Total synthesis of phorboxazole A

Full text of DOI:10.1021/ja980621g

J. Am. Chem. Soc. 1998, 120, 5597-5598
5597
assembly, as well as opportunities for the facile construction of
structural variants to probe the biological roles of specific
functionalities and architectural features of the phorboxazoles.
The carboxylic acid required for formation of the C16-C18
oxazole was obtained from the C18-C30 intermediate 27 by
sequential silylation of the C24 hydroxyl group and saponification
of the methyl ester (Scheme 1). The methylene-linked bis-oxane
half (C3-C17) of the macrolide was readied for coupling by
selective monodesilylation of the bis-silyl ether 46 to give vicinal
amino alcohol 5. Oxazole formation was then initiated by EDCI-
mediated coupling9 of 3 and 5 to yield hydroxy amide 6.
Application of Wipf’s improved procedure10 for 2,4-disubstituted
oxazole formation via cyclodehydration of an amide aldehyde11
involved oxidation of 6 with Dess-Martin periodinane12 followed
by bromooxazoline formation and elimination, which provided
oxazole 7 cleanly. Installation of the (Z)-acrylate linking the C24
hydroxyl to C3 was preceded by selective removal of the C24
triethylsilyl group of 7 to give secondary alcohol 8. The liberated
hydroxyl was acylated first with diethylphosphonoacetic acid to
give 9, which was then treated with 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone13 to cleave the C3 PMB ether selectively and
afford primary alcohol 11. Oxidation with Dess-Martin perio-
dinane gave the corresponding C24-diethylphosphonoacetate, C3-
aldehyde 13. Rapid cyclization of 13 occurred under Masamune-
Roush conditions (LiCl, Et3N, CH3CN)14 to give predominately
the (2E)-acrylate, (E)-15. Preliminary attempts to isomerize (E)-
15 to (Z)-15 were unrewarding. Alternatively, treatment of 13
with K2CO3 and 18-crown-6 in toluene15 gave a 4:1 ratio of (Z)-
15:(E)-15, respectively, but a prolonged reaction time was required
for substantial conversion at room temperature. A logical attempt
to improve the (Z)-stereoselectivity15 and rate of the cyclization
involved acylation of 8 with bis-(2,2,2-trifluoroethyl)phos-
phonoacetic acid to provide the corresponding acetate 10.
Conversion of 10 into aldehyde 14, followed by intramolecular
Horner-Emmons coupling again using Still’s conditions (K2CO3,
18-crown-6, toluene, -40 to -5 °C, 5 h)15 markedly enhanced
the rate of cyclization, but resulted in the same 4:1 ratio of (Z)-
15:(E)-15, respectively. Without further optimization or chro-
matographic separation, the acetonide protecting group was
removed from the isomeric mixture of (E,Z)-15. This facilitated
separation of the alkene isomers to give the primary alcohol (Z)-
16 as a crystalline solid. Gratifyingly, X-ray crystallographic
analysis of 16 confirmed that its stereochemistry2 and conforma-
tion1 are the same as those reported for the C1-C28 portion of
1.16
Total Synthesis of Phorboxazole A
Craig J. Forsyth,* Feryan Ahmed, Russell D. Cink, and
Chi Sing Lee
Department of Chemistry, UniVersity of Minnesota
Minneapolis, Minnesota 55455
ReceiVed February 24, 1998
Phorboxazole A (1) and its C13 epimer phorboxazole B are
remarkable natural products isolated recently from an Indian
Ocean sponge Phorbas sp.1 Complete structural assignments for
phorboxazoles A and B have resulted from extensive NMR,
derivatization, and degradation-correlation studies.1-3 Their
complex and unique structures distinguish the phorboxazoles as
a new class of natural products that contain an unprecedented
array of oxane, oxazole, macrolide, and polyene moieties. In
addition, phorboxazoles A and B have also been selected by the
National Cancer Institute for in vivo antitumor trials2 due to the
extraordinary levels of cytostatic activity displayed by 1 against
a broad range of human cancer cell lines.1-3 In contrast to known
potent anti-mitotic natural products, 1 appears to halt progression
of the cell cycle during the S phase,3 although the cellular mode
of action has apparently not been elucidated. Their novel
structures, intriguing biological activity, and limited availability4
combine to make the phorboxazoles compelling and important
targets of total synthesis.5-8 Reported here is a convergent total
synthesis of 1 that culminates our recent work in this area.5-7
Strategic disconnections at both of the oxazoles and the acrylate
moiety of 1 suggested assembly of the natural product from three
fragments, representing carbons 3-17, 18-30, and 31-46.
Complementary vicinal amino alcohol and carboxylic acid
partners were identified as logical precursors to the two oxazoles.
It was anticipated that an intramolecular Horner-Emmons
reaction between a C3 aldehyde and a C24 phosphonoacetate
could be relied upon to simultaneously install the C1-C3 (Z)-
acrylate moiety and close the C1-C24 macrolide. Further, it was
of interest to explore the effects of macrocyclic conformational
constraints on the stereoselectivity of acrylate formation in this
manner. Thus, a tricomponent coupling approach was adopted
wherein the macrolide domain would be assembled first via
sequential formation of the C16-C18 oxazole and bridging
acrylate moieties from two halves (C3-C176 and C18-C307),
and the C31-C465 fragment would subsequently be attached by
formation of the C29-C31 oxazole. Each of the three key
fragments has been synthesized in appropriately functionalized
form, as previously reported.5-7 Merits of this convergent
synthetic design include the potential for a concise and rapid
Final attachment of the C31-C46 fragment necessitated
removal of the t-Boc group from 16, which could be accomplished
selectively by brief treatment of 16 with 4 N HCl in dioxane.
EDCI-mediated coupling9 of the free amine liberated in situ from
17 with the C31-C46 carboxylic acid (19) derived from ester
185 (Scheme 2) gave hydroxy amide 20. In contrast to the
previous smooth formation of the C16-C18 oxazole via a
stepwise oxidation-cyclodehydration process,10 similar conver-
(9) Sheehan, J. C.; Cruickshank, P. A.; Boshart, G. L. J. Org. Chem. 1961,
26, 2525.
(10) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558.
(11) Sen, P. K.; Veal, C. J.; Young, D. W. J. Chem. Soc., Perkin Trans. 1
1981, 3503.
(12) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(13) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
(14) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune,
S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(15) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4495.
(16) The X-ray analysis of 16 was performed by Dr. Victor Young of the
University of Minnesota Chemistry Department. The use of (S)-serine as the
source of the C29 stereogenic center defines the absolute stereochemistry of
16, and the 1H and 13C NMR spectral data for 16 match well those of the
corresponding domain of the natural product.1 See the Supporting Information.
(1) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126.
(2) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W. J. Am.
Chem. Soc. 1996, 118, 9422.
(3) Molinski, T. F. Tetrahedron Lett. 1996, 37, 7879.
(4) Samples of 1 derived from natural sources are presently scarce. Prof.
T. F. Molinski, personal communication, 1997.
(5) Ahmed, F.; Forsyth, C. J. Tetrahedron Lett. 1998, 39, 183.
(6) Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1997, 62, 5672.
(7) Lee, C. S.; Forsyth, C. J. Tetrahedron Lett. 1996, 37, 6449.
(8) Tao, Y.; Pattenden, G. Tetrahedron Lett. 1998, 39, 319.
S0002-7863(98)00621-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/21/1998

5598 J. Am. Chem. Soc., Vol. 120, No. 22, 1998
Communications to the Editor
Scheme 1
Scheme 2
to cleave both the silyl ethers and the mixed methyl acetal to
deliver 1.18 Phorboxazole A was thus prepared in only 5 steps
from carboxylic acid 19 and amino alcohol 17 and in ca. 34 steps
in the longest linear sequence beginning with the synthesis of
the C3-C17 intermediate 4.6
This total synthesis represents an alternative source of 1 and
should be amenable to the generation of structural variants of
phorboxazole A. It relies upon the facile preparation and use of
highly functionalized building blocks,5-7 generally dependable
methods for their coupling,9,10 a late stage, stereoselective15
installation of the (Z)-acrylate, and judicious protecting group
deployment. Finally, this work corroborates the structural as-
signments made for 11-3 and provides an atomic-level definition
of the phorboxazole macrolide conformation via the X-ray analysis
of intermediate 16. The latter may prove useful in guiding the
rational design of phorboxazole analogues and in studying
potential receptor-ligand interactions.
Acknowledgment. Financial support from the NIH (R01-GM55756),
a University of Minnesota McKnight Land-Grant Professorship, and a
1997 Zeneca Pharmaceuticals Excellence in Chemistry Award is gratefully
acknowledged (C.J.F.). We thank Drs. Ed Larka and Victor Young of
the University of Minnesota Chemistry Department for mass spectrometric
and X-ray crystallographic analyses, respectively. We also thank Prof.
T. F. Molinski (U.C. Davis) for providing comparison 1H NMR spectral
data of naturally occurring 1.
Supporting Information Available: Experimental procedures for
compounds 1, 3, 5-8, 10, 12, and 14-21; physical and spectral data for
1
compounds 1-3, 5-8, 10, 12, 14-16, and 18-21; photocopies of H
NMR spectra for compounds 1, 5-8, 10, 12, 14-16, and 18-21;
photocopies of 13C NMR spectra for compounds 5-8, 10, 12, 16, 18,
and 19; and X-ray crystallographic data for 16 (59 pages, print/PDF).
See any current masthead page for ordering information and Web access
instructions.
sion of 20 into the C29-C31 oxazole 21 has proven, thus far, to
be only modest yielding. However, the separate C1-C30 (17)
and C31-C46 (19) domains of 1 were advanced to an intermedi-
ate (21) representing the trihydroxyl-protected form of 1 in only
three steps. The TBDPS ether at C13 resisted initial attempts to
remove cleanly all three protecting groups from 21 in one
additional step using aqueous HF.17 However, sequential treat-
ment of 21 with TBAF/EtOAc and 6% aqueous HCl/THF sufficed
JA980621G
(17) Newton, R. F.; Reynolds, D. P. Tetrahedron Lett. 1979, 41, 3981.
1
(18) The H NMR (500 MHz, CDCl3), HRMS (MALDI), and IR data of
synthetic 1 match those recorded for the natural product;1 see the Supporting
Information for full experimental details and characterization data.