Stereoselective synthesis of substituted N-heterocycles via sequential cross metathesis-reductive cyclization

Article abstract of DOI:10.1016/j.tetlet.2004.11.030

A diastereoselective synthesis of substituted piperidine and pyrrolidine derivatives is presented, employing a highly selective cross metathesis (CM) reaction followed by a domino reduction-cyclization process. A diastereoselective synthesis of substituted mono- and bicyclic-piperidine and pyrrolidine derivatives is presented, employing a highly selective cross metathesis (CM) reaction followed by a domino reduction-cyclization process.

Full text of DOI:10.1016/j.tetlet.2004.11.030

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 43–46
Stereoselective synthesis of substituted N-heterocycles
via sequential cross metathesis—reductive cyclization
Julian Gebauer, Purnama Dewi and Siegfried Blechert*
Technische Universita¨t Berlin, Institut fu¨r Chemie, Strasse des 17. Juni 135, D-10623 Berlin, Germany
Received 18 October 2004; revised 4 November 2004; accepted 5 November 2004
Available online 23 November 2004
Abstract—A diastereoselective synthesis of substituted mono- and bicyclic-piperidine and pyrrolidine derivatives is presented,
employing a highly selective cross metathesis (CM) reaction followed by a domino reduction–cyclization process.
Ó 2004 Elsevier Ltd. All rights reserved.
Substituted mono- and bicyclic-piperidine and pyrrol-
idine derivatives are among the most ubiquitous natural
building blocks for which a huge amount of synthetic
effort has been spent on their preparation.1 While
numerous examples of ring-closing metathesis (RCM)
and ring-rearrangement metathesis (RRM) for the
synthesis of N-heterocycles are known,2 the efficiency
of cross metathesis (CM) reactions has not yet been
explored as much. As an extension of previous work
within the group3 we herein present the highly selective
cross-coupling reaction of N-protected allylic and
homoallylic amines with a,b-unsaturated ketones and
acrylates followed by reductive cyclization as a general
approach towards their synthesis.
undergo a further diastereoselective cyclization yielding
bicycles of type 7 (Scheme 1).7
This tandem sequence should therefore allow flexible
and rapid access to N-heterocyclic compounds such
as pyrrolidines, piperidines, pyrrol-, indol- and quinol-
izidines.
The commercially available phosphine free ruthenium-
catalyst 3 was found to efficiently catalyze CM reactions
between alkyl-substituted and electron-deficient olefins
with high selectivities.4 Consequently, cross-coupling
of N-protected allylic and homoallylic amines with
enones or acrylates should easily afford aminoenones
of type 4, which upon catalytic hydrogenation are con-
verted into the saturated N-heterocycles 5 or 6 in a
sequence of double bond reduction, N-deprotection
and cyclization.5 While simple reductive aminations
affording piperidines and pyrrolidines of type 6 are
known to proceed cis-selectively under the control of
the stereocentre adjacent to the nitrogen,6 aminoenones
containing a second carbonyl group are expected to
Keywords: Cross metathesis; Reductive amination; Ruthenium cata-
lyst; Indolizidines; Pyrrolizidines.
*
Corresponding author. Tel.: +49 30 31422255; fax: +49 30
31423619; e-mail: blechert@chem.tu-berlin.de
Scheme 1. Synthesis of substituted N-heterocycles.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.030

44
J. Gebauer et al. / Tetrahedron Letters 46 (2005) 43–46
Table 1. Substrates for CM reactions
methyl acrylate 2a, methyl vinyl ketone 2b, n-butyl vinyl
ketone 2c9 and a series of enones 2d–h, (Table 1) pre-
pared as shown in Scheme 2.
1a
1b
1c
1d
2a
2b
R1 = CO2Me
R1 = CH2OBn
R1 = CH2OTBS
R1 = Bn
n = 1
n = 0
n = 0
n = 0
2c
2d
2e
2f
R2 = n-Bu
R2 = (CH2)3OTBS
R2 = Bn
R2 = 2-furyl
R2 = (CH2)2CHO
R2 = (CH2)2COMe
Protection of Weinreb amide 8, which is readily pre-
pared by aluminium promoted amidation of c-butyro-
lactone,10 and treatment with vinyl magnesium
bromide in THF at 0°C furnished enone 2d in high over-
all yield after acidic workup. Under the same conditions,
2e,f were obtained in excellent yield from Weinreb
amides 10a,b derived from the commercially available
acid chlorides 9a,b. While the synthesis of enedione 2h
has been reported by Stetter and Landscheidt,9 aldehyde
2g was prepared by condensation of lithiated methoxy-
allene, serving as an ester homoenolate equivalent,11
with commercially available 2-(2-bromoethyl)-1,3-
dioxolane to provide acetal 12 after acidic workup.
Deprotection with aqueous HCl gave the unstable
aldehyde 2g.
R2 = OMe
2g
2h
R2 = Me
The results and conditions of the CM reactions and sub-
sequent catalytic reductions are presented in Table 2.
All CM reactions were carried out in DCM at reflux
temperature utilizing 2.5–10% of Ru-catalyst 3.12 Except
the rather volatile (2a,b) or less reactive (2f) substrates
both coupling partners were preferably reacted in a 1:1
ratio giving exclusively the E-configurated alkenes
(E/Z > 20:1) in moderate to good yields. The prolonged
reaction times and increased amounts of catalyst needed
for the cross-coupling of allylic carbamates 1b,c may be
Scheme 2. Synthesis of substrates 2d–g.
To demonstrate the general applicability of this concept
we decided to react the known carbamates 1a–d8 with
Table 2. Results and conditions of CM and catalytic hydrogenation reactions
Substrates
CM product
Cyclization product
5% 3; 3 h
ƒƒƒƒƒƒ!
DCM; 40 ꢀC
1a+2a (1:2)
1b+2a (1:2)
4a (76%)
4b (71%)
5a: R = CO2Me, n = 1 (97%)a
(
)
H2; Pd=C
ƒƒƒƒƒ!
MeOH; 1 h
n
10% 3; 48 h
ƒƒƒƒƒƒ!
DCM; 40 ꢀC
R
N
O
5b: R = CH2OBn, n = 0 (91%)b
H
H2; Pd=C
ƒƒƒƒ!
Et2O; 3 h
2:5% 3; 3 h
ƒƒƒƒƒƒ!
DCM; 40 ꢀC
1a+2b (1:2)
1a+2c (1:1)
4c (85%)
4d (83%)
6a: R = Me (85%)
6b: R = n-Bu (83%)
MeO2C
N
H
R
1a+2d (1:1)
1a+2e (1:1)
1a+2f (1:2)
4e (64%)
4f (78%)
4g (73%)
6c: R = (CH2)3OTBS (96%)
6d: R = Bn (71%)
6e: R = 2-furyl (74%)
H2; Pd=C
ƒƒƒƒƒ!
MeOH; 3 h
5% 3; 16 h
ƒƒƒƒƒƒ!
DCM; 40 ꢀC
H2; Pd=C; 5 h
ƒƒƒƒƒƒƒ!
MeOH=AcOH
1b+2b (1:2)
1c+2b (1:2)
4h (77%)
4i (80%)
6f: R = Bn (72%)c
10% 3; 48 h
ƒƒƒƒƒƒ!
DCM; 40 ꢀC
RO
N
H
H2; PdðOHÞ2
ƒƒƒƒƒƒ!
MeOH; 5 h
6g: R = TBS (87%)d
H2; Pd=C; 24 h
ƒƒƒƒƒƒƒƒ!
MeOH=HCl
1a+12 (1:1)
1a+2h (1:1)
4j (65%)
4k (74%)
7a: R = H (81%)
7b: R = Me (77%)
5% 3; 16 h
ƒƒƒƒƒƒ!
DCM; 40 ꢀC
MeO2C
N
H2; Pd=C
ƒƒƒƒƒƒ!
MeOH; 16 h
R
R
1c+2h (1:1)
1d+2h (1:1)
4l (71%)
4m (62%)
7c: R = OTBS (73%)
7d: R = Ph (68%)
H2; Pd=C
ƒƒƒƒƒƒ!
MeOH; 72 h
N
10% 3; 72 h
ƒƒƒƒƒƒ!
DCM; 40 ꢀC
a After 5h in refluxing glyme.
b After 5h in refluxing MeOH.
c cis/trans = 1:1.
d cis/trans = 4:1.

J. Gebauer et al. / Tetrahedron Letters 46 (2005) 43–46
45
ascribed to the intramolecular chelation of the inter-
mediate ruthenium species.13 Higher temperatures
(toluene, 80°C) resulted in somewhat lower yields
presumably due to the concurrent decomposition of
the catalyst.
The subsequent catalytic reductions of aminoenones 4a–
m were performed in MeOH or Et2O (in case of rather
volatile products) at rt with 5mol% [Pd] under 1atm
of hydrogen.14 Single cyclizations gave rise to the pipe-
colates 6a–e with complete cis-selectivity, as determined
by NOE experimental analysis, and the lactams 5a,b
upon heating. In case of pyrrolidines, the facial selectiv-
ities of catalytic hydrogenations have been shown to
depend on substrate structure, catalyst and reaction
conditions.6e,f For example, when the reduction of sub-
strate 4h was performed in methanol using Pd/C the
reaction stopped after formation of the intermediate
pyrroline. Complete reduction could be achieved in the
presence of acetic acid,6f resulting in a 1:1 mixture of
diastereomers, or with PearlmanÕs catalyst causing par-
tial O-debenzylation. To rule out simultaneous depro-
tection, hydrogenation of the corresponding silylether
4i was investigated. Reduction using PearlmanÕs catalyst
was complete within 5h affording a 4:1 mixture of dia-
stereomers in favour of the cis-isomer 6g as assigned
by 1H NMR analysis (two doubled-doublets for the
CH2OTBS methylene protons at 3.55 and 3.62ppm,
respectively).15
Scheme 3. Synthesis of ( )-Xenovenine.
Scheme 4. Synthesis of ( )-Indolizidine 209D.
Scheme 3, the isolated pyrrolizidine was identical with
the natural product in all considerable respects.
Although mechanistically unexpected, these results are
somehow advantageous as access to the more attractive
class of naturally occurring (5Z,8E)-3,5-disubstituted
pyrrolizidines19 is enabled.
In order to verify the effect of a second reductive amin-
ation on the diastereoselectivity of the piperidine forma-
tion, the CM product of 1a and aldehyde 2g was
subjected to hydrogenation. Unfortunately, the first
cyclization attempts produced only small amounts of
the desired bicycle (20%), probably due to intermolecu-
lar side reactions. Alternatively, reduction of protected
analogue 4j in acidic media afforded the stereoisomer
7a as the only product whose relative configuration
was ascertained by comparison with the known ethyl
ester.16
Finally, we applied our two-step sequence on the diaste-
reoselective synthesis of the indolizidine alkaloid 209D,
a potent neurotransmitter exuded by the skin of neo-
tropical dendrobatid frogs.20 Starting from precursor
15, derived from heptaldehyde in a sequence of allyl-
ation, azidation and introduction of the benzyl carba-
mate,21 ( )-Indolizidine 209D could be conveniently
obtained in 77% overall yield (Scheme 4).
Since an additional methyl group would simplify the
determination of the diastereoselectivity of the second
reductive amination, we continued with the hydrogena-
tion of diketone 4k, which proceeded smoothly yielding
the disubstituted indolizidine 7b exclusively, whose spec-
troscopical data were identical with the ones reported.17
In conclusion, our proposed CM reaction—reductive
cyclization sequence has been successfully applied on
the convergent synthesis of various piperidine, pyrroli-
dine, indolizidine and pyrrolizidine derivatives as well
as on the diastereoselective total synthesis of ( )-Xeno-
venine and ( )-Indolizidine 209D. Considering the high
functional group tolerance of Ru-metathesis catalyst 3,
this concept should as well offer an efficient and stereo-
selective entry to structurally more diverse natural prod-
ucts. Further applications are therefore under
investigation and will be reported in due course.
Pleased by these results we turned to the reductive amin-
ations of the pyrrolizidine precursors 4l,m. The disap-
pearance of the imine intermediate was comparably
slow in both cases as monitored by TLC. Moreover,
the spectroscopical properties of the obtained products
were not in accordance with the expected trans-fused
isomers (cis-configuration at both pyrrolidine rings)
but with the less strained cis-fused isomers (trans-config-
uration at both pyrrolidine rings) lacking the specific
Bohlmann bands in their infrared spectra. To confirm
this observation we decided to prepare aminoenone 14
via precursor 138d and compare its cyclization product
with (+)-Xenovenine, a pyrrolizidine alkaloid found in
the thief ant Solenopsis xenovenum.18 As depicted in
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