[reaction: see text] New methods for the palladium-catalyzed cyanation of aryl and heteroaryl chlorides have been developed, featuring sterically demanding, electron-rich phosphines. Highly challenging electron-rich aryl chlorides, in addition to electron-neutral and electron-deficient substrates, as well as nitrogen- and sulfur-containing heteroaryl chlorides can all undergo efficient cyanation under relatively mild conditions using readily available materials. In terms of substrate scope and temperature, these methods compare very favorably with the state-of-the-art cyanations of aryl chlorides.
CC-1065 (l),1 duocarmycin SA (2),2 and duocarmycin A (3)3 45678910constitute the parent agents of a class of potent antitumor antibiotics that derive their biological properties through a sequence selective alkylation of DNA.4-7 The now characteristic alkylation reaction has been shown to proceed by a stereoelectronically-controlled adenine N3 addition to the least substituted carbon of the activated cyclopropane within selected AT-rich sites of the minor groove.8-12 Although the intracellular target for the agents has been shown to be DNA, the mechanism by
The synthesis of
7-cyano-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one
(CCBI), a substituted
CBI derivative bearing a C7 cyano group, is described in efforts that
establish the magnitude of
potential electronic effects on the functional reactivity of the
agents. The CCBI alkylation subunit
was prepared by a modified Stobbe condensation/Friedel−Crafts
acylation for generation of the
appropriately functionalized naphthalene precursors followed by
5-exo-trig aryl radical−alkene
cyclization for synthesis of the
1,2-dihydro-3H-benz[e]indole skeleton
and final Ar-3‘ alkylation for
introduction of the activated cyclopropane. The most concise
approach provided the CCBI subunit
and its immediate precursor in 14−15 steps in superb overall
conversions (15−20%). Resolution
of an immediate CCBI precursor and its incorporation into both
enantiomers of 34−39, analogs of
CC-1065 and the duocarmycins, are detailed. A study of the
solvolysis reactivity and regioselectivity
of N-BOC-CCBI (25) revealed that introduction of
the C7 nitrile slowed the rate of solvolysis but
only to a surprisingly small extent. Classical Hammett
quantitation of the effect provided a
remarkably small ρ (−0.3), indicating an exceptionally small C7
substituent electronic effect on
functional reactivity. Additional kinetic studies of
acid-catalyzed nucleophilic addition proved
inconsistent with C4 carbonyl protonation as the slow and
rate-determining step but consistent
with a mechanism in which protonation is rapid and reversible followed
by slow and rate-determining nucleophilic addition to the cyclopropane requiring both the
presence and assistance
of a nucleophile (SN2 mechanism). No doubt this
contributes to the DNA alkylation selectivity of
this class of agents and suggests that the positioning of an accessible
nucleophile (adenine N3)
and not C4 carbonyl protonation is the rate-determining step
controlling the sequence selectivity
of the DNA alkylation reaction. This small electronic effect on
the solvolysis rate had no impact
on the solvolysis regioselectivity, and stereoelectronically-controlled
nucleophilic addition to the
least substituted carbon of the activated cyclopropane was observed
exclusively. Consistent with
past studies, a direct relationship between solvolysis stability and
cytotoxic potency was observed
with the CCBI-derived agents providing the most potent analogs in the
CBI series, and these
observations were related to the predictable Hammett substituent
effects. For the natural
enantiomers, this unusually small electronic effect on functional
reactivity had no perceptible effect
on their DNA alkylation selectivity. Similar effects of the C7
cyano substituent on the unnatural
enantiomers were observed, and they proved to be 4−10× more
effective than the corresponding
CBI-based unnatural enantiomers and 4−70× less potent than the CCBI
natural enantiomers.
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