Asymmetric total synthesis of natural pyrrolizidine alkaloid, (+)-alexine

Article abstract of DOI:10.1016/S0040-4039(00)01314-9

The total synthesis of the potent glycosidase inhibitor (+)-alexine with five contiguous stereogenic centres [(1R,2R,3R,7S,7aS)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine alkaloid] is described featuring the efficient and stereodefined novel elaboratio

Full text of DOI:10.1016/S0040-4039(00)01314-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7661–7665
Asymmetric total synthesis of natural pyrrolizidine alkaloid,
(+)-alexine
Hidemi Yoda,* Hideaki Katoh and Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Hamamatsu 432-8561, Japan
Received 3 July 2000; revised 27 July 2000; accepted 28 July 2000
Abstract
The total synthesis of the potent glycosidase inhibitor (+)-alexine with five contiguous stereogenic
centres [(1R,2R,3R,7S,7aS)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine alkaloid] is described featuring
the efficient and stereodefined novel elaboration of the functionalized homochiral lactam derived from
2,3,5-tri-O-benzyl-b-
D
-arabinofuranose. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: pyrrolizidine alkaloid; alexine; stereoselective reduction; chiral lactam;
D
-arabinofuranose.
Structurally complex alkaloidal sugar mimics with a nitrogen in the ring have been isolated
from plants and microorganisms and inhibit various glycosidases in a reversible and competitive
manner.1 Since such glycosidase inhibitors proved to have the potential to produce antiviral,
insect antifeedant, antidiabetic, and anticancer effects, as well as immune modulatory properties,
they have held considerable interest in the context of the synthesis of nitrogen-containing
natural products. Noteworthy members among this class of compounds are alexine (1),2
australine (2),3 and casuarine (3) (Fig. 1).4 These display powerful glycosidase inhibitory
properties and, in addition, exhibit viral and retroviral5 including anti-HIV activity.6 These are
also a unique subset of pyrrolizidine alkaloids possessing five contiguous stereogenic centres,
Figure 1.
* Corresponding author. Tel: +81-53-478-1150; fax: +81-53-478-1150; e-mail: yoda@mat.eng.shizuoka.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01314-9

7662
and the presence of a hydroxymethyl group adjacent to the ring nitrogen [C(3)] distinguishes this
group from the larger class of necine bases, which contain carbon substituents at C(1).
The diverse array of potentially useful activities make them inviting targets for synthesis. In
particular, the preparation of unnatural epimers and other structural analogs of these com-
pounds has generated much interest since the biological activity of these molecules varies
substantially with the number, position and stereochemistry of the hydroxy groups into the
pyrrolizidine skeleton.7 However, despite interesting pharmacological activity and unique struc-
tural features, to our knowledge, only one approach to the total synthesis of the parent alkaloid
1 of alexines has been reported to date based on an optical resolution method.8 With these
considerations in mind, we wish to communicate herein a novel and efficient asymmetric
synthesis of 1 by means of requisite stereoselective elaboration of the functionalized homochiral
lactam (II) through a pyrrolidine intermediate (III) derived from -arabinofuranose (I) (Fig. 2).
D
Figure 2.
As shown in Scheme 1, the functionalized homochiral lactam 6 (>99% d.e.) was obtained from
nucleophilic addition of vinylmagnesium bromide to the furanosylamine 4, followed by oxida-
tive degradation with PCC9 in high yield. The olefinic part in 6 was then cleaved via
dihydroxylation to give the aldehyde intermediate 7, which was in turn subjected to BF3·OEt2-
induced allylation at low temperature, leading to the corresponding desired allyl alcohol 810
predominantly (97:3)11 in 80% yield (three steps) through attack on the carbonyl group from the
less hindered face. After removal of the N-MPM moiety and protection of the hydroxyl group
in 8 with MOMCl, 9 thus obtained was submitted to oxidative cleavage again followed by
reduction to the corresponding alcohol, which was stepwisely treated with DPSCl and (Boc)2O
to give the N-Boc lactam 10 in an 81% five steps yield from 9. Then, the second vinyl-Grignard
addition to 10 easily afforded the labile quaternary a-hydroxypyrrolidine intermediate,12 which
was subsequently effected by reduction with NaBH4 in the presence of CeCl3 to provide the
desired stereoisomer 1112b,c with five contiguous stereogenic centres as a sole product13 (deter-
mined by 13C NMR and chiral HPLC analysis).
In light of the above outcome, we turned our attention to the construction of a pyrrolizidine
ring system. Thus, cyclization of 11 under basic conditions via mesylation was performed to
yield the pyrrolidine derivative 12 in 84% yield. This was then successively effected by reactions
of oxidative cleavage, reduction, and MOM-protection to lead to the functionalized N-Boc
derivative 13. Construction of the bicyclic pyrrolizidine ring was accomplished under mild basic
conditions with K2CO3 in MeOH after replacement of the silyl substituent in 13 by the leaving
Ts group, followed by simultaneous deprotection of two hydroxyl and amino functions with

7663
Scheme 1. Reagents and conditions: (a) 1, MPMNH2, benzeneꢀCHCl3 (1:1), MS 4A, reflux; quant.; (b) 1,
vinylmagnesium bromide, THF, −78 to −40°C; 70%; 2, PCC, MS 4A, CH2Cl2; 68%; (c) 1, OsO4, NMO, acetoneꢀH2O
(1:1); 98%; 2, NalO4, Et2O–H2O (2:1); (d) allyltrimethylsilane, BF3·OEt2, CH2Cl2, −78 to −20°C; 82% (two steps); (e)
1, CAN, CH3CN–H2O (9:1); 71%; 2, MOMCl, N,N-diisopropylethylamine, CH2Cl2; 75%; (f) 1, OsO4, NMO,
acetone–H2O (1:1); 91%; 2, NalO4, Et2O–H2O (2:1); 3, NaBH4, EtOH; 90% (two steps); 4, DPSCl, imidazole, DMF;
quant.; 5, (Boc)2O, DMAP, Et3N, CH2Cl2, 99%; (g) 1, vinylmagnesium bromide, THF, −78°C; 2, NaBH4–CeCl3,
MeOH, −45°C; 66% (two steps); (h) 1, MsCl, Et3N, CH2Cl2; 2, t-BuOK, THF; 84% (two steps); (i) 1, OsO4, NMO,
acetone–H2O (1:1); 92%; 2, NalO4, Et2O–H2O (2:1); 3, NaBH4, EtOH; 74% (two steps); 4, MOMCl, N,N-diisopropyl-
ethylamine, CH2Cl2; 99%; (j) 1, Bu4NF, THF; quant.; 2, p-TsCl, pyridine; 92%; 3, conc. HCl, MeOH; 4, K2CO3,
MeOH; 94% (two steps); (k) H2, 10% Pd/C, EtOH; 70%
conc. HCl, leading to the alexine dibenzyl derivative 14 in an 86% four steps yield. Finally,
removal of the benzyl groups in 14 was performed with 10% Pd on carbon to complete the total
synthesis of alexine (1), ([h]2D7 +39.13 (c 0.30, H2O) [lit. [h]D20 +40.0 (c 0.25, H2O)],2 mp 160–161°C

7664
[lit. 162–163°C]2) in 70% yield. The spectral data of synthetic 1 were identical to those of the
reported natural product.2
This work constitutes the first asymmetric synthesis of natural (+)-alexine from the -arabino-
D
furanose derivative and will be widely applicable to the synthesis of other pyrrolizidine
alkaloidal sugar mimics.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific Research from Japan
Society for the Promotion of Science.
References
1. (a) Elbein, A. D. Inhibitors of the Biosynthesis and Processing of N-linked Oligosaccharide Chains. Annu.
Rev. Biochem. 1987, 56, 497. (b) Fellows, L. E.; Kite, G. C.; Nash, R. J.; Simmonds, M. S. J.; Scofield, A.
M. In Plant Nitrogen Metabolism; Poulton, J. E.; Romero, J. T.; Conn, E. E., Eds. Plenum: New York, 1989;
p. 395. (c) Legler, G. Adv. Carbohydr. Chem. Biochem. 1990, 48, 319.
2. Isolation: Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W. J.; Derome, A. E.; Hamor, T. A.; Scofield,
A. M.; Watkin, D. J. Tetrahedron Lett. 1988, 29, 2487.
3. Isolation: Molyneux, R. J.; Benson, M.; Wong, R. Y.; Tropea, J. E.; Elbein, A. D. J. Nat. Prod. 1988, 51,
1198.
4. Isolation: Nash, R. J.; Thomas, P. I.; Waigh, R. D.; Fleet, G. W. J.; Wormald, M. R.; de Q. Lilley, P. M.;
Watkin, D. J. Tetrahedron Lett. 1994, 35, 7849.
5. Elbein, A. D.; Tropea, J. E.; Molyneux, R. J. US Pat. Appl. US 289,907; Chem. Abstr. 1990, 113, P91444p.
6. Fellows, L. E.; Nash, R. J. PCT Int. Appl. WO GB Appl. 89/7,951; Chem. Abstr. 1990, 114, 143777f.
7. Recent syntheses: (a) Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61, 5546. (b) Hall, A.; Meldrum, K.
P.; Therond, P. R.; Wightman, R. H. Synlett 1997, 123. (c) Bell, A. A.; Pickering, L.; Watson, A. A.; Nash,
R. J.; Pan, Y. T.; Elbein, A. D.; Fleet, G. W. J. Tetrahedron Lett. 1997, 38, 5869. (d) Ikota, N.; Nakagawa,
H.; Ohno, S.; Noguchi, K.; Okuyama, K. Tetrahedron 1998, 54, 8985. (e) White, J. D.; Hrnciar, P.; Yokochi,
A. F. T. J. Am. Chem. Soc. 1998, 120, 7359. (f) Denmark, S. E.; Martinborough, E. A. J. Am. Chem. Soc.
1999, 121, 3046. (g) Denmark, S. E.; Hurd, A. R. Org. Lett. 1999, 1, 1311. (h) Denmark, S. E.; Hurd, A. R.
J. Org. Chem. 2000, 65, 2875. (i) Denmark, S. E.; Herbert, B. J. Org. Chem. 2000, 65, 2887. (j) Yoda, H.;
Asai, F.; Takabe, K. Synlett 2000, 1001.
8. Fleet, G. W. J.; Haraldsson, M.; Nash, R. J.; Fellows, L. E. Tetrahedron Lett. 1988, 29, 5441.
9. (a) Lay, L.; Nicotra, F.; Paganini, A.; Pangrazio, C.; Panza, L. Tetrahedron Lett. 1993, 34, 4555. (b)
Hashimoto, M.; Terashima, S. Chem. Lett. 1994, 1001. (c) Yoda, H.; Yamazaki, H.; Kawauchi, M.; Takabe,
K. Tetrahedron: Asymmetry 1995, 6, 2669.
10. The absolute stereochemistry of the newly created carbon centre in 8 was proved to be S by the transforma-
tion into the acetonide 16 after deprotection as shown below, since the observed vicinal coupling constants
(Ja,b and Jb,c) of HaꢀHb and HbꢀHc in 16 were 2.4 and 7.3 Hz, respectively, indicating an equatorial–axial
relationship.

7665
11. The ratio of the two diastereomers was easily determined by chromatographic separation after derivatization to
N-Boc-methoxymethyl ether of 8.
12. (a) Yoda, H.; Nakajima, T.; Takabe, K. Tetrahedron Lett. 1996, 37, 5531. (b) Yoda, H.; Nakajima, T.; Takabe,
K. Synlett 1997, 911. (c) Yoda, H.; Shimojo, T.; Takabe, K. Tetrahedron Lett. 1999, 40, 1335.
13. The absolute configuration of the generated stereogenic centre in 11 was unambiguously assigned to be S based
on our previous results12 and the spectral data of synthesized (+)-1.
.