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