A new strategy for the synthesis of (+)-vernolepin related compounds: An unusual sulfene elimination leads to the 2-oxa-cis-decalin skeleton

Article abstract of DOI:10.1016/S0040-4039(00)01334-4

A new strategy for the synthesis of (+)-vernolepin (1), (+)-vernodalin (2), and (+)-8-deoxyvernolepin (3), from the accessible germacrolides (+)-salonitenolide (4) and (+)-costunolide (5), has been developed. The key steps in the synthesis are a Cope rearrangement from the germacradiene to the elemadiene skeleton, the cyclization of a trans-fused δ-lactone from an epoxy ester, and an unusual sulfene elimination, which promotes a reaction cascade leading to the 2-oxa-cis-decalin skeleton. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01334-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7639–7643
A new strategy for the synthesis of (+)-vernolepin related
compounds: an unusual sulfene elimination leads to the
2
-oxa-cis-decalin skeleton
´
Alejandro F. Barrero,* J. Enrique Oltra and M ´ı riam Alvarez
Departamento de Qu ´ı mica Org a´ nica, Instituto de Biotecnolog ´ı a, Facultad de Ciencias, Universidad de Granada,
Campus Fuentenueva s/n, 18071 Granada, Spain
Received 5 June 2000; accepted 2 August 2000
Abstract
A new strategy for the synthesis of (+)-vernolepin (1), (+)-vernodalin (2), and (+)-8-deoxyvernolepin (3),
from the accessible germacrolides (+)-salonitenolide (4) and (+)-costunolide (5), has been developed. The
key steps in the synthesis are a Cope rearrangement from the germacradiene to the elemadiene skeleton,
the cyclization of a trans-fused d-lactone from an epoxy ester, and an unusual sulfene elimination, which
promotes a reaction cascade leading to the 2-oxa-cis-decalin skeleton. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: antibiotics; antitumour compounds; lactones; terpenoids; sulfonyl compounds.
1
(
+)-Vernolepin (1) and (+)-vernodalin (2), from the Ethiopian plants Vernonia hymenolepis
2
3
and V. amygdalina, respectively, and the synthetic derivative 8-deoxyvernolepin (3), form a
small group of sesquiterpene dilactones with a 10-vinyl-2-oxa-cis-decalin skeleton. They have
3–7
interesting biological properties, such as antitumour capacity both in vitro and in vivo, and
8
8
8
9
10
anti-aggregating, de-aggregating, spasmolytic, antiparasitic and potent antibiotic activities.
These properties together with their unique chemical structure have attracted the attention of
3
,11
12
13,14
chemists. Thus, the groups of Grieco,
Danishefsky, and others
have reported the total
synthesis of 1 and/or 3, but these syntheses all require numerous steps and generally provide low
overall yields of racemic products. Vernodalin (2) has not been synthesised yet.
Semisynthesis constitutes a valuable alternative for the enantiospecific preparation of bio-
active substances. In this way, some procedures for the synthesis of (+)-8-deoxyvernolepin from
7
,15–17
(
−)-a-santonin have been reported.
Nevertheless, these procedures have not been extended
to the synthesis of 1 and 2, probably due to the lack of an adequate functional group at C-8 in
a-santonin. We recently developed a new strategy for the synthesis of 8-epi-vernolepin deriva-
1
8,19
tives.
With some modifications, this procedure can be adapted to the enantiospecific
synthesis of 1–3 from the accessible germacrolides (+)-salonitenolide (4) and (+)-costunolide (5)
(
Scheme 1). (+)-Salonitenolide is abundant in several species of the widespread genus
*
Corresponding author. Fax: +34 958 243318; e-mail: afbarre@goliat.ugr.es
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01334-4

7640
1
9,20
Centaurea,
, whilst (+)-costunolide can be isolated in (multi)gram quantities from the
21,22
commercially available extract Costus Resinoid.
Scheme 1. Retrosynthesis from 1–3 to the germacrolides 4 and 5
Taking the first step of Scheme 1 (from 6 and 7 to 1–3) to be feasible using conventional
methodology, the second step was planned on the basis of our experience gained from previous
1
8,19
work.
Thus, 6 and 7 could be obtained from 8 and 9, respectively, via an intramolecular
substitution of the corresponding iodine atom by the carboxylate ion derived from selective
saponification of the enol lactone group. The synthesis of dienes 8 and 9, by means of
b-elimination reactions from mesylates 12 and 13, must be quite straightforward. Halohydrins
1
0 and 11 could be prepared from alcohols 14 and 15 by remote functionalization at C-14,
taking advantage of the adequate spatial arrangement of the OH groups. Electrophilic opening
of the epoxides 16 and 17 could lead to ring closure of the d-lactones 14 and 15, probably
leaving their hydroxymethyl groups in the expected equatorial position. Finally, the method-
ology for the Cope rearrangements from germacrolides (4 and 5) to elemanolides (18 and 19)
19,21
would be that previously proven in our laboratory.
Following Scheme 1, we started the synthesis of 3 (Scheme 2) with the chemoselective
reduction of a-methylen-g-lactone 5, in order to avoid subsequent complications with this
reactive Michael acceptor group. Thus, mild hydrogenation of 5 took place stereoselectively by
the b face of the conjugated double bond.
Scheme 2. Reagents, conditions and yields. (a) H atmospheric pressure, Pd/C 10%, MeOH, mild stirring, 2 h, 93%.
2
(
b) Sealed tube, 205°C, 5 min, 88%. (c) i. SeO , t-BuOOH, CH Cl ; ii. PDC; iii. NaClO , 2-methyl-2-butene t-BuOH,
2 2 2 2
H O; iv. CH N , 72% from 19. (d) Dimethyldioxirane, Me CO, 77%. (e) BF ·OEt , CH Cl , 93%. (f) H /Pd, MeOH,
2
2
2
2
3
2
2
2
2
81%. (g) DBU, toluene, 100°C, 80%. (h) Ref. 17

7641
Thermal Cope rearrangement conditions produced an equilibrium mixture of the germ-
acrolide 20 itself and the elemanolide 19 at a 1/2 (20/19) ratio. The remaining germacrolide was
recovered from the mixture and re-used, giving 88% yield of 19 after three turnovers. Ester 21,
23
obtained from 19, reacted with dimethyldioxirane to give a mixture of 17a (77%) and its
R-epimer 17b (11%). As we had expected, electrophilic opening of the oxirane 17a provided
1
†
dilactone 15 in high yield. The 1R configuration of 15 was indicated by the chemical shift of
C-14 and was confirmed by NOE experiments. Under the same conditions 17b gave a mixture
of 15 and its 1S-epimer (C-14 at 20.2 ppm). Catalytic hydrogenation of 15 led to 22, which
isomerized to the more stable epimer 23 under basic treatment. The chemical transformation of
17
2
3 into (+)-8-deoxyvernolepin (3) has been recently reported and thus the preparation of 23
(
Scheme 2) constitutes a formal synthesis of 3 from 5.
Two reports, however, deal with the difficulties involved in building the D exocyclic double
3
7,15
bond of 3, avoiding mixtures with an endocyclic regioisomer and the corresponding yield fall.
Therefore, we decided to preserve the exocyclic double bond of 15 and develop a new procedure
to accomplish the last steps in the synthesis of 8-deoxyvernolepin (Scheme 3). In this way,
24
transformation of 15 into 11 was attempted using different reagents. Under the conditions
indicated in Scheme 3, a 30% yield of 11 was obtained, but 60% of 15 could be recovered and
re-used, increasing the iodohydrin yield to almost 50%. Unexpectedly, base treatment of the
‡
1
mesylate 13, obtained from 11, directly gave the cis-fused d-lactone 24 (in its H NMR
spectrum, the signals from the C-3 and C-14 methylenes show chemical shifts, multiplicities and
25
J values in agreement with those of the cis-fused a-methylen-d-lactone unit of vernolepin).
Compound 9 (see Scheme 1) was not detected. Under the same conditions, iodohydrin 11
produced only ether 26 (Fig. 1), indicating the critical role sustained by the mesylate group in
the formation of 24. The base-promoted elimination of sulfene from a mesylate is an unusual
reaction, although evidence of sulfene formation from methanesulfonyl chloride in the presence
2
6
of pyridine has been reported. With this idea in mind, the reaction cascade depicted in Scheme
is proposed to explain the base-promoted formation of 24 from 13.
4
†
25
Compound 15: white powder; 169–170°C; [h] +60.6 (c 0.53, CHCl ); IR (film) w 3477, 2939, 1779, 1720, 1627,
max
D
3
−
1 1
1
185 cm ; H NMR (CDCl , 300 MHz): l 6.63 (1H, d, J=2.5 Hz, H-3a), 6.10 (1H, d, J=2.5 Hz, H-3b), 4.28 (1H,
3
t, J=5.2 Hz, H-1), 3.97 (1H, t, J=10.3 Hz, H-6), 3.78 (2H, m, H-2), 2.66 (1H, dt, J=2.5, J=10.3 Hz, H-5), 2.34 (1H,
dq, J=12.4, J=6.9 Hz, H-11), 1.25 (3H, d, J=6.9 Hz, H-13), 0.95 (3H, s, H-14); NOE-dif experiments: H irradiated
13
(
NOE observed), H-1 (H-5), H-2 (H-1, H-14), H-5 (H-1), H-6 (H-11, H-14), H-14 (H-6, H-2); C NMR (CDCl , 100
3
MHz): l 178.3 (s, C-12), 164.1 (s, C-15), 133.5 (s, C-4), 130.2 (t, C-3), 89.7 (d, C-1), 79.3 (d, C-6), 61.3 (t, C-2), 51.8
d, C-7), 49.9 (d, C-5), 40.5 (d, C-11), 38.4 (s, C-10), 34.3 (t, C-9), 22.7 (t, C-8), 13.9 (q, C-14), 12.5 (q, C-13); NMR
(
+
assignments have been made with the aid of 2D NMR experiments; EIMS m/z (rel. int.) 280 (4) [M] , 249 (100), 203
(
34), 175 (28), 147 (22), 91 (44), 55 (56); HRFABMS m/z 281.1391 (calcd for C H O 281.1389); anal. C, 63.76; H,
15 21 5
7
.56%, calcd for C H O , C, 64.27; H, 7.19%.
15 20 5
1
‡
Compound 24: oil, H NMR (CDCl , 300 MHz): l 6.76 (1H, t, J=1.0 Hz, H-3a), 5.98 (1H, t, J=1.0 Hz, H-3b),
3
4.55 (1H, d, J=12.3 Hz, H-14a), 4.14 (1H, dd, J=12.3, J=1.6 Hz, H-14b), 3.89 (1H, dd, J=10.7 Hz, H-6), 2.95 (1H,
dd, J=3.9, J=2.8 Hz, H-1), 2.82 (1H, dd, J=3.9 Hz, H-2a), 2.79 (1H, dd, J=3.9, J=2.8 Hz, H-2b), 2.66 (1H, da,
13
J=10.7 Hz, H-5), 2.37 (1H, dq, J=12.5, J=6.9 Hz, H-11), 1.30 (3H, d, J=6.9 Hz, H-13); C NMR (CDCl , 75
3
MHz): l 177.95 (s, C-12), 163.71 (s, C-15), 135.17 (t, C-3), 131.41 (s, C-4), 81.01 (d, C-6), 70.01 (t, C-14), 56.99 (d,
C-1), 50.11 (d, C-7), 45.84 (t, C-2), 42.82 (d, C-5), 41.53 (d, C-11), 29.77 (t, C-9), 23.02 (t, C-8), 12.61 (q, C-13).
HRFABMS m/z 301.1056 (calcd for C H O Na 301.1052).
15
18
5

7642
Scheme 3. Reagents, conditions and yields. (a) HgO, I , hw (two 100 W tungsten filament lamps), CH Cl /CCl , reflux,
2
2
2
4
8
h, 49%; (b) MsCl, Et N, CH Cl , 75%; (c) DBU, THF, 0°C, 43%; (d) Ref. 15
3
2
2
Figure 1.
Scheme 4. Mechanism proposed for the chemical transformation of 13 into 24
The direct transformation from 13 into 24 reduces the number of steps foreseen in retrosyn-
thetic Scheme 1. This fact, together with the excellent yields reported for the procedures used to
1
1,13
3
7,15
restore the D
double bond of 3 (in contrast to those for D ),
are encouraging incentives to
complete the syntheses of 1–3 following the strategy developed through this work.
Acknowledgements
This research has been supported by the Spanish DGICYT (Projects No. PB 95-1192 and PB
9
8-1365). The authors thank Angela Tate for revising our English text and the Spanish
´
Ministerio de Educaci o´ n y Cultura for the grant provided to M ´ı riam Alvarez.
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