SO2-extrusion reactions of sulfonylated nucleosides: A novel strategy for the synthesis of exocyclic olefinic thymidines

Article abstract of DOI:10.1055/s-2008-1078265

Analogues of 3′-C-methylidene-2′,3′-dideoxy-5- methyluridine have been synthesized from the 3′-deoxy-3′- sulfonylated derivatives of thymidine using sulfur dioxide extrusion reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078265

LETTER
2263
SO2-Extrusion Reactions of Sulfonylated Nucleosides: A Novel Strategy for the
Synthesis of Exocyclic Olefinic Thymidines
Olefinic Thymi
a
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Fax +91(3222)282252; E-mail: tpathak@chem.iitkgp.ernet.in
Received 14 May 2008
reactions for C–C bond formation as this strategy has
Abstract: Analogues of 3¢-C-methylidene-2¢,3¢-dideoxy-5-meth-
yluridine have been synthesized from the 3¢-deoxy-3¢-sulfonylated
derivatives of thymidine using sulfur dioxide extrusion reaction.
turned out to be one of the useful methods for the creation
of double bonds in organic molecules.9 Therefore, the
easy availability of various 3¢-S-sulfonylated thy-
midines10 from naturally occurring thymidine in high
overall yields prompted us to look into the possibility of
using SO2-extrusion reaction for the synthesis of a series
of exo-olefinic thymidines. A perusal of the literature re-
vealed that in most of the reports S-glycoside dioxides
were used as substrates for the synthesis of exo-glycals via
SO2-extrusion reaction.9b It was not clear whether Ram-
berg–Bäcklund reaction would be equally efficient with
nonanomeric sulfones derived from carbohydrates.
Therefore, in order to standardize the reaction conditions,
we selected two easily accessible pyranosyl sulfones 6
and 7 as model compounds (Scheme 1).
Key words: nucleosides, sulfones, olefination, antiviral agents,
carbohydrates
The selective reverse transcriptase inhibitory properties of
the unsaturated nucleoside, 2¢,3¢-didehydro-2¢,3¢-dide-
oxythymidine (d4T, stavudine), have triggered the design-
ing of a plethora of unsaturated furanosyl nucleosides
having variations at either or both of the 2¢- and 3¢-posi-
tions.1 Nucleosides with exocyclic methylene groups
show antiviral as well as antitumor properties.2 These
compounds can also be used as intermediates for the syn-
thesis of various sugar ring modified nucleosides and the
corresponding oligomers.3
R1
TsO
HO
HO
O
O
HO
1
R2O
a
c
Although Wittig reaction is one of the most efficient pro-
cedures for the conversion of a keto compound to the cor-
responding methylene analogues,4 treatment of the 2¢-
deoxy-3¢-keto-nucleosides with the Wittig reagent, meth-
ylenetriphenyl phosphorane, failed to afford 3¢-methylene
R2O
R2O
OMe
OMe
2 R1 = SBn; R2 = H
3 R1 = SBn; R2 = Bn
4 R1 = Si-Pr; R2 = H
5 R1 = Si-Pr; R2 = Bn
X
b
b
5
derivatives.5 Only reagents like Zn/CH2Br2/TiCl4 or Zn/
[(Me2N)3PCF2Br]Br6 were effective in generating the
exocyclic methylene and the corresponding difluoro de-
rivatives. A lengthy synthesis starting from 3-methyl-2-
butenal produced an anomeric mixture of the exo-methyl-
ene nucleosides.2b Although 3¢-C-methylidene-2¢,3¢-di-
deoxy-5-methyluridine has been prepared from 2-deoxy-
D-ribose, the method was also found to be quite ineffi-
cient.7 It is abundantly clear from the literature that there
is a serious problem in converting the naturally occurring
nucleosides into 2¢,3¢-dideoxy-3¢-methylidene analogues
or to any related derivatives. In spite of the extensive stud-
ies on the chemistry and biology of unsaturated nucleo-
sides,1 virtually nothing is reported on the synthesis of
nucleosides with substituted exocyclic double bonds at
the 3¢-site.
R1
Y
O
BnO
d
O
BnO
BnO
BnO
BnO
BnO
OMe
OMe
6 R1 = SO2Bn
7 R1 = SO2i-Pr
8 X = Ph; Y = H
9 X = Y = Me (not formed)
Scheme 1 Reagents and conditions: (a) benzylthiol or isopropylthi-
ol, NaOMe, DMF, 5 h, 90 °C; (b) benzyl bromide, NaH, DMF, 3 h,
r.t.; (for 3, yield 81%, in two steps; for 5, yield 53%, in two steps); (c)
MMPP, MeOH, 6 h, r.t.; (for 6, yield 97%; for 7, yield 85%); (d)
CBr2F2, CH2Cl2, t-BuOH, KOH/Al2O3, 0 °C to r.t., 1 h, 71%.
The first step for the synthesis of these sulfones was the
treatment of the 6-O-tosylated glucopyranoside 1 with
benzylthiol and isopropylthiol to obtain the 6-deoxy-6-
thio analogues 2 and 4, which were isolated as the triben-
zyl derivatives 3 and 5, respectively. Compounds 3 and 5
were oxidized with magnesium monoperoxyphthalate
hexahydrate (MMPP) in high yields to the corresponding
sulfones 6 and 7, respectively. When compound 6 was
treated under modified Ramberg–Bäcklund conditions
[CBr2F2, KOH/Al2O3, CH2Cl2–t-BuOH (1:1), 0 °C to r.t.]11
for one hour, compound 8 was formed in good yield in se-
lectively trans form which was confirmed from the cou-
pling-constant values of the olefinic protons.12 However,
Our research in the area of sulfonylated carbohydrates8
prompted us to look for strategies for the removal of SO2
from sulfonylated carbohydrates. Although we were suc-
cessful in removing the aryl sulfone groups under reduc-
tive conditions,8 we wanted to apply SO2-extrusion
SYNLETT 2008, No. 15, pp 2263–2266
1
5
.0
9
.2
0
0
8
Advanced online publication: 21.08.2008
DOI: 10.1055/s-2008-1078265; Art ID: G15608ST
© Georg Thieme Verlag Stuttgart · New York

2264
T. K. Pal, T. Pathak
LETTER
Table 1 Synthesis of 3¢-C-Methylidene-2¢,3¢-dideoxy-5-methyluri-
the isopropyl derivative 7 under similar reaction condi-
tions, did not afford any olefinic compound; the starting
material was recovered from the reaction mixture
(Scheme 1). It was clear from this set of preliminary ex-
periments that the benzyl sulfone analogue 6 was a better
substrate than isopropyl sulfone 7 in Ramberg–Bäcklund
reaction.11
dine and Its Analoguesa
Starting material
Product
O
N
O
NH
NH
O
O
O
O
TrO
H
With the above information in hand we set out to imple-
ment the reaction conditions on various sulfones derived
from thymidine. Thus, the easily available mesylated thy-
midine 10 was treated with a series of alkyl thiols under
basic conditions to generate the sulfides 11a–d which
were oxidized with MMPP to afford the sulfones 12a–d in
high yields (Scheme 2).13 Compounds 12a–d were treated
under modified Ramberg–Bäcklund conditions for longer
duration (5 h).
O
N
TrO
O
O
SO2Me
H
12a
13 (31%)
O
O
NH
NH
N
O
TrO
O
N
O
TrO
TrO
TrO
O
O
O
SO2Et
NH
NH
NH
Me
12b
14 (35%, 5:3)
O
O
N
N
N
O
TrO
TrO
TrO
O
O
O
O
O
OMs
a
b
NH
NH
O
SR
SO2R
12a R = Me13
10
N
TrO
Me
N
O
11a R = Me13
O
12b R = Et (93%)
12c R = i-Pr (94%)
12d R = Bn (94%)
11b R = Et (73%)
11c R = i-Pr (61%)
11d R = Bn (75%)
SO2i-PR
Me
12c
15 (34%)
Scheme 2 Reagents and conditions: (a) alkylmercaptan, NaOMe,
DMF, 5 h, 120–140 °C; (b) MMPP, MeOH, 6 h, r.t.
O
O
NH
NH
Interestingly and in contrary to the observation reported in
Scheme 1, the methyl sulfone derivative 12a, ethyl sul-
fone derivative 12b, and the isopropyl derivative 12c were
all converted to the corresponding olefinic compounds 13
(31%),14 14 (35%),15 and 15 (34%),16 respectively
(Table 1). Compound 14 was formed as a mixture in 5:3
ratios. The benzyl derivative 12d, however, produced a
single isomer 16 in 47% yield.17 In this case also the ben-
zyl sulfone 12d was a better substrate than other alkyl sul-
fones 12a–c for SO2-extrusion reaction as evident by
shorter reaction time and better yield of the product. We
opined that the strongly basic reaction conditions were re-
sponsible for the competitive elimination of the nucleo-
base thymine,5b resulting into the moderate yields of the
desired products. However, at this stage the relationship
between the structures of substrates and the efficiency of
SO2-extrusion reaction could not be established. It was
also not possible to improve the yields of the olefinic nu-
cleosides by varying temperature, reagent ratio or reaction
time.
N
O
TrO
O
N
O
SO2Bn
Ph
12d
16 (47%)
a Reaction conditions: CBr2F2, KOH/Al2O3, CH2Cl2–t-BuOH (1:1),
1–5 h.
O
NH
a
O
N
HO
16
O
17
Scheme 3 Reagents and conditions: (a) 10% Pd/C, HCOONH4,
MeOH, H2, 35%.
the less hindered a-face of the sugar ring yielding 17. As
far as we know this is the first report on the synthesis of a
nucleoside carrying a benzyl group at the 3¢-carbon and
accordingly it may be considered as a new analogue of the
anti-HIV drug AZT.20 Interestingly, a computer-assisted
molecular design program identified 3¢-benzyl-3¢-deoxy-
thymidine as a potentially active anti-AIDS compound.21
Compound 16 underwent smooth reduction of the double
bond with concomitant detritylation to produce a new
branched-chain nucleoside 17 in moderate overall yield
(Scheme 3).18,19 Since the b-face of the olefin 16 was
blocked by 5¢CH2OR (R1 = Tr or H) group and thymine
residue, it was expected that the delivery of hydrogen
would preferentially, if not exclusively take place from
Synlett 2008, No. 15, 2263–2266 © Thieme Stuttgart · New York

LETTER
Olefinic Thymidines
2265
(9) For reviews, see: (a) Taylor, R. J. K. Chem. Commun. 1999,
217. (b) Taylor, R. J. K.; McAllister, G. D.; Franck, R. W.
Carbohydr. Res. 2006, 341, 1298.
(10) (a) Bera, S.; Sakthivel, K.; Langley, G. J.; Pathak, T.
Tetrahedron 1995, 51, 7857. (b) Bera, S.; Langley, G. J.;
Pathak, T. J. Org. Chem. 1998, 63, 1754. (c) Bera, S.;
Pathak, T. Synlett 2004, 2147.
(11) Tze-Lock, C.; Sun, F.; Yu, L.; Tim-On, M.; Chi-Duen, P.
J. Chem. Soc., Chem. Commun. 1994, 1771.
(12) Synthesis of Compound 8
In summary we reported the synthesis of a new series of
3¢-exo-methylene nucleosides using Ramberg–Bäcklund
SO2-extrusion reactions from easily accessible 3¢-sulfide
analogues of thymidine. Notwithstanding the less than
moderate yields of the olefinic nucleosides, this paper re-
ports for the first time the most difficultly accessible and
hitherto unreported olefinic thymidines 14–16, and the
benzyl derivative 17. Synthesis of other exocyclic meth-
ylidene nucleosides using this strategy and the biological
screening of some of these compounds are currently under
way.
Dibromodifluoromethane (1 mL) was dropwise added to a
vigorously stirred mixture of the sulfone 6 (0.2 g, 0.33
mmol), alumina-supported KOH (2 g),11 t-BuOH (10 mL)
and CH2Cl2 (10 mL) kept at 0 °C. The reaction mixture was
stirred at r.t. for an additional 1 h after which the solid
catalyst was removed by suction filtration through a Celite
bed. The filtrate was evaporated to dryness. The filter cake
was washed thoroughly with CH2Cl2 and the washes were
combined with the residue from the first filtrate. The
resultant organic solution was washed with brine and H2O,
dried, and evaporated. The residue was purified on silica gel
to obtain compound 8 (0.127 g, 71%); EtOAc–PE (1:4) as
eluent; white solid; mp 96 °C; [a]D29.2 +44.9 (c 0.13, CHCl3).
1H NMR (400 MHz, CDCl3): d = 3.33 (t, J = 9.6 Hz, 1 H),
3.41 (s, 3 H), 3.56–3.59 (m, 1 H), 4.04 (t, J = 9.2 Hz, 1 H),
4.23–4.27 (m, 1 H), 4.59–4.63 (m, 2 H), 4.69 (d, J = 12.0 Hz,
1 H), 4.76–4.88 (m, 3 H), 4.98 (d, J = 10.8 Hz, 1 H), 6.16
(dd, J = 5.4, 16.0 Hz, 1 H), 6.71 (d, J = 16.0 Hz, 1 H), 7.23–
7.44 (m, 20 H). 13C NMR (100 MHz, CDCl3): d = 55.3, 71.4,
73.4 (CH2), 75.2 (CH2), 75.9 (CH2), 79.8, 81.7, 82.2, 98.2,
126.3, 126.5, 127.6, 127.7, 127.8, 127.9, 128.0, 128.1,
128.2, 128.3, 128.4, 128.5, 128.6, 133.2, 136.5, 137.9,
138.2, 138.7. HRMS (ES+): m/z calcd for C35H36O5Na:
559.2460 [M + Na+]; found: 559.2454.
Acknowledgment
T.K.P thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi, India for a fellowship. Financial support by the
Department of Science and Technology (DST), New Delhi, India is
gratefully acknowledged.
References and Notes
(1) Len, C.; Mackenzie, G. Tetrahedron 2006, 62, 9085.
(2) (a) Fedorov, I. I.; Kazmina, E. M.; Novicov, N. A.;
Gurskaya, G. V.; Bochkarev, A. V.; Jasko, M. V.; Viktorova,
L. S.; Kukhanova, M. K.; Balzarini, J.; De Clercq, E.;
Krayevsky, A. A. J. Med. Chem. 1992, 35, 4567.
(b) Riehokainen, E.; Mikerin, I. E.; Slobodyan, N. N.;
Tulebaev, M. B.; Severin, S. E. Carbohydr. Res. 1999, 320,
161. (c) Yoo, S. J.; Kim, H. O.; Lim, Y.; Kim, J.; Jeong,
L. S. Bioorg. Med. Chem. 2002, 10, 215.
(3) (a) Joergensen, P. N.; Stein, P. C.; Wengel, J. J. Am. Chem.
Soc. 1994, 116, 2231. (b) Wengel, J.; Schinazi, R. F.;
Caruthers, M. H. Bioorg. Med. Chem. 1995, 3, 1223.
(c) Mikhailopulo, I. A.; Poopeiko, N. E.; Tsvetkova, T. M.;
Marochkin, A. P.; Balzarini, J.; De Clercq, E. Carbohydr.
Res. 1996, 285, 17. (d) Winqvist, A.; Stromberg, R. Eur. J.
Org. Chem. 2001, 4305. (e) Obika, S.; Osaki, T.; Sekiguchi,
M.; Somjing, R.; Harada, Y.; Imanishi, T. Tetrahedron Lett.
2004, 45, 4801. (f) Obika, S.; Sekiguchi, M.; Somjing, R.;
Imanishi, T. Angew. Chem. Int. Ed. 2005, 44, 1944.
(g) Osaki, T.; Obika, S.; Harada, Y.; Mitsuoka, Y.; Sugaya,
K.; Sekiguchi, M.; Roongjang, S.; Imanishi, T. Tetrahedron
2007, 63, 8977.
(13) Compounds 11a and 12a are reported in the literature, see:
(a) Mansuri, M. M.; Wos, J. A.; Martin, J. C. Nucleosides
Nucleotides 1989, 8, 1463. (b) Herdewijn, P.; De Bruyn, A.;
Wigerinck, P.; Hendrix, C.; Kerremans, L.; Rozenski, J.;
Busson, R. J. Chem. Soc., Perkin Trans. 1 1994, 249.
(14) Compound 12a (0.2 g, 0.37 mmol) was converted into
compound 13 (0.055 g, 31%) following the procedure
described for the synthesis of compound 8.
(15) Compound 12b (0.2 g, 0.35 mmol) was converted into 14
(0.062 g, 35%) following the procedure described for the
synthesis of compound 8.
(16) Compound 11c
(4) Zhdanov, Y. A.; Alekseev, Y. E.; Alekseeva, V. G. Adv.
Carbohydr. Chem. 1972, 27, 227.
White solid; mp 78 °C. 1H NMR (400 MHz, CDCl3): d =
1.15 (d, J = 6.8 Hz, 3 H), 1.24 (d, J = 6.6 Hz, 3 H), 1.43 (d,
J = 1 Hz, 3 H), 2.39–2.56 (m, 2 H), 2.73–2.86 (m, 1 H), 3.35
(dd, J = 3.6, 10.8 Hz, 1 H), 3.57–3.69 (m, 2 H), 3.89–3.96
(m, 1 H), 6.15 (dd, J = 3.6, 6.6 Hz, 1 H), 7.23–7.37 (m, 9 H),
7.41–7.46 (m, 6 H), 7.81 (d, J = 1.2 Hz, 1 H), 8.51 (br s, 1
H). 13C NMR (100 MHz, CDCl3): d = 11.9, 23.4, 24.0, 35.4,
39.2, 41.6 (CH2), 61.8 (CH2), 84.9, 85.8, 87.1, 110.6, 127.4,
127.9, 128.6, 135.5, 143.2, 150.2, 164.4. HRMS (ES+): m/z
calcd for C32H34N2O4SNa: 565.2137 [M + Na]+; found:
565.2112.
(5) (a) Matsuda, A.; Okajima, H.; Ueda, T. Heterocycles 1989,
29, 25. (b) Sharma, M.; Bobek, M. Tetrahedron Lett. 1990,
31, 5839. (c) Svendsen, M. L.; Wengel, J.; Dahl, O.;
Kirpekar, F.; Roepstorff, P. Tetrahedron 1993, 49, 11341.
(d) Prasad, C. V. C.; Caulfield, T. J.; Prouty, C. P.; Saha,
A. K.; Schairer, W. C.; Yawman, A.; Upson, D. A.; Kruse,
L. I. Bioorg. Med. Chem. Lett. 1995, 5, 411. (e) Wengel, J.;
Svendsen, M. L.; Joergensen, P. N.; Nielsen, C. Nucleosides
Nucleotides 1995, 14, 1465. (f) Jorgensen, P. N.; Svendsen,
M. L.; Nielsen, C.; Wengel, J. Nucleosides Nucleotides
1995, 14, 921.
(6) Serafinowski, P. J.; Barnes, C. L. Synthesis 1997, 225.
(7) Reactions of 1-(5¢-O-benzoyl-3¢-C-methyl-2¢-deoxy-b-D-
threo-pentofuranosy1)thymine with SOCl2 produced 3¢-C-
methylidene-2¢,3¢dideoxy-5methyluridine in 11% yield.2a
(8) For reviews on the formation of a wide range of products
from vinyl sulfone modified carbohydrates, see: (a) Pathak,
T. Tetrahedron 2008, 64, 3605. (b) Pathak, T.;
Compound 12c
White solid; mp 102 °C. 1H NMR (400 MHz, CDCl3): d =
1.25 (d, J = 6.8 Hz, 3 H), 1.31 (d, J = 6.8 Hz, 3 H), 1.53 (s,
3 H), 2.39–2.54 (m, 1 H), 2.90–3.06 (m, 2 H), 3.34 (dd,
J = 2.6, 10.9 Hz, 1 H), 3.74 (dd, J = 2.2, 10.9 Hz, 1 H), 4.02–
4.09 (m, 1 H), 4.61–4.64 (m, 1 H), 6.24 (t, J = 6.4 Hz, 1 H),
7.14–7.47 (m, 15 H), 7.63 (s, 1 H), 8.63 (s, 1 H). 13C NMR
(100 MHz, CDCl3): d = 11.9, 15.0, 15.1, 33.8 (CH2), 52.4,
56.3, 63.5 (CH2), 78.1, 85.3, 87.4, 111.4, 127.5, 128.1,
128.4, 135.2, 142.9, 149.8, 163.4. HRMS (ES+): m/z calcd
Bhattacharya, R. Carbohydr. Res. 2008, 343, 1980.
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T. K. Pal, T. Pathak
LETTER
66.5 (CH2), 82.2, 84.5, 87.2 (C), 111.3 (C), 123.5,127.3,
127.4, 127.9, 128.3, 128.5, 128.6, 135.6, 136.3, 136.8,
143.4, 150.5, 164.1. HRMS (ES+): m/z calcd for
C36H32N2O4Na: 579.2260 [M + Na]+; found: 579.2247.
for C32H34N2O6SNa: 597.2035 [M + Na]+; found: 597.2027.
Compound 15
Compound 12c (0.2 g, 0.34 mmol) was converted into
compound 15 (0.06 g, 34%) following the procedure
described for the synthesis of compound 8. Glassy liquid. 1H
NMR (400 MHz, CDCl3): d = 1.33 (s, 3 H), 1.55 (d, J = 1.3
Hz, 3 H), 1.84 (s, 3 H), 2.77–2.81 (m, 1 H), 3.15–3.23 (m, 2
H), 3.37–3.44 (m, 1 H), 4.73 (br s, 1 H), 6.16 (dd, J = 5.8, 8.7
Hz, 1 H), 7.20–7.34 (m, 9 H), 7.39–7.47 (m, 6 H), 7.86 (d,
J = 0.9 Hz, 1 H), 8.88 (br s, 1 H). 13C NMR (100 MHz,
CDCl3): d = 11.6, 19.9, 22.0, 37.0 (CH2), 65.7 (CH2), 79.6,
84.2, 87.2, 110.9, 126.4, 127.2, 127.9, 128.4, 128.6, 136.2,
143.5, 150.4, 163.9. HRMS (ES+): m/z calcd for
(18) Compound 17
A mixture of compound 16 (0.05 g, 0.09 mmol), 10% Pd/C
(0.01 g) and ammonium formate (catalytic amount) in
MeOH (15 mL) was heated under reflux under H2
atmosphere. After 1 h, the reaction mixture was brought to
r.t. The suspension was filtered through a Celite bed, and the
bed was washed with MeOH. The filtrate was evaporated
under vacuum to afford a thick viscous liquid. The residue
was dissolved in H2O, and the water layer was washed with
CHCl3. The CHCl3 layers were pooled together, dried over
anhyd Na2SO4, filtered, and the filtrate was evaporated to
dryness. The residue was purified over silica gel to afford
compound 17 (0.01 g, 35%). Glassy liquid. 1H NMR (400
MHz, CDCl3): d = 1.93 (s, 3 H, CH3), 1.97–2.05 (m, 1 H, H-
2¢¢), 2.14–2.20 (m, 1 H, H-2¢), 2.42 (br s, 1 H, OH), 2.80–
2.88 (m, 2 H, H-3¢, one of benzyl CH2), 2.91–3.00 (m, 1 H,
one of benzyl CH2), 3.82–3.85 (m, 1 H, H-5¢¢), 3.95–3.98 (m,
1 H, H-5¢), 4.21–4.23 (m, 1 H, H-4¢), 5.98 (dd, J = 5.2, 8.8
Hz, 1 H, H-1¢), 7.17–7.23 (m, 3 H, arom.), 7.26–7.31 (m, 2
H, arom.), 7.65 (s, 1 H, H-6), 8.58 (br s, 1 H, NH). 13C NMR
(100 MHz, CDCl3): d = 12.6 (CH3), 34.9 (benzyl CH2), 36.6
(C-2¢), 42.0 (C-2¢), 63.1 (C-5¢), 80.8 (C-4¢), 86.1 (C-1¢),
110.8 (C), 126.4 (arom.), 128.4 (arom.), 128.6 (arom.),
136.6 (C-6), 139.7 (C), 150.4 (CO), 164.4 (CO). HRMS
(ES+): m/z calcd for C17H21N2O4: 317.1501 [M + Na]+;
found: 317.1510.
C32H32N2O4Na: 531.2260 [M + Na]+; found: 531.2237.
(17) Compound 11d
White solid; mp 82 °C. 1H NMR (400 MHz, CDCl3): d =
1.39 (s, 3 H), 2.38–2.45 (m, 2 H), 3.28–3.34 (m, 1 H), 3.48–
3.56 (m, 2 H), 3.67–3.68 (m, 2 H), 3.93–3.96 (m, 1 H), 6.17
(t, J = 6.4 Hz, 1 H), 7.16–7.43 (m, 20 H), 7.63 (s, 1 H), 8.59
(s, 1 H). 13C NMR (100 MHz, CDCl3): d = 11.8, 36.1 (CH2),
40.3, 40.5 (CH2), 62.2 (CH2), 84.7, 84.9, 87.2, 110.7, 127.3,
127.9, 128.7, 135.4, 137.3, 143.2, 150.2, 163.8. HRMS
(ES+): m/z calcd for C36H34N2O4SNa: 613.2137 [M + Na]+;
found: 613.2134.
Compound 12d
White solid; mp 106 °C. 1H NMR (400 MHz, CDCl3): d =
1.34 (s, 3 H), 2.30–2.40 (m, 1 H), 2.86–2.96 (m, 1 H), 3.27
(dd, J = 2.2, 10.8 Hz, 1 H), 3.55–3.60 (m, 1 H), 3.85–3.95
(m, 1 H), 4.21 (s, 2 H), 4.57–4.60 (m, 1 H), 6.24 (t, J = 6.6
Hz, 1 H), 7.11–7.49 (m, 20 H), 7.57 (s, 1 H), 8.65 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 11.8, 34.2 (CH2), 57.6,
59.0 (CH2), 63.5 (CH2), 77.2, 84.9, 87.3, 111.4, 127.2, 127.4,
128.0, 128.4, 129.2, 129.3, 130.5, 135.1, 142.9, 150.3,
164.6. HRMS (ES+): m/z calcd for C36H34N2O6SNa:
645.2035 [M + Na]+; 645.2025.
(19) The stereochemistry at C-3¢ of 17 was confirmed from
NOESY experiments. Thus, NOESY correlations were
observed between H-3¢ (d = 2.80–2.88) and H-4¢ (d = 4.21–
4.23), but no correlation was observed for H-3¢ (d = 2.80–
2.88) and H-5¢ (d = 3.95–3.98)/H-5¢¢ (d = 3.82–3.85),
suggesting H-3¢ and H-4¢ were in cis relationship and H-3¢
was away from H-5¢, H-5¢¢. This observation was further
supported by NOESY correlation between benzyl CH2
protons (d = 2.80–2.88 and d = 2.91–3.00) and H-5¢¢ (d =
3.82–3.85).
Compound 16
Compound 12d (0.2 g, 0.32 mmol) was converted into
compound 16 (0.085 g, 47%) following the procedure
described for the synthesis of compound 8. White solid; mp
78 °C. 1H NMR (400 MHz, CDCl3): d = 1.44 (s, 3 H), 3.04–
3.08 (m, 1 H), 3.44–3.49 (m, 3 H), 4.78 (br s, 1 H), 6.29 (t,
J = 7.2 Hz, 1 H), 6.37 (s, 1 H), 7.22–7.31 (m, 12 H), 7.37–
7.41 (m, 2 H), 7.44–7.46 (m, 6 H), 7.72 (s, 1 H), 8.13 (br s,
1 H). 13C NMR (100 MHz, CDCl3): d = 11.8, 37.4 (CH2),
(20) Pathak, T. Chem. Rev. 2002, 102, 1623.
(21) Contreras, M. L.; Gonzalez, F. D.; Munoz, V. C.; Rozas, R.
Bol. Soc. Chil. Quim. 1995, 40, 279; Chem. Abstr. 1995, 123,
305993.
Synlett 2008, No. 15, 2263–2266 © Thieme Stuttgart · New York

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