A new synthesis of p-hydroxy phenylglycine and some analogues from p-benzoquinone

[reaction: see text] A new route to p-hydroxy phenylglycine and N-substituted analogues has been developed starting from p-benzoquinone. 1,2-Addition of methyl lithioacetate to p-benzoquinone and subsequent quenching of the oxygen anion with methyl chloroformate, followed by an elimination-addition reaction with an appropriate amine, resulted in the desired amino acid derivatives. A diastereoselectivity of 60% was achieved using 8-phenylmenthyl acetate as the chiral auxiliary.     

Stereoselective synthesis of some acetylenic analogues of leukotrienes A and D

The stereocontrolled synthesis of methyl 5(E)-epoxyeicosa-7-ynoate (7) and its conversion to a 7,8-acetyleno-LTD analog is described. Chiral acetyleno-LTA analogs are prepared following a novel and versatile “one pot” procedure from 5(S)-benzoyloxy-5-formylpentanoate (3).     

New concise total synthesis of (+)-lentiginosine and some structural analogues

An efficient and concise total synthesis of (+)-lentiginosine (1) starting from an L-tartaric acid-derived nitrone using organometallic addition, indium-catalyzed reduction, and ring-closing metathesis reaction as the key steps is reported. Structural analogues of (+)-1 have been also synthesized, and their inhibitory activity toward 22 commercially available glycosidases has been evaluated.     

Efficient synthesis of flupirtine analogues derived from pyrimidine

The synthesis of novel N²‐substituted 5‐alkoxycarbonylamino‐2,4‐diaminopyrimidines, 5‐acylamino‐2,4‐diaminopyrimidines, and 2,4‐diamino‐5‐ureidopyrimidines as analogues of the analgesic flupirtine is described. J. Heterocyclic Chem.,, (2012).     

Synthesis of asperopterin-B and some analogues

Homolytic 1-hydroxyalkylation on 8-methylisoxanthopterin by a primary or secondary alcohol and ammonium peroxydisulfate in a pH 5-6 phosphate buffer gave two naturally occuring pteridines, Asperopterin-B and 6-(1-hydroxypropyl)-8-methylisoxanthopterin, and several analogues.     

An efficient and general enantioselective synthesis of some isoxazole-containing analogues of the neuroexcitant glutamic acid

Isoxazole amino acids are an important class of neuroexcitant which are difficult to prepare in enantiopure form. Diastereoselective alkylation of the enantiomerically pure glycine derivative, tert-butoxycarbonyl-2-(tert-butyl)-3-methyl-4-oxo-1-imidazolidinecarboxylate (Boc-BMI) with 4-bromomethyl-2-methoxymethyl-5-methylisoxazolin-5-one 5 or 5-bromomethyl-4-bromo-3-methoxyisoxazole, gives intermediates which under mild hydrolysis conditions produce the amino acids (S)- and (R)-bromohomoibotenic acid and (S)- and (R)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid with e.e. >99%.     

Enantioselective synthesis of pantolactone analogues from an ephedrine-derived morpholine-dione

An efficient enantioselective synthesis of β,β-dialkyl α-hydroxy γ-butyrolactones, analogues of pantolactone, has been developed employing a stereoselective Prins reaction of chiral alkylidene morpholinones, as the key step. Enantioselective synthesis of a naturally occurring pantolactone homologue and a spiro analogue of pantolactone was achieved with this protocol.     

Divergent synthesis of two novel muscarine analogues from D-glucose

A divergent synthesis of two new muscarine analogues bearing the (5S)-dioxolanyl isosteric group was achieved starting from d-glucose, enabling access to libraries of potential muscarinic agonists or antagonists. The key step of the synthesis involved a regioselective epoxide ring opening in 2,5:3,4-dianhydro derivatives 5 and 15 with LiAlH₄, whereby the natural stereochemistry of (+)-muscarine (1) and (−)-allo-muscarine (2) was efficiently established.     

Multicomponent synthesis of Ugi-type ceramide analogues and neoglycolipids from lipidic isocyanides

Unique types of ceramide and glycolipid architectures were obtained by means of Ugi reactions incorporating lipidic isocyanides as surrogates of sphingolipids. The multicomponent nature of this approach allowed for a highly efficient assembly process, wherein two of the components provided the lipidic tails while a third one incorporated either the functionality suitable for the conjugation to sugar or the sugar moiety itself. Two dissimilar strategies were implemented: (i) the initial assembly of ceramide analogues followed by glycosylation to produce a glycolipid skeleton and (ii) the one-pot construction of glycolipid frameworks by condensation of lipidic isocyanides either with lipidic amines and oligosaccharidic acids or with fatty acids and oligosaccharidic amines. Whereas both approaches are amenable for accessing analogues of anticancer glycolipids, the latter one proved to have greater potential owing to its more straightforward and efficient character. Overall, the methodology developed shows great promise toward the massive (eventually combinatorial) production of neoglycolipids suitable for biological screening.     

Total synthesis of maesanin and analogues

An efficient total synthesis of maesanin and related quinones is reported, through direct alkylation of 1,2,4,5-tetramethoxybenzene with alkylbromides, followed by oxidation with ceric ammonium nitrate (CAN) which provokes formation of the quinone and deprotection of the more hindered methyl ether in one step, to furnish the desired 2-hydroxy-5-methoxy-1,4-benzoquinones 1a-h.     

One-step, nonenzymatic synthesis of O-acetyl-ADP-ribose and analogues from NAD and carboxylates

O-Acetyl-ADP-ribose (OAADPR) is a metabolite produced from nicotinamide adenine dinucleotide (NAD) as a product of sirtuin-mediated protein deacetylation. We present here a simple, one-step, nonenzymatic synthesis of OAADPR from NAD and sodium acetate in acetic acid. We extended the reaction to other carboxylic acids, demonstrating that the reaction between NAD and nonaqueous carboxylate buffers produces mixtures of the corresponding 2'- and 3'-carboxylic esters.     

Synthesis of some fluorinated putrescine analogues

Mono- and tetrafluoroputrescine were obtained in moderate yields from 2-hydroxy-1,4-dibromobutane and perfluorosuccinamide respectively.     

Solid-phase synthesis of nucleoside analogues

The synthesis of a 25 000 member library of nucleoside analogues as discrete compounds in milligram quantities is described. The use of the Nanokan technology developed by IRORI (Discovery Partners International) together with macroporous solid support allowed us to develop a highly reliable and practical synthetic route for the high-throughput derivatization of both the pyrimidine and purine nucleoside scaffold. A 2',3'-acetal linkage of the scaffolds to the solid support proved to be stable enough for the chemical transformations employed, yet labile enough for mild cleavage conditions to yield final products in high purity. The publication represents an example for combining synthetic organic chemistry on advanced scaffolds with the latest technologies of combinatorial chemistry in order to provide both industrial and academic institutions with compounds in high number and quality, thereby accelerating the search for novel biological targets and drug development.     

Solid-phase synthesis of anandamide analogues

The endocannabinoids are amides and esters of arachidonic acid that can mimic the pharmacological properties of Delta(9)-tetrahydrocannabinol (Delta(9)-THC). Anandamide, the most prominent of the endocannabinoids, has been implicated in both metabolic/physiological roles of the central nervous system, making it an attractive medicinal target. As such, we report the first solid-phase methodology that expedites access to various anandamide analogues. Our synthesis features a repetitive Cu-mediated coupling reaction between terminal alkynes and propargyl halides or allylic halides.     

Solid-phase synthesis of macrolide analogues

The synthesis of a solid-phase macrolide library is described. The library introduces three sites of diversity to a suitable macrolide scaffold via reductive aminations.     

Rapid synthesis of cyclopropane-dipeptide analogues

The synthesis of cyclopropane-substituted nitrile-dipeptides is reported. The straightforward transformation of the nitrile function into an amide or methylketone function leads to dipeptide analogues of potentially interesting pharmacologic profile.     

Solid-phase synthesis of chlorofusin analogues

We report an efficient and versatile solid-phase synthesis through which two series of chlorofusin analogues, one bearing varying chromophores and the other with various amino acid substitutions in the cyclic peptide, were synthesized. These peptides were prepared using a strategy involving side-chain immobilization, on-resin cyclization, and postcyclization modification. The success of these syntheses demonstrates the broad utility of the method. Both series of analogues were evaluated for their inhibitory activity against the p53/MDM2 interaction but were shown to be inactive in the concentration range tested. This suggests that the full chromophore structure may be required for activity.     

Formal synthesis of dictyostatin and synthesis of two dictyostatin analogues

A formal convergent synthesis of dictyostatin from (R)-Roche ester is described. Synthetic highlights include a Ni-catalyzed Nozaki-Hiyama-Kishi coupling between an aldehyde and a Z vinyl iodide to assemble the two main fragments, a diastereoselective Myers alkylation, a stereoselective Evans aldolization, two asymmetric Duthaler crotyltitanations, and a stereoselective Pd-catalyzed Marshall allenylindium addition to install the stereogenic centers of dictyostatin. The synthesis of (9R)-epi-dictyostatin and a new ring-contracted dictyostatin isomer were also achieved.