Communications
J . Org. Chem., Vol. 61, No. 19, 1996 6497
Sch em e 3
diol was subjected to oxidative cleavage using Pb(OAc)4
(1.2 equiv), affording the corresponding aldehyde 8 in
84% yield which was subsequently reduced with NaBH4
(2.0 equiv, EtOH) to give the primary alcohol in 87%
yield. This alcohol was protected as the MOM ether (1:1
DMM/CHCl3, P2O5) completing the construction of first
oxazole unit (A-ring) 9 differentiated at the 2 and 4
positions. Conversion of the ethyl ester to the amide with
aqueous NH4OH afforded the amido-oxazole 10 and
established the template for the construction of the
second oxazole ring. The synthesis of the bis-oxazole
subunit was carried out in 60% yield by subjecting the
amide to the Hantzsch conditions as described above with
recovery of starting amide. Hydrolysis of the ester by
treatment with (LiOH, THF/H2O) resulted in quantita-
tive conversion to the bis-oxazole carboxylic acid 11.
With the bis-oxazole 11 and chiral subunit 5 in hand,
an efficient amide coupling and oxidation/cyclodehydra-
tion protocol was developed to complete the synthesis of
the tris-oxazole fragment. Treatment of a solution of the
carboxylic acid 11 with the chiral secondary amine 5
under standard amide coupling conditions DCC (1.1
equiv) and HOBT (0.1 equiv, DMF, rt) cleanly afforded
the â-benzyloxy amide (68%) which was subjected to
hydrogenolysis (H2, 10% Pd-C, EtOH) to remove the
benzyl ether protecting group (87% yield). This series
of transformations gave the fully functionalized bis-
oxazole 12 bearing the C9-methyl stereocenter which was
now set for final conversion to the tris-oxazole fragment.
This two-step oxidation/cyclodehydration sequence was
completed through the intermediary bromo-oxazoline
employing similar conditions previously described by
Wipf.10 Treatment of a solution of the â-hydroxy amide
12, in CH2Cl2, with Dess-Martin periodinane11 (3.0
equiv) resulted in the oxidation to the aldehyde that was
directly cyclized to the oxazole. This aldehyde was
converted to the bromooxazoline with BrCl2CCCl2Br (5.0
equiv), and PPh3 (5.0 equiv), 2,6-di-tert-butylpyridine
(25.0 equiv) and without purification was dehydrohalo-
genated (DBU, 25.0 equiv; MeCN, rt), completing the
formation of the tris-oxazole 1a in 92% yield.
fragment-containing methyl stereocenter, which was
installed into the third oxazole as its side chain, and
illustrates the versatility of chiral silane methodology for
the construction small of chiral amine fragments.
The preparation of the bis-oxazole fragment 11, cou-
pling to the chiral amine 5, and completion of the
synthesis of chiral tris-oxazole fragment is summarized
in Scheme 3. The synthesis of the bis-oxazole fragment
began with the use of a modified Hantzsch synthesis.8
Reaction of trans-cinnamamide with R-bromo ethyl pyru-
vate (2.2 equiv) using NaHCO3-buffered conditions, fol-
lowed by cyclodehydration (TFAA/THF, 1:1 v/v), afforded
the functionalized oxazole 7 in 83% yield. It was our
intention to utilize the trans double bond as an inter-
changeable functional group that would allow the intro-
duction of a suitably modified side chain of the tris-
oxazole for eventual coupling through a phosphorus-
based olefination. The successful use of this intermediate
in the synthesis required a selective oxidative cleavage
of the trans-disubstituted double bond. Since it is known
that the oxazole ring is sensitive to ozone,5a this trans-
formation was accomplished via a two-step process,
employing dihydroxylation with catalytic OsO4, (10 mol
%) and TMANO (1.5 equiv) in 85% yield.9 The purified
In summary, the first asymmetric synthesis of a
suitably functionalized tris-oxazole fragment, identical
to those of the ulapualides and with general application
to the entire class of natural products, was accomplished
in a convergent manner using 11 steps in 12% overall
yield. An iterative Hantzsch-oxazole protocol was devel-
oped for the synthesis of the bis-oxazole subunit, while
a new application of our chiral silane bond construction
methodology was employed for the asymmetric synthesis
of the chiral amine subunit. This chemistry played a key
role in the synthesis of the third oxazole ring containing
the methyl-bearing side chain. The coupling of the C26-
C42 fragment described in the preceding paper to the tris-
oxazole fragment and completion of the synthesis of
ulapualide A will be reported at a later time.
Ack n ow led gm en t. We are grateful to Professor
Peter Wipf, D. J . Faulkner, and N. Fusetani for helpful
discussions. Financial support was obtained from the
NIH (RO1 CA56304).
(8) The condensation of amide and R-halo ketone under Hantzsh
conditions is typically driven either by heat or pressure, or through a
buffer in order to remove generated acidic HX series. After surveying
numerous reaction conditions involving changes in solvent (EtOH, CH2-
Cl2, THF, DME, acetone, CH3CN, and toluene) and buffer (K2CO3,
CaCO3, NaHCO3, Ag2CO3, and isoprene), the protocol was eventually
optimized with ethyl bromopyruvate (1.3 equiv) and NaHCO3 (5.0
equiv), in refluxing THF for 15 h followed by a second charge with
ethyl bromopyruvate and an additional 8 h reflux period. Following
filtration of solids and concentration under reduced pressure, the crude
hydroxyoxazole was quantitatively converted to the oxazole through
treatment with TFAA in THF at 0 °C.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures and spectral data for all intermediates and final
product (7 pages).
J O960532R
(9) VanRheenen, V.; Kelley, R. C.; Cha, D. J . Org. Chem. 1978, 43,
2480-2482.
(10) Wipf, P.; Lim, S. J . Am. Chem. Soc. 1995, 117, 558-559.
(11) (a) Dess, D. B.; Martin, J. C. J . Am. Chem. Soc. 1991, 113, 7277-
7287. (b) Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899-2900.