Synthesis and Characterization of a Cyclobutane Duocarmycin Derivative Incorporating the 1,2,10,11-Tetrahydro-9H-cyclobuta[c]benzo[e]indol-4-one (CbBI) Alkylation Subunit
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- 作者：James P. Lajiness ; Dale L. Boger
- 刊名：Journal of the American Chemical Society
- 出版年：2010
- 出版时间：October 6, 2010
- 年：2010
- 卷：132
- 期：39
- 页码：13936-13940
- 全文大小：260K
- 年卷期：v.132,no.39(October 6, 2010)
- ISSN：1520-5126
文摘
The synthesis of 1,2,10,11-tetrahydro-9H-cyclobuta[c]benzo[e]indol-4-one (17, CbBI), which contains a deep-seated fundamental structural modification in the CC-1065 and duocarmycin alkylation subunit consisting of the incorporation of a ring-expanded fused cyclobutane (vs cyclopropane), its chemical and structural characterization, and its incorporation into a key analogue of the natural products are detailed. The approach to the preparation of CbBI was based on a precedented (Ar-3′ and Ar-5′) but previously unknown Ar-4′ spirocyclization of a phenol onto a tethered alkyl halide to form the desired cyclobutane. The conditions required for the implementation of the Ar-4′ spirocyclization indicate that the entropy of activation substantially impacts the rate of reaction relative to that for the much more facile Ar-3′ spirocyclization, while the higher enthalpy of activation slows the reaction relative to an Ar-5′ spirocyclization. The characterization of the CbBI-based agents revealed their exceptional stability and exquisite reaction regioselectivity, and a single-crystal X-ray structure analysis of N-Boc-CbBI (13) revealed their structural origins. The reaction regioselectivity may be attributed to the stereoelectronic alignment of the two available cyclobutane bonds with the cyclohexadienone π-system, which resides in the bond that extends to the less substituted cyclobutane carbon for 13. The remarkable stability of N-Boc-CbBI (which is stable even at pH 1) relative to N-Boc-CBI containing a cyclopropane (t1/2 = 133 h at pH 3) may be attributed to a combination of the increased extent of vinylogous amide conjugation, the nonoptimal geometric alignment of the cyclobutane with the activating cyclohexadienone, and the intrinsic but modestly lower strain energy (1.8 kcal/mol) of a cyclobutane versus a cyclopropane.