Isoxazolinyl Spironucleosides: Stereoselectivity of 1,3-Dipolar Cycloadditions of 7-Methylenepyrrolo[1,2-c]pyrimidin-1(5H)-ones

Article abstract of DOI:10.1055/s-2003-42112

Novel 7-methylenepyrrolo[1,2-c]pyrimidin-1(5H)-ones 11a-c were synthesized from commercially available orotic acid (6). 1,3-Dipolar cycloadditions of mesitonitrile oxide to the exocyclic double bond of the dipolarophiles 11 proceed with complete regioselectivity and lead to the spiroisoxazolinyl nucleosides 13 and 14 in good yields. Attack of the dipole from the less sterically hindered side of the dipolarophile affords C-5/C-7 trans isoxazolines as major isomers predominantly. The protection of the free hydroxyl group by the bulky substituent (TBDPS) leads to formation C-5/C-7 trans isomer 14c exclusively.

Full text of DOI:10.1055/s-2003-42112

2364
LETTER
Isoxazolinyl Spironucleosides: Stereoselectivity of 1,3-Dipolar Cycloadditions
of 7-Methylenepyrrolo[1,2-c]pyrimidin-1(5H)-ones
I
soxazolinyl Spir
ó
a
Department of Organic Chemistry, Slovak University of Technology, 812 37 Bratislava, Slovak Republic
E-mail: fisera@cvt.stuba.sk
b
c
Institute of Applied Synthetic Chemistry, University of Technology, 1060 Vienna, Austria
Department of Chemistry, University Warsaw, 02 093 Warsaw, Poland
Received 14 July 2003
H
N
O
Abstract: Novel 7-methylenepyrrolo[1,2-c]pyrimidin-1(5H)-ones
11a–c were synthesized from commercially available orotic acid
(6). 1,3-Dipolar cycloadditions of mesitonitrile oxide to the exocy-
clic double bond of the dipolarophiles 11 proceed with complete re-
gioselectivity and lead to the spiroisoxazolinyl nucleosides 13 and
14 in good yields. Attack of the dipole from the less sterically hin-
dered side of the dipolarophile affords C-5/C-7 trans isoxazolines
as major isomers predominantly. The protection of the free hydrox-
yl group by the bulky substituent (TBDPS) leads to formation C-5/
C-7 trans isomer 14c exclusively.
O
O
HN
N
O
NH
O
HO
RO
( )n
O
HO
OH
RO
R1
2 n = 1, R, R1=H
1
3 n = 2, R=H, R1=OH
Key words: pyrrolo[1,2-c]pyrimidin-1(5H)-ones, dipolar cycload-
ditions, nitrile oxides, isoxazolines, modified spironucleosides
O
B
O
R
B
R2
N
N
HO
HO
R1
Spironucleosides are useful modifications of the natural
nucleosides with defined architecture around the N-glyco-
sidic bond. Stereochemical factors such as cis/trans glyc-
osyl configuration are important for biological activity
and can be changed when the molecules are bound to an
enzyme, but not in nucleosides, whose torsion angles are
fixed. In connection with the discovery of hydantocidin
(1),1 a natural spiro compound possessing herbicidal and
plant growth regulatory activities, new spiro structures 2¢-
deoxy-6,1¢-ethanouridine 22 and 6,1¢-propanouridine 33
were synthesised (Figure 1).
5
4
B = nucleoside base
Figure 1
For the preparation of the final dipolarophiles 11a–c
(Scheme 1) we decided to use orotic acid (6) as a suitable
and commercially available starting material in the syn-
thesis of 6-substituted pyrimidinones. The corresponding
methyl ester 7 was prepared by the procedure described in
the literature.9 Direct reduction with DIBAL-H/CH2Cl2/–
78 °C gave aldehyde 810 in 90% yield. According to the
literature,11 we carried out allylation of aldehyde 8 with
allyl bromide and Zn dust in anhydrous THF. After col-
umn chromatography we obtained pure homoallyl alcohol
9a as a colorless solid in 85% yield.12 Cyclization to the
more nucleophilic N-1 nitrogen through the bromonium
ion gave a mixture of two difficult to separate isomers 10a
(5,7-cis:5,7-trans = 70:30). In addition to the desired
product 10a the unprotected pyrimidinone 15 was also
isolated (Figure 2). Furthermore, more then one equiva-
lent of bromine results in formation of C-4 brominated de-
rivate 16 (Figure 2). Finally, 7-methylenepyrrolo[1,2-
c]pyrimidin-1(5H)one 11a14 was prepared by elimination
of HBr with DBU11 in 44% yield from the mixture of 5,7-
cis and 5,7-trans isomers of 10a. Lack of success in direct
silylation of the free hydroxyl group of 11a caused us to
turn our attention to the silylation of homoallyl alcohol 9a
using by TBDPSCl/imidazole in CH2Cl2, which gave
compound 9c in 95% yield. Cyclization and subsequent
Insertion of a nitrogen atom into the furanosyl ring gives
the possibility of constructing new modified nucleosides
(isoxazolidines 4 and isoxazolines 5).4 Nucleosides con-
taining nitrogen as the second heteroatom have received
considerable interest for their potential anti-HIV activity
over the last 10 years.5,6 The first example of an isoxazo-
lidinyl nucleoside branched in the C-5 anomeric position
was synthesized by Chiacchio and Romeo. (Figure 1, 4; R
= Me, R1 = H, R2 = CH2OH, B = thymine, adenine).7 1,3-
Dipolar cycloadditions of nitrile oxides and nitrones with
N-vinylated bases represents a means of accessing modi-
fied isoxazolinyl and isoxazolidinyl nucleosides directly.
Based on our previous results from this area,8 we focused
our attention onto the preparation of spiroisoxazolines
via 1,3-dipolar cycloaddition of mesitonitrile oxide 12
with the 7-methylenepyrrolo[1,2-c]pyrimidin-1(5H)-ones
11a–c.
SYNLETT 2003, No. 15, pp 2364–2368
0
1
.1
2
.2
0
0
3
Advanced online publication: 23.10.2003
DOI: 10.1055/s-2003-42112; Art ID: D17103ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Isoxazolinyl Spironucleosides
2365
O
OMe
4
3
HN
2
ref. 9
5
N
6
O
1 N
H
COOH
MeO
N
COOMe
OMe
6
7
OMe
OMe
4
3
H10a
H10b
N
5
N
N
e,f,g
a
b
2
7
OR
6
8
MeO
N
MeO
1 N
O
N
5
9
O
OR
7
9a R=H
8
Br
d
c
10a R = H
10b R = Bz
10c R = TBDPS
9b R = Bz
9c R = TBDPS
OMe
3
2
N
4
h,i,j
11a R = H
11b R = Bz
11c R = TBDPS
1
4a
OR
O
N
5
6
8
7
Scheme 1 (a) DIBAL-H (3 equiv), CH2Cl2, –78 °C, 4 h, 90%; (b) allyl bromide, Zn-dust, THF, reflux, 3 h, 85%; (c) TBDPSCl, imidazole,
CH2Cl2, reflux, 24 h, 95%; (d) BzCl, CH2Cl2, reflux, 48 h, 85%; (e) from 9a: Br2, CHCl3, 60 °C, 4 h, 80%; (f) from 9b: Br2, CHCl3, 60 °C, 4 h,
82%, ref.13; (g) from 9c: Br2, CHCl3, 60 °C, 4 h, 80%; (h) from 10a: DBU, 1,4-dioxane, 80 °C, 2 h, 44%; (i) from 10b: DBU, 1,4-dioxane, reflux,
1 h, 70%; (j) from 10c: DBU, 1,4-dioxane, reflux, 1 h, 70%
Figure 2
elimination afforded 7-methylenepyrrolo[1,2-c]pyrimi- with complete regioselectivity to provide 5-isoxazolines
din-1(5H)-one 11c in 56% yield over two steps.14 By the 13 and 14 in good yields (Scheme 2, Table 1).15 The ap-
same means benzoylated pyrrolo[1,2-c]pyrimidin-1(5H)- proach of the dipole takes place predominantly from the
one 11b was prepared from 9a in total yield of 49%.14
less sterically hindered side of dipolarophiles 11a and 11b
providing a mixture of two 5,7-cis 13a, 13b and 5,7-trans
14a, 14b isomers (Table 1, entries 1 and 2). On the other
Cycloadditions of 7-methylenepyrrolo[1,2-c]pyrimidin-
1(5H)-ones 11a–c with mesitonitrile oxide 12 proceeded
OMe
N
OMe
OMe
3
2
N
4
N
1,4-dioxane
reflux
1
4a
N
O
OR
OR
OR
O
N
O
N
7
O
N
5
6
1'O
O
5'
2'
4'
N
N
3'
11a R = H
11b R = Bz
11c R = TBDPS
12
Mst
13a,13b,13c
Mst
14a,14b,14c
Scheme 2
Synlett 2003, No. 15, 2364–2368 © Thieme Stuttgart · New York

2366
R. Fischer et al.
LETTER
(3) Yoshimura, Y.; Otter, B. A.; Ueda, T.; Matsuda, A. Chem.
Pharm. Bull. 1992, 40, 1761.
Table 1 1,3-Dipolar Cycloadditions of Mesitonitrile Oxide 12 to
Methylenepyrrolo[1,2-c] pyrimidinones 11a–c
(4) (a) Merino, P. Curr. Med. Chem. –Anti-Infective Agents
2002, 1, 389. (b) Pan, S.; Amankulor, N. M.; Zhao, K.
Tetrahedron 1998, 54, 6587.
(5) (a) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. J. Org.
Chem. 2000, 65, 5575. (b) Chiacchio, U.; Rescifina, A.;
Corsaro, A.; Pistara, V.; Romeo, G.; Romeo, R.
Entry
Dipolarophile Total yield (%) cis 13:trans 14a
1
2
3
11a
11b
11c
60
83
79
30:70
17:83
<5:95
Tetrahedron: Asymmetry 2000, 11, 2045. (c) Merino, P.;
Del Alamo, E. M.; Franco, S.; Merchan, F. L.; Simon, A.;
Tejero, T. Tetrahedron: Asymmetry 2000, 11, 1543.
(d) Colacino, E.; Coverso, A.; Liguori, A.; Napoli, A.;
Siciliano, C.; Sindona, G. Tetrahedron 2001, 57, 8551; and
references cited therein.
a Ratios were obtained by 13C NMR (125 MHz) integration of the
crude reaction mixture.
(6) (a) Dalpozzo, R.; De Nino, A.; Maiuolo, L.; Procopio, A.;
De Munno, G.; Sindona, G. Tetrahedron 2001, 57, 4035.
(b) Iannazzo, D.; Piperno, A.; Pistara, V.; Rescifina, A.;
Romeo, R. Tetrahedron 2002, 58, 581. (c) Chiacchio, U.;
Corsaro, A.; Iannazzo, D.; Piperno, A.; Pistara, A.; Procopio,
A.; Rescifina, A.; Romeo, G.; Romeo, R.; Siciliano, M. C.
R.; Valveri, E. Arkivoc 2002, 159.
(7) (a) Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno, A.;
Rescifina, A.; Romeo, R.; Romeo, G. Tetrahedron Lett.
2001, 42, 1777. (b) Iannazzo, D.; Piperno, A.; Pistara, V.;
Rescifina, A.; Romeo, R. Tetrahedron 2002, 58, 581.
(8) (a) Fischer, R.; Drucková, A.; Fišera, L.; Rybár, A.;
Hametner, C.; Cyránski, M. K. Synlett 2002, 1113.
(b) Fischer, R.; Drucková, A.; Fišera, L.; Hametner, C.
Arkivoc 2002, 80.
bulky silyl group proceeded with high stereoselectivity
providing 5,7-trans isoxazoline 14c exclusively. All iso-
mers were purified by column chromatography and were
identified by NMR spectroscopic analysis and NOE dif-
ference experiments.
Based on the results from the NOE experiments protons
H-5, H-6 and H-4¢, for the major isomers 14a–c we as-
signed the C-5/C-7 trans relative configuration
(Figure 3). Thus, attack of the dipole to the exocyclic dou-
ble bond of 11 occurs from the less sterically hindered
side of the ring (Figure 3).16 With a bulky hydroxyl pro-
tecting group at C-5, stereoselectivity of the cycloaddition
was increased in favor of major isomers 14.
(9) Gershon, H. J. Org. Chem. 1962, 27, 3507.
(10) Aldehyde 8 was prepared from 7 by a two-steps process via
selective oxidation of the corresponding alcohol in 84%
yield: Snider, B. B.; Chaoyu, X. Tetrahedron Lett. 1998, 39,
7021.
Acknowledgment
The autors are grateful to the Slovak grant Agency (No. 1/0057/03).
(11) Danel, K.; Pedersen, E. B.; Nielsen, C. Synthesis 1997, 1021.
(12) Procedure for 2,4-Dimethoxy-6-(1-hydroxybut-3-en-1-
yl)pyrimidine (9a): To a stirred suspension of Zn dust (1.98
g, 7.33 mmol) in anhyd THF (50 mL), allyl bromide (1.62
mL, 18.07 mmol) was added, followed by 2,4-dimethoxy-6-
pyrimidinecarbaldehyde (8, 0.60 g, 3.57 mmol) and the
mixture was stirred vigorously under reflux for 3 h. The
reaction mixture was cooled to r.t., quenched with sat. aq
NH4Cl and vigorously stirred with CH2Cl2 (30 mL) for 15
min. The solid was removed by filtration through the Celite®
and the organic layer was separated. The aq phase was
extracted with CH2Cl2 (20 mL) and the combined organic
layers were dried with Na2SO4, filtered and the solvent
removed. The final product was purified by the column
References
(1) Haruyama, H.; Takayama, T.; Kinoshita, T.; Kondo, M.;
Nakajima, M.; Haneishi, T. J. Chem. Soc., Perkin Trans. 1
1991, 1637.
(2) (a) Kittaka, A.; Tanaka, H.; Odanaka, Y.; Ohnuki, K.;
Yamaguchi, K.; Miyasaka, T. J. Org. Chem. 1994, 59, 3636.
(b) Kittaka, A.; Asakura, T.; Kuze, T.; Tanaka, H.; Yamada,
N.; Nakamura, K. T.; Miyasaka, T. J. Org. Chem. 1999, 64,
7081. (c) Chatgilialoglu, C.; Gimisis, T.; Spada, G. P.
Chem.–Eur. J. 1999, 5, 2866.
O
N
O
N
O
O
O
H4b'
N
H4b'
N
N
H
H
7
7
N
4a' H
O
H5
Bz
H4a'
H5
6a
H6b
6b
6a
Bz
O
H
O
H
H
5,7-trans
5,7-cis
14b
13b
Figure 3 Positive NOE’s for the protons H-4¢, H-5 and H-6 in the case of the both isomers 13b and 14b
Synlett 2003, No. 15, 2364–2368 © Thieme Stuttgart · New York

LETTER
chromatography on silica gel (hexane–EtOAc, 3:1) giving
Isoxazolinyl Spironucleosides
2367
130.3, 134.3 (COPh), 141.0 (C-7), 154.8 (C-1), 157.5
(COPh), 166.0 (C-8), 171.5 (C-3).
(15) General Procedure: Mesitonitrile oxide 12 and 7-
methylenepyrrolo[1,2-c]pyrimidin-1(5H)-one 11 were
homoallyl alcohol 9a (0.63 g) as a colourless solid; yield
85%; mp 131–133 °C. 1H NMR (400 MHz, CDCl3): d = 2.46
(ddddd, J7,8a = 7.3 Hz, J8a,8b = 14.3 Hz, J8a,9 = 7.3 Hz,
J8a,10a = 1.2 Hz, J8a,10b = 1.2 Hz, 1 H, H-8a), 2.63 (ddddd,
J7,8b = 4.7 Hz, J8a,8b = 14.0 Hz, J8b,9 = 7.0 Hz, J8b,10a = 1.5 Hz,
J8b,10b = 1.2 Hz, 1 H, H-8b), 3.37 (d, J7,OH = 5.0 Hz, 1 H, OH),
3.97, 4.00 (2 × s, 2 × 3 H, OCH3), 4.62 (ddd, J7,OH = 4.7 Hz,
dissolved in 1,4-dioxane and stirred under reflux. When no
starting material remained (TLC), the solvent was removed
in vacuo and the products of the cycloaddition were isolated
by column chromatography (hexane–ethyl acetate).
J7,8a = 7.6 Hz, J7,8b = 4.7 Hz, 1 H, H-7), 5.13 (dddd, J8a,10b
=
Selected data: (5,7-trans)-4¢,5¢,6,7-Tetrahydro-3¢-(2,4,6-
trimethylphenyl)-3-methoxy-5-hydroxyspiro[pyr-
rolo[1,2-c]pyrimidine-7(5H),5¢-izoxazol]-1-one (14a):
Yield 42%; colorless solid; mp 241–243 °C. 1H NMR (400
MHz, DMSO-d6): d = 2.26 (s, 3 H, 4-CH3Ph), 2.31 (s, 6 H,
2,6-CH3Ph), 2.41 (dd, J5,6a = 8.8 Hz, J6a,6b = 13.7 Hz, 1 H, H-
6a), 2.87 (dd, J5,6b = 7.6 Hz, J6a,6b = 13.7 Hz, 1 H, H-6b), 3.44
(d, J4a¢,4b¢ = 18.7 Hz, 1 H, H-4a¢), 3.85 (s, 3 H, OCH3), 4.22
(d, J4a¢,4b¢ = 18.7 Hz, 1 H, H-4b¢), 5.13 (dddd, J4,5 = 1.5 Hz,
J5,OH = 5.8 Hz, J5,6a = 8.8 Hz, J5,6b = 7.3 Hz, 1 H, H-5), 6.05
(d, J4,5 = 1.2 Hz, 1 H, H-4), 6.29 (d, J5,OH = 5.8 Hz, 1 H, OH),
6.93 (s, 2 H, Ph). 13C NMR (125 MHz, DMSO-d6): d = 20.4
(2,6-CH3Ph), 21.5 (4-CH3Ph), 46.3, 46.4 (C-6, C-4¢), 55.1
(OCH3), 68.4 (C-5), 90.7 (C-4), 102.6 (C-5¢/C-7), 126.4 (C-
4-Ph), 129.2 (CH-Ph), 137.7 (C-2,6-Ph), 139.1 (C-1-Ph),
153.8 (C-1), 158.4 (C-3¢), 164.9 (C-4a), 173.1 (C-3).
(5,7-trans)-4¢,5¢,6,7-Tetrahydro-3¢-(2,4,6-trimethyl-
phenyl)-3-methoxy-5-tert-butyldiphenylsilyloxy-
spiro[pyrrolo[1,2-c]pyrimidine-7(5H),5¢-izoxazol]-1-one
(14c): Yield 79%; colorless solid; mp 214–215 °C. 1H NMR
(400 MHz, CDCl3): d = 1.12 [s, 9 H, OSiC(CH3)3], 2.28 (s,
3 H, 4-CH3Ph), 2.37 (s, 6 H, 2,6-CH3Ph), 2.32 (dd, J5,6a = 8.8
Hz, J6a,6b = 13.2 Hz, 1 H, H-6a), 2.67 (dd, J5,6b = 7.3 Hz,
J6a,6b = 13.2 Hz, 1 H, H-6b), 3.09 (d, J4a¢,4b¢ = 18.4 Hz, 1 H,
H-4a¢), 3.94 (s, 3 H, OCH3), 4.52 (d, J4a¢,4b¢ = 18.4 Hz, 1 H,
H-4b¢), 5.25 (ddd, J4,5 = 1.2 Hz, J5,6a = 8.8 Hz, J5,6b = 7.3 Hz,
1 H, H-5), 5.77 (d, J4,5 = 1.2 Hz 1 H, H-4), 6.89 (s, 2 H, H-
Ph), 7.41–7.70 (m, 10 H, OSiPh2). 13C NMR (125 MHz,
CDCl3): d = 19.6 [OSiC(CH3)3], 20.4 (2,6-CH3Ph), 21.5
(4-CH3Ph), 27.3 [OSiC(CH3)3], 46.5, 47.6 (C-6, C-4¢), 55.3
(OCH3), 70.4 (C-5), 91.7 (C-4), 101.6 (C-5¢/C-7), 125.5 (C-
4-Ph), 128.5, 128.6, 129.0, 130.9, 131.0, 132.4, 132.8, 136.1
(CHPh, OSiPh2), 137.8 (C-2,6-Ph), 139.4 (C-1-Ph), 154.3
(C-1), 158.2 (C-3¢), 162.2 (C-4a), 173.2 (C-3).
(5,7-cis)-4¢,5¢,6,7-Tetrahydro-3¢-(2,4,6-trimethylphenyl)-
3-methoxy-5-benzoyloxyspiro[pyrrolo[1,2-c]pyrimidine-
7(5H),5¢-izoxazol]-1-one (13b): Yield 14%; colorless solid;
mp 164–165 °C. 1H NMR (400 MHz, CDCl3): d = 2.30 (s, 3
H, 4-CH3Ph), 2.43 (s, 6 H, 2,6-CH3Ph), 2.85 (dd, J5,6a = 7.0
Hz, J6a,6b = 15.1 Hz, 1 H, H-6a), 2.99 (dd, J5,6b = 2.3 Hz,
J6a,6b = 15.1 Hz, 1 H, H-6b), 3.23 (d, J4a¢,4b¢ = 18.4 Hz, 1 H,
H-4a¢), 3.97 (s, 3 H, OCH3), 4,50 (d, J4a¢,4b¢ = 18.4 Hz, 1 H,
H-4b¢), 6.14 (d, J4,5 = 0.9 Hz, 1 H, H-4), 6.22 (ddd, J4,5 = 0.9
Hz, J5,6a = 7.0 Hz, J5,6b = 2.3 Hz, 1 H, H-5), 6.92 (s, 2 H, Ph),
7.45–8.11 (m, 5 H, COPh). 13C NMR (125 MHz, CDCl3),
d = 20.4 (2,6-CH3Ph), 21.5 (4-CH3Ph), 44.5, 46.9 (C-6, C-
4¢), 55.5 (OCH3), 69.8 (C-5), 94.4 (C-4), 102.9 (C-5¢/C-7),
125.4 (C-4-Ph), 129.0, 130.5, 134.3 (CHPh, COPh), 137.9
(C-2,6-Ph), 139.5 (C-1-Ph), 154.2 (C-1), 156.9 (COPh),
158.0 (C-3¢), 166.2 (C-4a), 173.3 (C-3).
(5,7-trans)-4¢,5¢,6,7-Tetrahydro-3¢-(2,4,6-trimethyl-
phenyl)-3-methoxy-5-benzoyloxyspiro[pyrrolo[1,2-
c]pyrimidine-7(5H),5¢-izoxazol]-1-one (14b): Yield 69%;
colorless solid; mp 210–212 °C. 1H NMR (400 MHz,
CDCl3): d = 2.30 (s, 3 H, 4-CH3Ph), 2.42 (s, 6 H, 2,6-
CH3Ph), 2.57 (dd, J5,6a = 7.3 Hz, J6a,6b = 14.0 Hz, 1 H, H-6a),
3.25 (d, J4a¢,4b¢ = 18.4 Hz, 1 H, H-4a¢), 3.34 (dd, J5,6b = 7.6 Hz,
J6a,6b = 14.0 Hz, 1 H, H-6b), 3.98 (s, 3 H, OCH3), 4.58 (d,
1.2 Hz, J8b,10b = 1.2 Hz, J9,10b = 10.2 Hz, J10a,10b = 1.8 Hz, 1
H, H-10b), 5.14 (dddd, J8a,10a = 1.5 Hz, J8b,10a = 1.5 Hz,
J9,10a = 17.0 Hz, J10a,10b = 2.0 Hz, 1 H, H-10a), 5.81 (dddd,
J8a,9 = 7.0 Hz, J8b,9 = 7.0 Hz, J9,10a = 17.0 Hz, J9,10b = 10.2 Hz,
1 H, H-9), 6.39 (d, J5,7 = 0.6 Hz, 1 H, H-5). 13C NMR (125
MHz, CDCl3): d = 42.2 (C-8), 54.4, 55.2 (OCH3), 72.2
(C-7), 97.9 (C-5), 119.0 (C-10), 133.9 (C-9), 165.4 (C-6),
172.5, 173.0 (C-2, C-4).
(13) Procedure for 10a: The stirred solution of the homoallyl
alcohol 9b (0.20 g, 0.64 mmol) in CHCl3 (20 mL) was
warmed to 60 °C and a solution of Br2 (0.10 g, 0.03 mL, 0.64
mmol) in CHCl3 (10 mL) was slowly added dropwise over 4
h. The solvent was removed in vacuo and the reaction
products were isolated by column chromatography on silica
gel (hexane–EtOAc, 1:1) giving pyrimidinone 10b as a
mixture of cis/trans isomers (0.20 g, 82%) as colorless foam.
(14) Selected data: 6,7-Dihydro-5-hydroxy-3-methoxy-7-
methylenepyrrolo[1,2-c]pyrimidin-1(5H)-one (11a):
Yield 44%; colorless solid; mp 192–193 °C. 1H NMR (400
MHz, DMSO-d6): d = 2.60 (dddd, J5,6a = 6.1 Hz, J6a,6b = 16.1
Hz, J6a,10a = 2.1 Hz, J6a,10b = 2.4 Hz, 1 H, H-6a), 3.07 (dddd,
J5,6b = 8.2 Hz, J6a,6b = 16.1 Hz, J6b,10a = 1.5 Hz, J6b,10b = 1.8
Hz, 1 H, H-6b), 3.86 (s, 3 H, OCH3), 4.89 (dd, J6a,10a = 2.1
Hz, J6b,10a = 1.5 Hz, J10a,10b = 0 Hz, 1 H, H-10a), 4.98 (dddd,
J5,OH = 6.1 Hz, J4,5 = 1.2 Hz, J5,6a = 6.1 Hz, J5,6b = 8.2 Hz, 1
H, H-5), 6.08 (d, J4,5 = 1.2 Hz, 1 H, H-4), 6.10 (d, J5,OH = 6.1
Hz, 1 H, OH), 6.14 (dd, J6a,10b = 2.3 Hz, J6b,10b = 1.8 Hz, 1 H,
H-10b). 13C NMR (125 MHz, DMSO-d6): d = 38.2 (C-6),
55.1 (OCH3), 68.0 (C-5), 91.5 (C-4), 99.1 (C-10), 143.1 (C-
7), 154.2 (C-1), 164.7 (C-8), 171.6 (C-3).
6,7-Dihydro-5-tert-butyldiphenylsilyloxy-3-methoxy-7-
methylenepyrrolo[1,2-c]pyrimidin-1(5H)-one (11b):
Yield 66%; colorless syrup. 1H NMR (400 MHz, CDCl3):
d = 1.10 [s, 9 H, OSiC(CH3)3], 2.68 (dddd, J5,6a = 7.9 Hz,
J6a,6b = 15.2 Hz, J6a,10a = J6a,10b = 1.2 Hz, 1 H, H-6a), 2.76
(dddd, J5,6b = 7.3 Hz, J6a,6b = 15.2 Hz, J6b,10a = J6b,10b = 2.3 Hz,
1 H, H-6b), 3.95 (s, 3 H, OCH3), 4.82 (ddd, J6a,10a = J10a,10b
=
1.2 Hz, J6b,10a = 2.1 Hz, 1 H, H-10a), 4.98 (ddd, J4,5 = 1.2 Hz,
J5,6a = 7.9 Hz, J5,6b = 7.3 Hz, 1 H, H-5), 5.77 (d, J4,5 = 1.2 Hz,
1 H, H-4), 6.28 (ddd, J6a,10b = J10a,10b = 1.2 Hz, J6b,10b = 2.3
Hz, 1 H, H-10b), 7.40–7.68 (m, 10 H, OSiPh2). 13C NMR
(125 MHz, CDCl3): d = 19.6 [OSiC(CH3)3], 27.2
[OSiC(CH3)3], 39.3 (C-6), 55.2 (OCH3), 70.4 (C-5), 92.0
(C-4), 100.6 (C-10), 128.4, 128.5, 130.8, 132.7, 133.0, 136.1
(OSiPh2), 141.3 (C-7), 154.8 (C-1), 161.9 (C-8), 171.6
(C-3).
6,7-Dihydro-5-benzoyloxy-3-methoxy-7-methylene-
pyrrolo[1,2-c]pyrimidin-1(5H)-one (11c): Yield 80%;
colorless syrup. 1H NMR (400 MHz, CDCl3): d = 2.96
(dddd, J5,6a = 4.6 Hz, J6a,6b = 16.9 Hz, J = 1.8 Hz, J = 2.1 Hz,
1 H, H-6a), 3.33 (dddd, J5,6b = 8.2 Hz, J6a,6b = 16.9 Hz, J =
1.8 Hz, J = 2.1 Hz, 1 H, H-6b), 3.98 (s, 3 H, OCH3), 5.01
(ddd, J10a,10b = 1.2 Hz, J = 1.8 Hz, J = 2.1 Hz, 1 H, H-10a),
6.13 (d, J4,5 = 0.9 Hz, 1 H, H-4), 6.19 (ddd, J4,5 = 0.9 Hz,
J5,6a = 4.6 Hz, J5,6b = 8.2 Hz, 1 H, H-5), 6.46 (ddd, J10a,10b
=
1.2 Hz, J = 1.8 Hz, J = 2.1 Hz, 1 H, H-10b), 7.44–8.04 (m,
5 H, COPh). 13C NMR (125 MHz, CDCl3): d = 35.4 (C-6),
55.4 (OCH3), 69.8 (C-5), 94.0 (C-4), 101.1 (C-10), 129.1,
J
4a¢,4b¢ = 18.1 Hz, 1 H, H-4b¢), 6.06 (d, J4,5 = 1.2 Hz, 1 H, H-
Synlett 2003, No. 15, 2364–2368 © Thieme Stuttgart · New York

2368
R. Fischer et al.
LETTER
(16) (a) Pereira, S. M.; Savage, G. P.; Simpson, G. W.;
4), 6.37 (ddd, J4,5 = 1.2 Hz, J5,6a = 7.3 Hz, J5,6b = 7.6 Hz, 1 H,
H-5), 6.92 (s, 2 H, H-Ph), 7.46–7.65 (m, 5 H, COPh). 13
C
Greenwood, R. J.; Mackay, M. F. Aust. J. Chem. 1993, 46,
1401. (b) Fišera, L.; Jarošková, L.; Matejková, I.;
Heimgartner, H. Heterocycles 1995, 1, 271. (c) Micúch, P.;
Fišera, L.; Ondruš, V.; Ertl, P. Molecules 1997, 2, 57.
(d) Cheng, W.-C.; Liu, Y.; Wong, M.; Olmstead, M. M.;
Lam, K. S.; Kurth, M. J. J. Org. Chem. 2002, 67, 5673.
(e) Melsa, P.; Mazal, C. Collect. Czech. Chem. Commun.
2002, 67, 353.
NMR (125 MHz, CDCl3): d = 20.3 (2,6-CH3Ph), 21.5 (4-
CH3Ph), 44.9, 47.0 (C-6, C-4¢), 55.5 (OCH3), 70.4 (C-5),
93.1 (C-4), 102.3 (C-5¢/C-7), 125.4 (C-4-Ph), 129.0, 129.1,
130.3, 134.5 (CHPh, COPh), 137.9 (C-2,6-Ph), 139.6 (C-1-
Ph), 154.2 (C-1), 157.7 (COPh), 158.2 (C-3¢), 165.8 (C-4a),
173.2 (C-3).
(17) Crystallographic data for the structure 15 and 16 have been
deposited with the Cambridge Crystallographic Data Centre.
Copies of the data can be obtained on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (email:
deposit@ccdc.cam.ac.uk).
Synlett 2003, No. 15, 2364–2368 © Thieme Stuttgart · New York