Total synthesis of lansiumamides A and B and alatamide

Article abstract of DOI:10.1016/j.tetlet.2014.09.008

The total syntheses of lansiumamide A, lansiumamide B and alatamide have been completed taking advantage of the dihalo-olefination of N-formylimides. The syntheses are convergent, flexible and allow for the generation of analogues not accessible through o

Full text of DOI:10.1016/j.tetlet.2014.09.008

Tetrahedron Letters 55 (2014) 6042–6043
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of lansiumamides A and B and alatamide
Adele E. Pasqua a, Frank D. Ferrari a, James J. Crawford b, Rodolfo Marquez a,
⇑
a School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK
b Department of Medicinal Chemistry, AstraZeneca R&D, Charnwood, Bakewell Rd, Loughborough LE11 5RH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2014
Revised 21 August 2014
Accepted 3 September 2014
Available online 16 September 2014
The total syntheses of lansiumamide A, lansiumamide B and alatamide have been completed taking
advantage of the dihalo-olefination of N-formylimides. The syntheses are convergent, flexible and allow
for the generation of analogues not accessible through other routes.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Lansiumamide
Alatamide
Total synthesis
N-Formylimide
O
O
The tiger mosquito, Aedes albopictus, has been identified as a sig-
nificant vector in the transmission of dengue fever, yellow fever and
Chikungunya fever.1 Originally from Southeast Asia, the tiger mos-
quito has shown a remarkable ability to adapt quickly to different
climates. This adaptability has allowed it to invade and colonise vir-
tually every country, whilst making its control and suppression dif-
ficult to achieve.2
N
N
H
lansiumamide B
lansiumamide A
2
1
Plant extracts and their derivatives have been used in the fight
against the spread of mosquitos with mixed success. Recently Wan
and co-workers reported the use of petroleum ether extracts from
the seeds of Clausena lansium as antilarval agents.3 More impor-
tantly, Wan was able to isolate lansiumamide B (N-methyl-N-cis-
styrylcinnamamide, 2) as the active agent within the extract. Indeed,
isolated lansiumamide B (2) showed strong larvicidal activity (LC50
0.45 ppm) against the early fourth instar larvae of A. albopictus.3
Lansiumamides A (1) and B (2) are enamide-containing cinn-
amamide derivatives. First isolated in 1989,4 they have attracted
significant synthetic interest from Taylor, Maier and Fürstner.5 In
these syntheses, the enamide unit was obtained as a mixture of
E/Z isomers. More recently, Gooben reported the one-step synthe-
sis of the lansiumamides through the use of a ruthenium-catalysed
hydroamination of phenylacetylene and cinnamide. The geometry
of the enamide product is controlled by the nature of the ruthe-
nium catalyst.6,7
As part of our approach towards the synthesis of the lansiuma-
mides, we were interested in developing a synthetic route that
would allow the introduction of the enamide moiety in a stereocon-
trolled fashion (akin to the Gooben approach), whilst retaining the
flexibility to introduce substituents on the enamide core.
We recently reported the efficient and stereoselective genera-
tion of Z-b-bromo-enamides (5) through the selective dehalogen-
ation of the corresponding b,b-dibromo-enamides (4), which in
turn can be readily generated from N-formylimides (3) through
the use of modified Stork–Zhao olefination conditions (Scheme 1).8
Our synthesis began with trans-cinnamamide (6) which was
formylated with N-formylbenzotriazole to yield the key N-formyli-
mide 7.9 Treatment of N-formylimide 7 with (bromomethyl)tri-
phenylphosphonium bromide, under our previously reported
olefination conditions, generated the desired b,b-dibromo-ena-
mide 8 in high yield.8 Stereoselective debromination of 8 with
Pd/Bu3SnH then yielded the expected (Z)-b-bromo-enamide 9 in
good yield and with absolute stereocontrol (Scheme 2).
(Z)-b-bromo-enamide 9 was then subjected to Suzuki–Miyaura
coupling with phenylboronic acid to afford lansiumamide A (1) in
good yield, and as a single double bond isomer. Final methylation
⇑
Corresponding author. Tel.: +44 141 330 5953; fax: +44 141 330 4888.
E-mail address: rudi.marquez@glasgow.ac.uk (R. Marquez).
http://dx.doi.org/10.1016/j.tetlet.2014.09.008
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

A. E. Pasqua et al. / Tetrahedron Letters 55 (2014) 6042–6043
6043
O
O
O
n-BuLi,
O
O
N-formylbenzotriazole
CHO
Br
CHO
N
H
N
H
N
H
NH2
11
N
H
THF, 12 h
75%
Br
Br
12
3
5
4
O
Scheme 1.
Br Ph3PCH2Br
Pd(PPh3)4 (5 mol%),
K2CO3, 4-MeOC6H4B(OH)2
KOtBu
Br
N
THF, 12 h, 70 °C
THF, 12 h
79%
H
Br
13
O
O
n-BuLi,
N-formylbenzotriazole
CHO
N
H
NH2
OMe
OMe
THF, 12 h
70%
O
O
6
7
N
H
N
H
Br
Pd(PPh3)4 (10 mol%)
Bu3SnH
Br Ph3PCH2Br
O
N
KOtBu
15 12%
14
55%
Br
EtOAc, 12 h
64%
THF, 12 h
71%
H
Br
OMe
OMe
8
O
N
O
O
Zn-Cu couple
CH3COOH
Pd(PPh3)4 (5 mol%),
K2CO3, PhB(OH)2
N
N
H
THF/MeOH, 24 h
90%
H
Br
H
9
THF, 12 h, 70 °C
62%
10
1
Scheme 3.
O
N
NaH, MeI
THF, 70 °C, 3 h
100%
are convergent, flexible and allow for the generation of analogues
not accessible through other routes. We are currently using this
approach to generate novel analogues as antilarval agents.
2
Scheme 2.
Acknowledgments
of lansiumamide A (1) afforded lansiumamide B (2) in quantitative
yield.
We would like to thank Dr. Ian Sword for postgraduate support
(A.E.P.). The authors also thank Dr. Ian Sword and the EPSRC (Grant
EP/H005692/1) for funding.
Having completed the synthesis of the lansiumamides, we
decided to turn our attention to the synthesis of alatamide (10).
Alatamide (10) is a b-phenylethylamine-derived amide isolated
from the aerial parts of the plant Piper guayranum.10 Significantly,
and unlike the lansiumamides, alatamide (10) contains a 4-
methoxyphenyl substituted trans-enamide unit. Alatamide (10)
has attracted some synthetic interest, but not to the same degree
as the lansiumamides.11
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
09.008.
References and notes
OMe
O
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N
H
10
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Our synthesis of alatamide (10) began with the N-formylation of
benzamide (11) to afford N-formylbenzimide 12 in good yield.
Treatment of N-formylimide 12 under our modified Stork–Zhao
conditions then afforded the desired b,b-dibromo-enamide 13
(Scheme 3).
Suzuki–Miyaura cross-coupling of b,b-dibromo-enamide 13
with 4-methoxyphenylboronic acid afforded the desired phenyl
b-bromo-enamide 14 in 55% yield (75% based on recovered starting
material) together with a small amount of the disubstituted ena-
mide 15. Finally, reduction of bromo-enamide 14 afforded alata-
mide (10) in 90% yield.
In conclusion, we have completed the syntheses of lansiuma-
mide A (1), lansiumamide B (2) and alatamide (10) taking advan-
tage of the dihalo-olefination of N-formyl imides. The syntheses
10. Chatterjee, A.; Chakraborty, M.; Kundu, A. B. Aust. J. Chem. 1975, 28, 457.
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