Total synthesis of brevisamide

Article abstract of DOI:10.1021/ol901801h

A convergent synthesis of brevisamlde (1) is described based on the application of the crotyl silane-based [4 + 2]-annulatlon used for the preparation of the advanced oxygenated tetrahydropyran Intermediate 2. The side chain bearing a conjugated (E,E)-die

Full text of DOI:10.1021/ol901801h

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4390-4393
Total Synthesis of Brevisamide
Jihoon Lee and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Metcalf Center for Science and Engineering, Boston UniVersity,
590 Commonwealth AVenue, Boston, Massachusetts 02215
panek@bu.edu
Received August 5, 2009
ABSTRACT
A convergent synthesis of brevisamide (1) is described based on the application of the crotyl silane-based [4 + 2]-annulation used for the
preparation of the advanced oxygenated tetrahydropyran intermediate 2. The side chain bearing a conjugated (E,E)-diene was efficiently
constructed under modified Negishi cross-coupling conditions.
A family of polycyclic ether toxins produced by red tide
Dinoflagellate Karenia breVis have attracted significant
interest due to their toxicity and structural complexity. For
instance, the brevetoxins are known to exhibit potent
neurotoxicity, which causes open state of voltage-sensitive
sodium channel (VSSC) and disturbs inactivation, and
brevenal exhibits antagonism against toxic effects caused by
brevetoxins.1 These toxins isolated from K. breVis have been
attractive targets for synthetic chemists due to their unique
structures, cyclic polyether core, and biological activities.2
Brevisamide3 (1) was recently isolated by Wright’s group
(Center for Marine Science at University of North Carolina)
while conducting experiments aimed at the identification of
new metabolites from K. breVis. The structure elucidation,
as well as the assignment of both relative and absolute
stereochemistry of brevisamide (1), were initially established
by 1D and 2D NMR studies and later confirmed by total
synthesis.4 A second total synthesis has recently appeard
from Lindsley’s laboratory.5 Structural features of brevisa-
mide (1) include an oxygenated tetrahydropyran core and a
trisubstituted (E,E)-diene as a challenging component of the
side chain (Figure 1). Additionally, brevisamide is the only
metabolite of K. breVis that contains an amide. Since the
biological properties of this molecule have not been dis-
closed, developing efficient synthetic strategies for this
natural product will provide sufficient amounts to facilitate
further biological evaluation.
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Figure 1. Structures of brevisamide (1) and brevenal.
Our synthetic plan intended to utilize a palladium-catalyzed
Negishi cross-coupling to construct the conjugated (E,E)-
10.1021/ol901801h CCC: $40.75
Published on Web 09/08/2009
 2009 American Chemical Society

diene of brevisamide 1. In this regard, we initially planed to
disconnect C3-C4, which led to two fragments 2 and 3
(Scheme 1). Iodoalkene 3 will be an immediate precursor to
Scheme 1. Retrosynthetic Analysis of Brevisamide (1)
Figure 2. Stereochemical course of [4 + 2]-annulation of (E)- and
(Z)-crotylsilane reagents.
6-substituents of dihydropyran are dictated by syn- and anti-
relationship of crotylsilane. Therefore, syn- and anti-(E)-
crotylsilane give 2,6-cis- and 2,6-trans-dihydropyran, re-
spectively (Figure 2, eqs 1 and 2). In contrast, annulation of
(Z)-crotylsilane selectively affords 5,6-cis-dihydropyran.9b In
addition, 2,3-syn- and 2,3-anti-realtionships of (Z)-crot-
ylsilane provide 2,6-trans- and 2,6-cis-dihydropyran, re-
spectively (Figure 2, eqs 3 and 4), which is the opposite
and complementary stereochemical outcome to that of (E)-
crotylsilanes.
The synthesis of oxygenated tetrahydropyran fragment 2
was initiated with [4 + 2]-annulation of known (Z)-
crotylsilane 59b,10 with aldehyde 6 (Scheme 2), which
afforded 5,6-cis-trisubstituted dihydropyran 7 in 70% isolated
yield (dr ) 10:1). In our initial plan, we desired diastereo-
an alkenylzinc reagent generated in situ through lithium-
haolgen exchange and transmetalation.6 The hydroxyl-
bearing center with an (S)-configuration at C11 will be
introduced by diastereoselective hydroboration of an inter-
mediate dihydropyran.7 Further, the (E)-vinyl iodide in the
side chain of fragment 2 will be installed though SN2-type
propynyl substitution at C6 and subsequent regioselec-
tive hydrozirconation followed by trapping with iodine.8 The
trisubstituted dihydropyran precursor to fragment 4 with a
cis-cis relationship will be prepared through a [4 +
2]-annulation between (Z)-crotylsilane 5 and aldehyde 6.9
The stereochemical outcome of the annulation products
can be attributed to the configuration of the silane reagents
as illustrated in Figure 2. In the case of a [4 + 2]-annulation
with a (E)-crotylsilane,9a a 5,6-trans-dihydropyran is always
favored. Stereochemical relationships between the 2- and
Scheme 2. Synthesis of Hydroxytetrahydropyran Fragment 4
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Org. Lett., Vol. 11, No. 19, 2009
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selective hydroboration of dihydropyran 7 to directly intro-
duce the ꢀ-hydroxyl group at C11. Since hydroboration in a
trans,trans dihydropyran system has been previously studied
in our group,7c,d we applied the conditions that were used
in previous examples (2.0 M BH3·SMe2 in THF) to the
hydroboration of cis,cis dihydropyran 7. However, hydrobo-
ration of 7 was found to be problematic, which gave the
desired product in 40% yield (dr ) 2.5:1) with varying
amounts of degradation of 7. Other experiments utilizing
catecholborane in the presence of Wilkinson’s catalyst or
9-BBN7a,b also proved to be unsuccessful.
At this point, we concluded that cis,cis dihydropyran 7
was not conformationally suitable for the desired stereo-
chemical course of hydroboration. Therefore, we removed
the chiral center at C12 by isomerization of the olefin into
conjugation with the methyl ester in the presence of DBU,11
after which that stereocenter could be regenerated through
hydroboration of the allylic TBS ether. Then, LAH reduction
of methyl ester and subsequent protection of the resulting
allylic alcohol as a TBS ether gave a new hydroboration
precursor 9. Subsequently, hydroboration using BH3·SMe2
at 0 °C afforded the desired oxygenated tetrahydropyran 4
both in high yield and diastereoselectivity (90%, dr >11:1).
With useful quantities of secondary alcohol 4 in hand, we
turned our attention to extending the left-hand side chain.
Intermediate alcohol 4 was protected as its TBS ether, and
hydrogenolysis of benzyl ether in ethyl acetate afforded
primary alcohol 10 in high yield (Scheme 3). To install three
propyne solution in THF with n-BuLi at -78 °C to afford
alkyne 11. However, this reaction turned out to be sensitive
to the number of equivalents of nucleophile and cosolvent.
For instance, 1.5 equiv of propynyllitihium gave only
decomposition of triflate ester after 12 h. Using THF/HMPA
(10:1) mixed solvent system gave the desired product 11 in
60% yield within 30 min, but this result was not reproducible
when scaled up. An optimal condition was found when the
triflate ester was treated with 5 equiv of propynyllithium in
THF for 3 h, affording 11 in 78% (two steps).
Regioselective hydrozirconation of the internal alkyne 11
utilizing 2 equiv of Schwartz reagent in THF, followed by
trapping of the organozirconium intermediate with I2 suc-
cessfully furnished the coupling precursor (E)-iodoalkene
2 in 88% yield (E/Z ) 10:1).8 Alternatively, silylcupration
(5 equiv of CuCN, 10 equiv of PhMe2SiLi) gave the
desired vinyl iodide 2 with much lower regioselectivity
(E/Z ) ∼2:1).2f,13
The final stage of the synthesis required introduction of
the aldehyde side chain with the assembly of the conjugated
(E,E)-diene, which began with fragment coupling between
different (E)-vinyl iodide fragments 2 and 3 under modified
Negishi coupling conditions.5 Although it has been reported
that formation of this type of trisubstituted (E,E)-diene can
be achieved using Stille coupling conditions, the use of silyl-
protected vinyl stannane version of intermediate 3 afforded
the contaminated diene with its homocoupling product.2f
Treatment of vinyl iodide 314 with an excess amount of
t-BuLi and transmetalation of the resulting lithium anion with
anhydrous ZnCl2 generated an intermediate vinlyzinc species.
Coupling of the in situ prepared zinc intermediate with the
vinyl iodide 2 in the presence of 10 mol % of Pd(PPh3)4
provided a crude diene that was used without purification.
The selective cleavage15 of primary TBS ether using CSA
afforded, after purification on silica gel, the pure (E,E)-diene
12 in 58% as a single regioisomer.
Scheme 3. Synthesis of the Fragment 2
To install an acetyl amide in the right-hand side chain,
the resulting primary alcohol was activated and substituted
with azide using diphenylphosphoryl azide (DPPA) under
Mitsunobu conditions.16 Reduction of the azide17 in the
presence of NH4OH followed by acetylation of the primary
amine gave the acetyl amide 13 in 83% yield (two steps).
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an unstable intermediate triflate ester that was used without
purification. As such, this material was treated with 1-pro-
pynyllithium that was generated in situ by treatment of a
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Deprotection of the two silyl ethers using TBAF gave an
advanced diol intermediate, and chemoselective oxidation
of the primary allylic alcohol in the presence of the secondary
alcohol using excess amount of MnO2 successfully afforded
brevisamide 1 (Scheme 4).2f,4,18
from trans-(Z)-crotylsilane 5. The key feature of our
synthesis relied on the formation of highly substituted
oxygenated tetrahydropyran using our silicon-directed [4 +
2]-annulation strategy. In addition, construction of the
substituted (E,E)-diene through a modified Negishi cross-
coupling demonstrated that this method can be useful for
stereochemically challenging systems en route to complex
molecule synthesis. Studies to further explore the scope and
application of this strategy are currently underway.
Scheme 4. Completion of the Synthesis
Acknowledgment. Financial support was obtained from
NIH CA 53604. J.S.P. is grateful to Amgen, Johnson &
Johnson, Merck Co., Novartis, Pfizer, and GSK for financial
support. We are grateful to Dr. Jason Lowe, Dr. Paul Ralifo,
and Dr. Norman Lee at Boston University for helpful
discussions and assistance with NMR and HRMS experi-
ments.
Supporting Information Available: Experimental details
and selected spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL901801H
(18) (a) Yadav, J. S.; Sunitha, V.; Reddy, B. V. S.; Gyanchander, E.
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In summary, the total synthesis of the brevisamide has
been achieved in 17 steps with a 6.4% overall yield starting
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