Figure 1. Natural products and intermediate ketone 3.
In recent efforts targeting additional key members of the
Aspidosperma alkaloids including minovine,10 fendleri-
dine,11 vindorosine and vindoline,12 and their extension
to the total synthesis of vinblastine13 and related natural
products including vincristine,14 and key analogues,15 we
developed a powerful intramolecular [4 þ 2]/[3 þ 2]
cycloaddition cascade of 1,3,4-oxadiazoles that provides
the pentacyclic core and all the stereochemistry of the
natural products in a single step (Figure 2).16 Herein, we
report the extension ofthese studiestothe total synthesis of
1 and 2. This strategy was viewed as especially suited for
spegazzinine, whose C3 alcohol can be directly introduced
upon reduction of a stable cyanohydrin formed after
reductive oxido bridge cleavage of a nitrile derived from
such a cycloaddition product. An added bonus of the
approach is that late stage modification of a route needed
to explore the spegazzinine C3 alcohol stereochemistry
also permits a divergent17 synthesis of aspidospermine,
entailing removal of the C3 alcohol in an approach funda-
mentally different from all prior reports.
Figure 2. Cycloaddition cascade.
partners and provides an endo indole [3 þ 2] cycloaddition,
where the dipolarophile is sterically directed to the face
opposite the newly formed six-membered ring.16,20 Four
CꢀC bonds, three rings, five stereocenters, and the complete
natural product skeleton are assembled in a single trans-
formation.
The precursor tryptamine 6 to the key cycloaddition
substrate 4 was prepared from 7-benzyloxyindole and
modeled on a route first disclosed by Corey (Supporting
Information (SI) Scheme 1).21 Tryptamine 6 was treated
with 1,1-carbonyldiimidazole (CDI) to afford urea 7
(Scheme 1). Addition of methyl oxalyl hydrazide (8) to 7
(HOAcꢀTHF, 40 °C, 16 h) furnished 9, which was con-
verted to the 1,3,4-oxadiazole 10 (70%, 2 steps) upon
treatment with TsCl and Et3N. Coupling of 10 and
4-ethyl-4-pentenoic acid (11) provided 4 (87%).
The key cycloaddition is initiated by an intramolecular
DielsꢀAlder reaction of a 1,3,4-oxadiazole with a tethered
dienophile.18,19 Loss of N2 from the initial cycloadduct
generates a 1,3-dipole, which is stabilized by the comple-
mentary substitution at the dipole termini. The regioselectivity
of the subsequent 1,3-dipolar cycloaddition is dictated by the
tether, but is reinforced by the intrinsic polarity of the reacting
Scheme 1
(10) Yuan, Z. Q.; Ishikawa, H.; Boger, D. L. Org. Lett. 2005, 7, 741.
(11) Campbell, E. L.; Zuhl, A. M.; Liu, C. M.; Boger, D. L.
J. Am. Chem. Soc. 2010, 132, 3009.
(12) (a) Wolkenberg, S. E.;Boger, D. L. J. Org. Chem. 2002, 67, 7361. (b)
Choi, Y.; Ishikawa, H.; Velcicky, J.; Elliott, G. I.; Miller, M. M.; Boger,
D. L. Org. Lett. 2005, 7, 4539. (c) Elliott, G. I.; Velcicky, J.; Ishikawa, H.; Li,
Y.; Boger, D. L. Angew. Chem., Int. Ed. 2006, 45, 620. (d) Ishikawa, H.;
Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L. J. Am. Chem. Soc. 2006,
128, 10596. (e) Ishikawa, H.; Boger, D. L. Hetereocycles 2007, 72, 95. (f)
Kato, D.; Sasaki, Y.; Boger, D. L. J. Am. Chem. Soc. 2010, 132, 3685. (g)
Sasaki, Y.; Kato, D.; Boger, D. L. J. Am. Chem. Soc. 2010, 132, 13533.
(13) Ishikawa, H.; Colby, D. A.; Boger, D. L. J. Am. Chem. Soc. 2008,
130, 420.
(14) Ishikawa, H.; Colby, D. A.; Seto, S.; Va, P.; Tam, A.; Kakei, H.;
Rayl, T. J.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2009, 131, 4904.
(15) (a) Va, P.; Campbell, E. L.; Robertson, W. M.; Boger, D. L. J. Am.
Chem. Soc. 2010, 132, 8489. (b) Tam, A.; Gotoh, H.; Robertson, W. M.;
Boger, D. L. Biorg. Med. Chem. Lett. 2010, 20, 6408. (c) Gotoh, H.; Duncan,
K. K.; Robertson, W. M.; Boger, D. L. ACS Med. Chem. Lett. 2011, 2, 948.
(16) (a) Wilkie, G. D.; Elliott, G. I.; Blagg, B. S. J.; Wolkenberg, S. E.;
Soenen, D. R.; Miller, M. M.; Pollack, S.; Boger, D. L. J. Am. Chem. Soc.
2002, 124, 11292. (b) Elliott, G. I.; Fuchs, J. R.; Blagg, B. S. J.; Ishikawa, H.;
Tao, H.; Yuan, Z. Q.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 10589.
(17) Boger, D. L.; Brotherton, C. E. J. Org. Chem. 1984, 49, 4050.
(18) (a) Boger, D. L. Tetrahedron 1983, 39, 2869. (b) Boger, D. L.
Chem. Rev. 1986, 86, 781.
The key intramolecular [4 þ 2]/[3 þ 2] cycloaddition was
accomplished by warming a solution of 4 at 180 °C in
o-dichlorobenzene (o-DCB) to provide 5 as a single diaste-
reomer in yields as high as 71% (Scheme 2). The stereochem-
istry of 5 was confirmed upon X-ray analysis22 of 15 and was
in accordance with expectations. Treatment of 5 with
NH3ꢀMeOH cleanly provided the primary amide, and its
(19) Margetic, D.; Troselj, P.; Johnston, M. R. Mini-Rev. Org. Chem.
2011, 8, 49.
Org. Lett., Vol. 14, No. 8, 2012
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