1
518 J . Org. Chem., Vol. 64, No. 5, 1999
Franklin et al.
the mixture was filtered, and the filtrate was saturated with
S. The resulting white precipitated Zn salts were removed
acid (88%, 100 µL), and MeOH (10 mL) was stirred vigorously
under 50 psi of H in the presence of 5% Rh/Al O (245 mg,
2 2 3
H
2
by filtration through a Celite pad. The filtrate was then treated
with HCl (1 N aqueous, 2.4 mL, 2.4 mmol) and was concen-
trated. This light yellow residue was diluted in CH Cl (50 mL)
2 2
and filtered to remove the remaining Zn salts. The filtrate was
concentrated to give 620 mg (100%) of deprotected guanidine
0.120 mmol) for 18 h. The reaction was filtered through a
Celite pad, and the filtrate was concentrated to give 45 mg
(90%) of a 1:1 mixture of 29 and 30 as a colorless oil. This
mixture was purified by preparative HPLC (5 µm Alltima
reversed-phase C18 silica, 20:10:0.1 CH
3
CN-H O-TFA) to
2
5
as a 1:1 mixture of diastereoisomers. This light yellow oil
give 20 mg (45%) of 29 and 19 mg (42%) of 30, both as colorless
1
1
was used in the next step without further purification:
NMR (CDCl
6
3
H
3
oils. 29: H NMR (CD OD, 500 MHz) δ 3.95-3.92 (m, 1H),
3
, 500 MHz) δ 7.96 (app broad d, J ) 39.6 Hz, 1H),
3.85-3.82 (m, 1H), 3.7-3.74 (dd, J ) 10.9, 7.6 Hz, 1H), 3.71
(s, 3H), 3.56-3.52 (m, 1H), 3.15 (t, J ) 4.0 Hz, 1H), 2.35-2.89
(m, 1H), 2.24-2.17 (m, 2H), 1.76-1.41 (m, 4H), 1.28 (broad s,
14H), 1.25 (d, J ) 6.8 Hz, 3H), 0.89 (t, J ) 6.4 Hz, 3H);
DPFGSENOE enhancements observed between H-2a and H-3
(strong), H-2a and H-4 (strong), H-2a and H-8a (weak), H-3
and H-2a (strong), H-3 and H-4 (strong), H-3 and H-8a (weak),
.53 (m, 1H), 5.55 (d, J ) 16.6 Hz, 1H), 3.88 (m, 1H), 3.43-
.35 (m, 2H), 2.29-1.98 (m, 4H), 1.66-1.25 (broad m, 4H), 1.22
1
3
(
3
broad s, 10H), 0.85 (t, J ) 6.7 Hz, 3H); C NMR (CDCl , 125
MHz) 152.9, 152.6, 82.6, 81.0, 57.3, 55.0, 51.2, 50.4, 35.2, 35.1,
3
2
3.7, 33.5, 33.0, 32.7, 31.8, 29.9, 29.5, 29.4, 29.3, 29.2, 29.1,
5.3, 25.2, 22.6, 14.0 ppm; IR (film) 3311, 1652, 1622 cm-1
, M -
;
MS (FAB) m/z 235.2045 (235.2048 calcd for C14
H
)
1
H
25
N
3
H-8a and H-2a (weak); 13C NMR (CD
3
OD, 125 MHz) 171.1,
2
4
24
2
O), 410, 300, 262, 222, 194, 154, 136; [R]
D
) -27.6, [R] 577
151.4, 57.7, 57.2, 53.1, 49.3, 45.3, 36.8, 34.1, 33.0, 31.4, (30.6,
2
4
24
24
-30.1, [R] 546 ) -34.3, [R] 435 ) -58.6, [R] 405 ) -70.6 (c
.0, CHCl
30.5, 30.4), 29.3, 26.1, 23.6, 18.3, 14.4 ppm; IR (film) 3260,
-1
3
).
1732, 1682, 1644 cm ; MS (FAB) m/z 350.2801 (364.2977 calcd
for C21 , MH), 327, 281, 221, 207, 191, 147, 136. 30:
OD, 500 MHz) δ 4.10-4.02 (m, 1H), 3.84-3.72
Meth yl (2a R,7R,8a S)-7-Hep tyl-4-m eth yl-1,2,2a ,5,6,7,8,
38 3 2
H N O
H NMR (CD
3
1
8
a -oct a h yd r o-5,6,8b -t r ia za a ce n a p h t h yle n iu m -3-ca r -
boxyla te (10). A solution of guanidine 24b (0.612 mg, 2.11
mmol), morpholine (0.18 mL, 2.3 mmol), glacial acetic acid
(m, 1H), 3.74 (s, 3H), 3.72-3.57 (m, 1H), 3.57-3.43 (m, 1H),
2.94 (dd, J ) 10.8, 5.8 Hz, 1H), 2.48-2.41 (m, 1H), 2.23-2.28
(m, 1H), 2.24-2.20 (m, 1H), 1.71-1.17 (m, 19H), 1.14 (d, J )
6.5 Hz, 3H), 0.89 (t, J ) 6.4 Hz, 3H); DPFGSE-NOE enhance-
(0.13 mL, 2.2 mmol), methyl acetoacetate (0.45 mL, 4.2 mmol),
Na SO (900 mg, 6.33 mmol), and 1,1,1-trifluoroethanol (5 mL)
2
4
was heated to reflux for 36 h. The dark yellow reaction mixture
was concentrated and purified by flash column chromatogra-
phy (80:20:1 hexanes-i-PrOH-AcOH) to give 730 mg (94%)
of a 10:1 mixture of 10 and its C-2a epimer as a yellow oil. A
ments observed between H-2a and 4-CH
H-4 (strong), H-3 and 4-CH (medium), H-3 and H-6 (medium),
H-4 and H-3 (strong), H-4 and 4-CH (strong), 4-CH and H-2a
(strong), 4-CH and H-4 (medium), H-7 and H-8a (medium),
H-8a and H-2a (strong), H-8a and H-3 (strong); C NMR
(CD OD, 75 MHz) 171.0, 151.0, 57.1, 53.2, 52.9, 52.6, 36.8, 34.1,
33.0, 31.5, 30.6, 30.4, 26.2, 23.7, 19.6, 14.4 ppm; IR (film) 3266,
3
(strong), H-3 and
3
3
3
3
1
3
1
00 mg portion of this sample was separated by preparative
HPLC (5 µm Alltima reversed-phase C18 silica, 18:10:0.1
CH CN-H O-TFA) to give isomerically pure tricyclic guani-
dine 10 (82 mg, 82%) and 7 mg (7%) of the corresponding C2a
3
3
2
-
1
1732, 1651 cm ; MS (FAB) m/z 364.2974 (364.2964 calcd for
, MH), 304.
Ster eoselective P r ep a r a tion of 30 by Hyd r ogen a tion
2
4
24
24
epimer. Guanidine 10: [R]
D
) +97.2, [R] 577 ) +104, [R] 546
21 38 3 2
C H N O
2
4
24
)
3
+119, [R] 435 ) +221, [R] 405 ) +277 (c 0.93, CH OH),
1
13
2,9
showed H and C NMR in accord with reported data.
of 26a w ith P d /C in Meth a n ol. A solution of 26a (23 mg,
0.058 mmol), formic acid (88%, 50 µL), and MeOH (5 mL) was
stirred vigorously under 50 psi of H in the presence of 10%
2
Bigin elli Con d en sa tion of 24a w ith Meth yl Aceto-
acetate in Dich lor oeth an e To For m Tr icyclic Gu an idin es
2
5a a n d 26a . A solution of 24a (367 mg, 1.15 mmol),
morpholine (101 µL, 1.16 mmol), acetic acid (66 µL, 1.2 mmol),
methyl acetoacetate (0.25 mL, 2.3 mmol), Na SO (492 mg, 3.46
Pd/C (63 mg, 0.059 mmol) for 18 h. The reaction was filtered
through a Celite pad, and the filtrate was concentrated to give
22 mg (94%) of essentially isomerically pure 30.
2
4
mmol), and 1,2-dichloroethane (5 mL) was heated at reflux
for 36 h. The reaction was concentrated, and the residue was
purified by flash column chromatography (80:20:1 hexanes-
i-PrOH-AcOH) to give 436 mg (95%) of a 1.3:1 mixture of 25a
and 26a as a yellow oil. These epimers were separated by
Hyd r ogen a tion of 25a w ith P d /C in Meth a n ol. P r ep a -
r a t ion of Met h yl (2a S,3S,4R,7R,8a S)-4-Met h yl-7-n on yl-
1,2,2a ,3,4,5,6,7,8,8a -d eca h yd r o-5,6,8b -t r ia za a cen a p h t h -
ylen iu m ch lor id e-3-ca r boxyla te (28). A solution of 25a (29
mg, 0.073 mmol), formic acid (88%, 50 µL), and MeOH (5 mL)
preparative HPLC (5 µm Alltima silica, 97:3:0.5 CH
MeOH-AcOH) to give pure samples of both isomers. 25a :
H NMR (CDCl
2
Cl
2
-
2
was stirred vigorously under 50 psi of H in the presence of
1
Pd/C (10%, 77 mg, 0.072 mmol) for 18 h. The reaction was
filtered through a Celite pad, and the filtrate was concentrated
3
, 300 MHz) δ 4.46-4.37 (m, 1H), 3.73 (s, 3H),
.73-3.65 (m, 1H), 3.49-3.33 (m, 1H), 2.60-2.47 (m, 1H),
.42-2.28 (m, 1H), 2.35 (s, 3H), 2.20-2.10 (m, 1H), 2.10-1.16
3
2
to give 21 mg (71%) of isomerically pure 28 as a colorless oil:
1
H NMR (CD OD, 300 MHz) δ 4.04-3.90 (m, 2H), 3.87-3.76
3
1
3
(m, 19H), 0.86 (t, J ) 6.6 Hz, 3H); C NMR (CDCl
3
, 125 MHz)
(m, 1H), 3.75 (s, 3H), 3.51-3.39 (m, 1H), 2.86 (dd, J ) 11.3,
4.6 Hz, 1H), 2.41-2.17 (m, 3H), 1.80-1.21 (m, 19H), 1.13 (d,
J ) 6.6 Hz, 3H), 0.89 (t, J ) 6.6 Hz, 3H); DPFGSE-NOE
enhancements observed between H-2a and H-3 (strong), H-2a
and H-4 (strong), H-2a and H-8a (strong), H-3 and H-2a
1
3
1
C
65.3, 146.2, 144.4, 100.5, 57.0, 55.6, 51.3, 50.1, 33.4, 33.0, 32.9,
1.7, 29.3, 29.1, 26.7, 25.0, 22.5, 17.5, 14.0 ppm; IR (film) 3228,
694, 1591 cm ; MS (FAB) m/z 362.2813 (362.2807 calcd for
-
1
2
4
24
24
21
H
36
N
3
O
2
, MH), 149; [R]
D
) +95.2, [R] 577 ) +103.9, [R] 546
24
2
4
)
+117.6, [R] 435 ) +142.3, [R] 405 ) +48.5 (c 1.0, MeOH). 26a :
(strong), H-3 and H-4 (strong), H-3 and H-8a (weak), H-7 and
1
13
H NMR (CDCl
.71-3.60 (m, 1H), 3.70 (s, 3H), 3.51-3.44 (m, 1H), 2.63 (app
dt, J ) 12.4, 5.2 Hz, 1H), 2.36-2.27 (m, 1H), 2.33 (s, 3H), 1.88
ddd, J ) 23.4, 11.5, 5.5 Hz, 1H), 1.80-1.16 (m, 19H), 0.86 (t,
3
, 300 MHz) δ 4.10 (dd, J ) 11.0, 4.2 Hz, 1H),
3
H-8a (strong), H-8a and H-2a (medium); C NMR (CD OD,
3
75 MHz) 171.2, 150.2, 57.3, 54.6, 52.9, 51.6, 35.9, 34.4, 33.0,
31.0, 30.6, 30.4, 30.3, 26.2, 23.7, 18.0, 14.4 ppm; IR (film) 3441,
-
1
(
1731, 1651 cm ; MS (FAB) m/z 364.2968 (364.2964 calcd for
, MH), 304.
2 3
Hyd r ogen a tion of 25a w ith Rh /Al O in Meth a n ol.
1
3
J ) 6.4 Hz, 3H); C NMR (CDCl
1
2
3
, 125 MHz) 165.3, 149.1,
21 38 3 2
C H N O
48.2, 103.4, 55.3, 54.4, 52.0, 51.0, 34.8, 32.8, 31.8, 31.7, 29.4,
-
1
9.3, 29.2, 25.3, 22.6, 17.6, 14.0 ppm; IR (film) 3218, 1694 cm
;
P r ep a r a tion of Meth yl (2a S,3R,4S,7R,8a S)-4-Meth yl-7-
n on yl-1,2,2a,3,4,5,6,7,8,8a-decah ydr o-5,6,8b-tr iazaacen aph -
th ylen iu m ch lor id e-3-ca r boxyla te (27). A solution of 25a
(21 mg, 0.053 mmol), formic acid (88%, 50 µL), and MeOH (5
MS (FAB) m/z 362.2802 (362.2807 calcd for C21
36 3 2
H N O
, MH),
2
4
24
24
24
1
)
49; [R]
D
) +16.5, [R] 577 ) +16.1, [R] 546 ) +20.7, [R] 435
24
+65.1, [R] 405 ) +96.3 (c 1.0, MeOH).
Hyd r ogen a tion of 26a w ith Rh /Al
2
O
3
in Meth a n ol.
mL) was stirred vigorously under 50 psi of H
2
in the presence
P r ep a r a tion of Meth yl (2a R,3S,4R,7R,8a S)-4-Meth yl-7-
n on yl-1,2,2a ,3,4,5,6,7,8,8a -d eca h yd r o-5,6,8b -t r ia za a ce-
n a p h th ylen iu m ch lor id e-3-ca r boxyla te (29) a n d Meth yl
of Rh/Al (5%, 130 mg, 0.063 mmol) for 18 h. The reaction
was filtered through a Celite pad, and the filtrate was
2 3
O
concentrated to give 21 mg (99%) of a 20:1 mixture of 27 and
1
(
2a R,3R,4S,7R,8a S)-4-Meth yl-7-n on yl-1,2,2a ,3,4,5,6,7,8,8a -
28 as a colorless oil: H NMR (CD
3
OD, 300 MHz) δ 4.07-
d eca h yd r o-5,6,8b-t r ia za a cen a p h t h ylen iu m ch lor id e-3-
ca r boxyla te (30). A solution of 26a (50 mg, 0.14 mmol), formic
4.00 (m, 1H), 3.86-3.70 (m, 2H), 3.71 (s, 3H), 3.49-3.38 (m,
1H), 3.10 (app t, J ) 4.2 Hz, 1H), 2.29-2.13 (m, 3H), 1.88-