Ring-closing metathesis approach to dictyostatin

Article abstract of DOI:10.1021/ol0478279

(Chemical Equation Presented) An esterification/ring-closing metathesis approach to dictyostatin and discodermolide is introduced. The approach provides for facile fragment coupling of two main segments of these natural products at the C10-C11 alkene with

Full text of DOI:10.1021/ol0478279

ORGANIC
LETTERS
2005
Vol. 7, No. 3
379-382
Ring-Closing Metathesis Approach to
Dictyostatin†
Cyrous O. Kangani, Arndt M. Bru1ckner, and Dennis P. Curran*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
curran@pitt.edu
Received October 21, 2004 (Revised Manuscript Received December 10, 2004)
ABSTRACT
An esterification/ring-closing metathesis approach to dictyostatin and discodermolide is introduced. The approach provides for facile fragment
coupling of two main segments of these natural products at the C10−C11 alkene with high to complete Z-selectivity.
Dictyostatin is a potent antitumor agent that acts by micro-
tubule stabilization. It was first isolated in 1994 by Pettit
and co-workers,1a who correctly proposed the two-dimen-
sional structure from data collected on a very small sample
(about 1 mg). Later, Wright and co-workers isolated dicty-
ostatin from a different source, and their exciting biological
results1c,d further demonstrated the need for total synthesis
both to secure the structure and to provide material for
additional biological testing.
ostatin is a “tied back” analogue of the important antitumor
agent discodermolide 3.5 The scarcity and high biological
activity of dictyostatin encourage continued development of
Early on, Pettit and Cichacz proposed partial stereostruc-
ture 1 for dictyostatin (Figure 1).1b Very recently, Wright
and Paterson suggested that dictyostatin had structure 2,2 and
this proposal has just been confirmed by independent total
syntheses from Paterson’s group3a and ours.3b,4 Thus, dicty-
† Dedicated to Prof. Jeremiah P. Freemen in tribute to his 25 years of
tenure as Secretary of Organic Syntheses.
(1) (a) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Boyd, M. R.; Schmidt, J.
M. J. Chem. Soc., Chem. Commun. 1994, 1111-1112. (b) Pettit, G. R.;
Cichacz, Z. A. Isolation and structure of dictyostatin 1 PCT WO5430053,
1995; Chem. Abstr. 1995, 733500. (c) Wright, A. E.; Cummins, J. L.;
Pomponi, S. A.; Longley, R. E.; Isbrucker, R. A. Dictyostatin compounds
for stabilization of microtubules. PCT WO 0162239, 2001; Chem. Abstr.
2001, 635882. (d) Isbrucker, R. A.; Cummins, J.; Pomponi, S. A.; Longley,
R. E.; Wright, A. E. Biochem. Pharm. 2003, 66, 75-82.
(2) Paterson, I.; Britton, R.; Delgado, O.; Wright, A. E. Chem. Commun.
2004, 632-633.
(3) (a) Paterson, I.; Britton, R.; Delgado, O.; Meyer, A.; Poullennec, K.
G. Angew. Chem., Int. Ed. 2004, 43, 4629-4633. (b) Shin, Y.; Fournier,
J.-H.; Fukui, Y. Bru¨ckner, A. M.; Curran, D. P. Angew. Chem., Int. Ed.
2004, 43, 4634-4637.
Figure 1. Structures of dictyostatin and discodermolide.
10.1021/ol0478279 CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/07/2005

Scheme 1. RCM Reactions of 8a,b
Figure 2. Esterification/ring-closing metathesis strategy.
more efficient synthetic approaches to the natural product
and analogues.
Stereoselective construction of the C10-C11 (Z)-alkene
is a crucial concern in the synthesis of both discodermolide
and dictyostatin, and a number of successful approaches have
been implemented in a fragment coupling setting.5 We
originally favored a Wittig approach for simplified disco-
dermolide analogue synthesis6 similar to that implemented
by Smith in the total synthesis of discodermolide.7 But the
approach proved unreliable when we attempted to extend it
to dictyostatin,8 and we ultimately adapted the strategy to
make the C9-C10 bond by fragment coupling instead.3b We
report herein a series of simple and sophisticated model
studies probing a ring-closing metathesis9 approach to the
C10-C11 (Z)-alkene. The results suggest considerable
promise for extending this route to dictyostatin or discoder-
molide synthesis.
C4 fragment of the dienyl ester is excised with concomitant
lactonization of the new terminus C5 onto the C13 hydroxyl
group to give 10-membered lactone 5. This lactone in turn
can be made from alcohol 6 and acid 7 by esterification and
ring-closing metathesis. Will the metathesis reaction succeed
given the relatively crowded substitution pattern of the
alkene?9 If it succeeds, will it provide for stereocontrol in
the alkene formation?9,10
To bring experimental evidence to bear on these questions,
we selected model substrates 8a and 8b to study the ring-
closing metathesis (Scheme 1). These substrates were made
by esterification reactions from readily available alcohol and
acid fragments, as described in the Supporting Information.
Cyclization of 8a with 50 mol % of catalyst I provided 9a
in 71% yield as an inseparable 17/1 mixture of Z/E isomers.
Similar treatment of 8b this time with second-generation
Grubbs catalyst II provided 9b in 84% yield as a 10/1 Z/E
mixture. Reactions with 10% catalyst were not as successful,
and starting material was recovered along with the target
lactones. These encouraging results suggest that acceptable
yields and good stereocontrol are possible.
Figure 2 highlights the metathesis strategy in a dictyostatin
setting and omitting stereochemical concerns. Retrosyntheti-
cally, the E,Z-diene of 4 is terminated at C23, and the C1-
(4) Dictyostatin analogues and fragment synthesis: (a) Shin, Y.; Choy,
N.; Balachandran, R.; Madiraju, C.; Day, B. W.; Curran, D. P.; Turner, T.
R. Org. Lett. 2002, 4, 4443-4446. (b) O’Neil, G. W.; Phillips, A. J.
Tetrahedron Lett. 2004, 45, 4253-4256.
(5) (a) Myles, D. C. In Annual Reports In Medicinal Chem; Doherty, A.
M., Ed.; Academic Press: San Diego, CA, 2002; Vol. 37, 125-132. (b)
Paterson, I.; Florence, G. J. Eur. J. Org. Chem. 2003, 2193-2208.
(6) (a) Curran, D. P.; Furukawa, T. Org. Lett. 2002, 4, 2233-2235. (b)
Choy, N.; Shin, Y.; Nguyen, P. Q.; Curran, D. P.; Balachandran, R.;
Madiraju, C.; Day, B. W. J. Med. Chem. 2003, 46, 2846-2864. (c) Minguez,
J. M.; Giuliano, K. A.; Balachandran, R.; Madiraju, C.; Curran, D. P.; Day,
B. W. Mol. Cancer. Therapeut. 2002, 1, 1305-1313. (d) Minguez, J. M.;
Kim, S.-Y.; Giuliano, K. A.; Balachandran, R.; Madiraju, C.; Day, B. W.;
Curran, D. P. Bioorg. Med. Chem. 2003, 11, 3335-3357.
We next extended these studies to prepare a large subunit
of dictyostatin, as summarized in Scheme 2. The relative
stereostructure was targeted based on originally proposed
structure 1, which we converted to its enantiomer to make
it more similar to discodermolide.4a The alcohol 10 was
(7) (a) Smith, A. B.; Freeze, B. S.; Brouard, I.; Hirose, T. Org. Lett.
2003, 5, 4405-4408. (b) Smith, A. B.; Beauchamp, T. J.; LaMarche, M.
J.; Kaufman, M. D.; Qiu, Y. P.; Arimoto, H.; Jones, D. R.; Kobayashi, K.
J. Am. Chem. Soc. 2000, 122, 8654-8664.
(10) Variable stereoselectivities have been observed in medium ring
formation. See, for example: (a) Fu¨rstner, A.; Radkowski, K.; Wirtz, C.;
Goddard, R.; Lehmann, C. W.; Mynott, R. J. Am. Chem. Soc. 2002, 124,
7061-7069. (b) Liu, D.; Kozmin, S. A. Org. Lett. 2002, 4, 3005-3007.
(c) Murga, J.; Falomir, E.; Garcia-Fortanet, J.; Carda, M.; Marco, J. A.
Org. Lett. 2002, 4, 3447-3449. (d) Fink, B. E.; Kym, P. R.; Katzenellen-
bogen, J. A. J. Am. Chem. Soc. 1998, 120, 4334-4344.
(8) Shin, Y. Ph.D. Thesis, University of Pittsburgh, 2005.
(9) (a) Fu¨rstner, A. Alkene Metathesis in Organic Synthesis; Springer:
New York, 1998; Vol. 1, pp 37-72. (b) Handbook of Metathesis; Han,
S.-Y., Chang, S., Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003; Vol.
1, pp 5-119 (see especially sections 2.2.2.2, 2.2.6.2 and 2.2.7.1-2.2.7.3
for syntheses of medium and large rings).
380
Org. Lett., Vol. 7, No. 3, 2005

Scheme 2. RCM Model Study
oxidized to the corresponding aldehyde,11 which was im-
DIBAL-induced acetal opening to provide 16. Now, oxida-
tion, Wittig reaction, and deprotection with DDQ16 provide
the key alcohol fragment 17.
Coupling of 17 with acid 18 under Yamaguchi conditions17
provided 19 in 88% yield. Ring-closing metathesis as above
with catalyst I gave lactone 20 in 78% yield. In this case,
the reaction was highly Z-selective, and there was no
spectroscopic or chromatographic evidence for formation of
mediately reacted with Evans (R)-oxazolidinone 11 to
provide diol 12 after reductive removal of the oxazolidinone.
Formation of the cyclic thionocarbonate from 12 with
thiocarbonyl diimidazole (TCDI) followed by selective
Barton-McCombie deoxygenation with Bu3SnH provided
alcohol 13.12
The sequence now follows steps similar to those that were
ultimately used in the successful synthesis of dictyostatin.3
Oxidation of 13 with TPAP and Horner-Wadsworth-
Emmons coupling13 with readily available phosphonate 1414
provided enone 15. 1,4-Reduction of the enone with NiCl2/
NaBH415 followed by 1,2-reduction with NaBH4 provides a
readily separable mixture of alcohols. The major â-epimer
was taken on by silylation with TBSOTf followed by
(14) The phosphonate was prepared from the lactone shown below (Day,
B. W.; Kangani, C. O.; Avor, K. S. Tetrahedron: Asymmetry 2002, 13,
1161-1165) as follows. See the Supporting Information for details.
(11) Toshima, K.; Jyojima, T.; Yamaguchi, H.; Noguchi, Y.; Yoshida,
T.; Murase, H.; Nakata, M.; Matsumura, S. J. Org. Chem. 1997, 62, 3271-
3284.
(15) (a) Satoh, T.; Nanba, K.; Suzuki, S. Chem. Pharm. Bull. 1971, 19,
817-820. (b) Abe, N.; Fujisaki, F.; Sumoto, K.; Miyano, S. Chem. Pharm.
Bull. 1991, 39, 1167-1170.
(12) (a) Barton, D. H. R.; Subramanian, R. J. Chem. Soc., Perkin Trans.
1 1977, 1718-1723. (b) Barton, D. H. R.; McCombie, S. J. Chem. Soc.,
Perkin. Trans. 1 1975, 1574-1585. (c) The enantiomer of this compound
was recently reported: Lautens, M.; Colucci, J. T.; Hiebert, S.; Smith, N.
D.; Bouchain, G. Org. Lett. 2002, 4, 1879-1882.
(16) (a) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett.
1983, 1593-1596. (b) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahe-
dron Lett. 1982, 23, 885-892.
(17) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1995.
(13) Paterson, I.; Yeung, K. S.; Smaill, J. B. Synlett 1993, 774-776.
Org. Lett., Vol. 7, No. 3, 2005
381

the E-isomer. Finally, LAH reduction cleaved the lactone to
provide advanced intermediate 21.
Acknowledgment. We thank the National Institutes of
Health for funding of this work. A.M.B. thanks the German
Academic Exchange Service (DAAD) for a postdoctoral
fellowship. We thank Dr. J.-H. Fournier for helpful discus-
sions.
In the end, the further elaboration of 21 was discontinued
because we learned from parallel studies3 that this would
not lead to dictyostatin (configurations are incorrect at C6
and C14). Nonetheless, the viability of the esterification/
ring-closing metathesis approach stands, and this approach
could potentially be applied to advantage in either the
dictyostatin or discodermolide series. While catalyst loadings
in the key metathesis step need to be reduced before the
approach can be used for scale-up, the strategy appeals
because of its ease and high Z-selectivity. It could provide
a more convenient and reliable approach to C10-C11 bond
construction than the Wittig reaction.
Supporting Information Available: Complete experi-
mental details and compound characterization data, as well
1
as copies of H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
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