Synthesis of (+)-lycoricidine by the application of oxidative and regioselective ring-opening of aziridines

Article abstract of DOI:10.1021/ol100755v

A highly stereoselective total synthesis of (+)-lycoricidine has been described. The salient features of this synthesis are the one-pot elimination followed by allylation reaction, ring-closing metathesis, stereoselective aziridine formation, Dess-Martin periodinane, and silica gel mediated oxidative ring-opening of aziridine to form α,β-unsaturated ketone (allyl amine) and intramolecular Heck cyclization.

Full text of DOI:10.1021/ol100755v

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2544-2547
Synthesis of (+)-Lycoricidine by the
Application of Oxidative and
Regioselective Ring-Opening of
Aziridines
J. S. Yadav,* G. Satheesh, and Changalvala V. S. R. Murthy
Organic Chemistry DiVision, Indian Institute of Chemical Technology (CSIR),
Hyderabad-500 007, India
yadaVpub@iict.res.in
Received April 1, 2010
ABSTRACT
A highly stereoselective total synthesis of (+)-lycoricidine has been described. The salient features of this synthesis are the one-pot elimination
followed by allylation reaction, ring-closing metathesis, stereoselective aziridine formation, Dess-Martin periodinane, and silica gel mediated
oxidative ring-opening of aziridine to form r,ꢀ-unsaturated ketone (allyl amine) and intramolecular Heck cyclization.
Over the years, the plant extracts of the Amaryllidaceae
family have attracted a lot of attention from the synthetic
community because of their interesting structures and potent
biological activities.1 A unique subset of the phenanthridone
alkaloids lycoricidine (1)2 and narciclasine (2)3 have been
extracted from different daffodil bulbs (Figure 1). In the
1970s, structural determination of these protein synthesis
inhibitors showed that they are highly oxygenated ben-
zophenanthridone-type compounds. The antitumor activity
Figure 1. Structures of natural compounds.
of these compounds has also been investigated and seems
to be related to the oxygenated cycle and to the tricyclic
system. Compounds lacking this rigid arrangement failed to
exhibit any biological properties.4 Later, a related compound
pancratistatin (3)5 and its analogue 7-deoxypancratistatin (4)6
were isolated and proved to be very strong antitumor agents.7
The biological activities and stereochemical complexity made
them synthetically challenging and attractive.
In continuation of our ongoing research program on the
synthesis of bioactive complex natural products,8 considering
the biological activity and the exciting molecular architecture
of these alkaloids, we report herein a concise approach for
the total synthesis of (+)-lycoricidine.
(1) Reviews: (a) Ceriotti, G. Nature 1967, 213, 595. (b) Okamoto, T.;
Torii, Y.; Isogai, Y. Chem. Pharm. Bull. 1968, 16, 1860. (c) Piozzi, C.;
Fuganti, C.; Mondelli, R.; Ceriotti, G. Tetrahedron 1968, 24, 1119. (d)
Piozzi, F.; Marino, M. L.; Fuganti, C.; Di Martino, A. Phytochemistry 1969,
8, 1745. (e) Rinner, U.; Hudlicky, T. Synlett 2005, 365.
Scheme 1 illustrates the retrosynthetic analysis of 1.
Disconnection at C8 and C7 afforded fragment 5. Compound
10.1021/ol100755v  2010 American Chemical Society
Published on Web 05/04/2010

with zinc/allyl bromide in THF/H2O10 afforded diene 12
(87%, dr 85:15). Cyclization of diene 12 following the ring-
closing metathesis reaction furnished cyclohexenol derivative
9 (84%), and the unreacted isomer 9a was recovered in 5%
yield. The acetylation of the hydroxy group present in 9
yielded compound 13 in a high yield (92%).
Scheme 1. Retrosynthetic Analysis of the (+)-Lycoricidine 1
The strategy toward the synthesis of 7 began with the
acetylated compound 13. The compound 13 was transformed
to aziridine 7 in two different routes. In the first method
(Scheme 3), the acetate 13 was treated with PhINTs11 in the
presence of Cu(acac)2, which yielded the N-tosylaziridine
17f (52%) as a single isomer. Treatment of the compound
17f with sodium naphthalenide12 afforded the aziridine 7
(67%).
(3) (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) Reference 2n. (f) Gonzalez, D.; Martinot, T.;
Hudlicky, T. Tetrahedron Lett. 1999, 40, 3077. (g) Rigby, J. H.; Maharoof,
U. S. M.; Mateo, M. E. J. Am. Chem. Soc. 2000, 122, 6624. (h) Elango, S.;
Yan, T. H. J. Org. Chem. 2002, 67, 6954. (i) Hudlicky, T.; Rinner, U.;
Gonzalez, D.; Akgun, H; Schilling, S.; Siengalewez, P.; Martinot, T. A.;
Petit, G. R. J. Org. Chem. 2002, 67, 8726. (j) ent-Narciclasine: Matveenko,
M.; Banwell, M. G.; Willis, A. C. Tetrahedron 2008, 64, 4817.
(4) Chre’tien, F.; Ibn Ahmed, S.; Masion, A.; Chapleur, Y. Tetrahedron
1993, 49, 7463.
6 would be obtained by the DMP-silica-mediated oxidative
ring-opening of aziridine. Aziridine 7 could be prepared from
readily available D-(+)-mannose. The synthesis of compound
13 is summarized in Scheme 2.
(5) (a) Pettit, G. R.; Gaddamidi, V.; Cragg, G. M.; Herald, D. L.; Sagawa,
Y. J. Chem. Soc., Chem. Commun. 1984, 1693. (b) Danishefsky, S.; Lee,
J. Y. J. Am. Chem. Soc. 1989, 111, 4829. (c) Tian, X. R.; Hudlicky, T.;
Ko¨nigsberger, K. J. Am. Chem. Soc. 1995, 117, 3643. (d) Trost, B. M.;
Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143. (e) Keck, G. E.; McHardy,
S. F.; Murry, J. A. J. Am. Chem. Soc. 1995, 117, 7289. (f) Hudlicky, T.;
Tian, X. R.; Ko¨nigsberger, K.; Maurya, R.; Rouden, J.; Fan, B. J. Am. Chem.
Soc. 1996, 118, 10752. (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) Reference 3g. (k) Pettit, G. R.;
Melody, N.; Herald, D. L. J. Org. Chem. 2001, 66, 2583. (l) Kim, S.; Ko,
H.; Kim, E.; Kim, D. Org. Lett. 2002, 4, 1343. (m) Ko, H. J.; Kim, E.;
Park, J. E.; Kim, D.; Kim, S. J. Org. Chem. 2004, 69, 112. (n) Deoxygenated
pancratistatin: Moser, M.; Sun, X.; Hudlicky, T. Org. Lett. 2005, 7, 5669.
(o) Li, M.; Zhou, P. Tetrahedron Lett. 2006, 47, 3707. (p) Zhang, H.; Padwa,
A. Tetrahedron Lett. 2006, 47, 3905. (q) 10b(s)-epi-Pancratistatin: Petit,
G. R.; Melody, N.; Herald, D. L.; Knight, J. C.; Chapuis, J.-C. J. Nat. Prod.
2007, 70, 417. (r) Dam, J. H.; Madsen, R. Eur. J. Org. Chem. 2009, 4666.
(6) (a) Ghosal, S.; Singh, S. K.; Kumar, Y.; Srivastava, R. S. Phy-
tochemistry 1989, 28, 611. (b) Reference 2b. (c) Ohta, S.; Kimoto, S. Chem.
Pharm. Bull. 1976, 24, 2969. (d) Reference 2d. (e) Tian, X. R.; Maurya,
R.; Ko¨ nigsberger, K.; Hudlicky, T. Synlett 1995, 1125. (f) Keck, G. E.;
McHardy, S. F.; Murry, J. A. J. Am. Chem. Soc. 1995, 117, 7289. (g) Chida,
N.; Jitsuoka, M.; Yamamoto, Y.; Ohtsuka, M.; Ogawa, S. Heterocycles 1996,
43, 1385. (h) Keck, G. E.; Wager, T. T.; McHardy, S. F. J. Org. Chem.
1998, 63, 9164. (i) ent-7-Deoxypancratistatin: Akgun, H.; Hudlicky, T.
Tetrahedron Lett. 1999, 40, 3081. (j) Keck, G. E.; McHardy, S. F.; Murry,
J. A. J. Org. Chem. 1999, 64, 4465. (k) Acena, J. L.; Arjona, O.; Leon,
M. L.; Plumet, J. Org. Lett. 2000, 2, 3683. (l) Rinner, U.; Siengalewicz, P.;
Hudlicky, T. Org. Lett. 2002, 4, 115. (m) Reference 2q. (n) 7-Deoxypan-
cratistatin-1-carboxaldehyde: Collins, J.; Drouin, M.; Sun, X.; Rinner, U.;
Hudlicky, T. Org. Lett. 2008, 10, 361.
(7) Pettit, G. R.; Gaddamidi, V.; Herald, D. L.; Singh, S. B.; Cragg,
G. M.; Schmidt, J. M.; Boettner, F. E.; Williams, M.; Sagawa, Y. J. Nat.
Prod. 1986, 49, 995.
(8) (a) Yadav, J. S.; Chetia, L. Org. Lett. 2007, 9, 4587. (b) Yadav,
J. S.; Reddy, Ch.S. Org. Lett. 2009, 11, 1705. (c) Yadav, J. S.; Rajender,
V.; Rao, Y. G. Org. Lett. 2010, 12, 348.
(9) (a) Veeneman, G. H.; Gomes, L. F. J.; van Boom, J. H. Tetrahedron
1989, 45, 7433. (b) Evans, M. E.; Parish, F. W. Methods Carbohydr. Chem.
1980, 8, 173. (c) Kissman, H. M.; Baker, B. R. J. Am. Chem. Soc. 1957,
79, 5534. (d) Verhelst, S. H. L.; Wiedenhof, W.; Ovaa, H.; van der Marel,
G. A.; Overkleeft, H. S.; van Bockel, C. A. A.; van Boom, J. H. Tetrahedron
Lett. 2002, 43, 6451.
(10) (a) Hyldtoft, L.; Madsen, R. J. Am. Chem. Soc. 2000, 122, 8444.
(b) Hyldtoft, L.; Poulsen, C. S.; Madsen, R. Chem. Commun. 1999, 2101.
(11) (a) Yamada, Y.; Yamamoto, T.; Okawara, M. Chem. Lett. 1975,
361. (b) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Org. Chem. 1991,
56, 6744. (c) Knight, J. G.; Muldowney, M. P. Synlett 1995, 949.
Scheme 2. Synthesis of Compound 13
Thus, ω-iodo glycoside 11 was obtained from readily
available D-(+)-mannose 10 following the previously estab-
lished protocol in five steps.9 On treatment of compound 11
(2) (a) Ohta, S.; Kimoto, S. Tetrahedron Lett. 1975, 27, 2279. (b) Ohta,
S.; Kimoto, S. Chem. Pharm. Bull. 1976, 24, 2977. (c) Paulsen, H.; Stubbe,
M. Tetrahedron Lett. 1982, 23, 3171. (d) Paulsen, H.; Stubbe, M. Liebigs
Ann. 1983, 535. (e) Ugarkar, B. G.; DaRe, J.; Schubert, E. M. Synthesis
1987, 715. (f) Thompson, R. C.; Kallmerten, J. J. Org. Chem. 1990, 55,
6076. (g) Chida, N.; Ohtsuka, M.; Ogawa, S. Tetrahedron Lett. 1991, 32,
4525. (h) Hudlicky, T.; Olivo, H. F. J. Am. Chem. Soc. 1992, 114, 9694.
(i) Chida, N.; Ohtsuka, M.; Ogawa, S. J. Org. Chem. 1993, 58, 4441. (j)
Martin, S. F.; Tso, H. H. Heterocycles 1993, 35, 85. (k) McIntosh, M. C.;
Weinreb, S. M. J. Org. Chem. 1993, 58, 4823. (l) Hudlicky, T.; Olivo,
H. F.; Mckibben, B. J. Am. Chem. Soc. 1994, 116, 5108. (m) ent-
Lycoricidine: Keck, G. E.; Wager, T. T. J. Org. Chem. 1996, 61, 8366. (n)
(+)-Lycoricidine, (-)-lycoricidine, and (+)-narciclasine: Keck, G. E.;
Wager, T. T.; Rodriquez, J. F. D. J. Am. Chem. Soc. 1999, 121, 5176. (o)
Elango, S.; Yan, T. H. Tetrahedron 2002, 58, 7335. (p) Padwa, A.; Zhang,
H. Org. Lett. 2006, 8, 247. (q) Padwa, A.; Zhang, H. Org. Chem. 2007, 72,
2570. (r) ent-Lycoricidine, 3-epi-ent-lycoricidine, and 4-deoxy-3-epi-ent-
lycoricidine: Matveenko, M.; Kokas, O. J.; Banwell, M. G.; Willis, A. C.
Org. Lett. 2007, 9, 3683.
Org. Lett., Vol. 12, No. 11, 2010
2545

which was confirmed by spectral data to be R,ꢀ-unsaturated
ketone (allyl amine) 6a (82%).16 Such an unprecedented
oxidative ring-opening of aziridine was observed for the first
time by our group. This result provided the incentive for
further study of the reaction with various substrates. Interest-
ingly, methyl and ethyl carbamate derivatives (18c,d) and
N-tosylaziridine (18f) participated well in this reaction. In
all cases except for compound 18e, the reaction proceeded
well to afford the desired R,ꢀ-unsaturated ketones (allyl
amines) in good yields. The scope and generality of the
reaction are presented in Table 1.
Scheme 3. Synthesis of Aziridine 7
In the second method (Scheme 4), 13 was converted to
aziridine 7 by a four-step process which began by treatment
with NBS to form a mixture of bromohydrins, which was
subsequently treated with K2CO3 in dry acetonitrile to form
epoxide 14 (77%, two steps). The regioselective ring-opening
13
of epoxide with NaN3 and NH4Cl in ethanol afforded the
Table 1. DMP-Silica-Mediated Oxidative and Regioselective
Ring-Opening of Aziridine
azido alcohol 15 (75%). Mesylation followed by TPP and
DIPEA treatment gave the desired aziridine 7 (85%).
Scheme 4. Synthesis of Aziridine 7
Having compound 7 in hand, we turned our attention
toward the synthesis of the key intermediate 6a. Thus,
compound 7 was condensed with 6-iodopiperonylic acid14
(8a) using EDCI15 as the coupling reagent to obtain the
desired amide 17a in a high yield (85%) (Scheme 5).
Scheme 5. Synthesis of Amide 18
Hydrolysis of the acetyl group followed by Dess-Martin
periodinane (DMP) oxidation followed by purification of the
expected compound 19 through silica gel column chroma-
tography surprisingly afforded a new unexpeced product
a Products were characterized by 1H NMR, 13C NMR, IR, and mass
spectroscopy. b Isolated yield after column chromatography.
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Org. Lett., Vol. 12, No. 11, 2010

The Luche reduction of 6a gave an inseparable mixture of
alcohol which upon silylation allowed us to separate the mixture
by simple chromatography to get the diastereoisomers 20 and 21
(90%, two steps, dr 60:40) (Scheme 6). The undesired isomer 20
was converted to the required isomer 21 by following a repetative
oxidation and reduction process.
compound 5 was exposed to Pd(OAc)2, Tl(OAc), and
DIPHOS (1,2-bis-diphenylphosphinoethane) in anisole at
125 °C for 4 h gave the phenanthridone skeleton 22 in
35% yield. Removal of the protecting groups of compound
22 using 60% formic acid in THF at 60 °C for 1 h
completed the synthesis of (+)-lycoricidine (1) (95%)
(Scheme 7).
In summary, we have achieved an efficient and convergent
synthesis of a highly oxygenated phenanthridone (+)-
lycoricidine starting from commercially available D-(+)-
mannose. Highlights of the synthesis include one-pot elimi-
nation followed by allylation reaction, ring-closing metathesis,
and oxidative ring-opening of aziridine to form R,ꢀ-unsatur-
ated ketone (allyl amine). Following the above strategy, other
related natural product syntheses are in progress and will be
reported in due course.
Scheme 6. Synthesis of Compound 21
Protection of the carbamate nitrogen of 21 with a Boc
group gave the compound 5 (95%). Having compound 5
in hand, the next step was the ring closure to afford the
phenanthridone skeleton. Following Hudlicky2h and
Ogawa’s2g strategy of intramolecular Heck reaction,
Acknowledgment. G.S. thanks the Council of Scientific
and Industrial Research (CSIR), New Delhi, India, for
financial assistance.
Supporting Information Available: Experimental details,
selected spectral data, and copies of 1H NMR and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Scheme 7. Synthesis of (+)-Lycoricidine (1)
OL100755V
(12) (a) Katoh, T.; Itoh, E.; Yoshino, T.; Terashima, S. Tetrahedron
Lett. 1996, 37, 3471. (b) Nakajima, S.; Yoshida, K.; Mori, M.; Ban, Y.;
Shibasaki, M. J. Chem. Soc., Chem. Commun. 1990, 468. (c) Bergmeier,
S. C.; Seth, P. P. Tetrahedron Lett. 1999, 40, 6181.
(13) (a) Yoshino, T.; Nagata, Y.; Itoh, E.; Hashimoto, M.; Katoh, T.;
Terashima, S. Tetrahedron 1997, 30, 10239. (b) Legters, J.; Thijas, L.;
Zwanenburg, B. Tetrahedron 1991, 47, 5287.
(14) Kobayashi, S.; Kihara, M.; Hashimoto, T. Chem. Pharm. Bull. 1976,
24, 716.
(15) (a) Watts, P.; Wiles, C.; Haswell, S. J.; Pombovillar, E.; Styring,
P. Chem. Commun. 2001, 990. (b) Yun, W.; Li, B.; Wang, B.; Chen, L.
Tetrahedron Lett. 2001, 42, 175.
(16) See also: Nicolaou, K, C.; Montahnon, T.; Baran, P. S.; Zhong,
Y.-L. J. Am. Chem. Soc. 2002, 124, 2245.
Org. Lett., Vol. 12, No. 11, 2010
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