Asymmetric synthesis of a C1-C19 fragment of ulapualide A

Article abstract of DOI:10.1016/S0040-4039(02)01553-8

The stereocontrolled synthesis of a C1-C19 fragment of ulapualide A has been accomplished. The C3 hydroxyl-bearing stereocenter was established by Jacobsen's hydrolytic kinetic resolution (HKR) of a terminal epoxide, while the C9 methyl stereocenter was i

Full text of DOI:10.1016/S0040-4039(02)01553-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7043–7046
Asymmetric synthesis of a C1ꢀC19 fragment of ulapualide A
Cassandra A. Celatka† and James S. Panek‡*
Department of Chemistry and Center for Streamlined Synthesis, Metcalf Center for Science and Engineering, Boston University,
590 Commonwealth Avenue, Boston, MA 02215, USA
Received 27 June 2002; revised 18 July 2002; accepted 26 July 2002
Abstract—The stereocontrolled synthesis of a C1–C19 fragment of ulapualide A has been accomplished. The C3 hydroxyl-bearing
stereocenter was established by Jacobsen’s hydrolytic kinetic resolution (HKR) of a terminal epoxide, while the C9 methyl
stereocenter was introduced through an asymmetric crotylation using chiral organosilane (S)-7. Union of the C1ꢀC6 and the
C7ꢀC19 fragments by a Kishi–Nozaki coupling, followed by oxidation and conjugate addition of hydride completed the
preparation of the fragment. © 2002 Elsevier Science Ltd. All rights reserved.
Ulapualide A (1), first isolated from the red eggmasses
of the nudibranch Hexabranchus sanguineus, belongs to
a unique family of tris-oxazole containing marine
metabolites (Fig. 1).1 Other members of this family
include mycalolides,2 kabiramides,3 halichondramides,4
jaspisamides,5 and halishigamides.6 The ulapualides
exhibit inhibitory activity against L1210 leukemia cell
proliferation and also display ichthyotoxic and antifun-
gal properties. Complex natural products constitute
interesting targets for asymmetric synthesis, particularly
when new or improved methods are developed and
used to assign the relative and absolute stereochemistry.
In that context, the stereochemistry of the C20ꢀC35
subunit has been assigned through extensive degrada-
tion, synthetic, and spectroscopic studies and was
shown to be identical to the mycalolides.7,8 The abso-
lute stereochemistry of the C3-hydroxyl bearing
stereocenter9 and the C9-methyl bearing stereocenter10
of the ulapualides has not been unambiguously
assigned through experimental methods. Herein, we
report the synthesis of an advanced intermediate 2 of
ulapualide A,11 which constitutes the tris-oxazole linked
to the C1ꢀC9 tether.
In considering a retrosynthesis of ulapualide A 1, the
initial bond disconnection lead to a C1ꢀC19 tris-oxa-
zole subunit 2 and a C20ꢀC35 polypropionate derived
subunit 3 (Fig. 1).12 Further bond disconnection at
C6ꢀC7 provided two subunits, each containing one
stereocenter. The C3 stereocenter was established by
Jacobsen’s hydrolytic kinetic resolution (HKR) of a
terminal epoxide13 and the C9 stereocenter was intro-
Figure 1. Retrosynthetic analysis of ulapualide A.
Keywords: marine metabolites; tris-oxazole; ulapualide A.
* Corresponding author. Tel: (617) 353-2484; fax: (617) 353-6466; e-mail: panek@chem.bu.edu
† Current address: Suntory Pharmaceutical Research Laboratories LLC, One Kendall Square, Building 1400W, Cambridge, MA 02139, USA.
‡ Recipient of a 2002 Cope Scholar Award.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01553-8

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C. A. Celatka, J. S. Panek / Tetrahedron Letters 43 (2002) 7043–7046
duced through an asymmetric crotylation using a chiral
organosilane reagent.14 To accomplish the selective
deprotection of the fragment in late stages of the synthe-
sis, the C3-hydroxyl group was protected as its tert-
butyldiphenylsilyl ether and the C19 primary hydroxyl
was protected as a methoxymethyl ether.
Introduction of the third oxazole ring was accom-
plished through the oxidation, cyclization, dehydro-
halogenation protocol developed by Wipf.20 This
sequence was initiated with peptide coupling of the
secondary amine 12 and the bis-oxazole carboxylic acid
13 using DCC and HOBT in DMF to afford the
amide–oxazole 14 in 68% yield. The benzoate group
was hydrolyzed in the presence of K2CO3 in MeOH in
quantitative yield, and the resultant alcohol oxidized to
its aldehyde with Dess–Martin periodinane, readying
the fragment for cyclization.21 Treatment with
dibromotetrachloroethane, triphenylphosphine, and
2,6-lutidine gave the 5-bromo-oxazoline, which is
directly dehydrohalogenated with DBU in 90% yield to
provide the tris-oxazole 15. Removal of the tert-
butyldiphenylsilyl ether was effected with AcOH
buffered TBAF in 92% yield. Oxidation of the primary
alcohol to the corresponding aldehyde 16 with Dess–
Martin periodinane in 98% yield provided the C7ꢀC19
fragment.
Synthesis of the C1ꢀC6 subunit 4 was initiated by HKR
of the readily available racemic epoxide 515 with (R,R)-
Salen–Co complex to provide the (R)-epoxide 5 in 94%
yield and 99% ee (Scheme 1).16 Addition of vinylmagne-
sium bromide in the presence of catalytic copper(I) iodide
lead to epoxide ring opening and provided the secondary
alcohol in 76% yield. The resultant C3-hydroxyl was then
protected as its tert-butyldimethylsilyl ether 6 in 98%
yield. Oxidative cleavage of the terminal olefin with
ozone followed by Takai iodo-olefination provided the
C1ꢀC6 fragment 4 as a 5:1 mixture of isomers in 76%
yield (two steps.)17 This subunit is obtained in four steps
and 57% overall yield from the chiral epoxide (R)-5.
The C9 methyl-bearing stereocenter and the nitrogen of
the third oxazole ring were introduced through a
BF3·OEt2 promoted addition of (S)-silane 7 to an in situ
generated tert-butyl-N-acyliminium ion of a-benzyloxy-
acetaldehyde 8 (Scheme 2).18 This three component
crotylation proceeds in 73% yield and affords the syn-
homoallylic carbamate 9 with a dr >30:1. Oxidative
cleavage of the trans-olefin with ozone and homologa-
tion with the ylide of triphenylphosphonium methyl
bromide provided the terminal olefin 10 in 64% yield (two
steps). Subsequent hydroboration (9-BBN-H2O2)
afforded the primary alcohol in 84% yield, which was
protected as its tert-butyldiphenylsilyl ether 11 in 98%
yield. Removal of the benzyl protecting group with BCl3
in 82% yield was followed by protection as a benzoate
in 94% yield, which proved necessary as the benzyl ether
was difficult to remove from bis-oxazole 14. Finally,
treatment with TFA in CH2Cl2 provided the secondary
amine fragment 12, suitable for coupling with the bis-
oxazole fragment 13, whose preparation has been previ-
ously described using modified-Hantzsch methodology.19
The intermediate secondary amine was obtained in eight
steps in 30% overall yield.
Coupling of the C1ꢀC6 4 and C7ꢀC19 16 subunits by a
Kishi–Nozaki coupling with CrCl2/NiCl2 in THF/
DMSO afforded the C1ꢀC19 fragment 17 in 78% yield
as a 1:1 mixture of diastereomers.22 Treatment with
Dess–Martin periodinane provided the enone 18 in
>99% yield. The synthesis was completed by conjugate
addition of hydride to the enone using CuCl, PPh3,
TBAF, PhMe2SiH.23 This reaction proceeded in quanti-
tative yield, affording the fully protected C1ꢀC19 frag-
ment 2.
In summary, an advanced C1ꢀC19 fragment of ula-
pualide A was synthesized in 17 steps from 8 in 13%
overall yield. The C3-hydroxyl bearing stereocenter was
installed using Jacobsen’s HKR methodology while the
C9-methyl bearing stereocenter was introduced through
use of chiral (E)-crotylsilane bond construction
methodology. The completion of the synthesis and
stereochemical assignment of ulapualide A is currently
underway in our laboratory and will be reported in due
course.
Scheme 1. Synthesis of the C1ꢀC6 subunit.

C. A. Celatka, J. S. Panek / Tetrahedron Letters 43 (2002) 7043–7046
7045
Scheme 2. Synthesis of the C1ꢀC19 fragment.
Acknowledgements
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moto, K. Tetrahedron Lett. 1989, 30, 2809–2812; (b)
Rashid, M. A.; Gustafson, K. R.; Cardellina, J. H., II;
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Matsunaga, S.; Sugawara, T.; Fusetani, N. J. Nat. Prod.
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This work was financially supported by the NIH-NCI
(RO156304). The authors are grateful to Dr. Ping Liu
and Professor John D. Faulkner (TSRI) for helpful
discussions.
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