A formal stereoselective synthesis of (-)-brevisamide

Article abstract of DOI:10.1016/j.tetlet.2013.01.134

An efficient stereoselective formal synthesis of marine derived monocyclic ether (-)-brevisamide is reported. The key steps involved in this synthesis are syn-Aldol reaction, Sharpless asymmetric epoxidation, and stereoselective construction of tetrahydropyran ring by 6-endo-cyclization of suitably substituted hydroxy styrylepoxide.

Full text of DOI:10.1016/j.tetlet.2013.01.134

Tetrahedron Letters 54 (2013) 3227–3229
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Tetrahedron Letters
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A formal stereoselective synthesis of (ꢀ)-brevisamide
J. S. Yadav a, , A. Raju a,b, K. Ravindar a, B. V. Subba Reddy a
⇑
a Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 607, India
b University of Hyderabad, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient stereoselective formal synthesis of marine derived monocyclic ether (ꢀ)-brevisamide is
reported. The key steps involved in this synthesis are syn-Aldol reaction, Sharpless asymmetric epoxida-
tion, and stereoselective construction of tetrahydropyran ring by 6-endo-cyclization of suitably substi-
tuted hydroxy styrylepoxide.
Received 18 September 2012
Revised 1 January 2013
Accepted 3 January 2013
Available online 29 March 2013
Ó 2013 Published by Elsevier Ltd.
Keywords:
Brevisamide
Wittig reaction
Sharpless asymmetric epoxidation
syn-Aldol reaction
6-endo-Cyclization
OH
The isolation and structural elucidation of brevisamide (1), a
marine derived monocyclic ether was reported in 2008 by Satake
et al., (Fig. 1).1 It was isolated from Karenia brevis (Red tide dinofla-
gellate) which is a well known species to produce various cyclic
polyether toxins such as brevetoxins A and B, ciguatoxins, and mai-
totoxins. The absolute and relative stereochemistry of brevisamide
was determined by various research groups through its stereose-
lective total synthesis employing Brown’s crotylation, Curtius rear-
rangement, and SuzukiꢀMiyaura cross coupling as key
transformations.2 Very interesting structural features such as tet-
rahydropyran core coupled with dienal side chain and terminal
amide subunit of brevisamide (1) have attracted the attention of
many synthetic research groups for the last four years.3
In light of interesting structural features of brevisamide (1) and
in continuation of our interest in total synthesis of oxygen contain-
ing heterocyclic natural products,4 most recently, we have demon-
strated a stereoselective formal synthesis of (ꢀ)-brevisamide (1) by
means of an unprecedented redox reaction of palladium hydroxide
(Pd(OH)2) catalyzed isomerization of primary allylic alcohol to the
corresponding aldehyde and intramolecular oxa-Michael strategy
(IMOM) for the construction of a key tetrahydropyran core unit.5
Herein, we report an efficient formal synthesis of (ꢀ)-brevisamide
(1) employing syn-Aldol reaction, Sharpless asymmetric epoxida-
tion and stereoselective construction of tetrahydropyran moiety
via 6-endo-cyclization of hydroxy styrylepoxide.
H
O
N
O
H
H
H
O
1
Fig. 1. (ꢀ)-Brevisamide (1).
OH
H
15
1
O
N
4
O
5
H
H
H
O
H
(−)-Brevisamide (1)
OTBS
OEt
OEt
1
O
H
15
4
P
O
+
BnO
N
O
5
OEt
H
O
O
2
3
OTBS
BnO
Ph
BnO
OH
OH
OH
5
4
HO
6
Taking into consideration Lindsley’s protocol and our own
reported synthetic strategy,3a,5 we envisioned the retrosynthetic
Scheme 1. Retrosynthetic analysis of (ꢀ)-brevisamide (1).
analysis of (ꢀ)-brevisamide (1) as depicted in Scheme 1. (ꢀ)-
Brevisamide (1) could easily be synthesized via the Horner–
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4039/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.01.134

3228
J. S. Yadav et al. / Tetrahedron Letters 54 (2013) 3227–3229
L-(+)-DET, Ti(iPrO)4,
ref. 16
Wadsworth–Emmons (HWE) reaction between two coupling
HO
BnO
OH
O
OH
partners of C1–C4 side chain 2 and C5–C15 tetrahydropyran core
3 (by the use of corresponding C5 aldehyde intermediate). Tetrahy-
dropyran segment (C5–C15 fragment) 3 can be achieved via the
base induced 6-endo-cyclization of hydroxy styrylepoxide 4, which
could in turn be prepared from a commercially available 1,4-
butanediol 6 via syn-stereo-diad 5 employing asymmetric syn-
Aldol reaction, Sharpless asymmetric epoxidation, and Wittig
olefination sequence.
Initially, we planned the synthesis of stereo-diad 5 from the syn-
Aldol intermediate 9 via a nonaldol strategy using t-butyldimethyl-
silyltrifluoromethanesulfonate (TBSOTf) and Hunig’s base mediated
intramolecular epoxide opening reaction (Jung’s protocol)6 from
chiral epoxy alcohol 8. Accordingly, allylalcohol 7 was readily
prepared from 1,4-butanediol 6 using well precedented literature
procedures, which was then subjected to Sharpless asymmetric
TBHP, CH2Cl2, 4oA MS,
-20 oC, 8h, 90%
6
7
TBSOTf, iPr2EtN
CH2Cl2
OTBSO
BnO
BnO
OH
H
-42 oC, 4oA MS
2h,15%
8
9
OTBS
NaBH4, MeOH
oC to rt, 1 h
75%
BnO
0
OH
5
Scheme 2.
i
1. TBSOTf, Pr2EtN,
CH2Cl2, 0 oC, 1h
OH
O
S
ref. 5
HO
BnO
OH
N
S
2. NaBH4, MeOH,
6
10
0
oC to rt, 1h
Bn
(72% over 2 steps)
OTBS
OTBS
PPh3, CBr4, CH3CN,
BnO
BnO
oC to rt, 2h, 70%
Br
OH
0
5
11
OTHP
OTBS
1. BF3.Et2O, HSCH2CH2SH,
CH2Cl2, -20 oC, 0.5h, 90%
12
BnO
OTHP
n-BuLi, HMPA,
-45 oC, 5h, 65%
13
2. Red-Al, Et2O, rt, 4h, 80%
(72% over 2 steps)
L-(+)-DET
Ti(iPrO)4,
OH
O
BnO
BnO
OH
TBHP, CH2Cl2,
OTBS
OTBS
-20 oC, 8h,92%
14
15
1. DMP, pyridine,CH2Cl2,
0 oC to rt, 3h
O
Ph
TBAF, THF,
BnO
2. PPh3C6H5CHBr, NaHMDS,
0 oC to rt, 3h, 90%
OTBS
THF, 0 oC to rt, 1h
16
(54.8% over 2 steps)
OH
O
NaH, DMSO,
THF, rt, 92%
Ph
BnO
BnO
Ph
O
H
H
OH
17
4
1. O3, Me2S, CH2Cl2
-78 oC to rt
OTBS
TBSOTf, iPr2EtN,
BnO
2. NaBH4, MeOH,
Ph
CH2Cl2,
O
oC to rt, 1h
0 oC, 1h, 90%
H
H
0
(75.4% over 2 steps)
18
OTBS
OTBS
N3
DIAD, PPh3, DPPA,
THF, 0 oC to rt, 3h, 80%
BnO
OH
BnO
O
O
H
H
H
H
19
20
OTBS
Ac2O, DMAP,
PPh3,
THF-H2O,
BnO
NH2
O
Et3N, CH2Cl2,
0 oC to rt, 75%
oC to rt, 3h, 63%
H
H
0
21
OH
OTBS
H
H
ref. 3a
O
N
BnO
N
O
O
H
H
H
H
O
H
O
3
(−) -brevisamide 1
Scheme 3.

J. S. Yadav et al. / Tetrahedron Letters 54 (2013) 3227–3229
i
3229
epoxidation7 using t-BuOOH,
L
-(+)-diethyl tartrate, and Tið OPrÞ4 to
Uncited references
afford the epoxy alcohol 8 in 90% yield with excellent enantioselec-
tivity (95% ee, determined by chiral HPLC), which was then treated
with TBSOTf and Hunig’s base in order to accomplish the TBS pro-
tected syn-Aldol product 9. Unfortunately, the desired aldol product
9 was obtained only in 15% yield which could be due to the interfer-
ence of the C6–OBn group as has been reported by others.8 Alde-
hyde 9 was reduced using NaBH4 in MeOH to get the desired
stereo-diad 5 in 75% yield (Scheme 2).
Author: Please cite Ref. 16 in the text.
Acknowledgements
A.R. and K.R. thank the UGC and CSIR, New Delhi, for the award
of fellowships.
Unsatisfied with the above result, we adopted
a well
Supplementary data
precedented asymmetric Aldol addition strategy for the synthesis
of stereo-diad 5 via thiazolidinethione ester 10, as we have
reported in our previous synthetic approach to breviasmide.5 TBS
protection of secondary alcohol 10 and subsequent reductive
cleavage of chiral auxiliary furnished primary alcohol 5,9 which
was then converted into the corresponding bromide derivative
11 in 70% yield using triphenylphosphine (TPP) and CBr4 in anhy-
drous acetonitrile.10 The bromo compound 11 was then coupled
with lithiated 1-(tetrahydropyranyloxy)-2-propyne 12 to obtain
propargyl ether 13. Deprotection of THP group of 13 followed by
chemoselective reduction of alkyne moiety with Red-Al gave the
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.01.
134.
References and notes
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allyl alcohol 14 in 80% yield.11 Sharpless asymmetric epoxidation7
i
of the allyl alcohol 14 using
L
-(+)-diethyl tartrate, Tið OPrÞ4, and t-
BuOOH in anhydrous CH2Cl2 gave the epoxy alcohol 15 in 92%
yield. Dess–Martin periodinane oxidation12 followed by Wittig
olefination13 of the epoxy alcohol 15 gave styrylepoxide 16 in
63% yield with 9:1 E/Z ratio (Scheme 3).
Next we intended to attempt the 6-endo-cyclization of hydroxy
styrylepoxide 4 to access the tetrahydropyran 17. Accordingly,
compound 16 was treated with tetra-n-butylammonium fluoride
(TBAF) in anhydrous THF to provide the hydroxy styrylepoxide 4
in 90% yield. NaH induced 6-endo-cyclization of styryl epoxide 4
(Tadashi Nakata protocol)14 gave the desired tetrahydropyranyl
ether 17 in 90% yield with the requisite stereochemistry. Second-
ary hydroxyl group of tetrahydropyran 17 was protected as its
TBS ether 18 using t-butyldimethylsilyltrifluoromethanesulfonate
(TBSOTf), diisopropylethylamine in CH2Cl2 in 90% yield. Ozonoly-
sis13,15 of olefin 18 followed by the reduction of the resulting alde-
hyde with NaBH4 afforded the primary alcohol 19 in 82% yield.
Next, alcohol 19 was converted3c into the primary azide 20 using
Diisopropyl azodicarboxylate (DIAD), triphenylphosphine (TPP),
and diphenylphosphoryl azide (DPPA), which was then reduced
to the corresponding amine 21 using triphenylphosphine (TPP) in
THF/H2O system.3c Acylation of the primary amine 21 with Ac2O,
TEA in CH2Cl2 gave the desired C1–C15 fragment 3 of (ꢀ)-brevisa-
mide in 75% yield (Scheme 3). This route provided fragment 3 in a
1.35% overall yield in the longest linear sequence of 20 steps from
commercially available starting material. The spectral data and
optical rotation values of this advanced intermediate 3 (C1–C15
fragment) were in agreement with a known compound reported
in the literature.3a,5
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In conclusion, the formal synthesis of (ꢀ)-brevisamide has been
accomplished by constructing the tetrahydropyran core unit (C1–
C15 fragment of brevisamide). The base induced epoxide rear-
rangement strategy has been used to achieve syn-Aldol reaction.
The synthesis involves simple and straightforward reactions such
as the Sharpless asymmetric epoxidation and base induced 6-
endo-cyclization of hydroxy styrylepoxide.
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