Total syntheses of chelidonine and norchelidonine via an enamide-benzyne-[2+2] cycloaddition cascade

Article abstract of DOI:10.1021/ol300967a

Total syntheses of chelidonine and norchelidonine featuring an enamide-benzyne-[2 + 2] cycloaddition initiated cascade is described. The cascade includes a pericyclic ring-opening and intramolecular Diels-Alder reaction.

Full text of DOI:10.1021/ol300967a

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2742–2745
Total Syntheses of Chelidonine and
Norchelidonine via an
EnamideꢀBenzyneꢀ[2 þ 2]
Cycloaddition Cascade
Zhi-Xiong Ma, John B. Feltenberger, and Richard P. Hsung*
Department of Chemistry and Division of Pharmaceutical Sciences, University of
Wisconsin, Madison, Wisconsin 53705, United States
rhsung@wisc.edu
Received April 13, 2012
ABSTRACT
Total syntheses of chelidonine and norchelidonine featuring an enamideꢀbenzyneꢀ[2 þ 2] cycloaddition initiated cascade is described. The
cascade includes a pericyclic ring-opening and intramolecular DielsꢀAlder reaction.
Our laboratory recently unveiled a de novo cascade
of pericyclic ring-openings of amidobenzocyclobutanes
and N-tethered intramolecular DielsꢀAlder [IMDA]
cycloadditions initiated through an enamideꢀbenzyneꢀ
[2 þ 2] cycloaddition (1 f 2 f 3 f 4 in Scheme 1).1 This
tandem cascade possesses the unique feature of not only
linking together the prevailing benzyne chemistry2ꢀ4
with enamides that have become a highly versatile and
accessible functional group5ꢀ7 but also accentuating
the less developed thermally driven [2 þ 2] cycloaddition
reaction manifold8ꢀ10 while exploiting the powerful
Oppolzer-type N-tethered IMDA strategy.11ꢀ15 Accord-
ingly, an application of this cascade in the synthesis of
(1) Feltenberger, J. B.; Hayashi, R.; Tang, Y.; Babiash, E. S. C.;
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(2) For reviews on the aryne chemistry, see: (a) Sanz, R. Org. Prep.
~
ꢀ
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Proced. Int. 2008, 40, 215. (b) Pena, D.; Perez, D.; Guitian, E. Hetero-
~
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ꢀ
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Int. Ed. 2006, 45, 3579. (d) Guitian, E.; Perez, D.; Pena, D. In Topics in
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B. W.; Zhang, Y. In Science of Synthesis, Houben-Weyl Methods of
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~
(4) For recent examples, see: (a) Łaczkowski, K. Z.; Garcıa, D.; Pena,
(6) For reviews on Cu-mediated CꢀN and CꢀO bond formations for
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Rev. 2008, 108, 3054. (b) Dehli, J. R.; Legros, J.; Bolm, C. Chem.
Commun. 2005, 973. (c) Ley, S. V.; Thomas, A. W. Angew. Chem., Int.
Ed. 2003, 42, 5400. (d) Lindley, J. Tetrahedron 1984, 40, 1433. For
reviews on Pd-catalyzed N-arylations of amines and amides, see: (e)
Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046. (f) Wolfe, J. P.;
Wagaw, S.; Marcoux, J.-F.; Buchwald, S. Acc. Chem. Res. 1998, 31, 805.
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Carbery, D. R. Org. Biomol. Chem. 2008, 9, 3455. (b) Rappoport, Z. The
Chemistry of Enamines in The Chemistry of Functional Groups; John
Wiley and Sons: New York, 1994.
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D.; Cobas, A.; Perez, D.; Guitian, E. Org. Lett. 2011, 13, 960. (b) Biswas,
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r
10.1021/ol300967a
Published on Web 05/10/2012
2012 American Chemical Society

benzophenanthridine alkaloids [see 5 in the box] was
pursued. In particular, we have been focusing on
(þ)-chelidonine 6 and (þ)-norchelidonine 7, which de-
spite being known for well over a century,16ꢀ21 remain
an excellent proving ground for showcasing synthetic
methods.22,23 Our strategy would be based on the above
cascade using benzyne precursor 9 and enamide 10.
We report here the total syntheses of (()-chelidonine and
(()-norchelidonine.
Scheme 1. EnamideꢀBenzyneꢀ[2 þ 2] Cascade to Chelidonine
(8) For a leading review on thermal [2 þ 2] cycloaddition reactions,
see: Baldwin, J. E. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Pattenden, G., Eds.; Pergamon Press: New York, 1991; Vol. 5,
p 63.
(9) For [2 þ 2] cycloadditions of arynes with enamines, see: (a)
Gingrich, H. L.; Huang, Q.; Morales, A. L.; Jones, M. J. Org. Chem.
1992, 57, 3803. (b) Heaney, H.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1
1974, 2693. (c) Crews, P.; Beard, J. J. Org. Chem. 1973, 38, 522. (d)
Kametani, T.; Kigasawa, K.; Hiiragi, M.; Hayasaka, T.; Kusama, O.
J. Chem. Soc. (C) 1971, 1051.
(10) For reports on amidobenzocyclobutane formation as side pro-
ducts through enamideꢀbenzyneꢀ[2 þ 2] cycloaddition, see: (a) Castedo,
ꢀ
ꢀ
L.; Guitian, E.; Saa, C.; Suau, R.; Saa, J. M. Tetrahedron Lett. 1983, 24,
2107. (b) Blackburn, T.; Ramtohul, Y. K. Synlett 2008, 1159.
(11) (a) Oppolzer, W. J. Am. Chem. Soc. 1971, 93, 3833. (b) Oppolzer,
€
W.; Frostl, W. Helv. Chim. Acta 1975, 58, 590. (c) Oppolzer, W.;
Flaskamp, E.; Bieber, L. W. Helv. Chim. Acta 2001, 84, 141.
(12) For a recent example of such IMDA, see: Feltenberger, J. B.;
Hsung, R. P. Org. Lett. 2011, 13, 3114.
(13) For reviews, see: (a) Oppolzer, W. Synthesis 1978, 793. (b) Funk,
R. L.; Vollhardt, K. P. C. Chem. Soc. Rev. 1980, 9, 41. (c) Kametuni, T.;
Nemoto, H. Tetrahedron 1981, 37, 3.
(14) For reviews on chemistry of dienamides, see: (a) Overman, L. E.
Acc. Chem. Res. 1980, 13, 218. (b) Petrzilka, M. Synthesis 1981, 753. (c)
Campbell, A. L.; Lenz, G. R. Synthesis 1987, 421.
Scheme 2. Synthesis of Enamide 10
(15) For a leading review for intramolecular DielsꢀAlder strategies
for natural product synthesis, see: Padwa, A.; Bur, S. K. Tetrahedron
2007, 63, 5341.
(16) For isolation of (þ)-chelidonine from Chelidonium majus L., see:
Probst, J. M. Ann. Pharm. 1839, 29, 113.
(17) For structural assignment of (þ)-chelidonine, see: (a) von
Bruchhausen, F.; Bersch, H. W. Chem. Ber. 1930, 63, 2520. (b) von
€
Bruchhausen, F.; Bersch, H. W. Chem. Ber. 1931, 64, 947. (c) Spath, E.;
Kuffner, F. Chem. Ber 1931, 64, 370. (d) Bersch, H. W. Arch. Pharm.
ꢀ
ꢀ
1958, 291, 491. (e) Santavy, F.; Horak, M.; Maturova, M.; Brabenec, J.
Collect. Czech. Chem. Commun. 1960, 25, 1344. (f) Soane, E. An. Real
Soc. Espan. Fis. Quim. Ser. B 1965, 61, 755.
(18) Isolation of either enantiomer of chelidonine from a different
ꢀ
plant source, see: (a) Slavık, J.; Slavıkova, L. Collect. Czech. Chem.
ꢀ
Commun. 1957, 22, 279. (b) Slavık, J.; Slavıkova, L. Collect. Czech.
Chem. Commun. 1959, 24, 3141. The racemate of chelidonine was also
isolated but was named as diphylline, see: (c) Schlotterbeck, J. O.;
Synthesis of enamide 1024 could be expeditiously
achieved as shown in Scheme 2 from the commercially
available aldehyde 11, featuring Sonogashira coupling,25
reductive amination,26 and Cu(I)-catalyzed amidation of
vinyl bromide.27 For comparisons in the later benzyneꢀ
[2 þ 2] cycloaddition, we also desilylated 10 to access
enamide 14 with an unsubstituted alkyne. The benzyne
precursor, silylaryl triflate9, was preparedfromsesamol15
in two steps.28
ꢀ
Watkins, H. C. Chem. Ber. 1902, 35, 7. (d) Slavık, J.; Slavıkova, L.;
Brabenec, J. Collect. Czech. Chem. Commun. 1965, 30, 3697. (e)
ꢀ
Slavıkova, L. Collect. Czech. Chem. Commun. 1968, 33, 635.
(19) For absolute configuration of (þ)-chelidonine, see: (a) Takao,
N.; Bessho, N.; Kamiguuchi, M.; Iwasa, K.; Tomita, K.; Fujiwara, T.;
Fujii, S. Tetrahedron Lett. 1979, 20, 495. (b) Takao, N.; Morita, N.;
Kamiguuchi, M.; Iwasa, K.; Tomita, K.; Fujiwara, T.; Fujii, S. Acta
Crystallogr. 1981, B37, 2043.
(20) For a biosynthetic study on chelidonine, see: Battersby, A. R.;
Staunton, J.; Wiltshire, H. R.; Francis, R. J.; Southgate, R. J. Chem.
Soc., Perkin Trans. 1 1975, 1147.
(21) For isolation of (ꢀ)-norchelidonine, see: (a) Slavık, J. Collect.
ꢀ
Czech. Chem. Commun. 1959, 24, 3601. (b) Slavık, J.; Slavıkova, L.
ꢀ
Collect. Czech. Chem. Commun. 1959, 24, 3141. (c) Necas, M.; Dostal, J.;
(23) For enantioselective total synthesis of (þ)-chelidonine and (þ)-
norchelidonine, see: (a) Felming, M. J.; McManus, H. A.; Rudolph, A.;
Chan, W. H.; Ruiz, J.; Dockendorff, C.; Lautens, M. Chem.;Eur. J.
2008, 14, 2112. Also see: (b) McManus, H. A.; Felming, M. J.; Lautens,
M. Angew. Chem., Int. Ed. 2007, 46, 433.
(24) See the Supporting Information.
(25) Ohta, Y.; Kubota, Y.; Watabe, T.; Chiba, H.; Oishi, S.; Fujii, N.;
Ohno, H. J. Org. Chem. 2009, 74, 6299.
ꢀ
ꢀ
Kejnovska, I.; Vorlıckova, M.; Slavıık, J. J. Mol. Struct. 2005, 734, 1.
For isolation of (þ)-norchelidonine, see: (d) Kadan, G.; Gozler, T.;
Hesse, M. Planta Med. 1992, 58, 477.
(22) For total syntheses of (()-chelidonine and (()-norchelidonine,
see: (a) Oppolzer, W.; Kelier, K. J. Am. Chem. Soc. 1971, 93, 3836. (b)
Oppolzer, W. Heterocycles 1980, 14, 1615. (c) Oppolzer, W.; Robbiani,
C. Helv. Chim. Acta 1983, 66, 1119. (d) Cushman, M.; Choong, T.-C.;
Valko, J. T.; Kolek, M. P. Tetrahedron Lett. 1980, 21, 3845. (e) Cush-
man, M.; Choong, T.-C.; Valko, J. T.; Kolek, M. P. J. Org. Chem. 1980,
45, 5067. (f) Hanaoka, M.; Yoshida, S.; Mukai, C. Chem. Lett. 1986, 739,
24. For some approaches, see: (g) Vicario, J. L.; Badıa, D.; Domınguez,
E.; Crespo, A.; Carrillo, L. Tetrahedron: Asymmetry 1999, 10, 1947. (h)
Vicario, J. L.; Badıa, D.; Domınguez, E.; Carrillo, L. Tetrahedron:
Asymmetry 2000, 11, 1227.
ꢀ
(26) Dube, D.; Scholte, A. A. Tetrahedron Lett. 1999, 40, 2295.
(27) (a) Han, C.; Shen, R.; Su, S.; Porco, J. A., Jr. Org. Lett. 2004, 6,
27. (b) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809. (c) Langner, M.;
Bolm, C. Angew. Chem., Int. Ed. 2004, 43, 5984. (d) Jiang, L.; Job, G. E.;
Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667. (e) Shen, R.; Lin,
C. T.; Porco, J. A., Jr. J. Am. Chem. Soc. 2002, 124, 5650.
Org. Lett., Vol. 14, No. 11, 2012
2743

Table 1. EnamideꢀBenzyneꢀ[2 þ 2] Cycloaddition
Scheme 3. Ring-Opening and [4 þ 2] Cycloaddition Cascade
9
F
ꢀ source
(equiv)
time
(h)
yielda
(%)
entry
(equiv)
solvent
1
2
3
4
5
6
3.0
3.0
3.0
3.0
2.0
3.0
TBATb (5.0) CH2CI2
48
72
trace
43
TBAT (5.0)
TBAT (5.0)
KF (5.0)
THF
1,4-dioxane 96
THFc
80
96
15
11
CsF (4.0)
CsF (5.0)
CH3CN
79
1,4-dioxane 48
trace
a Isolated yields. b TBAT: tetra-n-butylammonium triphenyldifluor-
osilicate. c 18-Crown-6 (6.0 equiv) was used.
We proceeded with the key enamideꢀbenzyneꢀ[2 þ 2]
cycloaddition with some trepidation because we had failed
related cycloadditions using enamide tethered to an alkyne
motif such as 10 during our method development.1 Fol-
lowing Kobayashi’s fluoride-based conditions29 for in situ
generation of benzyne 16 from silylaryl triflate 9, we
initially explored TBAT (tetra-n-butylammonium triphenyl-
difluorosilicate).
As shown in Table 1, after screening a few solvents
(entries 1ꢀ3), 1,4-dioxane proved to be the optimal sol-
vent, leading to the desired amidobenzocyclobutane 17 in
80% yield at rt, although it took 96 h (entry 3). It is
noteworthy that the benzyneꢀ[2 þ 2] cycloaddition is
completely chemoselective in favor of the enamide motif
as long as the alkyne is substituted with TIPS. On the other
hand, when using enamide 14 with terminally unsubsti-
tuted alkyne, the cycloaddition was not clean. The crude
NMR suggests that the acetylene had likely attacked the
benzyne.
Figure 1. X-ray structure of tetracycle 20.
However, the reaction time was clearly too long using
TBATꢀdioxane conditions. Thus, inorganic fluorides
(entries 4ꢀ6) were also examined; CsF in CH3CN at rt
turnedout to be equallyeffective in providing 17, and more
importantly, the reaction time was reduced to 15 h (entry 5).
It should be noted here that to avoid the competing
removal of the TIPS group, we focused on low temperature
reaction conditionsinstead of110 °C adoptedin ourearlier
communication.1 As a result, an intriguing observa-
tion was made that these reactions appear to be much
faster when CH3CN is used as solvent than 1,4-dioxane
or THF.10b
tetracyclic benzophenanthridine 20 through a sequence of
[2π þ 2σ]-pericyclic ring-opening and intramolecular
DielsꢀAlder cycloaddition. An X-ray structure of 20 was
attained to ascertain the integrity of this sequence (Figure 1),
although 20 constitutes a formal synthesis of (()-chelido-
nine, as it matched spectroscopically with Oppolzer’s
intermediate.22aꢀc
Tetracycle 20 was found to be unstable, as it slowly
converted to a new set of chemical resonances in CDCl3
at rt. The new compound was ultimately assigned as the
aromatization product 21, which could be envisioned from
N-acyliminium ion 22. It was later confirmed that 21 was a
minor but persistent byproduct during the heating in
xylene and that an increasing amount of 21 was present
when prolonged heating took place.
Armed with the desired amidobenzocyclobutane 17, we
removed the TIPS group using TBAF as shown in Scheme 3.
Subsequent heating of 18 in xylene at 120 °C afforded the
Most critically, we succeeded in a tandem process or
one-pot formation of tetracycle 20. As shown in Scheme 4,
treatment of enamide10withCsF atrtinCH3CN followed
by heating at 80 °C and subsequently at 120 °C using
(28) Synthesis of aryl triflate 9, see: (a) Sato, Y.; Tamura, T.; Mori,
M. Angew. Chem., Int. Ed. 2004, 43, 2436. (b) Alexander, B. H.; Oda,
T. A.; Brown, R. T.; Gertler, S. I. J. Org. Chem. 1958, 23, 1969.
(29) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211.
2744
Org. Lett., Vol. 14, No. 11, 2012

Scheme 4. Tandem EnamideꢀBenzyneꢀ[2 þ 2]ꢀ[4 þ 2]
Scheme 5. Completion of the Total Syntheses
xylene as the solvent led to 20 in 65% yield overall.
Removal of CH3CN appeared to be critical prior to the
addition of xylene and further heating at elevated tem-
perature for the DielsꢀAlder cycloaddition. When the
mixture was directly heated at 120 °C without removing
CH3CN, an indistinguishable mixture was observed by
crude proton NMR. In the mixture, a ring-opened product
such as 24 is likely present, presumably derived from the
ring-opened zwitterionic intermediate 23 or directly from
tetracycle 20 via a based-promoted elimination.
On the other hand, further purifying the crude desily-
lated benzocyclobutane 18 even through a short bed silica
gel filtration proved to be unnecessary and provided no
better yield. It is noteworthy that the overall process
constitutes a four-bond and two-ring formation, thereby
further accentuating the synthetic imminence of an enamide-
benzyne-[2 þ 2] cycloaddition manifold.
To complete our total syntheses, tetracycle 20 was
subjected to BH3-hydroborationꢀoxidation conditions
to give a 1:1 separable isomeric mixture of alcohol 25-trans
and 25-cis [Scheme 5]. Relative stereochemistry ofthe three
contiguous stereocenters in 25-cis was unambiguously
assigned through X-ray structure of 250-cis, which has
the Cbz protecting group removed and is essentially the
C11-epimer of norchelidonine (Figure 2). Unfortunately,
we could not improve the diastereomeric ratio via other
boranes such as 9-BBN, c-hex2BH, and Et2BH. Never-
theless, (()-chelidonine 6 could be rapidly and efficiently
synthesized from 25-cis through DMP-oxidation and
alane reduction of both ketone and Cbz-urethane motifs.
This would complete a facile seven-step total synthesis
effort. Lastly, (()-norchelidonine 7 was also completed
through a sequence of DMP-oxidation, NaBH4 reduction,
and hydrogenation. Both synthetic samples spectroscopi-
cally matched the reported literature values.22
Figure 2. X-ray structure of 250-cis [C11-epi-norchelidonine].
and intramolecular DielsꢀAlder cycloaddition. While
Oppolzer’s 1971 seminal total synthesis22a inspired our efforts,
the current total syntheses underscore both the power of
enamides as synthetic building blocks and the significance
of benzyne chemistry, in particular, the benzyneꢀ[2 þ 2]
cycloaddition in the efficient assembly of complex targets.
Acknowledgment. We thank the NIH (GM066055) for
funding. We thank Dr. Victor G. Young and Mr. Gregory
T. Rohde of the University of Minnesota for providing
X-ray structural analysis.
Supporting Information Available. Experimental pro-
cedures as well as NMR spectra, characterizations, and
X-ray data for all new compounds. This material is
available free of charge via the Internet at http://
pubs.acs.org.
We have described here total syntheses of (()-chelido-
nine (seven steps; 8.5% overall yield) and (()-norchelido-
nine (eight steps, 8.7% overall yield), featuring an
enamideꢀbenzyneꢀ[2 þ 2] cycloaddition in a quadruple
tandem cascade that also includes pericyclic ring-opening
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
2745