Intramolecular C–H Amination Reaction Provides Direct Access to 1,2‐Disubstituted Diamondoids

Abstract

We present a new approach to disubstituted diamondoids from corresponding carboxylic acids. A dirhodium‐acetate‐catalyzed (1 mol‐%) nitrene insertion reaction of sulfamides was, for the first time, applied to intramolecular C–H functionalization reactions of rigid tricyclic frameworks. This straightforward approach enables the effective and regioselective synthesis of a variety of diamondoid‐based cyclic sulfamidates, which are synthetically valuable building blocks. Reductive deprotection of the sulfamidate moiety leads to corresponding 1,3‐amino alcohol derivatives. Oxidation of the sulfamidate moiety by KMnO4 provides access to 1,3‐keto alcohols or imines. Finally, we report the synthesis of Vildagliptin® analogues as new antidiabetic drug candidates (DPP‐4 inhibitors).

CH Bond Arylation of Diamondoids Catalyzed by Palladium(II) Acetate

“…Substituents in hyperconjugation with the cleaved C À H bond influence electronically the metal substitution step (see Supporting Information, page 53). [5,37] This results in regioselective arylation of the framework. In the case of bromo derivative 1 k, 1:1 mixture of epimers is obtained for 4 k in 50 % isolated yield.…”

“…Diamondoid derived carboxylic acids were condensed with pycolylamine to introduce the directing group and these amides 1 were used in the corresponding arylation reactions with 4‐iodoanisole 2 a to obtain compounds 4 (Figure 4). Substituents in hyperconjugation with the cleaved CH bond influence electronically the metal substitution step (see Supporting Information, page 53) 5. 37 This results in regioselective arylation of the framework.…”

“…As a consequence of the features of the adamantane framework (Bredt's rule), access to 1,2-disubstituted derivatives is synthetically demanding. [5] Two approaches were used to reach a 1,2-disubstitution pattern. The first strategy involves the opening of the adamantane cage to protoadamantanone and its further modifications (Figure 2, eq.…”

“…The development of new synthetic methods is required in order to reach different substitution pattern on the adamantane framework. As a consequence of the features of the adamantane framework (Bredt′s rule), access to 1,2‐disubstituted derivatives is synthetically demanding 5. Two approaches were used to reach a 1,2‐disubstitution pattern.…”

Transition metal catalyzed C-H activation for the synthesis of medicinally relevant molecules: A Review

“…Hrdina et al, have developed a straightforward way to prepare 1,2-disubstituted diamondoids by C-H bond amination reactions on a rigid tricyclic systems and applied this strategy to the synthesis of an enantiopure N-protected β-amino acid and new analogues of Vildagliptin. 22 Traditionally, the Scheme 7. Synthesis of SPT inhibitor.…”