Two independent chiral pool syntheses of both enantiomers of the TRPML inhibitor, trans‐ML‐SI3, were developed, starting from commercially available (1S,2R)‐ and (1R,2S)‐configured cis‐2‐aminocyclohexanols. Both routes lead to the target compounds in excellent enantiomeric purity and good overall yields. For the most attractive (−)‐trans‐enantiomer, the R,R‐configuration was identified by these unambiguous syntheses, and the results were confirmed by single‐crystal X‐ray structure analysis. These effective synthetic approaches further allow flexible variation of prominent residues in ML‐SI3 for future in‐depth analysis of structure–activity relationships as both the piperazine and the N‐sulfonyl residues are introduced into the molecule at late stages of the synthesis.

In a project aimed at the further development of the potent steroidal anti‐inflammatory Δ24‐dehydrocholesterol reductase (DHCR24) inhibitor SH‐42 we worked out routes to ring B seco‐steroidal analogues. The required building blocks, bearing rings C and D of the parent steroidal structure, were synthesised starting from ergocalciferol. The novel seco‐analogues carry aromatic residues as ring A equivalents at C‐4 position with variation of the linker length resulting in 4‐aryl‐, 4‐benzyl‐ and 4‐(arylethyl)perhydroindanes. As saturated analogues of the latter 4‐(cyclohexylethyl)perhydroindanes were prepared. Moreover, aromatic and aliphatic residues were attached to C‐5 position of the perhydroindane scaffold. Unfortunately, none of these structurally diverse seco‐analogues of SH‐42 showed noteworthy inhibition of target enzyme DHCR24, indicating the relevance of the intact steroidal structure for the development of potent inhibitors of this enzyme.