186183-64-2Relevant articles and documents
Asymmetric Reductive Carbocyclization Using Engineered Ene Reductases
Heckenbichler, Kathrin,Schweiger, Anna,Brandner, Lea Alexandra,Binter, Alexandra,Toplak, Marina,Macheroux, Peter,Gruber, Karl,Breinbauer, Rolf
supporting information, p. 7240 - 7244 (2018/06/15)
Ene reductases from the Old Yellow Enzyme (OYE) family reduce the C=C double bond in α,β-unsaturated compounds bearing an electron-withdrawing group, for example, a carbonyl group. This asymmetric reduction has been exploited for biocatalysis. Going beyond its canonical function, we show that members of this enzyme family can also catalyze the formation of C?C bonds. α,β-Unsaturated aldehydes and ketones containing an additional electrophilic group undergo reductive cyclization. Mechanistically, the two-electron-reduced enzyme cofactor FMN delivers a hydride to generate an enolate intermediate, which reacts with the internal electrophile. Single-site replacement of a crucial Tyr residue with a non-protic Phe or Trp favored the cyclization over the natural reduction reaction. The new transformation enabled the enantioselective synthesis of chiral cyclopropanes in up to >99 % ee.
Conformational restriction approach to β-Secretase (BACE1) inhibitors: Effect of a cyclopropane ring to induce an alternative binding mode
Yonezawa, Shuji,Higashino, Kenichi,Tanaka, Yoshikazu,Nakano, Toru,Yamamoto, Takahiko,Yamakawa, Hidekuni,Muto, Chie,Hosono, Motoko,Hattori, Kazunari,Yutsudo, Takashi,Sakagami, Masahiro,Takemoto, Hiroshi,Iwamoto, Hideo,Kondo, Yutaka,Togame, Hiroko,Arisawa, Mitsuhiro,Shuto, Satoshi
, p. 8838 - 8858,21 (2020/09/16)
Improvement of a drugs binding activity using the conformational restriction approach with sp3 hybridized carbon is becoming a key strategy in drug discovery. We applied this approach to BACE1 inhibitors and designed four stereoisomeric cyclopropane compounds in which the ethylene linker of a known amidine-type inhibitor 2 was replaced with chiral cyclopropane rings. The synthesis and biologic evaluation of these compounds revealed that the cis-(1S,2R) isomer 6 exhibited the most potent BACE1 inhibitory activity among them. X-ray structure analysis of the complex of 6 and BACE1 revealed that its unique binding mode is due to the apparent CH-π interaction between the rigid cyclopropane ring and the Tyr71 side chain. A derivatization study using 6 as a lead molecule led to the development of highly potent inhibitors in which the structure-activity relationship as well as the binding mode of the compounds clearly differ from those of known amidine-type inhibitors.
Olefin cross-metathesis in the preparation of polycyclopropanes: Formal synthesis of FR-900848
Verbicky,Zercher
, p. 8723 - 8727 (2007/10/03)
Olefin cross-metathesis was used for the efficient incorporation of an E-olefin between two cyclopropane residues. The generation of a bis-cyclopropyl alkene homodimer, followed by cross metathesis with a terminal vinyl polycyclopropane, provided excellent yields of the targeted compounds with good olefin stereoselectivity. The strategy was applied to generation of a quinta-cyclopropane intermediate found in a previous synthesis of the natural product FR-900848. (C) 2000 Elsevier Science Ltd.
