Synthesis of alkaloid 223A and a structural revision.

Article abstract of DOI:10.1021/ol025775m

[structure: see text] Synthesis of alkaloid 223A has been achieved by sequential use of our original conjugate addition reaction to enaminoesters as the key step. The proposed structure for natural 223A (A, absolute configuration unknown) was revised to B

Full text of DOI:10.1021/ol025775m

ORGANIC
LETTERS
2002
Vol. 4, No. 10
1715-1717
Synthesis of Alkaloid 223A and a
Structural Revision
Naoki Toyooka,* Ayako Fukutome, and Hideo Nemoto*
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical UniVersity,
Sugitani 2630, Toyama 930-0194, Japan
John W. Daly, Thomas F. Spande, H. Martin Garraffo, and Tetsuo Kaneko
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and DigestiVe and
Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
toyooka@ms.toyama-mpu.ac.jp
Received February 25, 2002
ABSTRACT
Synthesis of alkaloid 223A has been achieved by sequential use of our original conjugate addition reaction to enaminoesters as the key step.
The proposed structure for natural 223A (A, absolute configuration unknown) was revised to B, and the relative stereostructure was determined
to be 5R*,6R*,8R*,9S* by the present synthesis.
Amphibian skin has provided a wide range of biologically
active alkaloids (over 20 structural classes and over 500
alkaloids) including pyrrolidines, piperidines, decahydro-
quinolines, pyrrolizidines, indolizidines, and quinolizidines.1
The pharmacological activities associated with these alkaloids
together with the small amounts isolated from skins have
inspired many syntheses of these heterocycles.2 The alkaloid
223A (A), the first member of a new trialkyl-substituted
indolizidine class of amphibian alkaloids, was isolated from
a skin extract of a Panamanian population of the frog
Dendrobates pumilio Schmidt (Dendrobatidae) in 1997 along
with three higher homologues of A.3 The structure of this
alkaloid has been established to be A based upon GC-MS,
1
GC-FTIR, and H NMR spectral studies.3 In this paper, we
would like to report the first synthesis of alkaloid 223A by
sequential use of our original Michael-type of conjugate
addition reaction to enaminoesters (i, ii) as the key step4
(Figure 1). The proposed configuration at the 6-position of
223A was found to be incorrect. The correct structure was
proved by work reported here.
The synthesis began with (2S)-amide 1,5 which was
converted to the cyclic enaminoester 2 using triflation of the
intermediate imidourethane with Comins’ reagent6 followed
by a palladium-catalyzed CO insertion reaction7 of the
(1) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids: Chemical
and Biological PerspectiVes; Pelletier, S. W., Ed.; Pergamon Press: New
York, 1999; Vol. 13, pp 1-161. Daly, J. W. In The Alkaloids; Cordell, G.
A., Ed.; Academic Press: New York, 1998; Vol. 50, pp 141-169.
(2) Davis, F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169-3171. Kim,
G.; Jung, S.; Kim, W.-J. Org. Lett. 2001, 3, 2985-2987. Tan, C.-H.; Holmes,
A. B. Chem. Eur. J. 2001, 7, 1845-1854. Comins, D. L.; Huang, S.;
McArdle, C. L.; Ingalls, C. L. Org. Lett. 2001, 3, 469-471. Wei, L.-L.;
Hsung, R. P.; Sklenicka, H. M.; Gerasyuto, A. I. Angew. Chem., Int. Ed.
2001, 40, 1516-1518. Enders, D.; Thiebes, C. Synlett 2000, 1745-1748.
Michel, P.; Rassat, A.; Daly, J. W.; Spande, T. F. J. Org. Chem. 2000, 65,
8908-8918. Williams, G. M.; Roughley, S. D.; Davies, J. D.; Holmes, A.
B.; Adams, J. P. J. Am. Chem. Soc. 1999, 121, 4900-4901. Pearson, W.
H.; Suga, H. J. Org. Chem. 1998, 63, 9910-9918. Comins, D. L.;
LaMunyon, D. H.; Chen, X. H. J. Org. Chem. 1997, 62, 8182-8187 and
references therein.
(3) Garraffo, H. M.; Jain, P.; Spande, T. F.; Daly, J. W. J. Nat. Prod.
1997, 60, 2-5.
(4) Momose, T.; Toyooka, N. J. Org. Chem. 1994, 59, 943-945.
Toyooka, N.; Tanaka, K.; Momose, T.; Daly, J. W.; Garraffo, H. M.
Tetrahedron 1997, 53, 9553-9574.
(5) Hodgkinson, T. J.; Shipman, M. Synthesis 1998, 1141-1144.
(6) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299-
6302.
(7) Cacchi, S.; Morera, E.; Orter, G. Tetrahedron Lett. 1985, 26, 1109-
1112.
10.1021/ol025775m CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/09/2002

The stereoselectivity of the second and key Michael-type
conjugate addition reaction can be rationalized as follows.
The conformation of 5 will be restricted to 5-A as a result
of A(1,3) strain9 between the N-methoxycarbonyl and n-propyl
groups in 5-B. Attack of the vinyl anion from the stereo-
electronically favored R-axial direction provides the adduct
6 exclusively.
It is noteworthy that the stereochemical course of the above
reaction is controlled by the stereoelectronic effect despite
severe 1,3-diaxial steric repulsion between the axial ethyl
group at the 5-position and the incoming vinyl anion. This
remarkable stereoselectivity can be also explained by Cieplak’s
hypothesis.10 On the preferred conformation 5-A, the devel-
oping σ* of the transition state is stabilized by the anti-
periplanar donor σC-H at the C-4 position. Elaboration of
the adduct 6 into the indolizidine 10, previously proposed
as the structure for natural 223A,3 is shown in Scheme 2.
Figure 1. Basic strategy for the construction of the 2,3,5,6-
tetrasubstituted piperidine ring system.
resulting enol triflate. The first Michael-type conjugate
addition reaction of 2 proceeded smoothly giving the vinyl
adduct as a single isomer,4 which was transformed into the
methyl urethane 4 via the alcohol 3. The alcohol 4 was
converted to the methyl ester, which was transformed into
the cyclic enaminoester 5 using Rubio’s protocol.8 The
second Michael-type conjugate addition of 5 proceeded to
afford adduct 6, again as a single isomer. The stereochemistry
of 6 was determined by the coupling constants and NOE of
the oxazolizinone derivative 7 as shown in Scheme 1.
Scheme 2a
a Reagents and conditions: (a) Super-Hydride (99%); (b) Swern
oxidation, then NaH, (EtO)2P(O)CH2CO2Et (96% 2 steps); (c) 5%
Pd-C, H2 then Super-Hydride (89% 2 steps); (d) MOMCl, Hu¨nig
base (86%); (e) n-PrSLi, HMPA; (f) c. HCl, MeOH; (g) CBr4, Ph3P
(52% 3 steps).
Scheme 1a
Reduction of 6 with Super-Hydride followed by Swern
oxidation and Wittig-Horner reaction of the resulting
aldehyde afforded the R,â-unsaturated ester 8. Hydrogenation
of 8 and reduction of the resulting saturated ester gave the
corresponding alcohol, whose hydroxyl group was protected
as the MOM ether 9. Finally, deprotection11 of the meth-
oxycarbonyl group and cleavage of the MOM ether followed
1
by indolizidine formation12 furnished 10. However the H
and 13C NMR and IR spectra of 10 were not identical with
those for the natural product, nor was the GC retention time.
The close similarity of the Bohlmann bands in the vapor
phase FTIR spectra of 10 and natural 223A indicated the
same 5,9-Z configuration3 for both compounds. On the basis
1
of a detailed comparison of the H and 13C NMR spectra,13
we concluded that natural 223A differed from 10 only in
the 6-position configuration. Therefore, we commenced the
a Reagents and conditions: (a) n-BuLi, ClCO2Me (98%); (b)
LiHMDS, Comins’ reagent (96%); (c) CO, Pd(Ph3P)4, Et3N, MeOH
(88%); (d) (vinyl)2CuLi (96%); (e) Super-Hydride (96%); (f) Swern
ox., then n-BuLi, EtP+Ph3Br- (79% 2 steps); (g) 5% Pd-C, H2,
then TBAF (77% 2 steps); (h) Swern oxidation, then NaClO2,,
NaH2PO4, and then CH2N2 (90% 3 steps); (i) LiHMDS, PhSeCl
(77%); (j) (vinyl)2CuLi (90%); (k) Super-Hydride (99%); (l) NaH
(84%). TBDPS ) tert-butyldiphenylsilyl.
(8) Ezquerra, J.; Escribano, A.; Rubio, A.; Remuinan, M. J.; Vaquero,
J. J. Tetrahedron: Asymmetry 1996, 7, 2613-2626.
(9) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841-1873.
(10) Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540-4552.
(11) Corey, E. J.; Yuen, P. Tetrahedron Lett. 1989, 30, 5825-5828.
(12) Shishido, Y.; Kibayashi, C. J. Org. Chem. 1992, 57, 2876-2882.
(13) H-5 in 10 and 223A was a dt signal with J values of 11, 2.5 and
11, 4.7 Hz, respectively. Hindered rotation at C-5 in 223A leads to an 11-
Hz J5-10 coupling and does not reflect the J5-6 coupling as was erroneously
proposed initially.3
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Org. Lett., Vol. 4, No. 10, 2002

synthesis of the diastereomeric indolizidine 11 from piperi-
done 12.14
Scheme 3a
The piperidone 12 was converted to cyclic enaminoester
13 in the same manner as described in Scheme 1. Addition
of divinylcuprate to 13 provided the adduct 14 as a single
isomer in excellent yield. The indicated coupling constant
and NOE experiments of oxazolizinone 16 derived from 14
via the alcohol 15 confirmed that the stereogenic centers of
the key intermediate 14 were correct for the synthesis of the
target indolizidine 11. Stereoselectivity of this Michael
reaction can again be explained by A(1,3) strain and a
stereoelectronic effect as shown in Figure 2. The synthesis
a Reagents and conditions: (a) n-BuLi, ClCO2Me (97%); (b)
LiHMDS, Comins’ reagent (97%); (c) CO, Pd(Ph3P)4, Et3N, MeOH
(75%); (d) (vinyl)2CuLi (95%); (e) Super-Hydride (96%); (f) Swern
oxidation, then NaH, (EtO)2P(O)CH2CO2Et (92% 2 steps); (g) 5%
Pd-C, H2, then Super-Hydride (98% 2 steps); (h) MOMCl, Hu¨nig
base (89%); (i) TBAF (79%); (j) Swern oxidation, then n-BuLi,
EtP+Ph3Br- (83% 2 steps); (k) 5% Pd-C, H2; (l) n-PrSLi, HMPA;
(m) c. HCl, MeOH, then CBr4, Ph3P (51% 4 steps)
Figure 2. Stereochemical course of the key Michael-type conjugate
addition reaction of 5.
confers selectivity to the addition. More importantly, any
alkyl side chain could be introduced at the 3- and 5-positions
by our strategy in a stereoselective manner. The carbon chain
at the 2- and 6-positions can be elongated arbitrarily by
appropriate modifications of oxygenated functional groups.
This flexible route should be amenable to synthesis of other
alkaloids such as three higher homologues of 223A or
unnatural congeners of dendrobatid alkaloids bearing highly
substituted piperidine rings. Syntheses of the higher homo-
logues of 223A, such as 237L, 251H, and 267J, are now
under investigation.
of 11 was accomplished via the alcohols 17 and 18 in the
same manner as used in the synthesis of 10 in Scheme 2.
The spectral data for 11 (1H and 13C NMR, GC-FTIR,
GC-EIMS) were completely identical with those for the
natural product. Thus the structure of natural 223A is revised
to 11, and the relative stereostructure of this alkaloid was
determined to be 5R*,6R*,8R*,9S*15 by the present synthesis.
In summary, the first synthesis of alkaloid 223A has been
accomplished, the proposed structure has been revised, and
the relative stereostructure of natural 223A was determined.
In the key Michael-type conjugate addition reaction, allylic
1,3-strain effectively restricts the addition to one conforma-
tion of the enaminoester, where a stereoelectronic effect
Acknowledgment. We are grateful to Dr. Yoshihiko
Hirose, Amano Pharmaceutical Co., Ltd., for the generous
gift of lipase AK used in the synthesis of 12.14
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds and
1H and 13C NMR spectra of synthetic compounds 6, 7, 10,
11, 14, 16, and natural 223A‚DCl salt. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL025775M
(14) This piperidone was synthesized from known (2R)-2-(hydroxy-
methyl)butyl acetate (Izquierdo, I.; Plaza, M. P.; Rodriguez, M.; Tamayo,
J. Tetrahedron: Asymmetry 1999, 10, 449-455); see Supporting Information
for the experimental details.
(15) The optical rotation of the DCl salt synthetic 11 was [R]26D -40.9
(c 0.25, CHCl3). Although the small amount of natural 223A-DCl available
was sufficient only to indicate a very small negative rotation (observed
rotation -0.018° in CHCl3), we suggest from this that our synthetic
enantiomer 11 may have the natural absolute configuration. Additional work
will have to confirm this.
Figure 3. Stereochemical course of the key Michael-type conjugate
addition reaction of 15.
Org. Lett., Vol. 4, No. 10, 2002
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