Rapid entry into the cryptophycin core via an acyl-beta-lactam macrolactonization: total synthesis of cryptophycin-24.

Article abstract of DOI:10.1021/ol010044s

[see structure]. An efficient, concise approach to the macrolide core of the cryptophycins, potent antimitotic agents, has been achieved. The reaction sequence features a novel macrolactonization utilizing a reactive acyl-beta-lactam intermediate that inc

Full text of DOI:10.1021/ol010044s

ORGANIC
LETTERS
2001
Vol. 3, No. 12
1813-1815
Rapid Entry into the Cryptophycin Core
via an Acyl-â-lactam
Macrolactonization: Total Synthesis of
Cryptophycin-24
MariJean Eggen,† Sajiv K. Nair,† and Gunda I. Georg*
Department of Medicinal Chemistry, UniVersity of Kansas, Lawrence, Kansas 66045
georg@ukans.edu
Received March 7, 2001
ABSTRACT
An efficient, concise approach to the macrolide core of the cryptophycins, potent antimitotic agents, has been achieved. The reaction sequence
features a novel macrolactonization utilizing a reactive acyl-â-lactam intermediate that incorporates the â-amino acid moiety within the 16-
membered macrolide core. This highly modular approach, which allows for multiple alterations throughout the structure, was successfully
applied to the total synthesis of cryptophycin-24.
The cryptophycins are exceptionally potent, novel 16-
membered macrolides isolated from the blue-green algae
Nostoc sp.1 The simplest of the macrolides, cryptophycin-
24 (arenastatin A, 1, Figure 1), was also isolated from the
Okinawan marine sponge Dysidea arenaria.2 The most
abundant component, cryptophycin-1 (2), has demonstrated
both antifungal and antimitotic properties.1a,b In vivo studies
in human tumor xenografts in mice demonstrated remarkable
tumor burden reduction when compound 2 was administered
intravenously.3 A hydrolytically more stable synthetic ana-
logue, cryptophycin-52 (3), is currently in Phase II clinical
trials.4
Microtubules are eukaryotic cellular structures involved
in the movement and positioning of chromosomes during
mitosis as well as the movement of vesicles and organelles
† Current address: Pharmacia Corp., Kalamazoo, MI 49001.
(1) (a) Schwartz, R. E.; Hirsch, C. F.; Sesin, D. F.; Flor, J. E.; Chartrain,
M.; Fromtling, R. E.; Harris, G. H.; Salvatore, M. J.; Liesch, J. M.; Yudin,
K. J. Ind. Microbiol. 1990, 5, 113. (b) Trimurtulu, G.; Ohtani, I.; Patterson,
G. M. L.; Moore, R. E.; Corbett, T. H.; Valeriote, F. A.; Demchik, L. J.
Am. Chem. Soc. 1994, 116, 4729. (c) Subbaraju, G. V.; Golakoti, T.;
Patterson, G. M. L.; Moore, R. E. J. Nat. Prod. 1997, 60, 302.
(2) Kobayashi, M.; Aoki, S.; Ohyabu, N.; Kuroso, M.; Wang, W.;
Kitagawa, I. Tetrahedron Lett. 1994, 35, 7969.
(3) (a) Shih, C.; Gossett, L. S.; Gruber, J. M.; Grossman, C. S.; Andis,
S. L.; Schultz, R. M.; Worzalla, J. F.; Corbett, T. H.; Metz, J. T. Bioorg.
Med. Chem. Lett. 1999, 9, 69. (b) Trimurtulu, G.; Ohtani, I.; Patterson, G.
M. L.; Moore, R. E.; Corbett, T. H.; Valeriote, F. A.; Demchik, L. J. Am.
Chem. Soc. 1994, 116, 4729.
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Papers, 219th National Meeting of the American Chemical Society; San
Francisco, CA; American Chemical Society: Washington, DC, 2000; ORG
291.
Figure 1. Structures of the cryptophycins.
10.1021/ol010044s CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/10/2001

within these cells. The dynamic nature of the equilibrium
between microtubules and tubulin along with their involve-
ment in cell division has made them an important target in
anticancer research.5 Several agents that interact with tubulin,
such as the Vinca alkaloids, colchicine, podophyllotoxin,
maytansine, and the cryptophycins,6 disrupt this equilibrium
in favor of tubulin protein. Cryptophycin’s exceptional
potency has led to studies of other possible modes of action.7
Cryptophycin-1 (2) and -52 (3) stabilize microtubule dynam-
ics at low nanomolar concentrations which exhibit no effect
on the overall concentration of microtubules within the cell
but still lead to apoptosis.7b,8 Cryptophycin-52 (3) was
recently reported to be the most potent agent to cause the
expression of hyperphosphorylated Bcl2, rendering cancer
cells susceptible to apoptosis.4
Our continued interest in the interactions of these com-
pounds with tubulin protein led us to develop a novel, concise
approach toward the synthesis of the macrolide core of the
cryptophycins. Previous research with paclitaxel derivatives
in our laboratory utilized chiral â-lactam precursors as
reactive intermediates for incorporation of the phenylisoserine
side chain.16 Likewise, the presence of the â-amino acid
within the cryptophycin core provided a basis for our
retrosynthetic strategy (Figure 2). The key step would be
The potent bioactivity of the cryptophycins raised interest
in our group and others, leading to numerous reported formal9
and total syntheses.10 Significant structure-activity relation-
ship studies have also been carried out involving both
semisynthetic analogues derived from modifications of the
epoxide11 and synthetic analogues which differ in the tyrosine
fragment,12 â-amino acid moiety,13 or octadienoate ester
fragment14 or contain an isosteric replacement of the C5 ester
with an amide.15
(5) Jordan, A.; Hadfield, J. A.; Lawrence, N. J.; McGown, A. T. Med.
Res. ReV. 1998, 18, 259.
(6) (a) Smith, C. D.; Zhang, X.; Mooberry, S. L.; Patterson, G. M. L.;
Moore, R. E. Cancer Res. 1994, 54, 3779. (b) Kerksiek, K.; Mejillano, M.;
Schwartz, R. E.; Georg, G. I.; Himes, R. FEBS Lett. 1995, 377, 59. (c)
Smith, C. D.; Zhang, X. J. Biol. Chem. 1996, 271, 6192. (d) Bai, R.;
Schwartz, R. E.; Kepler, J. A.; Pettit, G. R.; Hamel, E. Cancer Res. 1996,
56, 4398. (e) Koiso, Y.; Morita, K.; Kobayashi, M.; Wang, W.; Ohyabu,
N.; Iwasaki, S. Chem.-Biol. Interact. 1996, 102, 183.
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Biochemistry 1997, 36, 12048. (c) Kessel, D. J. Chromatogr. B 1999, 735,
121.
Figure 2. Retrosynthetic analysis of cryptophycin-24.
(8) Panda, D.; DeLuca, K.; Williams, D.; Jordan, M. A.; Wilson, L. Proc.
Natl. Acad. Sci. U.S.A. 1998, 95, 9313.
the closure to the macrocycle via an intramolecular reaction17
of the â-hydroxy group in the leucic acid ester component
with the activated acyl â-lactam.
To make the synthesis as concise as possible, the leucic
acid segment was introduced first by esterification of the
secondary alcohol9b 7 with acid chloride 6 derived from bis-
silylated L-leucic acid (Scheme 1).18 The p-methoxybenzyl
ether was deblocked using DDQ to provide the desired
primary alcohol. Oxidation of this alcohol was somewhat
problematic as basic oxidation conditions led to decomposi-
(9) (a) Ali, S. M.; Georg, G. I. Tetrahedron Lett. 1997, 38, 1703. (b)
Eggen, M.; Georg, G. I. Bioorg. Med. Chem. Lett. 1998, 8, 3177. (c)
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A. I.; Zmijewski, M. J. Tetrahedron Lett. 1998, 39, 8405. (e) Liang, J.;
Hoard, D. W.; Khau, V. V.; Martinelli, M. J.; Moher, E. D.; Moore, R. E.;
Tius, M. A. J. Org. Chem. 1999, 64, 1459. (f) Fray, A. H. Tetrahedron:
Asymmetry 1998, 9, 2777.
(10) (a) Barrow, R. A.; Hemscheidt, T.; Liang, J.; Paik, S.; Moore, R.
E.; Tius, M. A. J. Am. Chem. Soc. 1995, 117, 2479. (b) Kobayashi, M.;
Wang, W.; Ohyabu, N.; Kurosu, M.; Kitagawa, I. Chem. Pharm. Bull. 1995,
43, 1598. (c) Salamonczyk, G. M.; Han, K.; Guo, Z.; Sih, C. J. J. Org.
Chem. 1996, 61, 6893. (d) Rej, R.; Nguyen, D.; Go, B.; Fortin, S.; Lavallee,
J.-F. J. Org. Chem. 1996, 61, 6289. (e) de Muys, J.-M.; Rej, R.; Go, B.;
Fortin, S.; Lavallee, J.-F. Bioorg. Med. Chem. Lett. 1996, 6, 1111. (f)
Dhokte, U. P.; Khau, V. V.; Hutchison, D. R.; Martinelli, M. J. Tetrahedron
Lett. 1998, 39, 8771. (g) White, J. D.; Hong, J.; Robarge, L. A. Tetrahedron
Lett. 1998, 39, 8779. (h) Kobayashi, M.; Kuroso, M.; Wang, W.; Kitagawa,
I. Chem. Pharm. Bull. 1994, 42, 2394. (i) White, J. D.; Hong, J.; Robarge,
L. A. J. Org. Chem. 1999, 64, 6206. (j) Gardinier, K. M.; Leahy, J. W. J.
Org. Chem. 1997, 62, 7098. (k) Ghosh, A. K.; Bischoff, A. Org. Lett. 2000,
2, 1573. (l) Christopher, J. A.; Kocienski, P. J.; Kuhl, A.; Bell, R. Synlett
2000, 4, 463. (m) Liang, J.; Moher, E. D.; Moore, R. E.; Hoard, D. W. J.
Org. Chem. 2000, 65, 3143. (n) Eggen, M.; Mossman, C. J.; Buck, S. B.;
Nair, S. K.; Bhat, L.; Ali, S. M.; Reiff, E. A.; Boge, T. C.; Georg, G. I. J.
Org. Chem. 2000, 65, 7792.
(13) Varie, D. L.; Shih, C.; Hay, D. A.; Andis, S. L.; Corbett, T. H.;
Gossett, L. S.; Janisse, S. K.; Martinelli, M. J.; Moher, E. D.; Schultz, R.
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(15) Norman, B. H.; Hemscheidt, T.; Schultz, R. M.; Andis, S. L. J.
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Ther. Pat. 1994, 4, 109 and references therein.
(11) (a) Trimurtulu, G.; Ogino, J.; Heltzel, C. E.; Husebo, T. L.; Jensen,
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(17) For other examples of â-lactam-mediated cyclizations, see: (a)
Romo, D.; Rzasa, R. M.; Shea, H. A.; Park, K.; Langenhan, J. M.; Sun, L.;
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Org. Lett., Vol. 3, No. 12, 2001

homologation under basic conditions once again provided
numerous undesired products with little isolable olefin. Even
the Masamune and Roush conditions (LiCl/DBU),19 which
are normally utilized when substrates or reagents are base
sensitive, failed in this case. Gratifyingly, the neutral
phosphorane 8 produced the desired bond linkage leading
to the ester 11.
Scheme 1
Deprotection of the tert-butyl ester with TFA followed
by coupling with aminoacylazetidinone 9 using HBTU/DIEA
incorporated all the elements necessary for macrocycle
formation. Deprotection of the tert-butyldimethylsilyl ether
with BF3‚Et2O provided the acyl-â-lactam intermediate 5 for
macrolactonization. The key macrolactonization using CH2Cl2-
soluble Bu4NCN17a cleanly provided the 16-membered mac-
rolide 4. The end game involved the attachment of the C3′-
phenyl under Heck conditions and epoxidation utilizing
dimethyldioxirane (DMD) to provide cryptophycin-24 (1).20
In summary, a unique and convergent synthesis of cryp-
tophycin-24 (1) has been developed. The modular approach
allows for multiple alterations throughout the structure by
modification of the amino acyl â-lactam, hydroxy acid, and
C3′-aromatic group. The reaction sequence features a novel
macrolactonization approach utilizing the reactive acyl-â-
lactam for the incorporation of the â-amino acid moiety. The
acyl-â-lactam macrolactonization strategy provides a concise
and efficient entry into the macrocyclic core of this promising
family of antitumor macrolides.
Acknowledgment. We thank the National Institutes of
Health for financial support (RO1 CA 70369). The Depart-
ment of the Army is acknowledged for financial support of
M.E. through a postdoctoral fellowship (DAMD 17-97-1-
7051). S.K.N. thanks the Kansas Health Foundation for a
postdoctoral fellowship.
Supporting Information Available: Experimental pro-
1
cedures, characterization data, and H NMR spectra for
compounds 1, 4, 5, 7, 10-12, and all other intermediates.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL010044S
(19) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(20) For separation of epoxides by RP-HPLC, see ref 10i. Alternatively,
for separation of epoxides using a halohydrin approach see ref 13.
tion and the production of numerous byproducts. However,
the Dess-Martin oxidation cleanly provided the required
aldehyde. Attempts to carry out a standard Horner-Emmons
Org. Lett., Vol. 3, No. 12, 2001
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