- Progress toward a rationally designed, chemically powered rotary molecular motor
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Building on prototype 1, which achieves 120° of phosgene-powered unidirectional rotation to rotamer 6 (see Figure 5 in the full article), 7 was designed to accomplish repeated unidirectional rotation (see Scheme 7). Compound 7 contains an amino group on each blade of the triptycene and a 4-(dimethylamino)pyridine (DMAP) unit to selectively deliver phosgene (or its equivalent) to the amine in the "firing position". The synthesis of 7 is described: the key constructive steps are a benzyne addition to an anthracene to generate the triptycene, a stilbene photocyclization to construct the helicene, and a Stille coupling to incorporate the DMAP unit. The DMAP unit was shown to regioselectively relay 1,1′-carbonyldiimidazole (but not phosgene) to the proximal amino group, as designed, but rotation of the triptycene does not occur. Extensive attempts to troubleshoot the problem led to the conclusion that the requisite intramolecular urethane formation, as demonstrated in the prototype (1 → 4), does not occur with 7 (to give 85) or 97 (to give 100). We speculate that either (i) hydrogen bonding between the hydroxypropyl group and functionality present in 7 but absent from 1 or (ii) a Buergi-Dunitz (or similar) interaction involving the DMAP (see 106) prevents achievement of a conformation conducive to intramolecular urethane formation.
- Kelly, T. Ross,Cai, Xiaolu,Damkaci, Fehmi,Panicker, Sreeletha B.,Tu, Bin,Bushell, Simon M.,Cornella, Ivan,Piggott, Matthew J.,Salives, Richard,Cavero, Marta,Zhao, Yajun,Jasmin, Serge
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p. 376 - 386
(2008/04/18)
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- Synthesis and properties of substituted CBI analogs of CC-1065 and the duocarmycins incorporating the 7-methoxy-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (MCBI) alkylation subunit: Magnitude of electronic effects on the functional reactivity
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The synthesis of 7-methosy-1,2,9,9a-tetrahydrocyclopropa[e]benz[e]indol-4-one (MCBI), a substituted CBI derivative bearing a C7 methoxy group para to the C4 carbonyl, is described in efforts that establish the magnitude of potential electronic effects on the chemical and functional reactivity of the agents. The core structure of the MCBI alkylation subunit was prepared by a modified Stobbe condensation/Friedel - Crafts acylation for generation of the appropriately functionalized naphthalene precursors (15 and 20) followed by 5-exo-trig aryl radical - alkene cyclization (24 → 25, 32 → 33) for completion of the synthesis of the 1,2-dihydro-3H-benz[e]indole skeleton and final Ar-3′ alkylation of 28 for introduction of the activated cyclopropane. Two approaches to the implementation of the key 5-exo-trig free radical cyclization are detailed with the former proceeding with closure of 24 to provide 25 in which the required product functionalization was introduced prior to cyclization and the latter with Tempo trap of the cyclization product of the unfunctionalized alkene substrate 32 to provide 33. The latter concise approach provided the MCBI subunit and its immediate precursor in 12-13 steps in superb overall conversions (27-30%). Resolution of an immediate MCBI precursor and its incorporation into both enantiomers of 39-46, analogs of CC-1065 and the duocarmycins, are detailed. A study of the solvolysis reactivity and regioselectivity of N-BOC-MCBI (29) revealed that introduction of the C7 methoxy group accelerates the rate of solvolysis by only 1.2-1.06x. This remarkably modest effect is inconsistent with C4 carbonyl protonation as the slow and rate-determining step of solvolysis or acid-catalyzed nucleophilic addition but is 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. For the natural enantiomers, this unusually small electronic effect on functional reactivity had little or no perceptible effect on their DNA alkylation selectivity, efficiency, and relative rates or on their biological properties. Perceptible effects of the C7 methoxy substituent on the unnatural enantiomers were observed and they proved to be 4-40x more effective than the corresponding CBI-based unnatural enantiomers and comparable in cytotoxic potency with the MCBI natural enantiomers. This effect is most consistently rationalized not by a C7 methoxy substituent effect on functional reactivity but rather through introduction of additional stabilizing noncovalent interactions which increase the unnatural enantiomer DNA alkylation efficiency and further stabilize its inherently reversible DNA alkylation reaction.
- Boger, Dale L.,McKie, Jeffrey A.,Cai, Hui,Cacciari, Barbara,Baraldi
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p. 1710 - 1729
(2007/10/03)
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