A formal total synthesis of eleutherobin through an unprecedented kinetically controlled ring-closing-metathesis reaction of a densely functionalized diene

Article abstract of DOI:10.1002/anie.200461767

The key step in a formal total synthesis of eleutherobin was an unprecedented kinetically controlled RCM reaction of a densely functionalized diene 1 bearing two PMP-protected allylic alcohols in the presence of a second-generation Grubbs catalyst. Subseq

Full text of DOI:10.1002/anie.200461767

Communications
Antitumor Agents
sarcodictyins, effecting mitotic arrest through tubulin poly-
merization.[4] Both sarcodictyins and eleutherobin (the “eleu-
theside” family of microtubule-stabilizing drugs) are charac-
terized by an activity profile different from that of taxol; they
are active against taxol-resistant tumor cell lines and there-
fore hold potential as second-generation microtubule-stabi-
lizing anticancer agents.[4,5] The scarce availability of 1 and 2
from natural sources makes their total syntheses vital for
further biological investigations.[5] To date, sarcodictyin A and
B have been synthesized successfully by Nicolaou et al.,[6]
A Formal Total Synthesis of Eleutherobin
Through an Unprecedented Kinetically
Controlled Ring-Closing-Metathesis Reaction
of a Densely Functionalized Diene**
Damiano Castoldi, Lorenzo Caggiano, Laura Panigada,
Ofer Sharon, Anna M. Costa, and Cesare Gennari*
who have also exploited a similar route to eleutherobin.[7]
A
Sarcodictyins A (1a) and B (1b) were isolated in 1987 by
Pietra and co-workers from the Mediterranean stoloniferan
subsequent report by Danishefsky and co-workers details an
elegant alternative access to eleutherobin.[8] A number of
synthetic approaches to the eleutheside natural products and
syntheses of simplified analogues have also been described.[9]
Herein we report the preparation of 3, a key intermediate
in the synthesis reported by Danishefsky and co-workers,[8]
and thus a formal total synthesis of eleutherobin (2)
(Scheme 1). The main step of our strategy, used for obtaining
coral Sarcodictyon roseum.[1] Their antitumor activity was
recognized about a decade later, and their taxol-like mech-
anism of action was discovered in 1996.[2] In the meantime, the
diterpene glycoside eleutherobin (2) was reported by Fenical
et al. from an Eleutherobia species of Australian soft coral,
accompanied by disclosure of its potent cytotoxicity in 1995.[3]
Two years later, eleutherobin was shown to act similarly to the
[*] D. Castoldi, Dr. L. Caggiano,[+] L. Panigada, Dr. O. Sharon,
Prof. Dr. C. Gennari
Dipartimento di Chimica Organica e Industriale
Centro di Eccellenza C.I.S.I., Universitꢀ degli Studi di Milano
Istituto di Scienze e Tecnologie Molecolari (ISTM) del CNR
Via G. Venezian 21, 20133 Milano (Italy)
Fax: (+39)02-5031-4072
Scheme 1. Retrosynthetic analysis of eleutherobin (2).
E-mail: cesare.gennari@unimi.it
Dr. A. M. Costa
Departamento de Quꢁmica Orgꢀnica
Universitat de Barcelona
the [8.4.0] fused bicyclic ring system 4, is a ring-closing
metathesis (RCM)[10] reaction of the densely functionalized
diene 5.
Av. Diagonal 647, 08028 Barcelona (Spain)
Diene 5 was synthesized from aldehyde 6 (prepared in six
steps on a multigram scale from R-(ꢀ)-carvone in 30%
overall yield)[9a,g] through multiple stereoselective Hafner–
Duthaler oxyallylations (Scheme 2).[11] The first oxyallylation,
in the presence of the [(S,S)-taddolCpTiCl] complex 7,
proceeded with complete stereocontrol to give the desired
stereoisomer 8 in 73% yield. After standard protection of the
alcohol as the methoxymethyl ether 9 in 95% yield, cleavage
of the dimethylacetal group and reduction with NaBH4 to give
10 in 75% yield, an efficient and well-established sequence of
steps[8c,9n] led to the homologated aldehyde 11 (95%). The
same oxyallylation procedure described above was applied,
this time in the presence of the [(R,R)-taddolCpTiCl] com-
plex 7, to give the desired alcohol 12 in 83% yield with
[+] Current address: Department of Chemistry
University of Sheffield
Dainton Building, Brook Hill, Sheffield, S37HF (UK)
[**] We thank the European Commission for financial support (IHP
Network grant “Design and synthesis of microtubule stabilizing
anticancer agents” HPRN-CT-2000-00018) and for postdoctoral
fellowships to L. C. (HPRN-CT-2000-00018) and O. S. (“Marie
Curie” MEIF-CT-2003-500880). We also thank “Merck Research
Laboratories” (Merck’s Academic Development Program Award to
C. G.) and Universitꢀ degli Studi di Milano for financial support and
for a graduate fellowship (to D. Castoldi). We thank Dr. Raphael
Beumer, Dr. Pau Bayꢂn, Dr. Joachim Telser, and Dr. Fabienne
Pradaux for preliminary experiments related to this work, as well as
Dr. Nicola Mongelli (Nerviano Medical Science) and Prof. Jaume
Vilarrasa (University of Barcelona) for inspiring discussions.
588
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DOI: 10.1002/anie.200461767
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Angewandte
Chemie
Scheme 3. Reagents and conditions: a) cat. 13 (30 mol%), toluene,
1108C, 6.5 h, 64%; b) CAN, CH3CN/H2O (4:1), 08C, 80%; c) DMP,
CH2Cl2, 258C, 90%; d) CDCl3, 258C; e) BF3·Et2O, Me2S, CH2Cl2,
ꢀ78!ꢀ208C, 78%. CAN=ceric ammonium nitrate;
DMP=Dess–Martin periodinane.
Scheme 2. Reagents and conditions: a) s-BuLi (1.3m in cyclohexane),
PMPOAllyl, [(S,S)-taddolCpTiCl] 7, THF/Et2O (57:43), ꢀ78!08C,
73%; b) DIPEA, TBAI, MOMCl, CH2Cl2, 258C, 95%; c) LiBF4, CH3CN/
H2O (98:2), 258C; d) NaBH4, EtOH, 258C, 75% over two steps;
e) MsCl, TEA, CH2Cl2, 0!258C, 95%; f) KCN, [18]crown-6, CH3CN,
808C, quant.; g) DIBAL-H, toluene/hexane (1:2), ꢀ788C, quant.; h) s-
BuLi (1.4m in cyclohexane), PMPOAllyl, [(R,R)-taddolCpTiCl] 7, Et2O/
THF (81:19), ꢀ78!258C, 83%; i) PivCl, DMAP, DIPEA, CH2Cl2, 258C,
96%. PMP=p-methoxyphenyl; DIPEA=diisopropylethylamine;
TBAI=tetrabutylammonium iodide; MOM=methoxymethyl;
Ms=methanesulfonyl; TEA=triethylamine; DIBAL-H=diisobutyl-
aluminum hydride; Piv=tert-BuCO; DMAP=4-(dimethylamino)pyri-
dine; taddol=1,1,4,4-tetraphenyl-2,3-O-isopropylidene-threitol.
and isolated in 64% yield. This result contrasts sharply with
many other Z-selective RCM reactions of diene cyclization
precursors less-densely functionalized than diene 5, that is,
bearing protected and/or free alcohol functionalities at both
the homoallylic positions and at only one allylic position.[9-
h,m,n,o] In the presence of a second-generation Grubbs catalyst,
these dienes lead to the more stable Z-cyclized products
under thermodynamic control.[15] Preliminary molecular-
mechanics calculations[16] show that the E stereoisomer A
(corresponding to 14) is less stable than the Z stereoisomer B
by ꢁ 6.6 kJmolꢀ1 (Figure 1). This energy difference increases
to approximately 15.0 kJmolꢀ1 when the lowest-energy con-
formers are optimized at the PM3 level.[17] The reasons why
the less stable E stereoisomer 14 was formed on this occasion
(under kinetic control) and no trace of the more stable Z
stereoisomer could be identified in the reaction mixture are
not completely clear and will be investigated in detail. At the
moment we can offer a tentative explanation as follows: the
trans ruthenium-cyclobutane intermediate might be more
stable than the cis species, leading to the E stereoisomer
under kinetic control. Once formed, the E double bond of 14,
flanked by two bulky OPMP groups, might be too sterically
hindered to react again with the ruthenium methylidene via
cycloaddition and cycloreversion, thus arresting the equili-
brium between the ring-closed and ring-opened products and
inhibiting thermodynamic control.[18]
complete stereocontrol. Homoallylic alcohol 12 was then
transformed into the pivalate 5 (96%), and this diene was
subjected to ring-closing metathesis.
The RCM reaction of a number of densely functionalized
diene cyclization precursors of type 5 (bearing protected and/
or free alcohol functionalities at both the allylic and the
homoallylic positions) had previously been investigated with
a variety of catalysts, but no desired cyclized frameworks were
obtained.[9o] However, none of the previously examined diene
precursors had the allylic alcohols protected as p-methoxy-
phenyl (PMP) ethers, which were discovered to facilitate the
RCM reaction in comparison with other protective groups
and with the free alcohols.[9o]
Based on these premises, diene 5 was treated with the
second-generation Grubbs RCM catalyst[12] 13 (Scheme 3).
Under forcing conditions[13] (slow addition by syringe pump
(over 2.5 h) of a solution of RCM catalyst 13 (30 mol%) in
toluene to a boiling solution of 5 in toluene, and additional
stirring for 4 h at 1108C), the E stereoisomer 14[14] was formed
Confident that the greater stability of the Z 10-membered
carbocycle would eventually prevail, we continued our
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589

Communications
DꢀAmbrosio, A. Guerriero (Pharmacia S.p.A.), PCT Int. Appl.
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Figure 1. Lowest energy conformers and relative energies of the
E stereoisomer A (corresponding to 14) and of the Z stereoisomer B,
obtained at the PM3 level.[16,17]
planned synthesis by removal of the PMP groups (CAN,
80%) and oxidation of the allylic diol (DMP, 90%). Enedione
15 (5-H, 6-H: d = 7.02, 6.64 ppm; 3J5,6-H = 17.3 Hz) showed
remarkable properties: while recording its 1H NMR spectrum
in CDCl3 it cleanly isomerized to the more stable Z stereo-
[7] a) K. C. Nicolaou, F. van Delft, T. Ohshima, D. Vourloumis, J. Y.
Xu, S. Hosokawa, J. Pfefferkorn, S. Kim, T. Li, Angew. Chem.
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isomer 4 (5-H, 6-H: d = 7.20, 6.13 ppm; 3J5,6-H = 14.0 Hz; t1/2
=
3
63 h). Bis-hemiacetal 16 (5-H, 6-H: d = 6.29, 6.18 ppm; J5,6-
H = 5.8 Hz) was obtained as the only product after flash
chromatography of the Z enedione 4, showing the propensity
of 4 to add water and equilibrate with its hydrated form.[19]
Finally, the MOM protecting group of the 15/4/16 mixture was
removed (BF3·Et2O, Me2S)[20] to give compound 3 (78%),
which produced analytical data identical to those previously
reported by Danishefsky and co-workers (1H NMR,
13C NMR, IR spectroscopy, HRMS, Rf, [a]D).[8c]
In summary, we have completed a formal total synthesis of
eleutherobin (2) through: 1) multiple stereoselective tita-
nium-mediated oxyallylations, 2) an unprecedented kineti-
cally controlled RCM reaction of a densely functionalized
diene bearing two allylic alcohols protected as PMP ethers in
the presence of a second-generation Grubbs catalyst, and 3)
the isomerization of an E 10-membered enedione to the more
stable Z 10-membered enedione.
[8] a) X.-T. Chen, C. E. Gutteridge, S. K. Bhattacharya, B. Zhou,
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Angew. Chem. Int. Ed. 1998, 37, 789 – 792; c) X.-T. Chen, S. K.
Bhattacharya, B. Zhou, C. E. Gutteridge, T. R. R. Pettus, S. J.
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Received: August 23, 2004
Published online: December 13, 2004
Keywords: antitumor agents · asymmetric synthesis ·
.
metathesis · natural products · total synthesis
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[18] The RCM reaction of a diastereoisomer of 5 (C) was also
investigated. The stereoisomer
(3J5,6-H = 17.0 Hz) was
obtained (27%) together with the rearranged product
E
D
E
(15%), which originates from a ring-opening metathesis/ring-
closing metathesis (ROM/RCM) process involving the trisub-
stituted double bond of the cyclohexene ring and the two
terminal alkenes. Compound D was transformed into the target
molecule 3 through the same sequence of reactions described in
Scheme 3. Reagents and conditions: a) PMPOAllyl, s-BuLi
(1.4m in cyclohexane), (+)-Ipc2BOMe, BF3·Et2O, THF,
ꢀ788C!258C, 40%; b) PivCl, DMAP, DIPEA, CH2Cl2, 258C,
83%; c) cat. 13 (30 mol%), toluene, 1108C, 6.5 h, 27% D, 15%
E. PMP = p-methoxyphenyl; Piv = tert-BuCO; DMAP = 4-
[11] A. Hafner, R. O. Duthaler, R. Marti, G. Rhis, P. Rothe-Streit, F.
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(dimethylamino)pyridine;
DIPEA = diisopropylethylamine;
[13] For a discussion of these optimized RCM conditions, see: K.
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to protons 5-H and 6-H) became two doublets whose coupling
constant, typical of an E double bond, was easily determined:
3J5,6-H = 16.5 Hz. The NOESY spectrum showed two positive
cross peaks due to scalar coupling (E double bond), instead of
two negative cross peaks due to NOE (Z double bond).
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MeOH/H2O (98:2) solution, gave the exact molecular ions
[M+Na]+ for 4 (calcd for C25H38NaO6: 457.25606; found:
457.25582; error= 0.52 ppm), the hydrated form 16 (calculated
for C25H40NaO7: 475.26662; found: 475.26681; error= 0.40 ppm),
and the hemiacetal-methylacetal corresponding to the addition
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[17] The lowest-energy conformers obtained with MacroModel for
isomers A and B (180 and 97 conformers respectively, using a
20.0 kJmolꢀ1 energy window from the global minima) were
optimized at the PM3 level using the Gaussian 03 package
(Gaussian 03 (RevisionB.04), M. J. Frisch, G. W. Trucks, H. B.
Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A.
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Angew. Chem. Int. Ed. 2005, 44, 588 –591
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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