic system À
hexahydro-2H-thieno[2,3-c]pyrrole 1,1-dioxide 2 À a combina-
tion of pyrrolidine and sulfolane rings. We demonstrated that
libraries of functionalized derivatives of 2 are easy to obtain and
studied their essentialy nonflattened, three-dimensional struc-
ture. Calculated values of some physicochemical properties of 2
(i.e., molecular weight 161.2, cLog P À1.25, TPSA 54.6 Å2)12
suggest the use of the derivatives of this scaffold in medicinal
chemistry as building blocks for drug design.
’ RESULTS AND DISCUSSION
To synthesize functionalized analogs of 2, we have tested
derivatives of 4 in the reaction with the compound 5. Using the
N-Boc-protected amino derivative 816 as the starting material,
compound 9 was obtained as a single diastereomer in 67% yield
(Scheme 3). It is interesting to note that the nonprotected (1,1-
dioxido-2,3-dihydro-3-thienyl)amine did not undergo reaction
with 5 under identical conditions. Debenzylation of 9 allowed
selectively monoprotected diamine 10 to be obtained.
Amino ester 12 was obtained in 92% yield as a single
diastereomer in the reaction between another derivative of 4,
compound 11,15 and the ylide generated from 5 (Scheme 4).
Compound 12 was transformed into 13 upon alkaline hydrolysis.
Finally, deprotection of 13 gave the amino acid 14.
Synthesis. Our approach to the synthesis of 2 and its deriva-
tives involved construction of a pyrrolidine ring via [3 + 2]
cycloaddition reaction13 to 2,3-dihydrothiophene 1,1-dioxide
derivatives. The latter can be obtained from readily available
sulfolene 3 by the methods reported in the literature
(Scheme 1).14À17 The presence of an electron-withdrawing
sulfone moiety was expected to activate the double bond in the
dipolarophiles toward the cycloaddition. It should be noted,
however, that only a few reports on the analogous transformations
involving vinyl sulfones were found in the literature to date.18
Reaction of the parent 2,3-dihydrothiophene 1,1-diox-
ide 414 with the ylide generated from N-(methoxymethyl)-
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Scheme 5a
The reaction of tosylate 1517 and 5 gave compound 16 as a
single diastereomer in 78% yield (Scheme 5), which also can be
used as an intermediate in syntheses of derivatives of 2. Direct
nucleophilic displacement of the OTs group in 16 was however
accompanied by the elimination reaction, resulting in the for-
mation of R,β-unsaturated sulfone 17. In particular, compound
17 was obtained in almost quantitative yield by treatment of 9
with sodium hydroxide in aqueous THF. Reaction of 16 and
potassium cyanide in aqueous methanol resulted in the forma-
tion of compound 18 instead of the expected nitrile. As the
configuration at the electrophilic center was retained during the
formation of 18, we believe that 17 might be involved in this
reaction as an intermediate.
To establish the relative stereochemistry of the obtained
hexahydro-2H-thieno[2,3-c]pyrrole 1,1-dioxide derivatives,
NOESY experiments and X-ray diffraction studies were per-
formed. In particular, correlations observed in the NOESY
spectrum of 9 were evident for the expected cis-fusion of the
five-membered rings and for the trans-disposition of the Boc-
amino substituent and the pyrrolidine ring (Figure 3). The trans-
configuration was also confirmed by X-ray diffraction studies of
10, 12, 16, and 18 (Figure 4).
a Relative configurations are shown.
Molecular Structure. Although compounds 10, 12, 16, and
18 have the same relative configuration, their conformations
observed in crystals are quite different (Figure 4; the atom
numbering in Figure 4 will be used throughout this section).
The five-membered rings adopt the envelope conformation
in compounds 10, 12, and 16 with deviation of the C2 and
N1 atoms from the mean plane of the remaining atoms of
Figure 3. Significant correlations observed in the NOESY spectra of 9.
Figure 4. Molecular structures of 10, 12, 16, and 18.
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Table 1. Values of the Parameters r, j1, j2, and θ Obtained
from the X-ray Diffraction Data on Hexahydro-2H-thieno-
[2,3-c]pyrrole 1,1-Dioxide Derivatives
ꢀ
Entry No.
Compound
r, Å
j1, deg
j2, deg
θ, deg
1
2
3
4
10
12
16
18
3.248
3.115
3.263
3.363
54.2
62.8
58.1
54.0
126.7
131.9
146.5
140.6
101.5
93.4
30.3
26.7
Figure 5. Conformations of 10, 12, 16, and 18 observed in crystals
(schematic representation).
unstable. The relative orientation of these vectors can be
described by four parameters: the distance r between the atoms
N1 and C2, the plane angles j1 (between vectors n1 and C2N1)
and j2 (between n2 and N1C2), and the dihedral angle θ defined
by vectors n1, N1C2, and n2 (Figure 6b).
If this approach is applied to a “linear” 1,4-disubstituted
benzene scaffold (Figure 6c), the following values of the angles
are obtained: j1 = j2 = 0° (θ is undefined). For 2,6-disubstituted
derivatives of 2H-thieno[2,3-c]pyrrole À a “flattened” aromatic
analogue of 2(Figure6d) À j1 and j2 are nonzero, whereas θ=0°.
These examples show that the values of j1 and j2 close to 0°
are characteristic of the “linear” relative disposition of the
substituents attached to the scaffold, whereas θ values close to 0°
(or 180°) correspond to the “flattened” structures.
The values of the above-defined geometric parameters for
compounds 10, 12, 16, and 18, calculated from the X-ray
diffraction data, are given in Table 1. As follows from these data,
there is a significant difference in the values of θ observed for the
compounds 10 and 12 (101.5° and 93.4°) and 16 and 18 (26.7°
and 30.3°, respectively). Nevertheless, all these values are far
from 0° or 180° characteristic of the “flattened” cores. The values
of j1 and j2 angles which are far from 0° also demonstrate
the three-dimensional nature of the hexahydro-2H-thieno
[2,3-c]pyrrole 1,1-dioxide core.
Figure 6. (a) Definition of vectors n1, n2 (scaffold 2 is given as
an example); (b) definition of geometric parameters r, j1, j2, and θ;
(c) vectors n1, n2 shown for benzene scaffold; (d) vectors n1, n2 shown
for 2H-thieno[2,3-c]pyrrole scaffold.
corresponding rings. However, the directions of these deviations
are different (Figure 5). The C2 and N1 atoms deviate corre-
spondingly to the exo and endo directions with respect to the
thienopyrrole bicycle in molecules of 10 and 12, leading to a
chairlike shape of the bicyclic fragment. In the case of 16, both the
C2 and N1 atoms deviate to the endo direction, which causes a
boat-like shape of the bicyclic fragment. Five-membered rings in
18 adopt a twist conformation; in this case, the bicyclic scaffold
also has a boat-like shape. These differences lead to the pseu-
doequatorial orientation of the substituent at the C-3 atom in the
molecules of 10 and 12 and the pseudoaxial orientation for 16
and 18.
All these differences indicate that the structure of the hexahy-
dro-2H-thieno[2,3-c]pyrrole 1,1-dioxide core depends signifi-
cantly on the nature of the substituent at C2. In particular, the
conformations observed in the solid state are more or less similar
for compounds 10 and 12 and different for 16 and 18.
An important aspect of the conformational preferences of the
hexahydro-2H-thieno[2,3-c]pyrrole 1,1-dioxide derivatives is
their deviation from the “flattened” structure. Recently, we have
proposed quantitative geometric parameters to estimate this
property of molecular scaffolds.20 In essence, a scaffold can be
characterized by the relative spatial orientation of the substitu-
ents attached to the variation points. The role of the scaffold itself
is reduced to providing this relative orientation. Hence only
those parts of the molecule which are the most significant to
interactions with potential biological targets are considered, an
idea which has been embodied in the pharmacophore concept.21
In the case of scaffold 2, the substituents attached to the
variation points of the scaffold can be simulated by two vectors,
n1 and n2 (Figure 6a).22 The attachment points N1 and C2 can
be regarded as the starting points of n1 and n2, respectively. To
define the direction of n2, the C2R2 vector can be used, whereas,
for n1, the normalized sum of the vectors C4N1 and C5N1 is
more convenient, as the nitrogen atom N1 is configurationally
’ CONCLUSIONS
A diastereoselective approach to 6-substituted hexahydro-2H-
thieno[2,3-c]pyrrole 1,1-dioxide derivatives was developed. The
method relied on [3 + 2] cycloaddition of the ylide generated
from N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine
and 4-substituted 2,3-dihydrothiophene 1,1-dioxides and allowed
the title compounds to be obtained in 67À92% yields. The structure
of the 2,6-disubstituted hexahydro-2H-thieno[2,3-c]pyrrole 1,1-diox-
ide core depends significantly on the substituents attached to the
scaffold; it opens an access to “nonflattened”, three-dimensionally
shaped derivatives. Favorable conformational and predicted physico-
chemical properties of the hexahydro-2H-thieno[2,3-c]pyrrole
1,1-dioxide core allowed us to assume that derivatives of this
previously unknown scaffold could be promising building blocks
for use in medicinal chemistry.
’ EXPERIMENTAL SECTION
General. Solvents were purified according to the standard proce-
dures. Compounds 414 and 15,17 (1,1-dioxido-2,3-dihydro-3-thienyl)
amine,16 and 1,1-dioxido-2,3-dihydro-3-thienylacetic acid15 were pre-
pared using the procedures reported in the literature. Melting points
were measured on an automated melting point system. Analytical TLC
was performed using Polychrom SI F254 plates. Column chromatog-
raphy was performed using silica gel (230À400 mesh) as the sta-
tionary phase. 1H, 13C NMR and all 2D NMR spectra were recorded
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at 499.9 or 400.4 MHz for protons and 124.9 or100.4 MHz for carbon-13.
Chemical shifts are reported in ppm downfield from TMS (1H, 13C) as
CHHC6H5), 3.68 (1H, d, J = 13.6 Hz, CHHC6H5), 3.77 (1H, m, 6a-
CH), 4.06 (1H, m, 3-CH), 7.11 (1H, d, J = 6.9 Hz, NH), 7.23À7.27 (1H,
m, 4-CH of C6H5), 7.30À7.34 (4H, m, C6H5). 13C NMR (DMSO-d6),
δ: 28.6 (C(CH3)3), 47.9 (3a-CH), 51.2 (3-CH), 53.2 (6-CH2), 55.2 (2-
CH2), 57.3 (4-CH2), 58.0 (CH2C6H5), 63.0 (6a-CH), 79.0
(CH(CH3)3), 127.3 (C6H5), 128.6 (C6H5), 128.7 (C6H5), 139.0 (1-C
of C6H5), 155.3 (CdO). MS (CI, m/z): 367 (MH+), 311 (MH+ À
C4H8), 268. Anal. Calcd for C18H26N2O4S: C, 58.99; H, 7.15; N, 7.64; S,
8.75. Found: C, 59.08; H, 7.31; N, 7.44; S, 8.65.
tert-Butyl rel-[(3S,3aS,6aR)-1,1-Dioxidohexahydro-2H-
thieno[2,3-c]pyrrol-3-yl]carbamate (10). Compound 10 (isolated
as a free base) was prepared from 9 in 92% yield as a white solid following
the procedure describedabove for the synthesis of2. Mp 150 °C (dec). 1H
NMR (DMSO-d6), δ: 1.40 (9H, s), 2.52 (1H, m), 2.65 (1H, m), 2.81
(2H, m), 2.96 (1H, m), 3.06 (1H, t, J = 11.2 Hz), 3.36 (2H, m), 3.71 (1H,
t, J = 8.4 Hz), 3.83 (1H, m), 7.18 (1H, d, J = 6.6 Hz). 13C NMR (CDCl3),
δ: 28.6, 47.8, 50.4, 50.7, 51.7, 55.8, 65.0, 79.0, 155.4. MS (CI, m/z):
277 (MH+), 221 (MH+ À C4H8). Anal. Calcd for C11H20N2O4S: C,
47.81; H, 7.29; N, 10.14; S, 11.60. Found: C, 47.97; H, 7.01; N, 10.01;
S, 11.21.
1
1
an internal standard. HÀ H COSY, HSQC/HETCOR, and HMBC
experiments were used to establish atom connectivities for compounds
9 and 18. MS analyses were done on an LCMS instrument with
chemical ionization (CI) or a GCMS instrument with electron impact
ionization (EI).
5-Benzylhexahydro-2H-thieno[2,3-c]pyrrole 1,1-Dioxide
(6). N-(Methoxymethyl)-N-(trimethylsilylmethyl)benzylamine 5 (20 g,
0.085 mol, 2 equiv) was added to a solution of sulfolene 414 (5 g, 0.042
mol, 1 equiv) in CH2Cl2 (75 mL) at 0 °C under an argon atmosphere.
To the obtained mixture, 1 M CF3COOH in CH2Cl2 (8 mL, 8 mmol)
was added dropwise upon stirring. The resulting mixture was warmed to
room temperature and then stirred for 12 h (monitored by TLC). The
reaction mixture was evaporated in vacuo, and the residue was purified by
column chromatography (EtOAcÀhexanesÀEt3N (5:5:1) as an eluent)
to give 6 (9.1 g, 85%) as a yellowish oil. 1H NMR (CDCl3), δ: 2.00 (1H,
m), 2.33 (1H, m), 2.50 (2H, m), 2.69 (1H, d, J = 9.3 Hz), 3.02 (1H, m),
3.11 (2H, m), 3.33 (1H, t, J = 7.8 Hz), 3.49 (1H, m), 3.51 (1H, m), 3.70
(1H, d, J = 13.2 Hz), 7.25À7.35 (5H, m, C6H5). 13C NMR (CDCl3),
δ: 27.4, 39.4, 50.0, 56.0, 58.9, 60.9, 61.5, 127.2, 128.40, 128.43, 138.2.
Methyl (1,1-Dioxido-2,3-dihydro-3-thienyl)acetate (11).
To a vigorously stirred solution of 1,1-dioxido-2,3-dihydro-3-thienyla-
cetic acid15 (20 g, 0.113 mol) in absolute methanol (200 mL) SOCl2
(14 g, 0.118 mol) was added dropwise. The resulting mixture was
refluxed for 1 h. After cooling, the solvent was evaporated under reduced
pressure. The residue was diluted with CH2Cl2 (250 mL), washed with
H2O (2 Â 50 mL) and saturated aq. NaHCO3 (2 Â 75 mL), then dried
over MgSO4, and evaporated to dryness. The product (19 g, 88%) was
MS (CI, m/z): 252 (MH+), 91 (C7H7 ). Anal. Calcd for C13H17NO2S:
+
C, 62.12; H, 6.82; N, 5.57; S, 12.76. Found: C, 62.20; H, 6.98; N, 5.64;
S, 12.68.
Hexahydro-2H-thieno[2,3-c]pyrrole 1,1-Dioxide (2), Hy-
drochloride. Compound 6 (5.1 g, 0.02 mol) was added to a suspen-
sion of 10% PdÀC (0.75 g) in anhydrous methanol (250 mL). This
mixture was hydrogenated at 20 atm and rt for 10 h. The catalyst was
filtered off through a pad of Celite, which was then washed with
anhydrous methanol (200 mL). The solvent was evaporated under
reduced pressure to afford the product 2 as a yellow oil. Crude 2 was
dissolved in 0.5 N aq. HCl (50 mL), treated with charcoal, and filtered.
1
obtained as a white solid. Mp 45À47 °C. H NMR (CDCl3), δ: 2.59
(1H, dd, J = 16.8 and 8.4 Hz), 2.68 (1H, dd, J = 16.8 and 6.1 Hz), 2.98
(1H, dd, J = 13.7 and 3.8 Hz), 3.49 (1H, m), 3.57 (1H, br s), 3.72 (3H, s),
6.67 (1H, dd, J = 6.6 and 1.7 Hz), 6.73 (1H, dd, J = 6.6 and 2.7 Hz). 13C
NMR (CDCl3), δ: 35.7, 37.8, 52.2, 53.6, 132.5, 141.6, 170.8. MS (EI, m/z):
190 (M+). Anal. Calcd for C7H10O4S: C, 44.20; H, 5.30; S, 16.86.
Found: C, 44.12; H, 5.22; S, 16.92.
The filtrate was evaporated to dryness to give 3.5 g (90%) of 2 HCl as a
3
white solid. Mp > 200 °C. 1H NMR (DMSO-d6), δ: 1.99 (1H, m), 2.21
(1H, m), 3.12 (1H, m), 3.26 (1H, m), 3.37 (3H, m), 3.53 (1H, m), 3.60
(1H, t, J = 9.5 Hz), 3.79 (1H, m), 9.93 (2H, br s). 13C NMR (CDCl3),
δ: 23.9, 40.6, 45.4, 49.6, 49.9, 60.6. MS (CI, m/z): 162 (MH+). Anal.
Calcd for C6H12ClNO2S: C, 36.46; H, 6.12; Cl, 17.93; N, 7.09; S, 16.22.
Found: C, 36.57; H, 6.23; Cl, 18.08; N, 7.01; S, 16.37.
Methyl rel-[(3S,3aR,6aR)-5-Benzyl-1,1-dioxidohexahydro-
2H-thieno[2,3-c]pyrrol-3-yl]acetate (12). Compound 12 was
prepared from 11 in 92% yield as a white solid following the procedure
described above for the synthesis of 6. Mp 99À102 °C. 1H NMR
(CDCl3), δ: 2.44À2.51 (2H, m), 2.59À2.64 (1H, m), 2.67À2.73 (2H,
m), 2.77 (1H, d, J = 9.5 Hz), 2.78À2.83 (1H, m), 2.99 (1H, dd, J = 13.2
and 5.4 Hz), 3.41 (1H, ddd, J = 13.2 Hz, 6.6 and 2.0 Hz), 3.51À3.57 (3H,
m), 3.69 (3H, s), 3.69À3.73 (1H, m), 7.26À7.35 (5H, m). 13C NMR
(CDCl3), δ: 36.5, 38.0, 46.4, 51.9, 54.5, 55.4, 58.7, 59.7, 62.1, 127.3,
128.4, 128.4, 138.0, 171.8. MS (CI, m/z): 324 (MH+). Anal. Calcd
C16H21NO4S: C, 59.42; H, 6.54; N, 4.33; S, 9.91. Found: C, 59.58; H,
6.63; N, 4.21; S, 9.79.
rel-[(3S,3aR,6aR)-5-Benzyl-1,1-dioxidohexahydro-2H-thieno-
[2,3-c]pyrrol-3-yl]acetic Acid (13). A solution of sodium hydroxide
(0.62 g, 0.015 mol) in water (25 mL) was added dropwise to a stirred
solution of the methyl ester 12 (5 g, 0.015 mol) in a mixture of methanol
(150 mL) and water (50 mL) at 5 °C over 15 min. When the addition was
complete, the mixture was stirred for 7 h. After evaporation of methanol
under reduced pressure, the remaining aqueous phase was washed with ethyl
acetate (3 Â 50 mL). The aqueous phase was then cooled to 5 °C and
acidified by the addition of 6 N HCl upon stirring to adjust to pH = 3. Then
the solution was carefully diluted with saturated aq. NH4OH (100 mL). The
aqueous phase was extracted with ethyl acetate (3 Â 100 mL). The
combined organic extracts were dried over MgSO4 and evaporated to
dryness under reduced pressure to give 4.1 g (87%) of the acid 13 as a white
solid. Mp 148À150 °C. 1H NMR (D2O), δ: 2.38 (2H, m), 2.56 (1H, m),
3.21 (2H, t, J = 11.5 Hz), 3.52 (3H, m), 3.66 (1H, m), 3.87 (1H, d, J = 13.0
Hz), 4.17 (1H, m, CHSO2), 4.34 (1H, d, J = 13.0 Hz), 4.43 (1H, d, J = 13.0
Hz), 7.45 (5H, s). 13C NMR (D2O), δ: 35.5, 40.4, 45.2, 51.4, 55.6, 57.0,
tert-Butyl (1,1-Dioxido-2,3-dihydro-3-thienyl)carbamate
(8). A solution of Boc2O (33 g, 0.15 mol) in CH2Cl2 (150 mL) was
added dropwise to a stirred mixture of (1,1-dioxido-2,3-dihydro-3-
thienyl)amine16 (20 g, 0.15 mol) and Et3N (20 g, 0.15 mol) in CH2Cl2
(200 mL) at room temperature over 30 min. After the addition was
complete, the reaction mixture was stirred at room temperature for 5 h
and then washed with H2O (2 Â 50 mL), 1 N aq. HCl (2 Â 50 mL),
H2O (2 Â 50 mL), saturated aq. NaHCO3 (2 Â 75 mL), and brine (2 Â
50 mL). After drying over MgSO4, the solvent was evaporated under
reduced pressure to give the N-Boc protected amine 8 (33 g, 0.142 mol,
95% yield) as a white solid. Mp 150 °C. 1H NMR (CDCl3), δ: 1.47 (9H,
s, (CH3)3), 3.12 (1H, d, J = 17.0 Hz), 3.63 (1H, q, J = 7.5 Hz), 4.97
(1H, s), 5.14 (1H, s), 6.69 (1H, m), 6.75 (1H, m). 13C NMR (CDCl3),
δ: 28.3, 49.2, 55.1, 81.2, 134.0, 138.8, 154.6. MS (EI, m/z): 218
(M+ À CH3), 177 (M+ À C4H8), 57 (C(CH3)3 ). Anal. Calcd for
+
C9H15NO4S: C, 46.34; H, 6.48; N, 6.00; S, 13.75. Found: C, 46.25; H,
6.53; N, 6.07; S, 13.54.
tert-Butyl rel-[(3S,3aS,6aR)-5-Benzyl-1,1-dioxidohexahy-
dro-2H-thieno[2,3-c]pyrrol-3-yl]carbamate (9). Compound 9
was prepared from 8 in 67% yield as a white solid following the
procedure described above for the synthesis of 6. Mp 150 °C (dec).
1H NMR (DMSO-d6), δ: 1.39 (9H, s, C(CH3)3), 2.28 (1H, m, 4-CHH),
2.33 (1H, m, 6-CHH), 2.81 (1H, d, J = 9.0 Hz, 4-CHH), 2.97 (1H, m, 3a-
CH), 3.11 (1H, dd, J = 12.8 and 9.0 Hz, 2-CHH), 3.26 (1H, d, J = 10.5
Hz, 6-CHH), 3.34 (1H, m, 2-CHH), 3.56 (1H, d, J = 13.6 Hz,
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The Journal of Organic Chemistry
ARTICLE
58.4, 60.4, 129.5, 129.6, 130.4, 130.8, 178.5. MS (CI, m/z): 310 (MH+).
Anal. Calcd for C15H19NO4S: C, 58.23; H, 6.19; N, 4.53; S, 10.36. Found: C,
58.14; H, 6.25; N, 4.42; S, 9.99.
Table 2. Crystallographic Data and Experimental Parameters
for 10, 12, 16, and 18 (at 20 °C)
Parameter
10
12
16
18
rel-[(3S,3aR,6aR)-1,1-Dioxidohexahydro-2H-thieno[2,3-c]
pyrrol-3-yl]acetic Acid (14), Hydrochloride. Compound 14
(isolated as hydrochloride) was prepared from 13 in 96% yield as a
white solid following the procedure described above for the synthesis of
2. Mp 122À124 °C. 1H NMR (D2O), δ: 2.62 (2H, m), 2.75 (1H, m),
3.27 (2H, m), 3.47 (2H, m), 3.64 (2H, m), 3.94 (1H, dd, J = 13.6 and 3.0
Hz), 4.21 (1H, m). 13C NMR (D2O), δ: 34.3, 36.9, 44.5, 45.5, 49.5, 55.0,
60.8, 175.0. MS (CI, m/z): 220 (MH+). Anal. Calcd for C8H14ClNO4S:
C, 37.58; H, 5.52; Cl, 13.86; N, 5.48; S, 12.54. Found: C, 37.45; H, 5.12;
Cl, 13.48; N, 5.61; S, 12.31.
Unit cell dimensions
ꢀ
a, Å
20.080(5) 27.707(1) 7.944(1) 6.6298(2)
5.978(1) 5.8066(2) 10.654(2) 7.9932(2)
12.389(2) 21.0351(8) 13.268(2) 26.5748(8)
ꢀ
b, Å
ꢀ
c, Å
R, deg
β, deg
γ, deg
À
À
107.76(1)
104.40(2) 103.144(4) 107.42(2) 92.578(3)
90.00(2)
1440.4(6) 3295.5(2) 1015.2(3) 1406.86(7)
À
À
À
À
ꢀ3
V, Å
rel-(3S,3aS,6aR)-5-Benzyl-1,1-dioxidohexahydro-2H-thieno-
[2,3-c]pyrrol-3-yl 4-Methylbenzenesulfonate (16). Compound 16
was prepared from 1518 in 78% yield as a light yellow solid following the
F(000)
592
1376
444
600
Crystal system
Space group
Z
Monoclinic Monoclinic Triclinic
Monoclinic
P21/n
4
P21/c
4
C2/c
8
P1
1
procedure described above for the synthesis of 6. Mp 132À135 °C. H
2
NMR (CDCl3), δ: 2.41 (2H, m), 2.46 (3H, s), 2.73 (1H, d, J = 9.6 Hz),
3.26 (3H, m), 3.59 (2H, m), 3.59 (1H, t, J = 8.1 Hz), 3.67 (1H, d, J = 13.2
Hz), 5.01 (1H, m), 7.36À7.24 (7H, m), 7.81 (2H, d, J = 8.1 Hz). 13C NMR
(CDCl3), δ: 21.7, 48.2, 54.7, 55.3, 57.4, 58.2, 62.0, 78.4, 127.4, 127.9, 128.4,
128.5, 130.1, 133.1, 137.5, 145.6. MS (CI, m/z): 422 (MH+), 250. Anal.
Calcd for C20H23NO5S2: C, 56.99; H, 5.50; N, 3.32; S, 15.21. Found: C,
57.37; H, 5.26; N, 3.32; S, 14.93.
μ, mmÀ1
0.233
1.274
50
0.213
1.304
60
0.294
1.379
55
0.234
1.328
60
dcalc, g/cm3
2θmax, deg
Measured reflections
10 006
18 279
4792
0.025
3869
8225
4678
0.016
4568
13 044
4086
0.020
3229
Independent reflections 2531
Rint
0.050
1795
5-Benzyl-4,5,6,6a-tetrahydro-3aH-thieno[2,3-c]pyrrole
1,1-Dioxide (17). A solution of NaOH (0.8 g, 0.02 mol) in H2O
(25 mL) was added dropwise to a stirred solution of tosylate 16 (8.4 g,
0.02 mol) in THF (50 mL) at 0 °C over 15 min. After the addition was
complete, the reaction mixture was stirred at rt for 5 h. The reaction
mixture was then extracted with Et2O (3 Â 50 mL). The combined
organic extracts were dried over MgSO4 and evaporated to give the
sulphone 17 (4.9 g, 97%). Mp 71À73 °C. 1H NMR (CDCl3), δ: 2.49
(1H, t, J = 8.1 Hz), 2.55 (1H, t, J = 8.8 Hz), 2.84 (1H, d, J = 8.8 Hz),
3.52À3.62 (3H, m), 3.69 (2H, s), 6.59 (1H, m), 6.70 (1H, d, J = 6.1 Hz),
7.26À7.33 (5H, m). 13C NMR (CDCl3), δ: 45.7, 54.2, 57.1, 58.2, 59.9,
127.3, 128.4, 128.5, 132.4, 137.6, 140.7. MS (CI, m/z): 250 (MH+).
Anal. Calcd for C13H15NO2S: C, 62.62; H, 6.06; N, 5.62; S, 12.86.
Found: C, 62.50; H, 6.15; N, 5.42; S, 12.97.
Reflections with
F > 4σ(F)
Parameters
R1
0.069
0.198
1.061
822804
0.039
0.111
1.047
822801
0.036
0.097
0.997
822802
0.035
0.101
1.045
822803
wR2
S
CCDC number
Positions of hydrogen atoms were located from electron density
difference maps and refined within isotropic approximation (10, 16,
and 18), or using a riding model with Uiso = nUeq (n = 1.5 for methyl
groups and 1.2 for other hydrogen atoms) (8). The crystallographic data
and experimental parameters are listed in Table 2. Final atomic
coordinates, geometrical parameters, and crystallographic data have
been deposited with the Cambridge Crystallographic Data Centre, 11
Union Road, Cambridge, CB2 1EZ, UK (fax: +44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk). The deposition numbers are given in Table 2.
rel-(3S,3aS,6aR)-5-Benzyl-3-methoxyhexahydro-2H-thieno-
[2,3-c]pyrrole 1,1-Dioxide (18). A solution of tosylate 16 (2.2 g, 5.2
mmol) in MeOH (15 mL) was added dropwise to a stirred solution of
KCN (0.390 g, 6.24 mmol) in MeOH (7.5 mL) and H2O (7.5 mL) at 0 °C
over 10 min. After the addition was complete, the reaction mixture was
stirred at rt for 3 h. This solution was then diluted with H2O (100 mL) and
extracted with ethyl acetate (3 Â 25 mL). The combined organic phases
were dried over MgSO4 and evaporated to dryness under reduced pressure
’ ASSOCIATED CONTENT
1
S
Supporting Information. Copies of NMR spectra and
b
to give 1.95 g (67%) of 16 as a yellow solid. Mp 84À87 °C. H NMR
crystallographic information files. This material is available free
(CDCl3), δ: 2.47 (2H, m, 4-CHH and 6-CHH), 2.78 (1H, d, J = 9.5 Hz,
4-CHH), 3.14 (1H, m, 3a-CH), 3.28 (2H, m, 2-CH2), 3.38 (3H, s, OCH3),
3.56 (2H, m, CHHC6H5 and 6-CHH), 3.60 (1H, m, 6a-CH), 3.73 (1H, d,
J = 13.5 Hz, CHHC6H5), 3.89 (1H, m, 3-CH), 7.27À7.35 (5H, m, C6H5).
13C NMR (CDCl3), δ: 47.8 (3a-CH), 54.4 (2-CH2), 54.9 (6-CH2), 57.4
(OCH3), 57.8 (4-CH2), 58.6 (CH2C6H5), 62.3 (6a-CH), 80.6 (3-CH),
127.3 (C6H5), 128.4 (C6H5), 128.4 (C6H5), 138.0 (1-C of C6H5). MS
(CI, m/z): 282 (MH+). Anal. Calcd for C14H19NO3S: C, 59.76; H, 6.81;
N, 4.98; S, 11.40. Found: C, 60.01; H, 6.82; N, 4.65; S, 11.92.
of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: gregor@univ.kiev.ua.
’ REFERENCES
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