Multicomponent Ligation of Steroids: Creating Diversity at the Linkage Moiety of Bis-spirostanic Conjugates by Ugi Reactions

Abstract

The diversity-oriented synthesis of novel bis-spirostanic conjugates utilizing two different Ugi four-component reactions (Ugi-4CR) is described. Spirostanic steroids were functionalized with Ugi-reactive groups, that is, amines, isocyanides, and carboxylic acids, and next were subjected to multicomponent ligation approaches leading to bis-steroidal conjugates featuring pseudo-peptidic and heterocyclic linkage moieties. Both the classic Ugi-4CR and its hydrazoic acid variant were implemented, proving good efficiency for the ligation of isocyanosteroids to spirostanic acids and equatorial amines. Axially oriented amines showed poorer results, although model studies proved that chemical efficiency could be significantly improved while increasing reaction times. Overall, the method comprises the rapid generation of molecular diversity at the bis-steroid linkage moiety and, consequently, shows promise toward the production of combinatorial libraries of bis-spirostanes for biological screening.

A review on steroid dimers: 2011–2019

“…The steroidal pyrazine dimers 12-14 were obtained by classical condensation of -amino ketones, which is considered the most efficient method of pyrazine ring formation [4]. The steroidal pyrazine dimers 12 (64%) and 13 (62%) were produced from diosgenin (11), respectively, in five-and four-steps. In a similar fashion, the epoxy pyrazine dimer 14 (65%) was synthesized from the same starting material (11) in four-steps [6].…”

“…The steroidal pyrazine dimers 12 (64%) and 13 (62%) were produced from diosgenin (11), respectively, in five-and four-steps. In a similar fashion, the epoxy pyrazine dimer 14 (65%) was synthesized from the same starting material (11) in four-steps [6]. The unique characteristics of the bile acids in relation to their chiral, rigid and curved framework and chemically diverse hydroxyl groups have made them important building blocks in tailoring supramolecular hosts [2].…”

Steroid diversification by multicomponent reactions

“…As shown in Scheme 17, amino steroids could be reacted in MeOH or MeOH/CH 2 Cl 2 at room temperature with peptide carboxylic acids and isocyanopeptides to furnish peptide–steroid conjugates such as 58 and 59 . Interestingly, the same solution-phase protocol proved to be equally effective for the conjugation of two different steroidal scaffolds [65], but it failed for the ligation of larger peptides to steroids due to the poor solubility of the former ones.…”

Mesoscale Assembly of Bisteroidal Esters from Terephthalic Acid

“…Several steroid dimers have been synthesized [25,26], and among them, acyclic dimers involving connections through A, B, C, or D rings directly or through spacers, form the major group of such molecules; these dimers are also referred as 'linear dimers' [1]. The synthesis of dimeric steroids involving the A rings from the steroid monomers, connected through spacer groups, can be accomplished by linking through the most convenient position, C-3 [27]. The self-assembly of molecular entities with significant molecular weight with amphiphilic properties is a useful strategy for the formation of well-controlled materials [28][29][30].…”