Synthesis and bridgehead reactions of 9-substituted 5,6,7,8,9,10-hexahydro-5,9-methanopyrimido[4,5-b]azocin-4(3H)-ones

Article abstract of DOI:10.3987/com-03-s3

The condensation of a variety of 6-amino-4(3H)-pyrimidinones with 2-cyclohexen-1-one in water, and replacement of the bridgehead 9-hydroxy group in the resulting Michael/cyclization adducts with carbon nucleophiles, are described. These reactions have bee

Full text of DOI:10.3987/com-03-s3

HETEROCYCLES, Vol. 61, 2003
113
HETEROCYCLES, Vol. 61, 2003, pp. 113 - 123
Received, 21st January, 2003, Accepted, 9th May, 2003, Published online, 13th May, 2003
SYNTHESIS AND BRIDGEHEAD REACTIONS OF
9-SUBSTITUTED 5,6,7,8,9,10-HEXAHYDRO-5,9-
METHANOPYRIMIDO[4,5-b]AZOCIN-4(3H)-ONES
Edward C. Taylor* and Beena Bhatia§
Department of Chemistry, Princeton University
Princeton, New Jersey 08544, USA
e-mail: etaylor@princeton.edu
Abstract - The condensation of a variety of 6-amino-4(3H)-pyrimidinones
with 2-cyclohexen-1-one in water, and replacement of the bridgehead 9-hydr-
oxy group in the resulting Michael/cyclization adducts with carbon nucleo-
philes, are described. These reactions have been exploited for the preparation
of a novel bridged tricyclic analog of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid
(DDATHF).
6-Amino-4(3H)-pyrimidinones behave as enaminones, with electrophilic reactions such as nitrosation,
nitration, acylation and diazo coupling taking place at C-5.1 Michael reactions have also been observed
to take place at C-5. a,b-Unsaturated carbonyl compounds lead directly to condensed pyrimidines such
as pyrido[2,3-d]pyrimidines and quinolino[2,3-d]pyrimidines (or their dihydro derivatives) by
intramolecular cyclization of the initial Michael adducts through participation of the pyrimidine 6-amino
grouping.2 Activated azo compounds (diethyl azodicarboxylate, 4-phenyl-1,2,4-triazoline-3,5-dione) can
also react as Michael acceptors to give 5-hydrazino derivatives that serve as versatile intermediates for
the synthesis of purines, isoalloxazines, alloxazines, toxoflavins, and fervenulins.3 Michael addition of
nitrosoolefins (prepared in situ by dehydrohalogenation of a-halo oximes)4 and of nitro olefins5 are also
known, and lead through subsequent transformations of the initial Michael adducts to pyrrolo[2,3-
d]pyrimidines, following the above mentioned intramolecular participation of the pyrimidine-6-amino
group.
NH
NH
2
NH
2
O
2
N
NH
N
NH
N
NH
+
H N
2
O
O
H N
2
O
HN
1a
2
4a (65%)
HO
O
3

114
HETEROCYCLES, Vol. 61, 2003
We recently reported an extension of this Michael addition/cyclization concept to the sodium
methoxide-promoted reaction of 2,6-diamino-4(3H)-pyrimidinone (1a) with 2-cyclohexen-1-one (2).6
The initially formed Michael adduct (3) undergoes irreversible hemiaminal formation through
intramolecular cyclization of the cyclohexanone carbonyl group with the 6-amino pyrimidine
substituent to give the novel tricyclic azabicyclo[3.3.1]nonane structure (4a). We have also described
a number of subsequent transformations of 4a involving conversion to (5),7 and replacement of the
hemiaminal –OH group by –SR, -OR, and -NR2 via a 2-azabicyclo[3.3.1]non-1-ene anti-Bredt
bridgehead imine intermediate.6,7 In view of the overall structural resemblance between these
O
NH
2
HN
N
N
NH
2
HN
NH
2
5
6
derivatives of 4a (such as 5) and Huperazine A (6) as well as initial molecular modeling studies
indicating that 5 appears to match trimethoprim reasonably well as a ligand for the active site of P.
carinii DHFR,8 we have studied several additional aspects of the chemistry of these readily available
tricyclic compounds, with the results reported herein.
Condensation of 1a with 2-cyclohexen-1-one (2) to give 4a, as carried out in our initial studies,
was promoted by sodium methoxide in methanol, but other 6-aminopyrimidines failed to react under
these conditions. We have now found that this reaction can be carried out very effectively simply by
heating the reactants in water, and that these conditions are successful with a variety of 6-
aminopyrimidines (see Table 1). Yields are generally good, and the products are readily obtained by
cooling and filtering the aqueous reaction mixture. Although 2,4,6-triaminopyrimidine (1g) failed to
react with 2 in aqueous solution, the reaction proceeded successfully in glacial acetic acid to give 4g,
as noted previously.7
We have now extended to carbon nucleophiles the protocol previously employed for replacement of
the tertiary hemiaminal –OH grouping in 4a with –SH, -OR, -NR2 and –H. Reaction of the N,O-
dipivaloyl derivative(7)6 with Grignard reagents (ethynylmagnesium bromide, ethylmagnesium
bromide, benzylmagnesium bromide, allylmagnesium bromide) resulted in smooth introduction of the
corresponding carbon nucleophile into the tertiary position to give 8a-d. A similar series of

HETEROCYCLES, Vol. 61, 2003
115
Table 1. Reaction of 6-Aminopyrimidines (1b-g) with 2-Cyclohexen-1-one
Substrate
Product (yield)
NH2
NH2
N
NH
N
NH
O
CH3N
HO
CH3NH
O
1b
4b (56%)
NH2
N
NH2
N
N
N
H2N
Cl
Cl
HN
HO
4c (34%)
1c
S
S
O
O
HN
H2N
NH
HN
HN
NH
O
O
1d
4d (73%)
HO
O
HN
NH
HN
NH
O
H2N
O
HN
1e
4e (62%)
HO
O
CH3N
HN
NCH3
CH3N
H2N
NCH3
O
O
1f
4f (58%)
HO
NH2
N
NH2
N
N
N
NH2
HN
H2N
NH2
1g
4g (41%)
HO
(in HOAc)

116
HETEROCYCLES, Vol. 61, 2003
Table 2. Introduction of Bridgehead Carbon Substituents
NHPiv
NHPiv
NH
N
NH
N
O
RMgBr
HN
O
HN
R
PivO
7
8
NHPiv
N
NHPiv
N
N
N
RMgBr
NHPiv
NHPiv
HN
HN
R
PivO
9
10
a, R = -CH2CH=CH2
b, R = C CH
c, R = -C2H5
d, R = -CH2C6H5
Scheme 1
NHPiv
NH
N
C2H5O2C
O
C2H5O2C
N
H
O
+
HN
I
NHPiv
NH
8a
N
O
C2H5O2C
C2H5O2C
O
HN
N
H
11
1. [H]
2. HO-
NH2
NH
N
O
HO2C
O
HN
HO2C
N
H
12

HETEROCYCLES, Vol. 61, 2003
117
derivatives (10a-d) was prepared from 9, the tripivaloyl derivative of 4g7 (see Table 2). The
bridgehead allyl derivative (8a) was subjected to a palladium-catalyzed Heck coupling with diethyl 4-
iodobenzoyl-L-glutamate to give 11. Hydrogenation of 11 followed by hydrolysis of the pivaloyl and
ester groups gave the intriguing lipophilic analog (12) of DDATHF.9
EXPERIMENTAL
2-Amino-5,6,7,8,9,10-hexahydro-9-hydroxy-5,9-methanopyrimido[4,5-b]azocin-4(3H)-one (4a).
To a suspension of 2,6-diamino-4(3H)-pyrimidinone (1a) (0.63 g, 5 mmol ) in 10 mL of distilled
water, 2-cyclohexen-1-one (2) (0.48 g, 5 mmol) was added and the mixture was heated at 80 ˚C for 20
h. The resulting solid was collected by filtration, washed with water (2x10 mL) followed by methanol
(2x10 mL) and dried under vacuum to give 0.72 g (65%) of 4a as a white powder, mp 310-312 ˚C
(from methanol/ether). This compound was identical in all respects (mp, NMR, MS, IR) with an
authentic sample of 4a.6
2-Amino-5,6,7,8,9,10-hexahydro-9-hydroxy-10-methyl-5,9-methanopyrimido[4,5-b]azocin-
4(3H)-one (4b).
To a suspension of 2-amino-6-methylamino-4(3H)-pyrimidinone (1b) (0.32 g, 2.5 mmol) in 10 ml of
H O, 2-cyclohexen-1-one (2) (0.48 g, 5 mmol) was added. After heating the reaction mixture at 90
2
˚C for 25 h, a light brown solid precipitated. The solid was absorbed on silica gel and purified by
column chromatography using 10% MeOH/CH Cl as eluent to give 0.33 g (56%) of 4b as a pale
2
2
brown solid, mp 261-262 ˚C (from methanol/ether). This compound was identical in all respects (mp,
NMR, MS, IR) with an authentic sample of 4b.6
2-Amino-4-chloro-5,6,7,8,9,10-hexahydro-9-hydroxy-5,9-methanopyrimido(4,5-b)azocine (4c).
A solution of 4-chloro-2,6-diaminopyrimidine (1c) (0.65 g, 5 mmol) was heated with 2-cyclohexen-1-
one (2) (0.96 g, 10 mmol) in 10 mL of H O for 23 h. The suspended solid was collected by filtration
2
and subjected to column chromatography on silica using 2% MeOH/CH Cl as eluent. Evaporation
2
2
of the fractions corresponding to an R value of 0.5 on TLC, using 10% MeOH/CH Cl gave 0.41 g
f
2
2,
1
(34%) of 4c as a white solid, mp 183-185 ˚C (from methanol/ether); H NMR (DMSO-d , 500 MHz):
6
d 1.60 (m, 2H), 1.95 (m, 2H), 2.21 (m, 1H), 2.32 (dd, 2H, J =1.6 and 11.6 Hz), 2.52 (m, 1H), 4.18 (br
13
s, 1H), 5.68 (s, 1H),) 6.41 (s, 2H), 7.20 (d, 1H, J = 1.6 Hz); C NMR(DMSO-d , 500
6
MHz): d 208.82, 163.05, 162.93, 48.65, 47.32, 40.28, 40.01, 30.19, 21.61; MS m/z (relative intensity)
240(4), 197(22), 144(71), 109(1); HRMS calcd for C H N OCl: 240.0778; Found: 240.0779; Anal
10 13
4
Calcd for C H N OCl: C, 49.90; H, 5.44; N, 23.27. Found: C, 49.60; H, 5.38; N, 23.17.
10 13
4
5,6,7,8,9,10-Hexahydro-9-hydroxy-2-mercapto-5,9-methanopyrimido[4,5-b]azocin-4(3H)-one
(4d).

118
HETEROCYCLES, Vol. 61, 2003
To a suspension of 6-amino-2-mercapto-4(3H)-pyrimidinone (1d) (0.71 g, 5 mmol) in 10 mL of H O,
2
2-cyclohexen-1-one (2) (0.72 g, 7.5mmol) was added. The reaction mixture was heated at 80 ˚C for
26 h. The white suspension was collected by filtration, washed with H O (20 mL) followed by
2
methanol (20 mL) and dried under vacuum to give 4d (0.88 g, 73%) as a white powder, mp 298 ˚C
1
(decomp, after recrystallization from water); H NMR(DMSO-d , 500 MHz): d 1.30 (m, 2H), 1.48
6
(m, 2H), 1.56 (m, 2H), 1.74 (m, 2H), 2.97 (s, 1H), 6.04 (s, 1H), 6.17 (s, 1H), 11.33 (s, 1H), 11.62 (s,
1H). 13C NMR (DMSO-d6, 125 MHz); d 173.1, 159.3, 149.5, 88.3, 80.3, 40.7, 37.1, 29.6, 27.3, 19.3.
MS m/z (relative intensity) 239(67), 196(100), 137(19); HRMS calcd for C H N O S: 239.0728;
10 13 3 2
Found: 239.0735; Anal Calcd for C H N O S: C, 50.19; H, 5.47; N, 17.56. Found: C, 50.05; H,
10 13 3 2
5.33; N, 17.60.
5,6,7,8,9,10-Hexahydro-9-hydroxy-5,9-methanopyrimido[4,5-b]azocin-2,4(1H,3H)-dione (4e).
A suspension of 6-aminouracil (1e) (0.68 g, 5 mmol) was refluxed with 2-cyclohexen-1-one (2) (1.92
g, 20 mmol) in H O (10 mL) for 36 h. The suspension was filtered to give a white powder.
2
1
Recrystallization from aqueous DMF afforded 0.69 g (62%) of 4e, mp 291˚C decomp; H NMR
(DMSO-d , 500 MHz): d 1.32 (d, 2H, J = 9.0 Hz), 1.45 (m, 2H), 1.60 (m, 2H), 1.70 (m, 2H), 2.94 (s,
6
13
1H), 5.97 (s, 1H), 6.03 (s, 1H), 9.74 (s, 1H), 10.09 (s, 1H). C NMR (DMSO-d , 125 MHz):
6
d 161.9, 150.3, 150.2, 83.4, 80.3, 40.7, 37.8, 29.9, 19.3; IR(KBr) 3499, 3238, 2957, 1675, 1604, 1520
-1
cm ; MS m/z (relative intensity) 223(25), 180(77), 68(100); HRMS calcd for C H N O :
10 13
3 3
223.0957; Found: 223.0966; Anal Calcd for C H N O : C, 53.80; H, 5.86; N, 18.82. Found: C,
10 13
3 3
53.48; H, 5.73; N, 18.80.
1,3-Dimethyl-5,6,7,8,9,10-hexahydro-9-hydroxy-5,9-methanopyrimido[4,5-b]azocin-2,4-dione
(4f).
A solution of 6-amino-1,3-dimethyluracil (1f) (0.78 g, 5 mmol) was heated at 80 ˚C with 2-
cyclohexen-1-one (2) ( 0.48 g, 5 mmol) in 10 mL of water for 19 h and the reaction mixture was then
cooled to rt. The precipitated solid was collected by filtration and purified by chromatography on
silica using 5% MeOH/CH Cl as eluent. Evaporation of fractions with an R value of 0.5 (on TLC
2
2
f
using 20% MeOH/CH Cl gave 0.73 g (58%) of 4f as white flakes, mp 231-232 ˚C (from
2)
2
1
methanol/ether). H NMR(DMSO-d , 500 MHz): d 1.40 (m, 2H), 1.48 (m, 2H), 1.52 (m, 2H), 1.66 (d,
6
1H, J = 11.6 Hz), 1.74 (dd, 1H, J = 1.6, 11.6 Hz) 1.90 ( d, 1H, J = 12.8 Hz), 3.10 (s, 1H), 3.15 (s, 3H),
13
3.33 (s, 3H), 6.03 (s, 1H), 6.98 (s, 1H). C NMR (DMSO-d , 125 MHz): d 159.7, 151.0, 150.0, 84.7,
6
81.2, 40.5, 37.6, 29.8, 29.1, 28.1, 27.2, 19.3; MS m/z (relative intensity) 251(55), 234(24), 208(100);
HRMS calcd for C H N O : 251.1270. Found: 251.1275 ; Anal Calcd for C H N O : C, 57.34;
12 17
3
3
12 17 3 3
H, 6.82; N, 16.73. Found: C, 57.16; H, 6.65; N, 16.58.
General Procedure for the Preparation of 8a-d and 10a-d:

HETEROCYCLES, Vol. 61, 2003
119
The appropriate Grignard reagent (in THF or ether solution, 5 eq.) was added dropwise to the
solid 9-pivaloyloxy derivatives (7)6 and (9)7 at 0 ˚C, and the resulting mixture was stirred for 1h.
The reaction mixture was then partitioned between EtOAc (20 mL) and saturated aq. NH4Cl
solution (20 mL) and the aqueous phase was extracted with an additional 20 mL of EtOAc. The
combined organic phases were washed with 20 mL of a saturated aq. NaCl solution, dried over
MgSO4 filtered and concentrated in vacuo. The C-9 alkylated products were obtained as colorless
solids by purification of the residual solid by column chromatography using 2-5% MeOH/CH2Cl2
as eluent.
2-Pivaloylamino-9-allyl-5,6,7,8,9,10-hexahydro-5,9-methanopyrimido[4,5-b]azocin-4(3H)-
one (8a).
1
H NMR(CDCl , 500 MHz): d 1.29 (s, 9H), 1.38 (m, 2H), 1.43 (m, 2H), 1.1 (m, 2H), 1.67 (m,
3
1H), 1.80 (d, 1H, J = 10.5 Hz), 2.16 (dd, 1H, J = 8.8, 13.73), 2.30 (dd, 1H, J = 6.10, 12.73 Hz),
13
3.29 (s, 1H), 4.74 (s, 1H), 5.16 (m, 2H), 5.84 (m, 1H), 8.07 (s, 1H), 11.21 (s, 1H). C NMR
(CDCl , 125 MHz): d 19.0, 26.6, 27.2, 31.1, 35.6, 39.7, 40.3, 46.6, 52.7, 94.2, 119.8, 132.5, 148.5,
3
-1
159.6, 159.7, 179.7; IR (KBr) 3384, 3272, 2932, 1641, 1564 cm ; MS m/z (relative intensity)
330 (50), 289 (100), 287 (94); mp 209 °C. HRMS calcd for C H N O : 330.2055. Found:
18 26 4 2
330.2054.
2-Pivaloylamino-9-ethynyl-5,6,7,8,9,10-hexahydro-5,9-methanopyrimido[4,5-b]azocin-4(3H)-
one (8b).
1
H NMR(DMSO-d , 500 MHz): d 1.21 (s, 9H), 1.26 (m, 1H), 1.48 (m, 3H), 1.68 (m, 1H), 1.74
6
(m, 1H), 1.95 (d, 1H, J = 12.51 Hz), 1.98 (d, 1H, J = 3.66 Hz), 3.01(s, 1H), 3.39 (s, 1H), 6.91 (s,
13
1H), 10.55 (s, 1H), 11.27 (s, 1H). C NMR (DMSO-d , 125 MHz): d 181.1, 159.2, 158.4, 149.0,
6
118.9, 91.9, 87.3, 73.1, 47.8, 41.0, 36.1, 29.9, 26.3, 25.2, 17.9. IR (KBr) 3367, 3252, 2934, 1643,
-1
1567, 1459 cm ; mp >237 °C decomp; MS m/z (relative intensity) 314(46), 271(100), 187(50);
HRMS calcd for C H N O : 314.1742 Found: 314.1729.
17 22 4 2
2-Pivaloylamino-9-ethyl-5,6,7,8,9,10-hexahydro-5,9-methanopyrimido[4,5-b]azocin-4(3H)-
one (8c).
1
H NMR(CDCl , 500 MHz): d 0.89 (t, 3H, J = 6.63 Hz), 1.27 (s, 9H), 1.43 (m, 2H), 1.49 (m, 2H),
3
1.57 (m, 3H), 1.60 (m, 2H), 1.79 (d, 1H, J = 10.99 Hz), 3.25 (s, 1H), 4.60 (s, 1H), 8.26 (s, 1H),
13
11.22 (s, 1H). C NMR (CDCl , 125 MHz): d 179.8, 160.0, 159.6, 148.5, 94.1, 53.4, 40.3, 39.7,
3
-1
34.7, 34.1, 31.2, 28.2, 27.1, 26.5, 26.4, 19.1; IR (KBr) 3389, 3265, 2931, 1644, 1565, 1458 cm ;
MS m/z (relative intensity) 318(30), 289(35), 275(100); mp >210 °C; HRMS calcd for
C H N O : 318.2055. Found: 318.2062.
17 26 4 2

120
HETEROCYCLES, Vol. 61, 2003
2-Pivaloylamino-9-benzyl-5,6,7,8,9,10-hexahydro-5,9-methanopyrimido[4,5-b]azocin-4(3H)-
one (8d).
1
H NMR(CDCl , 500 MHz): d 1.27 (s, 9H), 1.50 (m, 3H), 1.69 (m, 2H), 1.78 (m, 2H), 1.91 (m,
3
1H), 2.73 (d, 1H, J = 13.43 Hz), 2.84 (d, 1H, J = 13.12 Hz), 2.97 (s, 1H), 4.63 (s, 1H), 7.19 (d,
13
2H, J = 7.02 Hz), 7.28 (m, 1H), 7.34 (t, 2H, J = 7.02 Hz), 7.87 (s, 1H), 11.17 (s, 1H). C NMR
(CDCl , 125 MHz): d 179.6, 159.6, 142.3, 13.9, 130.7, 128.6, 127.1, 94.3, 53.2, 51.3, 48.7, 40.3,
3
-1
39.4, 36.2, 31.0, 27.2, 26.6, 18.9; IR (KBr) 3409, 3262, 2933, 1651, 1567, 1457 cm ; MS m/z
(relative intensity) 380(43), 290(38), 289(100); HRMS calcd for C H N O : 380.2212. Found:
22 28 4 2
380.2216.
2,4-Bis(pivaloylamino)-9-allyl-5,6,7,8,9,10-hexahydro-5,9-methanopyrimido[4,5-b]azocine
(10a).
1
H NMR(CDCl , 500 MHz): d 1.28 (s, 9H), 1.29 (s, 9H), 1.51 (m, 4H), 1.63 (m, 2H), 1.68 (m,
3
2H), 2.20 (dd, 1H, J = 8.85, 13.73 Hz), 2.31 (dd, 1H, J = 6.41, 13.74), 3.10 (s, 1H), 5.17 (dd, 2H,
13
J = 6.41, 10.07 Hz), 5.45 (s, 1H), 5.82 (m, 1H), 7.41 (s, 1H), 7.82 (s, 1H). C NMR (CDCl ,
3
125 MHz): d 176.8, 176.2, 163.9, 155.4, 152.7, 131.9, 120.3, 103.7, 52.6, 46.5, 40.3, 40.1, 38.5,
-1
34.8, 31.5, 28.4, 27.7, 27.6, 18.6. IR (KBr) 3419, 3269, 2955, 2931, 1684, 1606, 1492 cm ; mp
205 °C; MS m/z (relative intensity) 413(15), 371(38), 356(100); HRMS calcd for C H N O :
23 35 5 2
413.2790. Found: 413.2806.
2,4-Bis(pivaloylamino)-9-ethynyl-5,6,7,8,9,10-hexahydro-5,9-methanopyrimido[4,5-b]azocine
(10b):
1
H NMR(DMSO-d , 500 MHz): d 1.17 (s, 9H), 1.19 (s, 9H), 1.51(m, 4H), 1.69 (d, 1H, J = 12.2),
6
1.74 (m, 1H), 1.93 (d, 1H, J = 12.8 Hz), 2.02 (d, 1H, J = 11.9 Hz), 2.97 (br s, 1H), 3.37 (s, 1H),
13
7.93 (s, 1H), 9.24 (s, 1H), 9.41 (s, 1H). C NMR (DMSO-d , 125 MHz): d 176.7, 175.8, 162.8,
6
155.6, 153.9, 118.9, 107.2, 83.1, 73.1, 47.5, 38.7, 35.2, 27.1, 26.9; IR (KBr) 3440, 3285, 2959,
-1
1701, 1606, 1482, 1418 cm ; mp 152 °C; MS m/z (relative intensity) 397(23), 358(57), 341(32),
340(100); HRMS calcd for C H N O : 397.2477. Found: 397.2475.
22 31 5 2
2,4-Bis(pivaloylamino)-9-ethyl-5,6,7,8,9,10-hexahydro-5,9-methanopyrimido[4,5-b]azocine
(10c):
1
H NMR(CDCl , 500 MHz): d 0.89 (t, 3H, J = 3.05 Hz), 1.23 (s, 9H), 1.24 (s, 9H), 1.40-1.26 (m,
3
13
2H), 1.48 (m, 4H), 1.58 (m, 4H), 3.03 (s, 1H), 5.55(s, 1H), 7.62 (s, 1H), 8.12 (s, 1H). C NMR
(CDCl , 125 MHz): d 176.7, 176.3, 163.9, 155.3, 152.5, 102.9, 52.9, 40.2, 40.0, 38.5, 34.4, 33.5,
3
-1
31.5, 28.1, 27.5, 18.6. IR (KBr) 3444, 3293, 2966, 1697, 1600, 1421 cm ; MS m/z (relative
intensity) 401(14), 372(29), 344(100); HRMS calcd for C H N O : 401.2790. Found:
22 35 5 2
401.2771.

HETEROCYCLES, Vol. 61, 2003
121
2,4-Bis(pivaloylamino)-9-benzyl-5,6,7,8,9,10-hexahydro-5,9-methanopyrimido[4,5-b]azocine
(10d):
1
H NMR(CDCl , 500 MHz): d 1.29 (s, 9H), 1.30(s, 9H), 1.51 (m, 4H), 1.62 (m, 1H), 1.72 (m, 3H),
3
2.75 (d, 1H, J = 13.12 Hz), 2.88 (d, 1H, J = 13.43 Hz), 3.12 (s, 1H), 5.46 (s, 1H), 7.21 (d, 2H,
J = 8.62 Hz), 7.29 (m, 1H), 7.33 (t, 2H, J = 8.63 Hz), 7.52 (s, 1H), 7.90 (s, 1H). 13C NMR (CDCl3,
125 MHz): d 176.5, 163.8, 155.2, 135.5, 130.7, 128.6, 127.1, 53.0, 48.6, 40.3, 40.1, 38.3, 35.0,
-1
31.3, 28.3, 27.6, 18.5. IR (KBr) 3408, 2932, 1700, 1609, 1417 cm ; MS m/z (relative intensity)
463(18), 407(26), 406(100), 372(54); HRMS calcd for C H N O : 463.2947. Found:
27 37 5 2
463.2935.
N-{4-[3-(2-Amino-4(3H)-oxo-5,6,7,8,9,10-hexahydro-5,9-methanopyrimido[4,5-b]azocin-9-
yl)propenyl]benzoyl}-L-glutamic Acid Diethyl Ester (11).
To a solution of 7a (0.66 g, 2 mmol) in 10 mL of anhydrous DMF were added diethyl 4-
iodobenzoyl-L-glutamate (0.95 g, 2.2 mmol), Pd(OAc) (0.03 g, 0.014 mmol), PPh (0.073 g, 0.28
2
3
mmol), CuI (0.026 mg, 0.014 mmol), and triethylamine (1.39 mL, 10 mmol) in 30 mL of
anhydrous acetonitrile. The reaction mixture was stirred at 60 ˚C for 10 h under a nitrogen
atmosphere. The solvent was evaporated under reduced pressure and the residue was purified by
column chromatography on a silica gel column using 2% MeOH/CH Cl as eluent to give 11, 0.85
2
2
1
g (68%) as a white solid. H NMR(CDCl , 500 MHz): d 1.24 (t, 3H, J = 7.02 Hz), 1.27 (s, 9H),
3
1.31(t, 3H, J = 7.02 Hz), 1.30 (m, 4H), 1.75 (d, 2H, J = 15.26 Hz), 1.79 (d, 2H, J = 8.86 Hz), 2.16
(m, 1H), 2.34 (m, 2H), 2.47 (m, 3H), 3.30 (s, 1H), 4.12 (dd, 2H, J = 7.02, 14.03 Hz), 4.24 (dd, 2H,
J = 7.02, 14.2 Hz), 4.69 (br s, 1H), 4.79 (m, 1H), 6.35 (m, 1H), 6.52 (d, 1H, J = 15.87 Hz), 7.08
(d, 1H, J = 6.63 Hz), 7.41 (d, 2H, J = 8.55 Hz), 7.77 (d, 2H, J = 8.20 Hz), 7.85 (s, 1H), 11.19 (s,
13
1H). C NMR (CDCl , 125 MHz): d 179.6, 173.5, 172.3, 166.8, 159.6, 159.5, 148.5, 140.5,
3
133.8, 132.7, 127.7, 126.5, 126.4, 94.4, 62.0, 61.1, 53.4, 52.6, 45.9, 40.3, 40.1, 35.9, 31.1, 30.8,
27.4, 27.2, 26.7, 19.1; MS m/z (relative intensity) 635(20), 290(36), 289(98), 287(100); HRMS
calcd for C H N O : 635.3318. Found: 635.3303.
34 45 5 7
N-{4-[3-(2-Amino-4(3H)-oxo-5,6,7,8,9,10-hexahydro-5,9-methanopyrimido[4,5-b]azocin-9-
yl)propyl]benzoyl}-L-glutamic Acid (12):
To a solution of 11 (0.64 g, 1 mmol) in MeOH (50 mL) was added 5% Pd-C (0.20 g). The reaction
mixture was hydrogenated on a Parr shaker for 5 h at 40 psi. The catalyst was filtered off through
Celite and the filtrate was concentrated in vacuo. The residue was purified by column
chromatography by using 2% MeOH/CH Cl as eluent to give the bridged reduced derivative of
2
2
1
11, 0.59 g (92%) as a white solid. H NMR (CDCl , 500 MHz): d 1.23 (t, 3H, J = 7.34 Hz), 1.30
3
(s, 9H), 1.33 (t, 3H, J = 7.44 Hz), 1.69-1.40 (m, 12H), 1.80 (d, 1H, J = 10.60 Hz), 2.15 (m, 1H),
2.31 (m, 1H), 2.45 (m, 2H), 2.67 (m, 2H), 3.25 (s, 1H), 4.12 (dd, 2H, J = 7.02, 14.0 Hz), 4.24 (dd,

122
HETEROCYCLES, Vol. 61, 2003
2H, J = 7.0, 14.01 Hz), 4.35 (d, 1H, J = 5.19 Hz), 4.80 (m, 1H), 7.03 (t, 1H, J = 7.94 Hz), 7.25
13
(d, 2H, J = 8.24 Hz), 7.75 (d, 2H, J = 7.93 Hz), 7.94 (d, 1H, J = 9.76 Hz), 11.18 (s, 1H).
C
NMR (CDCl , 125 MHz): 179.6, 173.5, 172.3, 167.3, 159.8, 159.6, 148.5, 146.3, 131.7, 128.8,
3
127.6, 94.3, 61.9, 61.0, 53.3, 52.6, 41.4, 40.5, 40.3, 36.2, 34.6, 31.2, 30.7, 27.5, 27.2, 26.5, 24.7,
19.1; MS m/z (relative intensity) 637(14), 332(19), 289(100); HRMS calcd for C H N O :
34 47 5 7
637.3475. Found: 637.3449.
A solution of 0.30 g, 0.30 g of this reduced derivative of 11 in 1N NaOH (10 mL) was stirred at
room temperature for 30 h. The reaction mixture was then acidified with excess glacial acetic acid
and filtered. The residue was washed with diethyl ether (20 mL), and water (50 mL) and dried in
1
vacuo to give 0.19 g (81%) of 12 as a white solid. H NMR (DMSO-d , 500 MHz): d 1.53-1.35
6
(m, 9H), 1.61 (m, 2H), 1.95 (m, 1H), 2.08 (m, 1H), 2.35 (t, 2H, J = 7.63 Hz), 2.61 (m, 2H), 2.92
(s, 1H), 4.40 (m, 1H), 6.27 (br s, 2H), 7.30 (d, 2H, J = 8.20 Hz), 7.81 (d, 2H, J = 8.24 Hz), 8.53
(d, 1H, J = 7.63 Hz), 9.81 (s, 1H), 10.36 (s, 1H), 12.22 (s, 2H). HRFABMS calcd for
C25H32N5O6 : (MH+) 498.2353. Found: 498.2363.
REFERENCES AND NOTES
§ Present address: Paratek Pharmaceuticals, Inc., 75 Kneeland St., Boston, MA 02111 (USA)
1. (a) D. J. Brown, “The Pyrimidines” In “The Chemistry of Heterocyclic Compounds”, Vol. 16 (a)
ed. by A. Weissberger, Interscience, New York, 1962; (b) D. J. Brown, “The Pyrimidines,
Supplement I”, In “The Chemistry of Heterocyclic Compounds”, Vol. 16, ed. by A. Weissberger
and E. C. Taylor, Wiley-Interscience, New York, 1970; (c) D. J. Brown, “The Pyrimidines,
Supplement II”, In “The Chemistry of Heterocyclic Compounds”, Vol. 16, ed. by A. Weissberger,
and E. C. Taylor, John Wiley and Sons, New York, 1985; (d) D. J. Brown, “The Pyrimidines” In
“The Chemistry of Heterocyclic Compounds” Vol. 52, ed. by E. C. Taylor, John Wiley and Sons,
New York, 1994.
2. J. C. Warner, In “The Chemistry of Heterocyclic Compounds”, ed. by T. J. Delia and E. C. Taylor,
Wiley, Vol. 24, Part 4, 1992, pp. 17-25; (b) G. L. Anderson, J. Heterocycl. Chem., 1985, 22, 1469;
(c) R. B. Mason, J. Org. Chem., 1977, 42, 1919; (d) A. D. Broom, J. L. Shim, and G. L. Anderson,
J. Org. Chem., 1976, 41, 1095; (e) M. J. Koen and J. E. Gready, J. Org. Chem., 1993, 58, 1104; (f)
E. Diaz, H. Barrios, J. L. Nava, R. G. Enriquez, A. Guzman, G. L. Leon, J. F. Fuentes, B. A.
Fuentes, A. Quintero, and J. D. Solano, J. Heterocycl. Chem., 1997, 34, 1037; (g) R. Troschuetz
and E. Anders, Arch. Pharm., 1992, 325, 341; (h) R. Troschuetz, Arch. Pharm., 1984, 317, 709;
(i) J. Cobo, C. Garcia, M. Melguizo, A. Sanchez, and M. Nogueras, Tetrahedron, 1994, 50,
10345; (j) J. Cobo, A. Sanchez, and M. Nogueras, Tetrahedron, 1998, 54, 5753; (k) A. A. S. El-
Ahl, S. A. A. El Bialy, and M. A. Ismail, Heterocycles, 2001, 55, 1315; (l) M. C. Bagley, J. W.
Dale, D. D. Hughes, M. Ohnesorge, N. G. Phillips, and J. Bower, Synlett, 2001, 1523; (m) J.

HETEROCYCLES, Vol. 61, 2003
123
Quiroga, B. Insuasty, H. Insuasty, R. Abonia, A. Ortiz, A. Sanchez, and M. Nogueras, J.
Heterocycl. Chem., 2001, 55, 339; (n) G. B. Bennett and R. B. Mason, J. Org. Chem., 1977, 42,
1919; (o) D. D. Hughes and M. C. Bagley, Synlett, 2002, 1332; (p) T. Kuwada, K. Harada, J.
Nobuhiro, T. Choshi, and S. Hibino, Heterocycles, 2002, 57, 2081; (q) M. C. Bagley and N. Singh,
Synlett, 2002, 1718.
3. (a) E. C. Taylor and F. Sowinski, J. Am. Chem. Soc., 1968, 90, 1374; (b) E. C. Taylor and F.
Sowinski, J. Am. Chem. Soc., 1969, 91, 2143; (c) F. Yoneda, Y. Sakuma, T. Nagamatsu, and S.
Mizumoto, J. Chem. Soc., Perkin Trans. 1, 1976, 2398; (d) F. Yoneda, M. Kawamura, S.
Matsumoto, and M. Higuchi, J. Chem. Soc., Perkin Trans. 1, 1977, 2285.
4. (a) C. L. Gibson, K. Ohta, K. Paulini, and C. J. Suckling, J. Chem. Soc., Perkin Trans. 1, 1998,
3025; (b) A. Lang, C. Dunn, K. Paulini, C. L. Gibson, M. J. Rice, and C. J. Suckling, Pteridines,
1995, 6, 90.
5. (a) A. S. Prasad, J. S. Sandhu, and J. N. Baruah, J. Heterocycl. Chem., 1984, 21, 1657; (b) E. C.
Taylor and B. Liu, Tetrahedron Lett., 1999, 40, 4023, 4027; (c) E. C. Taylor and B. Liu,
Tetrahedron Lett., 1999, 40, 4027; (d) D. Edmont and D. M. Williams, Tetrahedron Lett., 2000,
41, 8581.
6. E. C. Taylor, J. E. Dowling, T. Schrader, and B. Bhatia, Tetrahedron, 1998, 54, 9507.
7. E. C. Taylor, J. E. Dowling, and B. Bhatia, J. Org. Chem., 1999, 64, 441.
8. J. E. Dowling, Ph. D. Thesis, Princeton University, 1998.
9. (a) E. C. Taylor, P. J. Harrington, S. R. Fletcher, G. P. Beardsley, and R. G. Moran, J. Med. Chem.,
1985, 28, 914; (b) For a review of the design and synthesis of DDATHF analogs, see E. C. Taylor,
J. Heterocycl. Chem., 1990, 27, 1; E. C. Taylor, Adv. Exp. Med. Biol., 1993, 338, 387.