Synthesis of 2-Deoxybrassinosteroids Analogs with 24-nor, 22(S)-23-Dihydroxy-Type Side Chains from Hyodeoxycholic Acid

Abstract

Natural brassinosteroids are widespread in the plant kingdom and it is known that they play an important role in regulating plant growth. In this study, two new brassinosteroid analogs with shorter side chains but keeping the diol function were synthesized. Thus, the synthesis of 2-deoxybrassinosteroids analogs of the 3α-hydroxy-24-nor, 22,23-dihydroxy-5α-cholestane side chain type is described. The starting material is a derivative from hyodeoxycholic acid (4), which was obtained with an overall yield of 59% following a previously reported five step route. The side chain of this intermediate was modified by oxidative decarboxylation to get a terminal olefin at the C22-C23 position (compound 20) and subsequent dihydroxylation of the olefin. The resulting epimeric mixture of 21a, 21b was separated and the absolute configuration at the C22 carbon for the main product 21a was elucidated by single crystal X-ray diffraction analysis of the benzoylated derivative 22. Finally, lactonization of 21a through a Baeyer-Villiger oxidation of triacetylated derivative 23, using CF3CO3H/CHCl3 as oxidant system, leads to lactones 24 and 25 in 35% and 14% yields, respectively. Deacetylation of these compounds leads to 2-deoxybrassinosteroids 18 and 19 in 86% and 81% yields. Full structural characterization of all synthesized compounds was achieved using their 1D, 2D NMR, and HRMS data.

Synthesis and Structural Determination of New Brassinosteroid 24-Nor-5α-Cholane Type Analogs

“…This transformation can be accomplished by either of three different methods, namely: Direct Upjohn dihydroxylation; Epoxidation and subsequent opening of epoxide ring in acid medium; and Sharpless asymmetric dihydroxylation (Scheme 1). Below are described the results obtained by the application of these synthetic paths to dihydroxylation of olefin 9, which was previously synthesized from hyodeoxycholic acid [35]. All tested methods lead to epimeric mixtures of glycols 22S/22R (10a/10b) but in different ratios.…”

“…Alkene 9 was hydroxylated by the Upjohn method and a mixture of epimeric glycols 10a/10b was obtained with a 72% yield (Scheme 1). The diastereomeric ratio of each glycol in the mixture can be established by integration of 1 H-NMR signals assigned to the C21 methyl group, which appear at δH = 0.947 and 0.911 ppm in 10a and 10b epimers, respectively ( Figure 2) [35]. Based on these NMR measurements the ratio of 10a:10b obtained by this method was determined as 1.0:0.24.…”

“…The diastereomeric ratio of each glycol in the mixture can be established by integration of 1 H-NMR signals assigned to the C21 methyl group, which appear at δ H = 0.947 and 0.911 ppm in 10a and 10b epimers, respectively ( Figure 2) [35]. shown that the reaction product is a mixture of diastereomers with the 22S epimer as the major product [36][37][38][39].…”

“…This reaction was selected because the mixture product is obtained with the highest total reaction yield (95%) and glycols 10a/10b are found in similar proportion. The 22S benzoylated derivative (5) has been previously synthesized by reaction of pure compound 10a with PhCOCl/DMAP [35]. Thus, to get compound 7 the glycols mixture 10a/10b obtained by the Sharpless method was submitted to the same benzoylation reaction to obtain both epimers 5 and 7.…”

“…These spatial orientations can be indicated as distances or angles between the oxygen atoms present in a brassinosteroid. Following this line, we have previously reported the synthesis of BRs analogs with short side chain and structure (22S)-3α,22,23-trihydroxy-24-nor-5α-cholane (compounds 2-4, Figure 1) and a benzoylated derivative 5 [35]. However, to evaluate the effect of a C22 configuration on biological activity it is necessary to obtain the 22R epimers of these analogs.…”