Enantioselective synthesis of 2-substituted bicyclo[1.1.1]pentanes via sequential asymmetric imine addition of bicyclo[1.1.0]butanes and skeletal editing

Article

Author: Zhang, Hong-Bo ; Wang, Yong-Bin ; Xiang, Shao-Hua ; Ding, Wei-Yi ; Tan, Bin ; Che, Jin-Teng

The substitution of an aromatic ring with a C(sp³)-rich bicyclic hydrocarbon, known as bioisosteric replacement, plays a crucial role in modern drug discovery. Substituted bicyclo[1.1.1]pentanes (BCPs) are particularly noteworthy owing to their uniquely three-dimensional stereochemical complexity. 1,3-Difunctionalized BCPs have been widely used as bioisosteres for para-substituted phenyl rings, and they have been incorporated into numerous lead pharmaceutical candidates. 2-Substituted BCPs (substituted at the bridge position) can function as alternatives to ortho- or meta-substituted arene rings; however, the general and efficient construction of these scaffolds remains challenging, particularly if performed in an enantioselective manner. Here we present an approach for synthesizing enantioenriched 2-substituted BCPs by a nitrogen-atom insertion-and-deletion strategy, involving a chiral Brønsted acid-catalytic enantioselective cycloaddition of bicyclo[1.1.0]butanes with imines and nitrogen deletion of resulting aza-bicyclo[2.1.1]hexanes (aza-BCHs) with generally good enantiopurity retention. Mechanistic experiments verify the radical pathway. Chiral BCPs have been readily incorporated into medicinally relevant molecules, and a drug analogue has been successfully prepared enantioselectively.

18 Feb 2025·Advanced Synthesis & Catalysis

Diverse Synthesis of Azoles: Construction of ortho‐Azidotetrazoles/Triazoletetrazoles through N−N Cleavage of 2H‐Indazoles

Author: Hajra, Alakananda ; Laru, Sudip ; Bhattacharjee, Suvam

AbstractHerein, we report a conceptually new, general, and efficient approach for the synthesis of valuable ortho‐azido‐1,5‐disubstituted tetrazole and one‐pot synthesis of ortho‐triazoletetrazole derivatives mainly via PIDA mediated N−N cleavage of the azole ring of 2H‐indazoles using TMSN3. This current methodology represents an array of unsymmetrical ortho‐azidotetrazole and ortho‐triazoletetrazole derivatives with wide functional group tolerance in good to excellent yields under mild reaction conditions. The practical utility of this reaction was showcased through successful scale‐up synthesis and a variety of subsequent derivatizations of ortho‐azidotetrazole products. Mechanistic investigations indicate that the reaction proceeds through a radical pathway.

01 Feb 2025·Current Organic Chemistry

Synthesis of Pregna-1,4,16-triene-3,20-dione from a Mixture of Soybean Phytosterols using a Combination of Chemical and Microbiological Methods

Author: Savinova, Tatiana Stepanovna ; Huy, Luu Duc ; Kazantsev, Alexey Vitalievich ; Donova, Marina Viktorovna ; Fokina, Victoria Valerievna

:In this paper, we present an efficient procedure for the transformation of a soybean phytosterol mixture into pregna-1,4,16-triene-3,20-dione, which is a key intermediate for the synthesis of valuable corticoids. The possibility of using two alternative methods for 1(2)-dehydrogenation of pregna-4,16-diene-3,20-dione - chemical and microbiological - was shown. Microbiological 3-keto-4-ene steroid 1(2)-dehydrogenation was carried out using actinobacterial cells of Nocardioides simplex VKM Ac-2033D. The structures of the synthesized compounds were confirmed by the IR, MS, and 1H-NMR methods.

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Amenorrhea	China	Qinhuangdao Zizhu Pharmaceutical Co. Ltd.	-
Dysmenorrhea	China	Qinhuangdao Zizhu Pharmaceutical Co. Ltd.	-
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