Chemoenzymatic approaches to lycorine-type amaryllidaceae alkaloids: Total syntheses of enf-lycoricidine, 3-epi-ent-lycoricidine, and 4-deoxy-3-epi-ent- lycoricidine

Article abstract of DOI:10.1021/ol701552r

The readily available and enzymatically derived cis-1,2-dihydrocatechol 4 has been elaborated, over 11 steps including an Overman rearrangement, into the non-natural enantiomer, (-)-1, of the alkaloid lycoricidine [(+)-1]. Related chemistries have provided analogues 18, 19, and 26.

Full text of DOI:10.1021/ol701552r

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3683-3685
Chemoenzymatic Approaches to
Lycorine-Type Amaryllidaceae
Alkaloids: Total Syntheses of
ent-Lycoricidine, 3-epi-ent-Lycoricidine,
and 4-Deoxy-3-epi-ent-lycoricidine
Maria Matveenko, Okanya J. Kokas, Martin G. Banwell,* and Anthony C. Willis
Research School of Chemistry, Institute of AdVanced Studies, The Australian National
UniVersity, Canberra, ACT 0200, Australia
mgb@rsc.anu.edu.au
Received July 2, 2007
ABSTRACT
The readily available and enzymatically derived cis-1,2-dihydrocatechol 4 has been elaborated, over 11 steps including an Overman rearrangement,
into the non-natural enantiomer, (
−
)-1, of the alkaloid lycoricidine [(
+
)-1]. Related chemistries have provided analogues 18, 19, and 26.
The lycorine-type Amaryllidaceae alkaloids (+)-lycoricidine
[(+)-1], (+)-narciclasine [(+)-2], and (+)-pancratistatin [(+)-
3] have been known for many years and have been isolated
from, inter alia, plants of the genus Amaryllidaceae including
the bulbs of narcissi and daffodils.1 The potent biological
properties of such compounds, particularly their carcinostatic
and antiviral qualities, have resulted in their being considered
for use as therapeutic agents.2 For example, (+)-pancratistatin
and some of its derivatives have been the subject of
preclinical development studies as agents for the treatment
of certain cancers.2 This situation, together with the limited
availability of certain of these alkaloids from natural sources,
has prompted a substantial body of work directed at the
development of practical synthetic routes to these compounds
and various analogues. The extensive efforts devoted to this
matter have been the subject of a number of recent reviews.3
Work in the area continues unabated.4
As part of a continuing program to exploit readily
available, microbially derived and enantiomerically pure cis-
1,2-dihydrocatechols such as 4 as starting materials in
chemical synthesis,5 we have developed and now report
efficient synthetic sequences that enable the rather rapid
(1) For reviews dealing with this class of alkaloid, see: (a) Martin, S.
F. In The Alkaloids; Brossi, A., Ed.; Academic Press: San Diego, 1987;
Vol. 30, p 251. (b) Hoshino, O. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: San Diego, 1998; Vol. 51, p 323. (c) Jin, Z. Nat. Prod.
Rep. 2003, 20, 606.
(2) For useful points on entry into the literature concerned with the
biological properties of lycorine-type alkaloids and their analogues, see:
(a) Pettit, G. R.; Melody, N. J. Nat. Prod. 2005, 68, 207. (b) McNulty, J.;
Larichev, V.; Pandey, S. Bioorg. Med. Chem. Lett. 2005, 15, 5315. (c) Pettit,
G. R.; Eastham, S. A.; Melody, N.; Orr, B.; Herald, D. L.; McGregor, J.;
Knight, J. C.; Doubek, D. L.; Pettit, G. R., III; Garner, L. C.; Bell, J. A. J.
Nat. Prod. 2006, 69, 7.
(3) (a) Hudlicky, T. J. Heterocycl. Chem. 2000, 37, 535. (b) Rinner, U.;
Hudlicky, T. Synlett 2005, 365. (c) Chapleur, Y.; Chre´tien, F.; Ibn Ahmed,
S.; Khaldi, M. Curr. Org. Synth. 2006, 3, 341.
(4) For recent synthetic efforts in this area that have not been covered
in the above-mentioned reviews,3 see: (a) Zhang, H.; Padwa, A. Synlett
2006, 2317. (b) Zhang, H.; Padwa, A. Org. Lett. 2006, 8, 247. (c) Shukla,
K. H.; Boehmler, D. J.; Bogacyzk, S.; Duvall, B. R.; Peterson, W. A.;
McElroy, W. T.; DeShong, P. Org. Lett. 2006, 8, 4183. (d) Li, M.; Wu, A.;
Zhou, P. Tetrahedron Lett. 2006, 47, 3707. (e) Crich, D.; Krishnamurthy,
V. Tetrahedron 2006, 62, 6830. (f) Shin, I.-J.; Choi, E.-S.; Cho, C.-G.
Angew. Chem., Int. Ed. 2007, 46, 2303. (g) Padwa, A.; Zhang, H. J. Org.
Chem. 2007, 72, 2570.
10.1021/ol701552r CCC: $37.00
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Published on Web 08/08/2007

transformation of this material into ent-lycoricidine [(-)-1]
and various congeners. Hudlicky and co-workers have
exploited metabolite 4 and its enantiomer in cycloaddition
and aziridination protocols culminating in elegant total
syntheses of alkaloids 1-3 as well as various related
(especially deoxygenated) systems.3 The present work is
distinct in that very different protocols have been applied to
compound 4 in order to obtain the title compounds.
under the UpJohn conditions8 followed by treatment of the
resulting diol (6) with MOM-Cl in the presence of base
afforded the previously reported7 compound 7 (59% from
5). Treatment of this last compound with DIBAL-H resulted
in essentially completely regiocontrolled cleavage of the
PMP-acetal residue within the substrate and formation of
the alcohol 87 (84%) that was immediately protected, using
standard conditions, as the corresponding MOM-ether 9
(90%). Oxidative cleavage of the PMB-ether residue within
this last compound using DDQ then afforded alcohol 10
(95%), which was immediately converted into the corre-
sponding mesylate 11 using a minor modification of the
Crossland-Servis procedure.9 Reaction of compound 11 with
sodium azide afforded the expected SN2 product 12 (95%
from 10) that was reduced to the corresponding amine 13
(99%) using the Staudinger protocol.10 Subjection of com-
pound 13 to reaction with the commercially available
boronate ester 14 under Suzuki-Miyaura cross-coupling
conditions11 in a microwave reactor then provided the
tricyclic compound 16 in 50% yield. Thus far, we have been
unable to determine the precise order of events associated
with the conversion 13 + 14 f 16 but presume that the
cross-coupling reaction precedes the lactamization step. This
last step contrasts with most other protocols3 for establishing
the lactam ring of such isocarbostyrils that often involve the
application of a modified Bischler-Napieralski cyclization
reaction.3,12 Treatment of compound 16 with trimethylsilyl
bromide at -30 °C13 resulted in cleavage of the MOM-
protecting groups and formation of the corresponding triol
18 (43%). Reaction of boronate 1514 with compound 13
under the same conditions as just described afforded the
coupling product 17 (69%) that then gave 3-epi-ent-lycori-
cidine (19) (44%) upon exposure to trimethylsilyl bromide.
The synthesis of the 4-deoxy analogue of compound 19
was achieved in a similar manner (Scheme 2). Thus,
treatment of alcohol 87 with a mixture of triiodoimidazole,
imidazole, and triphenylphosphine gave the iodide 207 (81%)
that was immediately reduced with tri-n-butyltin hydride to
The syntheses of 3-epi-ent-lycoricidine and that analogue
lacking the methylenedioxy unit are shown in Scheme 1.
Scheme 1
Scheme 2
Thus, cis-1,2-dihydroxylation of the readily accessible p-
methoxybenzylidene acetal derivative 56,7 of metabolite 4
(5) For reviews on methods for generating cis-1,2-dihydrocatechols by
microbial dihydroxylation of the corresponding aromatics, as well as the
synthetic applications of these metabolites, see: (a) Hudlicky, T.; Gonzalez,
D.; Gibson, D. T. Aldrichim. Acta 1999, 32, 35. (b) Banwell, M. G.;
Edwards, A. J.; Harfoot, G. J.; Jolliffe, K. A.; McLeod, M. D.; McRae, K.
J.; Stewart, S. G.; Vo¨gtle, M. Pure Appl. Chem. 2003, 75, 223. (c) Johnson,
R. A. Org. React. 2004, 63, 117.
3684
Org. Lett., Vol. 9, No. 18, 2007

give the iodinated system 217 (85%). Subjection of the last
compound to treatment with DDQ afforded alcohol 22 (96%)
that was immediately converted into the corresponding
mesylate 23 under standard conditions. Treatment of com-
pound 23 with sodium azide afforded the expected product
247 (76% from 22) that was reduced directly to the amine
257 (96%) under Staudinger conditions. Suzuki-Miyaura
cross-coupling of this last compound with boronate ester 15
followed by treatment of the product lactam (62%) with
trimethylsilyl bromide then gave 4-deoxy-3-epi-ent-lycori-
cidine (26) in 92% yield.
Scheme 3
The synthesis of ent-lycoricidine [(-)-1] followed very
similar lines (Scheme 3) and involved initial reaction of
alcohol 10 with trichloroacetonitrile in the presence of DBU
to give the acetimidate 27. Subjection of this last compound
to microwave irradiation in the presence of K2CO315 resulted
in an Overman rearrangement16 and the formation of the
acetamide derivative 28 (65% from 10). To the best of our
knowledge the conversion 27 f 28 represents the first
example of such a rearrangement that involves a halogenated
alkene and that is effected by microwave irradiation. Hy-
drolysis of amide 28 was achieved using DIBAL-H17 and
provided amine 29 (89%) that could be subjected to a
Suzuki-Miyaura cross-coupling reaction with boronate ester
15. The ensuing lactam (83%) was treated with trimethylsilyl
bromide to give ent-lycoricidine [(-)-1]18 in 62% yield. The
NMR, MS, and IR spectral data derived from this material
were completely consistent with those reported for both the
natural product18 and its enantiomer.18 Similarly, the specific
rotation of our material {[R]D ) -141 (c 0.44, pyridine)}
was consistent with that reported18 previously {[R]D ) -164
(c 0.45, pyridine) for (-)-1}. Final confirmation of structure
followed a single-crystal X-ray analysis19 of the derived
triacetate 30 (70%): mp ) 224-228 °C (lit.18 mp ) 205-
210 °C); [R]D ) -196 (c 0.40, CHCl3) {lit.18 [R]D ) -205
(c 0.40, CHCl3)}.
Given the availability of the enantiomer of starting material
4,5 the work detailed above will also provide access to (+)-
lycoricidine [(+)-1]. Moreover, it seems reasonable to
suggest that rather straightforward modifications to these
reaction sequences should permit the efficient preparation
of other members of the lycorine alkaloid class. Work
directed to such ends is now underway in these laboratories
and results will be reported in due course.
(6) Banwell, M. G.; McRae, K. J.; Willis, A. C. J. Chem. Soc., Perkin
Trans. 1 2001, 2194.
(7) Banwell, M. G.; Kokas, O. J.; Willis, A. C. Org. Lett. 2007, 9, 3503.
(8) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973.
(9) Crossland, R. K.; Servis, K. L. J. Org. Chem. 1970, 35, 3195.
(10) Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353.
(11) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(12) Banwell, M. G.; Bissett, B. D.; Busato, S.; Cowden, C. J.; Hockless,
D. C. R.; Holman, J. W.; Read, R. W.; Wu, A. W. J. Chem. Soc., Chem.
Commun. 1995, 2551.
Acknowledgment. We thank the Institute of Advanced
Studies and the Australian Research Council for generous
financial support. Mr. Jose´ Basutto (Australian National
University) is warmly acknowledged for helpful discussions.
(13) Hanessian, S.; Delorme, D.; Dufresne, Y. Tetrahedron Lett. 1984,
25, 2515.
(14) Mentzel, U. V.; Tanner, D.; Tonder, J. E. J. Org. Chem. 2006, 71,
5807.
(15) Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M. J. Org. Chem. 1998,
63, 188.
(16) (a) Overman, L. E. Acc. Chem. Res. 1980, 13, 218. (b) Overman,
L. E.; Carpenter, N. E. Org. React. 2005, 66, 1 and references cited therein.
(17) Oishi, T.; Ando, K.; Inomiya, K.; Sato, H.; Iida, M.; Chida, N. Org.
Lett. 2002, 4, 151.
(18) Keck, G. E.; Wager, T. T.; Duarte Rodriquez, J. F. J. Am. Chem.
Soc. 1999, 121, 5176.
Supporting Information Available: Full experimental
procedures; crystallographic data and atomic displacement
ellipsoid plot for compound 30 (CCDC no. 648758); 1H and/
or 13C NMR spectra of compounds 18, 19, 26, 29, (-)-1,
and 30. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) Details of this analysis are provided in the Supporting Information.
OL701552R
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