Total synthesis of (+)-epiquinamide

Article abstract of DOI:10.1021/ol0515715

(Chemical Equation Presented) The stereoselective total synthesis of the novel quinolizidine alkaloid (+)-epiquinamide is presented, starting from the amino acid L-allysine ethylene acetal. Key steps in the synthesis involved a highly diastereoselective N

Full text of DOI:10.1021/ol0515715

ORGANIC
LETTERS
2005
Vol. 7, No. 18
4005-4007
Total Synthesis of (+)-Epiquinamide
Marloes A. Wijdeven,†,‡ Peter N. M. Botman,† Roel Wijtmans,‡
Hans E. Schoemaker,§ Floris P. J. T. Rutjes,‡ and Richard H. Blaauw*,†
Chiralix B.V., P.O. Box 31070, 6503 CB Nijmegen, The Netherlands, Radboud
UniVersity Nijmegen, IMM, ToernooiVeld 1, 6525 ED Nijmegen, The Netherlands, and
DSM Pharma Chemicals, AdVanced Synthesis, Catalysis & DeVelopment, P.O. Box 18,
6160 MD Geleen, The Netherlands
richard.blaauw@chiralix.com
Received July 5, 2005
ABSTRACT
The stereoselective total synthesis of the novel quinolizidine alkaloid (+)-epiquinamide is presented, starting from the amino acid L-allysine
ethylene acetal. Key steps in the synthesis involved a highly diastereoselective N-acyliminium ion allylation and a ring-closing metathesis
reaction to provide the bicyclic skeleton.
The novel quinolizidine alkaloid epiquinamide 1, recently
isolated from the skin of the Ecuadorian frog Epipedobates
tricolor, represents a new structural class of nicotinic
agonists, selective for â2 receptor subtypes.1 Similar to
epibatidine, it might function as a potential lead compound
for the development of new therapeutics for neuronal
receptors.1,2 Further investigations toward its biological
activity are hampered by the limited availability of the natural
product. In addition, the isolated amount of ∼240 µg of
epiquinamide proved to be sufficient for the determination
of the relative stereochemistry based on MS, IR, and NMR
analysis, resulting in the assignment of the (1R*,10R*)-1-
acetamidoquinolizidine isomer. However, the absolute ster-
eochemistry of the natural product to date remains unknown.
This communication details the stereoselective total synthesis
of (+)-epiquinamide, which confirms the relative stereo-
chemistry of the natural product and allows the production
of significant amounts of this biologically active compound.
As depicted in Scheme 1, we envisaged to obtain
epiquinamide from (2S,5R,6S)-hydroxypipecolic acid deriva-
tive 2. This key intermediate should provide the bicyclic
skeleton after a ring-closing metathesis reaction. Amide 2
could be derived from N-acyliminium ion precursor 3 via a
diastereoselective allylation reaction. For the synthesis of
N,O-acetal 3 we relied on our recently developed strategy
involving the cyclization of protected L-allysine ethylene
acetal 4 followed by a diastereoselective epoxidation/ring-
opening strategy applied on the obtained cyclic enamide.3
In turn, L-allysine ethylene acetal can be readily obtained in
enantiomerically pure form by biocatalytic resolution of the
corresponding amino acid amide.4,5
Scheme 1. Retrosynthetic Analysis
† Chiralix B.V.
‡ Radboud University Nijmegen.
§ DSM Pharma Chemicals.
(1) Fitch, R. W.; Garraffo, H. M.; Spande, T. F.; Yeh, H. J. C.; Daly, J.
W. J. Nat. Prod. 2003, 66, 1345.
(2) Baker, D. D.; Alvi, K. A. Curr. Opin. Biotechnol. 2004, 15, 576.
10.1021/ol0515715 CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/09/2005

The reaction sequence to Cbz-protected pipecolic acid
derivative 3a proceeds in an excellent yield of 94% over
four steps with a diastereoselectivity of 96:4 in favor of the
desired (2S,5R)-isomer (Scheme 2). Treatment of N,O-acetal
equiv of acryloyl chloride, whereafter the crude product was
used immediately for the next reaction. Indeed, treatment of
2a with a catalytic amount of the Grubbs second generation
ruthenium catalyst,9 followed by immediate hydrogenation
of the double bond, yielded the bicyclic product 7 in a yield
of 63% over three steps.
Scheme 2. Synthesis of the Bicyclic Corea
We also envisaged a more direct approach to quinolizidi-
none 7, by using an acrylate-type group instead of the Cbz
for nitrogen protection, prior to its use as a handle for the
ring-closing metathesis. However, since the acrylamide
moiety was already found to be prone to polymerization,
the expectedly more stable cinnamoyl group was chosen
instead (Scheme 3).
Scheme 3. Direct Introduction of the Cinnamoyl Moietya
3a with BF3‚OEt2 in the presence of allyltrimethylsilane gave
rise to a highly diastereoselective N-acyliminium ion reaction
yielding the (2S,5R,6S)-configured product 5 as a single
isolated product.3,6 Removal of the Cbz moiety under acidic
conditions7 allowed the subsequent introduction of an acry-
loyl group, setting the stage for the formation of the bicyclic
skeleton by ring-closing metathesis.8 It should be noted that
acrylamide 2a is a highly reactive intermediate, prone to
polymerization when treated with acid or heated above ∼40
°C. To circumvent the necessity of purification of the
unstable acrylamide, amine 6 was treated with exactly 1
Coupling of cinnamoyl chloride with amino acid 4
followed by methylation yielded amide ester 8 in a nearly
quantitative yield. Upon treatment with TsOH in refluxing
toluene the expected piperidine 9 was formed, although the
reaction suffered from extensive dimerization of the enamide
product. This could be circumvented by performing the
reaction in neat TFA, resulting in a fast and clean cyclization.
A completely selective epoxidation of the enamide double
bond was observed when 9 was treated with Oxone in
methanol, yielding N,O-acetal 3b. The conversion of 3b into
lactam 7 was accomplished in a manner analogous to the
protocol described in Scheme 2. Thus, N-acyliminium ion
allylation, followed by ring-closing metathesis and subse-
quent reduction of the double bond, afforded the desired
bicyclic product 7. Although all transformations from amide
8 to quinolizidinone 7 proceeded with good conversions, the
(3) Botman, P. N. M.; Dommerholt, F. J.; de Gelder, R.; Broxterman,
Q. B.; Schoemaker, H. E.; Rutjes, F. P. J. T.; Blaauw, R. H. Org. Lett.
2004, 6, 4941.
(4) For a racemic synthesis of L-allysine ethylene acetal, see: Rumbero,
A.; Mart´ın, F. C.; Lumbreras, M. A.; Liras, P.; Esmahan, C. Bioorg. Med.
Chem. 1995, 3, 1237.
(5) (a) Boesten, W. H. J.; Broxterman, Q. B.; Plaum, M. J. M.
EP0905257, 1999; Chem. Abstr. 1999, 130, 251283. (b) Wolf, L. B.; Sonke,
T.; Tjen, K. C. M. F.; Kaptein, B.; Broxterman, Q. B.; Schoemaker, H. E.;
Rutjes, F. P. J. T. AdV. Synth. Catal. 2001, 343, 662.
(6) For a recent review on N-acyliminium ion chemistry, see: (a)
Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817. (b)
Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C.
A. Chem. ReV. 2004, 104, 1431.
(7) The HBr salt of product 7 was treated with K2CO3 in MeOH in order
to liberate the partially acetylated 5-hydroxyl group.
(8) For a recent example of quinolizidine formation by RCM, see:
Kinderman, S. S.; de Gelder, R.; van Maarseveen, J. H.; Schoemaker, H.
E.; Hiemstra, H.; Rutjes, F. P. J. T. J. Am. Chem. Soc. 2004, 126, 4100.
(9) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
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Org. Lett., Vol. 7, No. 18, 2005

purification of the intermediates by column chromatography
over silica gel gave rise to substantial decomposition. For
this reason the products were taken through the five-step
sequence without intermediate purification, yielding 7 as a
single diastereomer in a reproducible yield of 22%.
X-ray structure analysis of the corresponding HCl salt
unequivocally proved the expected relative stereochemistry
of the final product (Figure 1).
The synthesis was completed as depicted in Scheme 4.
Mesylation of the alcohol, followed by treatment with sodium
Scheme 4. Completion of the Synthesis
Figure 1. Chem3D representation of the crystal structure of (+)-
1‚HCl.
In conclusion, a stereoselective total synthesis of (+)-
epiquinamide has been accomplished starting from L-allysine
ethylene acetal 4, confirming the structure and the relative
stereochemistry of the natural product. Key steps in the
synthesis involved a highly diastereoselective N-acyliminium
ion allylation and a ring-closing metathesis reaction to
provide the bicyclic skeleton. This synthesis allows the
generation of appreciable quantities of enantiomerically pure
epiquinamide, in 15 steps with an overall yield of 15.5%,
from readily available L-allysine ethylene acetal. Further-
more, this pathway is amenable to the synthesis of potentially
biologically active epiquinamide derivatives. Currently, we
are aiming at the elucidation of the absolute configuration
of natural epiquinamide, by comparison of the isolated
natural product with our synthetic material. The results of
these efforts will be detailed in due course.
azide, resulted in the formation of azide 10, in 79% yield.
After saponification of the methyl ester, a decarboxylation
was performed according to the method developed by
Barton.10 This involved the formation of the mixed anhydride,
followed by coupling with 2-mercaptopyridine-N-oxide. This
activated ester was then irradiated in the presence of
2-methylpropane-2-thiol, to afford 11 in 49% yield. The
sequence was completed by a LiAlH4-mediated reduction
of both the lactam as well as the azide, followed by acylation
of the primary amine yielding (+)-epiquinamide in a yield
of 84% over the last two steps.
Acknowledgment. SenterNovem (Ministry of Economic
Affairs, The Netherlands) is gratefully acknowledged for
providing financial support.
Supporting Information Available: Experimental details
and spectral data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(10) Barton, D. H. R.; Herve´, Y.; Potier, P.; Thierry, J. Tetrahedron 1988,
44, 5479.
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