Efficient synthesis of chiral Δ2-1,3,4-thiadiazolines from α-pinene and verbenone

Article abstract of DOI:10.1016/j.tetasy.2011.10.016

The synthesis of chiral cyclobutane 1,3,4-thiadiazoline derivatives starting from (-)-α-pinene and (-)-verbenone was studied. The diastereoisomeric excesses of the products obtained depended strongly upon the starting chiral ketone. The stereochemical assignments of the synthesized compounds were performed by NMR spectroscopy, X-ray analysis, and theoretical calculations.

Full text of DOI:10.1016/j.tetasy.2011.10.016

Tetrahedron: Asymmetry 22 (2011) 1924–1929
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Efficient synthesis of chiral
and verbenone
D a-pinene
2-1,3,4-thiadiazolines from
Gabriela P. Sarmiento a, Pablo D. Rouge a, Lucas Fabian b, Daniel Vega a,b,c, Rosa M. Ortuño c,
Graciela Y. Moltrasio a, Albertina G. Moglioni b,
⇑
a Department of Organic Chemistry, Faculty of Pharmacy and Biochemistry, Universidad de Buenos Aires, 956 Junín St., (1113) Buenos Aires, Argentina
b Department of Pharmacology, Faculty of Pharmacy and Biochemistry, Universidad de Buenos Aires, 956 Junín St., (1113) Buenos Aires, Argentina
c Faculty of Sciences, Universidad Autónoma de Barcelona, Bellaterra, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 October 2011
Accepted 28 October 2011
The synthesis of chiral cyclobutane 1,3,4-thiadiazoline derivatives starting from (ꢀ)- -pinene and (ꢀ)-
a
verbenone was studied. The diastereoisomeric excesses of the products obtained depended strongly upon
the starting chiral ketone. The stereochemical assignments of the synthesized compounds were per-
formed by NMR spectroscopy, X-ray analysis, and theoretical calculations.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
of a-pinene and verbenone, respectively, and the heterocyclization
of a suitable intermediate leading to two types of
D
2-1,3,4-thi-
Thiadiazolines and their derivatives constitute a group of com-
pounds that possess a wide range of biological activities.1 One of
the most commonly used routes to obtain 1,3,4-thiadiazolines
(TDZ) is the heterocyclization of thiosemicarbazones (TSC) pre-
pared from aldehydes and ketones (Scheme 1) under acylation
conditions, usually acetic anhydride and pyridine.2
adiazoline compounds (types I and II) (Fig. 1).
NHCOCH3
S
H3COCHN
S
N
N
N
R
*
N
H3COC
R
COCH3
Type II
*
S
H3COC-HN
Type I
O
N-NH-C-NH2
N
S
R
N
Figure 1. General structures for the TDZ compounds synthesized.
COCH3
R
R´
R
R´
R´
Ketone
TSC
TDZ
2. Results and discussion
Scheme 1. General procedure to obtain a TDZ from a ketone.
As stated in the introduction, the precursors used for the syn-
thesis of these compounds (types I or II) were ketones obtained
Using this methodology, we have described the synthesis and
biological activity of several TSC and TDZ compounds, derived from
aromatic ketones, indanones, tetralone, and terpenones.3,4 From
prochiral ketones, the corresponding TDZ compounds were formed
as a racemic mixture. In the case of chiral ketones, we have found
some examples, in addition to those previously described, where
we verified the influence of the steric hindrance present in the
by C@C oxidative cleavage of
a
-(ꢀ)-pinene and (ꢀ)-verbenone
through synthetic pathways previously described by our group.
Methylcyclobutyl ketones 1,6 2,6 3,7 6,7 8, and a substituted
cyclobutanone 98 were precursors for the synthesis of types I and
II compounds, respectively (Scheme 2). Ketone 8 was prepared
from hydroxy ketal 56 by treatment with t-butyldiphenylsilyl chlo-
ride and subsequent deprotection of the ketone group.
TSC to favor the p
-facial selectivity in the ring closure.4,5
Herein we report the results obtained in the preparations of TSC
compounds from ketones prepared through the oxidative cleavage
Ketones 1–3, 6, 8, 9 were reacted with thiosemicarbazide in eth-
anol, avoiding the use of mineral acids, to form enantiopure thio-
semicarbazones 7–10 (Scheme 3). Experimental observations
indicated that the use of sulfuric acid as a catalyst led to the forma-
tion of a mixture of isomeric thiosemicarbazones. It was not
⇑
Corresponding author.
E-mail address: amoglio@ffyb.uba.ar (A.G. Moglioni).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.10.016

G. P. Sarmiento et al. / Tetrahedron: Asymmetry 22 (2011) 1924–1929
1925
O
i, ii
COOCH3
(-)-α-pinene
1
O
iii
vii, viii, i
i, ii
O
COOCH3
COOR
O
9
2 R = CH3
3 R = t-Butyl
(-)-verbenone
O
O
iv
COOCH3
4
O
O
vi
OH
O
O
v
v
O
O
OTBDPS
OTBDPS
OH
6
7
8
5
Scheme 2. Synthesis of ketones 1–3, 6, 8, 9. Reagents and conditions: (i) NaIO4/RuOn/CH3CN/Cl4C/H2O; (ii) CH2N2/ether; (iii) ethylene glycol/PPTS/heat; (iv) LiBH4/THF;
(v) acetone/PPTS/heat; (vi) Cl-TBDPS/DMAP/Cl2CH2; (vii) m-CPBA/Cl2CH2; (viii) K2CO3/H2O/ethanol.
NHCOCH3
S
S
N
O
H2N-C-HN-N
i
N
H3COC
R
R
R
ii
*
10, 11, 12
14, 15, 16
10,14 R = CH2COOCH3
11,15 R = COOCH3
12,16 R = CH2OH
1 R = CH2COOCH3
2 R = COOCH3
6 R = CH2OH
S
H3COCHN
S
COOCH3
O
COOCH3
H2N-C-HN-N
COOCH3
ii
*
i
N
N
H3COC
9
17
13
Scheme 3. Synthesis of TSC 10–13 and TDZ 14–17. Reagents and conditions: (i) thiosemicarbazide/ethanol/heat; (ii) acetic anhydride/pyridine/heat.
possible to obtain the corresponding TSC for compounds 3 and 8,
which was attributed to the steric hindrance exerted by the bulky
substituent at the 1,3-cis position on the cyclobutane ring.
The configuration of the C@N double bond was assigned to be the
trans-isomer, for compounds 10–12, according to that observed in
the crystallographic structureof compound 12 (Fig. 2). X-ray crystal-
lography of compound 12 also confirmed the 1,3-cis relative stereo-
chemistry between the substituents present in the cyclobutane ring,
after six reaction steps from verbenone. The compound crystallizes
with one molecule in the asymmetric unit (Fig. 2). The crystal cohe-
sion is mainly due to the three hydrogen bonds provided by H-12, H-
8, and H-14B. These hydrogen bonds determine a chain of molecules
running along the c direction. The packing can be described as a
piling up of parallel chains along the b direction.
Figure 2. Crystal structure of compound 12.

1926
G. P. Sarmiento et al. / Tetrahedron: Asymmetry 22 (2011) 1924–1929
The reaction of thiosemicarbazones under acetylating condi-
The configuration of both isomers 17a and 17b was elucidated
from NMR data and theoretical calculations. The signal assignment
of each H and C was unequivocally performed on the basis of
HMQC experiments. Further structural insight was obtained from
NOESY experiments. In the case of 17a, protons bonded to C-3 (d
tions is the best known pathway known for the synthesis of thi-
adiazoline derivatives.2,9 Accordingly, heating of homochiral TSC
10–12 with anhydride acetic in pyridine gave the expected thio-
diazolines 14–16 (Scheme 3).
Specifically, TDZ compounds 14–16 were obtained as a mixture
of diasteroisomeric products in a 1:1 ratio, which were not resolv-
able by any traditional chromatographic methods such as thin
layer or column chromatography. The 13C NMR spectra of these
compounds presented several duplicated signals, for example
two signals for C-2 and C-5 corresponding to the heterocyclic moi-
ety. Our earlier experience working with 1,3-cis-disubstituted
methylcyclobutyl ketones indicated that the isomerization from a
cis- to a trans-structure via the keto-enol equilibrium was a prob-
able reaction.6 Aiming to establish which stereogenic center was
modified during the reaction of heterocyclization, the complete
assignment of the pair of diastereoisomers 16 was carried out.
Compound 16, obtained as an acetate, was selected because,
regardless of the presence of three stereogenic centers in the mol-
ecule, only two centers, C-10 and C-5, could be stereochemically
modified. The new stereogenic center generated in this reaction
(C-5) could be (R) or (S). Otherwise, according to the mechanism
accepted for this reaction (Scheme 4),2 C-10 could be modified via
transposition to an intermediate carbocation. The proposed mech-
anism (Scheme 4) for the formation of these thiadiazolines can be
explained on the basis of the hard and soft acid and base principle.2
The harder acylating reagent reacts with the harder nitrogen atom,
rather than the softer sulfur atom, and this acylation favors the
30.9 ppm) showed shifts of d 2.90 and 3.33 ppm (Dd 0.43 ppm),
the proton bonded at C-2 (d 45.7 ppm) appeared at d 3.78 ppm
(triplet). On the other hand, for 17b, the protons at C-3 (d
31.8 ppm) presented a
respectively), the methine proton was found at
D
d at 2.25 ppm (d 2.55 and 4.80 ppm,
2.60 ppm
d
(Fig. 4). The selectivity of the process may be governed by two fac-
tors, the relative stability of the two products or the rates of forma-
tion. To determine whether one or both factors had an influence on
the results of the reaction, the stabilities of the two possible diaste-
reoisomers 17a and 17b were studied by theoretical methods. The
geometry optimizations were performed at the B3LYP/6-31⁄⁄G le-
vel with the Gaussian G03 program package.10 Conformational
minima obtained for both epimers are shown in Figure 4. The cal-
culated energy difference for them is low (DE = 1.87 kcal/mol) with
a slight minimum for the configuration where the sulfur atom is in
a cis-position with regard to the carboxymethyl group at C-2 of the
cyclobutane ring. It is proposed that there is a considerable amount
of steric hindrance to the ring-closure from one side of the ring at
C-4 which might be explained on the basis that while the sulfur
atom is more bulky than the nitrogen atom, the N–COCH3 group
becomes more bulky than the sulfur atom during cyclization. Thus
the thiadiazoline ring closure at C-4, by the preferential attack of
the sulfur atom to the more hindered side, leaves the bulky (N–
COCH3) group on the less sterically hindered side, to give 17a.
The apparent disparity in the 1H NMR shifts, corresponding to
isomer 17b, especially in the case of H-3 at d 4.80 ppm, indicates
high deshielding due to the anisotropic effect of the two C@O
groups, the acetyl moiety bound to N-8 and the methoxycarbonyl
group bound to C-2, both of the spirane system (see Fig. 4). This
phenomenon was also observed for the proton bound to the C-2
of the cyclobutane in 17a, found at lower fields than the one corre-
cyclization of TSC to a
D
2-1,3,4-TDZ.
The separation of the diastereoisomeric products in the mixture
of 16 was accomplished by analytical HPLC using a chiral column.
Under these conditions, the two cis-diastereoisomers 16a and 16b,
which differed at the C-5 configuration, were isolated. The assign-
ment of the configuration at C-10 of 16 was made on the basis of
mono- and bi-dimensional NMR experiments, with the latter being
fundamental in establishing the unequivocal proton–carbon rela-
tionship. In addition, the NOESY spectra confirmed the identity of
cis-16a and cis-16b (Fig. 3). However, the C-5 configuration could
not be assigned.
sponding to 17b (
Dd 1.2 ppm).
The 1H chemical shifts were calculated with the B3LYP/6-31⁄⁄
G
optimized geometries of diastereoisomers 17a and 17b (Fig. 4) by
the GIAO method.11 A good correlation with the observed experi-
mental values was found (Table 1).
NHCOCH3
N
S
3. Conclusion
N
*
CH2OAc
5
1´
H3COC
Herein we have studied the stereoselectivity of the cyclization
procedure to obtain
D
2-1,3,4-TDZ compounds from the corre-
Figure 3. Structure of the cis diastereoisomers 16a and 16b.
sponding TSC precursors. While the TSC derived from methylcyc-
lobutyl ketones gave mixtures of heterocyclic derivatives, the TSC
of a cyclobutanone gave a main product, in accordance to those
previously described for other cycloalkanones, showing the influ-
ence of the steric hindrance during the ring closure process. We
have also reported spectroscopic and theoretical studies to confirm
our hypothesis regarding the influence of this effect on the ob-
served diastereoselectivity.
When the heterocyclization reaction was performed on 13, high
diastereoselectivity was observed, with stereoisomer 17a being
obtained as the main product. This was in accordance with the
behavior displayed by other TDZ derivatives obtained from verba-
none, camphor, and fenchone.4 After concentration of the mother
liquor, a relatively low amount of minor isomer 17b was isolated.
O
CH3C
O-
CH3
O
CH3
O
H
H
N
N
N
S
(CH3CO)2O/Py
N
N
N
NHCOCH3
R
NH2
R
NHCOCH3
R
S
S
R1
R1
R1
Scheme 4. The mechanism of reaction of TSC with acetic anhydride.

G. P. Sarmiento et al. / Tetrahedron: Asymmetry 22 (2011) 1924–1929
1927
H3COC
N
N
H2
H3
NHCOCH3
S
H3COOC
H3C
H3'
CH3
(2S,4R)-17a
17 a
NHCOCH3
N
H2
S
H3
N
H3COOC
H3C
H3'
CH3
COCH3
(2S,4S)-17b
17 b
Figure 4. Conformational minima obtained by theoretical calculations for epimers 17a and 17b.
lection strategy and data reduction followed standard procedures
implemented in the CrystAlisPro software.12 The structures were
solved using program SHELXS-9713 and refined using the full-ma-
trix LS procedure with SHELXL-97.13 Anisotropic displacement
parameters were employed for non-hydrogen atoms and H atoms
were treated isotropically with Uiso = 1.2 (for those attached to aro-
matic O and to N atoms) or 1.5 times (for those bonded to C atoms)
the Ueq of the parent atoms. All H atoms were located at the ex-
pected positions and they were refined using a riding model. In
the final cycle of refinement, LS weights of the form
Table 1
Chemical shifts found and calculated for H-2, H-3 and H-30for compounds 17a and
17b
H
17a Exp. d
17a Calcd d
17b Exp. d
17b Calcd d
(ppm)
(ppm)
(ppm)
(ppm)
H-2
H-3
H-30
3.78
3.34
2.90
4.02
3.40
3.17
2.60
4.80
2.45
2.89
5.46
2.46
2
4. Experimental
4.1. General
w ¼ 1=½r2ðF2Þ þ ða ꢁ PÞ þ b ꢁ Pꢂ, where P ¼ ½ðF2Þ þ 2 ꢁ F2Þꢂ=3, were
o
o
c
employed. Routines employed to create CIF files are from WinGX
package.14 Crystallographic data (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data Centre15
as supplementary publications N° CCDC 833332. Theoretical calcu-
lations were performed using B3LYP/6-31⁄⁄G level with the Gauss-
ian G03 program package.10 The GIAO method11 was used for the
simulation of 1H NMR spectra.
Melting points were measured in a Unimelt or in an Electrother-
mal IA 9000 apparatus. FT-IR spectra were recorded as a film from
chloroform with a Spectrum one FT-IR spectrometer Perkin–Elmer.
1H, 13C NMR spectra, heteronuclear correlation spectroscopy and
NOESY experiments were recorded in a Bruker 400-MHz or in a
Bruker 300-MHz spectrometers. Chemical shifts are expressed in
ppm (relative to the solvent). High resolution mass spectra (HRMS)
were determined in a VG AutoSPec (Micromass Inst.). Thin layer
chromatography (TLC) and preparative thin layer chromatography
were performed on Silica Gel GF254 (Merck). Optical rotations
were measured with Perkin–Elmer 141 polarimeter at 23 °C. Single
crystal X-ray diffraction data were collected at room temperature,
using a Gemini A diffractometer (Oxford Diffraction, UK). Data-col-
4.2. Procedures and analytical data
4.2.1. (1R,3S)-3-Butyldiphenylsilyloxymethyl-2,2-dimethyl-cycl
obutylmethylketone 8
A mixture of alcohol 56(1 mmol) and DMAP (3 mmol) in anhy-
drous methylene chloride (1 mL) was stirred under a nitrogen
atmosphere until complete dissolution at room temperature. The
solution was cooled at 0 °C and and tert-butyldiphenylsilylchloride

1928
G. P. Sarmiento et al. / Tetrahedron: Asymmetry 22 (2011) 1924–1929
(2 mmol) was added dropwise. The flask was sealed with a septum
and the reaction was left at room temperature with stirring under
a nitrogen atmosphere for 12 h. Then the mixture was diluted with
a mixture of methylene chloride and HCl 1% (5 mL). The organic
phase was separated, washed with water (2 ꢃ 10 mL), dried over
Na2SO4, and the solvent was removed until dryness. The compound
obtained was purified by preparative TLC (solvent Cl2CH2/hexane;
1:1) and the fraction with the higher Rf was eluted with Cl2CH2.
Product 7 was characterized by 1H NMR and used without further
purification in the next step. Compound 7 (1 mmol) was dissolved
in acetone (15 mL) and PPTS (0.33 mmol) was added. The mixture
was heated at reflux for 5 h. Then the solvent was removed and the
residue was diluted with diethyl ether (15 mL). The organic phase
was washed with NaHCO3 (saturated solution) and dried over
Na2SO4. The crude product obtained was purified by preparative
TLC eluting with hexane/chloroform (2:1). The fraction with the
higher Rf corresponded to compound 8 and was isolated as an oil
(yield 52%); IR mmax (cmꢀ1) (film) 2956, 1706 (C@O), 1427, 1112
(Si–O–C). 1H NMR (CDCl3) d 0.96 (s, 3H), 1.04 (s, 9H), 1.41 (s,
3H), 1.60–1.75 (m, 1H), 1.85 (dd, 1H, J = 7.4 Hz, J = 10.0 Hz), 2.04
(s, 3H), 2.20–2.30 (m, 1H), 2.83 (dd, 1H, J = 10.7 Hz, J = 21.5 Hz),
3.50–3.60 (m, 2H), 7.30 (m, 3H) and 7.65 (m, 1H) ppm. 13C NMR
(CDCl3) d 17.6, 19.8, 27.5 (three carbons), 30.8, 32.0, 44.0, 44.1,
50.2, 54.4, 64.8, 128.3 (two carbons), 130.3, 134.4, 136.2 (two car-
bons) and 208.7 ppm. HRMS: Calcd for C25H34NaO2Si 417.22203.
38.4, 38.8, 42.1, 42.9, 47.2, 48.5, 51.5 (two carbons), 83.3, 84.4,
142.7, 143.3, 168.1 (two carbons), 169.2, 169.6 and 173.4 (two car-
bons) ppm. HRMS: Calcd for C16H25N3O4S 355.15658. Found
355.15672.
4.2.6. [(1R,3S)-3-Methoxycarbonyl-2,2-dimethylcyclobut-1-yl]
methyl thiosemicarbazone 11
Compound 11 was obtained as a crystalline solid (yield 25%);
mp: 134.4–134.9 °C (ethanol); IR mmax (cmꢀ1) 3427, 3256, 3156
(NH and NH2), 1720 (C@O), 1583 (C@N), 1501 (C@S). 1H NMR
(DMSO-d6) d 0.70 (s, 3H), 1.30 (s, 3H), 1.80 (s, 3H), 1.70–1.80 (m,
1H), 2.45–2.65 (m, 1H), 2.70–2.90 (m, 2H), 3.60 (m, 3H), 7.51 (br
s, 1H), 8.15 (br s, 1H) and 9.95 (br s, 1H) ppm. 13C NMR (DMSO-
d6) d 17.3, 17.7, 19.9, 29.8, 40. 6, 44.2, 44.3, 51.1, 152.7 172.6 and
178.6 ppm. HRMS: Calcd for C11H19N3NaO2S 280.10902. Found
280.10996. ½a 2D3
¼ ꢀ45:0 (c 1.1, acetone).
ꢂ
4.2.7. (10R,3S0,5S)- and (10R,3S0,5R)-2-Acetamido-4-acetyl-5
-(30-methoxycarbonyl-20,20-dimethylcyclobutyl)-5-methyl-D2
-1,3,4-thiadiazoline 15
Compound 15 was obtained as an oil (yield 55%); IR m )
max (cmꢀ1
(as a mixture) 3171 and 3085 (N–H), 1734, 1713, and 1665 (C@O),
and 1621(C@N). 1H NMR (CDCl3) (as a mixture) d 0.95 (s, 3H), 1.02
(s, 3H), 1.10 (s, 3H), 1.20 (s, 3H), 1.80 (s, 3H), 1.86 (s, 3H), 1.95–2.00
(1H, m), 2.06 (s, 3H), 2.11 (s, 3H), 2.14 (s, 3H), 2.18–2.21 (m, 1H),
2.30–2.48 (m, 1H), 2.55–2.65 (m, 2H), 3.10–3.14 (m, 1H), 3.38–
3.42 (m, 1H) and 11.50 (br s, 2H) ppm. 13C NMR (CDCl3) (as a mix-
ture) d 16.9, 17.9, 21.0, 21.8, 23.0, 24.0, 24.2, 24.4, 27.1, 28.2, 31.2,
31.4, 44.4, 45.3, 45.5, 46.0, 46.4, 48.2, 51.3, 51.5, 82.0, 83.1, 144.0,
144.5, 169.4, 169.5, 169.6, 169.9, 172.8 and 173.2 ppm. HRMS:
Calcd for C15H23N3O4S 341.14093. Found 341.13907.
Found 417.22327. ½a D23
¼ ꢀ46:0 (c 0.5, chloroform).
ꢂ
4.2.2. Synthesis of thiosemicarbazones. General procedure
An ethanolic solution of ketone and thiosemicarbazide in equi-
molecular quantities was heated at reflux (for approximately 36 h)
and the reaction monitored by TLC. The corresponding thiosemi-
carbazones were isolated after evaporation of the solvent under re-
duced pressure. Thiosemicarbazones were purified by preparative
TLC (solvent: chloroform) or recrystallization as indicated for each
case.
4.2.8. [(1R,3S)-3-Hydroxymethyl-2,2-dimethylcyclobut-1-yl]
methyl thiosemicarbazone 12
Compound 12 was obtained as a crystalline solid (yield 60%);
mp 183.2–184.2 °C (ethanol). IR mmax (cmꢀ1) 3438, 3290, 3164
(NH and NH2), 1597 (C@N), and 1501 (C@S). 1H NMR (DMSO-d6)
d 0.78 (s, 3H), 1.23 (s, 3H), 1.60–1.70 (m, 1H), 1.81 (s, 3H), 1.90–
2.10 (m, 2H), 2.60–2.70 (m, 1H), 3.20–3.45 (m, 2H), 7.43 (s, 1H),
8.07 (s, 1H) and 9.89 (br s, 1H) ppm. 13C NMR (DMSO-d6) d 17.4,
22.1, 25.9, 31.9, 43.5, 44.7, 51.0, 63.4, 153.4, 172.4 ppm. HRMS:
4.2.3. Synthesis of thiadiazolines. General procedure
Thiosemicarbazones (0.25 mmol) were dissolved in a pyridine/
acetic anhydride mixture (1:1, 0.5 mL) and the mixtures were
heated with magnetic stirring at 110 °C for 1.5 h. Crude products
were purified by preparative TLC eluting with hexane/ethylace-
tate/chloroform (3.5:2.0:1.5) or by recrystallization as indicated
in each case.
Calcd
for
C
10H19N3OS:
229.12488.
Found
229.12441.
½ ꢂ
a 2D3
¼ ꢀ19:0 (c 0.4, acetone). Unit cell: a: 7.9523(3) Å, b:
9.2675(3) Å, c: 9.6965(3) Å,
a: 63.517(3)°, b: 83.499(3)°, c:
4.2.4. [(1R,3R)-3-Methylacetate-2,2-dimethylcyclobut-1-yl]
82.073(3)°, V: 632.43(4) Å3, number of collected reflections:
15070, Rint: 0.023, number of independent reflections: 3060, num-
methyl thiosemicarbazone 10
Compound 10 was obtained as an oil (yield 30%); IR
m
max (cmꢀ1
)
ber of reflection with I > 2r(I): 2064, number of parameters: 136,
(film) 3428, 3267, 2952 (NH and NH2), 1732 (C@O), 1591 (C@N),
and 1504 (C@S). 1H NMR (acetone-d6) d 0.75 (s, 3H), 1.25 (s, 3H),
1.80 (s, 3H), 1.90–2.05 (m, 2H), 2.15–2.35 (m, 3H), 2.65–2.70 (m,
1H), 3.65 (s, 3H), 6.55 (br s, 1H), 7.24 (br s, 1H) and 8.75 (br s, 1H)
ppm. 13C NMR (acetone-d6) d 17.7, 18.0, 25.7, 35.9, 39.4, 44.2, 50.6,
51.6, 52.1, 153.4, 174.1, 181.5 ppm. HRMS: Calcd for C12H22N3O2S
R1 (I > 2 (I)): 0.052, wR2 (all refl.): 0.166, S: 1.104.
r
4.2.9. (10R,30S,5S)- and (10R,30S,5R)-2-Acetamido-4-acetyl-5-(30-
acetoxymethyl-20,20-dimethylcyclobutyl)-5-methyl-
thiadiazoline 16
D
2-1,3,4-
Compound 16 was obtained as an oil (yield 32%). IR
m
max (cmꢀ1
)
272.14272. Found 272.14377. ½a D23
ꢂ
¼ ꢀ33:8 (c 0.3, acetone).
(as a mixture) 3170, 3084 (N–H), 1740, 1712, 1666, (C@0), and
1621 (C@N). Separation of 16a TDZ and 16b TDZ was performed
using HPLC (Waters 996 PDA HPL System) using methanol as a mo-
bile phase in an isocratic mode and with a chiral column CHIRA-
4.2.5. (10R,30R,5S)- and (10R,30R,5R)-2-Acetamido-4-acetyl-5-
(30-methylacetate-20,20-dimethylcyclobutyl)-5-methyl-D2
-1,3,4-thiadiazoline 14
DEX (MERCK) of 250 mm ꢃ 4.6 mm, with 5
lm of particle size.
Compound 14 was obtained as an oil (yield 62%); IR
m
max (cmꢀ1
)
Compound 16a 1H NMR (CDCl3) d 1.11 (s, 3H), 1.19 (s, 3H), 1.65
(m, 1H), 1.92 (s, 3H), 2.00–2.25 (m, 2H), 2.04 (s, 3H), 2.16 (s, 3H),
2.19 (s, 3H), 3.21 (dd, 1H, J = 8 Hz, J = 12 Hz), 4.00–4.15 (m, 2H),
8.00 (br s, 1H) ppm. 13C NMR (CDCl3) d 16.7, 21.7, 24.1, 24.8, 26.5,
29.3, 32.6, 41.4, 43.2, 49.0, 65.3, 82.3, 151.2, 170.0, 170.3, 171.7 ppm.
Compound 16b 1H NMR (CDCl3) d 1.11 (s, 3H), 1.21 (s, 3H),
1.75–1.95 (2H, m), 1.98 (s, 3H), 2.04 (s, 3H), 2.10–2.20 (1H, m),
2.16 (s, 3H), 2.19 (s, 3H), 3.50 (dd, 1H, J = 8 Hz, J = 12 Hz), 3.99
(film) (as a mixture) 3240, 3170, 3083 (NH and NH2), 1737, 1712,
1666, 1621 (C@O), 1504 (C@N). 1H NMR (CDCl3) (as a mixture) d
1.00 (s, 3H), 1.02 (s, 3H), 1.15 (s, 3H), 1.18 (s, 3H), 1.90 (s, 3H),
1.50–2.00 (m, 4H), 2.00 (s, 3H), 2.10–2.50 (m, 6H), 2.15 (s, 6H),
2.20 (s, 6H), 3.14 (m, 1H), 3.45 (m, 1H), 3.65 (s, 6H) and 8.30 (br
s, 2H) ppm. 13C NMR (CDCl3) d 16.2, 17.3, 23.4 (two carbons),
24.2, 24.6, 26.7, 27.3, 28.6, 28.9, 31.0, 31.2, 34.7 (two carbons),

G. P. Sarmiento et al. / Tetrahedron: Asymmetry 22 (2011) 1924–1929
1929
(dd, 1H, J = 8 Hz, J = 10 Hz), 4.09 (dd, 1H, J = 6 Hz, J = 8HZ), 7.98 (br
s, 1H) ppm. 13C NMR (CDCl3) d 17.7, 21.7, 24.1 (two carbons), 25.3,
28.1, 32.4, 41.0, 42.4, 47.5, 65.3, 85.0, 145.9, 170.0, 170.3,
authors thank PhD Liliana Finkielsztein, Lic. Juan Caturelli and
Pharm. Beatriz Brousse for their collaboration in the preparation
of some compounds.
171.7 ppm. HRMS (as
a mixture): Calcd for C16H25N3O4S:
355.15668. Found 355.15662.
References
4.2.10. (3S)-3-Methoxycarbonyl-2,2-dimethylcyclobutanone
thiosemicarbazone 13
1. (a) Kirkland, P. D.; Frost, M. J.; Finlaison, D. S.; King, K. R.; Ridpath, J. F.; Gu, X.
Virol. Res. 2007, 129, 126; (b) Yusuf, M.; Jain, P. Arab. J. Chem. 2011. doi:10.1016/
j.arabjc.2011.02.006; (c) Fatondji, H. R.; Gbaguidi, F.; Kpoviessi, S.; Bero, J.;
Hannaert, V.; Quetin-Leclercq, J.; Poupaert, J.; Moudachirou, M.; Accrombessi,
G. C. Afr. J. Pure Appl. Chem. 2011, 5, 59.
Compound 13 was obtained as a crystalline solid (yield 75%);
mp: 223.4–224.2 °C (ethanol); IR mmax (cmꢀ1) 3408, 3247, 3149
(NH and NH2), 1718 (C@O), 1600 (C@N), 1525 (C@S). 1H NMR
(DMSO-d6) d 1.04 (s, 3H), 1.29 (s, 3H), 2.90–3.00 (m, 1H), 3.05–
3.15 (m, 2H), 3.64 (s, 3H), 7.41 (s, 1H), 7.97 (s, 1H) and 10.48 (s,
1H) ppm. 13C NMR (DMSO-d6) d 21.0, 25.6, 31.8, 42.5, 51.1, 51.6,
158.6, 172.4 and 178.2 ppm. HRMS: Calcd for C9H16N3O2S
2. Kubota, S.; Ueda, Y.; Fujikane, K.; Toyooka, K.; Shibuya, M. J. Org. Chem. 1980,
45, 1473.
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´
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Asymmetry 2003, 14, 193.
230.09577. Found 230.09660. ½a D23
¼ ꢀ16:0 (c 0.9, acetone).
ꢂ
4.2.11. (1,1-Dimethyl-2-methoxycarbonyl-6-N-acetyl-8-
acetyl)spiro[3,4]-5-tia-7,8-diazaocta-6-eno 17
4.2.11.1. (2S,4R)-17a TDZ. Major product was obtained as a crys-
talline solid (yield 60%); mp: 157.5–158.8 °C (acetone); IR mmax
(cmꢀ1) (as a mixture) 3433 (N–H), 1733 (C@O), 1669 (C@O),
1636 (C@O) and 1615 (C@N). 1H NMR (CDCl3) d 1.08 (s, 3H), 1.15
(s, 3H), 2.19 (s, 3H), 2.26 (s, 3H), 2.80–3.00 (dd, 1H, J = 8 Hz,
J = 15 Hz), 3.30–3.40 (dd, 1H, J = 8 Hz, J = 15 Hz), 3.68 (s, 3H), 3.80
(t, 1H, J = 8 Hz) and 8.50 (br s, 1H) ppm. 13C NMR (CDCl3) d 23.6,
23.9, 24.8, 25.0, 30.9, 45.7, 52.1, 53.0, 83.9, 145.1, 169.2, 171.0
9. Somogyi, L. Tetrahedron 1991, 47, 9305.
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Cheeseman, J. R.; Montgomery, J. A. Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Lyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, L.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmam, R. E.; Yazyev, O.; Austin, A.
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Foresman, J. B.; Ortiz, L. V.; Cu, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, L.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe,
M.; Gili, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Popie, J. A.
Gaussian 03, Revision C.02, Gaussian, Inc.: Wallingfbrd CT, 2004.
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13. Sheldrick, G. M. Acta Cryst. A. 2008, 64, 112.
and 173.9 ppm. ½a D23
¼ þ4:5 (c 0.7, acetone). HRMS: Calcd for
ꢂ
C
13H20N3O4S: 314.11690. Found 314.11700.
4.2.11.2. (2S,4S)-17b TDZ. Minor product was obtained as an oil
(yield 1%). 1H NMR (CDCl3) d 1.23 (s, 3H), 1.30 (s, 3H), 2.20 (s,
3H), 2.23 (s, 3H), 2.50–2.70 (m, 2H), 3.71 (s, 3H), 4.79 (dd, 1H,
J = 8 Hz, J = 12 Hz) and 8.60 (br s, 1H) ppm. 13C NMR (CDCl3) d
20.7, 24.1, 24.8, 26.8, 31.8, 44.3, 52.3, 55.5, 82.7, 146.5, 168.9,
172.2 and 172.5 ppm.
Acknowledgments
14. Farrugia, L. J. J. Appl. Cryst. 1999, 32, 837.
15. Allen, F. H. Acta Cryst. B 2002, 58, 380.
The authors thank the financial support of the SECYT-Universi-
dad de Buenos Aires, Fundación Antorchas and CONICET. The