Corticosteroid Carboxylic Acid Esters

Minimising the payload solvent exposed hydrophobic surface area optimises the antibody-drug conjugate properties

“…1a) do not have a suitable nitrogen atom for linker attachment. Of the four oxygen functional groups the carbonyl at C3 via hydrazone attachment like in gemtuzumab ozogamicin 6 and the hydroxyl at C21 via ester attachment like in many steroid prodrugs 7 offer the best options for attachment.…”

Divergent Chemo‐ and Biocatalytic Route to 16β‐Methylcorticoids: Asymmetric Synthesis of Betamethasone Dipropionate, Clobetasol Propionate, and Beclomethasone Dipropionate

“…[17] As a crucial step of this strategy, the chiral C16β-Me and C17α-OH groups of the corticosteroid D ring could be installed via a substrate-controlled diastereo-and enantioselective Mn-catalyzed oxidation-reduction hydration employing Δ 4,9 (11), 16 -triene-3,20-dione 7 a. [18] We anticipated that straightforward access to 7 a could be achieved by an acid-catalyzed Rupe rearrangement of Δ 4,9 (11) -diene propargylic alcohol 8, [19] which could in turn be obtained through a modified four-step sequence of clockwise regioselective C9,11 dehydration, A-ring carbonyl enol etherification, C16 methylation, and ethynylation. [14] Thus, commercially available 9α-OH-AD ( 9), derived from the fermentation of phytosterols, was selected as the starting material.…”

“…The advanced intermediate 5 a was expected to be accessible through an engineered Δ 1 -KstD-catalyzed C1,2 dehydrogenation of 16β-methyl-17α-hydroxy-Δ 4,9(11) diene-3,20-dione 6 a. [17] As a crucial step of this strategy, the chiral C16β-Me and C17α-OH groups of the corticosteroid D ring could be installed via a substrate-controlled diastereo-and enantioselective Mn-catalyzed oxidation-reduction hydration employing Δ 4,9 (11), 16 -triene-3,20-dione 7 a. [18] We anticipated that straightforward access to 7 a could be achieved by an acid-catalyzed Rupe rearrangement of Δ 4,9 (11) -diene propargylic alcohol 8, [19] which could in turn be obtained through a modified four-step sequence of clockwise regioselective C9,11 dehydration, A-ring carbonyl enol etherification, C16 methylation, and ethynylation.…”

“…Our retrosynthetic analysis of 16β-methylcorticoids 1-3 is depicted in Scheme 1. We envisioned that the target compounds could be obtained from the common precursor Δ 1,4,9 (11) -triene-3,20-dione 5 a via a series of functional group manipulations. The advanced intermediate 5 a was expected to be accessible through an engineered Δ 1 -KstD-catalyzed C1,2 dehydrogenation of 16β-methyl-17α-hydroxy-Δ 4,9(11) diene-3,20-dione 6 a.…”

Divergent Chemo‐ and Biocatalytic Route to 16β‐Methylcorticoids: Asymmetric Synthesis of Betamethasone Dipropionate, Clobetasol Propionate, and Beclomethasone Dipropionate

“…The mesmerizing and complex structures of 16β-methylcorticoids coupled with their remarkable pharmacological profiles have garnered considerable interest, and these molecules have been popular targets for the synthetic chemistry community since the 1950s (Scheme S1). [11] Following Oliveto's pioneering stereoselective synthesis of betamethasone, [12] a precursor of 1, Wendler, [13] Hanley, Carruthers, [14] Andrews, [15] Noimai, [16] and numerous other groups have made significant contributions to the development of synthetic strategies for 16β-methylcorticoids. Despite remarkable progress in the asymmetric synthesis of members of this glucocorticoid family, the construction of the C16β-methyl functionality and C17α,21-dihydroxyacetone side chains in these batch syntheses still involved tedious and harsh stepwise and timeconsuming manipulations and troublesome purification of intermediates from readily available starting materials containing the key steroidal fragments featuring the desired stereochemistry.…”