First total synthesis of a new pyrrolizidine alkaloid, amphorogynine A

Article abstract of DOI:10.1016/S0040-4039(03)00070-4

An efficient and stereodefined strategy is described for the first asymmetric synthesis of a new type of pyrrolizidine alkaloids, amphorogynine A and its 1-epi-isomer. The key 2,4-disubstituted pyrrolidine ring was constructed by elaboration of the chiral

Full text of DOI:10.1016/S0040-4039(03)00070-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1643–1646
First total synthesis of a new pyrrolizidine alkaloid,
amphorogynine A
Hidemi Yoda,* Takahisa Egawa and Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Hamamatsu 432-8561, Japan
Received 21 November 2002; revised 19 December 2002; accepted 20 December 2002
Abstract—An efficient and stereodefined strategy is described for the first asymmetric synthesis of a new type of pyrrolizidine
alkaloids, amphorogynine A and its 1-epi-isomer. The key 2,4-disubstituted pyrrolidine ring was constructed by elaboration of the
chiral lactam derivative incorporating the
D-malic acid-derived skeleton through asymmetric cis-allylation of the functionalized
allysilane. © 2003 Elsevier Science Ltd. All rights reserved.
Amphorogynine A together with structurally related
compounds, amphorogynines B, C, and D, was first
isolated in 1998 by Pa¨ıs and co-workers from the leaves
of Amphorogyne spicata Stauffer and Hu¨rlimann (San-
talaceae) in a research for alkaloids in New Caledonian
plants.1 After structural characterization by the same
group based on spectroscopic methods using chemical
correlations, these were revealed to be a new class of
pyrrolizidine alkaloids possessing a 1,6-disubstituted
structure (Fig. 1).1 These alkaloids differ from the
position of the substituents on the pyrrolizidine ring.
Whereas amphorogynines possess a hydroxyl group at
the C(6) position, the well known necines generally bear
this substituent at the C(7) position of the
pyrrolizidine.2 Since such alkaloids showing substituted
functions at both C(1) and C(6) only have not been
reported previously,3 their structural and stereochemi-
cal complexity coupled with their diverse and poten-
tially useful characteristics would make them hereafter
inviting targets for synthesis. The synthesis of this type
of compounds poses interesting and often unsolved
problems of sterecontrol. Consequently, no report con-
cerning the total synthesis of 1 along with related
natural products has appeared to date.
With these considerations in mind, we wish to commu-
nicate the details of the first asymmetric synthesis of 1
and its 1-epimer (6-epi-amphorogynine B) by means of
requisite stereoselective allylation of the a-hydroxy-
pyrrolidine intermediate elaborated from
D-malic acid.
As shown in Scheme 1, N-MPM(p-methoxybenzyl)-
imide 6 obtained from -malic acid (5) was reduced
D
4
regioselectively with NaBH4 and readily effected by
BF3·OEt2-induced reductive deoxygenation with
Et3SiH5 to afford the acetoxylactam intermediate. After
Figure 1.
Keywords: amphorogynine; pyrrolizidine alkaloid; allylation; lactam; malic acid.
* Corresponding author. Tel.: +81 53 478 1150; fax: +81 53 478 1150; e-mail: tchyoda@ipc.shizuoka.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00070-4

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H. Yoda et al. / Tetrahedron Letters 44 (2003) 1643–1646
Scheme 1. Reagents and conditions: (a) 1, NaBH4, MeOH, 0°C; 2, BF3·OEt2, Et3SiH, CH2Cl2, 0°C; 69% (two steps); 3, K2CO3,
MeOH; 97%; 4, BnBr, Ag2O; DMF; 92%; (b) 1, CAN, CH3CN–H2O (9:1); 93%; 2, (Boc)2O, DMAP, Et3N, CH2Cl2, 0°C; quant.;
3, Pd (black), 4.4% HCOOH–MeOH, 45°C; quant.; 4, TBDPSCl, imidazole, CH2Cl2; 94%; (c) 1, NaBH4, MeOH, 0°C; 2,
CH2ꢀCHCH2SiMe3, BF3·OEt2, CH2Cl2, −78°C; 72%; (9a) (two steps); MPMO(CH2)2CHꢀCHCH2SiMe3, BF3·OEt2, CH2Cl2,
−78°C; 47%; (9b) (two steps); (d) 1, DDQ, CH2Cl2–H2O (11:1), 0°C; 90%; 2, CBr4, PPh3, CH2Cl2; 96%; (e) 1, OsO4, NMO,
acetone–H2O, 0°C; 2, NaIO4, ether–THF–H2O (1:1:2); 88% (two steps); 3, Br2, NaHCO3, MeOH–H2O (9:1); 89%; (f) 1, Bu4NF,
THF, 0°C; 87%; 2, 3-(p-benzyloxy-m-methoxyphenyl)propanoic acid, EDCI, DMAP, CH2Cl2; 0°C; 70%; (g) 1, BF3·OEt2, CH2Cl2;
−15°C; 2, NaHCO3, H2O; 85% (two steps); (h) H2, Pd/C, CH3COOEt; 58% (amphorogynine A (1)); 26% (1-epi-amphorogynine
A (6-epi-amphrogynine B)) (14).
exchange of the acetyl group to the benzyl moiety, the
lactam 7 thus obtained was transformed into the expected
N-Boc derivative 8, [h]D26+16.5° (c 1.03, CHCl3), by four
steps through both subsequent N- and O-deprotection
pyrrolidine derivative 10 thus obtained was then cleaved
via dihydroxylation to give the aldehyde intermediate,
which was successively subjected to bromine-induced
oxidation,13 leading to the corresponding methyl ester 11
in 89% yield. The remaining side unit in amphorogynines
prepared from vanillin was then introduced in the
presence of EDCI (1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide hydrochloride and DMAP14 after desilyla-
tion. Finally, the coupling product 12 was effected by
deprotection with BF3·OEt215 together with concomitant
cyclization, followed by debenzylation of the resulting
pyrrolizidine 13 with 5% Pd on carbon to produce the
desired compound, amphorogynine A (1), accompanying
with its 1-epimer (6-epi-amphorogynine B) 14. These
were readily separated by column chromatography on
silica gel and demonstrated that the less mobile com-
pound (CHCl3/MeOH=3:1; TLC Rf 0.55) corresponded
to the natural product 1 (58%), [h]2D6+52.1° (c 0.57,
CHCl3) {lit. [h]D+53° (c 1, CHCl3)1}, and the more
mobile substance (CHCl3/MeOH=3:1; TLC Rf 0.60)
was the 1-epi-isomer 1416 of amphorogynine A (6-epi-
amphorogynine B) (26%), [h]2D7−15.7° (c 0.38, CHCl3),
based on their spectral data,1 respectively. The spectral
data of synthetic (+)-1 were completely identical to those
of the reported natural product.1
and reprotection sequence (54% overall yield from
D-
malic acid) for further convenient transformation of the
functional groups. Initial experiments have been per-
formed on a coupling reaction via N-acyliminium ion
promoted by BF3·OEt2 at −78°C between allyltrimethyl-
silane and a-hydroxypyrrolidine derivative derived from
the partial reduction of 8.6 These conditions brought
about the desired allylated pyrrolidine 9a as a sole
product with complete cis-stereoselectivity.7 These
results are in accord with expectations based on the
preceding reports.6a,9 We were delighted to find that the
use of the functionalized allyltrimethylsilane reagent
(E/Z=3.1/1.0) prepared from 3-buten-1-ol according to
the Seyferth’s procedure10 also underwent fast reaction
to afford the corresponding coupling product 9b with
complete cis-relationship again11 in the pyrrolidine ring,
but with about 55% d.e. at the allylic position (deter-
mined by 1H NMR), which would be ascribed to the ratio
of the starting geometrical isomers.
For the purpose of the construction of a pyrrolizidine
ring system, 9b was in turn submitted to deprotection of
the MPM moiety followed by introduction of the bromo
function as the leaving group.12 The olefinic part in the
In summary this work constitutes the first synthesis of
the natural pyrrolizidine alkaloid, amphorogynine A,

H. Yoda et al. / Tetrahedron Letters 44 (2003) 1643–1646
1645
Scheme 2. Reagents and conditions: (a) 1, TBDMSCl, imidazole, DMF; 2, NaBH4, MeOH; 3, Ac2O, pyridine, DMAP; 4,
CH2ꢀCHCH2SnBu3, MgBr2, toluene; quant. (four steps); (b) 1, conc. HCl, MeOH; 2, BnBr, Ag2O, CH3COOEt; 58% (two steps);
3, CAN, CH3CN–H2O (9:1); 4, TBDMSCl, imidazole, DMF; 5, (Boc)2O, Et3N, DMAP; 64% (three steps); (c) 1, NaBH4, MeOH;
2, BzCl, Et3N, CH2Cl2; 3, Bu4NF, THF; 71% (three steps); (d) 1, Im2CS, THF, 40°C; 2, Bu3SnH, AIBN, toluene, 70°C; 38% (two
steps); 3, K2CO3, MeOH; 4, MsCl, Et3N, CH2Cl2; 5, t-BuOK, THF; 68% (three steps).
and verifies the structure proposed in the literature for
this natural product, since no report concerning the total
synthesis of amphorogynines has appeared to date.
Scand. 1989, 43, 290; (c) Shono, T.; Matsumura, Y.;
Tsubata, K.; Uchida, K. J. Org. Chem. 1986, 51, 2590.
7. The absolute stereochemistry of the newly created carbon
center in 9a was unambiguously proved to be S after
derivatisation of 9a to the benzyl ether by comparing its
spectral data with those of the trans-N-Boc-pyrrolidine 19,
Acknowledgements
which was in turn elaborated from D-tartaric acid-derived
This work was supported in part by a Grant-in-Aid
(No. 13640530) for Scientific Research from Japan
Society for the Promotion of Science.
C2-imide 15 employing cis-selective allylation reaction8 as
shown in Scheme 2.
8. Ryu, Y.; Kim, G. J. Org. Chem. 1995, 60, 103.
9. Renaud and Seebach9a have also observed a similar stere-
ochemical behavior in the synthesis of 2,4-cis-substituted
pyrrolidines;9b (a) Renaud, P.; Seebach, D. Helv. Chim.
Acta 1986, 69, 1704; (b) Boto, A.; Herna´ndez, R.; Sua´rez,
E. J. Org. Chem. 2000, 65, 4930; (c) Schuch, C. M.; Pilli,
R. A. Tetrahedron:Asymmetry2002, 13, 1973andreferences
cited therein. These results indicate that allylic A1,3-inter-
actions involving the substitutent a to the nitrogen atom
and the N-Boc group may determine the preferential
conformation of the t-butoxycarbonyl function in the
N-acyliminium ion intermediate. On the other hand,
Ogasawara and his co-workers recently reported that upon
reaction with allyltrimethylsilane in the presence of zinc(II)
chloride, N-Boc-5-acetoxy-2-methoxypiperidine afforded
the unexpected trans-selective allylation product predomi-
nantly (11:1) based on the anchimeric assistance of the
acetate group; Tanaka, H.; Sakagami, H.; Ogasawara, K.
Tetrahedron Lett. 2002, 43, 93; Sakagami, H.; Kamikubo,
T.; Ogasawara, K. Chem. Commun. 1996, 1433.
10. (a) Seyferth, D.; Wursthorn, K. R.; Mammarella, R. E. J.
Org. Chem. 1977, 42, 3104; (b) Seyferth, D.; Wursthorn,
K. R.; Lim, T. F. O.; Sepelak, D. J. J. Organometal. Chem.
1979, 181, 293.
11. Cis-stereochemistry in the pyrrolidine ring of 9b was
determined based on its spectral data of synthetic (+)-1.
12. To begin with, experiments have been performed on a
dihydroxylation reaction mediated by OsO4 employing the
tosylated compound 20 as shown below. The reaction,
however, resulted in the preparation of the corresponding
simultaneously cyclized products of 21 and 22 as an
inseparable mixture.
References
1. Huong, D. T. T.; Martin, M.-T.; Litaudon, M.; Se´venet,
T.; Pa¨ıs, M. J. Nat. Prod. 1998, 61, 1444.
2. (a) White, J. D.; Hrnciar, P. J. Org. Chem. 2000, 65, 9129
and references cited therein; (b) Pearson, W. H.; Hines, J.
V. J. Org. Chem. 2000, 65, 5785; (c) Denmark, S. E.; Hurd,
A. R. J. Org. Chem. 2000, 65, 2875; (d) Denmark, S. E.;
Martinborough, E. A. J. Am. Chem. Soc. 1999, 121, 3046;
(e) Denmark, S. E.; Thorarensen, A. J. Org. Chem. 1994,
59, 5672; (f) Wro´bel, J. T. In Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1985; Vol. 26 Chapt. 7.
3. Hartmann, T.; Witte, L. In Alkaloids Chemical and Biolog-
ical Perspectives; Pelletier, W. S., Ed.; Elsevier: Amsterdam,
1995; Vol. 9, p. 155.
4. (a) Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J. Am.
Chem. Soc. 1989, 111, 2588; (b) Hart, D. J.; Yang, T.-K.
J. Org. Chem. 1985, 50, 253; (c) Chamberlin, A. R.; Chung,
Y. L. J. Am. Chem. Soc. 1983, 105, 3653; (d) Yoda, H.;
Kitayama, H.; Katagiri, T.; Takabe, K. Tetrahedron 1992,
48, 3313.
5. (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc.
1982, 104, 4976; (b) Kraus, G. A.; Molina, M. T.; Walling,
J. A. J. Org. Chem. 1987, 52, 1273; (c) Yoda, H.; Kawauchi,
M.; Takabe, K. Synlett 1998, 137; (d) Yoda, H.; Nakajima,
T.; Takabe, K. Tetrahedron Lett. 1996, 37, 5531; (e) Yoda,
H.; Yamazaki, H.; Kawauchi, M.; Takabe, K. Tetrahedron:
Asymmetry 1995, 6, 2669 and references cited therein.
6. (a) Thaning, M.; Wistrand, L.-G. Acta Chem. Scand. 1992,
46, 194; (b) Thaning, M.; Wistrand, L.-G. Acta Chem.

1646
H. Yoda et al. / Tetrahedron Letters 44 (2003) 1643–1646
13. (a) Williams, D. R.; Klingler, F. D.; Allen, E. E.; Lich-
tenthaler, F. W. Tetrahedron Lett. 1988, 29, 5087; (b)
Lichtenthaler, F. W.; Jarglis, P.; Lorenz, K. Synthesis
1988, 790.
14. Kikuchi, H.; Saito, Y.; Komiya, J.; Takaya, Y.;
Honma, S.; Nakahata, N.; Ito, A.; Oshima, Y. J. Org.
Chem. 2001, 66, 6982.
Lett. 1997, 38, 3283.
16. 1H and 13C NMR data (CDCl3) for 14. 1H NMR l
1.71–2.36 (4H, m), 2.37–2.96 (7H, m), 2.98–3.44 (2H,
m), 3.57–3.94 (1H, m), 3.84 (3H, s), 3.89 (3H, s), 4.98–
5.63 (1H, m), 5.98 (1H, br), 6.62 (1H, d, J=8
Hz), 6.66 (1H, s), 6.79 (1H, d, J=8 Hz). 13C NMR l
30.5, 30.8, 36.1, 37.6, 49.9, 51.8, 54.2, 55.7, 59.7, 66.6,
76.5, 111.1, 114.7, 120.6, 131.9, 144.3, 146.8, 172.6,
173.9.
15. (a) Yoda, H.; Kawauchi, M.; Takabe, K. Synlett 1998,
137; (b) Yoda, H.; Oguchi, T.; Takabe, K. Tetrahedron