Total Synthesis of Melinonine-E and Strychnoxanthine
J . Org. Chem., Vol. 63, No. 4, 1998 975
H-18eq, 22), 1.86 (dm, J ) 12.5, 0.3 H, H-19eq, 21), 2.11 (dm, J
) 12.5, 0.3 H, H-16, 21), 2.16 (masked, 0.3 H, H-20ax, 21), 2.18
(qd, J ) 13, 4.5, 0.7 H, H-19ax, 22), 2.28 (dt, J ) 10, 3.5, 0.7 H,
H-20ax, 22), 2.28-2.38 (m, 1.4 H, H-16 and H-14eq, 22), 2.44
(m, 0.3 H, H-19ax, 21), 2.56 (ddd, 0.3 H, J ) 13, 11, 5, H-14eq,
21), 2.60-2.75 (m, 1H, H-6), 2.70 (m, W1/2 ) 20, 1 H, H-15eq),
2.95 (m, 0.7 H, H-17eq, 22), 3.2-3.8 (m, 3.3 H, H-5, H-6, and
H-17eq, 21), 3.99 (dm, J ) 12, 0.7 H, H-3ax, 22), 4.06 (dm, J )
12, 0.3 H, H-3ax, 21), 7.05 (td, J ) 7.25, 1.5, 0.7 H, H-10, 22),
7.06 (td, J ) 7.25, 1.5, 0.3 H, H-10, 21), 7.09 (td, J ) 7.25, 1.5,
0.7 H, H-11, 22), 7.11 (td, J ) 7.25, 1.5, 0.3 H, H-11, 21), 7.25
(d, J ) 8, 0.7 H, H-12, 22), 7.29 (d, J ) 8, 0.3 H, H-12, 21),
7.43 (d, J ) 8, 0.7 H, H-9, 22), 7.45 (d, J ) 8, 0.3 H, H-9, 21),
7.59 (br s, 0.7 H, NH, 22), 7.63 (br s, 0.3 H, NH, 21), 9.56 (s,
0.7 H, CHO, 22), 9.75 (s, 0.3 H, CHO, 21);13C NMR, Table 1.
Anal. Calcd for C19H22N2O: C, 77.52; H, 7.53; N, 9.52.
Found: C, 77.53; H, 7.63; N, 9.45.
9 h. The catalyst was filtered through a short pad of Celite
and washed with hot MeOH. The combined filtrate and
washings were concentrated to leave a yellowish solid, which
was mixed with water (1.5 mL). The resulting aqueous
suspension was neutralized with saturated aqueous NaHCO3,
and then a solution of NaClO4‚H2O (56 mg, 0.40 mmol) in
water (1 mL) was added. The precipitate was filtered off and
washed with water (1 mL) to give 1 perchlorate (58 mg, 63%).
Recrystallization from MeOH-Et2O (1:1) provided an analyti-
cal sample as a yellow solid: mp 254-256 °C; IR (KBr) 3425,
1
2926, 1635, 623; H NMR (CD3OD, COSY and ROESY) 1.30
(m, 1 H, H-19ax), 1.74 (dm, J ) 15, 1 H, H-19eq), 2.02 (dm, J )
14.5, 1 H, H-18eq), 2.12 (m, 1 H, H-20eq), 2.28 (tm, J ) 14, 1 H,
H-18ax), 2.32 (dm, J ) 14, 1 H, H-16syn), 2.52 (dt, J ) 14.5,
2.5, 1 H, H-16anti), 2.79 (br s, 1 H, H-15eq), 3.83 (dd, J ) 11,
7.5, 1 H, H-21), 3.92 (dd, J ) 11, 8, 1 H, H-21), 5.19 (br s, 1 H,
H-17eq), 7.55 (m, 1 H, H-10), 7.84-7.92 (m, 2 H, H-11 and
H-12), 8.44 (m, 1 H, H-5), 8.48 (m, 1 H, H-9), 8.60 (d, J ) 6.5,
1 H, H-6); 13C NMR, Table 1. Anal. Calcd for C19H21ClN2O5:
C, 58.15; H, 5.40; N, 7.14. Found: C, 58.11; H, 5.76; N, 6.97.
1 Perchlorate (40 mg) was loaded on a basic anion-exchange
resin (Amberlite IRA-400, chloride form) and eluted with
MeOH. Evaporation of the solvent quantitatively afforded
melinonine-E (1) chloride (47 mg), which was identical (mp,
IR, UV, 1H NMR, and 13C NMR) with the natural melinonine-E
chloride form.4,36 Melinonine-E (1) picrate was prepared from
1 chloride (20 mg, 0.06 mmol) by initial conversion to the
corresponding betaine on a basic anion-exchange resin (Am-
berlite IRA-401, hydroxide form) and elution with MeOH.
Treatment of the resulting betaine (13 mg, 0.04 mmol) with
an equivalent amount of picric acid (9.5 mg, 0.04 mmol)
quantitatively afforded 1 picrate as a yellow solid. Rf values
of synthetic picrate and an authentic sample36 were also
coincident.
(2R S ,3S R ,6S R ,14b S R )-3-(H y d r o x y m e t h y l)-2,3,4,
5,6,7,8,9,14,14b-d eca h yd r o-2,6-m eth a n o-1H-a zocin o[1′,2′:
1,2]p yr id o[3,4-b]in d ole (23). To a solution of nitrile 20 (500
mg, 1.71 mmol) in toluene (6.6 mL) at -20 °C was added
dropwise DIBALH (2.38 mL, 1 M in toluene). After the
mixture stirred at -20 °C for 1 h, 5% aqueous H2SO4 (13 mL)
was added. The resulting mixture was allowed to warm to rt
over 2 h. The reaction mixture was basified with aqueous
NaOH (2 N) and extracted with CH2Cl2. The dried extracts
were concentrated to give aldehyde 21 (430 mg), which was
immediately reduced to avoid an epimerization process. To a
solution of 21 (430 mg, 1.46 mmol) in MeOH (67 mL) at 0 °C
was added NaBH4 (116 mg, 3.07 mmol), and the reaction
mixture was stirred at rt for 4 h. Water (6.7 mL) was added,
MeOH was evaporated, and the organic phase was extracted
with CH2Cl2. The dried extracts were concentrated, and the
residue was chromatographed (CH2Cl2) to give alcohol 23 (332
mg, 67% overall yield from nitrile 20) as a yellow solid: mp
3-Ep im elin on in e-E (27) P er ch lor a te.40 Operating as in
the above axial series, from equatorial alcohol 24 (60 mg, 0.20
mmol), maleic acid (116 mg, 1 mmol), and Pd black (80 mg,
0.75 mmol) in water (7 mL) was prepared 3-epimelinonine-E
(27) perchlorate (50 mg, 63%) as a yellow solid. Recrystalli-
zation from MeOH-Et2O (1:1) provided an analytical
1
168-169 °C (EtOAc); IR (KBr) 3418, 2928; H NMR (COSY)
1.24-1.36 (m, 2 H, H-18ax and H-19eq), 1.42 (dm, J ) 13.5, 1
H, H-16), 1.45-1.62 (m, 3 H, H-14ax, H-18eq, and H-20eq), 2.00
(dm, J ) 12.5, 1 H, H-16), 2.25 (apparent dm, J ) 10.5, 1 H,
H-15eq), 2.36 (tm, J ) 13, 1 H, H-19ax), 2.53 (td, J ) 12, 5.5, 1
H, H-14eq), 2.65 (dm, J ) 11.5, 1 H, H-6), 2.87 (m, 3 H, H-5,
H-6, and H-17eq), 3.00 (m, 1 H, H-5), 3.68 (dd, J ) 11, 7.5, 1
H, H-21), 3.73 (dd, J ) 11, 8, 1 H, H-21), 4.06 (dm, J ) 12.5,
1 H, H-3ax), 7.03 (td, J ) 7.5, 1, 1 H, H-10), 7.11 (td, J ) 7.5,
1.5, 1 H, H-11), 7.31 (d, J ) 8, 1 H, H-12), 7.46 (d, J ) 7.5, 1
H, H-9), 7.75 (br s, 1 H, NH); 13C NMR, Table 1. Anal. Calcd
for C19H24N2O‚2/3H2O: C, 73.98; H, 8.28; N, 9.08. Found: C,
73.98; H, 8.00; N, 9.26. HRMS calcd for C19H24N2O 296.1888,
found 296.1878.
1
sample: mp 260-265 °C; IR (KBr) 3429, 2924, 1635, 625; H
NMR (CD3OD, COSY and ROESY) 0.57 (m, 1 H, H-19ax), 1.64
(dm, J ) 15, 1 H, H-19eq), 2.09 (br s, 1 H, H-20ax), 2.16 (m, 2
H, H-18), 2.31 (dm, J ) 14, 1 H, H-16anti), 2.49 (dm, J ) 14.5,
1 H, H-16syn), 2.76 (br s, 1 H, H-15eq), 3.59 (d, J ) 7, 2 H,
CH2O), 3.73-3.79 (m, 1 H, H-14), 5.25 (br s, 1 H, H-17eq), 7.54
(td, J ) 6, 2, 1 H, H-10), 7.86 (m, 2 H, H-11 and H-12), 8.45
(m, 2 H, H-5 and H-9), 8.57 (d, J ) 6.5, 1 H, H-6); 13C NMR,
Table 1. Anal. Calcd for C19H21N2O5Cl: C, 58.02; H, 5.55; N,
7.13; Cl, 9.02. Found: C, 58.02; H, 5.55; N, 7.13; Cl, 8.91.
3-Epimelinonine-E (27) chloride was obtained from 27
perchlorate using the preceding procedures described for
melinonine-E (1) chloride: UV (MeOH), λ (nm) 364, 306, 252,
204; HRMS (FAB) calcd for C19H21N2O+ 293.1653, found
293.1649. 3-Epimelinonine-E (27) picrate was prepared from
27 chloride using the preceding procedures described for
melinonine-E (1) picrate.
(2R S ,3R S ,6S R ,14b S R )-3-(H y d r o x y m e t h y l)-2,3,4,
5,6,7,8,9,14,14b-d eca h yd r o-2,6-m eth a n o-1H-a zocin o[1′,2′:
1,2]p yr id o[3,4-b]in d ole (24). Operating as above, nitrile 19
(700 mg, 2.40 mmol) was converted by reduction with DIBALH
(3.3 mL, 1 M in toluene) into aldehyde 22 (570 mg). Further
reduction with NaBH4 (116 mg, 4.3 mmol) in MeOH (95 mL)
gave alcohol 24 (483 mg, 69%) as a yellow solid after chroma-
tography (CH2Cl2): mp 161-164 °C (EtOAc); IR (KBr) 3252,
1
2928; H NMR (COSY) 1.15-1.25 (m, 3 H, H-16, H-18ax and
(()-Str ych n oxa n th in e (2) Ch lor id e. To a solution of
alcohol 23 (45 mg, 0.15 mmol) in pyridine (5 mL) was added
Ac2O (3 mL). The mixture was stirred at rt overnight.
Removal of excess reagent afforded a residue which was taken
up with CH2Cl2 and washed with water. The dried extracts
were concentrated to give a dark solid which was chromato-
graphed (EtOAc) to afford acetate 25 (28 mg, 55%): IR (KBr)
3373, 2928, 1718; 1H (300 MHz) 1.27 (dm, J ) 12.5, 1 H), 1.47
(tm, J ) 13, 1 H), 1.71 (m, 1 H), 1.94-2.20 (m, 2 H), 2.07 (s,
3 H), 2.36 (tm, J ) 13, 1 H), 2.49 (ddd, J ) 13, 11, 4.5, 1 H),
2.65 (dm, J ) 11, 1 H), 2.89 (m, 3 H), 2.98 (m, 1 H), 4.04 (dm,
J ) 12, 1 H), 4.11 (dd, J ) 11, 7.5, 1 H), 4.18 (dd, J ) 11, 8,
1 H), 7.07 (td, J ) 7, 1.5, 1 H), 7.12 (td, J ) 7, 1.5, 1 H), 7.30
(dd, J ) 7, 1.5, 1 H), 7.47 (dd, J ) 7, 1.5, 1 H), 7.72 (br s, 1 H);
13C NMR, Table 1.
H-19eq), 1.42 (td, J ) 12, 2, 1 H, H-14ax), 1.58-1.85 (m, 2 H,
H-18 and H-20ax), 2.10 (ddd, J ) 13, 11, 5, 1 H, H-14eq), 2.23-
2.30 (m, 3 H, H-15, H-16, and H-19ax), 2.62 (m, 1 H, H-6), 2.75-
2.87 (m, 2 H, H-6 and H-5), 2.85 (br s, 1 H, H-17eq), 2.92 (m,
1 H, H-5), 3.34 (dd, J ) 10.5, 6, 1 H, H-21), 3.37 (dd, J ) 10.5,
8, 1 H, H-21), 3.95 (dm, J ) 10, 1 H, H-3ax), 7.01 (td, J ) 7.5,
1, 1 H, H-10), 7.04 (td, J ) 7, 1, 1 H, H-11), 7.22 (d, J ) 8, 1
H, H-12), 7.38 (d, J ) 7.5, 1 H, H-9), 7.63 (br s, 1 H, NH); 13
C
NMR, Table 1. Anal. Calcd for C19H24N2O‚2/3H2O: C, 73.98;
H, 8.28; N, 9.08. Found: C, 73.97; H, 8.31; N, 8.85. HRMS
calcd for C19H24N2O 296.1888, found 296.1880.
(()-Melin on in e-E (1) P er ch lor a te. A stirred mixture of
alcohol 23 (70 mg, 0.23 mmol), maleic acid (135 mg, 1.16
mmol), and palladium black (80 mg, 0.75 mmol) in water (7
mL) was heated at reflux for 8.5 h. After cooling (5-10 °C)
overnight, a further portion of Pd black (50 mg, 0.46 mmol)
was added and the reaction mixture was heated at reflux for
To a solution of acetate 25 (28 mg, 0.08 mmol) in dioxane
(1.5 mL) was added SeO2 (73.5 mg, 0.66 mmol), and the
mixture was stirred for 45 h at reflux. The selenium that