Rapid and enantioselective assembly of the lycorine framework using chemoenzymatic techniques

Article abstract of DOI:10.1021/ol901364n

The pentacyclic framework associated with the alkaloid (-)-lycorine (1) can be assembled in as few as six steps from the enantiomerically pure cis-1,2-dihydrocatechol 3 which is itself readily available on a large scale through the whole-cell biotransform

Full text of DOI:10.1021/ol901364n

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3506-3509
Rapid and Enantioselective Assembly of
the Lycorine Framework Using
Chemoenzymatic Techniques
Matthew T. Jones, Brett D. Schwartz, Anthony C. Willis, and Martin G. Banwell*
Research School of Chemistry, Institute of AdVanced Studies, The Australian National
UniVersity, Canberra, ACT 0200, Australia
mgb@rsc.anu.edu.au
Received June 17, 2009
ABSTRACT
The pentacyclic framework associated with the alkaloid (-)-lycorine (1) can be assembled in as few as six steps from the enantiomerically
pure cis-1,2-dihydrocatechol 3 which is itself readily available on a large scale through the whole-cell biotransformation of bromobenzene. The
methodology has been used in developing the first synthesis of compound 2, a derivative of lycorine.
The alkaloid lycorine (1, Figure 1) constitutes up to 1%
of the dry weight of daffodil bulbs and is considered to
be the most abundant of the nitrogen bases of the
Amaryllidaceae.1 The determination of the structure of
this compound rests, in large measure, on the outstanding
efforts of several Japanese groups started in the mid-1930s
and which included degradation work whereby lycorine
was converted into derivative 2.2 The structural proposals
arising from these studies were confirmed through the
Figure 1. Alkaloid (-)-lycorine (1) and a degradation product 2.
(1) (a) Cook, J. W.; Loudon, J. D. In The Alkaloids; Manske, R. H. F.,
Holmes, H. L., Eds.; Academic Press: New York, 1952; Vol. 2, p 331. (b)
Dalton, D. R. The Alkaloids: The Fundamental Chemistry - A Biogenetic
Approach; Marcel Dekker: New York, 1979; p 2.
single-crystal X-ray analysis of the hydrobromide salt of
dihydrolycorine, the product of hydrogenation of com-
pound 1.3
(2) (a) Kondo, H.; Uyeo, S. Chem. Ber. 1935, 68, 1756. (b) Humber,
L. G.; Kondo, H.; Kotera, K.; Takagi, S.; Takeda, K.; Taylor, W. I.; Thomas,
B. R.; Tsuda, Y.; Tsukamoto, K.; Uyeo, S.; Yajima, H.; Yanaihara, N.
J. Chem. Soc. 1954, 4622. (c) Takagi, S.; Taylor, W. I.; Uyeo, S.; Yajima,
H. J. Chem. Soc. 1955, 4003. (d) Takeda, K.; Kotera, K. Chem. Pharm.
Bull. 1957, 5, 234. (e) Nakagawa, Y.; Uyeo, S. J. Chem. Soc. 1959, 3736.
(f) Kotera, K.; Hamada, Y.; Tori, K.; Aono, K.; Kuriyama, K. Tetrahedron
Lett. 1966, 7, 2009.
Lycorine displays a remarkable range of biological proper-
ties.4,5 During its initial isolation,1 it was recognized as a
(4) For a review of the chemistry and biological effects of lycorine and
related Amaryllidaceae alkaloids, see: Ghosal, S.; Saini, K. S.; Razdan, S.
Phytochemistry 1985, 24, 2141.
(3) Shiro, M.; Sato, T.; Koyama, H. Chem. Ind. 1966, 1229.
10.1021/ol901364n CCC: $40.75
Published on Web 07/10/2009
 2009 American Chemical Society

Scheme 1
potent emetic. It is also a strong inhibitor of growth and cell
Tomioka and co-workers described8b the first asymmetric
total synthesis of (-)-lycorine using a chiral ligand-controlled
cascade conjugate addition reaction. It is against this
background that we now describe an abbreviated and
chemoenzymatic synthesis of the natural enantiomeric form
of the lycorine framework that has allowed for the ready
assembly of degradation product 2 as well as a more heavily
functionalized system that is an isomer of lycorine. This
isomer may serve as a precursor to the natural product itself.
division in higher plants, algae, and yeast and has been shown
to inhibit protein and DNA synthesis in murine cells as well
as impacting on the in vivo growth of a murine-transplantable
ascite tumor. Potent antiviral and immunosuppressive prop-
erties have also been attributed to lycorine.4,5
Various studies directed toward the synthesis of lycorine
have been carried out6-8 with most of these leading to the
racemic modification of the alkaloid.7 A relay synthesis of
the natural product was described by Tsuda and co-workers
in 1975,7a while in 1993, Schultz and co-workers reported8a
the preparation of ent-lycorine and ent-1-deoxylycorine in
13 to 14 steps using the Birch-reductive alkylation of a chiral
benzamide as a key transformation. Very recently (2009)
The essential features of the present synthesis of the
lycorine framework are shown in Scheme 1. The reaction
sequence starts with the enantiomerically pure cis-1,2-
dihydrocatechol 3 which is available in large quantity through
the whole-cell biotransformation of bromobenzene.9 Thus,
conversion of diol 3 into the corresponding and well-known
(5) For more recent publications reporting on the biological properties
of lycorine and its derivatives see: (a) Dickneite, G.; Schorlemmer, H. U.;
Sedlacek, H. H. Ger. Offen. DE 3426109, Jan 23, 1986; Chem. Abstr. 1986,
104, 161979. (b) Toriizuka, Y.; Kinoshita, E.; Kogure, N.; Kitajima, M.;
(7) Total syntheses or formal total syntheses of (()-lycorine: (a) Tsuda,
Y.; Sano, T.; Taga, J.; Isobe, K.; Toda, J.; Irie, H.; Tanaka, H.; Takagi, S.;
Yamaki, M.; Murata, M. J. Chem. Soc., Chem. Commun. 1975, 933. (b)
Møller, O.; Steinberg, E.-M.; Torssell, K. Acta Chem. Scand. B 1978, 32,
98. (c) Umezawa, B.; Hoshino, O.; Sawaki, S.; Sashida, H.; Mori, K.
Heterocycles 1979, 12, 1475. (d) Martin, S. F.; Tu, C.; Kimura, M.;
Simonsen, S. H. J. Org. Chem. 1982, 47, 3634. (e) Boeckman, R. K., Jr.;
Goldstein, S. W.; Walters, M. A. J. Am. Chem. Soc. 1988, 110, 8250. (f)
Hoshino, O.; Ishizaki, M.; Kamei, K.; Taguchi, M.; Nagao, T.; Iwaoka,
K.; Sawaki, S.; Umezawa, B.; Iitaka, Y. J. Chem. Soc., Perkin Trans. 1
1996, 571.
j
Ishiyama, A.; Otoguro, K.; Yamada, H.; Omura, S.; Takayama, H. Bioorg.
Med. Chem. 2008, 16, 10182, and references cited therein. (c) Liu, X.; Jiang,
J.; Jiao, X.; Wu, Y.; Lin, J.; Cai, Y. Cancer Lett. 2009, 274, 16, and
references cited therein
.
(6) Synthetic approaches: (a) Hill, R. K.; Joule, J. A.; Loeffler, L. J.
J. Am. Chem. Soc. 1962, 84, 4951. (b) Hendrickson, J. B.; Alder, R. W.;
Dalton, D. R.; Hey, D. G. J. Org. Chem. 1969, 34, 2667. (c) Landeryou,
V. A.; Grabowski, E. J. J.; Autrey, R. L. Tetrahedron 1969, 25, 4307. (d)
Irie, H.; Nishitani, Y.; Sugita, M.; Uyeo, S. Chem. Commun. 1970, 1313.
(e) Ganem, B. Tetrahedron Lett. 1971, 12, 4105. (f) Dyke, S. F.; Sainsbury,
M.; Evans, J. R. Tetrahedron 1973, 29, 213. (g) Iida, H.; Aoyagi, S.;
Kibayashi, C. J. Chem. Soc., Chem. Commun. 1974, 499. (h) Kissel, W. S.;
Padwa, A. Tetrahedron Lett. 1999, 40, 4003. (i) Ishizaki, M.; Kai, Y.;
(8) Total synthesis of (+)- or (-)-lycorine: (a) Schultz, A. G.; Holoboski,
M. A.; Smyth, M. S. J. Am. Chem. Soc. 1996, 118, 6210. [(+)-lycorine].
(b) Yamada, K.-i.; Yamashita, M.; Sumiyoshi, T.; Nishimura, K.; Tomioka,
K. Org. Lett. 2009, 11, 1631. [(-)-lycorine].
Hoshino, O. Heterocycles 2002, 57, 2279
.
Org. Lett., Vol. 11, No. 15, 2009
3507

acetonide 4 (93%)10 is followed by treatment of the latter
compound with m-CPBA to give the previously reported10
epoxide 5 in 95% yield. Reaction of compound 5 with the
anion derived from acetonitrile then gave, as the exclusive
product of reaction, the γ-hydroxynitrile 6 (96%) arising from
attack of the nucleophile at the allylic carbon of the epoxide
ring of the former compound.11 Removal of the hydroxy
group within compound 6 was achieved using the Barton-
McCombie protocol12 although some care was required in
forming the intermediate xanthate ester 7 because the use
of an excess of carbon disulfide in this step led to dramati-
cally diminished yields of this product. Under the best
conditions identified so far (and leading to a 94% yield of
7), a close to 1:1:1 molar ratio of substrate, CS2, and MeI
was used. Reductive cleavage of ester 7 was readily achieved
with 2.1 mol equiv of n-Bu3SnH in refluxing benzene and
using AIBN as initiator. Under such conditions, the nitrile 8
was obtained in yields ranging from 67 to 82%. It was critical
to subject this compound to rigorous chromatographic
purification to remove coproduced carbonyl sulfide13 which,
when present, adversely affects the efficiency of the
Suzuki-Miyaura cross-coupling14 that is the next step in the
reaction sequence. So, when a mixture of a carbonyl sulfide-
free sample of compound 8, aryl boronate 9,15 6 mol %
PdCl2(dppf), and triethylamine was subjected to microwave
irradiation at 90 °C for 1.5 h, then the expected product,
arylcyclohexene 10, was obtained in 75% yield. Hydrolysis
of the acetonide residue within compound 10 was readily
achieved using a 4:1 v/v mixture of acetic acid and water at
80 °C, and the allylic alcohol so-revealed engaged in a
spontaneous lactonization reaction with the adjacent aryl ester
residue and thus forming the isolable lactone 11 in 89% yield.
In the most demanding and unusual step of the reaction
sequence, the nitrile moiety within compound 11 was
selectively reduced with dihydrogen, at 80 °C in the presence
of Raney-cobalt and using ammoniacal methanol as solvent.16
In this manner, the lactam 14 was obtained in 65% yield.
Presumably, the primary amine 12 is the initially formed
product of reaction, but this then undergoes an SN′ reaction17
with the pendant allylic lactone residue to give the amino
acid 13 which, in turn, lactamizes to give the observed
product 14. The structure of compound 14 was confirmed
through a single-crystal X-ray analysis of the readily gener-
ated p-nitrobenzoate derivative. The resulting ORTEP plot
is shown in Figure 2, while other details of this analysis are
provided in the Supporting Information (SI).
Figure 2. ORTEP plot derived from the single-crystal X-ray
analysis of the p-nitrobenzoate of alcohol 14. Only the major sites
of disordered atoms are shown. Anisotropic displacement ellipsoids
display 30% probability levels. Hydrogen atoms are drawn as circles
with small radii.
(9) Compound 3 can be obtained from the Aldrich Chemical Co.
(Catalogue Number 489492) or from Questor, Queen’s University of Belfast,
Northern Ireland. Questor Centre Contact Page: http://questor.qub.ac.uk/
newsite/contact.htm (accessed July 2, 2009). 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. Aldrichimica
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. (d) Hudlicky, T.; Reed, J. W. Synlett 2009, 685.
The conversion of compound 14 into the dihydrolycorine
degradation product 2 was achieved in a straightforward
manner by the pathway shown in Scheme 2. Thus, O-
methylation of the former compound using trimethyloxonium
tetrafluoroborate in the presence of Proton-sponge18 gave the
ether 15 (95%), and the lactam carbonyl within this product
(10) Hudlicky, T.; Price, J. D.; Rulin, F.; Tsunoda, T. J. Am. Chem.
Soc. 1990, 112, 9439.
(11) For related examples of this type of epoxide ring-opening process,
see: Banwell, M. G.; Haddad, N.; Hudlicky, T.; Nugent, T. C.; Mackay,
M. F.; Richards, S. L. J. Chem. Soc., Perkin Trans. 1 1997, 1779.
(12) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574.
(13) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron Lett.
1990, 31, 3991.
Scheme 2
(14) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513.
(15) In keeping with expectations (Chaumeil, H.; Signorella, S.; Le
Drian, C. Tetrahedron 2000, 56, 9655) the 2,2-dimethyl-1,3-propanediol
derived boronate 9, which was readily prepared by the methods defined in
the Supporting Information, proved a more effective coupling partner than
its pinacol-derived equivalent (Matveenko, M.; Kokas, O. J.; Banwell, M. G.;
Willis, A. C. Org. Lett. 2007, 9, 3683).
(16) For a related reduction process involving Raney-cobalt see: Janey,
J. M.; Orella, C. J.; Njolito, E.; Baxter, J. M.; Rosen, J. D.; Palucki, M.;
Sidler, R. R.; Li, W.; Kowal, J. J.; Davies, I. W. J. Org. Chem. 2008, 73,
3212.
3508
Org. Lett., Vol. 11, No. 15, 2009

The adaptation of the above-mentioned chemistry to the
synthesis of an isomer of lycorine (and a potential precursor
to the natural product) is shown in Scheme 3. Thus,
Suzuki-Miyaura cross-coupling of diol 6 with boronate 9,
under conditions similar to those used for the conversion 8
+ 9 f 10, gave the expected arylcyclohexene 16 in 79%
yield. Treatment of this last compound with acetic acid/water
then gave lactone 17 (65-82%), and exposure of this to
dihydrogen in the presence of Raney-cobalt afforded, in 51%
yield, lactam 18. Reaction of compound 18 with LiAlH4 in
THF then gave amine 19 (78%), the targeted isomer of
lycorine.
Scheme 3
Interestingly, reaction of diol 18 with one molar equivalent
of tert-butyldimethylsilyl triflate (TBDMSOTf) in the pres-
ence of triethylamine gave, in 48% yield, the monosilyl ether
20 which may represent a useful intermediate en route to
lycorine itself. The structure of compound 20 was confirmed
by a single-crystal X-ray analysis, details of which will be
described elsewhere.
The reaction sequences reported here provide ready access
to the lycorine framework and should enable the preparation
of a wide range of analogues of the natural product as well
as compound 1. Work directed toward the latter end is now
underway, and results will be reported in due course. Since
the cis-1,2-dihydrocatechol ent-3 is readily available,19 the
present work should also provide access to the non-natural
enantiomeric forms of members of the lycorine class of
alkaloid.
Acknowledgment. We thank the Institute of Advanced
Studies and the Australian Research Council for financial
support.
Supporting Information Available: Preparative proce-
dures and product characterization for compounds 2, 6-11,
and 14-20 are provided together with the data derived from
the single-crystal X-ray analyses of compound 2 and the
p-nitrobenzoate of alcohol 14 (CCDC numbers 735464 and
735465, respectively). This material is available free of
charge via the Internet at http://pubs.acs.org.
was readily removed using LiAlH4 in THF and thereby
affording the target 2 in 89% yield as a crystalline solid that
was also subjected to single-crystal X-ray analysis (see SI
for details). The melting point (mp 154-157 °C), specific
rotation {[R]D -64 (c 0.9, EtOH)}, and UV spectrum (see
SI) of our sample of ether 2 were in good agreement with
those recorded by Takeda and Kotera {mp 155-156 °C, [R]D
-80 (c 1.0, EtOH)}2d for the compound (assigned structure
2) they obtained by manipulating dihydrolycorine.
OL901364N
(17) For a review of this type of process, see: Magid, R. M. Tetrahedron
1980, 36, 1901.
(18) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. Tetrahedron
Lett. 1994, 35, 7171.
(19) Allen, C. C. R.; Boyd, D. R.; Dalton, H.; Sharma, N. D.; Brannigan,
I.; Kerley, N. A.; Sheldrake, G. N.; Taylor, S. C. J. Chem. Soc., Chem.
Commun. 1995, 117.
Org. Lett., Vol. 11, No. 15, 2009
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