An efficient synthesis of (±)-lycoricidine featuring a Stille-IMDAF cycloaddition cascade

Article abstract of DOI:10.1021/ol052524f

A highly efficient total synthesis of (±)-Lycoricidine is described. The synthesis features the ready preparation of the Lycoricidine skeleton by a Stille-IMDAF cycloaddition cascade. The resulting cycloadduct is then used for the stereocontrolled install

Full text of DOI:10.1021/ol052524f

ORGANIC
LETTERS
2006
Vol. 8, No. 2
247-250
An Efficient Synthesis of
)-Lycoricidine Featuring a
Stille IMDAF Cycloaddition Cascade
(±
−
Hongjun Zhang and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received October 18, 2005
ABSTRACT
A highly efficient total synthesis of (
±)-Lycoricidine is described. The synthesis features the ready preparation of the Lycoricidine skeleton by
a Stille IMDAF cycloaddition cascade. The resulting cycloadduct is then used for the stereocontrolled installation of the other functionality
−
present in the C-ring of the target molecule.
Many of the lycorine-type Amaryllidaceae alkaloids display
useful biological properties,1 and as a consequence this family
has captured the interest of a number of synthetic groups as
targets for total synthesis.2 The history of the hydroxylated
phenanthridones of the Amaryllidaceae group, their biologi-
cal profiles, and various syntheses have been reviewed on
several occasions,3 most recently by Hudlicky and Rinner
in 2005.4 Lycoricidine (1),5 the structurally related Narci-
clasine (2),6 as well as Pancratistatin (3)7 and 7-Deoxypan-
cratistatin (4)8 are popular synthetic targets primarily because
their heterocyclic framework provides a means to demon-
strate the utility of new synthetic strategies.4 In addition, the
narcissus alkaloids are available only in small quantities from
natural sources,9 and their use as therapeutic agents10 depends
on their ready availability. The principle hurdles to their
(5) For syntheses of Lycoricidine, see: (a) Ohta, S.; Kimoto, S. Chem.
Pharm. Bull. 1976, 24, 2977. (b) Paulsen, H.; Stubbe, M. Tetrahedron Lett.
1982, 23, 3171. (c) Paulsen, H.; Stubbe, M. Liebigs Ann. Chem. 1983, 535.
(d) Chida, N.; Ohtsuka, M.; Ogawa, S. Tetrahedron Lett. 1991, 32, 4525.
(e) Hudlicky, T.; Olivo, H. F. J. Am. Chem. Soc. 1992, 114, 9694. (f) Chida,
N.; Ohtsuka, M.; Ogawa, S. J. Org. Chem. 1993, 58, 4441. (g) Martin, S.
F.; Tso, H. H. Heterocycles 1993, 35, 85. (h) Hudlicky, T.; Olivo, H. F.;
McKibben, B. J. Am. Chem. Soc. 1994, 116, 5108. (i) Keck, G. E.; Wager,
T. T. J. Org. Chem. 1996, 61, 8366. (j) Elango, S.; Yan, T. H. Tetrahedron
2002, 58, 7375.
(6) For syntheses of Narciclasine, see: (a) Mondon, A.; Krohn, K.
Tetrahedron Lett. 1972, 13, 2085. (b) Mondon, A.; Krohn, K. Chem. Ber.
1975, 108, 445. (c) Krohn, K.; Mondon, A. Chem. Ber. 1976, 109, 855. (d)
Rigby, J. H.; Mateo, M. E. J. Am. Chem. Soc. 1997, 119, 12655. (e) Rigby,
J. H.; Maharoof, U. S. M.; Mateo, M. E. J. Am. Chem. Soc. 2000, 122,
6624. (f) Gonzalez, D.; Martinot, T.; Hudlicky, T. Tetrahedron Lett. 1999,
40, 3077.
(7) For syntheses of Pancratistatin, see: (a) Danishefsky, S.; Lee, J. Y.
J. Am. Chem. Soc. 1989, 111, 4829. (b) Tian, X.; Hudlicky, T.; Ko¨nigs-
berger, K. J. Am. Chem. Soc. 1995, 117, 3643. (c) Trost, B. M.; Pulley, S.
R. J. Am. Chem. Soc. 1995, 117, 10143. (d) Keck, G. E.; McHardy, S. F.;
Murry, J. A. J. Am. Chem. Soc. 1995, 117, 7289. (e) Hudlicky, T.; Tian, X.
R.; Ko¨nigsberger, K.; Mauray, R.; Rouden, J.; Fan. B. J. Am. Chem. Soc.
1996, 118, 10752. (f) Chida, N.; Jitsuoka, M.; Yamamoto, Y.; Ohtsuka,
M.; Ogawa, S. Heterocycles 1996, 43, 1385. (g) Doyle, T. J.; Hendrix, M.;
VanDerveer, D.; Javanmard, S.; Haseltine, J. Tetrahedron 1997, 53, 11153.
(h) Magnus, P.; Sebhat, I. K. Tetrahedron 1998, 54, 15509. (i) Magnus, P.;
Sebhat, I. K. J. Am. Chem. Soc. 1998, 120, 5341. (j) Pettit, G. R.; Melody,
N.; Herald, D. L. J. Org. Chem. 2001, 66, 2583. (k) Kim, S.; Ko, H.; Kim,
E.; Kim, D. Org. Lett. 2002, 4, 1343. (l) Ko, H. J.; Park, J. E.; Kim, S. J.
Org. Chem. 2004, 69, 112.
(1) (a) Hartwell, J. L. Lloydia 1967, 30, 379. (b) Fitzgerald, D. B.;
Hartwell, J. L.; Leiter, J. J. Nat. Cancer Inst. 1958, 20, 763. (c) Pettit, G.
R.; Gaddamidi, V.; Herald, D. L.; Singh, S. B.; Cragg, G. M.; Schmidt, J.
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(d) Ceriotti, G. Nature 1967, 213, 595. (e) Okamoto, T.; Torii, Y.; Isogai,
Y. Chem. Pharm. Bull. 1968, 16, 1860.
(2) For some leading references, see: (a) Hudlicky, T. J. Heterocycl.
Chem. 2000, 37, 535. (b) Martin, S. F. The Amaryllidaceae Alkaloids. In
The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1987; Vol.
30, Chapter 3, pp 251-376.
(3) (a) Polt, R. In Organic Synthesis: Theory and Applications; Hudlicky,
T., Ed.; JAI Press: Greenwich, CT; 1997; Vol. 3, p 109. (b) Hoshino, O.
In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1998;
Vol. 51, p 323. (c) Jin, Z. Nat. Prod. Rep. 2003, 20, 606.
(4) Rinner, U.; Hudlicky, T. Synlett 2005, 365.
10.1021/ol052524f CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/16/2005

synthesis include the introduction of the aryl group and the
stereocontrolled construction of the fused BC ring system.
dition of an amidofuran (IMDAF). The resulting cycloadduct
6 is then used for the stereocontrolled installation of the other
functionality present in the C-ring of Lycoricidine. The
carbomethoxy substituent is utilized as a critical control
element not only to facilitate the [4 + 2]-cycloaddition but
also to provide a handle for the introduction of the required
π-bond and to set the stereochemistry at the C4a-ring juncture.
Our synthesis of amidofuran 7 began by coupling the
known acid chloride 916 with the lithiated carbamate 10b
derived by treating furanyl-2-ylcarbamic acid tert-butyl ester
(10a) with n-BuLi. Removal of the t-Boc protecting group
from the resulting carbamate 11 with Mg(ClO4)2 afforded
NH amide 12 in 75% yield, and this was followed by reaction
with NaH and p-methoxybenzyl chloride to give 7 in 83%
yield.17 The methyl acrylate moiety was introduced by means
of a Stille coupling15 using methyl 2-tri-n-butylstannylacry-
late18 (Scheme 2). The optimum conditions for this reaction
A major strategy that is routinely employed for the
synthesis of the lycorine group consists of constructing two
fragments representing the A and C cycles, which are then
coupled together to form the B ring. This approach often
involves formation of the 10a-10b carbon-carbon bond by
either a palladium-based11 or photocyclization6d reaction,
although other coupling methods have also been used.3,4 An
alternate synthetic route would be the formation of the C-ring
from a suitable precursor in which the 10a-10b bond of
the target is already present.12,13 It is against this background
that we report a short and efficient synthesis of (()-Ly-
coricidine. Our approach derives from a general program
underway in our laboratory that is designed to exploit the
facile Diels-Alder reaction of amidofurans for the purposes
of natural product synthesis.14 Our retrosynthetic analysis
of (()-Lycoricidine is shown in Scheme 1 and makes use
Scheme 2
Scheme 1
were eventually determined to be those described by Corey
that utilize a combination of CuCl/Pd(0)/LiCl for the key
coupling.19 The use of DMSO with rigorous exclusion of
(11) Grubb, L. M.; Dowdy, A. L.; Blanchette, H. S.; Friestad, G. K.;
Branchaud, B. P. Tetrahedron Lett. 1999, 40, 2691.
(12) (j) Keck, G. E.; Wager, T. T.; Rodriquez, J. F. D. J. Am. Chem.
Soc. 1999, 121, 5176.
(13) Khaldi, M.; Chre’tien, F.; Chapleur, Y. Tetrahedron Lett. 1995, 36,
3003.
of a tandem cascade sequence consisting of a Stille coupling15
followed by a spontaneous intramolecular [4 + 2]-cycload-
(8) (a) Akgun, H.; Hudlicky, T. Tetrahedron Lett. 1999, 40, 3081. (b)
Rinner, U.; Siengalewicz, P.; Hudlicky, T. Org. Lett. 2002, 4, 115. (c) Tian,
X.; Maurya, R.; Ko¨nigsberger, K. Synlett 1995, 1125. (d) Keck, G. E.;
Wager, T. T.; McHardy, S. F. J. Org. Chem. 1998, 63, 9164. (e) Keck, G.
E.; McHardy, S. F.; Murry, J. A. J. Am. Chem. Soc. 1995, 117, 7289. (f)
Acena, J. L.; Arjona, O.; Leon, M. L.; Plumet, J. Org. Lett. 2000, 2, 3683.
(9) Pettit, G. R.; Backhaus, R. A.; Boettner, F. E. J. Nat. Prod. 1995,
58, 37.
(10) (a) Pettit, G. R.; Freeman, S.; Simpson, M. J.; Thompson, M. A.;
Boyd, M. R.; Williams, G. R.; Pettit, G. R., III; Doubek, D. L. Anti-Cancer
Drug Des. 1995, 10, 243. (b) Pettit, G. R.; Orr, S.; Ducki, S. Anti-Cancer
Drug Des. 2000, 15, 389.
(14) (a) Wang, Q.; Padwa, A. Org. Lett. 2004, 6, 2189. (b) Padwa, A.;
Ginn, J. D. J. Org. Chem. 2005, 70, 5197. (c) Padwa, A.; Bur, S. K.; Zhang,
H. J. Org. Chem. 2005, 70, 6833.
(15) Farina, V.; Krishnamurphy, V.; Scott, W. J. Org. React. 1997,
50, 1.
(16) McIntosh, M. C.; Weinreb, S. M. J. Org. Chem. 1993, 58, 4823.
(17) Replacement of the t-Boc group with the PMB functionality was
necessary for the subsequent Stille reaction.
(18) (a) Zhang, H. X.; Guiibe, F.; Balavoine, G. J. Org. Chem. 1990,
55, 1857. (b) Miyake, H.; Yamamura, K. Chem. Lett. 1989, 981. (c) Cochran,
J. C.; Bronk, B. S.; Terrence, K. M.; Philips, H. K. Tetrahedron Lett. 1990,
31, 6621.
248
Org. Lett., Vol. 8, No. 2, 2006

oxygen and moisture at 60 °C gave the best results. The
expected cross-coupled amidofuran 13, however, was not
isolated as it spontaneously underwent an intramolecular [4
+ 2]-cycloaddition to furnish cycloadduct 6 in 82% overall
yield for the two-step cascade. The increase in reactivity of
13 when compared to related furanyl carbamates20 (>150
°C) is due to both the placement of the carbonyl center within
the dienophilic tether and the presence of the carbomethoxy
group, which lowers the LUMO energy of the π-bond there-
by facilitating the cycloaddition. Dramatic effects on the rate
of the Diels-Alder reaction were previously noted to occur
when an amido group was used to anchor the diene and di-
enophile.21 Our ability to isolate oxabicyclic adduct 6 is pre-
sumably a result of the lower reaction temperature employed
(i.e., 60 °C) as well as the presence of the amido carbonyl
group, which diminishes the basicity of the nitrogen atom
thereby retarding the ring cleavage/rearrangement reaction
generally encountered with these systems.20 Moreover, the
IMDAF cycloaddition proceeds by a transition state where
the sidearm of the tethered vinyl group is oriented exo with
respect to the oxygen bridge.22 As a consequence of this pre-
ferred orientation, the carbomethoxy group and oxy-bridge
are disposed in an anti relationship in the resulting cycload-
duct 6.
to set the stereochemistry at the C4a position, insert the
remaining R-hydroxyl group at C2, and ultimately introduce
the required π-bond. All of these operations were facilitated
by making use of the available carbomethoxy group (vide
infra). First, diol 14 was converted to the corresponding
acetonide 15 in 80% yield by treatment with 2,2-dimethox-
ypropane and catalytic pyridinium p-toluenesulfonate. The
uniquely functionalized oxabicyclic adduct 15 contains a
“masked” N-acyliminium ion that can be released by
treatment with a Lewis acid such as TMSOTf. When the
resulting ring-opened iminium ion was treated with
Zn(BH4)2,23 alcohol 5 was obtained in 74% yield.
What was required for the end game leading to Lycori-
cidine (1) was to invert the stereochemistry of the C2-hy-
droxyl group, remove the carbomethoxy moiety, and generate
a double bond between the C1-C10b position of the C-ring.
To this end, compound 5 was treated with NaH followed by
the addition of CS2 and MeI to give the corresponding
xanthate ester, which upon heating at reflux in 1,2-dichlo-
robenzene for 12 h afforded the expected olefin derived from
a Chugaev elimination24 in 94% yield (Scheme 4). Since the
Scheme 4
With the rapid construction of the Lycoricidine framework
in hand, installation of the other functional groups present
on the C-ring with the correct relative stereochemistry was
investigated. To continue the synthesis, cycloadduct 6 was
transformed to diol 14 by reaction with catalytic OsO4 in
the presence of 4-methyl-morpholine-N-oxide. The dihy-
droxylation reaction occurred exclusively from the less
hindered exo face, producing 14 in 98% yield (Scheme 3).
Scheme 3
â-face of the π-bond of 16 was blocked by the bulky
acetonide, a dihydroxylation reaction was expected to take
place from the less hindered R-face, syn to the carbomethoxy
group, thereby setting the correct stereochemistry of the
C2-hydroxyl group. Indeed, when 16 was treated with OsO4/
NMO, the desired diol 17 was formed as a transient species
but underwent spontaneous cyclization with the adjacent
Having introduced the correct cis-stereochemistry of the
hydroxyl groups at the C3,C4 positions, we then proceeded
(19) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121,
7600.
(20) (a) Padwa, A.; Brodney, M. A.; Dimitroff, M. J. Org. Chem. 1998,
63, 5304. (b) Bur, S. K.; Lynch, S. M.; Padwa, A. Org. Lett. 2002, 4, 473.
(c) Ginn, J. D.; Padwa, A. Org. Lett. 2002, 4, 1515.
Org. Lett., Vol. 8, No. 2, 2006
249

carbomethoxy group to deliver γ-lactone 18. A subsequent
mesylation reaction afforded mesylate 19 in 76% yield for
the two-step sequence starting from 16. The γ-lactonization
of 17 to 18 permits the selective activation of the C1-hydroxyl
group. The PMB group was removed by the reaction of 19
with PdCl2 in the presence of acetic acid25 to furnish the
deprotected amide. Gratifyingly, the reaction of this amide
with LiOH in aqueous THF induced a novel tandem
hydrolysis/decarboxylation/elimination sequence26 to furnish
allylic alcohol 20. Deprotection of the acetonide with TFA
afforded (()-Lycoricidine in 90% yield.
In summary, we have described here a novel and highly
efficient synthesis of (()-Lycoricidine, which was achieved
in 14 steps with a 12.6% overall yield. The synthesis
illustrates (a) the use of a one-pot Stille-IMDAF cycload-
dition cascade to construct the ring skeleton, (b) a stereo-
controlled dihydroxylation and N-acyliminium ion reduction
to set the correct stereochemistry at carbon atoms C3, C4,
and C4a, and (c) the novel introduction of the C1-C10b π-bond
by a one-pot hydrolysis-decarboxylation-elimination se-
quence. The application of this approach to other members
of the lycorine family of alkaloids is currently under
investigation, the results of which will be disclosed in due
course.
(21) (a) Oppolzer, W.; Fro¨stl, W. HelV. Chem. Acta 1975, 58, 590. (b)
White, J. D.; Demnitz, F. W. J.; Oda, H.; Hassler, C.; Snyder, J. P. Org.
Lett. 2000, 2, 3313. (c) Padwa, A.; Ginn, J. D.; Bur, S. K.; Eidell, C. K.;
Lynch, S. M. J. Org. Chem. 2002, 67, 3412. (d) Tantillo, D. J.; Houk, K.
N.; Jung, M. E. J. Org. Chem. 2001, 66, 1938.
(22) Padwa, A.; Brodney, M. A.; Satake, K.; Straub, C. S. J. Org. Chem.
1999, 64, 4617.
Acknowledgment. We appreciate the financial support
provided the The National Institutes of Health (GM059384)
and The National Science Foundation (CHE-0450779).
(23) Gensler, W. J.; Johnson, F.; Sloan, A. D. B. J. Am. Chem. Soc.
1960, 82, 6074.
(24) Nace, H. R. Org. React. 1962, 12, 57.
(25) Keck, G. E.; Boden, E.; Sonnewald, U. Tetrahedron Lett. 1981,
22, 2615.
(26) For a related fragmentation reaction, see: Khim, S.; Dai, M.; Zhang,
X.; Chen, L.; Pettus, L.; Thakkar, K.; Schultz, A. G. J. Org. Chem. 2004,
69, 7728.
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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