Table 1. Representative Substrate Scope for Regioselective
C2-Cyclization of Pyrrolesa
Figure 2. Preliminary screen of aromatic cyclization candidates.
improvements in enantioselectivity were achieved after
exhaustive optimization of catalyst structure and reaction
conditions, including examination of solvent, temperature,
acidic additive, and reaction concentration. Ultimately, the
best results were obtained under conditions nearly identical
to those identified for indole cyclization.1b
Significant rate accelerations due to increased substitution
at the reactive electrophilic center were seen in the asym-
metric dehydrative N-acyl Pictet-Spengler cyclization of
indole substrates,1b consistent with an SN1-type mechanism.
We reasoned that improved reactivity might also result in
the pyrrole cyclization chemistry. Indeed, higher levels of
substrate conversion were obtained in pyrrole cyclization
reactions using hydroxylactam substrates prepared by imide
alkylation. In addition, an unexpected improvement in
enantioselectivity was also observed. Reinvestigation of the
experimental parameters resulted in identification of the
optimal reaction conditions outlined in Table 1. Hydroxy-
lactams prepared by alkylation of â-pyrrolo-ethylsuccinimide
afforded cyclization products in good-to-excellent yields and
high enantioselectivies (Table 1, entries 1-4). However, only
modest ee’s were obtained in the cyclization of glutarimide-
derived substrates (Table 1 entries 6-7), a limitation that is
observed to a lesser extent in the indole cyclizations.1b The
reductively prepared hydroxylactam (Table 1, entry 8)
afforded the cyclization product with only moderate (65%)
ee under these conditions.
a Absolute configuration assigned by analogy (see ref 3). b Isolated yield
after flash chromatography on SiO2. c Determined by chiral SFC using
commercial chiral columns. d Corresponding hydroxylactam was prepared
by imide reduction. See Supporting Information.
tion to the C3 (or C4) position, including pre-functionaliza-
tion of the C2 position with a labile, deactivating substituent,5
product isomerization from the C2 position to the C3
position,6 and protection of the pyrrole with an N-(phenyl-
sulfonyl) group.7 However, the most commonly used ap-
proach employs a sterically demanding protecting group, in
particular the bulky triisoproylsilyl (TIPS) group, on the
pyrrole nitrogen, effectively shielding the N1, C2, and C5
postions.4
Despite the structural and electronic similarities between
pyrroles and indoles, well-known reactivity differences exist
with respect to intermolecular electrophilic aromatic substitu-
tion reactions. While the C3 position of indole is generally
the most nucleophilic site, pyrroles undergo kinetic substitu-
tion selectively at the C2 (or C5) position.4 However,
strategies have been devised to direct electrophilic substitu-
(4) (a) Bray, B.; Mathies, P.; Naef, R.; Solas, D.; Tidwell, T.; Artis, D.;
Muchowski, J. J. Org. Chem. 1990, 55, 6317, and references therein. (b)
Gilchrist, T. Heterocyclic Chemistry, 3rd ed; Addison Wesley Longman,
Ltd.: Harlow, 1997; pp 193 and 231, and references therein. (c) Ru¨cker,
C. Chem. ReV. 1995, 95, 1009.
(5) Loader, C.; Anderson, H. Can. J. Chem. 1981, 59, 2673.
(6) DeSales, J.; Greenhouse, R.; Muchowski, J. J. Org. Chem. 1982,
47, 3668.
(3) Attempts to determine absolute configuration by X-ray crystal-
lographic analysis of heavy-atom derivatives (e.g., 6, 8, or 9) were
unsuccessful. The absolute configuration was assigned as R by analogy to
the face selectivity oserved in both the indole cyclizations (ref 1b) and the
regioisomeric pyrrole C4 cyclizations (vide infra).
1578
Org. Lett., Vol. 10, No. 8, 2008
Raheem, Izzat T.
