Synthesis and ring-chain-ring tautomerism of bisoxazolidines, thiazolidinyloxazolidines, and spirothiazolidines

Article abstract of DOI:10.1021/jo2008498

The synthesis of fused heterocycles such as thiazolidinyl-oxazolidine 3 is described starting from Tris·HCl. The mercaptomethyl bisoxazolidine 8 was found to convert to the corresponding thiazolidinyloxazolidine 3 and the spiro-heterocycle 4 by a ring-chain-ring tautomerism, depending on the electronic nature of the ring substituents as well as the reaction conditions. This equilibration pathway is absent in the hydroxymethyl bisoxazolidines 2. Computational studies confirm that both kinetic and thermodynamic control features play a role in the product distribution.

Full text of DOI:10.1021/jo2008498

ARTICLE
pubs.acs.org/joc
Synthesis and Ring-Chain-Ring Tautomerism of Bisoxazolidines,
Thiazolidinyloxazolidines, and Spirothiazolidines
Cecilia Saiz,† Peter Wipf,‡ and Graciela Mahler*,†
†Departamento de Química Orgꢀanica, Cꢀatedra de Química Farmacꢀeutica, Universidad de la Repꢀublica (UdelaR), Avda. General Flores 2124,
CC1157, Montevideo, Uruguay
‡Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
S Supporting Information
b
ABSTRACT: The synthesis of fused heterocycles such as
thiazolidinyl-oxazolidine 3 is described starting from Tris HCl.
3
The mercaptomethyl bisoxazolidine 8 was found to convert to
the corresponding thiazolidinyloxazolidine 3 and the spiro-
heterocycle 4 by a ring-chain-ring tautomerism, depending on
the electronic nature of the ring substituents as well as the
reaction conditions. This equilibration pathway is absent in the
hydroxymethyl bisoxazolidines 2. Computational studies con-
firm that both kinetic and thermodynamic control features play a role in the product distribution.
Scheme 1. Dynamic Equilibrium and Carbonyl Group Ex-
change Reaction of Thiazolidinyloxazolidine 1
’ INTRODUCTION
Ring-chain tautomerism is a process that involves the rever-
sible movement of a proton accompanied by a change from an open
structure to a ring, often the result of an addition of a heteroatom to
a heteropolar double bond to form a heterocycle. The reaction is
usually acid-catalyzed and represents a key step in the synthesis of
five- and six-membered 1,3-heterocycles containing oxygen, nitro-
gen, or sulfur atoms.1 This process can be exploited in the construc-
tion of dynamic combinatorial libraries2 and has been applied to the
discovery of new materials and pharmacologically active com-
pounds.3 The transformation has been studied thoroughly in the
past decade, mainly in the context of ring-chain tautomeric equilibria
involving 1,3-X,N-heterocyclic systems (X = S, O, N).4
As a continuation of our investigations on new reactions and
scaffolds suitable to Dynamic Combinatorial Chemistry, we have
explored readily available building blocks useful for the exchange
of carbonyl units in a dynamic library pool. Recently, we have re-
ported the synthesis of thiazolidinyloxazolidine 1, which is capable
of exchanging carbonyl units in the oxazolidine moiety, retaining the
thiazolidine heterocycle, in the presence of p-TsOH in CH2Cl2
(Scheme 1).5
A logical extension of these studies was to investigate the bisoxa-
zolidine 2, a compound that had been reported in the literature a
number of years ago.6 We decided to prepare an analogous hetero-
cycle, i.e., the fused thiazolidinyloxazolidine 3 (Figure 1). Bisoxazo-
lidines 2 have been intensely studied during the past decades,7 and
some derivatives show interesting chemical and biological properties
as chiral catalysts,8 anticancer,9 and neuroprotective agents.10
It is important to note that the replacement of the oxygen
by a sulfur atom leads to a significant increase in the complexity
of the system due to a break in the symmetry, allowing the
potential formation of 23 fused bicycles upon variation of the
substituents R and R1.
The present paper describes our findings in the synthesis of
the thiazolidinyloxazolidine 3, a new bicyclic fused scaffold, and
its structural isomer, the spirothiazolidine 4 (see Figure 1).
’ RESULTS AND DISCUSSION
Our first objective was the synthesis of the fused thiazolidiny-
loxazolidine 3, the sulfur analogue of bicycle 2. Since this was a
hitherto unknown building block, we had to develop a new synthetic
strategy to access it. Tris HCl reagent (5) was used as a starting
3
material, and we explored two alternatives for its use in the synthesis
of bicycle 3. The key step was the replacement of a hydroxyl group
with a thiol in either the Tris HCl building block or the fused
3
bicycle (Scheme 2).
Path a) applied an early thiolation strategy involving as the key
step the synthesis of thiazolidinone-2-thione 7 starting from Tris
3
HCl and carbon disulfide.11 Subsequently, a hydrolysis was followed
by a cyclization to afford the target compound 3. Path b) represents
an alternative methodology that began with the protection of a diol
unit in Tris HCl, followed by the substitution of the free hydroxyl
3
group in 2 with thioacetic acid under Mitsunobu conditions.
Received: April 26, 2011
Published: June 02, 2011
r
2011 American Chemical Society
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Scheme 4. Cyclization and Product Distribution for Thia-
zolidin-2-thiones 7 and 9
Figure 1. Structures of bisoxazolidine 2, thiazolidinyloxazolidine 3, and
spirothiazolidine 4.
Scheme 2. Retrosynthetic Analysis of Bicycle 3
Table 1. Relative Energies for compounds syn/anti-11b, -12b,
and -13b
entry
compounds
relative energies [kcal/mol]
1
2
3
4
syn-11b vs anti-11b
syn-12b vs anti-12b
syn-13b vs anti-13b
syn-11b vs syn-13b
ꢀ0.6
ꢀ0.7
ꢀ3.0
ꢀ8.9
Scheme 3. Preparation of Thiazolidin-2-thiones (7 and 9)
and Oxazolidin-2-one 10
13 could not be observed; this cyclization process is disfavored by
Baldwin’s rules.
In order to gain further insight into these results, we under-
took a theoretical calculation using a geometry optimization with
Spartan 10 (DFT/B3LYP/6-311G*). The relative energy (E) for
selected compounds is shown in Table 1. In order to simplify the
calculations, we used a simple Ph subtituent.
Thioester hydrolysis and an oxazolidineꢀthiazolidine interconver-
sion in acidic media led to compound 3 (Scheme 2).
Recently, Darabantu et al. reported a synthesis of thiazolidi-
nyloxazolidine 3 (R1 = H), similarly starting from Tris 5 but
otherwise using a different sequence.12 A more detailed discus-
sion of these routes is provided below.
The spirocycles 11a and 12a were obtained as mixtures of syn-
and anti-diastereomers. The theoretical calculations of the re-
lative energies of the analogous products 11b and 12b predicted
the syn-configurations to have a slightly lower energy in accor-
dance with the experimental data and the configurations of the
major diastereomers assigned by NOESY experiments. The
differences in energy were ꢀ0.6 and ꢀ0.7 kcal/mol for spiro-
cycles 11b and 12b, respectively (see Table 1, entries 1 and 2).
These calculations were also able to suggest a rationale why
the fused bicycle 13a was not observed: the difference in energy
between spirocycle syn-11b and fused bicycle syn-13b, the more
stable of the two stereoisomers, was about ꢀ9 kcal/mol (Table 1,
entries 3 and 4), in preference for the formation of the spirocycle
as the major thermodynamically favored isomer.
Path a). The thiazolidine-2-thione 7 was prepared in moderate
yields by heating a mixture of 5 M NaOH, Tris HCl, and carbon
3
disulfide at reflux for several hours.13 Various conditions were
attempted in order to improve the selectivity and yield, but our
best result was achieved by simply heating the reaction mixture for
1 day at 60ꢀ70 °C. A mixture of two thiazolidin-2-thiones (7 and 9)
and the oxazolidin-2-thione 10 was obtained (Scheme 3).
Thiazolidin-2-thiones 7 and 9 were subjected to a monocycli-
zation protocol in MeCN in the presence of p-TsOH and R1CHO
under microwave irradiation (90 °C, 12 min). Under these
conditions, these substrates yielded exclusively the corresponding
spirocycles 11a and 12a, instead of the expected fused bicycle 13a,
in analogy to the results obtained under conventional heating
(Scheme 4).
Hydrolysis of thiazolidin-2-thione 7 in conc HCl at reflux led
to formation of Tris-SH HCl 6 in 90% yield (Scheme 5).
3
Cyclization in PhMe/DMF (9:1) with p-ClPhCHO and p-TsOH
acid for 3 h using a DeanꢀStark trap led to a mixture of the fused
bicycle syn-3a (32%) and a small amount of spiro compound 4a
(3%). The presence of spirocycle 4a was unexpected because it
had not been described for the oxygen analogues 2.
The spiro product syn-12a shows long-range couplings (4J)
due to the characteristic W-arrangement of the connecting bonds
between Ha and Hb (“W-coupling”). The hydrogen atoms Ha and Hb
are close to coplanar equatorial positions (Scheme 4).
The formation of the spiro products corresponding to a
6-endo-trig cyclization is a favored process according to Baldwin’s
rules. The corresponding 5-endo-trig process leading to bicycle
Attempts to synthesize other fused heterocycles, using alde-
hydes such as p-FPhCHO and p-CF3PhCHO, led to complex
reaction mixtures with low recovery of the desired products,
syn-3b (R1 = p-FPh, 8%), spiro-4b (R1 = p-FPh, 3%), and syn-3c
(R1 = p-CF3Ph, 2%).
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Scheme 5. Synthesis of Fused Bicycle 3a
Table 3. Product Yields and Diastereomeric Ratios for
Compounds 15aꢀe and 8aꢀe
Table 2. Product Yields and Diastereomeric Ratios for
Compounds 2aꢀe, 14a and 14cꢀe
entry
R1
syn-15, yield (%)
syn-8, yield (%)
8a (66)
1
2
3
4
5
p-ClPh
15a (75)
15b (54)
15c (71)
15d (84)
15e (78)
p-FPh
8b (62)
p-CF3Ph
m-BrPh
p,m-diClPh
8c (65)
8d (44) þ 16d (43)
8e (25) þ 16e (53)
entry
R1
compd 2, yield % (syn:anti)b compd 14, yield %
1
2
3
4
5
p-ClPh
2a, 77, (98:2)
2b, 34, (98:2)
p-FPh
According to our previous work, which is relevant to the ability of
this class of bicycles to exchange carbonyl units at the oxazolidine
site,5 we decided to explore such an interconversion in these new
heterocycles. When using CH2Cl2 at reflux for 6 h, in the presence of
p-TsOH acid (cat.) and aldehyde (1 equiv) for the re-equilibration
of syn-8aꢀd, we obtained thiazolidinyloxazolidines anti-syn-3aꢀdas
main products (Table 4, entries 1, 3ꢀ5). These results were in
accordance with our previous work with regard to the ability of these
compounds to establish an equilibrium in favor of the most stable
bicycle thiazolidinyloxazolidine 3 versus the bisoxazolidine 2.
For the thiols 8d and 8e, the situation was different under the
same re-equilibration conditions. Starting from 8d (R1 = m-BrPh
derivative), we observed the formation of a mixture of fused 3d and
the corresponding spiro compound 4d. Starting from 8e (R1 = m,p-
diClPh), we observed the exclusive formation of spirocycle 4e
instead of the bicycle 3e, (Table 4, entry 7). In contrast, when using
PhMe/p-TsOH at reflux, we observed a different product distribu-
tion. For thiols 8a and 8d, we obtained a mixture of syn-syn-fused-3
and spiro-4 (Table 4, entries 2 and 6).
It is noteworthy that the product distribution was strongly depen-
dent on the electronic character of the substituents R1, the solvent,
and the temperature. Bicycle 8e, bearing the most electron-with-
drawing group, only equilibrated to the spiro compound 4e.
The new spiro-4a,d,e compounds were fully characterized in
order to confirm their structure. Important evidence was the long-
range coupling constant 4J indicative of a typical W arrangement for
Ha and Hb in the 1H NMR spectra. In addition, a significant shift in
some carbon signals, such as the quaternary carbon C2, the CH2OR
C3, and the acetal carbon of the oxazolidine or oxazine C1, indicated
thepresenceofcompound4(Table 5). The absence of the hydroxyl-
stretching band in the IR spectra confirmed the spiro structure 4.
Intrigued by the formation of spirocycle 4, we calculated the
difference in energy for the fused bicycle 3f and the spirocycle 4f
(R1 = Ph). According to the computation the spirocycle 4f is more
stable than the thiazolidinyloxazolidine 3f by about 5 kcal/mol
(Figure 2). In agreement with the computational results for fused
bicycles 3, the diastereomer syn-syn-3f is 1.9 kcal more stable than
the anti-syn-3f. This result was also experimentally confirmed since
the apparent kinetic product anti-syn-3 was obtained at a lower
p-CF3Ph
m-BrPh
p,m-diClPh
2c, 32, (81:19)
2d, 30, (80:20)
2e, 20, (83:17)
14c, 13
14d, 25
14e, 35
b Ratio based on integration of separated 1H NMR signals.
Our methodology for the synthesis of 6 provides a 40% overall
yield in a two-step sequence; reported synthesis of Tris-SH was
achieved in three steps with 48% overall.12 The authors only report
the synthesis of bicycle 3 derived from formaldehyde, possibly
indicating the limitation of the cyclization process starting from 6.
Due to the difficulties we encountered in path a), i.e., the low
yield and limited scope for the formation of 7 and 3, the tedious
purification steps, the instability of Tris-SH 6, and the low
solubility of the intermediate 6 under several reaction conditions,
we decided to explore path b) as a new alternative.
For this purpose, we studied the direct substitution of the
alcohol moiety in bisoxazolidine 2, using Mitsunobu conditions.
Oxabicycles 2aꢀd were synthesized as described previously by
heating Tris HCl, p-TsOH, and aldehydes in PhMe at reflux,
3
using a DeanꢀStark trap.4
Using these conditions, we obtained the desired product syn-
2aꢀe in moderate yields, mainly due to the formation of the
dimer 14 (Table 2). The proportion of the side product 14
seemed to increase with the electron-withdrawing character of
the aldehyde side chain R1.
For the continuation of the synthesis of target molecule 3, the
substitution of the hydroxyl group present in the bicycles 2aꢀd
with thioacetic acid was achieved under Mitsunobu conditions to
give bicycles syn-15aꢀd in good yield, as shown in Table 3.
Smooth solvolisis of esters 15 in MeOH/NH3 at room
temperature led to the 5-thiomethyl-bisoxazolidines 8, in good
yields, except when R1 = m-BrPh and 3,4-diClPh, where the
dimeric compound 16 was obtained as a byproduct. This
methodology allowed us to prepare the new bisoxazolidines
syn-8aꢀe, substituted at C5 with a thiomethyl group (Table 3).
Disulfur dimers 16d and 16e could be recycled to the corre-
sponding thiols 8d (70%) and 8e (60%) by treatment with
NaBH4 in MeOH at room temperature.
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Table 4. Product Distribution for Compounds 3 and 4
product distribution, yield
3 [%], (anti-syn:syn-syn)c
entry
R1
starting material
reaction conditions
4 [%]
1
2
3
4
5
6
7
p-ClPh
8a
8a
8b
8c
8d
8d
8e
Aa
Bb
Aa
Aa
Aa
Bb
Aa
62, (99:1)
41, (10:90)
44, (90:10)
64, (81:19)
64, (95:5)
66, (7:93)
p-ClPh
46
p-FPh
p-CF3Ph
m-BrPh
m-BrPh
m,p-di-ClPh
20
20
80
a A: R1CHO, p-TsOH, CH2Cl2, reflux 6 h; b B: R1CHO, p-TsOH, PhMe, DeanꢀStark, reflux 4 h; c ratio based on integration of distinct 1H NMR signals.
Table 5. Characteristic 13C NMR δ Signals for Fused-3 and
Spiro-4 Heterocycles
Figure 2. Calculated energies for spiro 4f and fused 3f.
13C NMR δ (ppm)
compound
C1
C2
C3
Scheme 6. Isomerization of anti-syn-3 into syn-syn-3
fused anti-syn-3a
fused syn-syn-3a
spiro anti-4a
94.6
98.4
79.8
79.7
64.1
79.6
79.8
64.1
65.8
66.9
73.4
65.9
66.9
73.4
101.1
94.1
fused anti-syn-3d
fused syn-syn-3d
spiro anti-4d
98.3
100.8
temperature in CH2Cl2, while higher temperatures in toluene
yielded the thermodynamically preferred syn-syn-3.
However, attempts to obtain the spiro compound by further
heating the fused anti-syn-3a at reflux using different solvents
(MeCN, PhMe) and acidic conditions (p-TsOH or HClO4/
SiO214) led only to the isomerization of the starting material into
the thermodynamic syn-syn-3 bicycle, without an apparent for-
mation of the spiro product (Scheme 6).
opened by ring-chain tautomerism, leading to the formation of
two possible intermediates: oxonium ion I1 and the probably
more stable iminium ion I2. Under kinetic conditions, intermediate
I2 is preferentially formed and reacts faster than I1, leading again to
the 5-endo-trig cyclization product 3. In contrast, under thermo-
dynamic conditions, the more stable spiro-thiazolidine 4 is formed.
The selectivity of this product distribution can be explained on the
basis of the ring-chain tautomeric equilibration of the intermediates,
The proposed mechanism for bicycle and spirocycle forma-
tion is depicted in Figure 3. In acidic media, fused bicycle 3 can be
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anticipate that this information can be utilized for the construc-
tion of new dynamic combinatorial libraries.
’ EXPERIMENTAL SECTION
Path a
4,4-Bis(hydroxymethyl)thiazolidine-2-thione (7). To an ice-
cooled solution of NaOH (5.0 g, 0.12 mol) in H2O (9 mL) were added
with stirring Tris HCl (5.0 g, 31.8 mmol), CS2 (4.8 mL, 79.2 mmol),
3
and PEG 400 (2 drops). The mixture was heated at 60 °C for 24 h, then
cooled down, poured into H2O (100 mL), extracted with EtOAc (3 ꢁ
100 mL), dried (Na2SO4), and filtered. The solvent was removed under
reduced pressure. The yellow oil crude was purified chromatography on
SiO2 (1:2, EtOAc/hexanes) to afford 7 (2.57 g, 45%), 9 (0.65 g, 11%),
and 10 (0.91 g, 18%).
Thiazolidinethione 7:whitesolid;mp90ꢀ91 °C; 1HNMR(CD3OD) δ
3.45 (s, 2 H), 3.63 (d, J = 11.5 Hz, 2 H), 3.70 (d, J = 11.5 Hz, 2 H), 4.88 (bs,
2 H); 13C NMR (CD3OD) δ 36.5, 63.3, 76.4, 202.0; HRMS calcd for
C5H9NO2S2 [M]þ 179.0075, found 179.0035.
Figure 3. Mechanistic proposal for the formation of fused bicycles 3
and spirocycle 4.
4-Hydroxymethyl-4-thiomethyl-thiazolidine-2-thione (9): oil; IR (NaCl)
ν = 3300ꢀ3200 bs, 2926, 2513, 1732, 1458, 1007; 1H NMR (CD3CN) δ
1.78 (dd, J= 9.7, 8.4 Hz, 1 HSH), 2.79 (dd, J= 14.3, 9.7 Hz, 1 H), 2.93 (dd, J=
14.3, 8.4 Hz, 1 H), 3.41 (d, J= 11.6 Hz, 1 H), 3.44 (t, J=5.9Hz, 1HOH), 3.53
(d, J = 11.6 Hz, 1 H), 3.62 (dd, J = 11.4, 5.9 Hz, 1 H), 3.68 (dd, J = 11.4, 5.9
Hz, 1 H) 7.96 (s, 1 HNH); 13C NMR (CD3CN) δ 30.0, 38.4, 64.8, 75.5,
201.4 (CdS); HRMS calcd for C5H10NOS3 [M þ H]þ 195.9925, found
195.9957.
4,4-Bis(hydroxymethyl)oxazolidine-2-thione (10): solid; mp 111ꢀ
112 °C; 1H NMR (DMSO-d6) δ 3.37 (d, J = 5.6 Hz, 4 H), 4.36 (s, 2 H),
5.16 (t, J = 5.6 Hz, 1 H), 5.17 (t, J = 5.6 Hz, 1 H), 9.84 (s, 1 H); 13C NMR
(DMSO-d6) δ 62.1, 67.9, 73.1, 188.0; HRMS calcd for C5H10NO3S,
[M þ H]þ 164.0381, found 164.0389.
with a kinetic preference for the formation of the bicyclic product 3
under mild conditions, or a complete equilibration toward the spiro
product 4 under more forcing conditions.
The reaction conditions are critical to the product distribu-
tion. There is a correlation with lower temperatures favoring the
kinetic products and higher temperatures establishing a thermo-
dynamic equilibrium.
There is no clear correlation between the electronic effect of
substituents at R1 and the product distribution bicycle versus
spirocycle. The values of the Hammet coefficients are σ = 0.60 (m,
p-diCl) > 0.54(p-CF3) > 0.39(m-Br) > 0.23 (p-Cl) > 0.06 (p-F).15
Electron-withdrawing groups at R1 destabilize cationic intermedi-
ates I1 and I2, but probably more so in the iminium ion I2 than the
alkoxycarbenium ion I1, thus for example favoring, in CH2Cl2, the
formation of spirocycles 4d (m,p-diCl) and 4e (m-Br). Otherwise
compound 8c (p-CF3) having also a high σ value did not evolve to
the spiro and led exclusively to bicycle 3c formation (Table 4).
(syn/anti)-8-(4-Chlorophenyl)-7,9-dioxa-3-thia-1-azaspiro-
[4.5]decane-2-thione (11a). To a stirred solution of 7 (300 mg,
1.68 mmol) in MeCN (1 mL) were added p-Cl-benzaldehyde (0.47 g,
3.4 mmol) and p-TsOH acid (30 mg, 0.17 mmol). The reaction mixture
was heated with stirring under microwave irradiation for 12 min at 90 °C.
Then it was cooled, poured into H2O, neutralized with NaHCO3 (satd
solution), and extracted with EtOAc (3 ꢁ 30 mL). The solvent was
removed under reduced pressure, and the crude was purified by
chromatography on SiO2 (1:4, EtOAc/hexanes) to afford compound
11a (206 mg, 43%, diasteromeric ratio = 7:3). Major diastereomer:
white solid; mp 208ꢀ209 °C; IR (NaCl) ν = 3098, 2914, 1489, 1317,
1010, 829, 750; 1H NMR (DMSO-d6) δ 3.78 (s, 2 H), 3.87 (d, J = 11.0
Hz, 2 H), 4.20 (d, J = 11.0 Hz, 2 H), 5.56 (s, 1 H), 7.46 (m, 4 H), 10.29
(bs, 1 HNH); 13C NMR (DMSO-d6) δ 39.7, 64.8, 71.0, 100.3, 128.6,
128.7, 134.1, 136.9, 199.8; HRMS calcd for C12H11ClNO2S2 [M ꢀ H]ꢀ
299.9925, found 299.9932.
’ CONCLUSIONS
We were able to synthesize the fused thiobicycles 3aꢀe for the
first time. As described in the literature, the oxygen-containing
heterocycles 2b and 2c have attractive biological properties as
neuroprotectives, which is likely shared or further enhanced by the
sulfur analogues 3b and 3c. The methodology developed in path b
allowed the selective preparation of both diastereomers of these
heterocycles, the syn-syn-3 in PhMe as well as the anti-syn-3, in
CH2Cl2. The replacement of oxygen by a sulfur atom in the structure
of Tris (5) to form Tris-SH (6) has a remarkable impact in the
cyclization process in the presence of aldehydes compared to Tris.
The spirocyclic compound 4 represents a novel molecular
scaffold. It was obtained in a ring-chain-ring tautomeric equili-
bration of mercaptomethyl bisoxazolidine 8. These compounds
can be synthesized in acidic media by tuning the reaction con-
ditions (temperature, solvent), and their formation is strongly
dependent on the electronic properties of the substituents R1.
Thiazolidines are known to be more stable than oxazolidines,16
this property is likely the reason why thiazolidin-spirocycle 4 is
formed, but the corresponding analogue oxazolidin-spirocycle
remains unknown.
(5RS,syn/anti)-8-(4-Chlorophenyl)-7-oxa-3,9-dithia-1-azas-
piro[4.5]decane-2-thione (12a). Prepared in an analogous route as
described for 11a to give compound 12a (225 mg, 45%, diastereomeric
ratio = 8:2). Major diastereomer: solid; mp 75ꢀ76 °C; IR (NaCl) ν =
3209, 2993, 2853, 1489, 1190, 1032, 817; 1H NMR (DMSO-d6) δ 3.11
(dd, J = 12.9, 2.5 Hz, 1 H), 3.38 (d, J = 12.9 Hz, 1 H), 3.65 (d, J = 11.5 Hz,
1 H), 3.77 (d, J = 11.6 Hz, 1 H), 3.90 (d, J = 11.6 Hz, 1 H), 4.11 (dd, J =
11.5, 2.5 Hz, 1 H), 5.99 (s, 1 H), 7.45 (m, 4 H), 10.33 (s, 1 HNH); 13
C
NMR (DMSO-d6) δ 35.6, 39.7, 64.4, 71.7, 81.9, 128.1, 128.4, 133.2,
137.0, 198.7 (CdS); HRMS calcd for C12H11ClNOS3 [M ꢀ H]ꢀ
315.9697, found 315.9704.
2-Amino-2-(thiomethyl)propane-1,3-diol Tris-SH HCl (6).
3
Diol 7 (400 mg, 2.24 mmol) was dissolved with stirring in conc HCl
(3 mL) and heated at reflux for 24 h. Then, water (15 mL) was added,
and the mixture was washed with EtOAc (30 mL). The aqueous layer
was evaporated at reduced pressure to afford compound 6 (350 mg,
These findings represent a significant extension of the number
of small but densely functionalized scaffolds that can be obtained
from relatively simple and readily available buildings blocks. We
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90%). This residue was used without further purification. The 1H NMR
syn-2c: the sample had spectroscopic data in agreement with the
literature data;10 white solid; mp 100ꢀ101 °C; IR (NaCl) ν = 2936, 2874,
1618, 1412, 1327, 1165, 1124, 1018, 827; 1H NMR (CDCl3) δ 1.58 (t, J =
5.6 Hz, 1 HOH), 3.49 (d, J = 5.6 Hz, 2 H), 3.97 (d, J = 9.0 Hz, 2 H), 4.06 (d,
J=9.0 Hz, 2H), 5.63(s, 2 H), 7.56 (d, J= 8.3 Hz, 4 H), 7.64 (d, J=8.3Hz, 4
H); 13C NMR (CDCl3) δ 65.6, 72.7, 75.1, 96.8, 123.9 (q, JCF = 270.5 Hz),
125.6 (q, JCF = 3.6 Hz), 127.12, 131.0 (q, JCF = 32.5 Hz), 143.4.
(2R,8S)-{Bis(2,8-di(p-trifluoromethylphenyl)-1-aza-3,7-dioxabicyclo-
[3.3.0]octane 5-methoxy)methyl)}-4-trifluoromethylbenzene (14c):
pale yellow oil; IR (NaCl) ν = 3067, 2879, 1620, 1412, 1327, 1124,
1067, 827; 1H NMR (CDCl3) δ 3.23 (d, J = 8.9 Hz, 2 H), 3.30 (d, J = 8.9
Hz, 2 H), 3.76 (d, J = 9.0 Hz, 2 H), 3.82 (d, J = 9.0 Hz, 2 H), 3.84 (s, 4 H),
5.36 (s, 1 H), 5.55 (s, 2 H), 5.56 (s, 2 H), 7.23 (d, J = 8.1 Hz, 2 H), 7.53
(m, 18 H); 13C NMR (CDCl3) δ 69.4, 73.0, 73.2, 73.3, 96.4, 96.5, 96.5,
100.7, 123.9 (q, JCF = 271.8 Hz), 125.3 (q, JCF = 3.6 Hz), 126.4, 126.5,
126.7, 127.2, 127.3, 130.9 (q, JCF = 32.0 Hz), 140.3, 143.1; HRMS calcd
for C48H38F15N2O6 [M þ H]þ 1023.2490, found 1023.2466.
(2R,8S)-2,8-Di(m-bromophenyl)-5-hydroxymethyl-1-aza-
3,7-dioxabicyclo[3.3.0]octane (syn-2d). Prepared in analogous
route as described for 2a to give compounds 2d (30% yield, syn/anti:
80:20) and dimer 14d (25% yield).
signals are in agreement with the reported spectroscopic data:12 1
H
NMR (DMSO-d6) δ 2.70 (d, J = 9.0 Hz, 2 H), 2.86 (t, J = 9.0 Hz, 1 HSH),
3.48 (d, J = 11.5 Hz, 2 H) 3.54 (d, J = 11.5 Hz, 2 H), 5.44 (bs, 2 H), 7.95
(s, 2 H).
(2S,5S,8R)- and (2R,5R,8S)-2,8-Di(p-chlorophenyl)-5-hy-
droxymethyl-1-aza-3-oxa-7-thiabicyclo [3.3.0]octane (syn-
syn-3a). To a suspension of Tris-SH (6) (200 mg, 1.16 mmol) in
PhMe (5 mL) and DMF (0.5 mL) were added p-Cl-benzaldehyde (404
mg, 2.87 mmol) and catalytic p-TsOH (2 mg, 0.01 mmol). The mixture
was heated at reflux in a DeanꢀStark trap for 3 h. Then, it was cooled,
poured into a saturated solution of NaHCO3, extracted with EtOAc
(3 ꢁ 50 mL), dried (Na2SO4), and filtered. The residue was purified
by chromatography on SiO2 (1:5, EtOAc/hexanes) to give syn-syn-3a
(140 mg, 32%) and spiro-anti-4a (15 mg, 3%).
syn-syn-3a: oil; IR (NaCl) ν = 3450ꢀ3350 bs, 2924, 1599, 1487, 1275,
1088, 1015, 825, 750; 1H NMR (CDCl3) δ 1.65 (t, J = 5.3 Hz, 1 H), 2.93
(d, J = 12.0 Hz, 1 H), 2.98 (d, J = 12.0 Hz, 1 H), 3.49 (dd, J = 10.5, 5.3 Hz,
1 H), 3.56 (dd, J = 10.5, 5.3 Hz, 1 H), 3.86 (d, J = 8.8 Hz, 1 H), 4.29 (d,
J = 8.8 Hz, 1 H), 5.19 (s, 1 H), 5.31 (s, 1 H), 7.24 (d, J = 8.4 Hz, 2 H),
7.37 (m, 4 H), 7.46 (d, J = 8.4 Hz, 2 H); 13C NMR (CDCl3) δ 39.2, 66.9,
73.4, 74.2, 79.7, 98.4, 128.5, 128.7, 128.9, 129.0, 133.6, 135.2, 137.3,
139.2; HRMS calcd for C18H17Cl2NO2SNa [M þ Na]þ 404.0249,
found 404.0239.
syn-2d: white solid; mp 103ꢀ104 °C; IR (NaCl) ν = 3500ꢀ3400,
2934, 2874, 1570, 1202, 1082, 1007, 773; 1H NMR (CDCl3) δ 1.64 (bs,
1 H), 3.49 (s, 2 H), 3.93 (d, J = 9.0 Hz, 2 H), 4.04 (d, J = 9.0 Hz, 2 H),
5.52 (s, 2 H), 7.24 (t, J = 7.8 Hz, 2 H), 7.35 (d, J = 7.8 Hz, 2 H), 7.47 (m, 2
H), 7.61 (m, 2 H); 13C NMR (CDCl3) δ 65.6, 72.6, 74.7, 95.9, 126.1,
128.7, 130.6, 132.7, 132.8, 139.6; HRMS calcd for C18H17Br2NO3Na
[M þ Na]þ 475.9467, found 475.9448.
(2SR,anti)-2,8-Bis(3-chlorophenyl)-7,9-dioxa-3-thia-1-azaspiro[4.5]-
decane (4a): white solid; mp 164ꢀ165 °C; IR (NaCl) ν = 2868, 1603, 1493,
1385, 1094, 1015, 824; 1H NMR (CDCl3) δ 3.25 (dd, J = 11.3 Hz, 4J = 1.1
Hz, 1 H), 3.58 (d, J = 11.3 Hz, 1 H), 3.82 (dd, J = 10.8 Hz, 4J = 1.1 Hz, 1 H),
4.01(m, 2H), 4.25(dd, J= 10.8 Hz, 4J= 2.2 Hz, 1H), 5.46 (s, 1 H), 5.48 (s, 1
H), 7.34 (m, 4 H), 7.44 (m, 4 H); 13C NMR (CDCl3) δ 42.1, 64.1, 69.3,
73.4, 73.7, 101.1, 127.5, 128.5, 128.6, 128.8, 134.3, 135.0, 136.0; HRMS calcd
for C18H18Cl2NO2S [M þ H]þ 382.0430, found 382.0443.
anti-2d: pale yellow oil; IR (NaCl) ν = 3500ꢀ3400, 2870, 1572, 1475,
1
1433, 1377, 1207, 1070, 758; H NMR (CDCl3) δ 2.36 (bs, 1 HOH),
3.70 (d, J = 11.1 Hz, 1 H), 3.75 (d, J = 11.1 Hz, 1 H), 3.82 (d, J = 8.8 Hz,
1 H), 3.86 (d, J = 8.9 Hz, 1 H), 4.08 (d, J = 8.9 Hz, 1 H), 4.19 (d, J = 8.8
Hz, 1 H), 5.08 (s, 1 H), 5.46 (s, 1 H), 6.86 (d, J = 7.6 Hz, 1 H), 7.03 (d, J =
7.6 Hz, 1 H), 7.06 (s, 1 H), 7.08 (d, J = 7.6 Hz, 1 H), 7.20 (d, J = 7.6 Hz, 1
H), 7.34 (m, 1 H), 7.40 (m, 1 H), 7.45 (bs, 1 H); 13C NMR (CDCl3) δ
65.1, 71.7, 74.4, 74.5, 92.5, 93.1, 122.0, 122.4, 125.6, 125.7, 129.5, 129.6,
130.2, 130.3, 131.6, 131.8, 136.0, 141.7; HRMS calcd for C18H18NO3Br2
[M þ H]þ 453.9653, found 453.9665.
Path b
Representative Procedure for the Synthesis of Bisoxazo-
lidines syn-2aꢀe. (2R,8S)-2,8-Di(p-chlorophenyl)-5-hydro-
xymethyl-1-aza-3,7-dioxabicyclo[3.3.0]octane (syn-2a). To
a stirred suspension of Tris HCl (5) (1.0 g, 6.4 mmol) in toluene
3
(25 mL) were added p-Cl-benzaldehyde (2.0 g, 14.0 mmol) and catalytic
p-TsOH (0.1 g, 0.6 mmol). The mixture was heated at reflux in a
DeanꢀStark trap for 12 h. Then, it was cooled, poured into a saturated
solution of NaHCO3, extracted with EtOAc (3 ꢁ 100 mL), dried
(Na2SO4), and filtered. The solvent was removed under reduced
pressure, and the residue was purified by chromatography on SiO2
(1:9, EtOAc/hexanes) to afford 2a (1.8 g, 77%, syn/anti: 98:2): yellow
oil; IR (NaCl) ν = 3500ꢀ3400 bs, 2872, 1597, 1489, 1379, 1207, 1088,
1014, 812; 1H NMR (CDCl3) δ 3.46 (s, 2 H), 3.91 (d, J = 9.0 Hz, 2 H),
4.02 (d, J = 9.0 Hz, 2 H), 5.53 (s, 2 H), 7.35 (m, 8H); 13C NMR (CDCl3)
δ 65.5, 72.6, 74.9, 96.6, 128.1, 128.8, 134.6, 137.9; HRMS calcd for
C18H18Cl2NO3 [M þ H]þ 366.0664, found 366.0632.
(2R,8S)-{Bis(2,8-di(m-bromophenyl)-1-aza-3,7-dioxabicyclo[3.3.0]-
octane 5-methoxy)methyl)}-3-bromobenzene (14d): pale yellow oil; IR
(NaCl) ν = 3061, 2870, 1572, 1469, 1377, 1199, 1086, 779; 1H NMR
(CDCl3) δ 3.25 (d, J = 9.1 Hz, 2 H), 3.28 (d, J = 9.1 Hz, 2 H), 3.77 (d, J =
9.0 Hz, 2 H), 3.81 (s, 2 H), 3.84 (s, 2H), 3.89 (d, J = 9.0 Hz, 2 H), 5.31 (s,
1 H), 5.44 (s, 2 H), 5.48 (s, 2 H), 7.18 (m, 5 H), 7.31 (m, 5 H), 7.44 (m, 5
H), 7.58 (bs, 5 H); 13C NMR (CDCl3) δ 69.4, 72.9, 73.2, 73.5, 96.0,
96.4, 100.7, 122.4, 122.5, 125.6, 125.7, 129.4, 129.9, 130.0, 130.1, 131.7,
131.8, 132.0, 139.1, 141.5, 141.6; HRMS calcd for C43H37N2O6Br5Na
[M þ Na]þ 1098.8425, found 1098.8402.
(2R,8S)-2,8-Di(3,4-dichlorophenyl)-5-hydroxymethyl-1-aza-
3,7-dioxabicyclo[3.3.0]octane (syn-2e). Prepared in an analogous
route as described for 2a to give 2e (20% yield, syn/anti 83:17) and dimer
14e (35% yield).
(2R,8S)-2,8-Di(p-fluorophenyl)-5-hydroxymethyl-1-aza-3,
7-dioxabicyclo[3.3.0]octane (syn-2b). Prepared in an analogous
route as described for syn-2a to give compound 2b (34%, syn/anti: 98:2).
syn-2b: the sample had spectroscopic data in agreement with the
literature data;10 IR (NaCl) ν = 3500ꢀ3400 b, 2935, 2874, 2367, 2345,
1607, 1508, 1225, 1078, 1007, 837; 1H NMR (CDCl3) δ 3.47 (s, 2 H), 3.92
(d, J = 9.2 Hz, 2 H), 4.03 (d, J = 9.2 Hz, 2 H), 5.54 (s, 2 H), 7.04 (m, 4 H),
syn-2e: oil; IR (NaCl) ν = 3500 bs, 2936, 2874, 1468, 1204, 1086,
1032, 828, 756; 1H NMR (CDCl3) δ 3.50 (s, 2 H), 3.92 (d, J = 9.0 Hz, 2
H), 4.03 (d, J = 9.0 Hz, 2 H), 5.49 (s, 2 H), 7.23 (m, 2 H), 7.45 (d, J = 8.3
Hz, 2 H), 7.54 (d, J = 2.0 Hz, 2 H); 13C NMR (CDCl3) δ 65.7, 72.7, 74.9,
96.1, 126.1, 128.8, 130.7, 132.8, 132.9, 139.7; HRMS calcd for
C18H15Cl4NO3Na [M þ Na]þ 455.9698, found 455.9683.
7.41 (m, 4 H); 13C NMR (CDCl3) δ 65.6, 72.6, 74.9, 96.6, 115.4 (d, JCF
21.4 Hz), 115.5 (d, JCF = 21.2 Hz), 128.5 (d, JCF = 7.7 Hz), 128.6 (d, JCF
7.5 Hz), 135.2 (d, JCF = 3.0 Hz), 162.9 (d, JCF = 245.8 Hz).
=
=
anti-2e: white solid; mp 122ꢀ124 °C; IR (NaCl) ν = 3500ꢀ3400 bs,
2870, 1472, 1412, 1366, 1213, 1082, 1032, 827; 1H NMR (CDCl3) δ
3.71 (d, J = 11.1 Hz, 1 H), 3.76 (d, J = 11.1 Hz, 1 H), 3.83 (J = 8.9 Hz, 1
H), 3.88 (d, J = 9.0 Hz, 1 H), 4.09 (d, J = 9.0 Hz, 1 H), 4.19 (d, J = 8.9 Hz,
1 H), 5.04 (s, 1 H), 5.45 (s, 1 H), 6.82 (dd, J = 8.3, 2.0 Hz, 1 H), 7.03 (d, J
= 2.0 Hz, 1 H), 7.12 (dd, J = 8.3, 1.7 Hz, 1 H), 7.27 (d, J = 8.3 Hz, 1 H),
(2R,8S)-2,8-Di(p-trifluoromethylphenyl)-5-hydroxymethyl-
1-aza-3,7-dioxabicyclo[3.3.0]octane (syn-2c). Prepared in an
analogous route as described for syn-2a to give compounds 2c (32%,
syn/anti: 81:19) and dimer 14c (13%).
5743
dx.doi.org/10.1021/jo2008498 |J. Org. Chem. 2011, 76, 5738–5746

The Journal of Organic Chemistry
ARTICLE
7.31 (d, J = 8.3 Hz, 1 H), 7.38 (d, J = 1.7 Hz, 1 H); 13C NMR (CDCl3) δ
65.1, 72.0, 74.4, 74.5, 92.0, 92.6, 126.3, 126.4, 129.2, 129.3, 130.1, 130.2,
132.3, 132.6, 132.7, 133.1, 134.0, 139.7; HRMS calcd for C18H16NO3Cl4
[M þ H]þ 433.9884, found 433.9862.
analogous route as described for 15a in 78% yield as white solid; mp
134ꢀ135 °C; IR (NaCl) ν = 2932, 2868, 1757, 1701, 1466, 1259, 1105,
1030; 1H NMR (CDCl3) δ 2.31 (s, 3 H), 3.05 (s, 2 H), 3.85 (d, J = 9.0
Hz, 2 H), 3.90 (d, J = 9.0 Hz, 2 H), 5.45 (s, 2 H), 7.32 (dd, J = 8.2, 2.0 Hz,
2 H), 7.46 (d, J = 8.2 Hz, 2 H), 7.59 (d, J = 2.0 Hz, 2 H); 13C NMR
(CDCl3) δ 30.5, 36.0, 73.9, 74.3, 96.3, 126.5, 129.1, 130.6, 132.2, 132.3,
132.7, 132.9, 139.3, 194.7; HRMS calcd for C20H17Cl4NO3SNa [M þ
Na]þ 513.9575, found 513.9584.
Representative Procedure for the Preparation of Thiols
syn-8aꢀe. (2R,8S)- and (2R,8S)-2,8-Di(4-Chlorophenyl)-5-thio-
methyl-1-aza-3,7-dioxabicyclo[3.3.0]octane (syn-8a). To an ice-
cooled solution of MeOH saturated with NH3 was added compound syn-
15a (100 mg, 0.27 mmol). The reaction mixture was stirred at rt overnight
under N2. The solvent was removed under reduced pressure, and the
residue was purified by chromatography (1:6 EtOAc/hexanes) to afford
syn-8a (55 mg, 66% yield) as an oil: IR (NaCl) ν = 2868, 2804, 1701, 1605,
1508, 1225, 1078, 837; 1H NMR (CDCl3) δ 1.33 (t, J = 8.8 Hz, 1 HSH),
2.61 (d, J = 8.8 Hz, 2 H), 3.94 (d, J = 9.0 Hz, 2 H), 4.01 (d, J = 9.0 Hz, 2 H),
5.52 (s, 2 H), 7.33 (d, J = 8.2 Hz, 4 H), 7.42 (d, J = 8.2 Hz, 4 H); 13C NMR
(CDCl3) δ32.0, 73.8, 75.2, 96.9, 128.4, 129.6, 134.5, 137.8; HRMS calcd for
C18H17Cl2NO2SNa [M þ Na]þ 404.0249, found, 404.0230.
(2R,8S)-{Bis(2,8-di(m,p-dichlorophenyl)-1-aza-3,7-dioxabicyclo[3.3.0]-
octane 5-methoxy)methyl)}-3,4-dichlorobenzene (14e): pale yellow solid;
mp 79ꢀ90 °C; IR (NaCl) ν = 3065, 2872, 1566, 1469, 1367, 1204, 1032,
825, 737; 1H NMR (CDCl3) δ 3.22 (d, J = 9.1 Hz, 2 H), 3.26 (d, J = 9.1 Hz,
2 H), 3.75 (d, J = 9.1 Hz, 2 H), 3.82 (d, J = 9.1 Hz, 2 H), 3.83 (d, J = 9.2 Hz,
2 H), 3.86 (d, J= 9.2 Hz, 2 H), 5.30 (s, 1H), 5.41 (s, 2 H), 5.44 (s, 2 H), 6.95
(dd, J = 8.3, 2.0 Hz, 1H), 7.19 (m, 4 H), 7.25 (d, J = 2.0 Hz, 1H), 7.37 (t, J =
8.3 Hz, 5 H), 7.49 (d, J = 1.9 Hz, 4 H); 13C NMR (CDCl3) δ 69.1, 73.0,
73.2, 95.7, 95.9, 126.2, 126.3, 128.9, 129.0, 130.5, 132.6, 132.8, 132.9, 139.4;
HRMS calcd for C43H32Cl10N2O6Na [M þ Na]þ 1044.9038, found
1044.9040.
Representative Procedure for the Synthesis of 5-Acetyl-
hythiomethyl-bisoxazolidines 14aꢀe. (2R,8S)-2,8-Di(4-chlo-
rophenyl)-5-acetylthiomethyl-1-aza-3,7-dioxabicyclo [3.3.0]-
octane (syn-15a). To an ice-cold solution of triphenylphosphine
(5.7 g, 21.6 mmol) in benzene (30 mL) was added diethyl azodicarboxylate
(3.4 mL, 21.6 mmol) over 5 min. After 30 min of stirring, compound syn-2a
(3.0 g, 9.8 mmol) was added, and stirring was continued for 10 min. To the
resulting suspension was added dropwise a solution of thioacetic acid
(1.6 mL, 21.6 mmol) in benzene (5 mL), and stirring was continued for
another 1 h at 0 °C. The mixture was stirred at rt overnight and heated for 5
h to reflux. The solvent was removed under reduced pressure, and the crude
residue was purified by chromatography on SiO2 (1:4, EtOAc/hexanes) to
afford compound syn-15a (1.09 g, 75%) as a light yellow oil: IR (NaCl) ν =
2868, 1693, 1489, 1267, 1121, 1089, 1015, 812, 627; 1H NMR (CDCl3) δ
2.30 (s, 3 H), 3.04 (s, 2 H), 3.85 (d, J = 9.0 Hz, 2 H), 3.90 (d, J = 9.0 Hz, 2
(2R,8S)- and (2R,8S)-2,8-Di(4-fluorophenyl)-5-thiomethyl-
1-aza-3,7-dioxabicyclo[3.3.0]octane (syn-8b). Prepared in an
analogous route as described for 8a, to afford 8b (62%) as an oil: IR
(NaCl) ν = 3073, 2934, 2868, 1605, 1506, 1225, 1153, 1076, 1015, 839;
1H NMR (CDCl3) δ 1.34 (t, J = 8.6 Hz, 1 HSH), 2.63 (d, J = 8.6 Hz, 2 H),
3.94 (d, J = 9.0 Hz, 2 H), 4.02 (d, J = 9.0 Hz, 2 H), 5.53 (s, 2 H), 7.04 (m,
4 H), 7.47 (m, 4 H); 13C NMR (CDCl3) δ 32.1, 73.9, 75.2, 97.0, 115.3
(d, JCF = 21.7 Hz), 128.8 (d, JCF = 8.3 Hz), 135.0 (d, JCF = 3.0 Hz), 162.9
(d, JCF = 245.7 Hz); HRMS calcd for C18H18F2NO2S [M þ H]þ
350.1021, found 350.1025.
H), 5.48 (s, 2 H), 7.34 (d, J = 8.4 Hz, 4 H), 7.44 (d, J = 8.4 Hz, 4 H); 13
C
NMR (CDCl3) δ 30.5, 36.2, 73.7, 74.3, 96.8, 128.5, 128.6, 132.2, 132.3,
134.6, 137.6, 194.9; HRMS calcd for C20H19Cl2NO3SNa [M þ Na]þ
446.0355, found 446.0349.
(2R,8S)- and (2R,8S)-2,8-Di(4-trifluoromethylphenyl)-5-
thiomethyl-1-aza-3,7-dioxabicyclo[3.3.0]octane (syn-8c). Pre-
pared in an analogous route as described for 8a, to afford 8c (65%) as a
white solid; mp 63ꢀ64 °C; IR (NaCl) ν = 2938, 2870, 1412, 1327, 1124,
1067, 827; 1H NMR (CDCl3) δ 1.34 (t, J = 8.6 Hz, 1 HSH), 2.63 (d, J = 8.6
Hz, 2 H), 3.99 (d, J = 9.1 Hz, 2 H), 4.03 (d, J = 9.1 Hz, 2 H), 5.62 (s, 2 H),
(2R,8S)-2,8-Di(p-fluorophenyl)-5-acetylthiomethyl-1-aza-
3,7-dioxabicyclo[3.3.0]octane (syn-15b). Prepared in an analo-
gous route as described for 15a, in 54% yield, as a white solid; mp 78ꢀ79 °C;
IR (NaCl) ν = 2932, 2868, 1701, 1605, 1508, 1225, 1078, 1015, 837; 1H
NMR (CDCl3) δ 2.31 (s, 3 H), 3.05 (s, 2 H), 3.86 (d, J = 9.0 Hz, 2 H), 3.90
(d, J=9.0Hz, 2H),5.49(s, 2H),7.05(t,J=8.6Hz, 4H),7.48(d,J=8.6Hz,
2 H), 7.50 (d, J = 8.6 Hz, 2 H); 13C NMR (CDCl3) δ 30.5, 36.4, 73.6, 74.4,
96.8, 115.3 (d, JCF = 21.6 Hz), 129.0 (d, JCF = 8.3 Hz), 134.8 (d, JCF = 2.9
Hz), 163.0 (d, JCF = 245.7 Hz), 195.0; HRMS calcd for C20H19F2NO3SNa
[M þ Na]þ 414.0946, found 414.0927.
7.62 (m, 8H); 13C NMR (CDCl3) δ 31.8, 73.9, 75.5, 97.1, 123.9 (q, JCF
=
270.6 Hz), 125.5 (q, JCF = 3.7 Hz), 127.4, 131.0 (q, JCF = 32.0 Hz), 143.2;
HRMS calcd for C20H17F6NO2SNa [M þ Na]þ 472.0776, found 472.0767.
(2R,8S)- and (2R,8S)-2,8-Di(3-bromophenyl)-5-thiomethyl-
1-aza-3,7-dioxabicyclo[3.3.0]octane (syn-8d). Prepared in an ana-
logous route as described for 8a, except that the mixture was stirred for 3 h,
to give a mixture of 8d (44%), disulfide 16d (43%), and recovered starting
material 15d (10%).
(2R,8S)-2,8-Di(p-trifluoromethylphenyl)-5-acetylthiomethyl-
1-aza-3,7-dioxabicyclo[3.3.0]octane (syn-15c). Prepared in an ana-
logous route as described for syn-15a, in 71% yield as a white solid; mp
71ꢀ72 °C; IR (NaCl) ν = 3022, 2872, 1695, 1327, 1126, 1018, 827, 762; 1H
NMR (CDCl3) δ 2.28 (s, 3 H), 3.05 (s, 2 H), 3.87 (d, J = 9.1 Hz, 2 H), 3.94
(d, J = 9.1 Hz, 2 H), 5.58 (s, 2 H), 7.64 (m, 8 H); 13CNMR(CDCl3) δ30.5,
36.0, 73.9, 74.3, 97.0, 124.0 (q, JCF = 271.0 Hz), 125.5 (q, JCF = 3.7 Hz),
127.5, 130.8 (q, JCF = 32.3 Hz), 130.9 (q, JCF = 32.3 Hz), 143.0, 194.8;
HRMS calcd for C22H19F6NO3SNa [M þ Na]þ 514.0882, found 514.0909.
(2R,8S)-2,8-Di(m-bromophenyl)-5-acetylthiomethyl-1-aza-3,
7-dioxabicyclo[3.3.0]octane (syn-15d). Prepared in an analogous
route as described for 15a, in 84% yield as white solid; mp 101 °C dec; IR
(NaCl) ν = 2934, 2868, 1701, 1686, 1560, 1123, 1070, 773; 1H NMR
(CDCl3) δ 2.31 (s, 3 H), 3.06 (s, 2 H), 3.86 (d, J = 9.0 Hz, 2 H), 3.90 (d,
J = 9.0 Hz, 2 H), 5.48 (s, 2 H), 7.25 (m, 2 H), 7.46 (m, 4 H), 7.67 (s, 2
H); 13C NMR (CDCl3) δ 30.5, 36.1, 73.8, 74.3, 96.8, 122.6, 125.8, 130.1,
130.3, 131.8, 141.4, 194.8; HRMS calcd for C20H19Br2NO3SNa [M þ
Na]þ 533.9345, found 533.9347.
syn-8d: white solid; mp 79ꢀ80 °C; IR (NaCl) ν = 3065, 2932, 2868,
1570, 1202, 1121, 997, 773; 1H NMR (CDCl3) δ 1.33 (t, J = 8.6 Hz, 1
HSH), 2.64 (d, J = 8.6 Hz, 2 H), 3.95 (d, J = 9.1 Hz, 2 H), 4.02 (d, J = 9.1
Hz, 2 H), 5.52 (s, 2 H), 7.24 (t, J = 7.8 Hz, 2 H), 7.40 (d, J = 7.8 Hz, 2 H),
7.46 (m, 2 H), 7.65 (m, 2 H); 13C NMR (CDCl3) δ 31.9, 73.8, 75.4,
96.9, 122.6, 125.7, 130.1, 131.8, 141.6; HRMS calcd for C18H16Br2NO2S
[M ꢀ H]ꢀ 467.9274, found 467.9294.
(2R,8S)- and (2R,8S)-Bis(2,8-di(3-bromophenyl)-1-aza-3,7-dioxabicy-
clo[3.3.0]octane 5-methyldisulfide (syn-16d): oil; IR (NaCl) ν = 2868,
1572, 1469, 1435, 1199, 1119, 1069, 1009, 775; 1H NMR (CDCl3) δ 2.86
(s, 4 H), 3.87 (d, J = 9.1 Hz, 4 H), 4.01 (d, J = 9.1 Hz, 4 H), 5.47 (s, 4 H),
7.23 (t, J = 7.8 Hz, 4 H), 7.41 (d, J = 7.8 Hz, 4 H), 7.47 (d, J = 7.8 Hz, 4 H),
7.65 (s, 4 H); 13C NMR (CDCl3) 47.5, 73.9, 74.4, 96.5, 122.5, 125.7, 130.0,
130.1, 131.8, 141.3; HRMS calcd for C36H33Br4N2O4S2 [M þ H]þ
936.8610, found 936.8592.
(2R,8S)- and (2R,8S)-2,8-Di(3,4-dichlorophenyl)-5-thio-
methyl-1-aza-3,7-dioxabicyclo[3.3.0]octane (syn-8e). Prepared
in an analogous route as described for 8a, except that the mixture was
(2R,8S)-2,8-Di(m,p-Dichlorophenyl)-5-acetylthiomethyl-
1-aza-3,7-dioxabicyclo[3.3.0]octane (syn-15e). Prepared in an
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stirred for 3 h, to give a mixture of syn-8e (25%), disulfide 16e (53%), and
recovered starting material 15e (10%).
Hz), 162.8 (d, JCF = 246.5 Hz); HRMS calcd for C18H18F2NO2S
[M þ H]þ 350.1021, found 350.1022.
syn-8e: oil; IR (NaCl) ν = 2932, 2868, 1701, 1686, 1466, 1130, 1030,
827, 625; 1H NMR (CDCl3) δ 1.33 (t, J = 8.6 Hz, 1 HSH), 2.62 (d, J = 8.6
Hz, 2 H), 3.95 (d, J = 9.1 Hz, 2 H), 4.01 (d, J = 9.1 Hz, 2 H), 5.49 (s, 2 H),
7.30 (dd, J = 8.2, 2.1 Hz, 2 H), 7.44 (d, J = 8.2 Hz, 2 H), 7.57 (d, J = 2.1
Hz, 2 H) ; 13C NMR (CDCl3) δ 31.9, 73.8, 75.4, 96.4, 126.3, 129.0,
130.6, 132.7, 132.9, 139.5; HRMS calcd for C18H16Cl4NO2S [M þ H]þ
449.9656, found 449.9647.
(2R,8S)- and (2R,8S)-Bis(2,8-di(3,4-dichlorophenyl)-1-aza-3,7-
dioxabicyclo[3.3.0]octane 5-methyldisulfide (syn-16e): white solid;
mp 147ꢀ148 °C; IR (NaCl) ν = 2932, 2870, 1468, 1367, 1204, 1113,
1030, 737; 1H NMR (CDCl3) δ 2.84 (s, 4 H), 3.87 (d, J = 9.2 Hz, 4 H),
3.99 (d, J = 9.2 Hz, 4 H), 5.43 (s, 4 H), 7.30 (dd, J = 8.3, 2.0 Hz, 4 H),
7.43 (d, J = 8.3 Hz, 4 H), 7.57 (d, J = 2.0 Hz, 4 H); 13C NMR (CDCl3) δ
47.6, 73.9, 74.4, 96.1, 126.4, 129.1, 130.6, 132.7, 133.0, 139.2; HRMS
calcd for C36H29Cl8N2O4S2 [M þ H]þ 896.9072, found 896.9058.
Reduction of Disulfide 16d. To a stirred solution of dimer 16d
(90 mg, 0.10 mmol) in MeOH (3 mL) and CH2Cl2 (1 mL) was added
portionwise NaBH4 (21 mg, 0.60 mmol). The mixture was stirred at rt for 4
h. Then, the solvent was removed under reduced pressure. The crude
residue was poured into H2O (15 mL), the pH was adjusted to 6 with HCl
5%, and the mixture was extracted with CH2Cl2 (3 ꢁ 50 mL). The solvent
was removed under reduced pressure,and the residue was purified by
chromatography on SiO2 (1:4, EtOAc/hexanes) to afford syn-8d (20 mg,
25% yield, 60% yield based on recovered starting material 16d).
syn-syn-3b: pale yellow oil; IR (NaCl) ν = 3350ꢀ3450 bs, 2924, 2855,
1604, 1508, 1226, 1045, 837; 1H NMR (CDCl3) δ 2.93 (d, J = 12.0 Hz, 1
H), 3.00 (d, J = 12.0 Hz, 1 H), 3.50 (d, J = 10.0 Hz, 1 H), 3.55 (d, J = 10.0
Hz, 1 H), 3.86 (d, J = 8.8 Hz, 1 H), 4.28 (d, J = 8.8 Hz, 1 H), 5.21 (s, 1 H),
5.32 (s, 1 H), 6.95 (t, J = 8.6 Hz, 2 H), 7.10 (t, J = 8.6 Hz, 2 H), 7.41 (dd,
JHH = 8.6 Hz, JHF = 5.2 Hz, 2 H), 7.51 (dd, JHH = 8.6 Hz, JHF = 5.6 Hz, 2
H); 13C NMR (CDCl3) δ 39.3, 67.0, 73.4, 74.3, 79.7, 98.4, 115.2 (d,
JCF = 21.3 Hz), 115.6 (d, JCF = 21.8 Hz), 129.1 (d, JCF = 8.2 Hz), 129.5
(d, JCF = 8.7 Hz) 134.7 (d, JCF = 2.8 Hz), 136.3 (d, JCF = 3.1 Hz), 162.3
(d, JCF = 247.0 Hz), 163.3 (d, JCF = 247.6 Hz); HRMS calcd for
C18H17F2NO2S [M þ H]þ 350.1021, found 350.1024.
(2R,5S,8R)- and (2S,5R,8S)-2,8-Di(4-trifluoromethylphenyl)-
5-hydroxymethyl-1-aza-3-oxa-7-thiabicyclo[3.3.0]octane
(anti-syn-3c). Prepared in an analogous route as described for anti-
syn-3a, to give 3c (64%, anti-syn/syn-syn 81:19).
anti-syn-3c: white solid; mp 106ꢀ107 °C; IR (NaCl) ν = 3309, 2932,
2870, 1738, 1697, 1327, 1163, 1126, 1069, 837; 1H NMR (CDCl3) δ
2.30 (t, J = 5.6 Hz, 1 H), 3.12 (d, J = 11.9 Hz, 1 H), 3.30 (d, J = 11.9 Hz, 1
H), 3.81 (dd, J = 10.9, 5.6 Hz, 1 H), 3.91 (d, J = 8.8 Hz, 1 H), 3.93 (dd, J =
10.9, 5.6 Hz, 1 H), 4.06 (d, J = 8.8 Hz, 1 H), 5.15 (s, 1 H), 5.61 (s, 1 H),
7.10 (d, J = 8.2 Hz, 2 H), 7.36 (m, 6 H); 13C NMR (CDCl3) δ 39.7, 66.0,
69.5, 73.0, 79.7, 94.2, 124.9 (q, JCF = 3.5 Hz), 126.4 (q, JCF = 276.0 Hz),
127.14, 127.72, 129.7 (q, JCF = 32.0 Hz), 130.9 (q, JCF = 32.1 Hz),
137.78, 145.2; HRMS calcd for C20H17F6NO2SNa [M þ Na]þ
=
Reduction of Disulfide 16e. Prepared in an analogous route as
described for the reduction of disulfide 16d to give 8e (40%, 70% yield
based on recovered starting material 16e).
472.0776 found: 472.0773.
syn-syn-3c: oil; IR (NaCl) ν = 3500ꢀ3400 b, 2934, 2876, 1419, 1327,
1124, 1069, 839; 1H NMR (CDCl3) δ 1.64 (t, J = 5.0 Hz, 1 H), 2.98 (s, 2
H), 3.52 (dd, J = 10.6, 5.0 Hz, 1 H), 3.63 (dd, J = 10.6, 5.0 Hz, 1 H), 3.90
(d, J = 8.8 Hz, 1 H), 4.34 (d, J = 8.8 Hz, 1 H), 5.28 (s, 1 H), 5.41 (s, 1 H),
7.53 (d, J = 8.7 Hz, 2 H), 7.57 (d, J = 8.7 Hz, 2 H), 7.64 (d, J = 8.6 Hz, 2
H), 7.68 (d, J = 8.6 Hz, 2 H); 13C NMR (CDCl3) δ 39.2, 67.0, 73.7, 74.3,
80.0, 98.4, 123.9 (q, JCF = 270.8 Hz), 125.3 (q, JCF = 3.4 Hz), 125.7 (q,
JCF = 3.7 Hz), 127.7, 127.9, 130.1 (q, JCF = 32.4 Hz), 131.5 (q, JCF = 32.1
Hz) 142.8, 144.7 (q, JCF = 1.0 Hz); HRMS calcd for C20H17F6NO2S [M
þ H]þ 450.0957, found 450.0953.
Representative Procedure for the Synthesis of anti-syn-
Thiazolidinyl-oxazolidines 3aꢀd, Conditions A. (2R,5S,8R)-
and (2S,5R,8S)-2,8-Di(p-chlorophenyl)-5-hydroxymethyl-1-
aza-3-oxa-7-thiabicyclo[3.3.0]octane (anti-syn-3a). To a stir-
red solution of thiol syn-8a (40 mg, 0.10 mmol) in CH2Cl2 (8 mL) was
added p-TsOH ac. (4 mg, 0.02 mmol). The mixture was heated to reflux
for 6 h and left overnight at rt. The solvent was removed under reduced
pressure, and the crude residue was poured into a saturated solution of
NaHCO3, extracted with EtOAc (3 ꢁ 50 mL), dried (Na2SO4), and
filtered. The solvent was removed under reduced pressure and the crude
residue was purified by chromatography on SiO2 (1:4 EtOAc/hexanes)
to afford compound 3a as an oil (25 mg, 62%, anti-syn/syn-syn 99:1).
anti-syn-3a: white solid; mp 106ꢀ107 °C; IR (NaCl) ν = 3500ꢀ3400
bs, 2932, 2872, 1560, 1491, 1089, 1045, 1014, 827; 1H NMR (CDCl3) δ
2.33 (bs, 1 HOH), 3.07 (d, J = 11.8 Hz, 1 H), 3.24 (d, J = 11.8 Hz, 1 H),
3.76 (d, J = 10.8 Hz, 1 H), 3.86 (d, J = 10.8 Hz, 1 H), 3.88 (d, J = 8.7 Hz, 1
H), 4.02 (d, J = 8.7 Hz, 1 H), 5.13 (s, 1 H), 5.54 (s, 1 H), 6.96 (d, J = 8.5
Hz, 2 H), 7.10 (d, J = 8.5 Hz, 2 H), 7.19 (m, 4 H); 13C NMR (CDCl3) δ
39.8, 65.8, 69.4, 72.8, 79.8, 94.6, 128.1, 128.2, 128.3, 128.7, 132.6, 133.1,
134.7, 140.3; HRMS calcd for C18H17Cl2NO2SNa [M þ Na]þ
404.0249, found 404.0235.
(2R,5S,8R)- and (2S,5R,8S)-2,8-Di(3-bromophenyl)-5-hy-
droxymethyl-1-aza-3-oxa-7-thiabicyclo[3.3.0]octane (anti-
syn-3d). Prepared in an analogous route as described for anti-syn-3a,
to give a mixture of 3d (64%, anti-syn/syn-syn (95:5) and spiro-4d (20%,
diastereomeric ratio = 7:3).
anti-syn-3d: oil; IR (NaCl) ν = 3500ꢀ3400 b, 3067, 2928, 2872, 1570,
1213, 1045, 997, 787, 727; 1H NMR (CDCl3) δ 2.46 (bs, 1 HOH), 3.08 (d,
J = 11.9 Hz, 1 H), 3.26 (d, J = 11.9 Hz, 1 H), 3.77 (d, J = 10.9 Hz, 1 H), 3.86
(d, J= 8.7 Hz, 1 H), 3.87 (d, J= 10.9 Hz, 1 H), 4.01 (d, J= 8.7 Hz, 1 H), 5.11
(s, 1 H), 5.49 (s, 1 H), 6.99 (m, 3 H), 7.10 (t, J = 1.8 Hz, 1 H), 7.15 (d, J =
7.8 Hz, 1H), 7.25 (m, 1 H), 7.37 (d, J = 7.8 Hz, 1 H), 7.42 (bs, 1 H); 13
C
NMR (CDCl3) δ 39.7, 65.9, 69.5, 72.7, 79.6, 94.1, 121.9, 122.3, 125.5,
125.9, 129.4, 129.5, 130.0, 130.6, 130.7, 131.9, 136.0, 143.5; HRMS calcd for
C18H18Br2NO2S [M þ H] þ 469.9420, found 469.9432.
(2R,5S,8R)- and (2S,5R,8S)-2,8-Di(4-fluorophenyl)-5-hy-
droxymethyl-1-aza-3-oxa-7-thiabicyclo[3.3.0]octane (anti-
syn-3b). Prepared under conditions A, in an analogous route as
described for anti-syn-3a, to give 3b (44% yield, anti-syn/syn-syn 90:10).
anti-syn-3b: white solid; mp 90ꢀ91 °C; IR (NaCl) ν = 3500ꢀ3400
syn-syn-3d: oil; IR (NaCl) ν = 3500ꢀ3400 bs, 2928, 2870, 1574,
1469, 1433, 1367, 1209, 1068, 997, 785; 1H NMR (CDCl3) δ 1.65 (bs,
1 H), 2.94 (d, J = 12.1 Hz, 1 H), 3.00 (d, J = 12.1 Hz, 1 H), 3.51 (d, J =
10.6 Hz, 1 H), 3.60 (d, J = 10.6 Hz, 1 H), 3.86 (d, J = 8.8 Hz, 1 H), 4.30
(d, J = 8.8 Hz, 1 H), 5.20 (s, 1 H), 5.29 (s, 1 H), 7.15 (t, J = 7.9 Hz, 1 H),
7.29 (t, J = 7.9 Hz, 1 H), 7.35 (m, 2 H), 7.44 (d, J = 7.9 Hz, 1 H), 7.52 (d,
J = 7.9 Hz, 1 H), 7.66 (d, J = 7.9 Hz, 2 H); 13C NMR (CDCl3) δ 39.2,
66.9, 73.4, 74.3, 79.8, 98.3, 122.6, 122.7, 126.0, 126.3, 129.9, 130.3, 130.5,
130.8, 130.9, 132.5, 141.1, 143.1; HRMS calcd for C18H17Br2NO2SNa
[M þ Na]þ 491.9239, found 491.9215.
1
bs, 2929, 2872, 1605, 1510, 1385, 1227, 1155, 1047, 839; H NMR
(CDCl3) δ 2.37 (bs, 1 HOH), 3.09 (d, J = 11.8 Hz, 1 H), 3.23 (d, J = 11.8
Hz, 1 H), 3.77 (d, J = 10.9 Hz, 1 H), 3.86 (d, J = 10.9 Hz, 1 H), 3.87 (d,
J = 8.8 Hz, 1 H), 4.02 (d, J = 8.8 Hz, 1 H), 5.18 (s, 1 H), 5.53 (s, 1 H),
6.80 (t, J = 8.8 Hz, 2 H), 6.87 (t, J = 8.8 Hz, 2 H), 6.97 (dd, JHH = 8.5 Hz,
J
HF = 5.5 Hz, 2 H), 7.23 (dd, JHH = 8.5 Hz, JHF = 5.5 Hz, 2 H); 13C NMR
(CDCl3) δ 39.9, 65.8, 69.4, 72.7, 79.6, 94.6, 114.8 (d, JCF = 21.5 Hz),
114.9 (d, JCF = 21.4 Hz), 128.4 (d, JCF = 8.0 Hz), 129.2 (d, JCF = 8.2 Hz),
129.8 (d, JCF = 3.3 Hz), 137.1 (d, JCF = 2.8 Hz), 162.0 (d, JCF = 244.7
(2SR,syn/anti)-2,8-Bis(3-bromophenyl)-7,9-dioxa-3-thia-1-azaspiro-
[4.5]decane (spiro-4d), major product: pale yellow oil; IR (NaCl) ν =
3065, 2857, 1570, 1474, 1425, 1379, 1207, 1107, 783; 1H NMR (CDCl3) δ
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ARTICLE
2.71 (d, J = 10.9 Hz, 1 H), 2.85 (d, J = 10.9 Hz, 1 H), 3.83 (d, J = 11.7 Hz, 1
H), 4.07 (d, J = 11.4 Hz, 1 H), 4.15 (dd, J = 11.4 Hz, 4J = 2.9 Hz, 1 H), 4.35
(dd, J = 11.7, 4J = 2.9 Hz, 1 H), 5.53 (s, 1 H), 5.58 (s, 1 H), 7.22 (m, 2 H),
7.42 (m, 4 H), 7.67 (m, 1 H), 7.74 (m, 1 H); HRMS calcd for C18H18Br2-
NO2S [M þ H] þ 469.9420, found 469.9432.
UE Grant “PE-UE URY 2003-5906) and Dr. B. Godugu for HRMS
(Mass Spec Lab, Chemistry Department, Pittsburgh).
’ REFERENCES
(1) Lambert, J. B.; Wang, G. T.; Huseland, D. E.; Takiff, L. C. J. Org.
Chem. 1987, 52, 68–71.
(2SR,syn/anti)-2,8-Bis(3,4-dichlorophenyl)-7,9-dioxa-3-thia-
1-azaspiro[4.5]decane (spiro-4e). Prepared in an analogous route as
described for anti-syn-3a, to give spiro-4e (80%, syn/anti 8:2).
(2) Selected reviews: (a) Ladame, S. Org. Biomol. Chem. 2008,
6, 219–226. (b) Corbett, P. T.; Leclaire, J.; Vial, L.; West, K. R.; Wietor,
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L. I.; Chuvashev, Y. A.; Funtikova, E. A. Chem. Heterocycl. Compd. 2008,
44, 1466–1471. (c) Lazar, L.; Ful€op, F. Eur. J. Org. Chem. 2003, 3025–3042.
(5) Saiz, C.; Wipf, P.; Manta, E.; Mahler, S. G. Org. Lett. 2009,
11, 3170–3173.
syn-4e: solid; mp 108ꢀ109 °C; IR (NaCl) ν = 3323.35, 2926, 2855,
1472, 1375, 1101, 1031, 822; 1H NMR (CDCl3) δ 2.70 (d, J = 10.9 Hz,
1 H), 2.84 (d, J = 10.9 Hz, 1 H), 2.93 (bs, 1H), 3.83 (d, J = 11.5 Hz, 1 H),
4.05 (d, J = 11.5 Hz, 1 H), 4.13 (dd, J = 11.5, 2.9 Hz, 1 H), 4.33 (dd, J =
11.5, 2.9 Hz, 1 H), 5.51 (s, 1 H), 5.55 (s, 1 H), 7.33 (td, J = 8.4, 2.0 Hz,
2 H), 7.40 (d, J = 8.3 Hz, 1 H), 7.44 (d, J = 8.3 Hz, 1 H), 7.61 (d, J = 2.0
Hz, 1 H), 7.68 (d, J = 2.0 Hz, 1 H); 13C NMR (CDCl3) δ 36.4, 63.6, 66.4,
71.3, 74.8, 100.1, 125.4, 126.8, 128.2, 129.4, 130.2, 130.3, 132.2, 132.5,
132.6, 133.1, 137.4, 140.8; HRMS calcd for C18H16Cl4NO2S [M þ H]þ
449.9650, found 449.9634.
(6) Senkus, M. J. Am. Chem. Soc. 1945, 67, 1515–1519.
(7) Darabantu, M.; Maiereanu, C.; Silaghi-Dumitrescu, I.; Toupet,
L.; Condamine, E.; Ramondenc, Y.; Berghian, C.; Plꢀe, G.; Plꢀe, N. Eur. J.
Org. Chem. 2004, 12, 2644–2661.
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Chem. Soc. 2010, 132, 6638–6639.
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col. 1997, 40, 513–520.
(10) Desino, K. E.; Ansar, S.; Georg, G. I.; Himes, R. H.; Michaelis,
M. L.; Powell, D.; Reiff, E. A.; Telikepalli, H.; Audus, K. L. J. Med. Chem.
2009, 52, 7537–7543.
Representative Procedure for the Synthesis of syn-syn-3a
and -3d, Conditions B. (2S,5S,8R)- and (2R,5R,8S)-2,8-Di(p-
chlorophenyl)-5-hydroxymethyl-1-aza-3-oxa-7-thiabicyclo-
[3.3.0]octane (syn-syn-3a). To a stirred solution of thiol syn-8a (100
mg, 0.28 mmol) in PhMe (10 mL) were added p-TsOH acid (10 mg,
0.058 mmol) and p-Cl benzaldehyde (40 mg, 0.28 mmol). The mixture
was heated at reflux in a DeanꢀStark trap for 5 h. The solvent was
removed under reduced pressure and the crude residue was poured into
a saturated solution of NaHCO3, extracted with EtOAc (3 ꢁ 50 mL),
dried, and filtered. The solvent was removed under reduced pressure,
and the crude residue was purified by chromatography on SiO2 (1:5,
EtOAc/hexanes) to afford a mixture of 3a (41 mg, 41%, anti-syn/syn-syn
10:90) and spiro-anti-4a (46 mg, 46% yield).
Synthesis of syn-syn-3d, Conditions B. Prepared in analogous
route as described for syn-syn-3a (method B), except the reaction
mixture was heated for 2 h, to give a mixture of syn-syn-3d (66% yield,
anti-syn/syn-syn 7:93) and spiro-4d (20% yield, anti/syn 8:2).
(2RS,anti)-4d: oil, 1H NMR (CDCl3) δ 3.25 (dd, J = 11.2 Hz, 4J = 1.4
Hz, 1 H), 3.58 (d, J = 11.2 Hz, 1 H), 3.82 (dd, J = 10.8 Hz, 4J = 1.4 Hz, 1
H), 4.01 (s, 1 H), 4.02 (d, 4J = 2.4 Hz, 1 H), 4.25 (d, J = 10.8 Hz, 4J = 2.4
Hz, 1 H), 5.46 (s, 1 H), 5.47 (s, 1 H), 7.24 (m, 2 H), 7.45 (m, 4 H), 7.67
(m, 2 H); 13C NMR (CDCl3) 42.1, 64.1, 69.2, 73.4, 73.8, 100.8, 122.4,
122.7, 124.8, 126.0, 129.3, 129.9, 130.2, 130.3, 131.6, 132.2, 139.5, 142.1;
HRMS calcd for C18H17Br2NO2SNa [M þ Na]þ 491.9239, found
491.9215.
(11) Handrick, G. R.; Atkinson, E. R. J. Med. Chem. 1966,
9, 558–562.
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S.; Ramondenc, Y.; Darabantu, M. Lett. Org. Chem. 2010, 7, 283–290.
(13) For a discussion of S vs O nucleophilic attack, see:Baiget, J.;
Cosp, A.; Gꢀalvez, E.; Gꢀomez-Pinal, L.; Romea, P.; Urpí, F. Tetrahedron
2008, 64, 5637–5644.
(14) Kumar, R.; Kumar, D.; Chakraborti, A. K. Synthesis 2007,
2, 299–303.
(15) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165–195.
(16) Fulop, F.;Mattinen, J.;Pihlaja, K.Tetrahedron 1990, 46, 6545–6552.
’ ASSOCIATED CONTENT
Supporting Information. Copies of 1H and 13 C spectra
S
b
for 2cꢀe, 3aꢀd, 4a, 4d, 4e, 9, 11a, 12a, 8aꢀe, 15aꢀe, and
16eꢀd. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: gmahler@fq.edu.uy.
’ ACKNOWLEDGMENT
The National Institutes of Health-FIRCA (R03TW007772)
and CSIC-Grupos (UdelaR) supported this work. C.S. is grateful
to the Agencia Nacional de Investigaciꢀon e Innovaciꢀon (ANII)
for a Ph.D. fellowship. The authors would like to thank F. LLorente
and Dr. A. Rodríguez for HRMS (Polo Tecnꢀologico-FQ, UdelaR,
5746
dx.doi.org/10.1021/jo2008498 |J. Org. Chem. 2011, 76, 5738–5746