Asymmetric Organocatalytic Synthesis of aza‐Spirocyclic Compounds from Isothiocyanates and Isocyanides

Abstract

The spirocyclic motif is present in natural products, chiral ligands, and compounds of pharmacological interest. Isothiocyanates as well as isocyanides bearing electron-withdrawing groups in the α-position can be deprotonated and react as formal dipoles on account of the presence of a nucleophilic carbanion and an electrophilic atom in the isothiocyanate or isocyanide functional groups. In the last years a number of procedures involving the formal [3 + 2] cycloaddition reaction of isothiocyanates or isocyanides with cyclic compounds bearing electrophilic exocyclic double bonds have been developed for the enantioselective synthesis of aza-spirocyclic compounds. Among them, organocatalysis has played a predominant role in the development of asymmetric versions for these reactions. The synthesis of spirooxindoles by using this methodology has received especial attention, although other spirocyclic scaffolds are available depending on the structure of the dipolarophiles and the formal isothiocyanate and isocyanide dipoles.

H-Bond Mediated Phase-Transfer Catalysis: Enantioselective Generating of Quaternary Stereogenic Centers in β-Keto Esters

“…Using solid bases, as well as 50% aqueous solutions, provided similar results, however the best ones occurred for solid KF. Next, we screened the impact of the solvent (Table 1, entries [7][8][9][10][11]. As in our previous papers, the best results occurred for the toluene/CHCl 3 [7:3, v/v] mixture.…”

“…The generation of a quaternary stereogenic center in organic molecules has for many years been a demanding challenge that fits into the theme of organic catalysis, even in the asymmetric variant [1][2][3][4][5][6]. The development of enantioselective synthetic methods, including organocatalysis, has led to the possibility of obtaining synthetic mimetics of compounds of natural origin [7][8][9][10][11]. The presence of a quaternary carbon center in a molecule is very often a key factor in the biological activity of natural products or drugs [12][13][14][15][16][17].…”

Dehydroabietane-type bifunctional organocatalysts in asymmetric synthesis: recent progress

“…Owing to their specic strong hydrogen-bonding capabilities combined with the notable features of the dehydroabietane scaffold, a series of effective bifunctional organocatalysts based on the dehydroabietane structure have been employed in various catalytic asymmetric reactions so far. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] The dehydroabietane-type bifunctional organocatalysts can be broadly classied into two categories according to their hydrogen-bonding donor structures: thioureas (C1a-C8, including immobilized thioureas) and squaramides (C9-C11) as illustrated in Fig. 2.…”

Asymmetric α-Regioselective [3 + 2] Annulation of Morita–Baylis–Hillman Carbonates: Construction of Three Contiguous Stereocenters with Vicinal Quaternary Carbon Centers

“…The conformational restriction of vicinal quaternary carbons is helpful to alleviate the conformational entropy penalty upon binding to the target and improve the pharmaceutical properties of organic molecules in drug discovery . As a result of the intriguing structures, stereochemical complexity, and biological activities, the discovery of efficient asymmetric protocols to construct spirooxindoles with multiple contiguous stereogenic centers continues to be an important goal for both academic and industrial researchers . The catalytic enantioselective construction of sterically congested vicinal quaternary carbons in a single operation is one of the most difficult tasks in organic synthesis and represents a subject of longstanding interest .…”