Enantioselective Formal Synthesis of Eleuthesides

Article abstract of DOI:10.1055/s-2003-42467

An intramolecular Diels-Alder reaction of an enantiopure 3,5-hexadienyl acrylate and a chemoselective epimerization constitute the key steps of a highly stereoselective synthesis of triol 25, whose conversion to eleutherobin, eleuthosides A and B and sarcodictyins A and B is known.

Full text of DOI:10.1055/s-2003-42467

2422
LETTER
Enantioselective Formal Synthesis of Eleuthesides
Enantioselective
F
a
ormal
S
ynth
d
esis of Eleu
i
theside
n
s
e Ritter, Peter Metz*
Institut für Organische Chemie, Technische Universität Dresden, Bergstraße 66, 01069 Dresden, Germany
Fax +49(351)46333162; E-mail: peter.metz@chemie.tu-dresden.de
Received 17 September 2003
voted to developing a synthetic access to these com-
pounds, which have only been isolated in scarce amounts
from their natural sources. Thus, the total synthesis of
1,2a,3 2 and 32a as well as 4 and 52b has been accomplished,
and several synthetic studies4 toward the tricyclic core
have been reported. Recently, we5 and others6 have inves-
tigated construction of the cyclohexene moiety of the
eleuthesides via intramolecular Diels–Alder (IMDA) re-
action of 3,5-hexadienyl acrylates. Here, we communicate
the application of such a cycloaddition as one of the key
steps in an enantioselective and highly diastereoselective
synthesis of an advanced general precursor of eleuthe-
sides 1–5.
Abstract: An intramolecular Diels–Alder reaction of an enan-
tiopure 3,5-hexadienyl acrylate and a chemoselective epimerization
constitute the key steps of a highly stereoselective synthesis of triol
25, whose conversion to eleutherobin, eleuthosides A and B and
sarcodictyins A and B is known.
Key words: antitumor agents, stereoselective addition reactions,
organometallic reagents, intramolecular Diels–Alder reactions,
chemoselective epimerization
Eleutherobin (1), eleuthosides A (2) and B (3) and sarco-
dictyins A (4) and B (5) are members of the eleutheside
family of marine natural products with potent antitumor
properties and a mechanism of action similar to that of
taxol (Figure 1).1
Generation of the diene portion for the envisaged IMDA
process commenced with addition of the pentadienyllithi-
um species derived from 67 to TBS protected lactaldehyde
78a (Scheme 1). While complete Felkin–Anh selectivity9
was attained,10 regiocontrol was less pronounced, and
considerable silyl shift occurred to give a separable mix-
ture of isomers 8–11.11 The undesired regioisomers 10/11
were rearranged12 to increase the total yield of 8/9 to 55%
from 7. In order to probe the crucial IMDA step, alcohol
8 was esterified with (E)-4-methyl-2-pentenoic acid13 to
give 3,5-hexadienyl acrylate 12. Heating (sealed tube) a
toluene solution of 12 in the presence of 2,6-di-tert-butyl-
4-methylphenol (BHT) for 15 hours at 200 °C afforded a
separable 5:1 mixture of lactone 1314 with correct absolute
configuration at the three new stereogenic centers and di-
astereomer 1414 in a combined yield of 66% based on re-
covered starting material. As has been noted before,5,6 the
major cycloadduct was formed via an endo-boat transition
state with equatorial orientation of the carbon substituent
on the incipient d-lactone, whereas the minor cycloadduct
was produced via the corresponding exo-boat transition
state.15 Gratifyingly, using the bidentate Lewis acid
bis[chloro(methyl)aluminum]trifluoromethanesulfon-
amide in 1,2-dichloroethane,16 complete and clean con-
version of 12 to provide an 8:1 mixture of 13 and 14 was
achieved after only 1.5 hours at 80 °C, and a considerably
improved yield of the desired isomer 13 was isolated after
chromatographic separation.
Due to the exciting biological activity and the structural
complexity of the eleuthesides, much effort has been de-
With the aim of utilizing both regioisomers 8 and 9 in a
concise fashion, MOM analog 18 of TBS ether 12 was
prepared (Scheme 2). Simply by changing the order of
events (MOM protection, desilylation, esterification),
both 8 (via 12) and 9 were readily converted to 18. To our
delight, heating (sealed tube) a toluene solution of 18 in
the presence of BHT for 43 hours at 200 °C afforded endo
adduct 1914 in high yield next to minor amounts of exo
Figure 1
SYNLETT 2003, No. 15, pp 2422–2424
0
1
.1
2
.2
0
0
3
Advanced online publication: 07.11.2003
DOI: 10.1055/s-2003-42467; Art ID: G24203ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantioselective Formal Synthesis of Eleuthesides
2423
OMOM
OMOM
OTBS
a
b
H
9
+
6
7
OTBS
OH
O
15
16
a
c
OR2
OR2
OH
OMOM
+
OR1
OR1
d
a
O
O
O
O
12
8 : R1 = H, R2 = TBS
9 : R1 = TBS, R2 = H
10: R1 = H, R2 = TBS
11: R1 = TBS, R2 = H
17
18
b
e
OTBS
OMOM
OMOM
H
H
H
O
H
H
O
c
O
O
8
+
12
H
O
O
19
20
d or e
(5
:
1)
Scheme 2 Reagents and conditions: a) MOMCl, i-Pr2EtN, CH2Cl2,
0 °C to r.t., 95% 15, 98% 18; b) Bu4NF, THF, –10 °C to r.t., 99%; c)
(E)-4-methyl-2-pentenoic acid, DCC, DMAP, 0 °C to r.t., 76% (99%
on recovered s.m.); d) 40% HF, MeCN, r.t., 98%; e) 200 °C, toluene,
BHT, 75% 19, 15% 20.
OTBS
OTBS
H
H
H
O
H
H
H
O
+
O
O
13
14
DBU20b at room temperature was also effective but caused
some loss of material. Chelation-controlled addition9 of
ethinylmagnesium bromide to 23 furnished a 4:1
diastereomeric mixture of alcohols, from which the major
component 24 was easily secured in good yield. Finally,
reductive lactone cleavage with excess lithium aluminum
hydride provided triol 25,21 whose spectral and chromato-
graphic properties proved to be identical to the published
data for this compound in all respects.2b Since this ad-
vanced intermediate has been converted into eleutherobin
(1),2a eleuthosides A (2) and B (3)2a and sarcodictyins A
(4) and B (5),2b this synthesis of 25 constitutes a formal
synthesis of eleuthesides 1–5.
conditions d)
conditions e)
5
8
:
:
1
1
Scheme 1 Reagents and conditions: a) 6, BuLi, THF, –78 °C to r.t.
then 7, –78 °C to r.t., 43% 8 + 9 (1.2:1), 31% 10 + 11 (1.2:1); b) NaH,
18-crown-6, THF, 0 °C to r.t., 40% 8 + 9 (1.2:1); c) (E)-4-methyl-2-
pentenoic acid, DCC, DMAP, 0 °C to r.t., 75% (99% on recovered
s.m.); d) 200 °C, toluene, BHT, 36% 13, 7% 14, 35% recovered 12;
e) 1.1 equiv TfN[Al(Me)Cl]2, ClCH2CH2Cl, 80 °C, 84% 13, 10% 14.
epimer 20.14,17 Not quite unexpectedly, attempted IMDA
reaction of MOM ether 18 in the presence of bis[chlo-
ro(methyl)aluminum]trifluoromethanesulfonamide only
led to decomposition of the substrate.
Acknowledgment
Further elaboration of the major cycloadduct 19 towards
1–5 required an inversion of configuration at the lactone
carbinol center (Scheme 3). This second key transforma-
tion was achieved through chemoselective epimerization
of ketone 22, which was derived from 19 by
deprotection18 followed by oxidation of the resulting alco-
hol 21.19 In the event, subjecting 22 to 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) in dichloromethane20a for
45 minutes at room temperature smoothly delivered a
2.5:1 mixture of 23 and 22 that was separated by HPLC to
give 69% of 2314 next to 28% of recovered 22. Using neat
Financial support of this work by the Deutsche Forschungsgemein-
schaft (Graduierten-Kolleg ‘Struktur-Eigenschafts-Beziehungen
bei Heterocyclen’) and the Fonds der Chemischen Industrie is gra-
tefully acknowledged.
References
(1) For a review, see: Nicolaou, K. C.; Pfefferkorn, J.; Xu, J.;
Winssinger, N.; Ohshima, T.; Kim, S.; Hosokawa, S.;
Vourloumis, D.; van Delft, F.; Li, T. Chem. Pharm. Bull.
1999, 47, 1199.
Synlett 2003, No. 15, 2422–2424 © Thieme Stuttgart · New York

2424
N. Ritter, P. Metz
LETTER
(7) Wilson, S. R.; Jernberg, K. M.; Mao, D. T. J. Org. Chem.
1976, 41, 3209.
OH
O
H
H
H
O
H
H
H
O
(8) (a) Lattanzi, A.; Sagulo, F.; Scettri, A. Tetrahedron:
Asymmetry 1999, 10, 2023. (b) Mulzer, J.; Berger, M.
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(10) The relative configuration of 8 and 9 was elucidated by a
NOESY experiment with acetonide A (Figure 2) prepared
from 8/9 by desilylation (40% HF, MeCN, r.t., 90% from 8,
78% from 9) and subsequent acetalization of the resulting
single diol (acetone, PPTS, r.t., 91%).
a
b
19
O
O
21
22
c
O
OH
H
H
H
O
H
H
H
O
NOE
NOE
d
H
H
O
O
O
O
24
23
NOE
e
A
Figure 2
OH
H
H
(11) Upon changing the lactaldehyde protecting group to
TBDPS,8b silyl migration was slightly diminished, while
complete Felkin–Anh selectivity of addition was
maintained. However, the corresponding products were less
readily separated. With MOM protection8c the diastereo-
selectivity of addition was too low for synthetic utilization.
Transmetalation from Li to Al (Me2AlCl) or Mg (MgBr2
etherate) gave less 8/9.
(12) (a) Wilson, S. R.; Mao, D. T.; Jernberg, K. M.; Ezmirly, S.
T. Tetrahedron Lett. 1977, 18, 2559. (b) Shing, T. K. M.;
Zhu, X. Y.; Mak, T. C. W. Chem. Commun. 1996, 2369.
(13) Han, Y.; Liao, S.; Qiu, W.; Cai, C.; Hruby, V. J. Tetrahedron
Lett. 1997, 38, 5135.
OH
Ref 2
1–5
OH
25
Scheme 3 Reagents and conditions: a) CBr4, MeOH, reflux, 94%;
b) PCC, CH2Cl2, r.t., 97%; c) DBU, CH2Cl2, r.t., 69% (96% on re-
covered s.m.); d) ethinylmagnesium bromide, MgBr2 etherate,
Et2O, –70 °C to –40 °C, 58% (66% on recovered s.m.); e) LiAlH4,
Et2O, r.t., 85%.
(2) (a) Nicolaou, K. C.; Ohshima, T.; Hosokawa, S.; van Delft,
F. L.; Vourloumis, D.; Xu, J. Y.; Pfefferkorn, J.; Kim, S. J.
Am. Chem. Soc. 1998, 120, 8674. (b) Nicolaou, K. C.; Xu, J.
Y.; Kim, S.; Pfefferkorn, J.; Ohshima, T.; Vourloumis, D.;
Hosokawa, S. J. Am. Chem. Soc. 1998, 120, 8661.
(3) Chen, X.-T.; Bhattacharya, S. K.; Zhou, B.; Gutteridge, C.
E.; Pettus, T. R. R.; Danishefsky, S. J. J. Am. Chem. Soc.
1999, 121, 6563.
(4) For recent synthetic studies toward eleuthesides, see:
(a) Winkler, J. D.; Quinn, K. J.; MacKinnon, C. H.; Hiscock,
S. D.; McLaughlin, E. C. Org. Lett. 2003, 5, 1805.
(b) Kaliappan, K. P.; Kumar, N. Tetrahedron Lett. 2003, 44,
379; and references cited therein.
(14) The relative configuration was verified by detailed 2D NMR
experiments.
(15) (a) Jones, G. A.; Paddon-Row, M. N.; Sherburn, M. S.;
Turner, C. I. Org. Lett. 2002, 4, 3789. (b) Tantillo, D. J.;
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(16) Saito, A.; Ito, H.; Taguchi, T. Org. Lett. 2002, 4, 4619.
(17) Attempted IMDA reactions of alcohol 17 and the
corresponding ketone [DMSO, (COCl)2, Et3N, CH2Cl2,
–50 °C to r.t., 84% from 17] under similar conditions turned
out to be much less efficient (<25% yield).
(18) Lee, A. S.-Y.; Hu, Y.-J.; Chu, S.-F. Tetrahedron 2001, 57,
2121.
(19) Alcohol 21 was also obtained by desilylation of 13 (40% HF,
MeCN, r.t., 98%).
(5) Plietker, B. Ph.D. Thesis; Technische Universität Dresden:
Germany, 1999.
(20) (a) Ihara, M.; Suzuki, S.; Taniguchi, N.; Fukumoto, K. J.
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(21) Compound 25: [a]D25 +41.6 (c 0.6, CHCl3); ref.2b [a]D
25
+43.5 (c 0.2, CHCl3).
Synlett 2003, No. 15, 2422–2424 © Thieme Stuttgart · New York