Synthesis of botryllamides and lansiumamides via ruthenium-catalyzed hydroamidation of alkynes

Article abstract of DOI:10.1055/s-0029-1219961

Ruthenium-catalyzed hydroamidations of alkynes allow a concise synthetic entry to both E- and Z-configured enamide natural products. This was demonstrated by the synthesis of botryllamides C and E, lansiumamides A and B, and lansamide I in 1-3 steps and 57-98% yield from simple, commercially available precursors. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219961

LETTER
1685
Synthesis of Botryllamides and Lansiumamides via Ruthenium-Catalyzed
Hydroamidation of Alkynes
S
ynthesis of Bo
u
tryllamide
s
a
k
nd
L
ansiumamides s J. Gooßen,* Mathieu Blanchot, Matthias Arndt, Kifah S. M. Salih
Institut für Organische Chemie, TU Kaiserslautern, Erwin-Schrödinger-Str., Building 54, 67663 Kaiserslautern, Germany
Fax +49(631)2053921; E-mail: goossen@chemie.uni-kl.de
Received 26 March 2010
In memory of Keith Fagnou
synthesis of more complex structures, namely lansium-
amides, lansamides, and botryllamides (Figure 1).
Abstract: Ruthenium-catalyzed hydroamidations of alkynes allow
a concise synthetic entry to both E- and Z-configured enamide nat-
ural products. This was demonstrated by the synthesis of botrylla-
mides C and E, lansiumamides A and B, and lansamide I in 1–3
steps and 57–98% yield from simple, commercially available pre-
cursors.
O
O
R
Ar
Ph
N
N
H
Ph
OMe
botryllamides
Key words: alkyne, botryllamide, hydroamidation, lansamide, lan-
siumamide, ruthenium
OH
lansiumamides
Figure 1 Structures of lansiumamides and botryllamides
The enamide group is a substructure widely present in nat-
ural products with interesting biological activities,1 as
well as fungicides,2 metabolic drugs,3 and functional ma-
terials.4 Traditional synthetic entries to this substructure,
for example, condensation reactions, require harsh reac-
tion conditions and are usually not stereoselective.5 Met-
al-catalyzed coupling reactions offer much milder
reaction conditions but suffer from the limited availability
of the vinylic precursors, for example, vinyl halides or
pseudohalides.6 Based on pioneering studies by
Watanabe7 and inspired by catalytic additions of other nu-
cleophiles to alkynes,8,9 we have recently developed ru-
thenium-catalyzed hydroamidation reactions that allow
the anti-Markovnikov addition of various N–H nucleo-
philes to terminal alkynes under selective formation of ei-
ther E- or Z-configured enamide derivatives (Scheme 1).10
Lansiumamides including lansiumamides A and B, and
lansamide I have been isolated from the leaves and fruits
of Clausena lansium, a plant used in traditional chinese
medicine for the treatment, for example, of asthma and vi-
ral hepatitis.11 Total syntheses have been reported by
Taylor11b (4 steps, 8–28% overall yield) and Maier11d (5
steps, 11–12% overall yield). Taylor generated the enam-
ide moiety by adding vinylmagnesium reagents to isocy-
anates obtained via Curtius rearrangement of acyl azides.
Maier et al. employed various methods to condense alde-
hydes with amides. In all the above syntheses, the enam-
ides were obtained as mixtures of E- and Z-isomers in the
key step.
Botryllamides were first isolated from the marine ascidian
Botryllus tyreus as a complex mixture of ten structurally
closely related derivatives.12 They display activity as se-
lective inhibitors of the ABCG2 multidrug transporter.12c
While some of them have previously been prepared using
traditional methods for enamide synthesis (4 steps, 20%
yield),12d there are no published syntheses of botrylla-
mides C and E.
O
Ru cat. A
R3
R1
N
R2
O
H
+
R3
R1
N
R2
O
The synthesis of the above compounds can greatly be sim-
plified when employing Ru-catalyzed hydroamidation re-
actions to access the enamide moiety. The key advantage
of this strategy is that the stereoselectivity of the reaction
is controlled by the catalyst system, so that both (E)- and
(Z)-enamide products can selectively be synthesized from
the same, easily accessible amide and alkyne starting ma-
terials.
Ru cat. B
R1
N
R2
R3
Scheme 1 Hydroamidation of amides and terminal alkynes
The preparative utility of this synthetic strategy has so far
been demonstrated only using rather simple model sub-
strates. Based on the encouraging results obtained in these
studies, we decided to take the next hurdle and probe the
applicability of this methodology in the context of the
Lansiumamide A (3) is thus accessible in a single step
from commercially available phenylacetylene (2) and cin-
namide (1) in the presence of a ruthenium catalyst
(Scheme 2). We tested various catalyst systems and found
that this transformation is most effectively promoted by a
bimetallic catalyst generated in situ from bis(2-methal-
lyl)cycloocta-1,5-diene-ruthenium(II), 1,4-bis(dicyclo-
SYNLETT 2010, No. 11, pp 1685–1687
Advanced online publication: 04.06.2010
x
x
.x
x
.2
0
1
0
DOI: 10.1055/s-0029-1219961; Art ID: G10310ST
© Georg Thieme Verlag Stuttgart · New York

1686
L. J. Gooßen et al.
LETTER
O
syntheses, the same primary amide 9 was required. It was
obtained via an aldol condensation from commercially
available methyl 2-methoxyacetate (7) and 4-hydroxy-
benzaldehyde (8). The resulting ester was saponified in
situ and converted into the corresponding primary amide
9 in an overall 67% yield (Scheme 3). Its structure was
confirmed by X-ray crystal-structure analysis.13
[Ru(cod)(met)2]
dcypb, Yb(OTf)3
O
+
Ph
N
NH2
H
Ph
Ph
Ph
1
2
lansiumamide A (3)
98%, Z/E = 20:1
1. [Ru(cod)(met)2]
dcypb, Yb(OTf)3
2. 3 Å MS, Et3N
MeI, NaH
82%
Amide 9 was then treated with commercially available
4-methoxyphenylacetylene (10a) using the E-selective
hydroamidation protocol to give botryllamide E (11a) in
excellent yield (85%, E/Z = 20:1). We also synthesized
the Z-configured isomer (12a, 98%, Z/E = 9:1) using the
complementary hydroamidation protocol (Scheme 5).
O
O
O
N
MeI, NaH
NH
Ph
N
Ph
Ph
85%
Ph
Ph
Ph
5
85%, E/Z = 20:1
lansamide I (6)
72% overall yield
lansiumamide B (4)
78% overall yield
This isomer is sensitive to E/Z-isomerization under for-
mation of the thermodynamically favored botryllamide E
(11a). It is thus conceivable that 12a is also present in
Botryllus tyreus but isomerizes quantitatively during the
isolation procedure. The structure of this unnatural Z-con-
figured enamide 12a was confirmed by X-ray structure
analysis (Figure 2).14
Scheme 2 Syntheses of lansiumamides A and B and lansamide I
hexylphosphino)butane (dcypb), and ytterbium triflate
[Yb(OTf)3] in a DMF–water mixture. Within six hours,
the desired lansiumamide A (3) is formed in 98% yield
and a Z/E ratio of 20:1.10c Methylation of 3 according to
Maier’s protocol11d gave lansiumamide B (4) in 82%
yield. Lansamide I (6) was synthesized from the same
starting materials using the E-selective protocol, in which
a hydroamidation under the above conditions is combined
with an in situ double-bond isomerization (Scheme 2).
This way, the (E)-enamide 5 was obtained in 85% yield
and an E/Z ratio in excess of 20:1. The methylation pro-
ceeded in 85% yield, so that overall, lansamide I (6) was
obtained in 72% yield over two steps (Scheme 2).
The hydroamidation strategy was similarly effective for
the preparation of botryllamides C and E (11a,b). In both
Figure 2 X-ray structure of enamides 12a
OH
1. NaOMe, MeOH
OMe
O
O
2. HCl
3. (COCl)2, NH3
O
The synthesis of botryllamide C (11b) was carried out
analogously using the brominated phenylacetylene deriv-
ative 10b (Scheme 4). This was synthesized in near-quan-
titative yield from 3-bromo-4-methoxybenzaldehyde (13)
via a Bestmann–Ohira reaction.15
+
H
MeO
NH2
OMe
OH
7
8
9 (67%)
Scheme 3 Synthesis of amide 9
Again, the hydroamidation proceeded smoothly, and both
the Z-configured enamide 12b (88%, Z/E = 9:1) and the
E-configured botryllamide C (11b, 88%, E/Z = 20:1)
were obtained in high yields and selectivities (Scheme 5).
O
O
O
P
MeOH
K2CO3
H
+
OMe
OMe
MeO
MeO
N2
14
In conclusion, short and concise syntheses of lansium-
amides A and B, lansamide I, as well as botryllamides C
and E are possible using ruthenium-catalyzed hydroami-
dation reactions. Moreover, the sensitive Z-isomers of the
R
Br
13
10b R = Br (99%)
Scheme 4 Synthesis of alkyne 10b
OMe
R
9
OH
1. [Ru(cod)(met)2]
dcypb, Yb(OTf)3
2. 3 Å MS, Et3N
OMe
9
H
[Ru(cod)(met)2]
dcypb, Yb(OTf)3
N
OH
OMe
H
O
N
R = H (98%, Z/E = 9:1)
R = Br (88%, Z/E = 9:1)
R = H (85%, E/Z = 20:1)
R = Br (88%, E/Z = 20:1)
MeO
MeO
R
R
O
10a R = H
10b R = Br
11a R = H: botryllamide E
(57% overall yield)
11b R = Br: botryllamide C
(59% overall yield)
12a (66% overall yield)
12b (59% overall yield)
Scheme 5 Synthesis of botryllamides E and C
Synlett 2010, No. 11, 1685–1687 © Thieme Stuttgart · New York

LETTER
Synthesis of Botryllamides and Lansiumamides
1687
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Hydroamidation of Alkynes
An oven-dried flask was charged with the primary amide 1 or 9
(1.00 mmol), bis(2-methallyl)-cycloocta-1,5-diene-ruthenium(II)
(16.0 mg, 0.05 mmol), 1,4-bis(dicyclohexylphosphinobutane (27.0
mg, 0.06 mmol), and ytterbium triflate (24.8 mg, 0.04 mmol) and
flushed with nitrogen. Subsequently, dry DMF (3.0 mL), alkyne 2,
10a, or 10b (2.00 mmol), and H2O (108 mL, 6.00 mmol) were added
via syringe. The resulting solution was stirred for 6 h at 60 °C. To
access the (Z)-enamides, the reaction was worked up at this stage as
detailed below. To obtain the (E)-enamides, 3 Å MS (500 mg) and
Et3N (200 mL) were added to the reaction mixture, and stirring was
continued for 24 h at 110 °C.
For the workup, the reaction mixtures were poured into aq NaHCO3
(30 mL). The resulting mixture was extracted with EtOAc
(3 × 20 mL), the combined organic layers were washed with H2O
(20 mL) and brine (20 mL), dried over MgSO4, filtered, and the vol-
atiles were removed in vacuo. The residue was purified by column
chromatography (silica gel, EtOAc–hexane gradient). The identity
and purity of the enamide products were confirmed by 1H NMR and
13C NMR spectroscopy.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
complete experimental procedures and analytical data for com-
pounds 3–6, 9, 10b, 11, and 12.
Acknowledgment
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We thank the Deutsche Forschungsgemeinschaft for financial sup-
port and Umicore AG for generous donation of [Ru(cod)(met)2], the
Landesgraduiertenförderung Rheinland Pfalz and Deutscher Aka-
demischer Austauschdienst for scholarships to M.A. and K.S.M.S.
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(13) CCDC 768748 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(14) CCDC 768747 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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Synlett 2010, No. 11, 1685–1687 © Thieme Stuttgart · New York