Scheme 3. Formation of the Tetracyclic Core
30% of reduced product 9 that could be resubmitted to the
iodination-cyclization sequence (Table 1, entry 5).
While this system turned out to be quite similar to the
one we used for the synthesis of pyrroloindoles starting from
related 2-iodotryptophan derivatives,9 the presence of an
acyclic secondary amide and the formation of a six-
membered ring required the use of a more efficient ligand
in this case. Another striking difference is the proportion of
reduction products which could be minimized for the
formation of a five-membered ring but could not be
completely avoided in this case. This combination, however,
proved to be the most efficient one, and all other ligands,
bases, and solvent systems gave inferior results. Other metals
such as palladium(0)10 (Table 1, entry 6) or iron(III)11 (Table
1, entry 7) proved to be completely inefficient cyclization
promoters.
Having useful quantities of tricyclic precursor 10 in hand,
we next turned our attention to the installation of the two
remaining stereocenters as well as the formation of the
γ-lactam (Scheme 3). To this end, a diastereoselective
epoxidation of 10 was first envisioned. Upon reaction with
DMDO at low temperature in dichloromethane, we were
delighted to note that 10 was smoothly oxidized and
furnished a single compound which we expected to be
epoxide 11. Upon closer inspection, it however turned out
that epoxide 11 was indeed formed within the reaction
mixture but immediately underwent a rearrangement yielding
spirolactam 12 as a single stereoisomer. Its structure and
stereochemistry could be ascertained by X-ray diffraction
after removal of the Cbz protecting group. This unprec-
edented rearrangement probably involves ring opening of the
epoxide and migration of the amide at the benzylic posi-
tion.12,13
Even if the oxidative rearrangement of 10 to spiro-oxindole
12 clearly is a quite interesting transformation, it did seriously
compromise the formation of the tetracyclic ring system of
chaetominine. In order to avoid this rearrangement, we
decided to carry out the oxidation on a deprotected indole.
Indeed, the presence of the secondary amine in 4 allowed
for a clean isomerization of the intermediate amino epoxide
14 to hydroxy imine 3 before the undesired rearrangement
could occur. Simple treatment of 4 with DMDO at -85 °C
for 45 min allowed for the isolation of 94% of hydroxy imine
3 with complete diastereoselectivity. Steric interactions
between the bulky phthalimide and DMDO in the spiro
transition state usually invoked for related oxidations might
account for the high level of diastereoselectivity observed
in this epoxidation.14
Elaboration of the tetracyclic core then proceeded easily
(Scheme 3). Reaction of imine 3 with sodium cyanoboro-
hydride and acetic acid in methanol at room temperature
provided compound 15 as a single diastereoisomer, most
certainly through assistance of the free hydroxyl group.15
This compound, however, proved to be relatively unstable
upon purification on silica gel since it was isolated as a
mixture with a newly formed compound which gratifyingly
turned out to be the γ-lactam 16. Pleased by this most
(10) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996,
52, 7525.
(14) (a) Murray, R. W.; Singh, M.; Williams, B. L.; Moncrieff, H. M.
J. Org. Chem. 1996, 61, 1830. (b) Yang, D.; Jiao, G.-S.; Yip, Y.-C.; Wong,
M.-K. J. Org. Chem. 1999, 64, 1635. (c) Ouchi, H.; Mihara, Y.; Takahata,
H. J. Org. Chem. 2005, 70, 5207.
(11) Correa, A.; Elmore, S.; Bolm, C. Chem.sEur. J. 2008, 14, 3527.
(12) For oxidation of indoles with DMDO followed by epoxide opening/
alkyl shift, see: (a) Zhang, X.; Foote, C. S. J. Am. Chem. Soc. 1993, 115,
8867. (b) Adam, W.; Ahrweiler, M.; Peters, K.; Schmiedeskamp, B. J. Org.
Chem. 1994, 59, 2733.
(15) An equilibration of the trans isomer to the more stable cis isomer
through opening of the aminal might also account for the high level of
selectivity observed in this reduction. Basic AM1 calculations (MOPAC)
show a difference in energy of ca. 10 kcal·mol-1 between the two
isomers.
(13) For oxidation with DMDO followed by epoxide opening/oxygen
shift, see: Konno, F.; Ishikawa, T.; Kawahata, M.; Yamaguchi, K. J. Org.
Chem. 2006, 71, 9818.
Org. Lett., Vol. 10, No. 21, 2008
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