An easy access to spiroannulated glyco-oxetane, -thietane and -azetane rings: synthesis of spironucleosides

Article abstract of DOI:10.1016/j.tetlet.2006.03.175

The key intermediate 11 derived from d-glucose and possessing bis-mesylmethyl (MsO·CH₂-) functionality at C-4, was used to generate spirocycles 12, 13 and 15 via one-step procedures. The spirocompounds 12 and 13 were subsequently converted into

Full text of DOI:10.1016/j.tetlet.2006.03.175

Tetrahedron Letters 47 (2006) 3875–3879
An easy access to spiroannulated glyco-oxetane, -thietane
and -azetane rings: synthesis of spironucleosides
Ashim Roy, Basudeb Achari and Sukhendu B. Mandal*
Department of Chemistry, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700 032, India
Received 10 February 2006; revised 20 March 2006; accepted 29 March 2006
Available online 27 April 2006
Abstract—The key intermediate 11 derived from D-glucose and possessing bis-mesylmethyl (MsOÆCH2–) functionality at C-4, was
used to generate spirocycles 12, 13 and 15 via one-step procedures. The spirocompounds 12 and 13 were subsequently converted into
the corresponding spironucleosides 24 and 26 in good yield using Vorbruggen reaction conditions.
¨
ꢀ 2006 Elsevier Ltd. All rights reserved.
The synthesis of structurally modified nucleosides has
been emerging as an important area of research because
some members show biological activities of medicinal
interest.1 Prominent among these are the spirocyclic
nucleosides, which started to draw the attention of
synthetic chemists after the isolation of the naturally
occurring nucleoside hydantocidin,2 which possesses a
spirocyclic ring at the anomeric centre. Since then, there
have been notable contributions from Miyasaka’s3 and
Paquette’s groups4 in addition to others,5 to synthesize
10-spiro-,3 20-spiro-,5c 30-spiro-6 and 40-spironucleoside
derivatives4 as conformationally restricted analogues.
The synthesis of nucleosides bearing a spirocycle at
C-40 such as 1–4 (Fig. 1) has received attention only
recently. This class of nucleosides possess several
inherent advantages: (i) there is a restriction in confor-
mational flexibility, which may permit the molecule to
attain the optimal puckering needed for drug action;7
(ii) the free radical-induced degradation of nucleosides
or nucleotides by C-40–H abstraction is now prevented;8
and (iii) the compounds are expected to serve as
conformationally fixed models, which can be useful for
elucidating the glycosidic torsion angle of nucleosides.9
In our laboratory, we are engaged in the synthesis of a
wide variety of nucleosides10 (carbocyclic, bicyclic,
spirocyclic and conformationally locked). The above
promising features of C-40 spirocyclic nucleosides
prompted us to take up the synthesis of nucleosides
containing a four membered ring spirofused at C-40.
Although the synthesis of nucleosides that are [5,5]
spiro-fused at C-40 is well documented, the [5,4] type
of nucleosides have yet to be synthesized. The develop-
ment of simple and flexible synthetic routes to such
systems, therefore, represents
a worthwhile task.
Towards this endeavour we report herein results on
the synthesis of [5,4] fused spirocyclic nucleosides 5 from
D-glucose.
Our retrosynthetic analysis (Fig. 2) reveals that nucleo-
philic displacement of the 1,3-bis-electrophilic synthon
6 would allow construction of the spirocyclic ring. Such
R2
R2
R1
X
R1
X
B
B
1
2
R2
R2
R1
X
R1
X
B
B
3
HO
4
OH
HO
R
1 = OH/H, X = O/S/CH2
R2 = H/OH, X = O/S/CH2
B
O
X
HO
OH
Keywords: Synthesis; Oxetane; Thietane; Azetane; Spironucleosides;
D-glucose.
5
X = NH/O/S
Figure 1. Some structurally unique spironucleosides.
*
Corresponding author. Tel.: +91 332473 3491; fax: +91 332473
5197; e-mail: sbmandal@iicb.res.in
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.175

3876
A. Roy et al. / Tetrahedron Letters 47 (2006) 3875–3879
Y
BnN
O
B
O
S
O
O
X
O
O
O
+ X2-
or RX
Na2S, DMF,
110 oC
(76%)
BnNH2,
Y
11
110 oC
(71%)
O
O
PGO
O
HO
OH
BnO
BnO
6
5
12
13
O
O
NaH,
CH2(CO2Et)2,
DMF, 100 oC
(55%)
NaH, DMF, 100 oC
OHC
PGO
O
O
O
O
EtO2C
EtO2C
O
O
PGO
O
O
O
7
8
O
O
Figure 2. Retrosynthetic analysis of 5.
O
O
BnO
BnO
15
14
a synthon could easily be derived through a one-carbon
insertion into the 3-O-protected-5-aldo-1,2-diisopropyl-
idene-a-D-glucofuranose 7, which is readily synthesized
from the 1,2:5,6-di-O-isopropylidene-a-D-glucofuranose
derivative 8.
Ph3P, DEAD
THF, 0 oC
No reaction
10
Scheme 2. Synthesis of spirocycles 12, 13 and 15.
Based on the above strategy, the key intermediate
required for cyclization was prepared (Scheme 1) from
the easily accessible 5-aldo-3-O-benzyl-1,2-O-isopropyl-
idene-a-D-glucofuranose 9.11 Treatment of 9 with
formalin in the presence of NaOH solution (2 M)
afforded the 4-C-(hydroxymethyl)-1,2-O-isopropylidene-
b-L-threo-pento-furanose 10 through an aldol-Cannizaro
sequence. Subsequently 10 was subjected to mesylation
with MsCl and Et3N to furnish the bis-methanesulfo-
nate 11. The formation of 10 and 11 was evident from
spectral data. In the 1H NMR spectrum of 10, the
appearance of a 1H singlet at d 4.12 was attributed to
H-3 and the absence of a carbonyl absorption in the
1737 cmꢀ1 region of the IR indicated the structure
shown. The presence of two three-proton singlets at d
3.00 and 3.02 confirmed the presence of the bis-methane
sulfonate groups in 11.
11 upon NaH treatment) displaces the other sulfonate to
form a putative intermediate (Fig. 3), which during
hydrolytic work-up affords 15. To test whether DEM
has any role in fostering oxetane ring formation, com-
pound 11 was heated with NaH in DMF at 100 ꢁC.
The formation of the same product in virtually identical
yield ruled out any role of DEM in this reaction. To
confirm the unusual formation of 15, we synthesized
15 from 10 following a different reaction sequence as
depicted in Scheme 3. Selective protection of one hydro-
xyl group of 10 with TBDMS-Cl and imidazole at 0 ꢁC
followed by mesylation with mesyl chloride and triethyl-
amine furnished the mono-mesylated compound 17.
O
H3C
O
S
O
O
O
O
When 11 was treated with sodium sulfide (Scheme 2) in
dry DMF at 110 ꢁC, it afforded the spirothietane 1212
(76%). On the other hand, heating this compound in
benzylamine at 110 ꢁC furnished the spiroazetane 1312
(71%). However, when 11 was heated with diethyl
malonate (DEM) and an excess of NaH in DMF at
110 ꢁC (no reaction at rt), it failed to produce the
spirocyclobutane 14. Instead, the product isolated
appeared to be the oxetane 1512 (55%). This may be
rationalized by assuming that the initial attack of the
sulfonate-derived ambident nucleophile (generated from
O
S
O
O
H2C
O
O
H2C
-MsO
S O
O
BnO
NaH
O
O
BnO
OH
O
O
11
S
O
-MsO
O
H3C
H-O
15
O
O
BnO
OH
Figure 3. A proposed mechanism for the formation of 15 from 11.
HO
TBDMSO
O
OHC
O
O
O
O
O
HO
CH2O, NaOH,
TBDMS-Cl,
HO
H
10
imidazole, 0 oC
dioxane, rt, 4 h
(65%)
O
O
O
BnO
BnO
BnO
(60%)
16
9
10
MsCl, Et3N, 0 oC
MsCl, Et3N, 0 oC
(90%)
O
(89%)
MsO
MsO
-
+
O
TBDMSO
MsO
O
(i) Bu4NF, rt, 12 h
O
15
O
(ii) NaH, DMF
rt, 4 h
BnO
O
BnO
11
17
(45%)
Scheme 1. Synthesis of 1,2-O-isopropylidene-3-O-benzyl-bis(4,4-mesyl-
methyl)-a-D-glucofuranose (11).
Scheme 3. Alternative synthesis of spirocycle 15.

A. Roy et al. / Tetrahedron Letters 47 (2006) 3875–3879
3877
Subsequent deprotection of the TBDMS-group with
H
N
O
tetrabutylammonium fluoride and treatment of the
product so obtained with NaH in DMF afforded the
desired cyclized product 15 (identified from 1H and
13C NMR spectra). However, an attempted synthesis
of 15 by treating 10 with DEAD and PPh3 under
Mitsunobu conditions did not succeed (Scheme 2).
O
O
21
22
N
K2CO3, MeOH,
rt, 1 h
X
(80-85%)
OH
BnO
H
O
N
O
O
24 X = S
N
cyclohexene,
EtN
Regarding the identification of compounds 12 and 13,
the disappearance of signals in the d 3.00–3.10 region
25 X = NBn
Pd/C, EtOH, reflux,
6 h
1
OH
(70%)
in their H NMR spectra coupled with the appearance
HO
of two methylene proton signals in the d 3.2–3.7 region
in addition to extra aromatic proton signals (in the case
of 13) indicated their formation. The ring methylene
signals appeared at d 34.3 and 41.0 in the 13C NMR
of 12 but at d 60.0 and 63.2 in that of 13. Finally, the
presence of an ion peak at m/z 331 (M+Na)+ in the
ESI-mass spectrum of 12 and a protonated molecular
ion peak at m/z 382 in that of 13 confirmed the struc-
tures. The structure of 15 was deduced from similar con-
siderations. Of particular importance was the finding
that the chemical shift of the ring methylene protons
(ꢁd 4.6) and carbons (d 77.2 and 82.5) appeared down-
26
Scheme 5. Deprotections of nucleosides 21 and 22.
the opening of the oxetane ring in the presence of the
Lewis acid TMS-OTf. The formation of 21 and 22 was
deduced from the appearance of an acetoxy peak in the
d 2.0 ppm region of the 1H NMR spectrum, a doublet in
the d 5.6 region (uracil proton) and a broad singlet in
the d 8–9 region (for the NH). In the 13C NMR spectra
of the two compounds, signals for uracil carbons
appeared at about d 89, 140, 150 and 163, as expected.
1
field in the H and 13C NMR spectra while the sodiated
molecular ion peak was located at m/z 315.
For deprotection of the nucleosides 21 and 22 (Scheme
5), the acetoxy group was removed with dry K2CO3 in
MeOH to furnish 24 and 25. Transfer hydrogenolysis
of 24 with cyclohexene was unsuccessful. This may be
ascribed to poisoning of the catalyst by the substrate.
A similar reaction on compound 25, however, proceeded
smoothly. Interestingly, the product isolated proved to
be the N-ethyl derivative 2615 rather than the expected
secondary amine. The incorporation of the ethyl moiety
could be rationalized due to the presence of acetalde-
hyde as an impurity in EtOH, which conceivably could
condense with the deprotected amine to form an
iminium compound prior to reduction to produce 26.
A nucleobase could be successfully installed on 12 and 13
(Scheme 4) by cleavage of the acetonide group, followed
by acetylation to form a mixture of the di-acetates, and
reaction with 2,4-bis-(trimethylsilyloxy)pyrimidine in
the presence of TMS-OTf in CH3CN under refluxing
conditions13 to furnish the nucleoside derivatives 2114
and 22,14 the b-orientation of the base being anticipated
due to anchimeric assistance by the neighbouring acetoxy
group. However, several attempts toinstall auracil or thy-
midine base on 20 were unsuccessful. This may be due to
O
X
BnO
OAc
OAc
In conclusion, this study describes an approach to syn-
thesize nucleosides [5,4] spirofused at C-40 from a D-glu-
cose precursor. The strategy appears to be capable of
providing access to analogues based on ribose, 2-deoxy-
ribose, 2,3-dideoxyribose and 2,3-didehydro-2,3-di-
deoxyribose frameworks and may be implemented to
synthesize such nucleosides with different substitution
patterns through judicious selection and manipulation
of the sugar derived precursors.
12
13
15
(i) TFA-H2O (3:2), rt, 6 h
(ii) Ac2O, Py, DMAP, 12 h
(70-80%)
18 X = S
19 X = NBn
20 X = O
H
O
OTMS
N
N
O
N
O
X
BnO
N
TMSO
18
19
Acknowledgements
OAc
TMS-OTf, CH3CN,
reflux, 6 h
A grant from the Department of Science and Technology
(Govt. of India) has supported the work. The authors
gratefully acknowledge the Council of Scientific and
Industrial Research for providing a Senior Research
Fellowship (to A.R.) and an Emeritus Scientist scheme
(to B.A.).
21 X = S
22 X = NBn
(55-60%)
OTMS
H
O
N
R
N
O
O
R
N
O
N
TMSO
20
OAc
TMS-OTf, CH3CN, rt or,
BnO
References and notes
reflux
23
(R = H, Me)
1. (a) Meier, C.; Habel, C.; Haller-Meier, F.; Lomp, A.;
Herderich, M.; Klo¨cking, R.; Meerbach, A.; Wultzler, P.
Scheme 4. Synthesis of spironucleosides 21 and 22.

3878
A. Roy et al. / Tetrahedron Letters 47 (2006) 3875–3879
Antiviral Chem. Chemother. 1998, 9, 389; (b) Golan-
mass, which was then purified by column chromatography
over silica gel (60–120 mesh). Elution with CHCl3–petro-
leum ether (1:1) furnished 12 (1.25 g, 76%). For the
preparation of 13, a mixture of 11 (0.95 g, 2.04 mmol) and
benzyl amine (15 mL) was heated at 110 ꢁC for 10 h. Usual
work-up followed by column chromatography using
EtOAc–petroleum ether (3:22) as eluent yielded 13
(0.55 g, 71%). For 15, oil-free NaH (84 mg) was added
portionwise to a solution of 11 (0.8 g, 1.72 mmol) in
anhydrous DMF (15 mL) and the mixture was heated at
100 ꢁC for 6 h. Excess NaH was destroyed by slow
addition of cold water and the solvent was evaporated.
Usual work-up and purification by chromatography over
silica gel (60–120 mesh) using CHCl3–petroleum ether
(7:3) gave 15 (275 mg, 55%).
kiewicz, B.; Ostrowski, T.; Andrei, G.; Snoeck, R.;
De Clercq, E. J. Med. Chem. 1994, 37, 3187; (c) Agro-
foglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S.
R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611; (d)
Crimmins, M. T. Tetrahedron 1998, 54, 9229; (e) Robins,
R. K.; Kini, G. D. In Chemistry of Antitumor Agents;
Wilman, D. E. V., Ed.; Blackie and Son: UK, 1990; p 299;
(f) Jones, M. F. Chem. Brit. 1988, 1122; (g) Nishiyama, Y.;
Yamamoto, N.; Yamada, Y.; Daikoku, T.; Ichikawa,
Y.-I.; Takahasi, K. J. Antibiot. 1989, 42, 1854; (h)
Norbeck, D. W.; Kern, E.; Hayashi, S.; Rosenbrook,
W.; Sham, H.; Harin, T.; Plattener, J.; Erikson, J.; Clemn,
J.; Swanson, R.; Shipkowitz, N.; Hardy, D.; Marsh, K.;
Artnet, G.; Shannon, W.; Broder, S.; Mitsuya, H. J. Med.
Chem. 1990, 33, 1281.
25
Data for 12: white solid, mp 74–75 ꢁC, ½aꢂD ꢀ82.6 (c 1.3,
2. Haruama, H.; Takayama, T.; Kinoshita, T.; Kondo, M.;
Nakajima, M.; Haneishi, T. J. Chem. Soc. Perkin Trans. 1
1991, 1637.
3. (a) Kittaka, A.; Tanaka, H.; Odanaka, Y.; Ohnuki, K.;
Yamaguchi, K.; Miyasaka, T. J. Org. Chem. 1994, 59,
3636; (b) Kittaka, A.; Tanaka, H.; Yamada, N.;
Miyasaka, T. Tetrahedron Lett. 1996, 37, 2801; (c)
Kittaka, A.; Asakura, T.; Kuze, T.; Tanaka, H.; Yamada,
N.; Nakamura, K. T.; Miyasaka, T. J. Org. Chem. 1999,
64, 7081.
4. (a) Paquette, L. A.; Bibart, R. T.; Seekamp, C. K.;
Kahane, A. L. Org. Lett. 2001, 3, 4039; (b) Paquette, L.
A.; Owen, D. R.; Bibart, R. T.; Seekamp, C. K. Org. Lett.
2001, 3, 4043; (c) Paquette, L. A.; Hartung, R. E.; France,
D. J. Org. Lett. 2003, 5, 869; (d) Paquette, L. A.; Fabris,
F.; Gallou, F.; Dong, S. J. Org. Chem. 2003, 68, 8625; (e)
Paquette, L. A.; Kahane, A. L.; Seekamp, C. K. J. Org.
Chem. 2004, 69, 5555; (f) Dong, S.; Paquette, L. A. J. Org.
Chem. 2005, 70, 1580; (g) Hortung, R.; Paquette, L. A.
J. Org. Chem. 2005, 70, 1597; (h) Paquette, L. A.; Dong, S.
J. Org. Chem. 2005, 70, 5655.
5. (a) Gimisis, T.; Chatgilialoglu, C. J. Org. Chem. 1996, 61,
1908; (b) Gasch, C.; Pradera, M. A.; Salameh, B. A. B.;
Molina, J. L.; Fuentes, J. Tetrahedron: Asymmetry 2001,
12, 1267; (c) Ravindra Babu, B.; Keinicke, L.; Petersen,
M.; Nielsen, C.; Wengel, J. Org. Biomol. Chem. 2003, 1,
3514.
CHCl3) [found: C, 62.08; H, 6.43. C16H20O4S requires C,
62.31; H, 6.54]; IR (KBr): mmax 1451, 1380, 1211, 1102,
1075, 859, 740 cmꢀ1; 1H NMR (CDCl3, 300 MHz): d 1.28
and 1.46 (2 · s, 2 · 3H, CMe2), 3.24 (dd, 1H, J = 2.8,
9.0 Hz), 3.42 (dd, 1H, J = 2.8, 9.5 Hz), 3.61 (d, 1H,
J = 9.5 Hz), 3.69 (d, 1H, J = 9.2 Hz), 4.47 (s, 1H, 3-H),
4.62 (d, 1H, J = 3.7 Hz, 2-H), 4.72 and 4.80 (2 · d, 2 · 1H,
J = 11.7 Hz, –O–CH2), 5.83 (d, 1H, J = 3.7 Hz, 1-H),
7.31–7.38 (m, 5H, Ph–H); 13C NMR (CDCl3, 75 MHz): d
25.6 (CH3), 26.4 (CH3), 34.3 (SCH2), 41.1 (SCH2), 72.3
(OCH2), 82.4 (CH), 83.9 (CH), 87.9 (C–O), 105.5 (O–CH–
O), 111.8 (O–C–O), 127.5 (2 · CH), 127.9 (CH), 128.4
(2 · CH), 137.1 (C); ESIMS: m/z 331 (M+Na)+. Com-
25
pound 13: yellowish gum, ½aꢂD ꢀ66.5 (c 0.71, CHCl3)
[found: C, 72.12; H, 7.01; N, 3.61. C23H27NO4 requires C,
72.42; H, 7.13; N, 3.67]; IR (neat): mmax 1494, 1454, 1376,
1310, 1212 cmꢀ1; 1H NMR (CDCl3, 300 MHz): d 1.28 and
1.40 (2 · s, 2 · 3H, CMe2), 3.24 (t-like, 2H, J = 8.7,
9.3 Hz), 3.71 (br s, 3H), 3.87 (d, 1H, J = 7.3 Hz), 4.31 (s,
1H, 3-H), 4.60 (d, 1H, J = 3.0 Hz, 2-H), 4.68 and 4.74
(2 · d, 2 · 1H, J = 11.8 Hz, –O–CH2), 5.84 (d, 1H,
J = 3.2 Hz, 1-H), 7.31–7.34 (m, 10H, Ph–H); 13C NMR
(CDCl3, 75 MHz): d 25.8 (CH3), 26.6 (CH3), 60.0 (NCH2),
63.3 (NCH2), 65.9 (NCH2), 72.1 (OCH2), 81.9 (C–O), 82.4
(CH), 84.8 (CH), 105.1 (O–CH–O), 111.8 (O–C–O), 127.0
(CH), 127.6 (2 · CH), 127.8 (CH), 128.28 (2 · CH), 128.35
(2 · CH), 128.43 (2 · CH), 137.5 (C), 137.8 (C); ESIMS:
m/z 382 (M+H)+, 404 (M+Na)+. Compound 15: gummy
6. Nielsen, P.; Larsen, K.; Wengel, J. Acta Chem. Scand.
1996, 50, 1030.
7. (a) Meldgaard, M.; Wengel, J. J. Chem. Soc., Perkin
Trans. 1 2000, 3539; (b) Herdewijn, P. Liebigs Ann. 1996,
1337.
25
material, ½aꢂD ꢀ104.2 (c 0.22, CHCl3) [found: C, 65.66; H,
6.78. C16H20O5 requires C, 65.74; H, 6.90]; IR (neat): mmax
1379, 1247, 1213, 1163, 1074, 1020, 972, 860, 752,
1
698 cmꢀ1; H NMR (CDCl3, 300 MHz): d 1.29 and 1.39
8. (a) Pratbiel, G.; Bernadou, J.; Meunier, B. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 746; (b) Nicolaou, K. C.; Dai,
W.-M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387.
9. Liaw, Y. C.; Gao, Y. G.; Marquez, V. E.; Wang, A. H.
Nucleic Acids Res. 1992, 20, 459.
10. (a) Bar, N. C.; Patra, R.; Achari, B.; Mandal, S. B.
Tetrahedron 1997, 53, 4727; (b) Roy, A.; Chakrabarty,
K.; Dutta, P. K.; Bar, N. C.; Basu, N.; Achari, B.;
Mandal, S. B. J. Org. Chem. 1999, 64, 2304; (c) Singha,
K.; Roy, A.; Dutta, P. K.; Tripathi, S.; Sahabuddin, S.;
Achari, B.; Mandal, S. B. J. Org. Chem. 2004, 69, 6507.
11. Roy, A.; Roy, B. G.; Achari, B.; Mandal, S. B. Tetra-
hedron Lett. 2004, 45, 5811.
12. Procedures for the preparation of spirocycles 12, 13 and
15.To a solution of 11 (2.5 g, 5.36 mmol) in dry DMF
(15 mL) was added Na2S (0.63 g, 8.0 mmol) and the
mixture was heated at 110 ꢁC for 3 h. The solution was
cooled to rt and the solvent was evaporated under reduced
pressure. The residue was extracted with CHCl3
(3 · 30 mL), the combined extract was washed with water
(3 · 30 mL), dried (Na2SO4) and evaporated to a gummy
(2 · s, 2 · 3H, CMe2), 4.33 (s, 1H, 3-H), 4.60–4.64 (m,
3H), 4.73 (s, 1H), 4.76 (d, 1H, J = 3.7 Hz, 2-H), 4.83 (s,
2H, –OCH2Ph), 5.87 (d, 1H, J = 3.3 Hz, 1-H), 7.37 (m,
5H, Ph–H); 13C NMR (CDCl3, 75 MHz): d 25.7 (CH3),
26.7 (CH3), 72.2 (OCH2Ph), 77.2 (OCH2), 82.1 (CH), 82.5
(OCH2), 84.4 (CH), 85.4 (C–O), 105.4 (O–CH–O), 111.9
(O–C–O), 127.8 (2 · CH), 128.2 (CH), 128.6 (2 · CH),
137.0 (C); ESIMS: m/z 315 (M+Na)+.
13. Vorbruggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber.
¨
1981, 114, 1234.
25
14. Compound 21: foamy solid, ½aꢂD ꢀ24.3 (c 0.46, CHCl3)
[found: C, 56.30; H, 4.89; N, 6.70. C19H20N2O6S requires
C, 56.42; H, 4.98; N, 6.93]; IR (KBr): mmax 3208 (br), 1749,
1688, 1456, 1377, 1223, 1107, 754 cmꢀ1; 1H NMR (CDCl3,
300 MHz): d 2.14 (s, 3H, OCOCH3), 2.98 (d, 1H,
J = 9.0 Hz), 3.53 (d, 1H, J = 9.0 Hz), 3.66 (t-like, 2H,
J = 10.0, 11.4 Hz), 4.33 (s, 1H, 30-H), 4.74 and 4.83 (2 · d,
2 · 1H, J = 11.5 Hz, OCH2), 5.20 (s, 1H, 20-H), 5.59 (d,
1H, J = 7.9 Hz, 5-H), 6.10 (s, 1H, 10-H), 7.33–7.39 (m, 6H,
Ph–H and 6-H), 8.78 (br s, 1H, NH); 13C NMR (CDCl3,
75 MHz): d 21.2 (CH3), 34.2 (SCH2), 39.9 (SCH2), 72.8

A. Roy et al. / Tetrahedron Letters 47 (2006) 3875–3879
3879
(OCH2), 79.9 (CH), 82.6 (CH), 88.9 (CH), 89.1 (C–O),
102.9 (O–CH–N), 128.6 (2 · CH), 128.9 (CH), 129.1
(2 · CH), 136.7 (C), 140.5 (6-CH), 150.5 (4-CO), 163.6
(2-CO), 169.9 (O–CO); ESIMS: m/z 427 (M+Na)+.
128.0 (CH), 128.2 (CH), 128.3 (2 · CH), 128.5 (2 · CH),
128.9 (CH), 136.6 (C), 137.1 (C), 140.1 (6-CH), 150.2 (4-
CO), 163.4 (2-CO), 169.4 (O–CO); ESIMS: m/z 478
(M+H)+.
25
25
Compound 22: foamy solid, ½aꢂD ꢀ14.3 (c 0.58, CHCl3)
15. Compound 26: foamy solid, ½aꢂD ꢀ7.2 (c 0.27, MeOH)
[found: C, 65.15; H, 5.61; N, 8.59. C26H27N3O6 requires C,
65.40; H, 5.70; N, 8.80]; IR (KBr): mmax 3196 (br), 1749,
1693, 1453, 1375, 1224, 1110, 754 cmꢀ1; 1H NMR (CDCl3,
300 MHz): d 2.10 (s, 3H, OCOCH3), 3.16 (d, 1H,
J = 7.5 Hz), 3.27 (d, 1H, J = 7.9 Hz), 3.38 (d, 1H,
J = 5.9 Hz), 3.67 (s, 2H), 3.84 (d, 1H, J = 6.3 Hz), 4.14
(s, 1H, 30-H), 4.67 and 4.73 (2 · d, 2 · 1H, J = 11.5 Hz,
OCH2), 5.19 (s, 1H, 20-H), 5.54 (d, 1H, J = 8.3 Hz, 5-H),
6.04 (s, 1H, 10-H), 7.26–7.40 (m, 11H, 2 · Ph–H and 6-H),
8.41 (br s, 1H, NH); 13C NMR (CDCl3, 75 MHz): d 20.7
(CH3), 59.1 (NCH2), 63.0 (NCH2), 64.3 (NCH2), 72.0
(OCH2), 79.2 (CH), 82.6 (O–C–O), 83.3 (CH), 88.3 (CH),
102.1 (O–CH–N), 127.3 (CH), 127.7 (CH), 127.8 (CH),
[found: C, 50.77; H, 5.93; N, 14.68. C12H17N3O5 requires
C, 50.88; H, 6.05; N, 14.83]; IR (KBr): mmax 3384
(br), 1689, 1635, 1465, 1419, 1267, 1107, 1062 cmꢀ1 1H
;
NMR (Py-d5, 300 MHz): d 0.93 (t, 3H, J= 7.0 Hz, CH3),
2.48 (q, 2H, J = 7.0 Hz, CH2), 3.26 (d, 1H, J = 7.3 Hz),
3.34 (d, 1H, J = 7.4 Hz), 3.97 (d, 1H, J = 6.9 Hz), 4.24 (d,
1H, J = 7.9 Hz), 4.84–5.20 (4 · H merged with solvent
peak), 5.87 (d, 1H, J = 8.1 Hz, 5-H), 6.60 (s, 1H, 10-H),
8.09 (d, 1H, J = 8.1 Hz, 6-H), 13.30 (br s, 1H, NH); 13C
NMR (Py-d5, 75 MHz): d 13.1 (CH3), 54.0 (NCH2), 60.6
(NCH2), 65.8 (NCH2), 79.3 (CH), 82.2 (CH), 85.1 (C–O),
93.0 (CH), 101.7 (O–CH–N), 141.9 (6-CH), 152.2 (4-CO),
164.7 (2-CO); ESIMS: m/z 284 (M+H)+.