ABSTRACT
Hippuristanol is a marine derived steroidal natural product with promising anticancer activity. However, instability at low pH has precluded its development as an efficient therapy. We addressed this limitation by replacing one of the oxygen atoms of the spiroketal moiety with a carbon atom. Key steps in the synthesis include a Meyer-Schuster/Nazarov cascade, a hypoiodite mediated oxyfunctionalization, and the late-stage installation of a hydroxyl group on the C-ring of the steroid.
Subject(s)
Biological Products , Molecular Structure , Biological Products/chemistry , Biological Products/chemical synthesis , Spiro Compounds/chemistry , Spiro Compounds/chemical synthesis , Steroids/chemistry , Steroids/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacologyABSTRACT
Steroids are highly prevalent structures in small-molecule therapeutics, with the level of oxidation being key to their biological activity and physicochemical properties. These C(sp3 )-rich tetracycles contain many stereocentres, which are important for creating specific vectors and protein binding orientations. Therefore, the ability to hydroxylate steroids with a high degree of regio-, chemo- and stereoselectivity is essential for researchers working in this field. This review will cover three main methods for the hydroxylation of steroidal C(sp3 )-H bonds: biocatalysis, metal-catalysed C-H hydroxylation and organic oxidants, such as dioxiranes and oxaziridines.
Subject(s)
Oxidants , Steroids , Hydroxylation , Oxidation-Reduction , Oxidants/chemistry , Steroids/metabolism , BiocatalysisABSTRACT
The N-chloroformylimidazolidinone derivative of enantiopure l-alanine was deprotonated to form an enolate and functionalized with a series of allylic halides. Treatment of the resulting carbamoyl chlorides with potassium iodide led to cyclization of the allylic substituent onto the carbonyl group in an intramolecular aliphatic Friedel-Crafts-type acylation that corresponds to an aliphatic Bischler-Napieralski reaction. The product 3,4-dihydropyridinones were amenable to further functionalization, and finally hydrolysis, to deliver a series of enantio-enriched pipecolic acid derivatives.
ABSTRACT
N-acyl imidazolidinones, which are key intermediates in the stereoselective synthesis of amino acids by "self-regeneration of stereochemistry" methods, are classically made by only moderately diastereoselective methods. We now report that cyclization of pivaldimino-amides with phosgene in the presence of pyridine may be made fully diastereoselective for the trans-N-chloroformylimidazolidinones, and we detail the conformational features of the products. We show that despite the presence of the electrophilic carbamoyl chloride function the products show remarkable stability and may be deprotonated to form enolates with useful reactivity for the synthesis of amino acid derivatives.
ABSTRACT
N-Chloroformyl imidazolidinone derivatives of enantiopure amino acids may be deprotonated to give remarkably well-behaved enolates with both nucleophilic and electrophilic character. The enolates undergo diastereoselective C-alkylation with benzylic halides. A Bischler-Napieralski-like cyclization reaction onto the chloroformyl group, induced by either nucleophilic (KI, 2,6-lutidine) or Lewis acid (AlCl3) catalysis, gives substituted 3,4-dihydroisoquinolone derivatives in enantioenriched form. The reaction sequence constitutes a formal [3 + 3] route to the six-membered lactam ring of the dihydroisoquinolones.
ABSTRACT
Both E- and Z-N'-alkenyl urea derivatives of imidazolidinones may be formed selectively from enantiopure α-amino acids. Generation of their enolate derivatives in the presence of K+ and [18]crown-6 induces intramolecular migration of the alkenyl group from N' to Cα with retention of double bond geometry. DFT calculations indicate a partially concerted substitution mechanism. Hydrolysis of the enantiopure products under acid conditions reveals quaternary α-alkenyl amino acids with stereodivergent control of both absolute configuration and double bond geometry.
ABSTRACT
The first total synthesis of (+)-lophirone H (1) and its pentamethyl ether 29, featuring an oxonium-Prins cyclization/benzylic cation trapping reaction, is described.
ABSTRACT
Thermal Diels-Alder reactions of α-amido acrylates with N-Cbz-1,2-dihydropyridine and cyclopentadiene have been explored to investigate the factors influencing the endo/exo selectivity. For the dihydropyridine, steric factors allowed the diastereoselectivity to be modulated to favor either endo- or exo-ester adducts. For cyclopentadiene, the endo-ester adducts were favored regardless of steric perturbation, although catalysis by bulky Lewis acids increased the proportion of exo-ester adducts in some cases. These Lewis acids were incompatible with the dihydropyridine diene as they induced its decomposition.
ABSTRACT
A knowledge-based library of 2,3-dichlorophenylsulfonyl derivatives of commercially available aryl amines was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. Hits were required to be more potent than an existing indazole series, have better physicochemical properties (clogP <3.5, chrom logD7.4 <5.3 and CLND solubility >116 µg/mL), and be stable to acid and light. The benzimidazol-2-one core was identified as a hit suitable for further investigation. Substitution at N1 with small alkyl groups was tolerated; however, these analogues were inactive in the whole blood assay (pA2 <5). Azabenzimidazolone analogues were all found to be active, with compound 38 exhibiting whole blood activity of 6.1, low molecular weight (389) and chrom logD7.4 (2.4), high LE (0.43), and solubility (152 µg/mL). In addition, 38 had human serum albumin binding of around 93% and met all the criteria for progression to lead optimisation.