General approach for the synthesis of chiral perylenequinones via catalytic enantioselective oxidative biaryl coupling

Article abstract of DOI:10.1021/ja027745k

By using oxygen as the terminal oxidant, copper complexes derived from chiral 1,5-diaza-cis-decalin catalyze the enantioselective oxidative biaryl coupling of highly functionalized naphthols to provide octa- and decasubstituted binaphthalenes with high se

Full text of DOI:10.1021/ja027745k

Published on Web 05/16/2003
General Approach for the Synthesis of Chiral Perylenequinones via Catalytic
Enantioselective Oxidative Biaryl Coupling
Carol A. Mulrooney, Xiaolin Li, Evan S. DiVirgilio, and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104-6323
Received July 17, 2002; E-mail: marisa@sas.upenn.edu
Scheme 1
Cercosporin, phleichrome, and the calphostins belong to a class
of natural products1 that contain an extended oxidized aromatic unit
known as a perylenequinone (Figure 1). These potent protein kinase
C inhibitors with unique binding to the regulatory domain2 are
promising agents for photodynamic cancer therapy due to the
photochemical properties of perylenequinones.3
Application of the copper catalysts derived from 2 to the biaryl
coupling of 5a led to only trace amounts of the corresponding
binaphthol. Presumably, the unprotected C4 OH competes with the
C2 OH for catalyst or facilitates p-quinone formation. With
protection of the C4 OH as the methyl ether, these problems were
alleviated as seen by the formation of 7 in good yield (Chart 1).
Figure 1. Perylenequinone natural products.
Chart 1. Couplings with 10 mol % Catalyst under O2
The perylenequinone substitution renders these interesting struc-
tures helical (naphthalene dihedral ∼20°),4 introducing axial
chirality and contributing to their complexity. The biosynthetic
pathways to these compounds likely involve oxidative phenolic
coupling.1a Prior approaches5 by Broka,6 Coleman,7 and Merlic8
have utilized this concept by employing diastereoselective oxida-
tive couplings of chiral 2-naphthols (Figure 1). Typically, these
couplings yield the undesired diastereomer. Additional steps involv-
ing separation, isomerization, or Mitsunobu inversion are needed
to obtain the required diastereomer.
Utilizing the catalytic asymmetric oxidative phenolic coupling
method that we have developed (eq 1),9 we propose that this series
of compounds could be generated by an enantioselectiVe coupling
of a functionalized 2-naphthol (Figure 1). The C7/C7′ side-chain
stereogenic centers could then be introduced separately. Such a
versatile approach would allow the selective and convergent
synthesis of the complete diastereomeric series.
The enantioselectivity of 7, however, was low (3% ee) under
the same conditions used to obtain 3a (eq 1, R ) CO2Me) with
Since enantioselective oxidative binaphthol couplings have only
been reported for naphthalenes with a low degree of substitution,9,10
we began this effort by assessing the ability of our catalyst to form
highly functionalized chiral binaphthols. Installation of the majority
of the substituents found in perylenequinone natural products in
the 2-naphthol would obviate the need for multiple late-stage
functionalization. The substituted 2-naphthols required for this study
were generated11 by utilizing the optimized protocol outlined in
Scheme 1 for 6a-d.
high enantioselectivity and yield (85%, 93% ee).9 The three
methoxy groups in the substrate leading to 7 introduce additional
electron density which reduces the naphthalene oxidation potential
and stabilizes the intermediate 2-keto-1-radical. As a result, the
reaction was considerably more rapid than that leading to 3a. Milder
reaction conditions were therefore examined (CuCl cat., rt; Chart
1); the yield (81%) was again high, but the enantioselectivity re-
mained low (35% ee). Due to the high degree of similarity between
3a and 7, this result was unexpected. Analysis of the enantiomeric
9
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J. AM. CHEM. SOC. 2003, 125, 6856-6857
10.1021/ja027745k CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Figure 2. Conversion vs time and enantiomeric excess vs time (monitored by CSP HPLC) for the formation of 7-9.
Scheme 2
retention of axial chirality. This represents the first asymmetric
synthesis of a perylenequinone containing only an axial chirality
element.
Acknowledgment. Financial support was provided by the NSF
(CHE-0094187), the University of Pennsylvania Research Founda-
tion, a 3D Pharmaceuticals graduate fellowship (C.A.M.), and a
GAANN fellowship (E.S.D).
Supporting Information Available: Full experimental procedures
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
excess and conversion vs time proved key to understanding these
results (Figure 2a).
While conversion to 7 was very rapid, the enantiomeric excess
also eroded rapidly during the early stages of the reaction. After
initially observing 61% ee (R), the selectivity dropped and stabilized
at 35% ee (S). Enantioselective formation of the (R)-product under
kinetic control from the chiral catalyst accompanied by enanti-
omerization of 7 to a thermodynamic endpoint explains this trend.
The predominance of the (S)-enantiomer at the conclusion may arise
from a more stable catalyst-product complex with the (S)- vs (R)-
enantiomer.12
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(Scheme 2) to yield 12. MnO2 oxidation7b of 12 generated 13 with
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