Practical total syntheses of epiquinamide enantiomers

Article abstract of DOI:10.1021/ol061736p

Short and practical syntheses of epiquinamide and its enantiomer were accomplished with high overall yields and high stereoselectivity from readily available starting materials. American Chemical Society.

Full text of DOI:10.1021/ol061736p

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4541-4543
Practical Total Syntheses of
Epiquinamide Enantiomers
Takashi L. Suyama and William H. Gerwick*
UniVersity of California, San Diego, Scripps Institution of Oceanography,
9500 Gilman DriVe, MC 0212, La Jolla, California 92093
wgerwick@ucsd.edu
Received July 14, 2006
ABSTRACT
Short and practical syntheses of epiquinamide and its enantiomer were accomplished with high overall yields and high stereoselectivity from
readily available starting materials.
Rainforest frogs have been a rich source of neurologically
relevant alkaloids.1-3 Epibatidine 1 was isolated from an
Ecuadorian frog Epipedobates tricolor (Figure 1) in 1992
along with 1 from the same frog species in 20031 and has
attracted much attention due to its potent and selective
agonistic activities against â2 nicotinic receptors.1,3 Its
potential to be a lead compound in the development of
pharmacological agents seems promising, following the
history of epibatidine.2,4 The varying abundance of nAChRs
subtypes in different tissues should enable their selective
therapeutic targeting.5-7 However, the major limiting factor
in testing this compound has been its low availability (240
µg from the skins of 183 frogs).1 To date, two total syntheses
of (+)-epiquinamide,8,9 another synthesis of the antipode,10
and a racemic synthesis11 have been reported. However, these
enantiospecific syntheses are relatively long (12,8 14,9 and
13 steps,10 respectively) and/or their starting materials are
either highly expensive or not readily available. We therefore
Figure 1. Neurologically relevant alkaloids from Epipedobates.
by Daly and co-workers and has become one of the
cornerstone compounds in the field of nicotinic acetylcholine
receptor (nAChR) studies.3,4 Epiquinamide 2 was isolated
(5) Vincler, M. Expert Opin. InVest. Drugs 2005, 14, 1191-1198.
(6) Anthenelli, R. M. Clin. Neurosci. Res. 2005, 5, 175-183.
(7) Gotti, C.; Riganti, L.; Vailati, S.; Clementi, F. Curr. Pharm. Design
2006, 12, 407-428.
(8) Tong, S. K.; Barker, D. Tetrahedron Lett. 2006, 47, 5017-5020.
(9) Huang, P. Q.; Guo, Z. Q.; Ruan, Y. P. Org. Lett. 2006, 8, 1435-
1438.
(1) Fitch, R. W.; Garrafo, H. M.; Spande, T. F.; Yeh, H. J. C.; Daly, J.
W. J. Nat. Prod. 2003, 66, 1345-1350.
(2) Baker, D. D.; Alvi, K. A.Curr. Opin. Biotechnol. 2004, 15, 576-
583.
(3) (a) Daly, J. W. Cell. Mol. Neurobiol. 2005, 25, 513-552. (b) Daly,
J. W.; Spande, T. F.; Garrafo, H. M. J. Nat. Prod. 2005, 68, 1556-1575.
(4) Spande, T. F.; Garrafo, H. M.; Edwards, M. W.; Yeh, H. J. C.;
Pannell, L.; Daly, J. W. J. Am. Chem. Soc. 1992, 114, 3475-3478.
(10) Wijdeven, M. A.; Botman, P. N. M.; Wijtmans, R.; Schoemaker,
H. E.; Rutjes, F. P. J. T.; Blaauw, R. H. Org. Lett. 2005, 7, 4005-4007.
(11) Kanakubo, A.; Gray, D.; Innocent, N.; Wonnacott, S.; Gallagher,
T. Bioorg. Med. Chem. Lett. 2006, 16, 4648-4651.
10.1021/ol061736p CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/26/2006

undertook the development of a practical and flexible
synthesis that could provide substantial amounts of 2
(Scheme 1).
converted smoothly to the Weinreb amide 6 using a common
coupling condition (Scheme 2).14 After simple washings, the
Scheme 2. Synthesis of Mesylate 4
Scheme 1. Retrosynthesis of (+)-Epiquinamide
product was fairly pure and required no further purification.
Upon treatment with an allyl Grignard reagent, we obtained
the ketone 7 as white crystals. Chelation-controlled hydride
reduction of 7 yielded a highly crystalline alcohol, 8.15 By
1H and 13C NMR, none of the other diastereomer was
observed in the crystallized product, whose stereochemistry
was ultimately proven by completion of the total synthesis
and comparison to epi-epiquinamide (12).16 Mesylation of
the amino alcohol proceeded smoothly with an excellent
yield, and again the product was crystalline. Therefore, the
synthesis of the SN2 substrate 4 was accomplished very
conveniently and without chromatographic purification unless
recovery of the residual amount of the product in the filtrate
was desired.
Transformation of the mesylate 4 to the title compound
was accomplished as shown in Scheme 3. Removal of the
Boc group in TFA/CH2Cl2 followed by intramolecular SN2
cyclization induced by K2CO3 and subsequent N-alkylation
in acetonitrile yielded the diallyl piperidine 3 in good yield
(9 was not isolated or characterized).17-19
In the literature on epiquinamide, the optical rotation value
of the natural product was never reported due to its low
availability.1 Access to both enantiomers is therefore of great
importance. Herein described is the synthesis of epiquinamide
and its enantiomer.
The quinolizidine ring could be derived from a piperidine
with appropriate appendages that could be cyclized to give
the second ring. Initially, we were interested in developing
a reductive amination-type method for the construction of
the first ring because there has been little effort to synthesize
cis-2,3-disubstituted piperidines via such an approach.12 This
approach, however, was not fruitful in our hands; the
reductive amination cyclization yielded trans-piperidine 10
in excellent de. The relative stereochemistry of this product
was determined by X-ray crystallography after it was
converted to the Cbz-protected quinolizidine (11).13
We then envisioned a dissection of the molecule in a
manner similar to the first attempt but differing in the mode
of the first cyclization. The intramolecular SN2 cyclization
would yield the 2,3-disubstituted piperidine 3 with the
inverted stereochemistry. The substrate for the SN2 reaction
can be easily derived from a corresponding amino alcohol,
such as 8, which could be synthesized from ornithine. The
synthesis of the intramolecular SN2 substrate began with a
commercially available ornithine derivative 5, which was first
The synthesis of the epiquinamide skeleton was concluded
by ring-closing metathesis (RCM) reaction on 3 using the
Grubbs second-generation catalyst.20 It is noteworthy that
(14) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3818. (b) Mentzel, M.; Hoffmann, H. M. R. J. Prakt. Chem./ Chem.-Ztg.
1997, 339, 517-524.
(15) (a) So, R. C.; Ndonye, R.; Izmirian, D. P.; Richardson, S. K.;
Guerrera, R. L.; Howell, A. R. J. Org. Chem. 2004, 69, 3233-3235. (b)
Haug, B. E.; Rich, D. H. Org. Lett. 2004, 6, 4783-4786.
(16) The bridgehead proton of 2 has a chemical shift of δ 3.91 ppm,
and that of 12 has a shift of δ 3.95 ppm in MeOH-d4. Otherwise, the two
compounds have exactly the same carbon framework and molecular weight
by NMR and LRMS.
(12) (a) Pal, K.; Behnke, M. L.; Tong, L. Tetrahedron Lett. 1993, 34,
6205-6208. (b) Singh, R.; Ghosh, S. K. Tetrahedron Lett. 2002, 43, 7711-
7715. (c) Go´mez-Monterrey, I.; Gonza´lez-Mun˜iz, R.; Herranz, R.; Garc´ıa-
Lo´pez, M. T. Tetrahedron Lett. 1993, 34, 3593-3594. (d) Jefford, C. W.;
Wang, J. B. Tetrahedron Lett. 1993, 34, 2911-2914.
(17) (a) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2005,
127, 1473-1480. (b) Wang, Q.; Sasaki, N. A. J. Org. Chem. 2004, 69,
4767-4773.
(13) An initial attempt to asymmetrically synthesize the title compound
was made.
(18) Cyclization was extremely slow in the absence of base.
(19) (a) Sundberg, R. J.; Amat, M.; Fernando, A. M. J. Org. Chem. 1987,
52, 3151-3159. (b) Kinderman, S. S.; Wekking, M. M. T.; van Maarseveen,
J. H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. J. Org. Chem.
2005, 70, 5519-5527.
(20) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.,
Int. Ed. 2005, 44, 4490-4527.
4542
Org. Lett., Vol. 8, No. 20, 2006

from 5 were 38% and 28% for the longer and shorter
sequences, respectively ((+)-2 [R]22 ) +24° (c 0.10,
D
Scheme 3. Synthesis of (+)-Epiquinamide
CHCl3)).26 Only three chromatographic purification steps
were required throughout the synthesis.
The synthesis of the other enantiomer was performed in
the same manner starting with commercially available δN-
Boc-RN-Cbz-D-ornithine. This latter synthesis was accom-
plished in two weeks, demonstrating the practicality of this
synthetic route ((-)-2 [R]22 ) -22° (c 0.13, CHCl3)).27
D
Because neither the optical rotation value nor the circular
dichroism spectrum of the authentic natural product was
reported, the absolute stereochemistry of the natural product
could not be determined despite our access to both enanti-
omers. We then sought to learn the biological properties of
the two isomers. However, contrary to our expectation,
neither of the enantiomers showed activity in our routine
Na+ channel blocking/activation assays, H460 cancer cyto-
toxicity assay, or brine shrimp toxicity assay. Our results
are consistent with a recent report for synthetic (()-
epiquinamide which was inactive in competitive binding
assays using [3H]epibatidine and thus makes further uncertain
the identity of the pharmacologically active material from
the frogs.11
this is one of the first examples of a basic N-allyl group
undergoing ruthenium-catalyzed RCM.21 The scope of
functional group tolerance by the Grubbs second-generation
catalyst may be even greater than the current concensus.20b,22
However, the purification of this rather polar RCM product
presented difficulties.23 The problem was overcome when
Cho and Kim’s method was employed with a small modi-
fication.24 Deprotection, alkene reduction, and acetylation
were accomplished in one pot by hydrogenation of 10 in
ethanol with acetic anhydride.25 A better yield was observed
when this process was separated into two steps as shown in
Acknowledgment. The NIH (NS053398) is thanked for
their financial support for this research. We wish to thank
Mr. Joshua Wingerd at UCSD for Na+ channel and cyto-
toxicity assays. The Department of Chemistry at UCSD and
Prof. Emmanuel Theodorakis at UCSD are thanked for the
use of IR and a polarimeter, respectively.
1
Scheme 3.10 By H and 13C NMR, a single isomer was
observed. The reproducible overall yields of 2 beginning
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
of all intermediates leading to (+)-epiquinamide. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) To our knowledge, one such example was accomplished recently
with a water-soluble ruthenium catalyst. See: Hong, S. H.; Grubbs, R. H.
J. Am. Chem. Soc. 2006, 128, 3508-3509.
(22) Vernall, A. J.; Abell, A. D. Aldrichimica Acta 2003, 36, 93-105.
(23) Published methods for the removal of the ruthenium catalyst are
better suited for nonpolar compounds. For examples, see: (a) Maynard, H.
D.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 4137-4140. (b) Haack, K.
L.; Ahn, Y. M.; Georg, G. I. Mol. DiVersity 2005, 9, 301-303.
(24) Cho, J. H.; Kim, B. M. Org. Lett. 2003, 5, 531-533.
(25) Shinada, T.; Hayashi, K.; Yoshida, Y.; Ohfune, Y. Synlett 2000,
10, 1506-1508.
OL061736P
(26) The literature value of (+)-2 was [R]20 ) +28° (c 0.23, CHCl3)
D
(see ref 10) and [R]22 ) +26.2° (c 0.23, CHCl3) (see ref 8).
D
(27) The literature value of (-)-2 was [R]20 ) - 25° (c 0.26, CHCl3)
D
(see ref 9).
Org. Lett., Vol. 8, No. 20, 2006
4543