A formal total synthesis of (-)-brevisamide, a marine monocyclic ether amide

Article abstract of DOI:10.1016/j.tetlet.2015.01.065

A formal total synthesis of (-)-brevisamide, a monocyclic ether amide with architecturally unique structural features, has been achieved. The tetrahydropyran core part of the target was synthesized by the aldol reaction followed by ring-closing metathesis using the Grubbs second generation catalyst. After the stereochemistry at the carbon center bearing the hydroxy group was adjusted, the carbon-carbon double bond was stereoselectively reduced by catalytic hydrogenation. Finally, introduction of the amino group was followed by acetylation, which provided the desired advanced intermediate.

Full text of DOI:10.1016/j.tetlet.2015.01.065

Accepted Manuscript
A Formal Total Synthesis of (–)-Brevisamide, a Marine Monocyclic Ether
Amide
Jungmee Lee, Hong-Se Oh, Han-Young Kang
PII:
S0040-4039(15)00080-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.01.065
TETL 45735
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 October 2014
6 January 2015
9 January 2015
Please cite this article as: Lee, J., Oh, H-S., Kang, H-Y., A Formal Total Synthesis of (–)-Brevisamide, a Marine
Monocyclic Ether Amide, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.01.065
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

A Formal Total Synthesis of (–)-Brevisamide, a Marine Monocyclic
Ether Amide
Jungmee Lee, Hong-Se Oh, Han-Young Kang*
Department of Chemistry, Chungbuk National University, Cheongju, Chungbuk 361-763,
Republic of Korea
Graphic Abstract

A Formal Total Synthesis of (–)-Brevisamide, a Marine Monocyclic
Ether Amide
Jungmee Lee, Hong-Se Oh, Han-Young Kang∗
Department of Chemistry, Chungbuk National University, Cheongju, Chungbuk 361-763,
Republic of Korea
Abstract
A formal total synthesis of (–)-brevisamide, a monocyclic ether amide with
architecturally unique structural features, has been achieved. The tetrahydropyran core
part of the target was synthesized by the aldol reaction followed by ring-closing
metathesis using the Grubbs second generation catalyst. After the stereochemistry at the
carbon center bearing the hydroxy group was adjusted, the carbon-carbon double bond
was stereoselectively reduced by catalytic hydrogenation. Finally, introduction of the
amino group was followed by acetylation, which provided the desired advanced
intermediate.
Keywords: Brevisamide, Asymmetric synthesis, Natural products, Aldol reaction, Ring-
closing metathesis
Ladder-frame polyethers secreted by dinoflagellates have been the subject of much
interest in recent years. Marine toxins such as brevetoxins, which belong to the
polyether class of natural products, are responsible for the mass death of fishes and
marine animals in the Florida Coast and Gulf of Mexico. Brevetoxin B, the first
member of a new class of unique marine natural products with a ladder-like molecular
architecture, binds to the voltage-sensitive sodium channels in neurons. A simpler
polyether, brevenal (1), which is actually an antagonist of brevetoxins, has been isolated
from the marine dinoflagellate Karenia brevis. In 2008, Wright and co-workers
discovered a new alkaloid, (–)-brevisamide (2),1 from the same dinoflagellate. Based on
the structure of these two compounds, 2 has been assumed to be the biosynthetic
precursor to 1 (Fig 1).2,3 (–)-Brevisamide (2), a monocyclic ether amide, contains a
characteristic tetrahydropyran ring substituted with a 3,4-dimethylhepta-2,4-dienal side
∗
Corresponding author. Tel +82 43 261 2305; fax +82 43 267 2279.
E-mail address: hykang@chungbuk.ac.kr
1

chain. Ever since the first total synthesis of 2 was reported by Satake, Tachibana, and
co-workers,4a it has attracted increasing attention from synthetic chemists. Many
research groups have reported the total synthesis4 as well as formal total synthesis5 of 2.
OH
H
O
H
H
O
H
O
H
H
H3C
O
H
H
OH
O
H
CH3
CH3
H
1
Brevenal ( )
H3C
O
H3C
OH
CH3
H
O
N
CH3
O
H
H
H
CH3
O
2
Brevisamide ( )
Figure 1. Brevenal (1) and brevisamide (2).
We have been interested in the synthesis of 2 because of its unique tetrahydropyran
core structure with multiple stereocenters. The synthesis of 2 may also provide an
efficient synthetic route to oxacyclic natural products.
Retrosynthetic analysis of the target is shown in Scheme 1. The synthesis of
brevisamide (2) could be achieved by coupling the side chain part 3 with the
tetrahydropyran ring part 4, which, in turn, could be derived from the known
intermediate 5. The tetrahydropyran core part 5 could be synthesized from 6. The
compound 6 then could be derived from 7 by aldol reaction followed by ring-closing
metathesis (RCM), which is eventually synthesized from 1,4-butanediol. Because the
protected substituted tetrahydropyran core 5 has been known as a synthetic intermediate
for the target 2,4b successful synthesis of 5 could complete a formal total synthesis of 2.
2

Me
OH
Me
H
O
N
Me
O
H
H
H
Me
O
2
Brevisamide
OTBS
Me
OEt
O
+
O
NHAc
P OEt
O
H
H
Me
OEt
O
H
4
3
OH
OH
OTBS
NHAc
O
O
H
H
H
H
OR
5
6
OH
(known intermediate)
Bn
OH
O
N
O
HO
O
1,4-butanediol
O
OR
7
Scheme 1. Retrosynthetic analysis of brevisamide (2).
The synthetic sequence to the key precursor 13 for the cyclization is shown in
Scheme 2. Our synthesis commenced with 1,4-butanediol, which was first converted to
α,β-unsaturated ester 9a via a three-step sequence (a series) as reported in the
literature.5c
3

R
1) DIBALH, THF
OH
ref. 5c
HO
1,4-Butandiol
BnO
CO2Et
2) (+)-DET, 4A MS
Ti(OiPr)4
9a
9b
(65%, 3 steps)
(77%, 3 steps)
cumene
hydroperoxide
a series
b series
(R=H)
(R=CH3)
R
R
1) MsCl, Et3N, CH2Cl2
OH
NaH, bromoacetic acid
DMF, THF
BnO
BnO
O
OH
2) (a) NaI, THF, reflux
(b) Zn dust, I2
11a
11b
(91%, 3 steps)
(83%, 3 steps)
10a
10b
(60%, 2 steps)
(60%, 2 steps)
MeOH, 80oC reflux
Bn
TiCl4, DIPEA,
NMP, Acrolein
R
R
PivCl, Et3N, THF
N
O
OH
(S)-5-lithio-4-benzyl
-oxazolidin-2-one
THF, -78oC
O
O
CH2Cl2, -78oC
O
O
O
OBn
OBn
12a
12b
7a
7b
11a
)
(80%, 2 steps from
(83%, 2 steps from
11b
)
13a
(for
)
Bn
N
OH
OTBS
1) TBAF
2) DMP
R
OH
O
1) TBSCl, imidazole
2) LiBH4, MeOH(cat.)
O
O
O
O
3) NaBH4,
CeCl3
H
3) Grubbs 2nd
OMOM
OMOM
7H2O
O
4) MOMCl, DIPEA
OBn
OBn
(81%, 3 steps)
(72%, 4 steps)
OBn
14
15
13a
13b
(59%)
(54%)
OH
O
1) m-CPBA
2) TBSOTf,
2,6-lutidine
OTBS
OTBS
CuBrSXMe2, MeMgBr
O
O
THF,-78oC to 0oC
OMOM
OMOM
(83%, 2 steps)
OBn
17
OBn
16
Scheme 2. Synthesis of 13 and attempt to prepare functionalized tetrahydropyran 17.
After reduction of the ester group, the resulting allylic alcohol was subjected to
Sharpless asymmetric epoxidation to afford the optically pure epoxy alcohol 10a. Next,
mesylation of 10b followed by the reaction with NaI provided the corresponding iodide,
which was treated with Zn dust, successfully afforded the optically active allylic alcohol
11a in good yield. For synthesizing the substituted tetrahydropyran ring, we decided to
adopt the strategy developed by the Crimmins’ group.6 Thus, glycolic acid was first
attached to the alcohol 11a by the reaction with bromoacetic acid in order to prepare the
substrate for the aldol reaction. The resulting carboxylic acid 12a was then activated
with pivaloyl chloride to attach the Evans’ oxazolidinone chiral auxiliary to prepare the
desired aldol substrate 7a. The asymmetric aldol reaction of 7a with acrolein was then
4

successively accomplished via enolate generation with TiCl4 in the presence of a base.7
In this way, the desired aldol product 13a was prepared in reasonable yield. The TBS-
protection of hydroxy group followed by removal of the Evans’ chiral auxiliary (LiBH4
reduction) afforded the desired diene for cyclization to form the tetrahydropyran core.
RCM using the Grubbs second generation catalyst, 8 which was succeeded by a MOM
protection of the resulting hydroxy group, led to the dihydropyran 14, thus proving the
utility of the aldol-RCM strategy. Next, for introducing a methyl group stereoselectively,
we decided to use the stereoselective nucleophilic opening of an epoxide. Thus,
deprotection of the TBS group followed by a DMP oxidation afforded the corresponding
ketone, which was then subjected to Luche reduction (NaBH4, CeCl3).9 The hydride
attack exclusively produced the desired allylic alcohol 15 with an inverted
stereochemistry of the carbon bearing the hydroxy group. In this case, an excellent
selectivity (ca. 20:1 (1H NMR)) was achieved, compared with the NaBH4 reduction of a
similar ketone substrate that only afforded an 1:1 mixture of products.4e The subsequent
epoxidation was expected to be controlled by the hydroxy group. In fact, after
protection of the hydroxy group with TBS, epoxide 16 could be successfully prepared,
where the oxygen was delivered from the same side as that of the hydroxy group. We
expected at this stage that a cuprate (CuBr.SMe2, MeMgBr) attack would enable the
nucleophilic ring opening of the epoxide. Unfortunately, the reaction failed, presumably
due to the existence of a substituent at the carbon adjacent to the epoxide ring. This
forced us to modify the synthetic route.
We decided to introduce the methyl group before the RCM reaction, assuming that
the steric hindrance caused by an additional methyl group would be tolerated in the
RCM reaction. The synthetic sequence corresponding to this strategy is also
summarized in Scheme 2 (b series). The desired 2-methyl-substituted α,β-unsaturated
ester 9b was prepared according to the procedure reported in the literature.5c Reduction
of 9b followed by Sharpless asymmetric epoxidation afforded the epoxy alcohol 10b
(92% ee, determined by chiral HPLC). Then, allylic alcohol 11b was prepared by the
previously mentioned three-step sequence [(1) Et3N, MsCl, (2) NaI, THF, reflux, (3) Zn
dust, I2, MeOH, reflux]. Introduction of the glycolic acid followed by attachment of the
Evans’ chiral auxiliary secured the substrate 7b for the asymmetric aldol-RCM protocol.
Asymmetric aldol reaction was successfully performed in acceptable yield to provide
13b (dr 12:1 determened by 1H NMR analysis of 6b (vide infra)).
The synthesis of the key intermediate 5 from 13b is summarized in Scheme 3.
Removal of the chiral auxiliary by reduction now set the stage for the critical RCM
reaction. The RCM reaction of the resulting diol using the Grubbs second generation
5

catalyst indeed smoothly afforded the cyclic product 6b. After protection of the primary
hydroxy group of 6b with TBS, inversion of the carbon stereochemistry bearing
secondary hydroxy group by an oxidation-reduction sequence exclusively gave the
desired six-membered cyclic allylic alcohol 18 (with >20:1 selectivity (1H NMR)) with
a methyl group in good overall yield.
With the desired intermediate 18 in hand, selective reduction of the double bond of
18 was needed, through which the hydrogen atom would come from the same side of
the hydroxy group to afford the tetrahydropyran ring with the methyl group trans to the
hydroxy group. Catalytic hydrogenation of 18 under normal reaction conditions (Pd/C,
RT) in EtOAc provided the hydrogenated product with concomitant debenzylation. The
product with benzyl group that remained intact could not be obtained. A solvent change
from EtOAc to MeOH did not solve the problem. The use of PtO2, as the hydrogenation
catalyst, afforded the desired product in low yield with concomitant debenzylation.
Finally, to our delight, the selective hydrogenation of 18 without debenzylation was
achieved by adding Et3N to the reaction mixture.10 The desired product 19 was obtained
in good yield (86%). After the hydroxy group of 19 was protected (TBSOTf, 2,6-
lutidine), the primary hydroxy group of 20 was deprotected under the acidic condition
(CSA) to provide alcohol 21. An azido group was successfully introduced using the
Mitsunobu procedure to afford 22. Next, the azido group was reduced to an amine,
which was then acetylated to give 23. This acetamide 23 is previously known in the
literature as an advanced intermediate for the total synthesis of 2. The spectral data (1H
and 13C NMR) of 23 was consistent with those reported in the literature.4b Finally, the
benzyl group of 23 was removed under the standard conditions, to afford alcohol 5. The
spectral data and the optical rotation value of 5 were in agreement with those reported in
the literature.4b Because a five-step conversion of 5 to 2 has been reported in the
literature,4b the synthesis of 5 completes a formal total synthesis of 2.
In conclusion, a formal total synthesis of (–)-brevisamide, a monocyclic ether
amide, was achieved. We successfully synthesized the advanced intermediate 5, the
dihydropyran core of (–)-brevisamide with an overall yield of 4.5% in 23 steps starting
from 1,4-butanediol. This was performed by the asymmetric aldol and RCM reaction as
the key combination of reactions to construct the desired tetrahydropyran ring with
multiple stereocenters. Generation of the dihydropyran ring with a trisubstituted carbon-
carbon double bond was achieved by RCM efficiently. Selective hydrogenation was also
successfully conducted in the presence of the labile benzyl group, which resulted in the
effective installation of the required stereochemistry of the carbon bearing a methyl
group on the tetrahydropyran ring as well as the elimination of an additional protection
6

step for the hydroxy group.
Scheme 3. Completion of the formal total synthesis of brevisamide (2) (Synthesis of 5).
7

Acknowledgments
This research is supported by Basic Science Research Program through the
National Research Foundation of Korea (NRF) funded by the Ministry of Education,
Science and Technology (2012-008105). This work was conducted during the research
year of Chungbuk National University in 2013.
Supplementary data
Supplementary data associated with this article can be found in the on line version
at __________.
References and notes
1. Satake, M.; Bourdelais, A. J.; Van Wagoner, R. M.; Baden, D. G.; Wright, J. L. C. Org.
Lett. 2008, 10, 3465-3468.
2. Van Wagoner, R. M.; Satake, M.; Bourdelais, A. J.; Baden, D. G.; Wright, J. L. C. J.
Nat. Prod. 2010, 73, 1177-1179.
3. Shirai, T.; Kuranaga, T.; Wright, J. L. C.; Baden, D. G.; Satake, M.; Tachibana, K.
Tetrahedron Lett. 2010, 51, 1394-1396.
4. (a) Kuranaga, T.; Shirai, T.; Baden, D. G.; Wright, J. L. C.; Satake, M.; Tachibana, K.
Org. Lett. 2009, 11, 217-220; (b) Fadeyi, O. O.; Lindsley, C. W. Org. Lett. 2009, 11,
3950-3952; (c) Ghosh, A. K.; Li, J. Org. Lett. 2009, 11, 4164-4167; (d) Lee, J.; Panek,
J. S. Org. Lett. 2009, 11, 4390-4393; (e) Herrmann, A. T.; Martinez, S. R.; Zakarian,
A. Org. Lett. 2011, 13, 3636-3639; (f) Tsutsumi, R.; Kuranaga, T.; Wright, J. L. C.;
Baden, D. G.; Ito, E.; Satake, M.; Tachibana, K. Tetrahedron 2010, 66, 6775-6782;
(g) Yadav, J. S.; Reddy, N. M.; Rahman, M. A.; Prasad, A. R.; Reddy, B. V. S.
Tetrahedron 2013, 69, 8618-8625.
5. (a) Smith III, A. B.; Kutsumura, N.; Potuzak, J. Tetrahedron Lett. 2011, 52, 2117-
2119; (b) Sabitha, G.; Nayak, S.; Bhikshapathi, M.; Yadav, J. S. Org. Lett. 2011, 13,
382-385; (c) Yadav, J. S.; Raju, A.; Ravindar, K.; Reddy, B. V. S. Tetrahedron Lett.
2013, 54, 3227-3229; (d) Kumaraswamy, G.; Murthy, A. N.; Narayanarao, V.;
Vemulapalli, S. P. B.; Bharatam, J. Org. Biomol. Chem. 2013, 11, 6751-6765; (e)
Sudharani, C.; Venukumar, P.; Sridhar, P. R. Eur. J. Org. Chem. 2014, 8085-8093.
6. (a) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653-5660; (b)
Crimmins, M. T.; King, B. W.; Zuercher, W. J.; Choy, A. L. J. Org. Chem. 2000, 65,
8499-8509; (c) Crimmins, M. T.; Tabet, E. A. J. Org. Chem. 2001, 66, 4012-4018.
8

7. Crimmins, M. T.; She, J. Synlett 2004, 1371-1374.
8. Metathesis in Natural Product Synthesis; Cossy, J., Arseniyadis, S., Meyer, C., Eds.;
Wiley-VCH: Weinheim, 2010.
9. Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454-5459.
10. (a) Sajiki, H. Tetrahedron Lett. 1995, 36, 3465-3468; (b) Sajiki, H.; Hirota, K.
Tetrahedron 1998, 54, 13981-13996; (c) Säwén, E.; Roslund, M. U.; Cumpstey, I.;
Widmalm, G. Carbohyd. Res. 2010, 345, 984-993.
9