Studies directed toward the synthesis of ulapualide A. Asymmetric synthesis of the C26-C42 fragment

Full text of DOI:10.1021/jo960531z

6494
J . Org. Chem. 1996, 61, 6494-6495
Stu d ies Dir ected tow a r d th e Syn th esis of
Ula p u a lid e A. Asym m etr ic Syn th esis of th e
C26-C42 F r a gm en t
J ames S. Panek,* Richard T. Beresis,† and
Cassandra A. Celatka
Department of Chemistry, Metcalf Center for Science and
Engineering, 590 Commonwealth Avenue, Boston
University, Boston, Massachusetts 02215
Received March 20, 1996
Ulapualide A belongs to an emerging class of secondary
metabolites, first isolated from the egg masses of marine
nudibranches (sea slugs).1 Subsequent reports identified
structurally related members possessing a tris-oxazole
fragment, which include the halichondramides,2 my-
calolides,3 and kabiramides.4 Ulapualide A exhibits
inhibitory activity against L1210 leukemia cell prolifera-
tion and antifungal activity. Although the relative and
absolute stereochemical relationships of the ulapualides
have not been established, structural similarities be-
tween these macrolides provide circumstantial evidence
for a common stereochemical assignment. The stereo-
chemistry is based on a correlation with related marine
natural products, scytophycin C,5 whose stereostructure
has been determined by X-ray crystallography, and by
NMR analysis of kabiramide C.6 Molecular modeling
studies reported by Pattenden are consistent with the
illustrated stereochemistry and support the notion of a
common absolute stereochemistry.7 This prediction has
not been confirmed experimentally. It should be noted
that there is an apparent discrepancy in the ulapualide
stereochemical relationships originating from the assign-
ment of the C34 methyl group of scytophycin and kabi-
ramide C. To address this issue we have incorporated
into our synthesis a set of double stereodifferentiating
crotylation reactions capable of providing either a syn-
or anti-bond construction across C33-C34.
F igu r e 1.
Sch em e 1
As a result of their complex stereostructure and diverse
architecture these macrolides provide challenges to the
organic chemist.8 Herein we wish to report the asym-
metric synthesis of the C26-C42 fragment, and in the
accompanying communication we describe the prepara-
tion of the C8-C25 tris-oxazole fragment.
It was our intention to design a convergent route using
our chiral allylsilane bond construction methodology9 for
the introduction of the stereochemical relationships. The
synthesis would be adaptable with regard to the order
of fragment coupling. The first disconnection at the
C25-C26 and C7-C8 bonds and cleavage of the C1-ester
linkage produced three principal fragments including the
aliphatic and tris-oxazole portions (Figure 1). Further
disconnection of the C35-C36 bond produces two smaller
subunits which served as our initial subgoals.
C36-C42 Su bu n it. The preparation of this subunit
relied on the installation of three contiguous stereo-
centers through a chelation-controlled condensation of a
â-methyl-substituted (E)-crotylsilane with (R)-3-(benzyl-
oxy)-2-methylpropanal, followed by a one-carbon homolo-
gation of the benzyloxy terminus and cleavage of the
trisubstituted olefin to give the protected methyl ketone
equivalent. The synthesis was initiated with a Lewis
acid-promoted condensation of silane (S)-110 with alde-
hyde 2 (Scheme 1). In the presence of TiCl4 (1.2 equiv)
this anti-selective crotylsilation (15:1 anti/ syn) results
from a matched double stereodifferentiating pairing and
proceeds through a transition state involving a chelated
aldehyde to give the homoallylic alcohol in 76% yield.11
Deprotection of the primary hydroxyl group with BCl3
(2 equiv) in PhMe provided the 1,3-diol 3 in 90% isolated
† Recipient of a Graduate Fellowship from the Organic Chemistry
Division of American Chemical Society 1994-1995, sponsored by the
Upjohn Company.
(1) (a) Roesener, J . A.; Scheuer, P. J . J . Am. Chem. Soc. 1986, 108,
846-847. (b) Matsunaga, S.; Fusetani, N.; Hashimoto, K. J . Am. Chem.
Soc. 1986, 108, 847-849.
(2) (a) Matsunaga, S.; Fusetani, N.; Hashimoto, K.; Koseki, K.;
Noma, M.; Noguchi, H.; Sankawa, U. J . Org. Chem. 1989, 54, 1360-
1363. (b) Kernan, M. R.; Molinski, T. F.; Faulkner, D. J . J . Org. Chem.
1988, 53, 5014-5020.
(3) Fusentani, N.; Yasumuro, K.; Matsunaga, S.; Hashimoto, K.
Tetrahedron Lett. 1989, 30, 2809-2813. The carbon skeleton of ula-
pualide A is numbered according to reference 1a, reporting its isolation.
(4) Matsunaga, S.; Fusetani, N.; Hashimoto, K.; Koseke, K.; Noma,
M. J . Am. Chem. Soc. 1986, 108, 847-849.
(5) Kiefel, M. J .; Maddock, J .; Pattenden, G. Tetrahedron Lett. 1992,
22, 3227-3230.
(6) Fusentani, N.; Matsunaga, S. Personal communication.
(7) Maddock, J .; Pattenden, G.; Wight, P. G. Comput.-Aided Mol.
Des. 1993, 7, 573-575.
(10) For preparation of silane (S)-1 and (S)-15, see supporting
information.
(11) (a) J ain, N. F.; Cirillo, P. F.; Pelletier, R. Tetrahedron Lett. 1995,
36, 8728-8730. (b) Panek, J . S.; Beresis, R. T. J . Org. Chem. 1993,
58, 809-810.
(8) For earlier synthetic studies see (a) Chattopadhyay, S. K.;
Pattenden, G. Tetrahedron Lett. 1995, 36, 5271-5274. (b) Pattenden,
G. J . Heterocycl. Chem. 1992, 29, 607-618.
(9) Masse, C. E.; Panek, J . S. Chem. Rev. 1995, 95, 1293-1316.
S0022-3263(96)00531-2 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 19, 1996 6495
Sch em e 2
yield.12 Acetal formation with (PMBCHO, 1.3 equiv, cat.
p-TsOH) afforded the p-methoxybenzylidene 4 (88%)
which was subjected to nucleophilic opening (DIBAL-H,
5.0 equiv, CH2Cl2 -50 °C, 15 h) giving the primary
alcohol in 100% yield as a single diastereomer. With the
protection of the secondary hydroxyl group, the remain-
ing primary hydroxyl was oxidized under Swern condi-
tions providing aldehyde 5.13 A one-carbon homologation
with (methoxymethyl)triphenylphosphonium ylide re-
sulted in the formation of enol ether 6 (80% yield two-
steps) which was directly converted to the C42 acetal (2,2-
methyl-1,3-propanediol, PPTS, C6H6, ∆) in 90% yield.
This ketalization established a stable carbonyl synthon
for eventual elaboration to the terminal N-formyl enam-
ine. Cleavage of the trisubstituted olefin by ozonolysis
afforded the methyl ketone in 70% yield, which was
converted to the N,N-dimethylhydrazone 7 in 87% yield
through treatment with TMSCl (2.0 equiv) in N,N-
dimethylhydrazine.14 This sequence completed the syn-
thesis of 7 in nine steps, 26% overall yield from (S)-1.
C26-C35 Su bu n it. The synthesis of this subunit
(Scheme 2) relies on three sequential asymmetric crotyl-
and allylation reactions to establish the stereochemical
relationships at syn-C28-C29, anti-C29-C30, and anti-
C33-C34. In accord with previous reports from this
laboratory,15 the synthesis began with the addition of
silane (R)-810 to acetal 9 (BF3‚OEt2, 2.0 equiv, -50 °C)
to afford the syn homoallylic ether that was, without
purification, deprotected (aqueous HF-CH3CN) provid-
ing the primary alcohol 10 (75%, two steps). After
chromatographic removal of the minor diastereomer, the
primary hydroxyl group was protected as the pivalate
ester (PivCl, 2.0 equiv, CH2Cl2-pyridine 3:2) which gave
11 in 93% yield. Cleavage of the (E)-olefin with ozone
yielded the aldehyde 12 in quantitative yield which was
subjected to a chelate-controlled16 allylsilane addition
(TiCl4, 1.2 equiv, -80 °C, CH2Cl2) affording the homoal-
lylic alcohol 13 (78%). Protection of the secondary alcohol
(TBSOTf, 1.5 equiv, 2,6-lutidine, 3.0 equiv, 0 °C) followed
by oxidative cleavage (O3, SMe2) gave 14 in 89% yield
(two steps). At this stage the C26-C33 synthon of this
subunit is prepared for a second crotylation reaction to
install the final two stereocenters. Accordingly, silane
(S)-1510 (2.0 equiv) condensed with 14 in the presence of
TiCl4 (1.2 equiv, -80 °C, 15 h) to provide the homoallylic
alcohol 16 in 83% yield. The useful level of diastereose-
lection (5.5:1 anti/syn) in this reaction is consistent with
a nonchelation-controlled, partially mismatched process
which exhibits 1,3-induction.17 In this case, the stereo-
chemical bias of the aldehyde overrides the normal syn
preference of the (E)-silane reagent.11a
Methylation of 16 with Me3OBF4 (6.0 equiv) and proton
sponge (6.0 equiv) gave the homoallylic ether 17 in 85%
yield. Cleavage of the trans olefin under ozonolysis
conditions was immediately followed by reduction of the
crude aldehyde with NaBH4 (2.0 equiv) to give the
primary alcohol 18 in 80% yield. The synthesis of C26-
C35 subunit 19 was achieved in a 10-step sequence with
an overall yield of 24% by iodination (97%) utilizing
(PhO)3PMeI (1.2 equiv) in DMF at 0 °C.18
C26-C42 F r a gm en t. This fragment was prepared by
coupling of the hydrazone-derived methyl ketone enolate
7 to the C26-C35 subunit 19 by displacement of the
primary iodide. Hydrazone 7 was lithiated (LDA, 1.3
equiv, HMPA, 1.5 equiv, THF, 0 °C, 30 min) before the
addition of iodide 19 (1.5 equiv). The reaction was
maintained at 0 °C for 48 h to yield the C26-C42
segment 22 in 62% isolated yield (84% yield based on
recovered hydrazone). The hydrazone was oxidatively
removed with NaIO4 affording the ketone. The synthesis
of the C26-C42 fragment of ulapualide A was ac-
complished using chiral allylsilane bond construction
methodology for the introduction of the stereochemical
relationships. In the following paper, the synthesis of
the tris-oxazole fragment is described.
(12) Satisfactory spectroscopic data (1H and 13C NMR, IR, CIMS,
CIHRMS) were obtained for all new compounds. Ratios of diastereo-
mers were determined by 1H-NMR.
(13) Mancuso, A. J .; Huang, S.; Swern, D. J . Org. Chem. 1978, 43,
2480-2482.
(14) Evans, D. A.; Bender, S. L.; Morris, J . J . Am. Chem. Soc. 1988,
110, 2506-2526.
(15) Panek, J . S.; Yang, M. J . Org. Chem. 1991, 56, 5755-5788.
(16) Chelation-controlled carbonyl additions see Reetz, M. T. Acc.
Chem. Res. 1993, 26, 462-468.
(17) Massamune, S.; Choy, W.; Petersen, J . S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1-31.
Ack n ow led gm en t. We are grateful to Professors D.
J . Faulkner and N. Fusetani for helpful discussions. Fi-
nancial support was obtained from NIH (RO1 CA56304).
(18) Aldehyde 14 was condensed with silane (R)-15 under similar con-
ditions, to afford 20 in 84% yield and excellent syn diastereoselection.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures and stereochemical proofs as well as spectral
data for all intermediates and final products (15 pages).
J O960531Z