Synthesis of DOHNAA, a Mycobacterium tuberculosis Cholesterol CD Ring Catabolite and FadD3 Substrate

Abstract

DOHNAA (2) is a key catabolite in the Mycobacterium tuberculosis (Mtb) cholesterol degradation pathway. The CoA ester of 2 has been implicated in regulation of gene transcription that is ultimately responsible for degradation of the C and D rings of cholesterol. A synthetic route to 2 is reported here, by a key DMSO‐mediated Morita–Bayliss–Hillman‐type alkylation of the Hajos–Parrish dione. As DOHNAA has to date only been available from microbial sources in very small quantities, the synthesis described will enable further studies of the enzymes involved in cholesterol degradation in Mtb and facilitate ongoing structure–activity studies based on this compound scaffold.

Synthesis of 13C-Labeled Steroids

“…Following this work, in 1995 Joubert and co-workers reported a synthesis of [1,2,3,4,10,19-13 C 6 ]-testosterone 40 from enantioenriched CD-ring system building block 71 (Scheme 14). 50 The known diketo acid 71 35 was converted into the corresponding enol lactone (see Scheme 10), followed by stereoselective reduction of the remaining ketone group at C17 and silylation of the resulting alcohol; the key building block 72 was obtained in 40% yield over three steps. The critical condensation of enol lactone 72 with the anion of the labeled ketal phosphonate [ 13 C 5 ]-50 (its preparation is presented in Scheme 15) was investigated.…”

“…In this approach, the crucial issue is the access to the desired C,D-steroid nucleus, some of which have been obtained through microbial degradation of sterols 34 or by multistep synthesis. 35 It must be noted that in the context of the synthesis of labeled compounds as standard for isotope dilution technique, it is not necessary to prepare enantioenriched internal standards.…”

A Keto Reductase Involved in Steroid Degradation in Mycolicibacterium neoaurum

“…HIP and HIL can be accumulated by microbiological degradation of phytosterols with high yields. [13][14][15][16][17] However, due to lack of understanding of the full metabolic pathway of phytosterols, current industrial strains were not perfect for unstable production levels and undesired side products. Elucidation of the full metabolic pathway will allow the creation of improved industrial strains using metabolic engineering, with higher productivity and stability.…”

Total Synthesis of the Phenolic Steroid Myrmenaphthol A

“…For example, Brimble et al prepared 11 in eight steps from the Hajos−Parrish ketone. 12 In contrast, we began our synthesis with sitolactone (10), 13 which could be transformed to 11 via a one-pot lactone hydrolysis/Jones oxidation sequence. Specifically, saponification of 10, followed by oxidation of the resulting C9 hydroxyl group with Jones reagent in the same pot, delivered 11 in 70% yield.…”

“…Notably, synthetic chemists usually trace the 5/6-fused ring system of acid 11 , a common substructure in natural products, back to the Hajos–Parrish ketone. For example, Brimble et al prepared 11 in eight steps from the Hajos–Parrish ketone . In contrast, we began our synthesis with sitolactone ( 10 ), which could be transformed to 11 via a one-pot lactone hydrolysis/Jones oxidation sequence.…”