A formal total synthesis of (-)-brevisamide

Article abstract of DOI:10.1016/j.tetlet.2010.11.013

A formal total synthesis of (-)-brevisamide has been achieved. The synthetic approach highlights a chemoselective asymmetric dihydroxylation and a one-pot Fraser-Reid epoxidation/PMB protection reaction sequence.

Full text of DOI:10.1016/j.tetlet.2010.11.013

Tetrahedron Letters 52 (2011) 2117–2119
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Tetrahedron Letters
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A formal total synthesis of (À)-brevisamide
⇑
Amos B. Smith III , Noriki Kutsumura, Justin Potuzak
Department of Chemistry, Monell Chemical Senses Center, and Laboratory for Research on the Structure of Matter, The University of Pennsylvania, Philadelphia, PA 19104, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 13 November 2010
A formal total synthesis of (À)-brevisamide has been achieved. The synthetic approach highlights a
chemoselective asymmetric dihydroxylation and a one-pot Fraser-Reid epoxidation/PMB protection reac-
tion sequence.
Keywords:
Brevisamide
Ó 2010 Published by Elsevier Ltd.
Asymmetric dihydroxylation
One-pot
Fraser-Reid epoxidation
Formal total synthesis
Dinoflagellates, known to produce cyclic polyether toxins such
as the brevetoxins A and B, ciguatoxins, and maitotoxin,1 have at-
tracted significant interest in the scientific communities since the
first isolation and structural elucidation of the brevetoxins from
Karenia brevis in the early 1980’s, due to the significant toxicity
and ecological ramifications of the toxins produced. More recently
a related ladder-frame polyether, (À)-brevenal (1), was reported in
2005 to arise from the same species, that proved to be an antago-
nist of the sodium channel blocking ability of the brevetoxins.1c
This report was quickly followed in 2008 by the Wright et al. dis-
closure of a cyclic ether alkaloid, termed (À)-brevisamide (2), from
the same red tide dinoflagellate (Scheme 1).2 Due to the structural
similarity to the western portion of 1, Wright and co-workers rea-
soned that (À)-brevisamide (2) may prove useful in defining the
biosynthetic origin of the fused polyether class of dinoflagellate
toxins.
OH
H
H
O
E
H
O
H
H
D
H
O
C
A
O
B
O
Me
H
H
H
OH
O
(−)-brevenal (1)
OH
H
H
N
O
H
H
O
O
(−)-brevisamide (2)
3. TEMPO, PhI(OAc)2 or
Not surprisingly, the synthetic community quickly took up the
synthetic challenge of (À)-brevisamide (2), and in 2009 Tachibana
laboratory recorded the first total synthesis that comprised a linear
sequence of 21-steps from commercially available starting materi-
als.3 The highlight of their synthetic venture entailed the use of a
Suzuki–Miyaura reaction to achieve union between a dienol side
chain 3 and an advanced ether tetrahydropyran fragment (+)-4
(Scheme 1). More recently, three additional total syntheses of
(À)-brevisamide have been reported.4 From our perspective an
improved strategy, taking advantage of the Tachibana Suzuki–
Miyaura union, would entail the development of a more concise
approach to the requisite tetra-substituted tetrahydropyran ring.
In this Letter, we disclose a synthetic sequence that produced
the TBS-protected polysubstituted tetrahydropyran core (+)-4 in
1. 9-BBN, Cs2CO3, THF
PdCl2(dppf)
2. TBAF, THF
MnO2, CH2Cl2
24-35% over 3 steps
3a,4b
OTBS
∗
∗
H
HO
I
N
+
O
H
H
O
(+)-4
3
(known synthetic intermediate)
Bn
OPMB
N
O
∗
∗
O
O
OH
O
OH
(−)-5
(−)-15
⇑
Corresponding author. Tel.: +1 215 898 4860; fax: +1 215 898 5129.
E-mail address: smithab@sas.upenn.edu (A.B. Smith III).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.11.013

2118
A. B. Smith III et al. / Tetrahedron Letters 52 (2011) 2117–2119
14-steps (longest linear sequence) with an overall yield of 8.8%
from the known starting material (À)-5, thus constituting a formal
total synthesis of (À)-2.
dihydroxylation of (À)-9 employing K2OsO4Á2H2O (0.5 mol %) pro-
ceeded at the ,b-olefin, presumably a direct result of OTIPS ether
allylic to the terminal olefin. Complete chemoselectivity with
excellent diastereoselectivity (Table 1) was eventually achieved!
Assignment of the diol stereogenicity was based on Sharpless
precedent.7
a
We began the formal synthesis of (À)-brevisamide (2) with
known alcohol (À)-5, available in one step from acrolein exploiting
the Evans syn-aldol protocol,5 protection of the hydroxyl group in
(À)-5 as a TIPS ether (Scheme 2), followed by reductive-removal
of the auxiliary provided alcohol (À)-6 in excellent yield. Conver-
sion to the corresponding nitrile (À)-7 via an intermediate iodide
next proceeded in 96% yield, which was then reduced with DIBAL-H
and in turn subjected to Wittig olefination with 8 to furnish the
desired E-diene (À)-9 as the major product (E:Z = 14:1).
Following the chemo- and stereoselective Sharpless asymmetric
dihydroxylation, the resulting diol (À)-10a was reduced with
LiBH4 to furnish triol (À)-11. We then turned to the Fraser-Reid
epoxide protocol to install the terminal epoxide on the triol.8 Ini-
tially this reaction proved unsuccessful (Scheme 3). For example,
use of multiple equivalents of 2,4,6-triisopropyl-benzenesulfonyl
imidazole (TPS-Imid) led to formation of (+)-12a, possessing a
TPS group on the C11-hydroxyl, while use of one equivalent gener-
ated 12b, which unfortunately proved unstable during the workup.
Equally problematic, removal of the TIPS group from (+)-12a, fol-
lowed by the cyclization employing 1 N HCl, led to what we tenta-
tively assigned (1H NMR) as the five-membered tetrahydrofuran
13, not to the required six-membered ring tetrahydropyran 14.
Bn
1) TIPSOTf, 2,6-lutidine,
CH2Cl2, 0 ºC
2) LiBH4, Et2O, H2O, 0 ºC
O
OH
N
99%, 2 steps
OTIPS
(−)-6
OH
O
O
(−)-5
1) DIBAL-H, CH2Cl2,
−78 to 0 ºC
2) Ph3P=CHCO2Et 8
benzene, reflux
a) I2, PPh3, imidazole,
benzene, rt
b) NaCN, DMSO, 70 ºC
LiBH4
CN
OH
OH
THF-H2O
CO2Et
OTIPS
(−)-7
11
OH
96%
81%, 2 steps
60%
OTIPS
OH
OTIPS
OH
10α (desired)
(−)-11
CO2Et
Tris-Imid
(excess)
NaH / THF
99%
TPS-Imid (1 equiv)
NaH / THF
OTIPS
(−)-9 (E : Z = 14 : 1)
OH
O
Scheme 2.
OTPS
11
O
Our synthetic strategy next called for a chemoselective asym-
metric dihydroxylation of
,b-olefin in diene (À)-9. In general
dihydroxylations employing OsO4 of substrates containing both
an ,b-unsaturated olefin and a terminal double bond predominate
OTIPS
OTIPS
a
(+)-12a
12b (unstable)
a) TBAF / THF
b) 1 M. HCl aq.
74%
TPS = 2,4,6-triisopropylbenzenesulfonyl
a
at the terminal olefin. A careful search of the literature however
revealed a 2003 report by Greeves et al. that this chemoselectivity
can be inverted by employing the K2OsO4Á2H2O, when the terminal
olefin possesses an adjacent bulky substituent.6 Gratifyingly, after
careful adjustment of the reaction conditions (Table 1), Sharpless
HO
OTPS
11
11
OH
O
13
O
14
OH
Not observed
Table 1
Scheme 3.
OH
CO2Et
Consistent with the structure 13 would be nucleophilic attack of
water on the alkyl oxonium intermediate9 generated by the ring
opening of the epoxide by the oxygen atom of the tetrahydrofuran
ring (Scheme 4).
OTIPS
OH
dihydroxylation
CO2Et
(−)-10α (desired)
+
tBuOH-H2O (1/1)
OTIPS
(−)-9
OH
CO2Et
OTIPS
(+)-10β (undesired)
OH
HO
a) TBAF / THF
OTPS
b) 1 M. HCl aq.
11
11
Conditions
Yield
(%)
Selectivity (À)-
OH
O
O
10a
:(+)-10bb
OTIPS
(+)-12a
13
1
2
3
4
5
OsO4 in H2O (25 mol %), NMOa, 0–10 °C,
11 h
AD-mix-a, MeSO2NH2, OsO4 in H2O
(25 mol %), 0–10 °C, 11 h
AD-mix-b, MeSO2NH2, OsO4 in H2O
(25 mol %), 0–10 °C, 11 h
51
75
66
61
84
1.8:1.0
15.5:1.0
1.0:5.8
Proposed Mechanism
HO
⊕
⊕
OTPS
H
AD-mix-
(5 mol %), 0–10 °C, 28 h
AD-mix-
, MeSO2NH2, K2OsO4 Á2H2O
(0.5 mol %), 0–10 °C, 22 h
a
, MeSO2NH2, OsO4 in H2O
(À)-10
(À)-10
a
a
only
only
OH
O
O
O
a
⊕
OH
H2O
double inversion
a
NMO = N-methylmorpholine N-oxide.
b
Determined by 1H NMR.
Scheme 4.

A. B. Smith III et al. / Tetrahedron Letters 52 (2011) 2117–2119
2119
Eventually, after considerable experimentation, we discovered
that when one equivalent of TPS-Imid was employed, followed
by the addition of three equivalents of PMBBr, epoxide (À)-12c
could be isolated in good yield in a single operation (Scheme 5).
Removal of the TIPS group using tetrabutylammonium fluoride then
provided (À)-15, substrate for the key cyclization event. Pleasingly,
treatment of (À)-15 with CSA in CH2Cl2 furnished the desired
tetrahydropyran 16 which without purification was treated first
with PPh3 and DPPA, and in turn with DIAD to furnish azide (+)-
17 in 85% yield for the three steps. Reduction of (+)-17 employing
PPh3 followed by acetylation then proceeded smoothly to furnish
the advanced tetrahydropyran (+)-18. In parallel, known synthetic
intermediate (+)-4 was also prepared from the azide (+)-17 by a
three-step conversion: (a) DDQ, buffer/CH2Cl2; (b) TBSOTf, 2,6-
lutidine/CH2Cl2; (c) PPh3/THF–H2O followed by Ac2O, pyridine.
The spectroscopic and chiroptical properties of (+)-4 were identical
to those reported by Tachibana and co-workers.3a
In summary, an effective synthesis of (+)-4 completes a formal
total synthesis of (À)-brevisamide (2). Highlights of the tetrahydo-
pyran ring synthesis [cf. (+)-17] include a chemoselective Sharpless
asymmetric dihydroxylation and a one-pot Fraser-Reid epoxida-
tion/PMB protection reaction sequence.
Acknowledgments
Support for this research was provided by the National Insti-
tutes of Health (Institute of General Medical Sciences) through
grant GM-29028 and a Postdoctoral Fellowship to N.K. from the
Uehara Memorial Foundation.
This Tetrahedron Letter is dedicated to Professor Harry H.
Wasserman, scientist/scholar extraordinaire, long term editor/
mentor and friend on the occasion of his 90th birthday. Harry
thank you for all you have done for the chemical/scientific
community.
a) NaH, TPS-Imid
THF, 0 ºC
OH
OPMB
References and notes
b) PMBBr
0 ºC to rt
TBAF / THF
90%
OH
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Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773–6775; (b) Shimizu, Y.;
Chou, H. N.; Bando, H.; Van Duyne, G.; Clardy, J. J. Am. Chem. Soc. 1986, 108,
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O
OTIPS
OH
OH
OTIPS
(−)-12c
61%
(−)-11
OPMB
OPMB
OH
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CH2Cl2, rt
b) PPh3, DPPA,
c) DIAD, THF, rt
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O
O
85%, 3 steps
16
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4390–4393.
(−)-15
OPMB
N3
OPMB
NHAc
i) PPh3, THF-H2O
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O
(+)-17
O
98%, 2 steps
(+)-18
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12 steps, 17.7% overall yield
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CH2Cl2 (94%)
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CH2Cl2 (89%)
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i) PPh3, THF-H2O
ii) Ac2O, pyridine
OTBS
NHAc
OTBS
N3
O
(+)-4
O
58%
(+)-19
14 steps, 8.8% overall yield
(Formal Total Synthesis)
Scheme 5.