Total synthesis of brevisamide

Article abstract of DOI:10.1021/ol9015755

(Figure Presented) The second total synthesis of Brevisamide, a marine cyclic ether alkaloid from Karenla brevls, is reported. This streamlined synthesis proceeds in 21 steps, 14 steps longest linear sequence, in 5.2% overall yield and features a key Sml₂ reductive cyclization step to access the tetrasubstituted pyran core.

Full text of DOI:10.1021/ol9015755

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3950-3952
Total Synthesis of Brevisamide
Olugbeminiyi O. Fadeyi and Craig W. Lindsley*
Departments of Chemistry and Pharmacology, Vanderbilt UniVersity,
NashVille, Tennessee 37232
craig.lindsley@Vanderbilt.edu
Received July 10, 2009
ABSTRACT
The second total synthesis of Brevisamide, a marine cyclic ether alkaloid from Karenia brevis, is reported. This streamlined synthesis proceeds
in 21 steps, 14 steps longest linear sequence, in 5.2% overall yield and features a key SmI2 reductive cyclization step to access the tetrasubstituted
pyran core.
Recently, Satake, Tachibana, Wright, and co-workers re-
ported on the isolation and characterization of brevisamide
Scheme 1. Retrosynthetic Analysis of Brevisamide (1)
(1), an unprecendented monocylic ether alkaloid, from the
dinoflagellate Karenia breVis, a species known to produce
polycyclic ether toxins such as the brevetoxins.1 Identification
of 1, containing the same conjugated 3,4-dimethyl-2,4-dienal
side chain as the more complex polycylic ether brevenal,2
provided further support for the model of ladder-frame
initiation in the synthesis of polycyclic ether natural products,
and thus has garnered significant synthetic interest.1 Within
months of the publication of the isolation and characterization
of brevisamide (1), the first total synthesis and structural
confirmation of 1 was reported by the same group.3 The
synthesis proceeded in 28 steps, with the longest linear
sequence of 21 steps, for an overall yield of 1 from cis-but-
2-ene diol of 0.23%.3 In this letter, we report our efforts on
the total synthesis of brevisamide (1) employing a funda-
mentally different synthetic strategy that afforded 1 in 21
total synthetic steps and an overall yield of 5.2%.
Scheme 1 illustrates our retrosynthetic analysis of 1,
providing a convergent synthetic strategy. Inspired by the
elegant synthesis of brevenal by Takamura and co-workers,4
we envisioned the western C1-C4 side chain would be
installed through a Horner-Emmons-Wadsworth reaction
(1) Satake, M.; Bourdelais, A. J.; Van Wagoner, R. M.; Baden, D. G.;
Wright, J. L. C. Org. Lett. 2008, 10, 3465–3468.
(2) Bourdelais, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M.,
Jr.; Baden, D. G. J. Nat. Prod. 2005, 68, 2–6.
(3) Kuranaga, T.; Shirai, T.; Baden, D. G.; Wright, J. L. C.; Satake,
M.; Tachibana, K. Org. Lett. 2009, 11, 217–220.
(4) Takamura, H.; Kikuchi, S.; Nakamura, Y.; Yamagami, Y.; Kishi,
T.; Kadota, I.; Yamamoto, Y. Org. Lett. 2009, 11, 2531–2534.
10.1021/ol9015755 CCC: $40.75
Published on Web 07/29/2009
 2009 American Chemical Society

Scheme 2. Synthesis of Tetra-Substituted Pyran 3
utilizing 2, prepared from commercially available 4. Key
pyran 3, the C5-C15 fragment, was conceived to be derived
from 5 through a SmI2-mediated reductive cyclization
reaction.5-10
delivered the key intermediate 9 in 93% isolated yield.
Removal of the TBS group proved equally problematic. Upon
exposure to TBAF, a 1:1 mixture of the desired 10 and an
unanticipated 1,3-dioxepane 11 formed. While separable, this
undesired side product was detrimental at this stage of the
synthesis. After surveying a variety of reaction conditions,
we found that addition of a few drops of concentrated HCl
in MeOH at 0 °C smoothly delivered the alcohol 10 in
quantitative yield. Swern oxidation proceeded uneventfully
delivering the key template for the reductive cyclization.5-10
In the event, exposure to SmI2 provided the desired pyran
12 in 69% yield for the three steps. The relative stereochem-
istry of 12 was assigned by NMR and NOE analysis and in
agreement with literature precedent.5-10
The synthesis of pyran 3 is described in Scheme 2.
Monobenzyl protected-1,4-butane diol 6 was oxidized under
Swern conditions to the corresponding aldehyde which was
then subjected to a Brown crotylation reaction to afford 7
as a single diastereomer in 87% ee.11,12 Hydroboration and
chemoselective TBS protection of the primary alcohol
provided 8 in 89% yield for the two steps. 1,4-Addition of
8 to ethyl propiolate proved difficult, resulting in complex
mixtures under a number of reaction conditions.13 Ultimately,
slow addition of ethyl propiolate via syringe pump over 24 h
Once in hand, the secondary alcohol of 12 was protected
and the ester hydrolyzed to produce acid 13 in 85% yield
for the two steps. Curtius rearragement with (PhO)2P(O)N3
(DPPA) provided the aminomethyl congener 14 in 81%
yield.14,15 Finally, an acetylation, benzyl deprotection, and
oxidation sequence afforded target pyran 3, the C5-C15
fragment, in 81% yield for the three steps. Thus, the longest
(5) Gillmann, T. Tetrahedron Lett. 1993, 34, 607–610
(6) Suzuki, K.; Matsukura, H.; Matsuo, G.; Koshino, H.; Nakata, T.
Tetrahderon Lett. 2002, 43, 8653–8655
(7) McErlean, C. S. P.; Willis, A. C. Synlett 2009, 2, 233–236
(8) Clark, S. J.; Hayes, S. T.; Blake, A. J.; Gobbi, L. Tetrahedron Lett.
2007, 48, 2501–2503
.
.
.
.
(9) Saito, T.; Kimishima, A.; Nakata, T. Heterocycles 2006, 70, 177–
180
.
(10) Takahashi, S.; Ogawa, N.; Koshino, H.; Nakata, T. Org. Lett. 2005,
7, 2783–2786
(11) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401–404
(12) Williams, D. R.; Cortez, G. S.; Bogen, S. L.; Rojas, C. M. Angew.
.
(13) Kartika, R.; Gruffi, T. R.; Taylor, R. E. Org. Lett. 2008, 10, 5047–
.
5050.
(14) Davis, M. C. Synth. Commun. 2007, 37, 3519–3528
.
Chem., Int. Ed. 2000, 39, 4612–4617
Org. Lett., Vol. 11, No. 17, 2009
.
(15) Leogane, O.; Lebel, H. SYNTHESIS 2009, 11, 1935–1940.
3951

linear sequence, 14 steps, was completed in 14.9% overall
yield.
Scheme 4. Completion of the Synthesis of Brevisamide (1)
Attention now focused on the synthesis of phosphonate
ester 2.4 As shown in Scheme 3, a Wittig reaction with
Scheme 3. Synthesis of Phosphonate Ester 2
3-hydroxybutan-2-one 4, and subsequent bromination, gener-
ates the secondary bromide 15 in 90% yield for the two steps.
Application of an Arbuzov reaction delivers the key phos-
phoate ester 2, the C1-C4 side chain, in 92% yield.4,16
The Horner-Wadsworth-Emmons reaction between the
C1-C4 fragment 2 and the C5-C15 fragment 3 proceeded
well, installing the conjugated 3,4-dimethyl-2,4-dienal moiety
and delivering 16 in 78% yield (Scheme 4). DIBALH
reduction of the ester to the corresponding allylic alcohol4
and TBAF-mediated deprotection of the secondary TBS ether
delivered 17, the direct precursor to brevisamide, in 71%
yield for the two steps. A final MnO2 oxidation of the allylic
alcohol produced the natural product brevisamide (1) in 74%
yield. The synthetic 1 exhibited physical and spectroscopic
data identical to that of the natural brevisamide and that of
the previously prepared synthetic brevisamide.1,3,17
steps from this route include a SmI2 reductive cyclization to
generate the highly functionalized pyran 3 and a Horner-
Wadsworth-Emmons reaction to assemble the western
C1-C4 2 and eastern C5-C15 3 fragments. With a high-
yielding synthetic route in place, future efforts will focus
on the synthesis of unnatural brevisamide analogs and
attempts to employ 1 in the biomimetic, ladder-frame
initiated synthesis of more complex polyethers. These efforts
are in progress and will be reported in due course.
Acknowledgment. This work was supported, in part, by
the Department of Pharamacology and Vanderbilt University.
Funding for the NMR instrumentation was provided in part
by a grant from NIH (S10 RR019022). We thank Dr. Kyle
Emmitte (Vanderbilt University) for helpful conversations.
Thus, the second total synthesis of brevisamide (1) has
been accomplished in 21 synthetic steps, with 14 steps
longest linear sequence, and an overall yield from monoben-
zyl protected-1,4-butane diol 6 of 5.2%. Noteworthy synthetic
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) Alen, J.; Dobrzanska, L.; De Morggraeve, W. M.; Compernolle,
F. J. Org. Chem. 2007, 72, 1055–1057
.
(17) See Supporting Information for full details
.
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