A stereocontrolled synthesis of (±)-xenovenine via a scandium(III)-catalyzed internal aminodiene bicyclization terminated by a 2-(5-ethyl-2-thienyl)ethenyl group

Article abstract of DOI:10.1021/ol101646t

Figure Presented. A highly diastereoselective binary hydroamination of a 5-amino-1,8-diene containing a 2-(5-ethyl-2-thienyl)ethenyl terminator has been utilized in an efficient synthesis of (±)-xenovenine (1). A pronounced rate enhancement was observed for cyclization onto the 2-(heteroaromatic)ethenyl group in comparison to a simple 1,2-disubstituted alkene.

Full text of DOI:10.1021/ol101646t

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4271-4273
A Stereocontrolled Synthesis of
(()-Xenovenine via a
Scandium(III)-Catalyzed Internal
Aminodiene Bicyclization Terminated by
a 2-(5-Ethyl-2-thienyl)ethenyl Group
Tao Jiang and Tom Livinghouse*
Department of Chemistry and Biochemistry, Montana State UniVersity,
Bozeman, Montana 59717
liVinghouse@chemistry.montana. edu
Received July 15, 2010
ABSTRACT
A highly diastereoselective binary hydroamination of a 5-amino-1,8-diene containing a 2-(5-ethyl-2-thienyl)ethenyl terminator has been utilized
in an efficient synthesis of (()-xenovenine (1). A pronounced rate enhancement was observed for cyclization onto the 2-(heteroaromatic)ethenyl
group in comparison to a simple 1,2-disubstituted alkene.
The catalytic hydroamination of alkenes constitutes a syn-
thetic route to amines that is endowed with exceptional atom
economy. Although main-group metal complexes have been
used as catalysts for alkene hydroamination,1a the most
general cases for the synthesis of amines and their derivatives
involve transition metal catalysis using complexes of
rhodium,1b-d ruthenium,1e,f nickel1g-i and palladium,1j-p
gold,1q-s as well as the group 32a-n and group 42o-y metals.
In contrast to catalysis by complexes of the late transition
metals, hydroaminations involving complexes of the group
3 metals proceed via syn-addition of the metal-amido (M-N)
bond to the CdC double bond.2a,b In addition, diastereose-
lectivities associated with intramolecular hydroaminations of
chiral substrates by group 3 metals are correlated with both
the covalent radius of the metal and its ligand environment.2a
We have previously shown that a nonmetallocene complex
of Sc(III) supported by a strongly electron-donating chelating
diamide ligand (e.g., 3) provides superb trans/cis selectivities
in the cyclization of 2-substituted-4-pentenamines.2c In this
communication, we describe an efficient synthesis of (()-
xenovenine (1) that relies on rate enhancement attributable
to an unprecedented Sc(III)-catalyzed internal hydroamina-
tion involving a 2-(5-ethyl-2-thienyl)ethenyl terminator,
which serves as a surrogate for a conventional alkyl group.
The toxic pyrrolizidine alkaloid (+)-xenovenine (1) was
isolated from the skin of the frog Solenopsis xenoVeneum in
1980.3 From a biological standpoint it is noteworthy that
this defense alkaloid is not produced by the frog but instead
originates in the venom of ants that constitute, in part, the
diet of the amphibian. Xenovenine (1) has been the subject
of six total syntheses,4a-h one of which involved a sequential
bicyclization of an amino(allene)ene in the presence of a
constrained Sm(III) metallocene catalyst, where initial cy-
clization occurred at the more reactive allene.4c
We have reported that 5-amino-1,8-nonadiene (2a) un-
dergoes smooth sequential bicyclization to pyrrolizidine 5a
10.1021/ol101646t  2010 American Chemical Society
Published on Web 09/02/2010

via pyrrolidine 4a in the presence of complex 3 (5 mol %).2c
The most direct and obvious route to (()-xenovenine (1)
should therefore entail an analogous bicyclization of ami-
nodiene 2b. Unfortunately, common 1,2-disubstituted alkenes
are known to be very reluctant participants in internal
hydroaminations catalyzed by group 3 complexes.2d,e This
indeed proved to be the case as 2b, although subject to facile
monocyclization to provide 4b (t/c ) 49:1, characterized as
the p-toluenesulfonamide), underwent the required subse-
quent cyclization only with great lethargy and incompletely
at 120 °C (Scheme 1).
Scheme 1
.
Binary Hydroamination of Nonconjugated
Aminodienes
We have previously demonstrated that a representative
primary amine bearing a 2-(phenyl)ethenyl moiety (e.g.,
1-amino-2,2-dimethyl-5-phenyl-(E)-4-pentene) undergoes in-
ternal hydroamination at a significantly faster rate than simple
1,2-disubstituted aminoalkenes (i.e., 1-amino-2,2-dimethyl-
(E)-4-hexene).2d,h In light of this, it seemed reasonable that
terminal substitution by heteroaromatic groups might also
lead to rate acceleration of internal hydroamination. To test
this hypothesis in the context of the synthesis of (()-
xenovenine (1), the aminodiene 2c was prepared according
to the following protocol.
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Sequential lithiation of 5-hexen-2-one N,N-dimethyl-
hydrazone 6 (LDA, THF) followed by alkylation with 1,3-
dibromo-2-propene (THF, -78 f 0 °C) and subsequent
hydrolysis (H3O+) furnished ketone 7b as a mixture of Z-
and E-isomers in 94% overall yield. Coupling of 5-eth-
ylthiophene-2-boronic acid (8)5 with 7b [Pd(PPh)4 (5 mol
%), Na2CO3, LiCl, 1,2-DME] provided ketone 9 in 66%
yield as a 4:1 mixture of Z- and E-geometrical isomers,
from which the pure Z-isomer could be obtained in 48%
isolated yield by chromatography on silica gel. Reductive
amination of (Z)-9 (NaBH3CN, NH4OAc, MeOH) then
delivered the requisite aminodiene 2c in 85% isolated
yield. Exposure of 2c to complex 32c (10 mol %, toluene-
d8, 10 °C) resulted in an efficient and highly diastereo-
selective monocyclization to generate 2,5-disubstituted
pyrrolidine 4c (t/c ) 49:1, characterized as the p-
toluenesulfonamide) with >95% conversion. It is signifi-
cant that simply increasing the reaction temperature to
60 °C led to comparatively rapid (18 h) and stereospecific
bicyclization to afford pyrrolizidine 5c in 90% yield
[(NMR), 86% after chromatography]. Reductive desulfu-
rization of 5c (Raney-Ni, EtOH, 23 °C) ultimately secured
(()-xenovenine (1)6 in 98% yield (44% overall in five
steps from hydrazone 6) after purification by bulb-to-bulb
distillation (Scheme 2).
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(5) Conveniently prepared in 72% overall yield by the sequential
lithiation of 2-ethylthiophene (n-BuLi) followed by the addition of the
resulting organolithium to B(OMe)3 and hydrolysis.
(6) (()-Xenovenine prepared in this manner was spectroscopically
identical to the natural and previously synthesized products.
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Org. Lett., Vol. 12, No. 19, 2010

saturated 2-(alkyl)alkene in a Sc(III)-catalyzed hydroami-
nation. As the latter have proven substantial obstacles to the
general utilization of internal hydroaminations catalyzed by
early metal complexes in synthesis, the novel strategy
described here is expected to enable new pathways to target
molecules of interest.
Scheme 2
.
Internal Hydroamination of a 2-(Heteroaryl)ethenyl
Substituent
Acknowledgment. Generous financial support for this
research was provided by the National Institute of General
Medical Science. Support of the MSU mass spectrometry
facility has been provided in part by The Murdoch Charitable
Trust, INBRE P20 RR-16455-08, P20 RR-020185, and
1P20RR024237 from the NIH COBRE Program of the
National Center For Research Resources.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 1, 2b, 2c,
4bNTs, 4bNTs, 5c, 6, 7, 9, and their precursors. This material
is available free of charge via the Internet at http://pubs.acs.org.
The foregoing application vividly illustrates a pronounced
cyclization rate enhancement involving a 2-(heteroaromati-
c)ethenyl substituent as compared to the corresponding
OL101646T
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