Synthesis of Vinca Alkaloids and Related Compounds. 90.1 New Results in the Synthesis of Alkaloids with the Aspidospermane Skeleton. First Total Synthesis of (±)-3-Oxominovincine

Article abstract of DOI:10.1021/jo9713464

The tryptamine derivative 1 readily reacted with methyl 4-acetyl-5-bromopent-4-enoate (9) that had been built up from 2,4-pentanedione. On intramolecular dehydration and subsequent [4 + 2] cycloaddition, the reaction product 10 gave the epimers 12 and 13 having the D-secoaspidospermane skeleton. Compound 12 directly and 13 after epimerization yielded (±)-3-oxominovincine (14). Regioselective reduction of 14 furnished (±)-minovincine (17).

Full text of DOI:10.1021/jo9713464

9188
J . Org. Chem. 1997, 62, 9188-9191
Syn th esis of Vin ca Alk a loid s a n d Rela ted Com p ou n d s. 90.1 New
Resu lts in th e Syn th esis of Alk a loid s w ith th e Asp id osp er m a n e
Sk eleton . F ir st Tota l Syn th esis of (()-3-Oxom in ovin cin e
Gyo¨rgy Kalaus,† Imre J uha´sz,†,§ Istva´n Greiner,§ Ma´ria Kajta´r-Peredy, J a´nos Brlik,§
Lajos Szabo´,† and Csaba Sza´ntay*,†,
Department for Organic Chemistry, Technical University of Budapest, Gelle´rt te´r 4,
H-1521, Budapest, Hungary, Chemical Works of Gedeon Richter Ltd., Gyo¨mroˆi u´t 19-21,
H-1103 Budapest, Hungary, and Central Research Institute for Chemistry, Hungarian Academy of
Sciences, Pusztaszeri u´t 59-67, H-1525 Budapest, Hungary
Received J uly 22, 1997X
The tryptamine derivative 1 readily reacted with methyl 4-acetyl-5-bromopent-4-enoate (9) that
had been built up from 2,4-pentanedione. On intramolecular dehydration and subsequent [4 + 2]
cycloaddition, the reaction product 10 gave the epimers 12 and 13 having the D-secoaspidospermane
skeleton. Compound 12 directly and 13 after epimerization yielded (()-3-oxominovincine (14).
Regioselective reduction of 14 furnished (()-minovincine (17).
Sch em e 1
In the early 1990s we developed a convergent synthetic
strategy to build up alkaloids with the aspidosper-
mane2 and pseudoaspidospermane3 skeleton and some
related compounds.4,5 The key step of our method was
to allow the secondary amine 1 to react with a suitable
aldehyde (2) in boiling toluene or xylene, and the nonisol-
able primary intermediate (3) directly gave the molecule
having the D-secoaspidospermane skeleton (4) (Scheme
1). The target compounds were then prepared by deben-
zylation followed by intramolecular acylation or alkyla-
tion, occasionally involving epimerization.6
We also reported our attempts directed toward the
synthesis of (()-3-oxominovincine (14).1 However, when
using the method described above, the reaction of the
tryptamine derivative 1 and the aldehyde 2 (R1
)
C(OCH2CH2O)CH3; R2 ) CH2CH2COOCH3) did not give
the expected compound, because cleavage of the carbon-
carbon bond occurred, and the product was molecule 4
(R1 ) H; R2 ) CH2CH2COOCH3) with the D-secoaspi-
dospermane skeleton. In an independent way we suc-
ceeded in preparing the tetracyclic ester containing the
acetyl group (4, where R1 ) COCH3, R2 ) H), but our
alkylation and acylation experiments aimed at forming
the fifth ring, i.e., the aspidospermane skeleton, gave
products of unexpected structures,1 thus a new synthetic
approach had to be found.
(17).7 Several total syntheses of the latter alkaloid are
known, and the corresponding papers mentioned that the
â-acetyl group of the enamines used in those experiments
(e.g., 3, where R1 ) H; R2 ) COCH3) did not split off even
at high temperatures, i.e., in boiling toluene or xylene.8
This implied important information for us, since it could
be concluded that the cleavage of the carbon-carbon
bond, observed in our earlier work, had occurred before
the formation of the enamine; hence the problem could
be avoided by preparing the suitable enamine. Accord-
ingly, we substituted the key compound aldehyde by the
equivalent of its enol derivative. Formerly, activated
vinyl halide derivatives had also been successfully used
as the reaction partners of secondary amines in syntheses
of the aspidospermane skeleton,9 consequently we se-
lected methyl 4-acetyl-5-bromopent-4-enoate (9), an equiva-
This paper is an account of the successful continuation
of the above research. (+)-3-Oxominovincine (14), iso-
lated from Tabernaemontana riedelii, has only been
prepared up to now by the oxidation of (+)-minovincine
† Technical University of Budapest.
§ Chemical Works of Gedeon Richter Ltd.
Hungarian Academy of Sciences.
X Abstract published in Advance ACS Abstracts, November 15, 1997.
(1) For part 89, see: Kalaus, Gy.; J uha´sz, I.; Steinhauser, K.;
Greiner, I.; Kajta´r-Peredy, M.; Brlik, J .; Szabo´, L.; Sza´ntay. Hetero-
cycles, accepted for publication.
(2) Kalaus, Gy.; Greiner, I.; Kajta´r-Peredy, M.; Brlik, J .; Szabo´, L.;
Sza´ntay, Cs. J . Org. Chem. 1993, 58, 1434.
(3) Kalaus, Gy.; Greiner, I.; Kajta´r-Peredy, M.; Brlik, J .; Szabo´, L.;
Sza´ntay, Cs. J . Org. Chem. 1993, 58, 6076.
(4) Kalaus, Gy.; J uha´sz, I.; Greiner, I.; Kajta´r-Peredy, M.; Brlik, J .;
Szabo´, L.; Sza´ntay, Cs. Liebigs. Ann. Chem. 1995, 1245.
(5) Kalaus, Gy.; Va´go´, I.; Greiner, I.; Kajta´r-Peredy, M.; Brlik, J .;
Szabo´, L.; Sza´ntay, Cs. Nat. Prod. Lett. 1995, 7, 197.
(6) Kalaus, Gy.; Greiner, I.; Sza´ntay, Cs. Synthesis of Some Aspi-
dospermane and Related Alkaloids in Studies in Natural Products
Chemistry, Vol. 19; Rahman, A. U., Ed.; Elsevier Science: 1997; p 89.
(7) Cava, M. P.; Tjoa, S. S.; Ahmed, Q. A.; Da Rocha, A. I. J . Org.
Chem., 1968, 33, 1055.
(8) (a) Kuehne, M. E.; Earley, W. G. Tetrahedron 1983, 39, 3707.
(b) Kuehne, M. E.; Earley, W. G. Tetrahedron 1983, 39, 3715.
(9) Kuehne, M. E.; Bornmann, W. G.; Earley, W. G.; Marko, I. J .
Org. Chem. 1986, 51, 2913.
S0022-3263(97)01346-7 CCC: $14.00 © 1997 American Chemical Society

Synthesis of Vinca Alkaloids and Related Compounds
J . Org. Chem., Vol. 62, No. 26, 1997 9189
Sch em e 2a
Sch em e 4a
a
Conditions: (a) CH3OH, Na, CH2dCHCOOCH3, rt; (b) HCHO,
K2CO3, H2O, rt; (c) Br2, CH2Cl2, rt; (d) (nC4H9)4NCl, HMPA, rt.
a
Conditions: (a) Pd/C/H2, CH3COOH, rt; (b) TsOH, toluene, ∆;
Sch em e 3a
(c) P4S10, THF, rt; (d) Raney Ni, THF, rt.
carbonate11a to give the unsaturated compound 7; addi-
tion of bromine11b (8) and the elimination of hydrogen
bromide11b yielded the desired compound 9 (Scheme 2).
The secondary amine 1 and the halide 9 interacted in
methanol in the presence of triethylamine even at room
temperature as expected, and the stable enamine 10 was
isolated from the reaction mixture in about 70% yield. It
was then boiled in xylene in the presence of p-toluene-
sulfonic acid to givesvia the nonisolable intermediate
11sthe tetracyclic ketones 12 and 13 having the D-
secoaspidospermane ring system. The starting enamine
(10) disappeared from the reaction mixture on boiling for
about 24 h, and a 1:1 mixture of the resulting epimers
was isolated in a total yield of 38% (Scheme 3).
The epimers 12 and 13 were separated by chromatog-
raphy, and the benzyl group was removed by catalytic
hydrogenation at ambient temperature. In the case of
compound 12 the product was (()-3-oxominovincine (14),
directly resulting from spontaneous intramolecular N-
acylation. The epimer 13 gave first the secondary amine
15. Boiling of the latter in toluene in the presence of
p-toluenesulfonic acid furnished, with epimerization, the
same alkaloid, 14.
The lactam 14 was reduced regioselectively in two
steps, using the method reported earlier.2 The compound
was allowed to react with phosphorus pentasulfide, and
the thioxo derivative 16 was treated with Raney nickel
to give (()-minovincine (17) (Scheme 4).
Exp er im en ta l Section 12
a
Conditions: (a) NEt3, CH3OH, rt; (b) TsOH, xylene, ∆.
Meth yl 4-Acetylp en t-4-en oa te (7). To a mixture of 6
(10.00 g, 53.7 mmol) and 30% aqueous formaldehyde (11 mL)
was added a solution of K2CO3 (15.00 g, 108 mmol) in water
(11 mL) at rt. The heterogeneous reaction mixture was stirred
lent of the appropriate aldehyde. A simple reaction
pathway was devised for preparing this compound. 2,4-
Pentanedione (5) was alkylated with methyl acrylate, and
the resulting diketoester10 (6) was made to react with
aqueous formaldehyde in the presence of potassium
(11) For preparation of analogous compounds, see: (a) Ayed, T. B.;
Amry, H. Synth. Commun. 1995, 25 (23), 3813. (b) Ayed, T. B.; El
Gaied, M. M.; Amry, H. Synth. Commun. 1995, 25 (19), 2981.
(12) For general experimental information, see ref 4.
(10) J ackson, A. H.; Kenner, G. W.; Sach, G. S. J . Chem. Soc. C 1967,
2045.

9190 J . Org. Chem., Vol. 62, No. 26, 1997
Kalaus et al.
1
for 12 h and then was diluted with water (110 mL), and the
solution was extracted with ether three times (50 mL each).
The combined organic layers were dried with MgSO4, filtered,
and concentrated in vacuo. The residue was distilled to yield
7 (3.60 g, 43%): bp 105-115 °C (15 Torr); IR (neat) νmax 1738,
1684, 1608 cm-1; 1H NMR (CDCl3) δ 2.35 (s, 3H, COCH3), 2.47
(m, 2H, 2-H2), 2.60 (m, 2H, 3-H2), 3.67 (s, 3H, OCH3), 5.86 +
6.06 (2 × 1H, 5-H2); 13C NMR (CDCl3) δ 25.7, 26.2, 32.8, 51.5,
126.1, 147.2, 173.2, 199.1.
3417, 1741, 1703, 1674, 1639, 1622 cm-1; H NMR (CDCl3) δ
1.75 + 2.04 (2 × ddd, J gem ) 12.2, J 5,6 ) 5.6 + 1.5 and 11.6 +
6.6 Hz, respectively, 2 × 1H, 6-H2), 1.97 (s, 3H, 18-H3), 2.12-
2.23m + 2.36m + 2.63m (4H, 14-H2 + 15-H2), 2.62 + 2.93 (2
× d, J gem ) 15.5 Hz, 2 × 1H, 17-H2), 2.69 + 3.01 (2 × ddd,
J gem ) 9.5 Hz, 2 × 1H, 5-H2), 3.55 + 3.79 (2 × s, 2 × 3H, 2 ×
OCH3), 3.76 + 4.17 (2 × d, J gem ) 13.2 Hz, 2 × 1H, NCH2C6H5),
4.00 (d, J lr ) 2.0 Hz, 1H, 21-H), 6.80 (d, 1H, 12-H), 6.95 (dd,
1H, 10-H), 7.16 (dd, 1H, 11-H), 7.19 (d, 1H, 9-H), 7.25-7.50
(m, 5H, C6H5), 8.75 (br s, 1H, NH); 13C NMR (CDCl3) δ 25.9,
27.9, 28.7, 30.5, 42.4, 51.1, 51.8, 53.0, 58.5, 59.1, 61.7, 68.3,
89.7, 109.5, 121.2, 122.1, 127.1, 127.8, 128.4, 128.6, 137.2,
139.2, 142.5, 166.8, 167.8, 172.9, 211.5; MS m/z 488 (3.0, M+),
455 (8.0), 332 (15.0), 274 (100). Anal. Calcd for C29H32N2O5:
C, 71.29; H, 6.60; N, 5.73. Found: C, 71.32; H, 6.61; N, 6.04.
The less polar compound (13, Rf ) 0.54) was obtained as
white crystals after crystallization from methanol (0.18 g,
19%): mp 131-132 °C; IR (KBr) νmax 3365, 1738, 1690, 1615
Meth yl 4-Br om o-4-(br om om eth yl)-5-oxoh exa n oa te (8).
To a solution of 7 (10.00 g, 64 mmol) in CH2Cl2 (50 mL) was
added a solution of 3.5 mL (68 mmol) of bromine in 10 mL of
CH2Cl2 dropwise at rt. After the solution was stirred for 1 h,
the excess bromine was removed by washing with aqueous
sodium thiosulfate until the solution was discolored. The
organic layer was separated and washed with water (20 mL),
dried with MgSO4, and concentrated in vacuo. The residue
was crystallized from methanol to yield 8 (15.60 g, 78%); mp
1
1
55-56 °C; IR (KBr) νmax 1730, 1727 cm-1; H NMR (CDCl3) δ
cm-1; H NMR (CDCl3) δ 1.14m + 1.92m + 2.00-2.12m (4H,
2.36-2.69 (m, 4H, 2-H2 + 3-H2), 2.46 (s, 3H, COCH3), 3.72 (s,
3H, OCH3), 3.76 + 4.09 (2 × d, J gem ) 10.6 Hz, 2 × 1H, 4-CH2-
Br); 13C NMR (CDCl3) δ 24.4, 30.0, 31.0, 34.1, 52.0, 66.8, 172.5,
199.0.
14-H2 + 15-H2), 1.69 + 2.21 (2 × ddd, J ) 12.2, J 5,6 ) 5.5 +
∼1 and 6.8 + 12.2 Hz, respectively, 2 × 1H, 6-H2), 2.45 (s, 3H,
18-H3), 2.68 + 2.97 (2 × ddd, J gem ) 9.6 Hz, 2 × 1H, 5-H2),
2.88 + 2.93 (2 × d, J gem ) 15.0 Hz, 2 × 1H, 17-H2), 3.28 (d, J lr
) 1.4 Hz, 1H, 21-H), 3.57 + 3.80 (2 × s, 2 × 3H, 2 × OCH3),
3.63 + 4.06 (2 × d, J gem ) 13.0 Hz, 2 × 1H, NCH2C6H5), 6.80
(br d, J 9,10 ) 7.4 Hz, 1H, 9-H), 6.85 (br d, J 11,12 ) 7.6 Hz, 1H,
12-H), 6.86 (ddd, J 10,11 ) 7.4, J 10,12 ) 1.2 Hz, 1H, 10-H), 7.17
(ddd, J 11,12 ) 7.8, J 9,11 ) 1.3 Hz, 1H, 11-H), 7.25-7.37 (m, 5H,
C6H5), 8.97 (br s, 1H, NH); 13C NMR (CDCl3) δ 23.9, 28.6, 28.9,
31.3, 40.4, 51.2, 51.6, 56.3, 57.7, 60.9, 76.4, 88.6, 109.5, 121.0,
122.8, 127.1, 128.2, 128.3, 129.2, 136.6, 138.2, 142.7, 164.6,
168.2, 173.4, 213.3; MS m/z 488 (10.0, M+), 457 (15.0), 445
(17.0), 332 (10.0), 274 (83.0), 91 (100). Anal. Calcd for
C29H32N2O5: C, 71.29; H, 6.60; N, 5.73. Found: C, 71.08; H,
6.66; N, 5.52.
Meth yl 4-Acetyl-5-br om op en t-4-en oa te (9). To a homo-
geneous solution of tetrabutylammonium chloride (11.10 g, 40
mmol) in 25 mL of HMPA was added 8 (10.00 g, 31 mmol)
over a 30 min period at rt. After being stirred for 12 h at rt,
the brown mixture was cooled (0 °C) and quenched with an
aqueous solution of sulfuric acid (1 M, 65 mL) and then
extracted with hexane five times (20 mL each). The combined
organic extracts were washed with water until neutrality of
the aqueous layer. The organic layer was dried with MgSO4
and concentrated in vacuo. The main component was sepa-
rated by column chromatography (eluent: CH2Cl2) to yield 9
(1.19 g, 16%) as an yellow oil (Rf ) 0.47): IR (neat) νmax 1730,
1675, 1582 cm-1; 1H NMR (CDCl3) δ 2.34 (s, 3H, COCH3), 2.43
(t, J ) 7.5 Hz, 2H, 2-H2), 2.77 (t, 2H, 3-H2), 3.67 (s, 3H, OCH3),
7.32 (s, 1H, 5-H); 13C NMR (CDCl3) δ 21.9, 26.0, 31.7, 51.7,
134.8, 142.8, 172.8, 195.1.
(()-3-Oxom in ovin cin e (14). Meth od a . A mixture of
1.00 g of 12 (2.00 mmol) and 0.50 g of 10% palladium/charcoal
in 20 mL of glacial acetic acid was hydrogenated for 1 h at rt
and then filtered. The filtrate was poured into 50 mL of ice-
water and neutralized with saturated Na2CO3 solution. The
solution was extracted three times with CH2Cl2 (30 mL each),
En a m in e 10. To a mixture of 1.00 g (2.48 mmol) of 1,2 0.40
g (4 mmol) of triethylamine, and 100 mL of methanol was
added 0.70 g (3 mmol) of 9. After being stirred for 24 h at rt,
the mixture was concentrated in vacuo. The residue was
purified by column chromatography (eluent: hexane/acetone
1:1) to yield 10 (1.00 g, 70%) as an amorphous solid (Rf )
and the combined organic layers were dried with MgSO4
and
evaporated in vacuo. The main component was separated by
preparative TLC (eluting with hexane/acetone 2:1) to yield a
yellow oil (Rf ) 0.28), which was crystallized from methanol
to afford 14 (0.48 g, 64%) as white crystals: mp 245-246 °C;
0.76): IR (KBr) νmax 3390, 1740, 1730, 1608, 1574 cm-1 1H
;
1
NMR (CDCl3) δ 1.99 (s, 3H, COCH3), 2.29 + 2.34 (2 × ddd,
IR (KBr) νmax 3345, 1702, 1671, 1602 cm-1; H NMR (CDCl3)
J gem ) 15.5, J vic ) 6.0 + 9.8 and 6.0 + 9.3 Hz, respectively, 2
δ 1.77 + 2.17 (2 × ddd, J gem ) 14.0, J 14,15 ) 4.8 + 11.2 and 4.8
+ 5.6 Hz, respectively, 2 × 1H, 15-H2), 1.88 + 1.97 (2 × ddd,
J gem ) 12.2, J 5,6 ) 5.8 + ∼1 and 12.4 + 7.5 Hz, respectively, 2
× 1H, CH2COOCH3), 2.64 + 2.70 (2 × ddd, J gem ) 14.0, J vic
)
6.0 + 9.3 and 6.0 + 9.8 Hz, respectively, 2 × 1H, CH2Cd),
3.02 + 3.07 (2 × dt, J gem ) 14.2, J vic ) 7.0 Hz, 2 × 1H, 3-CH2),
3.44 (br, 1H, OH), 3.55 (t, J ) 7.0 Hz, 2H, CH2CN), 3.58 +
3.68 (2 × s, 2 × 3H, 2 × OCH3), 4.00-4.12 (m, 3H, 2-CHCH2),
× 1H, 6-H2
), 2.08 (s, 3H, 18-H3), 2.28 + 3.19 (2 × d, J gem
)
15.5 Hz, 2 × 1H, 17-H2
), 2.34 + 2.43 (2 × ddd, J gem ) 15.6 Hz,
2 × 1H, 14-H2
), 3.48 + 4.24 (2 × ddd, J gem ) 11.6 Hz, 2 × 1H,
)
)
5-H2
(d, 1H, 12-H), 6.97 (dd, 1H, 10-H), 7.21 (dd, 1H, 11-H), 7.28
13C NMR (CDCl3) δ 25.0,
), 3.80 (s, 3H, OCH3), 4.71 (d, J lr ) 2.0 Hz, 1H, 21-H), 6.86
4.46 (s, 2H, NCH2C6H5), 7.09 (ddd, J 4,5 ) 7.8, J 5,6 ) 7.1, J 5,7
1.1 Hz, 1H, 5-H), 7.16 (m, 2H, 2′-H + 6′-H), 7.17 (ddd, J 6,7
8,0, J 4,6 ) 1.3 Hz, 1H, 6-H), 7.22 (s, 1H, -CHd), 7.29 (m, 1H,
4′-H), 7.33 (br d, 1H, 7-H), 7.35 (m, 2H, 3′-H + 5′-H), 7.41 (br
d, 1H, 4-H), 9.04 (br s, 1H, NH); 13C NMR (CDCl3) δ 20.1, 23.9,
24.9, 34.5, 44.8, 51.5, 52.6, 53.6, 57.4, 63.9, 109.3, 109.7, 111.3,
118.0, 119.7, 122.4 126.9, 127.2, 127.8, 128.9, 129.9, 135.7,
137.0, 150.5, 172.6, 174.0, 196.6; MS m/z 507 (4.0, M+), 467
(8.0), 445 (10.0), 332 (17), 274 (80), 91 (100).
(()-2,16-Dideh ydr o-14,16-bis(m eth oxycar bon yl)-3-ph en -
yl-3,14-secoa sp id osp er m id in -19-on e (12) a n d (()-2,16-
Did eh yd r o-14,16-b is(m et h oxyca r b on yl)-3-p h en yl-3,14-
seco-20-ep ia sp id osp er m id in -19-on e (13). A solution of 1.00
g (1.97 mmol) of 10 and 0.01 g (0.06 mmol) of p-toluenesulfonic
acid monohydrate in 100 mL of xylene was refluxed under
argon for 24 h. The reaction mixture was extracted twice with
brine (40 mL), and the combined brine washes were extracted
twice with CH2Cl2 (40 mL each). The combined organic layers
were dried with MgSO4 and evaporated in vacuo. The two
main components were separated by column chromatography
(eluent: CH2Cl2/ether 30:1). The more polar compound (12,
Rf ) 0.48) was obtained as white crystals after crystallization
from methanol (0.18 g, 19%): mp 187-188 °C; IR (KBr) νmax
(d, 1H, 9-H), 8.82 (br s, 1H, NH);
28.6, 28.9, 30.7, 40.3, 43.4, 51.3, 53.7, 57.1, 62.3, 89.7, 109.9,
121.4, 121.7, 128.5, 135.4, 142.4, 165.3, 167.4, 169.8, 209.0;
MS m/z 366 (40.0, M+), 227 (85.0), 214 (100). Anal. Calcd for
C21
H22N2O4: C, 68.84; H, 6.05; N, 7.65. Found: C, 68.67; H,
6.35; N, 7.25. Meth od b. The solution of 1.00 g of 15 in 100
mL of anhydrous toluene and 0.01 g (0.06 mmol) of p-
toluenesulfonic acid monohydrate was refluxed under argon
for 1 h. The reaction mixture was extracted twice with brine
(40 mL each), and the combined aqueous layers were extracted
twice with CH2Cl2 (40 mL each), dried with MgSO4, and
evaporated in vacuo. The main component was separated as
described above to yield 14 (0.39 g, 43%) which was identical
spectroscopically to the material prepared by method a.
Secon d a r y Am in e 15. A mixture of 1.00 g of 13 (2.0 mmol)
and 0.50 g of 10% palladium/charcoal in 20 mL of glacial acetic
acid was hydrogenated for 1 h at rt. The filtrate was worked
up as in the case of compound 14 to yield 15 (0.59 g, 73%, Rf
) 0.77, eluent: hexane/acetone 2:1): mp 186-187 °C (crystal-
lized from methanol); IR (KBr) νmax 3400, 3368, 1731, 1710,
1
1673, 1646, 1619 cm-1; H NMR (CDCl3) δ 1.37 + 1.71 (2 ×

Synthesis of Vinca Alkaloids and Related Compounds
J . Org. Chem., Vol. 62, No. 26, 1997 9191
ddd, J gem ) 14.2, J 14,15 ) 5.5 + 11.6 and 4.5 + 11.5 Hz,
respectively, 2 × 1H, 15-H2), 1.78 + 1.97 (2 × ddd, J gem ) 11.8,
J 5,6 ) 4.6 + 1.5 and 11.3 + 7.0 Hz, 2 × 1H, 6-H2), 1.85 + 2.11
(2 × ddd, J gem ) 16.0 Hz, 2 × 1H, 14-H2), 1.90 (br, 1H, N(4)-
H), 2.28 (s, 3H, 18-H3), 2.56 + 2.84 (2 × d, J gem ) 15.6 Hz, 2
× 1H, 17-H2), 3.04-3.14 (m, 2H, 5-H2), 3.56 + 3.79 (2 × s, 2 ×
3H, 2 × OCH3), 3.76 (d, J lr ) 2.0 Hz, 1H, 21-H), 6.85 (d, 1H,
12-H), 6.91 (dd, 1H, 10-H), 7.18 (d, 1H, 9-H), 7.19 (dd, 1H, 11-
H), 9.00 (br s, 1H, N(1)-H); 13C NMR (CDCl3) δ 22.0, 27.9,
28.6, 28.8, 44.0, 45.1, 51.1, 51.6, 56.8, 57.6, 68.4, 89.2, 109.6,
120.9, 121.7, 128.2, 137.1, 142.9, 165.4, 168.4, 173.1, 211.9;
MS m/z 398 (35.0, M+), 367 (10.0), 325 (5.0), 214 (64), 42 (100).
Anal. Calcd for C22H26N2O5: C, 66.32; H, 6.58; N, 7.03.
Found: C, 66.12; H, 6.66; N, 6.79.
J gem ) 15.3 Hz, 2 × 1H, 14-H2), 3.80 (s, 3H, OCH3), 3.82 +
4.67 (2 × ddd, J gem ) 13.0 Hz, 2 × 1H, 5-H2), 4.72 (br s, 1H,
21-H), 6.87 (d, 1H, 12-H), 6.99 (dd, 1H, 10-H), 7.23 (dd, 1H,
11-H), 7.30 (d, 1H, 9-H), 8.84 (br s, 1H, NH); 13C NMR (CDCl3)
δ 24.8, 28.9, 30.2, 39.1, 41.0, 49.9, 51.4, 54.6, 57.0, 64.7, 89.9,
110.0, 121.5, 121.9, 128.9, 134.7, 142.4, 164.5, 167.3, 198.9,
208.1; MS m/z 382 (40.0, M+), 349 (8.0), 238 (100.0), 227 (76).
Anal. Calcd for C21H22N2O3S: C, 65.95; H, 5.80; N, 7.32;
S,8.38. Found: C, 65.84; H, 5.83; N, 6.91; S, 8.25.
(()-Min ovin cin e (17). To a solution of 0.10 g (0.26 mmol)
of 16 in 10 mL of anhydrous THF were added ∼1 g of water,
methanol, and anhydrous THF-washed Raney Ni. The sus-
pension was stirred for 2 h at rt and filtered. The Raney Ni
was washed with 10 mL of anhydrous THF, and the combined
filtrate was evaporated in vacuo. The residue was purified
by column chromatography (eluent: hexane/acetone 2:1) to
yield a yellow oil (Rf ) 0.51), which was crystallized from
methanol to afford 17 (0.85 g, 93%) as white crystals; mp 140-
141 °C (lit.8a mp 141-142 °C); 13C NMR (CDCl3) δ 22.4, 25.1,
25.9, 45.3, 49.8, 51.1, 51.5, 53.9, 56.2, 67.7, 91.4, 109.4, 120.7,
121.1, 127.2, 138.2, 142.4, 168.2, 168.3, 212.1. Its 1H NMR,
IR, and MS spectral data were identical with those previously
described in the literature.8a
(()-3-Th ioxom in ovin cin e (16). To the solution of 0.10 g
(0.27 mmol) of 14 in 30 mL of anhydrous THF was added 0.13
g (0.30 mmol) of P4S10. The reaction mixture was stirred for
1 h at rt and was diluted with 30 mL of CH2Cl2. The solution
was extracted with 20 mL of brine, and the brine was extracted
with 10 mL of CH2Cl2. The combined organic layers were dried
with MgSO4 and evaporated in vacuo. The residue was
purified by column chromatography (eluent: hexane/acetone
2:1) to yield a yellow oil (Rf ) 0.38), which was crystallized
from methanol to afford 16 (0.95 g, 91%) as white crystals:
mp 253-254 °C; IR (KBr) νmax 3410, 3381, 1700, 1674, 1610
1
cm-1; H NMR (CDCl3) δ 1.59 + 2.21 (2 × ddd, J gem ) 14.2,
Ack n ow led gm en t. The authors are grateful to the
National Scientific Research Foundation (OTKA T/8-
19574) for financial support of this work.
J 14,15 ) 13.5 + 3.5 and 4.8 + 3.0 Hz, respectively, 2 × 1H, 15-
H2), 2.01 + 2.12 (2 × ddd, J gem ) 12.5, J 5,6 ) 6.4 + ∼1 and
12.5 + 7.7 Hz, 2 × 1H, 6-H2), 2.12 (s, 3H, 18-H3), 2.18 + 3.29
(2 × d, J gem ) 15.8 Hz, 2 × 1H, 17-H2), 2.53 + 3.12 (2 × ddd,
J O9713464