Total synthesis of elisabethin A: Intramolecular Diels-Alder reaction under biomimetic conditions

Article abstract of DOI:10.1021/ja034397t

We describe the first total synthesis of the marine diterpenoid elisabethin A. The synthesis uses (S)-hydroxy-2-methyl-propionate as the chiral starting material, which is elaborated into a dienyl-iodide and added to an aryl acetic acid ester via enolate

Full text of DOI:10.1021/ja034397t

Published on Web 03/27/2003
Total Synthesis of Elisabethin A: Intramolecular Diels-Alder Reaction under
Biomimetic Conditions
Thilo J. Heckrodt and Johann Mulzer*
Institut fu¨r Organische Chemie der UniVersita¨t Wien, Wa¨hringerstrasse 38, A-1090 Wien, Austria
Received January 29, 2003; E-mail: johann.mulzer@univie.ac.at
The marine diterpenoid elisabethin A (1) was isolated, along with
its structurally related isomers elisapterosin B (2) and colombiasin
A (3), from the chemically rich Caribbean gorgonian Pseudo-
pterogorgia elisabethae (Octocorallia) in the late 1990s (Figure 1).1
Detailed pharmacological properties of 1-3 have not yet been
communicated; however, some members of the elisabethane class
do show significant activity against Mycobacterium tuberculosis,
as well as in vitro cancer cell cytotoxicity.1 Moreover, 1 has
attracted particular attention as a potential biosynthetic intermediate
Figure 1. Marine natural products from Pseudopterogorgia elisabethae.
Scheme 1. Retrosynthetic Analysis of Elisabethin A (1)
of 2 and 3.
The complex molecular architecture and rich functionalization
of these molecules make them interesting and attractive synthetic
targets.2 We now report the first total synthesis of 1.3
According to our retrosynthetic plan (Scheme 1) the elisabethane
carbon skeleton should be assembled via an intramolecular Diels-
Alder (IMDA) cyclization4 of quinone 5 which should be generated
by oxidation of the corresponding hydroquinoid precursor.
The synthesis of the benzenoid fragment (Scheme 2) started from
commercially available aldehyde 6 which was converted to phenol
7. Selective 4-O-demethylation was achieved via an oxidation/
reduction sequence to give hydroquinone 8.5 O-Silylation and
regioselective bromination with NBS led to aryl bromide 9, which
was subsequently converted to aryl acetic ester 11a using a
palladium-catalyzed Negishi-Reformatsky coupling with stannane
10.6 To obtain the Evans’ oxazolidinone 11b, ester 11a was
transformed into acid 12 in a three-step reduction/oxidation
sequence which was necessary because ester 11a remained un-
changed even after refluxing it in concentrated NaOH/EtOH for
14 h. Acid 12 was converted to the desired imide 11b via the mixed
anhydride because the corresponding acid chloride did not react,
probably due to formation of the ketene.7
Scheme 2. Synthesis of the Aryl Acetic Acid Derivatives 11a/ba
The dienyl iodide 18 was synthesized from known aldehyde 13
(Scheme 3).8 Olefination with phosphonate 14 furnished the desired
(E)-Weinreb-enamide 15, which was reduced to the R,â-unsaturated
aldehyde 16. The Z-geometry of the second double bond was
installed by a “salt-free” Wittig reaction (NaHMDS, Ph3PEtBr) to
give isomerically pure diene 17, which was converted into iodide
18 by two additional steps.
The alkylation of ester 11a with iodide 18 (Scheme 4) proceeded
smoothly to 19a but with a moderate de of 42%. In contrast,
oxazolidinone 11b gave a significantly higher de (86%); however,
the reaction required recycling of unreacted starting material to
furnish 19b in an overall yield of 69%. Reduction of 19a/b to the
alcohol with LiBH4 allowed separation of diastereoisomers by
column chromatography. Swern oxidation delivered aldehyde 20
which was converted to the desired Diels-Alder precursor 21 by
a Wittig reaction. The choice of the hydroquinone 1,4-OH-
protecting groups turned out to be a very crucial issue. An earlier
attempt to accomplish an oxidative 1,4-O-di-demethylation under
various conditions such as CAN, AgO/HNO3, and so forth had
totally failed to produce any of the desired quinone.3 A complex
a Reagents and conditions: (a) MCPBA (1.5 equiv), CH2Cl2, rt, 5 h; (b)
NaOH (3.0 equiv), MeOH/H2O, rt, 4 h; (c) CAN (2.5 equiv), MeCN/H2O,
rt, 1 h; (d) Na2S2O4 (5.0 equiv), MeCN/H2O, 4 h, rt; (e) TBSCl (3.0 equiv),
im (4.0 equiv), DMF, rt, 20 h; (f) NBS (1.0 equiv), MeCN, rt, 6 h; (g)
ZnBr2 (1.4 equiv), 10 (1.4 equiv), PdCl2(o-tol3P)2 (0.08 equiv), DMF, 80
°C, 12 h; (h) DIBAL-H (3.0 equiv), CH2Cl2, -78 f 0 °C, 6 h; (i) (COCl)2
(2.0 equiv), DMSO (4.0 equiv), Et3N (6.0 equiv), CH2Cl2, -78 °C f rt;
(j) NaClO2 (5.0 equiv), KH2PO4 (5.0 equiv), H2O/tBuOH/Me2CdCMe2,
rt, 12 h; (k) PivCl (1.1 equiv), Et3N (1.3 equiv), then deprotonated Evans’
oxazolidinone (1.2 equiv), THF, 14 h, -78 °Cf rt, (MCPBA )
m-chloroperbenzoic acid, im ) imidazole, PivCl ) pivaloyl chloride).
mixture of products was formed, probably due to the decomposition
of the diene under the strongly acidic conditions. However, the
OTBS-modified precursor 21 was easily deprotected with TBAF
and oxidized9 with aqueous FeCl3 to form quinone 5 (detectable
by TLC and NMR) which cyclized in situ to adduct 4.
The significance of this IMDA reaction lies in (1) the use of of
a terminal (Z)-olefinsto our knowledge the first case that has been
successfully developed, (2) the unusually mild and virtually
biomimetic conditions (aqueous medium, ambient temperature), and
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C O M M U N I C A T I O N S
Scheme 3. Synthesis of the Diene Fragment 18a
Figure 2. Endo transition state of the IMDA cyclization.
a Reagents and conditions: (a) 14 (1.02 equiv), NaH (1.02 equiv), THF,
5 h, 0 °C f rt; (b) DIBAL-H (3.0 equiv), THF, 2 h, -78 °C; (c) Ph3PEtBr
(1.5 equiv), NaHMDS (1.5 equiv), THF, 12 h, -78 °C f rt; (d) BCl3 (1.4
equiv), CH2Cl2, 1 h, -40 f -10 °C; (e) Im (2.0 equiv), Ph3P (2.0 equiv),
I2 (2.0 equiv), benzene, 2 h, rt (NaHMDS ) sodium bis(trimethylsilyl)a-
mide).
natural 11a: [R]25D +133.0 (c ) 0.45, CHCl3). This means that we
have synthesized the natural enantiomer of 1 on a stereochemically
unambiguous route and have thus proven its absolute configuration.
In conclusion we have accomplished a convergent and highly
stereocontrolled total synthesis of elisabethin A (1) in 17-20 steps
and 7% overall yield along the longest linear sequence. The
synthesis is flexible and potentially allows the introduction of a
variety of nonnatural substituents. The preparation of such analogues
and the evaluation of the bioprofile of 1 is currently underway in
our laboratory.
Scheme 4. Completion of the Total Synthesisa
Acknowledgment. A Kekule´ fellowship (to T.J.H.) from the
“Fonds der chemischen Industrie” and financial support (project
P14729-CHE) from the Austrian Research Fund (FWF) is gratefully
acknowledged. Thanks are also due to Dr. Hanspeter Kaehlig for
help with the NMR spectra and Sabine Schneider for HPLC
separations.
Supporting Information Available: Detailed experimental pro-
cedures and characterization data for 4, 11a/b, 18, 19a/b; copies of 1H
and 13C NMR spectra of Diels-Alder adduct 4 and synthetic elisabethin
A (PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
References
a Reagents and conditions: (a) NaHMDS (1.1 equiv), then 18 (1.5 equiv),
HMPA (10 equiv), THF, 4 h, -78 f -40 °C; for 19b: 30 equiv HMPA,
-78 °C f rt; (b) LiBH4 (1.1 equiv), H2O (1.1 equiv), Et2O, 2 h, 0 °C; (c)
(COCl)2 (2.0 equiv), DMSO (4.0 equiv), Et3N (6.0 equiv), CH2Cl2, -78
°C f rt; (d) (CH3)2CHPPh3I (2.0 equiv), n-BuLi (2.0 equiv), THF, 4 h, 0
°C; (e) TBAF (2.4 equiv), THF, 1 h, rt, then FeCl3 (10 equiv), H2O, 6 h,
rt; (f) Pd/C (0.1 equiv), H2 (1 atm), EtOAc, 1 h, rt; (g) NaOH (5 equiv),
MeOH/H2O, 5 h, 80 °C; (h) BBr3 (6 equiv), THF, 0.5 h, -100 °C. (HMPA
) hexamethylphosphoramide).
(1) Elisabethin and elisapterosin: (a) Rodr´ıguez, A. D.; Gonza´lez, E.; Huang,
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Nicolaou, K. C.; Vassilikogiannakis, G.; Ma¨gerlein, W.; Kranich, R. Chem.
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(3) For earlier work, see: (a) Heckrodt, T. J.; Mulzer, J. Synthesis 2002, 1857.
For an approach to an unfunctionalized racemic elisabethin A skeleton,
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Chem., Int. Ed. 2001, 40, 2145. (c) Nicolaou, K. C.; Sugita, K.; Baran, P.
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(3) the high yield and stereoselectivity (1H NMR: no isomers
detectable, HPLC: less than 3%).
The relative configuration of 4 was confirmed by extensive
NOESY experiments. The observed stereochemical course of the
IMDA reaction can be rationalized in terms of the endo transition-
state geometry shown in Figure 2. The facial selectivity of the
diene-quinone attack is controlled by a minimization of allylic
strain between the substituents at C9 and the quinoid carbonyl
functionality. Selective hydrogenation of the disubstituted olefin 4
followed by base-catalyzed epimerization at C2 and cleavage of
the methyl ether with BBr3 led to compound 1, whose NMR, MS,
and IR data were in agreement with those reported for the natural
elisabethin A. The optical rotation of 1 compared well to the
(4) For a recent review on DA reactions, see: (a) Nicolaou, K. C.; Snyder,
S. A.; Montagnon, T.; Vassilikogiannakis, G. E. Angew. Chem., Int. Ed.
2002, 41, 1668. For quinone-based IMDA reactions, see (b) refs 2 a,b.
(c) Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002,
124, 773.
(5) Luly, J. R.; Rapoport, H. J. Org. Chem. 1981, 46, 2745.
(6) Kosugi, M.; Negishi, Y.; Kameyama, M.; Migita, T. Bull. Chem. Soc.
Jpn. 1985, 58, 3383.
(7) Prashad, M.; Kim, H.-Y.; Har, D.; Repic, O.; Blacklock, T. J. Tetrahedron
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(8) Mulzer, J.; Dupre´, S.; Buschmann, J.; Luger, P. Angew. Chem., Int. Ed.
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(9) For FeCl3 oxidations see: Rodd’s Chemistry of Carbon Compounds, 2nd
ed.; Elsevier Science: Amsterdam, London, New York, 1974; Vol. III B,
p 10 ff.
literature value (synthetic 1: [R]25 +129.7 (c ) 0.05, CHCl3),
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