Synthesis of vinca alkaloids and related compounds. 100. Stereoselective oxidation reactions of compounds with the aspidospermane and quebrachamine ring system. First synthesis of some alkaloids containing the epoxy ring

Article abstract of DOI:10.1021/jo020386r

The first syntheses of the alkaloids (-)-mehranine (3), (+)-voaphylline/conoflorine (4), (+)-N_a-methylvoaphylline/hecubine (5), and (-)-lochnericine (2) were achieved by stereoselective epoxidation starting from (-)-tabersonine (1), through intermediates with the aspidospermane and quebrachamine skeleton.

Full text of DOI:10.1021/jo020386r

Syn th esis of Vin ca Alk a loid s a n d Rela ted Com p ou n d s. 100.
Ster eoselective Oxid a tion Rea ction s of Com p ou n d s w ith th e
Asp id osp er m a n e a n d Qu ebr a ch a m in e Rin g System . F ir st Syn th esis
of Som e Alk a loid s Con ta in in g th e Ep oxy Rin g1a
J a´nos EÄ les,†,‡ Gyo¨rgy Kalaus,*,† Istva´n Greiner,‡ Ma´ria Kajta´r-Peredy,§ Pa´l Szabo´,§
Gyo¨rgy Miklo´s Keseruˆ,‡ Lajos Szabo´,† and Csaba Sza´ntay*,†,§
Department for Organic Chemistry, Budapest University of Technology and Economics, Gelle´rt te´r 4,
H-1111, Budapest, Hungary, Chemical Works of Gedeon Richter Ltd, Gyo¨mro´i u´t 19-21,
H-1103 Budapest, Hungary, and Institute of Chemistry, Chemical Research Center,
Hungarian Academy of Sciences, Pusztaszeri u´t 59-67, H-1025 Budapest, Hungary
szantay@mail.bme.hu
Received J une 6, 2002
The first syntheses of the alkaloids (-)-mehranine (3), (+)-voaphylline/conoflorine (4), (+)-Na-
methylvoaphylline/hecubine (5), and (-)-lochnericine (2) were achieved by stereoselective epoxidation
starting from (-)-tabersonine (1), through intermediates with the aspidospermane and quebra-
chamine skeleton.
SCHEME 1a
In tr od u ction
In a previous publication1b we reported the oxidation
of (-)-tabersonine (1) with dimethyldioxirane. In this
reaction, instead of the expected oxidation of the C14-
C15 double bond, ring transformation of the aspidosper-
mane f eburnane skeleton2 was only experienced. Simi-
larly, no product with an epoxy ring was formed in the
oxidation with dimethyldioxirane of (+)-14,15-didehy-
droquebrachamine (6),3 obtainable from (-)-tabersonine
(1). In our further experiments aimed at forming an
epoxy ring the oxidizing agents m-chloroperoxy-benzoic
acid (m-CPBA) and tert-butyl hydroperoxide were tried.
Resu lts a n d Discu ssion
a
Reaction conditions: (a) m-CPBA, MeOH, 0 °C; (b) NaOH,
The forming of the epoxy ring on the (+)-14,15-
didehydroquebrachamine (6) molecule was tried first
with m-CPBA. However, instead of the expected reaction,
a mixture of diastereomeric derivatives was obtained,
presumably through the intermediates 7;1b the isomers
were isolated as their chlorides (8 and 9) (Scheme 1). The
pure substances could not be isolated from the salt
mixture. Then, to avoid the formation of the intermediate
7, the nitrogen atom of the indole ring in molecule 6 was
methylated. This was achieved with methyl iodide in
dimethylformamide (DMF) in the presence of sodium
H2O; (c) HCl, MeOH, hexane.
SCHEME 2a
a
Reaction condition: MeI, NaH, DMF.
* To whom correspondence should be addressed. Fax: +361-
4633297.
hydride. The product was (+)-Na-methyl-14,15-didehy-
droquebrachamine (10) in a fair yield (Scheme 2). The
oxidation of 10 with m-CPBA did not give isolable prod-
uct; therefore another oxidizing agent was tried. (+)-Na-
Methyl-14,15-didehydroquebrachamine (10) was made to
react with tert-butyl-hydroperoxide in tetrahydrofuran in
the presence of trifluoroacetic acid, resulting in the sole
product (+)-Na-methyl-(14S,15R)-epoxyquebrachamine
(12). This reaction was also effected with the derivative
† Budapest University of Technology and Economics.
‡ Chemical Works of Gedeon Richter Ltd.
§ Hungarian Academy of Sciences.
(1) (a) For part 99, see: Cso´ka´si, P.; Baitz-Ga´cs, E.; Sza´ntay, Cs.
Submitted for publication. (b) EÄ les, J .; Kalaus, Gy.; Le´vai, A.; Greiner,
I.; Kajta´r-Peredy, M.; Szabo´, P.; Szabo´, L.; Sza´ntay, Cs. J . Heterocycl.
Chem. 2002, 39, 767.
(2) Aimi, N.; Asada, Y.; Sahaai, S.; Haginiwa, J . J . Chem. Pharm.
Bull. (Tokyo) 1978, 26, 1182.
(3) Zsadon, B.; Otta, K. Acta Chim. Sci. Hung. 1971, 69, 87.
10.1021/jo020386r CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/21/2002
J . Org. Chem. 2002, 67, 7255-7260
7255

Kalaus et al.
SCHEME 4a
F IGURE 1.
a
Reaction conditions: (a) ClCOOCH2CCl3, CH2Cl2; (b) m-CPBA,
MeOH, HClO4; (c) Zn, MeOH, ∆.
Compound 13 was prepared from (-)-tabersonine (1)
as described in the literature3 (hydrolysis with 1 M HCl,
decarboxylation, and reduction by means of lithium
aluminum hydride (LAH)). The secondary nitrogen atom
of the molecule was protected with chlorotrichloroethyl
formate. Surprisingly, the resulting compound (14) did
not react with tert-butyl hydroperoxide. The oxidation
was tried then with m-CPBA. The isolable product was
molecule 15, containing exclusively the epoxy ring with
14R and 15S configurations. The stereoselectivity of the
reaction could be successfully explained also in this case
by molecular-mechanical computations. The structure of
the molecule containing the aspidospermane ring system
in the conformation with the lowest energy (14a ) shows
(Figure 2) that the rings A and D are nearly planar. We
presume that during the oxidation m-CPBA is inserted
between rings A and D, parallel to ring A, and then the
ensuing π-π interaction will stabilize the transient state
effected by the oxidation. In this way a molecule (15)
containing the epoxy ring with 14R and 15S configura-
tions is formed.
F IGURE 2.
SCHEME 3a
The protecting group of the intermediate 15 was
removed with zinc dust in boiling methanol (Scheme 4).
Methylation of the secondary nitrogen atom in (14R,15S)-
epoxyaspidospermidine (16) with methyl iodide in dichlo-
romethane in the presence of triethyl-amine resulted in
the synthesis with a good yield of (-)-mehranine (3),4
which was isolated from Tabernaemontana bovina. The
molecule 16 was found suitable also for the syntheses of
(+)-voaphylline/conoflorine (4),5 occurring in Stemma-
denia grandiflora, as well as of (+)-Na-methylvoaphylline/
hecubine (5).5 First the secondary amine 16 was oxidized
with potassium permanganate in the presence of 18-
crown-6 ether phase transfer catalyst, and the reduction
of the product (17) with sodium borohydride in boiling
ethanol gave (+)-voaphylline (4) containing the epoxy
ring. The synthesis of (+)-hecubine (5) was achieved from
(+)-voaphylline (4), with methyl iodide in DMF by
alkylation in the presence of sodium hydride (Scheme 5).
a
Reaction condition: t-BuOOH, THF, CF3COOH.
6, which gave again only one product, (+)-(14S,15R)-
epoxyquebrachamine (11) (Scheme 3). The stereoselec-
tivity of the oxidation reaction is due to the geometry of
the ring system, as was substantiated by molecular-
mechanical computations.The conformation with the
lowest energy of the molecule 6a , protonated on the basic
nitrogen atom, is shown in Figure 2. On the basis of the
results it is concluded that owing to the orientation of
the indole ring the bulky oxidizing agent can attack ring
D from one side only, and consequently, solely a molecule
(11) containing the carbon atoms in 14S and 15R
configurations can be found.
(4) (a) Kurt, M.; Phoung, L. T.; Van, S. T.; Helmut, R.; Guenter, A.
Phytochemistry 1998, 49, 1457. (b) Kam T. S.; Amuradha, S. Phy-
tochemistry 1995, 40, 313. (c) Merzweiler, K.; Lien, T. P.; Sung, T. V.;
Ripperger, M., Adam, G. J . Prakt. Chem./ Chem.-Ztg. 1999, 341(1), 69.
(5) (a) Atta-ur-Rahman; Danlatabadi, N.; Smith, D. Z. Naturforsch.
1983, 38b, 117. (b) Torrenegra, R.; Pedrozo, P. J .; Achenbach, H.;
Baureiss, P.; Phytochemistry 1988, 27(6), 1843.
In our further research we intended to form the epoxy
ring in (-)-14,15-didehydroaspidospermidine (13), a com-
pound readily obtained from (-)-tabersonine (1).
7256 J . Org. Chem., Vol. 67, No. 21, 2002

Aspidospermane and Quebrachamine Ring Systems
SCHEME 5a
couplings are given only once, at their first occurrence. Mass
spectra were obtained on a double focusing high-resolution
mass spectrometer.
All molecular mechanics calculations were performed on a
Silicon Graphics Indigo R10000. Calculations on the confor-
mational space of 6a and 14a were carried out using the
MacroModel 6.0 package.8 The MM2* force field available in
MacroModel was applied, which differs from the authentic
MM2 force field only in that it employs the point charge
Coulomb electrostatic equation. The electrostatic treatment of
6a and 14a was based on our positive experience of reproduc-
ing crystal structures by using calculations in vacuo with
attenuated electrostatics. Therefore a distance-dependent
dielectric constant was employed, which was further attenu-
ated by a factor of 10. The conformational space of 6a and 14a
was explored by the particularly efficient Monte Carlo Multiple
Minimum (MCMM)9 search available in MacroModel. Struc-
tures generated during the conformational search were mini-
mized to yield unique conformers within an energy window of
50 kJ /mol above the global minimum. TNCG truncated New-
ton conjugate gradient technique (maximum iteration 150,
convergence criterion in gradient 0.01) was used for all
minimization.
a
Reaction conditions: (a) MeI, Et3N, CH2Cl2; (b) KMnO4,
18crown6, benzene; (c) NaBH4, EtOH, ∆; (d) MeI, NaH, DMF.
SCHEME 6a
(2R,7S,20S)-14,15-Did eh yd r o-r h a zid in (8) a n d (2S,7R,-
20S)-14,15-Did eh yd r o-r h a zid in (9). To a stirred solution of
6 (200 mg, 0.7 mmol) in MeOH (10 mL) were added a few drops
of HClO4 and the mixture was cooled to -10 °C; 0.2 g (1.2
mmol) m-CPBA was added. The reaction mixture was main-
tained at 0 °C for 10 h, and then the solvent was evaporated.
To the residue was added 10% Na2CO3 solution (5 mL) and
the mixture was extracted with CH2Cl2. The combined organic
layers were dried and evaporated in vacuo. The residue was
dissolved in absolute MeOH (5 mL) and was acidified with
methanolic HCl to pH value 4-5. Compounds 8 and 9 were
crystallized from the reaction mixture. The crude product was
filtered and recrystallized from absolute methanol to afford
131 mg (62%) as white crystals: mp 210-212 °C; IR (KBr) ν
3423, 2928, 1612, 1476, cm-1; MS (FAB) m/z 297.1971
(C19H25N2O + H requires 297.1967).
a
Reaction conditions: (a) NaBH4, CH3COOH, 90 °C; (b) t-
BuOOH, THF, CF3COOH; (c) Hg(OAc)2, CH3COOH.
On the basis of the above results, the synthesis of (-)-
lochnericine (2),6 isolated from Catharanthus roseus, was
achieved by reacting (-)-tabersonine (1) with sodium
borohydride in acetic acid at 90 °C. Next the mixture of
the 14,15-didehydrocleavamine isomers (55% of 18 and
45% of 19) was oxidized with tert-butyl hydroperoxide in
THF in the presence of trifluoroacetic acid. According to
previous experience, the reaction gave the mixture of
14,15-epoxycleavamine isomers (70% of 20 and 30% of
21) containing the carbon atoms exclusively in 14S,15R
configuration. Without separation this mixture was al-
lowed to react with mercury(II) acetate in acetic acid.
This transannular ring cyclization7 gave the expected
alkaloid (2) in a reasonable yield. A molecule with
alloibogane skeleton (22) was also successfully isolated
from the reaction mixture in a moderate yield (Scheme
6).
Compound 8: 1H NMR (CD3OD) δ 0.97(3H, t, J ) 7.5 Hz;
18-H3), 1.48-1.68(3H, m; 19-H2 + 17-HA), 1.98(1H, ddd,
J gem ) 12.7, J 16,17B ) 12.3 + 4.2 Hz; 17-HB), 2.06(1H, ddd,
J gem ) 14.8, J 16A,17 ) 12.3 + 5.5 Hz; 16-HA), 2.33-2.45 (2H, m;
16-HB + 6-HA), 2.81(1H, ddd, J gem ) 14.5, J 5,6B ) 12.9 + 8.6
Hz; 6-HB), 3.35-3.51(3H, m; 5-H2 + 21-HA), 3.69(1H, ddd,
J gem ) 12.0, J lr ) 2.0 + 1.5 Hz; 21-HB), 3.95 + 4.22(2 × 1H,
2 × dm, J gem ) 17.6 Hz; 3-H2), 5.79(1H, dm; J 14,15 ) 10.3 Hz;
15-H), 5.94(1H, m; 14-H), 6.70(1H, dm; 12-H), 6.89(1H, ddd;
10-H), 7.17(1H, ddd; 11-H), 7.28(1H, dm; 9-H); 13C NMR (CD3-
OD) δ 7.89(C18), 28.45(C16), 33.64(C17), 31.47(C19), 36.95-
(C20), 40.07(C6), 55.43(C3), 60.43(C5), 60.68 (C21), 90.59(C7),
103.37(C2), 111.47(C12), 122.18(C10), 122.60(C14), 124.28(C9),
131.11(C11), 133.07(C8), 133.09(C15), 147.08(C13).
Compound 9: 1H NMR (CD3OD) δ 0.99(3H, t, J ) 7.5 Hz;
18-H3), 1.5-1.65(2H, m; 19-H2), 1.70 + 2.08(2 × 1H, 2 × m;
17-H2), 1.78 + 2.25(2 × 1H, 2 × ddd, J gem ) 14.3, J 16,17
)
Con clu sion
4.0 + 2.0 and 13.0 and 4.6 Hz, respectively; 16-H2), 2.41(1H,
m; 6-HA), 2.70(1H, ddd, J gem ) 14.4, J 5,6B ) 12.8 + 8.0 Hz,
6-HB), 3.35-3.72(4H, m; 21-H2 + 5-H2), 4.04+4.84(2 × 1H,
2 × brd, J gem ) 18.0 Hz; 3-H2), 5.90-5.98(2H, m; 14-H + 15-
H), 6.80(1H, dm;12-H), 6.89(1H, ddd; 10-H), 7.17(1H, ddd; 11-
H), 7.27(1H, dm; 9-H); 13C NMR (CD3OD) δ 7.89(C18), 23.04-
(C16), 29.98(C17), 31.19(C19), 36.54(C20), 41.97(C6), 58.68(C3),
59.03(C21), 62.85(C5), 87.09(C7), 104.23(C2), 112.08(C12),
122.13(C10), 123.09(C14), 123.16(C9), 130.82(C11), 133.32-
(C15), 133.61(C8), 145.97(C13).
The first syntheses of the alkaloids (-)-mehranine (3),
(+)-voaphylline (4), (+)-hecubine (5), and of (-)-lochneri-
cine (2), all of them containing the epoxy ring, was
achieved. The stereoselectivity of the oxidation reactions
were rationalized by molecular-mechanical computations.
Exp er im en ta l Section
Melting points are uncorrected. 1H and 13C NMR spectra
chemical shifts (in ppm) are relative to Me4Si. Mutual H-1H
1
(+)-Na -Met h yl-14,15-d id eh yd r o-qu ebr a ch a m in e (10).
To a stirred solution of 6 (200 mg,0.7 mmol) in anhydrous DMF
(5 mL) was added oil-free NaH (20 mg, 0.38 mmol). The
(6) (a) Kurz, W. G. W.; Chaston, K. B.; Constabel, F.; Kutney, J . P.;
Choi, L. S. L.; Kolodziedczky, P.; Sleigh, S. K.; Smart, K. L.; Worth, B.
R. Helv. Chim. Acta 1980, 63, 1891. (b) Furuya, T.; Sakamoto, K.; Iida,
K.; Yoshikawa, Y. Phytochemistry 1992, 31(9), 3065.
(7) Kutney, J . P.; Preis, E.; Brown, R. T. J . Am. Chem. Soc. 1970,
92, 1700.
(8) MacroModel 6.0; Schro¨dinger Inc.: U.S.
(9) Goodman, J . M.; Still, W. C. J . Comput. Chem. 1991, 12, 1110.
J . Org. Chem, Vol. 67, No. 21, 2002 7257

Kalaus et al.
suspension was allowed to stir for 0.5 h. To the suspension
was added CH3I (0.045 mL, 0.7 mmol). After 0.5 h of stirring,
the solvent was evaporated in vacuo (1 mmHg). To the residue
was added 10% Na2CO3 solution (10 mL) and the mixture was
extracted with CH2Cl2. The combined organic layers were dried
(MgSO4) and evaporated in vacuo. The residue was purified
by preparative TLC (eluting with ether/hexane ) 1/5, Rf )
0.79) to afford 73 mg (35%) of product 10 as yellow crystals
J 16,17 ) 7.4 + 1.8 and 10.5 + 1.9 Hz, respectively; 17-H2),
1.85 + 2.79(2 × 1H, 2 × d, J gem ) 12.2 Hz; 21-H2), 2.34 + 2.37-
(2 × 1H, 2 × ddd, J gem ) 11.8, J 5,6 ) 5.6 + 4.2 and 8.7 + 4.2
Hz, respectively; 5-H2), 2.70-2.80(3H, m; 3-HA, 16-HA, 15-H),
2.82 + 2.92(2 × 1H, 2 × ddd, J gem ) 14.8 Hz; 6-H2), 2.89(1H,
m; 3-HB), 3.03(1H, ddd, J gem ) 15.5 Hz; 16-HB), 3.15(1H, dd,
J 3B,14 ) 5.2, J 14,15 ) 4.2 Hz; 14-H), 3.68(3H, s; N-Me), 7.06-
(1H, ddd; 10-H), 7.14(1H, ddd; 11-H), 7.25(1H, dd;12-H), 7.46-
(1H, dd; 9-H); 13C NMR (CDCl3) δ 8.03(C18), 18.71(C16),
22.49(C6), 29.07(C19), 29.57(NMe), 33.16(C17), 39.51(C20),
49.18(C21), 52.26(C3), 52.45(C14), 52.59(C5), 58.76(C15), 108.50-
(C7), 108.58(C12), 117.46(C9), 118.52(C10), 120.23(C11), 127.53-
(C8), 136.37(C13), 140.89(C2). Anal. Calcd for C20H26N2O: C,
77.38; H, 8.44; N, 9.02. Found: C, 77.43; H, 8.40; N, 8.97.
mp 75-77 °C; IR (KBr) ν 2935, 2820, 1465, 1365, 1305 cm-1
MS m/z (relative intensity) 294(100.0), 265(20.0), 199(20.0),
170(75.0), 158(39.0), 122(65.0), 79(39.0), 42(48.0); [R]D
;
)
1
+107.1 (c 0.5, CHCl3); H NMR (CDCl3) δ 0.72(3H, t, J ) 7.6
Hz; 18-H3), 1.10 + 1.13(2 × 1H, 2 × dq, J gem ) 13.8 Hz; 19-
H2), 1.70 + 1.81(2 × 1H, 2 × ddd, J gem ) 14.0, J 16,17 ) 10.2 +
1.3 and 8.8 + 1.2 Hz, respectively; 17-H2), 2.29 + 2.52(2 ×
1H, 2 × brd, J gem ) 11.5, J lr ) 1.7 and 1.5 + 1.5 Hz,
respectively; 21-H2), 2.40(1H, ddd, J gem ) 13.3, J 5,6 ) 10.8 and
2.5 Hz; 5-HA), 2.68 + 3.83(2 × 1H, 2 × ddd, J gem ) 14.5 Hz;
16-H2), 2.70-2.90(3H, m; 5-HB + 6-H2), 3.07 + 3.25(2 × 1H,
2 × ddd, J gem ) 16.0, J 3,14 ) 1.6 and 4.7, J 3,15 ) 2.2 and 1.6
Hz, respectively; 3-H2), 3.69(3H, s; N-Me), 5.37(1H, dddd,
J 14,15 ) 10.0, J lr ) 1.5 Hz; 15-H), 5.83(1H, ddd; 14-H), 7.07-
(1H, ddd; 10-H), 7.14(1H, ddd; 11-H), 7.25(1H, dd; 12-H), 7.49-
(1H, dd; 9-H); 13C NMR (CDCl3) δ 7.98(C18), 20.84(C16),
25.87(C6), 30.01(NMe), 33.22(C19), 38.74(C17), 40.01(C20),
51.83(C3), 54.26(C5), 58.52(C21), 108.41(C12), 109.59(C7),
117.71(C9), 118.43(C10), 120.22(C11), 126.61(C14), 127.92(C8),
(16S)-(14S,15R)-Epoxy-cleavam in e (20) an d (16R)-(14S,-
15R)-Ep oxy-clea va m in e (21): Rf ) 0.33 (ether/hexane )
1/1); IR (neat) ν 3300, 2928, 2832, 1728, 1696, 1608, 1464, 1432
cm-1; MS m/z (relative intensity) 354(100.0), 295(11.0), 257-
(17.0), 228(21.0), 215(47.0), 138(74.0), 97(34.0), 8339.0). The
exact molecular mass for
C21H26N2O3 m/z 354.1943 was
confirmed by HRMS (EI, 70 eV). Compound 20: 1H NMR
(CHCl3) δ 0.78(3H, t, J 18,19 ) 7.5 Hz; 18-H3), 1.17 + 1.32(2 ×
1H, 2 × dq, J gem ) 13.7 Hz; 19-H2), 1.93 + 2.06(2 × 1H, 2 ×
brd, J gem ) 12.0 Hz; 21-H2), 2.11 + 2.23(2 × 1H, 2 × dd,
J gem ) 14.8, J 16,17 ) 1.3 and 10.2 Hz, respectively; 17-H2),
2.26 + 2.59(2 × 1H, 2 × ddd, J gem ) 13.9, J 5,6 ) 9.0 + 5.2 and
3.3 + 3.2 Hz, respectively; 5-H2), 2.81(2H, m; 6-H2), 2.86(1H,
brd, J 14,15 ) 4.0 Hz; 15-H), 2.87 + 3.32(2 × 1H, 2 × ddd,
J gem ) 13.0, J 3,14 ) <1 and 5.2, J lr∼1 and 1.7 Hz, respectively;
3-H2), 3.52(1H, dd; 14-H), 3.70(3H, s; OMe), 5.25(1H, dd; 16-
H), 7.08(1H, ddd; 10-H), 7.15(1H, ddd; 11-H), 7.33(1H, dm; 12-
H), 7.48(1H, dm; 9-H), 8.55(1H, brs; NH); 13C NMR (CDCl3) δ
7.00(C18), 25.35(C6), 31.05(C19), 37.52(C20), 39.16(C16), 40.38-
(C17), 50.86(C3), 52.28(OMe), 53.58(C5), 54.28(C14), 55.81-
(C21), 57.75(C15), 110.75(C12), 111.87(C7), 118.22(C9), 119.12-
(C10), 121.72(C11), 127.78(C8), 133.87(C13), 135.92(C2),
175.56(COOMe). Compound 21: 1H NMR (CHCl3) δ 1.00(3H,
t, J 18,19 ) 7.5 Hz; 18-H3), 1.51(2H, q; 19-H2), 1.86 + 2.85(2 ×
1H, 2 × brd, J gem ) 12.7 Hz; 21-H2), 2.03+2.15(2 × 1H, 2 ×
dd, J gem ) 14.0, J 16,17 ) 2.4 and 5.3 Hz, respectively; 17-H2),
2.31 + 2.39(2 × 1H, 2 × ddd, J gem ) 11.5, J 5,6 ) 12.5 + 4.5
and 4.5 + 1.8 Hz, respectively; 5-H2), 2.72 + 2.76(2 × 1H, 2 ×
ddd, J gem ) 12.8, J 3,14 ) 1.0 and 4.4, J lr ) 1 and 1.9 Hz,
respectively; 3-H2), 2.75(1H, m; 15-H), 2.88 + 2.95(2 × 1H,
2 × ddd, J gem ) 15.0 Hz; 6-H2), 3.03(1H, ddd, J 14,15 ) 4.0 Hz;
14-H), 3.93(1H, dd; 16-H), 7.07(1H, ddd; 10-H), 7.13(1H, ddd;
11-H), 7.33(1H, dm; 12-H), 7.48(1H, dm; 9-H), 8.90(1H, brs;
NH); 13C NMR (CDCl3) δ 7.96(C18), 21.27(C6), 27.43(C19),
37.21(C16), 38.74(C17), 40.61(C20), 47.34(C21), 51.40(C5),
51.68(C14), 52.47(OMe), 52.65(C3), 58.14(C15), 109.64(C7),
110.83(C12), 117.73(C9), 119.09(C10), 121.34(C11), 127.82(C8),
134.92(C13), 135.21(C2), 175.98(COOMe).
134.00(C15), 136.67(C13), 141.05(C2). Anal. Calcd for C20H26
-
N2: C, 81.59; H, 8.90; N, 9.51. Found: C, 81.40; H, 8.87, N,
9.54.
Syn th esis of Ep oxy-Rin g-Con ta in in g Com p ou n d s w ith
Qu ebr a ch a m in e Sk eleton (11, 12, 20, a n d 21). A 0.5 mmol
portion of starting compound (6, 10, 18, and 19) was stirred
in anhydrous THF (15 mL). A few drops of TFAA were added
and the mixture was cooled to 0 °C; 1.5 equiv of t-BuOOH
(solution 80% in di-tert-buthylperoxide) was added dropwise.
The reaction mixture was maintained at room temperature
for 10 h, and then the solvent was evaporated. To the residue
was added 10% Na2CO3 solution (5 mL) and the mixture was
extracted with CH2Cl2. The combined organic layers were dried
(MgSO4) and evaporated in vacuo. The residue was purified
by preparative TLC to afford 11 (82%) as white crystals; 12
(78%) as yellow crystals; and the mixture of 20 and 21 (62%)
as brown oil.
(+)-(14S,15R)-Ep oxy-qu ebr a ch a m in e (11): Rf ) 0.52
(ether/hexane ) 1/1); mp 86-88 °C; IR (KBr) ν 3400, 2950,
2750, 1460, 1338 cm-1; MS m/z (relative intensity) 296(35.0),
267(9.0), 168(43.0), 156(100.0), 143(90.0), 77(55.0), 57(65.0);
[R]D ) +87.0 (c 0.5, CHCl3); 1H NMR (CDCl3) δ 0.92(3H, t,
J ) 7.5 Hz; 18-H3), 1.33 + 1.40(2 × 1H, 2 × dq, J gem ) 13.8
Hz; 19-H2), 1.85(2H, m; 17-H2), 1.87 + 2.64(2 × 1H, 2 × brd,
J gem ) 12.2 Hz; 21-H2), 2.31 + 2.42(2 × 1H, 2 × ddd, J gem
)
12.0, J 5,6 ) 5.5 + 3.7 and 8.9 + 4.0 Hz, respectively; 5-H2),
2.75 + 2.98(2 × 1H, 2 × ddd, J gem ) 12.8, J 3,14 < 1 and 5.2,
J lr < 1 and 1.8 Hz, respectively; 3-H2), 2.75 + 3.06(2 × 1H,
2 × dm, J gem ) 15.0 Hz; 16-H2), 2.78(1H, brd, J 14,15 ) 4.1 Hz;
15-H), 2.78 + 2.88(2 × 1H, 2 × ddd, J gem ) 14.6 Hz; 6-H2),
3.22(1H, dd; 14-H), 7.0-7.15(2H, m; 10-H + 11-H), 7.27(1H,
dd; 12-H), 7.46(1H, ddd; 9-H), 8.00(1H, br; indole-NH); 13C
NMR (CDCl3) δ 7.78(C18), 21.62(C16), 22.69(C6), 29.25(C19),
34.23(C17), 38.85(C20), 50.28(C21), 51.96(C3), 52.60(C5), 52.75-
(C14), 58.49(C15), 108.92(C7), 110.13(C12), 117.47(C9), 118.76-
(C10), 120.52(C11), 128.62(C8), 135.08(C13), 138.97(C2). Anal.
Calcd for C19H24N2O: C, 76.99; H, 8.16; N, 9.45. Found: C,
77.13; H, 8.12; N, 9.38.
(-)-Na -(2,2,2-Tr ich lor oet h yloxyca r b on yl)-14,15-d id e-
h yd r o-a sp id osp er m id in e (14). To a stirred solution of 13
(2 g, 7.1 mmol) in CH2Cl2 (40 mL) was added ClCO2CH2CCl3
(1.3 mL, 9.4 mmol). The reaction mixture was allowed to stir
for 24 h at room temperature; 10% Na2CO3 solution (20 mL)
was added. After separation of the two phases, the aqueous
layer was extraced with CH2Cl2. The combined organic layers
were dried and evaporated in vacuo. The residue was purified
by column chromatography (eluting with hexane/acetone ) 2/1,
Rf ) 0.63) to afford 2.86 g (88%) of product 14 as brown oil:
IR (neat) ν 2968, 2792, 1724, 1480, 1464, 1408 cm-1; [R]D
)
-2.4 (c 0.5, CHCl3); 1H NMR (CDCl3) δ 0.76(3H, t, J 18,19 ) 7.5
Hz; 18-H3), 1.21(2H, m; 19-H2), 1.35 + 2.13(2 × 1H, 2 × dddd,
J gem ) 13.0, J 2,16 ) 11.0 and 6.0, J 16,17 ) 13.0 + 3.3 and 3.0 +
4.0 Hz, respectively; 16-H2), 1.40 + 1.75(2 × 1H, 2 × ddd,
(+)-Na -Met h yl-(14S,15R)-ep oxy-q u eb r a ch a m in e (12):
Rf ) 0.71 (ether/hexane ) 1/1); mp 105-107 °C; IR (KBr) ν
2910, 2790, 1470,1370 cm-1; MS m/z (relative intensity) 310-
(38.0), 226(30.0), 170(93.0), 158(100.0), 115(28.0) 77(24.0),
57(35.0); [R]D ) +80.2 (c 0.5, CHCl3); 1H NMR (CDCl3) δ 0.96-
J gem ) 14.0 Hz; 17-H2), 1.66 + 2.22(2 × 1H, 2 × ddd, J gem
)
13.2, J 5,6 ) 10.2 + 3.4 and 8.5 + 8.0 Hz, respectively; 6-H2),
2.36 + 3.32(2 × 1H, 2 × ddd, J gem ) 9.0 Hz; 5-H2), 2.73(1H,
(3H, t, J ) 7.5 Hz; 18-H3), 1.40 + 1.44(2 × 1H, 2 × dq, J gem
)
brs; 21-HR), 2.81 + 3.47(2 × 1H, 2 × ddd, J gem ) 16.0, J 3,14
)
13.8 Hz; 19-H2), 1.71 + 1.87(2 × 1H, 2 × ddd, J gem ) 13.7,
1.5 and 4.8, J 3,15 ) 2.0 and 1.5 Hz, respectively; 3-H2), 4.37-
7258 J . Org. Chem., Vol. 67, No. 21, 2002

Aspidospermane and Quebrachamine Ring Systems
(1H, dd;2-H), 4.79 + 4.96(2 × 1H, 2 × d, J gem ) 11.7 Hz; OCH2),
5.55(1H, ddd, J 14,15 ) 10.0 Hz; 15-H), 5.69(1H, ddd; 14-H), 7.06-
(1H, ddd; 10-H), 7.23(1H, brd; 9-H), 7.24(1H, brdd; 11-H), 7.85-
(1H, brd; 12-H); 13C NMR (CDCl3) δ 7.76(C18), 24.20(C16),
27.57(C19), 29.02(C17), 38.65(C20), 40.96(C6), 51.87(C7), 52.98-
(C5), 53.41(C3), 66.26(C21), 68.10(C2), 74.63(OCH2), 95.47-
(CCl3), 115.90(C12), 122.00(C9), 122.78(C14), 124.00(C10),
127.89(C11), 134.02(C15), 138.37(C8), 139.76(C13), 151.07-
(NCOO); MS m/z (relative intensity) 456(13.0), 446(19.0), 310-
(100.0), 281(22.0), 199(23.0), 158(47), 144(62), 121(47.0), 108-
(23.0). The exact molecular mass for C22H25N2O2Cl3 m/z
454.0981 was confirmed by HRMS (EI, 70 eV).
maintained at room temperature for 10 h, abd then the solvent
was evaporated. The residue was purified by preparative TLC
(eluting with hexane/acetone 2/1, Rf ) 0.46) to afford 108 mg
(69%) of product 3 as white crystals: mp 105-106 °C (lit.4c
mp 102-104 °C); IR (KBr) ν 2928, 2912, 2784, 1600, 1488,
1456, 1432, 1380 cm-1; MS m/z (relative intensity) 310(100.0),
199(22.0), 170(18.0), 158(46.0), 144(60.0), 108(23.0); [R]D
)
-48.1 (c 1, CHCl3) (lit.4b [R]D ) -49 (c 0.831, CHCl3)); 1H NMR
(CDCl3) δ 0.82(3H, t, J 18,19 ) 7.5 Hz; 18-H3), 1.14(1H, m; 16-
HA), 1.25 + 1.30(2 × 1H, 2 × dq, J gem ) 14.2 Hz; 19-H2), 1.47-
(1H, m; 17-HA), 1.63 + 2.27(2 × 1H, 2 × ddd, J gem ) 12.8,
J 5,6 ) 8.5 + 2.5 and 9.5 + 8.3 Hz, respectively; 6-H2), 1.74-
1.83(2H, m; 16-HB + 17-HB), 2.20 + 3.18(2 × H, 2 × ddd,
J gem ) 8.5 Hz; 5-H2), 2.25(1H, brs; 21-HR), 2.36 + 3.57(2 × 1H,
2 × dd, J gem ) 13.0, J 3,14 ) 1.0 and 1.8 Hz, respectively; 3-H2),
2.75(3H, s; NMe), 2.96(1H, d, J 14,15 ) 4.0 Hz; 15-H), 3.34(1H,
ddd; 14-H), 3.36(1H, dd, J 2,16 ) 10.8 + 5.2 Hz; 2-H), 6.39(1H,
(-)-Na -(2,2,2-Tr ich lor oet h yloxyca r b on yl)-(14R,15S)-
ep oxy-a sp id osp er m id in e (15). To a stirred solution of 14
(1 g, 2.2 mmol) in MeOH (30 mL) were added a few drops of
HClO4 and the mixutre was cooled to 0 °C. MCPBA (560 mg,
3.2 mmol) was added. The reaction mixture was stirred at
room temperature for 18 h, and then the solvent was evapo-
rated. To the residue was added 10% Na2CO3 solution (15 mL)
and the mixture was extracted with CH2Cl2. The combined
organic layers were dried and evaporated in vacuo. The residue
was purified by column chromatography (eluting with hexane/
acetone 2/1, Rf ) 0.36) to afford 817 mg (79%) of product 15
as yellow oil: IR (neat) ν 2968, 2760, 1724, 1590, 1480, 1408
brd, J 11,12 ) 7.8 Hz; 12-H), 6.63(1H, ddd, J 9,10 ) 7.7, J 10,11
)
7.3, J 10,12 ) 1.1 Hz; 10-H), 7.01(1H, dd, J 9,11 ) 1.3 Hz; 9-H),
7.08(1H, ddd; 11-H); 13C NMR (CDCl3) δ 7.56(C18), 20.05(C16),
23.56(C17), 27.85(C19), 31.59(NMe), 34.74(C20), 41.24(C6),
51.43(C7), 53.09(C14), 53.25(C5), 53.79(C3), 57.37(C15), 67.80-
(C21), 73.35(C2), 106.56(C12), 117.13(C10), 121.44(C9), 127.70-
(C11), 136.84(C8), 150.21(C13). Anal. Calcd for C20H26N2O: C,
77.38; H, 8.44; N, 9.02. Found: C, 77.40; H, 8.48; N, 8.99.
1
cm-1; [R]D ) -15.9 (c 1, CHCl3); H NMR (CDCl3) δ 0.85(3H,
t, J 18,19 ) 7.5 Hz; 18-H3), 1.20-1.37(3H, m; 19-H2 + 16-HA),
1.49 + 1.92(2 × 1H, 2 × ddd, J gem ) 14.5, J 16,17 ) 3.8 + 3.5
and 14.0 + 3.0 Hz, respectively; 17-H2), 1.63 + 2.19(2 × 1H,
2 × dm, J gem ) 12.5 Hz; 6-H2), 2.18(1H, m; 16-HB), 2.26 + 3.23-
(2 × 1H, 2 × ddd, J gem ) 8.5, J 5,6 ) 9.0 + 8.5 and 8.0 + 3.0 Hz,
respectively; 5-H2), 2.40(1H, brs; 21-HR), 2.42 + 3.59(2 × 1H,
2 × dd, J gem ) 13.0, J 3,14 ) 1.0 and 1.5 Hz, respectively; 3-H2),
2.99(1H, d, J 14,15 ) 4.0 Hz; 15-H), 3.37(1H, ddd; 14-H), 4.35-
(1H, dd, J 2,16 ) 10.8 + 5.8 Hz; 2-H), 4.82 + 4.90(2 × 1H, 2 ×
d, J gem ) 11.7 Hz; OCH2), 7.06(1H, ddd; 10-H), 7.19(1H, dd;
9-H), 7.25(1H, ddd; 11-H), 7.84(1H, dd; 12-H); 13C NMR
(CDCl3) δ 7.43(C18), 23.41(C17), 23.53(C16), 27.56(C19), 34.72-
(C20), 41.86(C6), 51.31(C7), 52.94(C14), 53.24(C3+C5), 56.99-
(C15), 67.46(C21), 68.30(C2), 74.65(OCH2), 95.33(CCl3), 115.93-
(C12), 121.87(C9), 123.95(C10), 128.06(C11), 138.35(C8),
139.55(C13), 150.90(NCOO). MS m/z (relative intensity) 471-
(100.0), 437(26.0), 296(30.0), 185(27.0), 93(41.0). The exact
molecular mass for C22H25N2O3Cl3 m/z 471.1009 was confirmed
by HRMS (EI, 70 eV).
(-)-(14R,15S)-Epoxy-aspidosper m idin e (16). To a stirred
solution of 15 (1 g, 2.1 mmol) in MeOH (30 mL) was added Zn
dust (1.2 g) and the mixture was refluxed for 18 h. The reaction
mixture was filtered. The filtrate was evaporated. The residue
was purified by by column chromatography (eluting with
hexane/acetone 1/1, Rf ) 0.44) to afford 345 mg (55%) of
product 16 as white crystals: mp 174-175 °C; IR (KBr) ν 2960,
2750, 1600, 1480, 1440 cm-1; MS m/z (relative intensity)
296(100.0), 267(11), 204(15.0), 185(31), 156(22.0), 144(46.0),
130(49.0), 108(21.0); [R]D ) -71.1 (c 1, CHCl3); 1H NMR
(CDCl3 + DMSO-d6) δ 0.84(3H, t, J 18,19 ) 7.5 Hz; 18-H3), 1.22-
1.37(3H, m; 19-H2 + 16-HA), 1.40 + 1.82(2 × 1H, 2 × ddd,
J gem ) 14.0, J 16,17 ) 4.0 + 3.0 and 14.0 + 3.0 Hz, respectively;
17-H2), 1.58(1H, m; 6-HA), 1.65(1H, m; 16-HB), 2.18-2.32(2H,
m; 6-HB + 5-HA), 2.30(1H, brs; 21-HR)2.40 + 3.56(2 × 1H, 2 ×
dd, J gem ) 13.0, J 3,14 ) 1.0 and 1.6 Hz, respectively; 3-H2), 2.95-
(1H, d, J 14,15 ) 4.0 Hz; 15-H), 3.18(1H, m; 5-HB), 3.35(1H, dm;
12-H), 6.70(1H, ddd; 10-H), 7.01(1H, ddd; 11-H), 7.07(1H, dm;
9-H); 13C NMR (CDCl3 + DMSO-d6) δ 7.49(C18), 23.48(C17),
26.04(C16), 27.50(C19), 34.80(C20), 40.79(C6), 52.16(C7), 52.89-
(C14), 53.20(C5), 53.59(C3), 57.07(C15), 67.00(C2), 67.54(C21),
110.09(C12), 118.53(C10), 121.97(C9), 127.41(C11), 135.51(C8),
149.17(C13). Anal. Calcd for C19H24N2O: C, 76.99; H, 8.16; N,
9.45. Found: C, 76.73; H, 8.06; N, 9.41.
(-)-1,2-Did eh yd r o-(14R,15S)-ep oxy-a sp id osp er m id in e
(17). A mixture of potassium permanganate (50 mg, 0.32
mmol) and 18-crown-6 ether (100 mg, 0.4 mmol) in anhydrous
benzene (5 mL) was stirred at room temperature for 15 min.
Then 16 (100 mg, 33 mmol) was added and the stirring was
continued for 2 h. The mixture was filtered through a What-
man GF/A glass microfiber filter and the filtrate was washed
with 10% Na2CO3 solution (5 mL). It was dried and evaporated
in vacuo. The residue was purified by preparative TLC (eluting
with hexane/acetone 1/1, Rf ) 0.72) to afford 39 mg (39%) of
product 17 as brown oil: IR (neat) ν 3312, 2968, 2750, 1700,
1
1576, 1450 cm-1; [R]D ) -91.4 (c 1, CHCl3); H NMR (CDCl3)
δ 0.78(1H, t, J 18,19 ) 7.3 Hz; 18-H3), 0.84-1.02(2H, m; 19-H2),
1.62 + 2.30(2 × 1H, 2 × ddd, J gem ) 12.0, J 5,6 ) 4.7 + ∼1 and
11.5 + 6.5 Hz, respectively; 6-H2), 1.83 + 2.67(2 × 1H, 2 ×
dddd, J gem ) 14.3, J 16,17 ) 9.2 + 2.0 and 10.8 + 9.2, J lr ) 1.8
and ∼0.6 Hz, respeectively; 17-H2), 2.48(1H, d, J lr ) 1.8 Hz;
21-HR), 2.81 + 3.62(2 × 1H, 2 × dd, J gem ) 12.8, J 3,14 ) 1.2
and 1.3 Hz, respectively; 3-H2), 2.85 + 3.25(2 × 1H, 2 × ddd,
J gem ) 8.5 Hz; 5-H2), 2.89 + 2.99(2 × 1H, 2 × ddd, J gem ) 17.2
Hz; 16-H2), 2.92(1H, d, J 14,15 ) 3.9 Hz; 15-H), 3.24(1H, ddd;
14-H), 7.16(1H, ddd; 10-H), 7.28-7.33(2H, m; 9-H + 11-H),
7.52(1H, dm; 12-H); 13C NMR (CDCl3) δ 7.76(C18), 23.21(C17),
24.26(C16), 26.67(C19), 35.97(C6), 36.18(C20), 50.47(C3), 52.66-
(C14), 53.04(C5), 53.83(C7), 57.33(C15), 73.96(C21), 120.15-
(C12), 121.10(C9), 125.28(C10), 127.80(C11), 147.32(C8), 154.21-
(C13), 188.80(C2); MS m/z (relative intensity) 295.3(25.0),
287.2(100.0). The exact molecular mass for C19H22N2O m/z
294.1732 was confirmed by HRMS (EI, 70 eV).
(+)-Voa p h yllin e (4). Compound 17 (100 mg, 0.34 mmol)
was heated in ethanol (10 mL) at the boiling point and sodium
borohydride (20 mg, 0.52 mmol) was added in portions. After
addition of the reducing agent, the mixture was refluxed for 1
h. It was poured onto ice-water. The solution was extracted
with CH2Cl2, and the combined organic layers were dried and
evaporated in vacuo. The residue was purified by preparative
TLC (eluting with ether/hexane 1/1, Rf ) 0.52) to afford 80
mg (80%) of product 4 as white crystals: mp 166-167 °C (lit.5b
mp 166-167 °C); IR (KBr) ν 3400, 2920, 2824, 1464, 1336 cm-1
;
MS m/z (relative intensity) 297(100.0), 179.1(5.0), 101.1(10.0),
78.9(10.0); [R]D ) +27,1 (c 1, CHCl3) (lit.5b [R]D ) +26 (c 0.64,
CHCl3)); 1H NMR (CDCl3) δ 0.74(3H, t, J 18,19 ) 7.5 Hz; 18-
H3), 1.12(2H, m; 19-H2), 1.71 + 2.37(2 × 1H, 2 × brd, J gem
)
(-)-Meh r a n in e (3). To a stirred solution of (-)-(14R,15S)-
epoxy-aspidospermidine (16) (150 mg, 0.5 mmol) in CH2Cl2 (10
mL) was added Et3N (0.1 mL, 0.7 mmol). Then CH3I (0.05 mL,
0.8 mmol) was added dropwise. The reaction mixture was
12.2 Hz; 21-H2), 1.73 + 2.23(2 × 1H, 2 × ddd, J gem ) 14.2,
J 16,17 ) 12.1 + 1.4 and 7.5 + 1.5 Hz, respectively; 17-H2),
2.32 + 2.60(2 × 1H, 2 × ddd, J gem ) 13.3, J 5,6 ) 9.5 + 4.0 and,
3.5 + 4.0 Hz, respectively; 5-H2), 2.67 + 3.29(2 × 1H, 2 × dd,
J . Org. Chem, Vol. 67, No. 21, 2002 7259

Kalaus et al.
J gem ) 12.5, J 3,14 ) 1.0 and 1.5 Hz, respectively; 3-H2), 2.72 +
4.17(2 × 1H, 2 × ddd, J gem ) 14.4 Hz; 16-H2), 2.81 + 2.84(2 ×
1H, 2 × ddd, J gem ) 13.8 Hz; 6-H2), 2.92(1H, dd, J 14,15 ) 4.0,
J lr ) 1.5 Hz; 15-H), 3.13(1H, ddd; 14-H), 7.06(1H, ddd; 10-H),
7.09(1H, ddd; 11-H), 7.28(1H, dm; 12-H), 7.44(1H, dm; 9-H),
7.82(1H, brs; indole-NH); 13C NMR (CDCl3) δ 7.39(C18), 23.26-
(C16), 26.04(C6), 32.33(C19), 33.64(C20), 36.54(C17), 52.32-
(C14), 53.53(C5), 53.82(C3), 58.58(C21), 59.35(C15), 109.72-
(C7), 110.06(C12), 117.72(C9), 118.78(C10), 120.61(C11),
175.96(COOMe). Compound 19: 1H NMR (CHCl3) δ 0.91(3H,
t, J 18,19 ) 7.5 Hz; 18-H3), 1.39 + 1.46(2 × 1H, 2 × dq, J gem
)
14.0 Hz; 19-H2), 1.94 + 3.42(2 × 1H, 2 × brd, J gem ) 12.0 Hz;
21-H2), 1.98 + 22.27(2 × 1H, 2 × dd, J gem ) 14.2, J 16,17 ) 2.4
and 5.5 Hz, respectively; 17-H2), 2.44-2.55(2H, m; 5-H2), 2.8-
2.9(2H, m; 3-H2), 2.9-3.0(2H, m; 6-H2), 3.77(3H, s; OMe), 3.96-
(1H, dd; 16-H), 5.37(1H, ddd, J 14,15 ) 9.8, J 3,14 ) 4.0+1.9 Hz;
14-H), 5.56(1H, dddd, J lr ) 2.2 + 2 + 2 Hz; 15-H), 7.06(1H,
ddd; 10-H), 7.11(1H, ddd; 11-H), 7.31(1H, dm; 12-H), 7.49(1H,
dm; 9-H), 8.96(1H, brs; NH); 13C NMR (CDCl3) δ 8.52(C18),
21.55(C6), 29.60(C19), 38.34(C16), 41.24(C20), 44.57(C17),
51.83(C21), 51.79(C5), 52.31(OMe), 54.72(C3), 109.54(C7),
110.77(C12), 117.66(C9), 118.90(C10), 121.09(C11), 125.03-
(C14), 128.00(C8), 135.07(C13), 135.46(C2), 135.87(C15), 176.22-
(COOMe).
128.57(C8), 135.59(C13), 139.36(C2). Anal. Calcd for C19H24
-
N2O: C, 76.99; H, 8.16; N, 9.45. Found: C, 76.90; H, 8,12; N,
9.40.
(+)-Hecu bin e (5). To a stirred solution of 6 (80 mg, 0.2
mmol) in anhydrous DMF (5 mL) was added oil-free NaH (10
mg, 0.19 mmol). The suspension was allowed to stir for 0.5 h
at room temperature. To the suspension was added CH3I
(0.012 mL, 0.2 mmol). After 1.5 h of stirring, the solvent was
evaporated in vacuo (1 mmHg). To the residue was added 10%
Na2CO3 solution (10 mL) and the mixture was extracted with
CH2Cl2. The combined organic layers were dried (MgSO4) and
evaporated in vacuo. The residue was purified by preparative
TLC (eluting with ether/hexane 1/1, Rf ) 0.71) to afford 29
mg (35%) of product 5 as amorphous crystals: IR (KBr) ν 2928,
(-)-Loch n er icin e (2) a n d (+)-(14S,15R)-E p oxy-a llo-
ca th a r a n tin e (22). To a stirred solution of 20 and 21 (1 g,
2.8 mmol) in glacial acetic acid (5 mL) was added mercury(II)
acetate (3.3 g, 10.6 mmol). The reaction mixture was allowed
to stir at room temperature for 2 h. The precipitated mercurous
acetate was filtered off and the filtrate was treated with
hydrogen sulfide gas. The resulting mixture was filtered
through Celite, and the filtrate was poured onto ice-water and
neutralized with saturated Na2CO3 solution. The solution was
extracted with CH2Cl2, and the combined organic layers were
dried (MgSO4) and evaporated in vacuo. The residue was
purified by preparative TLC (eluting with hexane/acetone 3/1).
The less polar compound (2, Rf ) 0.51), was obtained as white
crystals (350 mg, 35%): mp 190-191 °C (lit.6b mp 193-195
°C); IR (KBr) ν 3360, 2992 1666, 1604, 1464 cm-1; MS m/z
(relative intensity) 353.2(100.0), 308.2(4.0); [R]D ) -498.5 (c
0.1, EtOH) (lit.6b [R]D ) -505 (c 0.1, EtOH)); 1H NMR (CDCl3)
δ 0.74(3H, t, J 18,19 ) 7.5 Hz; 18-H3), 0.90 + 1.14(2 × 1H, 2 ×
dq, J gem ) 14.3 Hz; 19-H2), 1.71 + 1.94(2 × 1H, 2 × ddd,
J gem ) 11.5, J 5,6 ) 4.5 + <1 and 12.0 + 6.4 Hz, respectively;
6-H2), 2.47 + 2.87(2 × 1H, 2 × m; 5-H2), 2.47(1H, brs; 21-HR),
2.50 + 2.58(2 × 1H, 2 × d, J gem ) 14.8 Hz; 17-H2), 2.89 + 3.51-
(2 × 1H, 2 × m; 3-H2), 3.11(1H, d, J 14,15 ) 3.5 Hz; 15-H), 3.49-
(1H, m; 14-H), 3.79(3H, s; OMe), 6.81(1H, dd; 12-H), 6.86(1H,
ddd; 10-H), 7.13(1H, m; 11-H), 7.14(1H, m; 9-H), 8.95(1H, brs;
NH); 13C NMR (CDCl3) δ 7.24(C18), 23.29(C17), 24.41(C19),
41.07(C20), 44.76(C6), 50.16(C3), 50.66(C5), 51.08(OMe) 53.96-
(C14), 54.94(C7), 57.26(C15), 67.59(C21), 90.70(C16), 109.44-
(C12), 120.72(C10), 121.43(C9), 127.78(C11), 137.56(C8), 143.03-
(C13), 167.73(C2), 168.88(COOMe). Anal. Calcd for C21H24N2O3:
C, 71.57; H, 6.86; N, 7.95. Found: C, 71.70; H, 6.74; N, 7.91.
The more polar compound (22, Rf ) 0.3) was obtained as a
yellow oil (80 mg, 8%): IR (neat) ν 3376, 2920, 1728, 1632,
1460 cm-1; [R]D ) +48.0 (c 1, CHCl3); 1H NMR (CDCl3) δ 0.97-
1
2832, 1472, 1368 cm-1; [R]D ) +22.2 (c 0.2, CHCl3); H NMR
(CDCl3) δ 0.75(3H, t, J 18,19 ) 7.5 Hz; 18-H3), 1.15(2H, m; 19-
H2), 1.72 + 2.22(2 × 1H, 2 × ddd, J gem ) 14.2, J 16,17 ) 12.1 +
1.4 and 7.5 + 1.5 Hz, respectively; 17-H2), 1.75 + 2.51(2 ×
brd, J gem ) 12.2 Hz; 21-H2), 2.37 + 2.60(2 × 1H, 2 × ddd,
J gem ) 13.3, J 5,6 ) 9.5 + 4.0 and 3.5 + 4.0 Hz, respectively;
5-H2), 2.67 + 3.28(2 × 1H, 2 × dd, J gem ) 12.5, J 3,14 ) 1.0 and
1.5 Hz, respectively; 3-H2), 2.78 + 4.21(2 × 1H, 2 × ddd,
J gem ) 14.4 Hz; 16-H2), 2.87(2H, m; 6-H2), 2.92(1H, dd,
J 14,15 ) 4.0, J lr ) 1.5 Hz; 15-H), 3.15(1H, ddd; 14-H), 3.70(3H,
s; NMe), 7.06(1H, ddd; 10-H), 7.14(1H, ddd; 11-H), 7.25(1H,
dm; 12-H), 7.45(1H, dm; 9-H); 13C NMR (CDCl3) δ 7.48(C18),
20.98(C16), 26.34(C6), 30.01(NMe), 32.46(C19), 33.82(C20),
35.26(C17), 52.41(C14), 53.57(C5), 53.82(C3), 58.10(C21), 59.39-
(C15), 108.51(C12), 109.31(C7), 117.63(C9), 118.51(C10), 120.26-
(C11), 127.79(C8), 136.94(C13), 140.84(C2); MS m/z (relative
intensity) 311.2(100.0), 295.0(20.0). The exact molecular mass
for C20H26N2O m/z 310.2045 was confirmed by HRMS (EI,
70 eV).
(16S)-14,15-Did eh yd r o-clea va m in e (18) a n d (16R)-14,-
15-Did eh yd r o-clea va m in e (19). Compound 1 (3 g, 8.9 mmol)
was heated in glacial acetic acid (5 mL) at 90 °C and sodium
borohydride (2 g, 5.3 mmol) was added in portions. After
addition of the reducing agent, the mixture was poured onto
ice-water and neutralized with saturated Na2CO3 solution.
The solution was extracted with CH2Cl2, and the combined
organic layers were dried (MgSO4) and evaporated in vacuo.
The residue was purified by column chromatography (eluting
with ether/hexane 1/5, Rf ) 0.45) to afford 1.96 g (68%) the
mixture of products 18 and 19 as brown oil: IR (neat) ν 3392,
2920, 2872, 1724, 1464 cm-1; MS m/z (relative intensity) 339.1-
(100.0), 299.2(5.0). The exact molecular mass for C21H26N2O2
m/z 338.1995 was confirmed by HRMS (EI, 70 eV). Compound
18: 1H NMR (CHCl3) δ 0.70(3H, t, J 18,19 ) 7.5 Hz; 18-H3),
1.09 + 1.13(2 × 1H, 2 × dq, J gem ) 13.5 Hz; 19-H2), 1.93 +
2.12(2 × 1H, 2 × dd, J gem ) 14.2, J 16,17 ) 1.1 and 10.0 Hz,
respectively; 17-H2), 2.24(2H, brs; 21-H2), 2.35 + 2.74(2 × 1H,
2 × ddd, J gem ) 13.5, J 5,6 ) 10.6 + 3.6 and 3.5 + 3.0 Hz,
respectively; 5-H2), 2.8-2.9(2H, m; 6-H2), 3.07 + 3.29(2 × 1H,
2 × ddd, J gem ) 16.0, J 3,14 ) 1.7 and 4.8, J lr ) 2.3 and 1.7 Hz,
respectively; 3-H2), 3.65(3H, s; OMe), 5.28(1H, dd; 16-Hâ), 5.35-
(1H, ddd, J 14,15 ) 9.8, J lr ) 2.3 + 2.0 Hz; 15-H), 5.89(1H, ddd;
14-H), 7.08(1H, ddd; 10-H), 7.14(1H, ddd; 11-H), 7.33(H, dm;
12-H), 7.50(1H, dm; 9-H), 8.58(1H, brs; NH); 13C NMR (CDCl3)
δ 7.74(C18), 26.06(C6), 33.18(C19), 39.19(C16), 39.61(C20),
43.65(C17), 52.11(OMe), 51.90(C3), 53.75(C5), 58.83(C21),
110.65(C12), 111.81(C7), 118.21(C9), 118.94(C10), 121.50(C11),
127.26(C14), 127.97(C8), 133.10(C15), 134.58(C13), 135.81(C2),
(3H, t, J 18,19 ) 7.5 Hz; 18-H3), 1.42 + 1.48(2H, 2 × dq, J gem
)
14.1 Hz; 19-H2), 1.63 + 2.74(2 × 1H, d and dd, respectively,
J gem ) 13.9, J 17, 21â ) 3.2 Hz; 17-H2), 2.43 + 3.15(2 × 1H, brd
and dd, respectively, J gem ) 9.0; 21-H2), 2.85 + 3.23(2 × 1H,
2 × m; 6-H2), 3.07(1H, dd, J 14,15 ) 5.0, J 15,21R ) 1.3 Hz; 15-HR),
3.19 + 3.45((2 × 1H, 2 × m; 5-H2), 3.33(1H, dd, J 3,14 ) 3.9 Hz;
14-HR), 3.83(3H, s; OMe), 4.26(1H, brd; 3-Hâ0, 7.10(1H, ddd,
J 9,10 ) 7.7, J 10,11)7.1, J 10,12 ) 1.2 Hz; 10-H), 7.16(1H, ddd,
J 11,12 ) 7.9, J 9,11 ) 1.4 Hz; 11-H), 7.25(1H, brd; 12-H), 7.48-
(1H, brd; 9-H), 7.72(1h, brs; NH); 13C NMR (CDCl3) δ 8.56-
(C18), 20.94(C6), 29.29(C19), 37.44(C20), 41.74(C17), 51.40-
(C14), 52.72(C21), 52.97(OMe), 53.59(C5), 54.04(C15), 54.30-
(C16), 56.85(C3), 110.57(C12), 111.25(C7), 118.38(C9), 119.68-
(C10), 122.27(C11), 128.95(C8), 134.91(C13), 136.16(C2), 174.52-
(COOMe). The exact molecular mass for C21H24N2O3 m/z
352.1796 was confirmed by HRMS (EI, 70 eV).
Ack n ow led gm en t. The authors are grateful to the
National Scientific Research Foundation (OTKA T31920)
for financial support of this work.
J O020386R
7260 J . Org. Chem., Vol. 67, No. 21, 2002