Asymmetric synthesis of (-)-indolizidine 209D via B-alkyl Suzuki coupling and amination reactions

Article abstract of DOI:10.1021/ol0163171

matrix presented (-)-Indolizidine 209D has been synthesized using consecutive amination reactions of compound 11. The precursor was prepared concisely using B-alkyl Suzuki cross coupling of chiral homoallyl amine and vinyl iodide compounds.

Full text of DOI:10.1021/ol0163171

ORGANIC
LETTERS
2001
Vol. 3, No. 19
2985-2987
Asymmetric Synthesis of (−)-Indolizidine
209D via B-Alkyl Suzuki Coupling and
Amination Reactions
Guncheol Kim,* Sung-do Jung, and Won-jeoung Kim
Department of Chemistry, College of Natural Science, Chungnam National UniVersity,
Taejon 305-764, Korea
guncheol@cuVic.cnu.ac.kr
Received June 21, 2001
ABSTRACT
(−)-Indolizidine 209D has been synthesized using consecutive amination reactions of compound 11. The precursor was prepared concisely
using B-alkyl Suzuki cross coupling of chiral homoallyl amine and vinyl iodide compounds.
The indolizidine alkaloids have been isolated from the skin
secretions of neotropical frogs,1 and some have been shown
to function as noncompetitive blockers for muscle-type and
ganglionic nicotinic receptor channels.2 Of these, indoliz-
idines 167B and 209D, the structurally simpler bicyclic
gephyrotoxin alkaloids possessing a single substituent at C5
of the indolizidine skeleton,3 have been isolated in minute
quantities from unidentified dendrobatid frogs in a single
population and have been attractive synthetic targets.4
of nitrogen under reductive conditions, inducing condensation
followed by amination (Scheme 1). The stereochemistry of
Scheme 1
Figure 1.
the chiral center would determine the delivery of hydrogen
atom at the developing tetrahedral center at C9 from the least
To suggest a new route, we envisioned that cyclization to
the indolizidine skeleton would be feasible upon deprotection
(1) Tokuyama, T.; Nishimori, N.; Karle, I. L.; Edwards, M. W.; Daly, J.
W. Tetrahedron 1986, 42, 3453.
10.1021/ol0163171 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/21/2001

hindered site with respect to hexyl group.4b,5 For the
consecutive amination reactions, we considered the inter-
mediate 3 to be an ideal precursor in which N-Cbz, carbonyl,
and mesyl groups are arranged in proper position.
We thought the requisite intermediates for the route could
be prepared via B-alkyl Suzuki coupling of a homoallyl
amine moiety and the vinyl iodide compound containing a
mesyl leaving group. Recently, Suzuki-Miyamura coupling
has been applied appropriately for the synthesis of potent
natural molecules by taking advantage of its mild reaction
condition, substrate versatility, control of olefin geometry,
and even tolerance for water.6 We expected the mesyl group
would be compatible in the coupling and serve as a good
leaving group in the final step.
plex, and B(OMe)3 (50 mol %) to prepare 7, which was
synthesized in 70% yield.8 After treatment of the alcohol 7
with MsCl (90% yield), inversion of the chiral center was
carried out by reaction of the mesylate intermediate with
NaN3 in 97% yield. The azide 8 was reduced by LAH in
THF to an amine, which was readily protected by ClCO2Bn
in THF with K2CO3 to provide the desired compound 4 in
94% yield for two steps (Scheme 2).
Scheme 2a
Synthesis of intermediate 4 was initiated by preparing the
known chiral homoallylic alcohol 7 from heptanal. Among
many well developed methods of catalytic asymmetric
allylation of aldehydes,7 we chose a relatively practical route
using allyltributyltin, (R)-BINOL-Ti(IV) (10 mol %) com-
(2) Aronstam. R. S.; Daly, J. W.; Spande, T. F.; Narayanan, T. K.;
Albuquerque, E. X. Neurochem. Res. 1986, 11, 1227.
a (a) AllSnBu3, (R)-BINOL-Ti(IV), B(OMe)3, CH2CH2, 0 °C,
70%; (b) MsCl, Et3N, CH2Cl2, 0 °C, 90%; (c) NaN3, HMPA, 40
°C, 97%; (d) LAH, THF, rt; (e) ClCO2Bn, THF, K2CO3, 94% for
2 steps.
(3) Their structures have been tentatively assigned on the basis of the
mass spectrum [Daley, J. W. Fortschr. Chem. Org. Naturst. 1982, 41, 205].
(4) For asymmetric syntheses of indolizidine 167B, see: (a) Polniaszek,
R. P.; Belmont, S. E. J. Org. Chem. 1990, 55, 4688. (b) Jefford, C. W.;
Tang, Q.; Zaslona, A. J. Am. Chem. Soc. 1991, 113, 3513. (c) Jefford, C.
W.; Wang, J. B. Tetrahedron Lett. 1993, 34, 3119. (d) Takahata, H.; Bandoh,
H.; Momose, T. Heterocycles 1995, 41, 1797. (e) Lee, E.; Li, K. S.; Lim,
J. Tetrahedron Lett. 1996, 37, 1445. (f) Weymann, M.; Pfrengle, W.;
Schollmeyer, D.; Kunz, H. Synthesis 1997, 1151. (g) Angle, S. R.; Henry,
R. M. J. Org. Chem. 1997, 62, 8549. (h) Chalard, P.; Remuson, R.; Gelas-
Mialhe, Y.; Gramain, J.-C.; Canet, I. Tetrahedron Lett. 1999, 40, 1661. (i)
Cheˆnevert, R.; Ziarani, G. M.; Dasser, M. Heterocycles 1999, 51, 593. For
asymmetric syntheses of indolizidine 209D, see:. (j) Åhman, J.; Somfai, P.
Tetrahedron Lett. 1995, 36, 303. (k) Åhman, J.; Somfai, P. Tetrahedron
1995, 51, 9747. (l) Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J.
Org. Chem. 1995, 60, 398. (m) Jefford, C. W.; Sienkiewicz, K.; Thornton,
S. R. HelV. Chim. Acta 1995, 78, 1511. (n) Takahata, H.; Kubota, M.; Ihara,
K.; Okamoto, N.; Momose, T.; Azer, N.; Eldefrawi, A. T.; Eldefrawi, M.
E. Tetrahedron: Asymmetry 1998, 9, 3289. (o) Cheˆnevert, R.; Ziarani, G.
M.; Morin, M. P.; Dasser, M. Tetrahedron: Asymmetry 1999, 10, 3117.
(p) Yamazaki, N.; Ito, T.; Kibayashi, C. Org. Lett. 2000, 2, 465. (q) Back,
T. G.; Nakajima, K. J. Org. Chem. 2000, 65, 4543.
The coupling partner, internal alkenyl iodide 5, was made
selectively by treatment of 4-pentyne-1-ol with HI, generated
in situ,9 affording an internal iodoalkenyl alcohol as a major
compound in a 6:1 mixture of inseparable regioisomers, and
reaction of the resulting alcohol with MsCl in CH2Cl2 gave
the compound 5 in 36% yield for two steps (Scheme 3).
Scheme 3a
(5) Robins, D. J.; Sakdaret, S. J. Chem. Soc., Perkins Trans. 1 1981,
909.
a (a) TMSCl, NaI, CH3CN/H2O, rt; (b) MsCl, CH2Cl2, Et3N, 36%
for 2 steps.
(6) (a) Miyamura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147. For recent application to natural
product syntheses, see: (c) Ohba, M.; Kawase, N.; Fujii, T. J. Am. Chem.
Soc. 1996, 118, 8250. (d) Su, D.-S.; Sorensen, E. J.; Danishefsky, S. J.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2801. (e) Takemoto, T.; Sodeoka,
M.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1996, 61, 4876. (f) Meng, D.;
Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.; Sorensen, E.; Dan-
ishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10073. (g) Su, D.-S.; Balog,
A.; Meng, D.; Bertinato, P.; Danishefsky, S. J.; Zheng, Y.-H.; Chou, T.-
C.; He, L.; Horwitz, S. B. Angew. Chem., Int. Ed. Engl. 1997, 36, 2093.
(h) Fu¨rstner, A.; Seidel, G. J. Org. Chem. 1997, 62, 2332. (i) Trost, B. M.;
Lee, C. B. J. Am. Chem. Soc. 1998, 120, 6818. (j) Balog, A.; Harris, C.;
Savin, K.; Zhang, G.; Chou, T.-C.; Danishefsky, S. J. Angew. Chem., Int.
Ed. Engl. 1998, 37, 2675. (k) Fu¨rstner, A.; Konetzki, I. J. Org. Chem. 1998,
63, 3072. (l) Sasaki, M.; Fuwa, H.; Inoue, M.; Tachibana, K. Tetrahedron
lett. 1998, 39, 9027. (m) Meng, D.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 1999, 38, 1485. (n) Meng, D.; Tan, Q.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 1999, 38, 3197. (o) Trauner, D.; Schwartz, J. B.; Danishefsky, S.
J. Angew. Chem., Int. Ed. 1999, 38, 3542. (p) Trauner, D.; Danishefsky, S.
J. Tetrahedron lett. 1999, 40, 6511. (q) Harris, C. R.; Kuduk, S. D.; Balog,
A.; Savin, K.; Glunz, P. W.; Danishefsky, S. J. J. Am. Chem. Soc. 1999,
121, 7050. (r) Zhu, B.; Panek, J. S. Org. Lett. 2000, 2, 2695. (s) Lee, C.
B.; Chou, T.-C.; Zhang, X.-G.; Wang, Z.-G.; Kuduk, S. K.; Chappell, M.;
Stachel, S. J.; Danishefsky, S. J. J. Org. Chem. 2000, 65, 6525. (t) Sasaki,
M.; Noguchi, K.; Fuwa, H.; Tachibana, K. Tetrahedron Lett. 2000, 41,
1425-1428. (u) Fuwa, H.; Sasaki, M.; Tachibana, K. Tetrahedron Lett.
2000, 41, 8371-8375. (v) Nakamura, T.; Shiozaki, M. Tetrahedron Lett.
2001, 42, 2701-2704. (w) Takakura, H.; Noguchi, K.; Sasaki, M.;
Tachibana, K. Angew. Chem., Int. Ed. 2001, 40, 1090-1093.
The Suzuki coupling of 4 and 5 furnished the methylene
compound 10 in 64% yield, and conversion of 10 to the
carbonyl precursor 11 was performed by ozonolysis in CH2-
Cl2/MeOH in 80% yield. To obtain the optimal yield in the
ozonolysis process, immediate aqueous workup, after addi-
tion of DMS to the resulting peroxide intermediates at -78
°C, was necessary (Scheme 4).10
(7) (a) Yanagisawa, A. In ComprehensiVe Asymmetric Catalysis; Jacob-
sen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Chapter
27. (b) Kii, S.; Maruoka, K. Tetrahedron Lett. 2001, 42, 1935 and references
therein.
(8) Yu, C.-M.; Choi, H.-S.; Yoon, S.-K.; Jung, W.-H. Synlett 1997, 889.
1
The enantiomeric purity was determined to be >92% via H NMR using
Eu(hfc)3 in CDCl3.
(9) Kamiya, N.; Chikami, Y.; Ishii, Y. Synlett 1990, 675.
(10) Otherwise, an increasing amount of byproducts was formed,
presumably by reaction with MeOH under these conditions. However, after
separation, the product was relatively stable in MeOH solution even at room
temperature.
2986
Org. Lett., Vol. 3, No. 19, 2001

and 13C NMR and MS) were identical to those reported:4a
[R]24D -77.7 (c 0.70, CH2Cl2) [lit.4n [R]20D -89.64 (c 1.880,
CH2Cl2)].
Scheme 4a
In conclusion, we described the asymmetric synthesis of
(-)-indolizidine 209D by employing a new consecutive
amination-reductive amination pathway. A B-alkyl Suzuki
reaction was efficiently applied to furnish the precursors.
Further application of this strategy for related compounds
and investigation of the mechanism for the reductive process
is under study.
Acknowledgment. The authors thank the CMDS in
KAIST for generous funding.
Supporting Information Available: Experimental pro-
cedures and spectral data of new compounds and copies of
1H NMR spectrum of 5 and 1H NMR and 13C NMR spectra
of 4, 8, 10, 11. This material is available free of charge via
the Internet at http://pubs.acs.org.
a (a) (i) 9-BBN-H, THF, 23 °C, (ii) 5, Pd(dppf)Cl2, AsPh3,
Cs2CO3, DMF, H2O, 64%; (b) (i) O3, CH2Cl2/MeOH, -78 °C, (ii)
DMS, -78 °C, 80%; (c) H2, 10% Pd-C, MeOH, Et3N, 77%.
OL0163171
Gratifyingly, under 1 atm of H2 the precursor 11 was
smoothly converted to (-)-indolizidine 209D 211 in 12 h at
room temperature and in 77% yield. The spectral data (1H
(11) The formation of diastereomer 2 was not observed by NMR.
Org. Lett., Vol. 3, No. 19, 2001
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