Synthesis of vinca alakaloids and realated compounds 98 [1]. Oxidation with dimethyldioxirane of compounds containing the aspidospermane and quebrachamine ring system. A simple synthesis of (7s,20S)-(+)-rhazidigenine and (2R,7S,20S)-(+)-rhazidine

Article abstract of DOI:10.1002/jhet.5570390423

The oxidation of (-)-tabersonine (1) with dimethyldioxirane (DMD) in neutral and acidic medium gave 16-hydroxytabersonine-N-oxide (3) and the didehydrovincamine isomers 4 and 5, respectively. (+)-14,15-Didehydro-quebrachamine (7) furnished the hydroxyindolenine 9, and the pentacyclic derivative 11. (+)- Quebrachamine (8) and DMD in neutral medium gave (7S,20S)-(+)-rhazidigenine (12) which was converted to (2R,7S,20S)-(+)-rhazidine (13b) with hydrochloric acid.

Full text of DOI:10.1002/jhet.5570390423

Jul-Aug 2002
Synthesis of Vinca Alakaloids and Realated Compounds 98 [1].
Oxidation with Dimethyldioxirane of Compounds Containing the
Aspidospermane and Quebrachamine ring system. A Simple Synthesis
of (7S,20S)-(+)-Rhazidigenine and (2R,7S,20S)-(+)-Rhazidine
767
János Éles [a,b], György Kalaus [a], Albert Lévai [c], István Greiner [b],
Mária Kajtár-Peredy [d], Pál Szabó [d], Lajos Szabó [a] and Csaba Szántay [a,d]
[a] Institute of Organic Chemistry, Budapest University of Technology and Economics,
Gellért tér 4, H–1111, Budapest, Hungary
[b] Chemical Works of Gedeon Richter Ltd, Gyömro´´i út 19-21, H-1103 Budapest, Hungary
[c] Institute of Organic Chemistry, Debrecen University, Egyetem tér 1,H-4010 Debrecen, Hungary
[d] Institute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences,
Pusztaszeri út 59-67, H-1025 Budapest, Hungary
Received December 3, 2001
The oxidation of (-)-tabersonine (1) with dimethyldioxirane (DMD) in neutral and acidic medium gave
16-hydroxytabersonine-N-oxide (3) and the didehydrovincamine isomers 4 and 5, respectively. (+)-14,15-
Didehydro-quebrachamine (7) furnished the hydroxyindolenine 9, and the pentacyclic derivative 11. (+)-
Quebrachamine (8) and DMD in neutral medium gave (7S,20S)-(+)-rhazidigenine (12) which was converted
to (2R,7S,20S)-(+)-rhazidine (13b) with hydrochloric acid.
J. Heterocyclic Chem., 39, 767 (2002).
Introduction.
In the 90′s we developed a convergent synthetic strategy
for constructing alkaloids with the aspidospermane and
pseudoaspidospermane skeleton, together with some other
alkaloid-like molecules [2]. The method was successfully
used for the synthesis of several compounds such as (±)-
tabersonine (±1) which proved suitable for the preparation
of alkaloids with an epoxide ring, obtained by oxidation of
the C14-C15 double bond. Now we attempted the con-
struction of the epoxide ring with dimetyldioxirane
(DMD) [3], an electrophilic oxidizing agent developed in
the mid-eighties, and applicable also in neutral medium.
Results and Discussion.
Our first target was the synthesis of lochnericine (2) [4],
isolated from Catharanthus roseus (Figure 1). (-)-
Tabersonine (1) [5] was allowed to react with a solution of
Since the formation of the epoxide ring was not observed
in either of the above experiments, we attempted with DMD
to achieve the synthesis of an alkaloid of simpler structure:
voaphylline (conoflorine) (6) [8], isolated from Ervatamia
coronaria (Figure 2). (+)-14,15-Didehydroquebrachamine
(7) was prepared from (-)-tabersonine (1) in the known way
[9], by hydrolysis with 1 N hydrochloric acid, subsequent
decarboxylation and reduction with sodium borohydride.
Compound 7 was made to react with DMD in neutral
dimethyldioxirane in acetone at 4-5 °C. The reaction gave
16-hydroxytabersonine-N-oxide (3) [6]. The oxidation
was then effected in the presence of acid; the isolated
products were again known compounds: the didehy-
drovincamine isomers 4 and 5 [7], formed by the well-
known aspidospemane→eburnane ring transformation [7]
(Scheme 1).

768
J. Éles, G. Kalaus, A. Lévai, I. Greiner, M. Kajtár-Peredy, P. Szabó, L. Szabó and C. Szántay
Vol. 39
medium, whereupon hydroxyindolenine crystallized from
the reaction mixture. The 7-hydroxyindolenine structure (9)
was unequivocally confirmed by the NMR data of the sam-
ple recorded in a solution of deuteriochloroform and
as well as the N1-H protons. The stereointeractions shown
in the 2D ROESY spectrum confirmed the given configura-
tion. (For characteristic NOE interactions, see
Experimental.)
dimethylsulfoxide-d , with characteristic chemical shifts of
As the conversion 9→9a affects neither C7 nor the C20
stereocenter, the configuration of 9a substantiates the rela-
tive steric positions of the 7-hydroxy and 20-ethyl groups
in compound 9.
The reaction was also carried out in the presence of tri-
fluoracetic acid or borotriflouride etherate, whereupon the
secondary amine 10 was isolated from the reaction mixture
in a moderate yield. This molecule, containing a conju-
gated double bond system, suffered intramolecular conver-
sion even on standing exposed to air, to give the penta-
cyclic derivative 11 (Scheme 2).
6
the C2 and C7 atoms (192.04 and 86.76 ppm, respectively).
When the solution was allowed to stand for a few days, the
compound suffered conversion. The formation of the cation
9a was indicated by detailed NMR data, such as the
increased proton and carbon chemical shifts in the methyl-
ene groups adjacent to the nitrogen atom, the long-range
correlations between C2 and the methylene protons, further,
the interactions between the C8 carbon atom and the 7-OH
Scheme 2
The one- and two-dimensional NMR spectra unambigu-
ously indicated structure 11. Correlations between the C2
quaternary carbon atom and the 21-H and 5-H methylene
2
2
protons verified the presence of the C2-N4 bond; further,
the interaction of the C16 methine carbon with the 14-H
olefin and 22-H methylene protons evidenced the forma-
2
tion of the C16-C3 bond. The stereochemistry of the ring
system was deduced from the ROESY spectra. (For char-
acteristic NOE interactions, see Experimental.)
A possible pathway of the reaction may be pictured as
follows: in the first step protonation is followed by the for-
mation of the epoxide ring in the 2 and 3 positions of the
indole ring; then nucleophilic attack by the enolic form of
acetone may occur in the direction of the C3 atom which
has acquired a positive character. The reaction sequence is
closed by deprotonation. However, the resulting molecule
is not stable, and DMD still being present, it effects the
formation of the conjugated system which, by attacks
involving proton movements shown in Scheme 3, gives
rise to the final product.

Jul-Aug 2002
Synthesis of Vinca Alakaloids and Realated Compounds 98
Conclusion.
769
Although the synthesis of voaphylline (conoflorine) (6)
remained unsuccessful, the foregoing results held out the
promise of a practicable synthesis of rhazidigenine (12)
containing the hydroxy-indolenine structure, starting from
(+)-quebrachamine (8). The correct structure of rhazidige-
nine was not reported in the literature [10], while its syn-
thesis was mentioned [11]. In order to obtain the missing
information we prepared (+)-quebrachamine (8) [12] from
(+)-14,15-didehydroquebrachamine (7) and studied the
oxidation of the compound. The oxidation was effected in
neutral medium with a solution of DMD in acetone.
Crystalline (+)-rhazidigenine (12) was separated from the
reaction mixture. The NMR spectra taken in deuteriochlo-
We attempted the construction of epoxide ring contain-
ing alkaloids by oxidation with dimethyldioxirane (DMD)
of the C14-C15 double bond of (-)-tabersonine (1) and (+)-
14,15-didehydroquebrachamine (7). In these experiments
we observed only ring transformations. Although the
preparation of epoxid ring containing compounds
remained unsuccessful, we synthesized and defined the
fine structure of (+)-rhazidigenine (12) and (+)-rhazidine
(13) starting from (+)-quebrachamine (8) using DMD.
EXPERIMENTAL
General Methods.
roform containing a few drops of dimethylsulfoxide-d
6
substantiated the hydroxyindolenine structure
(δ =190.44, δ =85.20 ppm), however, the relative con-
Melting points (uncorrected): Hotstage microscope Boetius.
1
13
— IR spectra: Specord JR-75 Spectrophotometer. — H and
C
C2
C7
NMR spectra: Varian Unity INOVA-400. Chemical shifts (in
figuration of the hydroxyl group at C7 could not be
1
1
ppm) are relative to Me Si. Mutual H- H couplings are given
1
13
4
unequivocally decided. Both the H- and C-NMR spec-
only once, at their first occurrance. — Mass spectra: VG ZAB-
SEQ double focusing high resolution mass spectrometer. —
Specific rotations were measured on Perkin Elmer polarimeter
241. — Preparative thin-layer chromatography: Silica gel plates
tra taken subsequently in methyl-d alcohol-d evidenced
3
the formation of a quaternary cation (13a) similar to 9a.
Although the N1-H and the 7-OH protons exchanged with
deuterium in this solution, then giving no signal in the pro-
ton spectra, the NOE interactions of the unchanged pro-
F254 (Merck). — The organic layers were dried with MgSO .
4
16-Hydroxy-tabersonine-N-oxide (3).
tons, such as the characteristic NOE effect between 21-H
β
To a stirred solution of (-)-tabersonine (1) (150 mg, 0.44
and 6-H , proved the given stereochemistry. It is notewor-
mmol) in CH Cl (15 mL) was added dropwise 1.05 equiv. DMD
α
2
2
thy that when (+)-rhazidigenine (12) is let to stand for a
in acetone (0.08 M) at 0 ºC. The reaction mixture was maintained
at 4-5 ºC for 24 hours. The solvent was removed in vacuo. The
residue was purified by preparative TLC (eluting with
longer period in deuteriochloroform+dimethylsulfoxide-d
6
solution, it also undergoes conversion to a cation of type
13a, similarly to the 9→9a reaction.
CH Cl/MeOH=4/1) to afford 50 mg (31%) of product 3 as yel-
3
21
low crystals. [α]
-27° (CHCl , c 0.27). Its authenticity was
D
3
In order to obtain chemical evidence about the reaction,
(+)-rhazidigenine (12) was dissolved in methanol and
acidified with a methanolic solution of hydrochloric acid,
whereupon crystalline (+)-rhazidine (13b) [10b] was iso-
lated. As the stereochemistry of (+)-rhazidine (13b) and
that of 13a, having identical structures, and containing the
quaternary cation, are known, and since the configuration
of the hydroxyl group at C7 remains unchanged during the
reactions, now we can give also the absolute configura-
tions of the products: (7S,20S) for (+)-12 and (2R,7S,20S)
for (+)-13b (Scheme 4).
1
confirmed by comparison of R [6], mp [6], ir [6], H nmr [6], ms
f
[6] with those of genuine sample.
17
17
∆ -Vincamine (4) and 14-epi-∆ -vincamine (5).
Method A.
To a stirred solution of (-)-tabersonine (1) (300 mg, 0.88 mmol) in
CH Cl (30 mL) a few drops of TFAA were added and cooled to -10
2
2
ºC. 1.05 equiv. DMD in acetone (0.08 M) was added dropwise. The
reaction mixture was maintained at 0 ºC for 10 hours, then the sol-
vent was evaporated. To the residue 10% Na CO solution (15 mL)
2
3
was added and extracted with CH Cl (2x30 mL). The combined
2
2
organic layers were dried and evaporated in vacuo. The residue was
purified by preparative TLC (eluting with benzene/EtOH/ammo-
nia=89/10/1) to afford 90 mg (29%) of product 4 as yellow crystals
and 84 mg, (27%) of product 5 as yellow crystals. The authenticity
of products were confirmed by comparison of R [6], mp [6,7] ir [7],
f
1
H-nmr, [7] ms [7] and α [13] with those of genuine sample.
D
Method B.
To a stirred solution of (-)-tabersonine (1) (300 mg, 0.88
mmol) in CH Cl (30 mL) a few drops of BF •Et O were added
2
2
3
2
and then the solvent removed in vacuo. The residue was dis-
solved in acetone (30 mL) and cooled to -10 Cº. The solution was
treated with 1.05 equiv. DMD using the procedure described in
Method A to afford 84 mg (27%) of product 4 and 71 mg (23%)
of product 5 which were identical to that prepared by Method A.

770
J. Éles, G. Kalaus, A. Lévai, I. Greiner, M. Kajtár-Peredy, P. Szabó, L. Szabó and C. Szántay
Vol. 39
(+)-14,15-Didehydro-rhazidigenin (9).
Hz; 15-H), 6.09 (1H, brd, J=15.0 Hz; 22-H), 6.18 (1H, ddd,
J=12.0, 12.0 and <1 Hz;14-H), 6.56 (1H, dd, J=7.8 and 1.0 Hz;
12-H), 6.73 (1H, ddd, J=7.5, 7.3 and 1.0 Hz; 10-H), 7.06 (1H,
ddd, J=7.8, 7.3 and 1.3 Hz; 11-H), 7.25 (1H, dd, J=7.5 and 1.3
To a stirred solution of 7 (300 mg, 1.07 mmol) in acetone (15
mL) was added 1.5 equiv. DMD in acetone (0.08 M) at –60 ºC.
The reaction mixture was allowed to warm up to room tempera-
ture. The crude product was isolated by filtration and purified by
13
Hz; 9-H), 7.62 (1H, ddd, J=15.0, 12.0 and 1.0 Hz; 3-H); C nmr
(deuteriochloroform): δ 8.51 (C18), 27.49 (C19), 28.20 (C24),
34.05+34.08+42.24 (C16+C17+C6), 41.94 (C20), 49.28 (C5),
56.24 (C21), 88.16+89.43 (C2+C7), 109.70 (C12), 118.99 (C10),
123.41 (C9), 127.37 (C14), 129.21 (C11), 130.70 (C22), 132.36
(C8), 138.83 (C3), 147.62 (C15), 148.69 (C13), 198.56 (C23);
ms m/z (rel inten) 352(14.0), 309(22.0) 146(73.0), 91(86.0),
77(100.0), 57(59.0), 43(55.0).
preparative TLC (eluting with CHCl /EtOAc/MeOH=3/1/1) to
3
afford 180 mg (57%) of product 9 as an amorphous solid
24
(R =0.15); [α]
+9.2° (MeOH, c 0.5); ir (potassium bromide)
f
D
3208, 2968, 2392, 2368, 1960, 1616, 1476, 1384, 1140, 896, 748
-1 1
cm ; H nmr (deuteriochloroform+dimethylsulfoxide-d ): δ 0.84
6
(3H, t, J=7.5 Hz;18-H ), 1.24+1.28 (2x1H, 2xdq, J =13.7 Hz;
3
gem
19-H ), 1.50+2.40 (2x1H, 2xddd, J =13.8, J =10.9+1.5 and
2
gem
5,6
5.0+2.2 Hz, respectively; 5-H ), 1.57+2.55 (2x1H, 2xdddd,
Method B.
2
J
=14.0, J
=7.7+1.2 and 12.0+1.5, J =2.2 and <1Hz,
gem
16,17 lr
Compound 10 was obtained from 7 (300 mg, 0.12 mmol) by
the procedure described for 4 and 5 (Method B) to give 42 mg
(11%), which were identical to that prepared by Method A.
respectively; 17-H ), 2.04+2.24 (2x1H, 2xddd, J =13.4 Hz; 6-
H ), 2.27+3.27 (2x1H, 2xddd, J =15.0 Hz; 16-H ), 2.29+2.53
(2x1H, 2xbrd, J=11.5 Hz; 21-H ), 2.85+3.24 (2x1H, 2xddd,
2
gem
2
gem
2
2
Synthesis of 11 [16].
J
=16.3, J =1.7 and 4.5, J =2.3 and 1.5 Hz respectively;
gem
3,14 3,15
3-H ), 5.31 (1H, dddd, J
ddd; 14-H), 7.11 (1H, ddd, J =7.3, J
=9.8, J =1.7 Hz; 15-H), 5.77 (1H,
lr
2
14,15
A CHCl (5 mL) solution containing 10 (50 mg, 0.14 mmol)
was stirred at room temperature for 72 hours. The solvent was
removed in vacuo. The residue was purified by preparative TLC
3
=7.5, J
=1.2Hz;
9,10
10,11
10,12
10-H), 7.24 (1H, ddd, J
=7.5, J =1.4 Hz; 11-H), 7.28 (1H,
11,12
9,11
13
ddd, J =0.7 Hz; 9-H), 7.34 (1H, ddd; 12-H); C nmr (deuteri-
9,12
(eluting with hexane/acetone=2/1) to afford 21 mg (42 %) of
ochloroform+dimethylsulfoxide-d ): δ 7.96 (C18), 27.23 (C16),
24
6
product 11 as an amorphous solid (R =0.51); [α]
+20.6°
f
D
32.31 (C19), 34.77 (C17), 38.73 (C20), 41.25 (C6), 50.12 (C5),
50.68 (C3), 58.32 (C21), 86.76 (C7), 118.91 (C12), 122.29 (C9),
125.05 (C10), 125.64 (C14), 128.74 (C11), 133.21 (C15), 142.56
(CHCl , c 0.5); ir (potassium bromide) 3416, 3120, 2928, 2840,
3
1
2808, 1704, 1608, 1488, 1432, 1368, 1264, 1104, 900, 744; H
nmr (deuteriochloroform): δ 0.90 (3H, t, J =7.5 Hz; 18-H ),
vic
3
(C8), 153.63 (C13), 192.04 (C2); hrms (FAB) m/z calcd for
1.35+1.40 (2x1H, 2xdq, J
=13.5 Hz; 19-H ), 1.37+1.54
gem
2
+
C H N O 297.1967 found for [M+H] 297.1966.
19 26
2
(2x1H, 2xddd, J =13.2, J
=3.0 and 3.2, J =1.5 and 1.8 Hz,
gem
16,17
lr
1
NMR data of 9a: H nmr (deuteriochloroform+dimethylsulfox-
ide-d ): δ 0.94 (3H, t, J=7.6 Hz; 18-H ), 1.51+1.57 (2x1H, 2xdq,
respectively; 17-H ), 1.92 (1H, br ddd, J ~0.5 Hz; 16-H),
2
16,3
6
3
2.06+2.24 (2x1H, 2xddd, J =12.0, J =6.0+0.8 and 11.2+7.8
gem
5,6
J
J
=14.3 Hz; 19-H ), 1.58+1.97 (2x1H, 2xddd, J =13.2,
gem
2 gem
Hz respectively; 6-H ), 2.08 (3H, s; 24-H ), 2.44+2.53 (2x1H,
2
3
=5.5+~2 and 12.8+4.2 Hz, respectively; 17-H ), 2.07+2.46
16,17
2
2xd, J =11.0 Hz; 21-H ), 2.50+2.76 (2x1H, 2xddd, J =8.4
gem
2
gem
(2x1H, 2xddd, J =14.2 Hz; 16-H ), 2.41+2.82 (2x1H, 2xddd,
gem
2
Hz; 5-H ), 2.51+2.56 (2x1H, 2xdd, J =19.0, J =10.5 and 3.6
2
gem
3,22
J
= 14.5, J =7.0+~1 and 13.3+8.0 Hz; 6-H ), 3.40+3.51
gem
5,6 2
Hz, respectively; 22-H ), 3.77 (1H, ddddd, J =3.6, J =2.0
2
3,14
3,15
(2x1H, 2xddd, J =12.0 Hz; 5-H ), 3.41+3.68 (2x1H, 2xbrd,
gem
2
Hz; 3-H), 4.2 (1H, br; NH), 4.64 (1H, brs; OH), 5.58 (1H, ddd,
=9.7, J =1.0 Hz; 14-H), 5.65 (1H, ddd, J =1.5 Hz; 15-H),
Jgem=12.0 Hz; 21-H ), 3.90+4.37 (2x1H, 2xddm, Jgem=17.5,
2
J
14,15
lr
lr
J
=2.0 and 4.3, J =2.5 and 1.5+1.5 Hz, respectively; 3-H ),
3,14
l
r
2
6.49 (1H, ddd, J
=7.8, J
=1.0, J =0.5 Hz; 12-H), 6.74
11, 12
10,12 9,12
5.71 (1H, dm; J
=10.5 Hz; 15-H), 5.79 (1H, brs; NH), 5.94
14,15
(1H, ddd, J =7.3, J
=7.4; 10-H), 7.04 (1H, ddd, J =1.3
9,10
10,11
9,11
(1H, ddd; 14-H), 6.22 (1H, brs; OH), 6.80 (1H, dm; 12-H), 6.88
(1H, ddd; 10-H), 7.15 (1H, ddd; 11-H), 7.29 (1H, dm; 9-H);
nmr (deuteriochloroform+dimethylsulfoxide-d ): δ 7.53 (C18),
27.43 (C16), 30.31 (C19), 32.46 (C17), 35.58 (C20), 39.14 (C6),
54.41 (C3), 59.21 (C5), 59.75 (C21), 89.13 (C7), 102.46 (C2),
110.99 (C12), 120.95 (C10), 121.53 (C14), 123.13 (C9), 130.00
(C11), 131.26 (C15), 131.44 (C8), 145.47 (C13); NOE: 5.79(N1-
Hz; 11-H), 7.35 (1H, ddd; 9-H); NOE: 4.64 (7-OH) → 3.77 (3-
H), 1.92 (16-H), 7.35 (9-H); 3.77 (3-H) → 5.58 (14-H), 4.64 (7-
13
C
6
OH), 1.92(16-H), ~2.5 (22-H ); 2.51+2.56 (22-H ) → 5.58 (14-
2
2
H), 3.77 (3-H), 2.08 (24-H ), 1.92; (16-H), 1.54 (17-H ); 1.92
3
β
(16-H) → 3.77 (3-H), ~2.5 (22-H ), 1.37+1.54 (17-H ), 4.64 (7-
2
2
13
OH); C nmr (deuteriochloroform): δ 7.81 (C18), 29.52 (C17),
30.15 (C24), 31.01 (C3), 31.42 (C19), 35.15 (C20), 38.93 (C16),
42.42 (C6), 48.62 (C22), 48.82 (C5), 56.22 (C21), 89.65 (C7),
91.12 (C2), 108.48 (C12), 118.64 (C10), 123.49 (C9), 128.64
(C11), 131.63 (C14), 133.86 (C15), 134.12 (C8), 147.73 (C13),
210.45 (C23); hrms m/z calcd for C H N O 352.2151 found
H)→6.80(12-H), 4.37(3-H ), 2.07(16-H ); 6.22(7-
β
β
OH )→7.29(9-H), 2.82(6-H ), 1.97(17-H ), 3.68(21-H );
α
α
α
β
2.82(6-H )→2.41(6-H ), 3.51(5-H ), 3.68(21-H ) 6.22(7-OH ).
α
β
α
β
α
Synthesis of 10 [15].
22 28
2 2
+
for [M] 352.2153.
Method A.
(+)-Quebrachamine (8).
Compound 10 was obtained from 7 (300 mg, 1.07 mmol) by
the procedure described for 4 and 5 (Method A) to give 30 mg
A mixture of 7 (1.00 g 3.6 mmoles) and 0.50 g of 10 % palla-
dium/charcoal in 20 ml of glacial acetic acid was hydrogenated
for 5 hour at room temperature and then filtered. The filtrate was
poured onto ice-water and neutralized with saturated Na CO
solution. The solution was extracted with CH Cl (3x30 mL),
(8%) as an amorphous solid (R =0.47 hexane/acetone=2/1); ir
f
(potassium bromide) 3400, 3357, 2955, 1639, 1600, 1475, 1466,
-1
1
1300, 1249, 1110, 1095, 900, 745 cm ; H nmr (deuteriochloro-
form): δ 0.83 (3H, t, J=7.5 Hz; 18-H ), ~1.5m+1.75m (2x1H; 19-
2
3
3
2
2
H ), 1.4-2.2 (6H, m; 16-H +17-H +6-H ), 2.24 (3H, s; 24-H ),
and the combined organic layers were dried and evaporated in
vacuo. The residue was crystallized from methanol to yield 0.95g
(94%) of product 8 as white crystals. The authenticity of products
2
2
2
2
3
2.45 brd+2.90 dd (2x1H, J =11.5, J <1 and 2.0 Hz, respec-
gem
lr
tively; 21-H ), 2.47-2.83 (2H, m; 5-H ), 5.96 (1H, brd, J=12.0
2
2

Jul-Aug 2002
Synthesis of Vinca Alakaloids and Realated Compounds 98
771
1
(C10), 124.28 (C9), 131.09 (C11), 132.32 (C8), 147.57 (C13); ms
m/z (rel inten) 299(99), 179(4), 101(10), 79(13).
were confirmed by comparison of mp [14], ir [14], H nmr [12],
13
C nmr [12] ms [14] and α [14] with those of genuine sample.
D
Anal. Calcd for C H ClN O: C, 68.56; H, 7.57; Cl, 10.65; N,
8.41. Found: C, 68.39; H, 7.60; Cl, 10.91; N, 8.10.
19 27
2
(7S,20S)-(+)-Rhazidigenin (12).
Compound 12 was obtained from 8 (300 mg, 1.06 mmol) by the
procedure described for 9 to give 160 mg (49%) as an amorphous
Acknowledgement.
24
25
solid (R =0.18); [α]
+43.4° (MeOH, c 1.0); [α]
+138.5°
The authors are grateful to the National Scientific Research
Foundation (OTKA T/12-31920) for financial support of this
work.
f
D
D
(DMF, c 0.5); ir (potassium bromide) 2936, 2736, 1620, 1480,
-
1380, 1320, 1312, 1192, 1136, 1084, 1008, 944, 840, 756, 692 cm
1 1
; H nmr (deuteriochloroform+dimethylsulfoxide-d ): δ 0.89 (3H,
6
t, J=7.5 Hz; 18-H ), 0.98 (1H, ddd, J =13.2, J =12.0+4.5 Hz;
3
gem
vic
REFERENCES AND NOTES
15-H ), 1.21+1.25 (2x1H, 2xdq, J = 13.5 Hz; 19-H ), 1.22-1.37
A
gem
2
(2H, m; 14-H +15-H ), 1.38+3.00 (2x1H, 2xbrd, J =11.8 Hz,
A
B
gem
[1] For part 97 see: I. Moldvai, Cs. Szántay jr. and Cs. Szántay,
Heterocycles 55, 2147, (2001).
[2] Gy. Kalaus, I. Greiner and Cs. Szántay, Studies in Natural
Products Chemistry, Vol. 19. Structure and Chemistry (Part E), ed. by
Atta-Ur-Rahman, Elsevier, 1997, pp. 89-116.
21-H ), 1.75-2.25 (8H, m;. 17-H +6-H +14-H +3-H +5-H ),
2
2
A
B
2
2
2.44+2.51 (2x1H, 2xddd, J =15.2, J =7.5+2.5 and 11.5+2.0
gem
vic
Hz, respectively; 16-H ), 2.64 (1H, ddd, J =14.2, J =13.7+4.5
2
gem
vic
Hz; 6-H ), 2.8+4.6 (1H, 2xbr, OH or NH), 7.07 (1H, ddd; 10-H),
B
13
7.24 (1H, ddd; 11-H), 7.27-7.31 (2H, m; 9-H+12-H); C nmr
[3] R. W. Murray and R. J. Jeyaraman, J. Org. Chem., 50, 2847
(1985).
(deuteriochloroform+dimethylsulfoxide-d ): δ 7.58 (C18), 20.17
6
[4] W. G. W. Kurz, K. B. Chaston, F. Constabel, J. P. Kutney,
L. S. L. Choi, P. Kolodziejczyk, K. Sleigh, K. L. Stuart and B. R.
Worth, Helv. Chim. Acta, 63, 1891 (1980).
[5] B. Zsadon, M. Rákli and R. Hubay, Acta. Chim. Acad. Sci.
Hung., 67, 71 (1971).
(C14), 24.40 (C16), 32.25 (C17), 34.47 (C19), 35.55 (C6), 36.11
(C15), ~40 (C20), 51.56 (C5), 55.47 (C3), 56.72 (C21), 85.20
(C7), 118.32 (C12), 122.22 (C9), 123.86 (C10), 129.12 (C11),
139.68 (C8), 155.93 (C13), 190.44 (C2); hrms m/z calcd for
+
C H N O 298.2045 found for [M] 298.2044.
19 26
2
[6] L. Calabi, B. Danieli, G. Lesma and G. J. Palmisano, J.
Chem. Soc. Perkin Trans. 1, 1370 (1982).
(2R,7S,20S)-(+)-Rhazidin (13b).
[7] N. Aimi, Y. Asada, S. Sahaai and J. Haginiwa, Chem.
Pharm. Bull. (Tokyo), 26, 1182 (1978-1187).
[8] J. J. Dugan, M. Hesse, U. Renner and H. Schmid, Helv.
Chim. Acta, 50, 60 (1967).
[9] B. Zsadon and K. Otta, Acta. Chim. Acad. Sci. Hung., 69,
87 (1971).
[10a] M. Spiteller-Friedman, R. Kaschnitz and C. Spiteller,
Monatsh. Chem., 95, 1228 (1964); [b] S. Markey, K. Biemann and B.
Witkop, Tetrahedron Lett., 157 (1967); [c] J. A. Postigo and R. Erra-
Baesells, J Org. Chem., 54, 3174 (1989).
To a stirred solution of 12 (300 mg, 1.00 mmol) in absolute
methanol (10 mL) was acidified with methanolic HCl to pH
value 4-5. 13b crystallized from the reaction mixture. The crude
product was isolated by filtration and recrystallized from
absolute methanol to afford 280 mg (84%) as white crystals;
24
24
melting point: 291-294 °C; [α]
+39.2° (MeOH, c 1.0); [α]
D
D
+11.2° (DMF, c 0.5); ir (potassium bromide) 3368, 3312, 2936,
1616, 1548, 1312, 1192, 1120, 1072, 1028, 968, 944, 856, 752;
1
H nmr (methyl-d alcohol-d): δ 0.94 (3H, t, J=7.5 Hz; 18-H ),
3
3
[11a] B. Witkop, J. Am. Chem. Soc., 79, 3193 (1957); [b] G.
Venkatachalam Sesha and P. Stayesh Chandra, Indian IN 160402
Chem. Abstr., 108, 187036e (1987).
[12] O. Temme, S-A. Taj and P. G. Andersson, J. Org. Chem.
63, 6007 (1998).
[13] J. Bruneton, A.Bouquet and A. Cavé, Phytochemistry 12,
1475 (1973).
[14] R. Torrenegra, P. J. Pedrozo, H. Achenbach and P.
Banereiss, Phytochemistry, 6, 1843 (1988).
1.39 (2H, q; 19-H ), 1.63+1.86 (2x1H, 2xddd, J
=14.0,
2
gem
J
=13.0+6.8 and 5.5+~1 Hz, respectively; 15-H ), 1.77-1.97
14,15
2
(3H, m; 17-H +14-H ), 2.22+2.52 (2x1H, 2xddd, J =15.7,
2
A
gem
J
=10.6+8.2 and 5.5+4.5 Hz, respectively; 16-H ), 2.37-2.50
16,17
2
(2H, m; 14-H +6-H ), 2.76 (1H, ddd, J =14.0, J =13.2+8.0
B
A
gem
5,6B
Hz; 6-H ), 3.13+3.63 (2x1H, 2xdm, J =12.3, J =1.3 and
B
gem
lr
2.3+2.0 Hz, respectively; 21-H ), 3.25-3.44 (3-H, m; 3-H +5-
2
A
H ), 3.71 (1H, br dd, J =13.0, J
=5.5+~2 Hz; 3-H ), 6.73
2
gem
3B,14
B
(1H, ddd, J
=7.8, J
=1.0, J =0.5 Hz; 12-H), 6.89 (1H,
11,12
10,12 9,12
[15] IUPAC name of 10: 6-(12-ethyl-17-oxa-8,14-diazatetracy-
ddd, J =7.5, J
=7.5 Hz, 10-H), 7.18 (1H, ddd, J =1.2 Hz;
1,9 2,7
9,10
10,11
9,11
clo[7.7.1.0 .0 ]heptadeca-2,4,6-trien-12-yl)-(3E,5Z)-3,5-hexa-
13
11-H), 7.29 (1H, ddd; 9-H); C nmr (methyl-d alcohol-d): δ
3
dien-2-one.
7.22 (C18), 20.85 (C14), 29.96 (C16), 31.81 (C15), 32.07 (C17),
33.14 (C20), 35.43 (C19), 39.42 (C6), 57.67 (C3), 61.48 (C5),
63.63 (C21), 90.81 (C7), 101.98 (C2), 111.34 (C12), 121.95
[16] IUPAC name of 11: 1-(15-ethyl-10-hydroxy-3,13-diaza-
pentacyclo[13.3.1.0 .0 .0 ]nonadeca-4,6,8,16-tetraen-18-yl)-
acetone.
2,10 2,13 4,9