Synthesis of the C(1)-C(25) fragment of amphidinol 3: Application of the double-allylboration reaction for synthesis of 1,5-diols

Article abstract of DOI:10.1021/ol050250q

(Chemical Equation Presented) A synthesis of the C(1)-C(25) fragment of amphidinol 3 is described. The synthesis features two applications of double allylboration reaction methodology for the highly stereoselective synthesis of 1,5-diol units in the C(1)-

Full text of DOI:10.1021/ol050250q

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1411-1414
Synthesis of the C(1)−C(25) Fragment of
Amphidinol 3: Application of the
Double-Allylboration Reaction for
Synthesis of 1,5-Diols
Eric M. Flamme and William R. Roush*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109-1055
roush@umich.edu
Received February 5, 2005
ABSTRACT
A synthesis of the C(1)−C(25) fragment of amphidinol 3 is described. The synthesis features two applications of double allylboration reaction
methodology for the highly stereoselective synthesis of 1,5-diol units in the C(1)
−C(15) segment.
The amphidinols are a class of polyketide natural products
isolated from toxic phytoplanktons contained within the
waters surrounding the coasts of Japan.1-5 These polyhy-
droxylated marine natural products possess antifungal,
hemolytic, cytotoxic, and ichthyotoxic activities.2,3 Amphi-
dinol 3 (AM 3), isolated in 1996 from cultures of the marine
dinoflagellate Amphidinium klebsii, is reported to have the
greatest antifungal and hemolytic activity of the eight
amphidinols isolated to date.6 AM 3 contains a 67-carbon
atom backbone and 25 stereocenters, along with two highly
oxygenated tetrahydropyrans and an uncommon structural
motif consisting of a series of 1,5-diols within its C2-C15
polyol chain (Scheme 1).3,7
The promising biological activity and complex molecular
architecture make AM 3 an interesting and challenging target
for total synthesis. BouzBouz and Cossy have reported a
synthesis of the C(1)-C(14) fragment of AM 3 using
enantioselective allylation reactions of aldehydes promoted
by a chiral allyltitaium reagent coupled with chemoselective
olefin cross-metathesis.8 We report herein an efficient and
convergent synthesis of the C(1)-C(25) fragment of AM 3
utilizing a newly developed method from our laboratory for
the synthesis of secondary 1,5-diols.9
The C(1)-C(14) fragment of AM 3 contains three stere-
ochemically and structurally distinct 1,5-diol units. The one-
pot double allylboration methodology that we introduced in
2002 for the enantio- and diastereoselective synthesis of 1,5-
diols seemed to be an ideal method for synthesis of the C(1)-
C(14) fragment.9 Accordingly, we targeted aldehydes 2 and
3 as key intermediates for a fragment coupling sequence via
a double allylboration reaction (Scheme 1). Aldehyde 2 also
contains a 1,5-diol subunit which can be prepared via a
double allylboration reaction.
(1) Houdai, T.; Matsuoka, S.; Murata, M.; Satake, M.; Ota, S.; Oshima,
Y.; Rhodes, L. L. Tetrahedron 2001, 57, 5551.
(2) Paul, G. K.; Matsumori, N.; Konoki, K.; Murata, M.; Tachibana, K.
J. Mar. Biotech. 1997, 5, 124.
(3) Paul, G. K.; Matsumori, N.; Nonoki, K.; Sasaki, M.; Murata, M.;
Tachibana, K. In Harmful and Toxic Algal Blooms. Proceedings of the
SeVenth International Conference on Toxic Phytoplankton; Yasumoto, T.,
Oshima, Y., Fukuyo, Y., Eds.; UNESCO: Sendai, Japan, 1996; p 503.
(4) Paul, G. K.; Matsumori, N.; Murata, M.; Tachibana, K. Tetrahedron
1995, 36, 6279.
(7) For assignment of absolute stereochemistry: Murata, M.; Matsuoka,
S.; Matsumori, N.; Paul, G. K.; Tachibana, K. J. Am. Chem. Soc. 1999,
121, 870.
(5) Satake, M.; Murata, M.; Yasumoto, T.; Fujita, T.; Naoki, H. J. Am.
Chem. Soc. 1991, 113, 9859.
(6) AM 3 is reported to be several times more potent in vitro than the
commercial anti-fungal agent amphotericin-B; see ref 3.
(8) BouzBouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451.
(9) Flamme, E. M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 13644.
10.1021/ol050250q CCC: $30.25
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Published on Web 03/04/2005

Scheme 1. Amphidinol 3: Retrosynthetic Analysis of the C(1)-C(25) Fragment
The synthesis of 2 commenced with a double allylboration
by oxidation of the vinylzirconium intermediate with NBS
provided vinyl bromide 10 in 75% combined yield.18
using in situ generated 4,9 aldehyde 5,10 and R-tert-butyldim-
ethylsilyloxy acetaldehyde 6.11 Thus, addition of 0.5 equiv
of 5 to a solution of 4 at -78 °C for 2 h, followed by addition
of an excess of 6 with warming to ambient temperature
overnight gave (E)-1,5-diol 7 in 73% yield and 94% ee
(Scheme 2). Protection of diol 7 as the bis-TBS ether,
deprotection of the p-methoxybenzyl ether, and Parikh-
Doering oxidation12 of the resulting primary alcohol provided
aldehyde 8 in 73% yield. Treatment of 8 with N-methyl-N-
(trimethylsilyl)acetamide and catalytic DBU afforded the
TMS enol ether13 which was immediately oxidized with Pd-
(OAc)2 to give the desired R,â-unsaturated aldehyde 2.14
A
Suzuki coupling19,20 of 10 using Pd(dppf)‚CH2Cl2, and the
alkylborane generated from olefin 11 and 9-BBN provided
an inseparable 15:1 mixture of two products in 67% yield.
The major product was the desired trans-olefin 12, and the
minor product was assigned as the 1,1-disubstituted olefin
13.21 Sharpless asymmetric dihydroxylation22 of this mixture
using AD-mix-R and subsequent protection of the resulting
diols with triphosgene and pyridine afforded the cyclic
Scheme 2. Synthesis of Aldehyde 2
The synthesis of aldehyde 3 began from TBS-protected
homoallylic alcohol 9 (Scheme 3).15 Hydroboration and
oxidation of 9, Parikh-Doering oxidation12 of the alcohol
to the aldehyde, Gilbert-Seyforth homologation to the
alkyne,16,17 and hydrozirconation of the acetylene followed
(10) Lemaire-Audoire, S.; Vogel, P. J. Org. Chem. 2000, 65, 3346.
(11) Jones, K.; Storey, J. M. D. Tetrahedron 1993, 49, 4901.
(12) Parikh, J. R.; von Doering, E. W. J. Am. Chem. Soc. 1967, 89, 5505.
(13) Tanabe, Y.; Misaki, T.; Kurihara, M.; Iida, A.; Nishii, Y. J. Chem.
Soc., Chem. Commun. 2002, 1628.
(14) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(15) Ireland, R.; Liu, L.; Roper, T. D. Tetrahedron 1997, 53, 13221.
(16) Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971, 36,
1379.
(17) Brown, D. G.; Velthuisen, E. J.; Commerford, J. R.; Brisbois, R.
G.; Hoye, T. R. J. Org. Chem. 1996, 61, 2540-2541.
(18) Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1975,
97, 679.
(19) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314.
(20) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 2001, 40, 4544.
(21) The origin of 13 is unclear, especially since vinyl bromide 10 used
in the Suzuki reaction was not contaminated by the 2-bromo regioisomer.
(22) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
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Org. Lett., Vol. 7, No. 7, 2005

Scheme 3. Synthesis of Aldehyde 3
carbonate 14 (in 86% yield from 12) as a 15:1 mixture of
afford allylboronate 17 in 85% yield. Subsequent treatment
of allylboronate 17 with 2 equiv of aldehyde 3 at 23 °C for
48 h then provided homoallylic alcohol 18 in 55% yield
along with a 15% yield of other unidentified materials.
Compound 18 contains all the necessary carbons for
elaboration to the C(1)-C(25) fragment 1 of AM 3. All that
remained to complete the synthesis of this intermediate
was hydrogenation of the C(11,12) olefin. The ability to
isolate allylboronate 16 from the allylboration of reagent 15
and aldehyde 2 and to protect the C(10) hydroxyl group
of 16 to generate 17 were critical to the overall success of
this strategy, since the C(10), C(14)-diol of 18 emerges in
fully differentiated form from the final allylboration reac-
tion. This permitted us to contemplate utilizing a hydroxyl-
directed hydrogenation reaction to reduce the now unneeded
C(11,12) olefin.25,26 In initial experiments, treatment of 18
with Wilkinson’s catalyst, RhCl(P(C6H5)3)3, using conditions
reported by Fisher provided a nonselective mixture of olefin
reduction products.27 However, treatment of 18 with Noyori’s
ruthenium catalyst, (S)-Ru(BINAP)(OAc)2,28,29 in CH2Cl2-
diastereomers. The cyclic carbonates arising from dihydroxy-
lation products of 13 were easily separated by flash chro-
matography at this stage. Deprotection of the primary acetate
in 14 by treatment with guanidine and guanidinium nitrate
in MeOH23 followed by Dess-Martin oxidation24 yielded
aldehyde 3.
With 2 and 3 in hand, we were ready to perform the
fragment assembly double allylboration reaction to complete
the synthesis of 1. Instead of performing this reaction
according to the one-pot reaction protocol that we have
described previously,9 the double allylboration of 2 and 3
was carried out in an interrupted three-pot process in order
to differentiate the two secondary alcohols that are generated
during the double allylboration reaction sequence. Thus,
treatment of 2 with in situ generated 159 at -78 °C for 1.5
h followed by quenching with MeOH provided the â-hy-
droxy-substituted allylboronate 16 in 63% yield as a 10:1
mixture of diastereomers (Scheme 4). The allylic alcohol so
produced was protected using TBSOTf and 2,6-lutidine to
Scheme 4. Synthesis of the C(1)-C(25) Fragment of AM 3
Org. Lett., Vol. 7, No. 7, 2005
1413

MeOH under 1500 psi of H2 afforded 1, a protected form of
the C(1)-C(25) fragment of AM 3, in 88% yield.
allowed for the key intermediate 18 to be prepared with the
C(10) and C(14) alcohols fully differentiated, thereby setting
the stage for a highly chemoselective hydroxyl-directed
reduction of the C(11,12) olefin. Additional progress on the
development of an efficient total synthesis of AM 3 will be
reported in due course.
In summary, we have developed a highly stereoselective
synthesis of the C(1)-C(25) fragment of AM 3 using our
double allylboration methodology in both a one-pot and
three-pot sequence. We refer to the latter process as the
“interrupted double allylboration sequence”. The ability to
execute the interrupted double allylboration of 2 and 3
Acknowledgment. Financial support by the National
Institutes of Health (GM 38436) is gratefully acknowledged.
We thank Prof. J. K. Coward for providing (S)-Ru(BINAP)-
(OAc)2 used in this synthesis.
(23) Ellervik, U.; Magnusson, G. Tetrahedron Lett. 1997, 38, 1627.
(24) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(25) Brown, J. M. Angew. Chem., Int. Ed. Engl. 1987, 26, 190.
(26) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307.
(27) Chabala, J. C.; Mrozik, H.; Tolman, R. L.; Eskola, P.; Lusi, A.;
Peterson, L. H.; Woods, M. F.; Fisher, M. H. J. Med. Chem. 1980, 23,
1134.
Supporting Information Available: Experimental pro-
cedures and tabulated spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(28) Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.;
Inoue, S.-I.; Kasahara, I.; Noyori, R. J. Am. Chem. Soc. 1987, 109, 1596.
(29) Imperiali, B.; Zimmerman, J. W. Tetrahedron Lett. 1988, 29, 5343.
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