Diastereoselective Reformatsky reaction of methyl 4-bromocrotonate with 1,2:5,6-di-O-isopropylidene-α-D-ribo-hexofuranos-3-ulose: Application to novel bicyclic nucleosides

Article abstract of DOI:10.1016/j.tet.2004.08.092

This paper describes an efficient synthetic route for novel bicyclic nucleosides. The stereochemistry of the targeted bicyclic nucleosides was successfully achieved by vinylogous Reformatsky reaction and ring closing metathesis reaction on a carbohydrate

Full text of DOI:10.1016/j.tet.2004.08.092

Tetrahedron 60 (2004) 10269–10275
Diastereoselective Reformatsky reaction of methyl
4-bromocrotonate with
1,2:5,6-di-O-isopropylidene-a-D-ribo-hexofuranos-3-ulose:
application to novel bicyclic nucleosides
*
Mukund K. Gurjar, Dandepally Srinivasa Reddy, Mohan M. Bhadbhade
and Rajesh G. Gonnade
National Chemical Laboratory, Pune 411 008, India
Received 27 May 2004; revised 30 July 2004; accepted 26 August 2004
Abstract—This paper describes an efficient synthetic route for novel bicyclic nucleosides. The stereochemistry of the targeted bicyclic
nucleosides was successfully achieved by vinylogous Reformatsky reaction and ring closing metathesis reaction on a carbohydrate backbone.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Due to the inherent structural complexity associated with
carbohydrate precursors, many organometallic C–C bond
forming reactions occur with impressive stereoselectivity.1
For instance, the 3-ulose derivative of 1,2:5,6-di-O-
isopropylidene-a-D-glucofuranose (1) has been particularly
targeted with significant successes.2 The conformationally
rigid 1,2-O-isopropylidene functionality of 1 dictates3 the
approach of the nucleophile from the b-face giving rise to
the 3-C-substituted-D-allose derivative. In most C–C bond
Scheme 1.
forming reactions studied so far, only one new chiral center
at C-3 has been created.4 We were interested in exploring
the organometallic reaction of 1 with a specific organo-
nucleosides have been developed in the recent past, and the
quest for more analogues is still in progress. In particular,
metallic reagent which is tuned to produce two new chiral
nucleoside analogues with bicyclic carbohydrate moieties
centers as shown in Scheme 1. We believe that this study
have been designed as potential antiviral agents. Due to the
would be of significant interest for synthesizing novel
decrease in conformational freedom introduced by the
molecules including bicyclic derivatives.
bicyclic nucleosides, these oligonucleotides have displayed
very promising results as compounds with improved
The design of conformationally restricted nucleosides is a
recognition of complementary RNA and DNA sequences.6
very important approach towards potential antiviral agents
Leumann and co-workers introduced the concept of bicyclic
and monomers in conformationally restricted oligonucleo-
oligonucleotides by synthesizing the several bicyclic
tides, for potential antisense therapeutic and diagnostic
purposes.5 Anticipating better biological activity, many
nucleosides (2 and its analogues) and incorporating them
into oligonucleotides.7 Since then, numerous approaches for
useful strategies for modification of naturally occurring
a variety of bicyclic sugar nucleosides have appeared in the
literature.8 Recently, Nielson and co-workers have syn-
Keywords: Bicyclic nucleosides; Vinylogous Reformatsky reaction; Ring
thesized various bicyclic nucleoside analogues (3 and 4)
from diacetone-D-glucose and carried out extensive studies
on their ability to incorporate into oligonucleotides.8a,9 In
closing metathesis; Grubbs’ catalyst; Vorbru¨ggen-type coupling reaction.
* Corresponding author. Tel.: C91-20-25893614; fax: C91-20-25882456;
e-mail: gurjar@dalton.ncl.res.in
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.092

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M. K. Gurjar et al. / Tetrahedron 60 (2004) 10269–10275
Figure 1.
this report we describe the synthesis of novel bicyclic
nucleosides 5, 6 and their analogues (Fig. 1).10
The carbomethoxy moiety of 7 was reduced with LiAlH4
and then the resulting hydroxyl group was protected as its
benzylic ether (9) by using benzyl bromide–Ag2O. In order
to derive the diene 10, the successive hydrolysis of 5,6-O-
isopropylidene group with 0.8% H2SO4 in methanol,
dimesylation of the 5,6-diol derivative with MsCl and
iPr2EtN, and elimination with NaI in ethyl methyl ketone
were carried out. The ring closing metathesis reaction of
10 with 4 mol% of Grubbs’ 1st generation catalyst in
refluxing benzene provided the bicyclic derivative 11 in
87% yield (Scheme 2).13 The stereochemistry of 11 was
unambiguously assigned by NOE studies (Fig. 4). Strong
NOE correlations among bridgehead hydroxyl group and
the adjacent allylic protons were noticed.
2. Results and discussion
The vinylogous Reformatsky reaction of 3-ulose deriva-
tive11 (1) was attempted with methyl 4-bromocrotonate and
Zn–Cu couple.12 This reaction gave two products chro-
matographically separated on silica gel. The major product
obtained in 52% yield was assigned as structure 7 based on
the 1H NMR, 13C NMR, mass spectra and elemental
analysis. The stereochemical assignment of 7 was confirmed
by single crystal X-ray diffraction studies (Fig. 2). The
minor product obtained in 26% yield, was given the
structure 8 based on spectroscopic and analytical data.
The formation of a single diastereomer 7 could be explained
by considering the two transition states A and B. The
preferred E-dienolate of Zn (transition state A) seemed to be
more preferred while Z-dienolate based transition state B
has steric hindrance (Fig. 3).
Our final concern was to introduce pyrimidine bases at the
anomeric center. The 1,2-O-isopropylidene moiety of 11
was cleaved with 60% AcOH followed by acetylation with
Ac2O and Et3N to afford the triacetylated derivative 12. The
modified Vorbru¨ggen-type coupling reaction of 12 with
Scheme 2. Reagents and conditions: (a) methyl 4-bromocrotonate, Zn–Cu
couple, ether, reflux, 1 h; (b) (i) LiAlH4, ether, 0 8C–rt, 2 h, 83%; (ii) BnBr,
Ag2O, CH2Cl2, rt, 1 h, 95%; (c) (i) 0.8% H2SO4, MeOH, rt, 24 h, 80%; (ii)
MsCl, iPr2EtN, CH2Cl2, 0 8C, 5 min, 95%; (iii) NaI, Et–CO–Me, reflux, 4 h,
83%; (d) Grubbs’ catalyst, C6H6, reflux, 8 h, 87%.
Figure 2. ORTEP diagram of 7.
Figure 4. NOE studies on 11.
Figure 3. Possible transition states.

M. K. Gurjar et al. / Tetrahedron 60 (2004) 10269–10275
10271
Scheme 3. Reagents and conditions: (a) 60% AcOH, reflux, 2 h, 93%; (b) Ac2O, Et3N, DMAP, CH2Cl2, rt, 1 h, 96%; (c) uracil/thymine, BSA, TMSOTf,
CH3CN, 50 8C, 2 h, 69%/77%; (d) NaOMe, MeOH, 0 8C, 20 min; (e) BCl3, CH2Cl2, K78 8C, 5 h; (f) 20% Pd(OH)2/C, H2, MeOH, rt, 12 h.
uracil was achieved in the presence of N,O-bis(trimethyl-
silyl)acetamide (BSA) and TMSOTf to afford exclusively
the b-nucleoside 13, attributed to the anchimeric assistance
from 4-O-acetyl group.14
(60F-254) with UV, I2 and anisaldehyde in ethanol as
development reagents.
3.1.1. 3-C-[(S)-1-Carbomethoxy-prop-2-enyl]-1,2;5,6-di-
O-isopropylidene-a-D-allofuranose (7) and 3-C-(3-carbo-
methoxy-prop-2-enyl]-1,2;5,6-di-O-isopropylidene-a-D-
allofuranose (8). To a suspension of activated Zn–Cu
couple (40.0 g, 611.7 mmol) and iodine (50 mg) in
anhydrous ether (140 mL) were gradually added methyl
4-bromocrotonate (45 g, 251.4 mmol) and the solution of 1
(40.0 g, 155.0 mmol in 50 mL of ether) over a period of
30 min. The reaction mixture was heated under reflux for
30 min, cooled and poured over saturated NH4Cl. The
organic layer was separated, washed with brine, dried
(Na2SO4), and concentrated. The residue was chromato-
graphed on silica gel by using EtOAc–light petroleum (1:7)
as eluent to give 716 (28.9 g, 52%) as a colorless solid, mp
88–90 8C; [a]DZK42.5 (c 1, CHCl3); nmax (CHCl3) 3462,
´
The de-protection of the two acetyl groups under Zemplen
reaction condition15 and the benzylic ether with BCl3 of 13
afforded 5. Simultaneously, compound 13 was hydrogen-
ated in the presence of 20% Pd(OH)2/C, followed by
´
deacetylation using NaOMe (Zemplen conditions) to give
compound 15. Similarly, the triacetate 12 was coupled to
thymine using N,O-bis(trimethylsilyl)acetamide and
TMSOTf to obtain 14. Compound 14 was transformed
into 6 and 16 as described above (Scheme 3).
In conclusion, we described an elegant methodology to
synthesize the novel bicyclic nucleosides having the
structural framework of some carbocyclic nucleosides and
bridgehead hydroxyl moiety. The biological activity of
these novel bicyclic nucleosides is under study and will be
published in due course.
1
2990, 1737, 1384, 1216, 1167, 1075, 1015, 756; H NMR
(300 MHz, CDCl3): d 1.37, 1.45, 1.58 (3s, 12H), 3.32 (s,
1H), 3.74 (s, 3H), 3.78–3.81 (m, 2H), 3.87 (dd, 1H, JZ5.1,
8.8 Hz), 4.08–4.12 (m, 1H), 4.21 (dt, 1H, JZ9.1, 5.6 Hz),
5.04 (d, 1H, JZ3.9 Hz), 5.28–5.35 (m, 2H), 5.61 (d, 1H, JZ
4.1 Hz), 5.83 (ddd, 1H, JZ8.6, 10.1, 17.5 Hz); 13C NMR
(50 MHz, CDCl3): d 24.9, 26.0, 26.2, 51.3, 51.4, 67.9, 72.2,
79.5, 79.6, 82.9, 103.5, 109.3, 111.6, 119.6, 130.0, 171.0;
EIMS (m/z) 343 [MCK15]. Anal. Calcd for C17H26O8: C,
56.97; H, 7.31. Found: C, 56.68; H, 7.52.
3. Experimental
3.1. General
The NMR spectra were recorded in CDCl3 or DMSO-d6
with TMS as an internal standard on AC-200 MHz, MSL-
300 MHz, DRX-500 MHz. Optical rotations were measured
with a JASCO DIP 370 digital polarimetrometer. EI Mass
spectra were recorded on Finngan MAT-1020. Combustion
data were recorded on Elmentar-Vario-EL (Heraeus Com-
pany Ltd., Germany). IR spectra were obtained from
Perkin–Elmer 68515 PC-FTIR spectrophotometer. Melting
points were measured on Buchi 535 melting point apparatus
and are uncorrected. Starting materials and reagents were
purchased from Aldrich or Lancaster and used as received.
Reactions were monitored by thin layer chromatography
(TLC) carried out on 0.25 mm E-Merck silica gel plates
Further elution with EtOAc–light petroleum (1:5) gave 8
(14.4 g, 26%) as a colorless solid, mp 106–108 8C;
[a]DZK25.6 (c 1, CHCl3); nmax (CHCl3) 3440, 3020,
1716, 1376, 1166, 1079, 759; 1H NMR (300 MHz, CDCl3):
d 1.34, 1.36, 1.45, 1.59 (4s. 12H), 2.30 (dd, 1H, JZ9.1,
14.7 Hz), 2.78 (s, 1H, OH), 2.80 (ddd, 1H, JZ1.6, 5.8,
14.7 Hz), 3.75 (s, 3H), 3.78 (m, 1H), 3.87–3.95 (m, 1H),
4.06–4.14 (m, 2H), 4.24 (d, 1H, JZ3.8 Hz), 5.66 (d, 1H, JZ
3.8 Hz), 5.94 (d, 1H, JZ15.8 Hz), 7.12 (ddd, 1H, JZ5.4,
8.8, 15.8 Hz); 13C NMR (125 MHz, CDCl3): d 25.2, 26.4,
26.6, 26.7, 34.9, 51.6, 68.1, 73.2, 78.9, 81.3, 81.9, 103.5,

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M. K. Gurjar et al. / Tetrahedron 60 (2004) 10269–10275
109.9, 112.8, 124.7, 143.1, 166.3; EIMS (m/z) 343 [MCK
15]. Anal. Calcd for C17H26O8: C, 56.97; H, 7.31. Found: C,
56.86; H, 7.27.
The above compound (10.0 g, 26.3 mmol), iPr2EtN (16 mL,
92.0 mmol), and MsCl (5 mL, 65.7 mmol) in CH2Cl2
(40 mL) were stirred at 0 8C for 5 min. The reaction mixture
was quenched with saturated Na2CO3, water, dried
(Na2SO4), and concentrated. The crude oily compound
was purified on silica gel with EtOAc–light petroleum (1:5)
to afford the 5,6-dimesylate derivative (13.4 g, 95%), as a
clear oil: [a]DZK10.1 (c 1.45, CHCl3); 1H NMR
(200 MHz, CDCl3): d 1.35, 1.58 (2s, 6H), 3.00–3.04 (m,
1H), 3.06 (s, 3H), 3.13 (s, 3H), 3.56–3.67 (m, 1H), 3.74 (dd,
1H, JZ5.4, 9.4 Hz), 3.94 (dd, 1H, JZ3.9, 9.4 Hz), 4.00 (d,
1H, JZ9.1 Hz), 4.32 (dd, 1H, JZ5.7, 11.5 Hz), 4.45–4.63
(m, 3H), 4.83 (d, 1H, JZ3.8 Hz), 5.21–5.41 (m, 2H), 5.55–
5.74 (m, 1H), 5.62 (d, 1H, JZ3.8 Hz), 7.21–7.39 (m, 5H);
13C NMR (50 MHz, CDCl3): d 26.0, 26.1, 37.0, 39.0, 44.8,
68.3, 70.6, 72.7, 73.6, 78.8, 79.7, 103.4, 111.8, 118.9, 127.1,
127.9, 133.3, 137.6. Anal. Calcd for C22H32O11S2: C, 49.24;
H, 6.01; S, 11.95. Found: C, 48.97; H, 5.77; S, 12.14.
3.1.2. 3-C-[(R)-1-Benzyloxymethyl-prop-2-enyl]-1,2;5,6-
di-O-isopropylidene-a-D-allofuranose (9). A solution of 7
(28.0 g, 78.0 mmol) and LiAlH4 (4.15 g) in anhydrous ether
(150 mL) was stirred for 2 h at rt, quenched with EtOAc and
filtered through a plug of Celite. The filtrate was
concentrated and purified on silica gel column with
EtOAc–light petroleum (1:3) to afford 3-C-[(R)-1-hydroxy-
methyl-prop-2-enyl]-1,2;5,6-di-O-isopropylidene-a-D-
allofuranose (16.8 g, 83%) as a colorless solid, mp
78–80 8C; [a]DZK3.4 (c 1.1, CHCl3); nmax (CHCl3) 3401,
1
2989, 1384, 1217, 1074, 1010, 757; H NMR (200 MHz,
CDCl3): d 1.38 (s, 6H), 1.45, 1.59 (2s, 6H), 2.72–2.89 (br s,
1H, OH), 2.91–3.07 (m, 1H), 3.12 (s, 1H, OH), 3.68–3.90
(m, 3H), 3.99–4.17 (m, 2H), 4.24–4.36 (m, 1H), 4.50 (d, 1H,
JZ3.9 Hz), 5.17–5.32 (m, 2H), 5.60 (d, 1H, JZ3.9 Hz),
5.71 (ddd, 1H, JZ8.7, 10.7, 17.1 Hz); 13C NMR (50 MHz,
CDCl3): d 25.3, 26.3, 26.5, 26.6, 47.1, 63.2, 68.4, 72.5, 80.5,
81.0, 84.1, 103.9, 109.7, 112.2, 118.5, 134.3; EIMS (m/z)
315 [MCK15]. Anal. Calcd for C16H26O7: C, 58.17; H,
7.93. Found: C, 57.87; H, 8.18.
The 5,6-dimesylate (12.0 g, 22.4 mmol) and NaI (33.5 g,
223.6 mol) in 2-butanone (100 mL) were heated under
reflux for 4 h and concentrated. The residue was partitioned
between EtOAc and saturated aq Na2S2O3. The organic
layer was washed with brine, dried (Na2SO4), and
concentrated. The residue was purified by silica gel with
EtOAc–light petroleum (1:9) to afford 10 (6.43 g, 83%) as a
syrup: [a]DZK15.2 (c 0.95, CHCl3); nmax (CHCl3) 3402,
The above product (16.0 g, 48.4 mmol), freshly prepared
Ag2O (33.7 g, 145.3 mmol) and benzyl bromide (6.9 mL,
58.0 mmol) in CH2Cl2 (50 mL) were stirred for 1 h at rt,
filtered through Celite and concentrated. The residue was
purified on silica gel by using EtOAc–light petroleum (1:9)
to get 9 (19.35 g, 95%) as a syrup: [a]DZC13.7 (c 1.1,
CHCl3); nmax (CHCl3) 3402, 2936, 1385, 1275, 1217, 1045,
1
2933, 1403, 1276, 1092, 1027, 755; H NMR (200 MHz,
CDCl3): d 1.35, 1.58 (2s, 6H), 2.68 (dt, 1H, JZ9.2, 5.1 Hz),
3.46 (s, 1H, OH), 3.75–3.82 (m, 2H), 4.33 (dt, 1H, JZ1.4,
2.8 Hz), 4.46–4.53 (m, 2H), 4.59 (d, 1H, JZ3.9 Hz), 5.09–
5.46 (m, 4H), 5.64 (d, 1H, JZ3.9 Hz), 5.70–6.00 (m, 2H),
7.23–7.39 (m, 5H); 13C NMR (50 MHz, CDCl3): d 25.9,
26.0, 44.6, 69.8, 72.6, 79.9, 80.2, 83.8, 103.4, 111.1, 117.1,
117.3, 126.9, 127.7, 131.4, 134.1, 137.7; EIMS (m/z) 331
[MCK15]. Anal. Calcd for C20H26O5: C, 69.34; H, 7.56.
Found: C, 69.18; H, 7.71.
1
756; H NMR (200 MHz, CDCl3): d 1.33, 1.35, 1.44, 1.59
(4s, 12H), 2.85–2.94 (m, 1H), 3.17 (s, 1H, OH), 3.75–3.96
(m, 4H), 4.08–4.16 (m, 1H), 4.25–4.36 (m, 1H), 4.46–4.55
(m, 2H), 4.75 (d, 1H, JZ7.7 Hz), 5.18–5.29 (m, 2H), 5.62
(d, 1H, JZ3.8 Hz), 5.75–5.94 (m, 1H), 7.26–7.42 (m, 5H);
13C NMR (50 MHz, CDCl3): d 25.2, 26.2, 26.4, 45.6, 68.2,
70.7, 72.4, 72.9, 79.7, 81.0, 83.9, 103.6, 109.2, 111.5, 117.5,
127.1, 127.8, 135.2, 138.2; EIMS (m/z) 405 [MCK15].
Anal. Calcd for C23H32O7: C, 65.70; H, 7.67. Found: C,
65.47; H, 7.58.
3.1.4. (1R,2R,6R,8R,11R)-11-Benzyloxymethyl-1-hydroxy-
4,4-dimethyl-3,5,7-trioxatricyclo[6.3.0.02,6]undec-9-ene
(11). Compound 10 (6.0 g, 17.3 mmol) and Grubbs’ catalyst
(0.57 g, 0.69 mmol) in anhydrous benzene (250 mL) were
heated under reflux for 8 h and then evaporated. The residue
was purified on silica gel with EtOAc–light petroleum (1:4)
to obtain 11 (4.8 g, 87%), as an oil: [a]DZC112 (c 1.1,
CHCl3); nmax (CHCl3) 3498, 2988, 2935, 2861, 1455, 1383,
1374, 1219, 1166, 1096, 1002, 750, 700; 1H NMR
(500 MHz, CDCl3): d 1.37, 1.59 (2s, 6H), 3.06–3.10 (m,
1H), 3.29 (s, 1H, OH), 3.40 (dd, 1H, JZ7.2, 10.1 Hz), 3.53
(dd, 1H, JZ4.2, 10.1 Hz), 4.50 (ABq, 2H, JZ12.1 Hz),
4.61 (d, 1H, JZ3.8 Hz), 4.75 (d, 1H, JZ1.9 Hz), 5.62 (d,
1H, JZ3.8 Hz), 5.85 (dt, 1H, JZ5.9, 2.7 Hz), 5.89 (dd, 1H,
JZ2.7, 5.9 Hz), 7.29–7.37 (m, 5H); 13C NMR (125 MHz,
CDCl3): d 27.1, 27.4, 54.2, 68.6, 73.2, 80.3, 86.2, 93.1,
106.9, 112.6, 127.9, 128.0, 128.5, 129.8, 136.9, 137.7;
EIMS (m/z) 318 [MC]. Anal. Calcd for C18H22O5: C, 67.91;
H, 6.96. Found: C, 67.96; H, 7.18.
3.1.3. 3-C-[(R)-1-Benzyloxymethyl-prop-2-enyl]-5,6-
dideoxy-1,2-O-isopropylidene-a-D-ribo-hex-5-enofura-
nose (10). Compound 9 (16.0 g, 38.0 mmol) and 0.8%
H2SO4 (20 mL) in MeOH (50 mL) were stirred at rt for 24 h,
and then neutralized with solid NaHCO3. The solid was
filtered, concentrated and the residue purified on silica gel
using EtOAc–light petroleum (1:2) to give 3-C-[(R)-1-
benzyloxymethyl-prop-2-enyl]-1,2-O-isopropylidene-a-D-
allofuranose (11.6 g, 80%) as a syrup: [a]DZK11.4 (c 1,
CHCl3); nma1x (CHCl3) 3418, 2988, 1385, 1275, 1217, 1087,
1027, 757; H NMR (200 MHz, CDCl3): d 1.34, 1.58 (2s,
6H), 2.37–2.53 (br s, 1H, OH), 2.90–3.07 (m, 2H), 3.56–
3.88 (m, 6H), 3.91–4.03 (m, 1H), 4.46–4.57 (m, 2H), 4.66
(d, 1H, JZ3.9 Hz), 5.17–5.27 (m, 2H), 5.57 (d, 1H, JZ
3.9 Hz), 5.66–5.84 (m, 1H), 7.21–7.37 (m, 5H); 13C NMR
(50 MHz, CDCl3): d 26.0, 26.1, 44.9, 64.3, 68.9, 70.3, 72.8,
80.0, 80.2, 80.7, 103.7, 111.5, 117.7, 127.1, 127.8, 134.3,
137.8; EIMS (m/z) 322 [MCK58]. Anal. Calcd for
C20H28O7: C, 63.14; H, 7.42. Found: C, 62.88; H, 7.74.
3.1.5. (3R/S,1R,4R,5R,6R)-3,4,5-Triacetoxy-6-benzyloxy-
methyl-2-oxa-bicyclo[3.3.0]oct-7-ene (12). Compound 11
(2.0 g, 6.3 mmol) and 60% AcOH (15 mL) were heated
under reflux for 2 h. The reaction mixture was neutralized
with solid Na2CO3 and evaporated. The residue was

M. K. Gurjar et al. / Tetrahedron 60 (2004) 10269–10275
10273
extracted with EtOAc, dried (Na2SO4), concentrated, and
purified by silica gel chromatography with EtOAc–light
petroleum (1:1) to give (3R/S,1R,4R,5R,6R)-6-benzyloxy-
methyl-3,4,5-trihydroxy-2-oxa-bicyclo[3.3.0]oct-7-ene
(1.63 g, 93%) as a solid: mp 92–94 8C; nmax (CHCl3) 3359,
silica gel column chromatography with MeOH–CH2Cl2
(1:9) to afford (1R,3R,4R,5R,6R)-6-benzyloxymethyl-4,5-
dihydroxy-3-(uracil-1-yl)-2-oxa-bicyclo[3.3.0]oct-7-ene
(0.145 g, 85%), as a solid: mp 150–152 8C; [a]DZK24 (c
1
0.95, CHCl3); H NMR (300 MHz, CDCl3): d 3.10 (t, 1H,
1
2936, 1454, 1401, 1366, 1081, 1027, 749, 698; H NMR
JZ6.5 Hz), 3.72 (d, 2H, JZ6.5 Hz), 4.07 (br s, 1H, OH),
4.25 (d, 1H, JZ7.2 Hz), 4.53 (s, 2H), 4.60 (br s, 1H, OH),
5.05 (s, 1H), 5.66 (d, 1H, JZ8.2 Hz), 5.82 (dd, 2H, JZ6.4,
12.3 Hz), 6.13 (d, 1H, JZ7.6 Hz), 7.25–7.35 (m, 6H), 10.0
(br s, 1H, NH); 13C NMR (75 MHz, CDCl3CMeOD): d
52.8, 68.1, 73.1, 74.8, 85.4, 88.3, 92.8, 102.6, 127.5, 128.1,
130.0, 134.5, 137.5, 139.5, 151.1, 163.8. Anal. Calcd for
C19H20O6N2: C, 61.28; H, 5.41; N, 7.52. Found: C, 61.09;
H, 5.42; N, 7.69.
(200 MHz, CDCl3): d 3.06–3.19 (m, 1H), 3.35 (d, 1H, JZ
4.7 Hz, OH), 3.44 (s, 1H, OH), 3.60–3.79 (m, 2H), 3.86 (d,
1H, JZ5.8 Hz, OH) 4.07 (t, 1H, JZ4.0 Hz), 4.54–4.60 (m,
2H), 5.14 (s, 1H), 5.29–5.33 (m, 1H), 5.57 (d, 1H, JZ
6.0 Hz), 5.79 (dt, 1H, JZ6.0, 2.1 Hz), 7.28–7.39 (m, 5H);
13C NMR (50 MHz, CDCl3): d 52.7, 68.8, 72.0, 73.0, 85.6,
92.8, 97.4, 127.5, 128.2, 130.7, 132.8, 137.5. Anal. Calcd
for C15H18O5: C, 64.74; H, 6.52. Found: C, 64.39; H, 6.42.
The above product (1.5 g, 5.39 mmol), Ac2O (3.1 mL,
32.76 mmol), Et3N (7.5 mL), DMAP (135 mg) in anhydrous
CH2Cl2 (20 mL) were stirred at rt for 1 h. The reaction
mixture was partitioned between water–CH2Cl2, the organic
layer washed with saturated NaHCO3, water, dried
(Na2SO4) and concentrated. The residue was purified on
silica gel with EtOAc–light petroleum (1:4) as an eluent to
obtain 12 (2.1 g, 96%) as an oil: nmax (CHCl3) 3410, 3018,
The above product (0.125 g, 0.34 mmol) in anhydrous
CH2Cl2 (4 mL) was stirred at K78 8C and then a 1 M
solution of BCl3 in CH2Cl2 (0.53 mL, 0.67 mmol) was
added dropwise. After being stirred for 5 h at K78 8C the
mixture was treated with MeOH (3 mL) and water (0.2 mL)
and stirred at rt for 1 h. The solvents were removed under
vacuum and the residue purified on silica gel using MeOH–
CH2Cl2 (1:9) to afford 5 (0.09 g, 95%) as a solid: mp 62–
64 8C; [a]DZK47.4 (c 0.75, MeOH); nmax (CHCl3) 3204,
1
2958, 1720, 1452, 1374, 1276, 1084, 1027, 756, 714; H
1
NMR (200 MHz, CDCl3): d 2.01, 2.09, 2.13 (3s, 9H), 3.39
(t, 1H, JZ5.2 Hz), 3.69–3.74 (m, 2H), 4.49 (ABq, 2H, JZ
11.9 Hz), 5.50 (s, 1H), 5.58 (d, 1H, JZ4.3 Hz), 5.80–5.89
(m, 2H), 6.29 (d, 1H, JZ4.3 Hz), 7.20–7.34 (m, 5H); 13C
NMR (50 MHz, CDCl3): d 20.1, 20.6, 21.2, 51.4, 68.4, 70.9,
72.9, 90.0, 92.6, 95.2, 95.9, 127.4, 128.1, 135.4, 137.8,
168.6, 169.0, 169.6. Anal. Calcd for C21H24O8: C, 62.37; H,
5.98. Found: C, 62.09; H, 6.12.
3019, 1693, 1462, 1400, 1272, 1216, 1105, 757; H NMR
(500 MHz, DMSO-d6): d 2.67–2.72 (m, 1H), 3.47 (dd, 1H,
JZ9.0, 10.6 Hz), 3.77 (dd, 1H, JZ5.2, 10.6 Hz), 4.00 (d,
1H, JZ8.4 Hz), 4.74 (s, 1H), 5.68 (dd, 1H, JZ2.0, 8.1 Hz),
5.80 (dt, 1H, JZ1.8, 6.2 Hz), 5.90 (d, 1H, JZ6.2 Hz), 5.92
(d, 1H, JZ8.1 Hz), 7.42 (d, 1H, JZ8.1 Hz), 11.35 (s, 1H,
NH); 13C NMR (125 MHz, DMSO-d6): d 55.5, 59.3, 72.6,
84.5, 86.8, 92.2, 102.4, 130.1, 135.0, 140.2, 150.9, 162.9.
Anal. Calcd for C12H14O6N2: C, 51.06; H, 4.99; N, 9.92.
Found: C, 51.19; H, 4.81; N, 9.69.
3.1.6. (1R,3R,4R,5R,6R)-4,5-Diacetoxy-6-benzyloxy-
methyl-3-(uracil-1-yl)-2-oxa-bicyclo[3.3.0]oct-7-ene
(13). Compound 12 (0.36 g, 0.89 mmol), uracil (0.20 g,
1.78 mmol), N,O-bis(trimethylsilyl)acetamide (1.1 mL,
4.45 mmol) in anhydrous CH3CN (8 mL) were heated
under reflux for 15 min, cooled to 0 8C and then TMSOTf
(0.32 mL, 1.78 mmol) was added. The reaction mixture was
stirred at 50 8C for 2 h, quenched with ice-cold saturated aq
NaHCO3 and extracted with EtOAc. The organic layer was
washed with water, dried (Na2SO4), concentrated, and the
residue purified on silica gel with EtOAc–light petroleum
(1:1) to give 13 (0.28 g, 69%), as a syrup: [a]DZC16.8 (c
0.8, CHCl3); nmax (CHCl3) 3022, 1748, 1693, 1455, 1373,
1240, 1048, 755; 1H NMR (200 MHz, CDCl3): d 2.02, 2.15
(2s, 6H), 3.26–3.36 (m, 1H), 3.80 (dd, 1H, JZ4.3, 10.0 Hz),
4.02–4.13 (m, 1H), 4.50 (ABq, 2H, JZ11.2 Hz), 5.03 (dd,
1H, JZ2.0, 8.1 Hz), 5.16 (d, 1H, JZ1.6 Hz), 5.86–6.01 (m,
3H), 6.17 (d, 1H, JZ7.5 Hz), 7.08 (d, 1H, JZ8.1 Hz), 7.25–
7.37 (m, 5H), 9.62 (br s, 1H, NH); 13C NMR (50 MHz,
CDCl3): d 20.3, 21.2, 53.2, 68.6, 71.8, 73.1, 86.3, 90.8, 92.2,
103.2, 127.1, 127.7, 128.4, 137.4, 137.7, 139.3, 150.8,
162.9, 169.1, 169.9. Anal. Calcd for C23H24O8N2: C, 60.52;
H, 5.30; N, 6.14. Found: C, 60.29; H, 5.00; N, 6.32.
3.1.8. (1R,3R,4R,5R,6R)-4,5-Dihydroxy-6-hydroxy-
methyl-3-(uracil-1-yl)-2-oxa-bicyclo[3.3.0]octane (15).
Compound 13 (0.11 g, 0.24 mmol) and 20% Pd(OH)2
(0.025 g) in MeOH (4 mL) were stirred under a H2
atmosphere for 12 h, filtered through a pad of Celite and
concentrated. The residue was purified on silica gel with
EtOAc–light petroleum (4:1) to give (1R,3R,4R,5R,6R)-4,5-
diacetoxy-6-hydroxymethyl-3-(uracil-1-yl)-2-oxa-bi-
cyclo[3.3.0]octane (0.075 g, 84%) as a syrup: [a]DZK30.4
(c 1, CHCl3); 1H NMR (300 MHz, CDCl3): d 1.89–1.98 (m,
4H), 2.05, 2.13 (2s, 6H), 2.43–2.53 (m, 1H), 3.79 (dd, 1H,
JZ5.7, 11.2 Hz), 4.06 (dd, 1H, JZ4.0, 11.2 Hz), 4.77 (d,
1H, JZ2.7 Hz), 5.74 (d, 1H, JZ7.4 Hz), 5.77 (dd, 1H, JZ
2.2, 7.4 Hz), 6.07 (d, 1H, JZ7.5 Hz), 7.52 (d, 1H, JZ
7.5 Hz), 9.45 (br s, 1H, NH); 13C NMR (50 MHz, CDCl3): d
20.4, 21.2, 26.3, 29.4, 49.9, 60.8, 71.5, 87.2, 87.3, 90.6,
102.9, 140.0, 150.6, 163.3, 169.6, 170.1. Anal. Calcd for
C16H20O8N2: C, 52.17; H, 5.47; N, 7.60. Found: C, 52.29;
H, 5.76; N, 7.71.
The above product (0.07 g, 0.19 mmol) 1 M methanolic
NaOMe (20 mL) in MeOH (4 mL) were stirred for 20 min
and worked up as described above to give 15 (0.04 g, 74%)
as a solid: mp 185–187 8C; [a]DZK20.2 (c 1, MeOH); nmax
(MeOH) 3361, 2945, 2833, 1698, 1451, 1402, 1113, 1029;
1H NMR (500 MHz, DMSO-d6): d 1.54–1.65 (m, 2H), 1.70–
1.83 (m, 2H), 1.88–1.94 (m, 1H), 3.41 (dd, 1H, JZ8.7,
10.5 Hz), 3.72 (dd, 1H, JZ4.7, 10.5 Hz), 3.88 (d, 1H,
3.1.7. (1R,3R,4R,5R,6R)-4,5-Dihydroxy-6-hydroxy-
methyl-3-(uracil-1-yl)-2-oxa-bicyclo[3.3.0]oct-7-ene (5).
To a solution of 13 (0.21 g, 0.46 mmol), 1 M methanolic
NaOMe (50 mL) in MeOH (3 mL) were stirred at 0 8C for
20 min. The reaction mixture was neutralized with concd
HCl, filtered and concentrated. The residue was purified by

10274
M. K. Gurjar et al. / Tetrahedron 60 (2004) 10269–10275
JZ8.2 Hz), 4.12 (d, 1H, JZ6.7 Hz), 4.90–5.07 (br s, 1H,
OH), 5.11–5.27 (br s, 1H, OH), 5.66 (d, 2H, JZ8.8 Hz),
7.67 (d, 1H, JZ8.8 Hz), 11.34 (s, 1H); 13C NMR (125 MHz,
DMSO-d6): d 27.0, 29.3, 51.6, 60.1, 70.9, 83.2, 85.3, 88.5,
102.0, 140.6, 150.8, 162.7. Anal. Calcd for C12H16O6N2: C,
50.70; H, 5.67; N, 9.85. Found: C, 50.49; H, 6.02; N, 9.69.
3.50 (dt, 1H, JZ9.9, 5.6 Hz), 3.79 (dt, 1H, JZ9.9, 4.8 Hz),
4.05 (t, 1H, JZ7.7 Hz), 4.58 (t, 1H, JZ5.0 Hz), 4.73 (s, 1H,
OH), 5.21 (d, 1H, JZ6.9 Hz, OH), 5.45 (s, 1H, OH), 5.79–
5.81 (m, 1H), 5.90–5.93 (m, 2H), 7.29 (s, 1H), 11.33 (s, 1H,
NH); 13C NMR (125 MHz, DMSO-d6): d 11.9, 55.6, 59.3,
72.0, 84.3, 86.5, 92.0, 109.8, 129.8, 134.9, 135.4, 150.9,
163.4. Anal. Calcd for C13H16O6N2: C, 52.70; H, 5.44; N,
9.45. Found: C, 52.52; H, 5.76; N, 9.52.
3.1.9. (1R,3R,4R,5R,6R)-4,5-Diacetoxy-6-benzyloxy-
methyl-3-(thymin-1-yl)-2-oxa-bicyclo[3.3.0]oct-7-ene
(14). Compound 12 (0.50 g, 1.23 mmol), thymine (0.31 g,
2.47 mmol), N,O-bis(trimethylsilyl)acetamide (1.5 mL,
6.18 mmol) in anhydrous CH3CN (10 mL) were heated
under reflux for 15 min, cooled to 0 8C and then TMSOTf
(0.45 mL, 2.47 mmol) was added. The reaction mixture was
stirred at 50 8C for 2 h, quenched with ice-cold saturated aq
NaHCO3 and extracted with EtOAc. The organic layer was
washed with water, dried (Na2SO4), concentrated, and the
residue purified on silica gel with EtOAc–light petroleum
(1:1) to give 14 (0.45 g, 77%) as a colorless syrup: [a]DZ
K20.9 (c 1.7, CHCl3); nmax (CHCl3) 3195, 3030, 2929,
1748, 1694, 1466, 1371, 1234, 1097, 753; 1H NMR
(300 MHz, CDCl3): d 1.61 (s, 3H), 2.01, 2.15 (2s, 6H),
3.35–3.40 (m, 1H), 3.75 (dd, 1H, JZ5.1, 10.2 Hz), 3.96 (dd,
1H, JZ3.2, 10.2 Hz), 4.53 (ABq, 2H, JZ11.9 Hz), 5.2 (s,
1H), 5.88–5.99 (m, 3H), 6.24 (d, 1H, JZ7.7 Hz), 7.08 (d,
1H, JZ1.3 Hz), 7.28–7.34 (m, 5H), 9.22 (br s, 1H, NH); 13C
NMR (75 MHz, CDCl3): d 12.0, 20.2, 21.2, 52.4, 68.2, 71.9,
72.8, 86.1, 90.9, 91.7, 111.7, 127.3, 127.5, 128.2, 134.5,
136.9, 137.7, 150.9, 163.5, 169.2, 169.9. Anal. Calcd for
C24H26O8N2: C, 61.27; H, 5.57; N, 5.95. Found: C, 60.94;
H, 5.81; N, 5.83.
3.1.11. (1R,3R,4R,5R,6R)-4,5-Dihydroxy-6-hydroxy-
methyl-3-(thymin-1-yl)-2-oxa-bicyclo[3.3.0]octane (16).
Compound 14 (0.20 g, 0.42 mmol) and 20% Pd(OH)2
(0.035 g) in MeOH (6 mL) were stirred under a H2
atmosphere for 12 h. After the usual work up,
(1R,3R,4R,5R,6R)-4,5-diacetoxy-6-hydroxymethyl-3-(thy-
min-1-yl)-2-oxa-bicyclo[3.3.0]octane (0.15 g, 92%) was
isolated as a colorless syrup: [a]DZK28.7 (c 1.2,
CHCl3); nmax (CHCl3) 3462, 3020, 1745, 1694, 1469,
1373, 1241, 1057, 755; 1H NMR (300 MHz, CDCl3): d 1.92
(s, 3H), 1.93–1.96 (m, 4H), 2.07, 2.12 (2s, 6H), 2.45–2.54
(m, 1H), 2.60–2.74 (m, 1H, OH), 3.81 (dd, 1H, JZ5.8,
11.3 Hz), 4.01–4.09 (m, 1H), 4.76 (d, 1H, JZ2.6 Hz), 5.76
(d, 1H, JZ6.8 Hz), 6.05 (d, 1H, JZ6.8 Hz), 7.31 (s, 1H),
9.48–9.62 (m, 1H, NH); 13C NMR (75 MHz, CDCl3): d
12.2, 20.2, 21.1, 26.3, 29.3, 49.8, 60.7, 71.1, 86.9, 90.5,
111.1, 135.6, 150.7, 163.7, 169.4, 170.0. Anal. Calcd for
C17H22O8N2: C, 53.40; H, 5.80; N, 7.33. Found: C, 53.54;
H, 5.52; N, 7.56.
The above compound (0.12 g, 0.31 mmol) and 1 M
methanolic NaOMe (0.1 mL) in MeOH (2 mL) were stirred
for 20 min and worked up as described above to give 16
(0.075 g, 80%) as a solid: mp 182–184 8C; [a]DZK32.9 (c
0.8, MeOH); nmax (MeOH) 3369, 2946, 2834, 1704, 1450,
3.1.10. (1R,3R,4R,5R,6R)-4,5-Dihydroxy-6-hydroxy-
methyl-3-(thymin-1-yl)-2-oxa-bicyclo[3.3.0]oct-7-ene
(6). To a solution of 14 (0.16 g, 0.34 mmol), 1 M methanolic
NaOMe (46 mL) in MeOH (3 mL) were stirred at 0 8C for
20 min. The reaction mixture was neutralized with concd
HCl, filtered and concentrated. The residue was purified by
silica gel column chromatography with MeOH–CH2Cl2
(1:9) to give (1R,3R,4R,5R,6R)-6-benzyloxymethyl-4,5-
dihydroxy-3-(thymin-1-yl)-2-oxa-bicyclo[3.3.0]oct-7-ene
(0.11 g, 88%) as colorless syrup: [a]DZK51.6 (c 0.6,
1
1404, 1111, 1029, 758; H NMR (500 MHz, DMSO-d6): d
1.56–1.60 (m, 1H), 1.65–1.80 (m, 2H), 1.82 (s, 3H), 1.81–
1.85 (m, 1H), 1.89–1.96 (m, 1H), 3.45 (dt, 1H, JZ9.6,
5.5 Hz), 3.73 (dt, 1H, JZ9.6, 4.4 Hz), 3.92 (t, 1H, JZ
7.7 Hz), 4.1 (d, 1H, JZ6.1 Hz), 4.32 (t, 1H, JZ4.9 Hz,
OH), 4.97 (s, 1H, OH), 5.13 (d, 1H, JZ6.9 Hz, OH), 5.65 (d,
1H, JZ8.5 Hz), 7.49 (s, 1H), 11.32 (s, 1H, NH); 13C NMR
(125 MHz, DMSO-d6): d 11.7, 27.0, 29.3, 51.7, 60.1, 70.5,
83.2, 85.0, 88.4, 109.7, 135.8, 150.9, 163.4. Anal. Calcd for
C13H18O6N2: C, 52.34; H, 6.08; N, 9.39. Found: C, 52.12;
H, 6.36; N, 9.37.
1
CHCl3); H NMR (500 MHz, CDCl3): d 1.86 (s, 3H), 3.12
(br s, 1H), 3.73 (d, 2H, JZ6.4 Hz), 4.23 (d, 1H, JZ7.2 Hz),
4.54 (s, 2H), 5.06 (s, 1H), 5.83 (ABq, 2H, JZ5.9 Hz), 6.10
(d, 1H, JZ7.4 Hz), 7.12 (s, 1H), 7.27–7.36 (m, 5H), 9.56 (br
s, 1H, NH); 13C NMR (125 MHz, CDCl3): d 12.5, 52.7,
68.5, 73.5, 75.6, 86.6, 89.1, 93.1, 111.4, 127.8, 127.9, 128.5,
130.6, 134.2, 134.9, 137.6, 151.5, 163.7. Anal. Calcd for
C20H22O6N2: C, 62.17; H, 5.74; N, 7.25. Found: C, 62.12;
H, 5.86; N, 7.52.
Acknowledgements
D.S.R. thanks CSIR, New Delhi for financial support in the
form of Senior Research Fellowship.
The above product (0.065 g, 0.168 mmol) in anhydrous
CH2Cl2 (3 mL) was stirred at K78 8C and then a 1 M
solution of BCl3 in CH2Cl2 (0.42 mL, 0.42 mmol) was
added dropwise. After being stirred for 5 h at K78 8C the
mixture was treated with MeOH (3 mL) and water (0.2 mL)
and stirred at rt for 1 h. The solvents were removed under
vacuum and the residue purified on silica gel using MeOH–
CH2Cl2 (1:9) to afford 6 (0.04 g, 80%) as a solid: mp 90–
92 8C; [a]DZK57.1 (c 0.75, MeOH); nmax (CHCl3) 3391,
2947, 2835, 1675, 1450, 1404, 1111, 1027; 1H NMR
(500 MHz, DMSO-d6): d 1.80 (s, 3H), 2.69–2.73 (m, 1H),
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16. The crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre as deposition No.
CCDC-233198. Copies of the data can be obtained, free of
charge, on application to the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: C44-1223-336033; e-mail:
deposit@ccdc.cam.ac.uk].