Our retrosynthetic analysis focused on construction of
the main tetracycle 12 in which the pendant terminal
alkyne and cycloheptene functionalities provided an ideal
entry to the DEF ring system (11) via the intramolecular
PausonꢀKhand reaction12 (IPKR). In order to test our
hypothesis and to demonstrate the possible versatility in
the total synthesis of the resultant tricyclic core, we chose
to target the cyclopentenone-containing portion of daph-
nilongeranin B (2) and daphniyunnine D (3), since the
latter shows interesting cytotoxic activity against two
tumor cell lines, P-388 and A-549, with IC50 values of 3.0
and 0.6 μM, respectively.7
For the synthesis of daphnilongeranin B (2), following
the IPKR, we envisioned a double-bond migration to the
most substituted and thermodynamically most stable cy-
clopentenone isomer (Scheme 1).13 This novel two-step
Scheme 1. Retrosynthetic Analysis of Daphnilongeranin B and
Daphniyunnine D
Figure 1. Daphniphyllum alkaloids bearing the [7ꢀ5ꢀ5] all-
carbon tricyclic core.
daphlongamine F and G (10, 7),5 daphnilongeranin B (2),6
daphniyunnine CꢀE (6, 3, 4).7 Although direct synthetic
approachestowardthe[6ꢀ5]bicycle(ACringsinFigure1),
[6ꢀ6ꢀ5] tricycle (ABC rings), and [6ꢀ5ꢀ7] tricycle (ACD
rings) of this subgroup of alkaloids have been reported by
our group8 and others,9 no specific study of a realistic
endgame involving a synthesis of the aforementioned core
of this subgroup has been reported.10,11 For a successful
total synthesis of any member of this subclass, a robust and
practical route for the rapid assembly of this common
structural motif is required. Herein we present our findings
toward this aim.
tandem strategy was a realistic alternative to a controlled
late stage construction of a strained cycloheptyne moiety,
necessary if a direct one-step IPKR approach was to be
adopted.14 A late stage regio- and stereoselective allylic
oxygenation would provide the second target, daphniyun-
nine D (3).
(7) Zhang, H.; Yang, S.-P.; Fan, C.-Q.; Ding, J.; Yue, J.-M. J. Nat.
Prod. 2006, 69, 553–557.
(8) Sladojevich, F.; Michaelides, I. N.; Darses, B.; Ward, J. W.;
(13) For similar carbonꢀcarbon double-bond migrations via alkaline
aldol condensation conditions, see: (a) Sisido, K.; Kurozumi, S.;
Utimoto, K. J. Org. Chem. 1969, 34, 2661–2664. (b) Begley, M. J.;
Cooper, K.; Pattenden, G. Tetrahedron Lett. 1981, 22, 257–260. (c)
Cooper, K.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1984, 799–809.
(14) For examples of IPKR performed on Co-complexed: (a)
Cycloheptyne functionalities, see: Mohamed, A. B.; Green, J. R.;
Masuda, J. Synlett 2005, 1543–1546. (b) Cyclooctyne funtionalities,
see: Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L.
J. Am. Chem. Soc. 1997, 119, 4353–4363.
Dixon, D. J. Org. Lett. 2011, 13, 5132–5135.
(9) For studies towards: (a) The [6ꢀ5] bicycle, see: Cordero-Vargas,
A.; Urbaneja, X.; Bonjoch, J. Synlett 2007, 2379–2382. (b) The [6ꢀ6ꢀ5]
ꢀ
tricycle, see: Sole, D.; Urbaneja, X.; Bonjoch, J. Org. Lett. 2005, 7, 5461–
5464. (c) The [6ꢀ5ꢀ7] tricycle, see: Xu, C.; Liu, Z.; Wang, H.; Zhang, B.;
Xiang, Z.; Hao, X.; Wang, D. Z. Org. Lett. 2011, 13, 1812–1815.
(10) For an isolated example of the construction of an all-carbon
[7ꢀ5ꢀ5] tricyclic system using a combination of ring closing metathesis
ꢀ
and the PausonꢀKhand reaction, see: Rosillo, M.; Arnaiz, E.; Abdi, D.;
(15) (a) de Armas, J.; Kolis, S. P.; Hoveyda, A. H. J. Am. Chem. Soc.
2000, 122, 5977–5983. (b) Muto, R.; Ogasawara, K. Tetrahedron Lett.
2001, 42, 4143–4146.
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Blanco-Urgoiti, J.; Domınguez, G.; Perez-Castells, J. Eur. J. Org. Chem.
2008, 3917–3927.
(11) (a) For a specific construction of the [7ꢀ5ꢀ5] tricyclic core in the
total synthesis of (þ)-daphmanidin E, a daphmanidin A-type daph-
niphyllum alkaloid, see: Reference 2h. See also: (b) Weyermann, P.;
Keese, R. Tetrahedron 2011, 67, 3874–3880. (c) Funel, J.-A.; Prunet, J.
Synlett 2005, 235–238.
(16) (a) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 5881–5898. (b) Cassayre, J.; Zard, S. Z. J. Am. Chem.
€
€
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see: (d) Kerr, W. J.; McLaughlin, M.; Morrison, A. J.; Pauson, P. L. Org.
Lett. 2001, 3, 2945–2948.
(12) (a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.;
Foreman, M. I. J. Chem. Soc., Perkin Trans. 1 1973, 977–981. For
relevant reviews, see: (b) Pauson, P. L. Tetrahedron 1985, 41, 5855–5860.
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ꢁ
(17) (a) Castro, J.; Moyano, A.; Pericas, M. A.; Riera, A. J. Org.
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~
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