Synthesis of regioselectively brominated cellulose esters and 6-cyano-6-deoxycellulose esters

The control of regiochemistry in the synthesis of polysaccharide derivatives is one of the most significant scientific challenges in the field. Its importance is only further highlighted by the individual successes in synthesis of regioselectively substituted derivatives, in particular cellulose esters and ethers, over the last 20 years. The availability of these samples and studies of their properties versus randomly substituted analogs has shown clearly that properties like solubility, aggregation phenomena, and optical properties depend heavily on the regiochemistry of substitution. We report here on the one-pot synthesis of novel 6-bromo-6-deoxy-2,3-O-acylcellulose derivatives, which as more organic soluble derivatives of 6-bromo-6-deoxycellulose should allow broader exploitation of the highly regioselective cellulose 6-bromination chemistry. We illustrate the potential of these new derivatives by conversion to 6-cyano-6-deoxycellulose esters.     

2,4-Dioxohexahydropyrimidine derivatives V. 5-Bromo-6-alkoxydihydroorotic acids,amides, and esters

The corresponding 5-bromo-6-alkoxydihydroorotic acid derivatives were obtained by reaction of orotic acid, its methyl ester, and amide with bromine in methanol and ethanol. The reaction of methyl and butyl orotates with methyl and ethyl hypobromites gives 5,5-dibromo-6-alkoxydihydroorotic acid esters. Isoorotic acid reacts with methyl hypobromite to give 5,5-dibromo-6-methoxydihydrouracil.     

Stereoselective formal synthesis of (−)-mesembrane by intramolecular condensation of chiral amide and 1,3-cyclohexanedione moiety

A new stereoselective formal synthesis of (−)-mesembrane has been achieved by intramolecular condensation of chiral amide and 1,3-cyclohexanedione moiety. The precursor amide was readily prepared by condensation of the corresponding chiral amine and acid. Condensation provided moderate ratios of ene-amide derivatives and the following transformation of functional groups has yielded the known precursor for (−)-mesembrane, resulting in formal synthesis.     

Synthesis of Calix[4]resorcinarene Amide Derivatives

Three different synthetic routes were developed to introduce carbamoyloxy functional groups at the upper periphery of two calix[4]resorcinarenes. By treating activated esters 2a-b with excess corresponding amine such as 3-(dimethylamino)propylamine 3, ct-phenethylamine 4 and triethylenetetramine 5, six amide derivatives 6a-8b were obtained in high yield (Route 1). The pyridine-linked amide derivatives 9a-b were prepared by using acid chloride intermediate (Route 2).The amide derivatives 10a-b were obtained in moderate yields by direct alkylation of phenolic hydroxyl groups of la-b with N,N-dipropylchloroacetoamide in the presence of K2CO3/KI in acetone (Route 3).     

A novel approach to functionalised 5,7,8,9-tetrahydropyrimido[4,5-b][1,4]diazepin-6-ones using intramolecular palladium-catalysed amidation

The development of a novel palladium-catalysed amidation approach towards 5,7,8,9-tetrahydropyrimido[4,5-b][1,4]diazepin-6-one templates is highlighted. The route proceeds through the reaction of an amino amide, generated by 1,4-addition of an amine to an acrylamide, with 5-bromo-2,4-dichloropyrimidine and final palladium-catalysed cyclisation to provide the functionalised scaffold in up to 60% isolated yield over three steps. The route offers efficiency advantages over the previously reported nitro-reduction cyclisation approach to these molecules. It also provides alternative means to introduce bulky alkyl substituents at the amide nitrogen. The application of this route in the synthesis of a variety of analogues is described.     

Chemistry of diazocarbonyl compounds: XXX. Development of a synthetic approach to pyridazine structure via wittig reaction of fluoroalkyl-containing diazo keto esters

3,4,6-Trisubstituted pyridazines were synthesized from fluoroalkyl-containing diazo keto esters in three steps along two different reaction sequences: (1) Wittig, Staudinger, and diaza-Wittig and (2) Staudinger, Wittig, and diaza-Wittig. According to the first of these with the initial Wittig reaction, the yield of the target 4-fluoroalkyl-substituted pyridazines is almost twice as large as in the reaction sequence involving the corresponding N-phosphanylidene derivatives as intermediates. In both sequences, the final steps (synthesis of vinylphosphazenes and the subsequent diaza-Wittig reaction) occurred as a tandem process, and intermediate vinylphosphazenes could not be isolated. Non-fluorinated diazo keto esters and the respective phosphazenes failed to react with alkoxycarbonylmethylidene(triphenyl)phosphoranes under the same conditions.     

Solid-Phase Total Synthesis of Yaku'amide B Enabled by Traceless Staudinger Ligation

We report a solid-phase strategy for total synthesis of the peptidic natural product yaku'amide B ( 1 ), which exhibits antiproliferative activity against various cancer cells. Its linear tridecapeptide sequence bears four β,β-dialkylated α,β-dehydroamino acid residues and is capped with an N-terminal acyl group (NTA) and a C-terminal amine (CTA). To realize the Fmoc-based solid-phase synthesis of this complex structure, we developed new methods for enamide formation, enamide deprotection, and C-terminal modification. First, traceless Staudinger ligation enabled enamide formation between sterically encumbered alkenyl azides and newly designed phosphinophenol esters. Second, application of Eu(OTf)₃ led to chemoselective removal of the enamide Boc groups without detaching the resin linker. Finally, resin-cleavage and C-terminus modification were simultaneously achieved with an ester–amide exchange reaction using CTA and AlMe₃ to deliver 1 in 9.1 % overall yield (24 steps from the resin).     

Solid‐Phase Total Synthesis of Yaku'amide B Enabled by Traceless Staudinger Ligation

We report a solid‐phase strategy for total synthesis of the peptidic natural product yaku'amide B ( 1 ), which exhibits antiproliferative activity against various cancer cells. Its linear tridecapeptide sequence bears four β,β‐dialkylated α,β‐dehydroamino acid residues and is capped with an N‐terminal acyl group (NTA) and a C‐terminal amine (CTA). To realize the Fmoc‐based solid‐phase synthesis of this complex structure, we developed new methods for enamide formation, enamide deprotection, and C‐terminal modification. First, traceless Staudinger ligation enabled enamide formation between sterically encumbered alkenyl azides and newly designed phosphinophenol esters. Second, application of Eu(OTf)₃ led to chemoselective removal of the enamide Boc groups without detaching the resin linker. Finally, resin‐cleavage and C‐terminus modification were simultaneously achieved with an ester–amide exchange reaction using CTA and AlMe₃ to deliver 1 in 9.1 % overall yield (24 steps from the resin).     

Staudinger ligation of peptides at non-glycyl residues

The Staudinger ligation provides a means to form an amide bond between a phosphinothioester and azide. This reaction holds promise for the ligation of peptides en route to the total chemical synthesis of proteins. (Diphenylphosphino)methanethiol is the most efficacious of known reagents for mediating the Staudinger ligation of peptides, providing high (> 90%) isolated yields for equimolar couplings in which a glycine residue is at the nascent junction. Surprisingly, the yields are lower (< 50%) for non-glycyl couplings due to an aza-Wittig reaction that diverts the reaction toward a phosphonamide byproduct. Here, the partitioning of the reaction toward Staudinger ligation (and away from the aza-Wittig reaction) is shown to increase with increasing electron density on phosphorus. This electron density can be tuned either by installing functional groups on the phenyl substituents of (diphenylphosphino)methanethiol or by changing the polarity of the solvent. Installing p-methoxy groups and using a solvent of low polarity (such as toluene or dioxane) provide especially high (> 80%) isolated yields for the ligation of two non-glycyl residues. These conditions retain the high chemoselectivity of the reaction and do not lead to a substantial change in reaction rate. The traceless Staudinger ligation is now poised to enable the iterative ligation of peptides with little regard for their sequence, as well as the synthesis of amide bonds for other purposes.     

Synthesis and characterization of nucleobase functionalized monothiophenes

The synthesis of a series of nucleobase functionalized thiophene monomers has been accomplished through the reaction of 2-bromo-1-thiophen-3-yl-ethanone with the corresponding DNA base anion. The distinctive pK_a values for the various amine groups in the nucleobases provided a pathway for the creation of specific anions through selective deprotonation of these groups. Using the appropriate anion it is possible to create an amine linkage between the thiophene and nucleobase that is, analogous to that found between the deoxyribose sugar and nucleobase, in the biologically occurring nucleoside.     

Solution phase structures of enantiopure and racemic lithium N-benzyl-N-(α-methylbenzyl)amide in THF: low temperature 6Li and 15N NMR spectroscopic studies

The antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide are highly efficient enantiopure ammonia equivalents for the asymmetric synthesis of β-amino acid derivatives via conjugate addition to α,β-unsaturated esters. ⁶Li and ¹⁵N NMR spectroscopic studies of doubly labelled ⁶lithium (S)-¹⁵N-benzyl-¹⁵N-(α-methylbenzyl)amide in THF at low temperature reveal the presence of lithium amide dimers as the only observable species. Either a monomeric or dimeric lithium amide reactive species can be accommodated within the transition state mnemonic for this class of conjugate addition reaction. This enantiopure lithium amide offers unique opportunities over achiral (e.g., lithium dibenzylamide) and C₂-symmetric (e.g., lithium bis-N,N-α-methylbenzylamide) counterparts for further mechanistic study owing to the ready distinction of the various dimers formed.     

The synthesis of 3,4-dihydro-2-methyl-3-oxo-2H-benzo-1,4-thiazine-2-carboxylic acids

The synthesis of 3,4-dihydro-2-methyl-3-oxo-2H-benzo-1,4-thiazine-2-carboxylic acids 4a, b, 6a -e is presented. After the condensation of o-aminothiophenols with diethyl 2-bromo-2-methylmalonate in the presence of KF as a catalyst the nitrogen in the fused derivatives 3a, b , was alkylated to provide 5a-f , the corresponding esters 3a, b, 5a-f were hydrolysed.     

Synthesis of deoxy sugar esters: a chemoenzymatic stereoselective approach affording deoxy sugar derivatives also in the form of aldehyde

A chemoenzymatic synthesis of deoxy sugar esters is described. The synthesis is based on the O-alkylation of carboxylic acid with 2-bromo-5-acetoxypentanal. The method allows treatment of hydroxy carboxylic acids without protection of alcoholic hydroxyl groups. Several stereoisomeric deoxy sugar esters were resolved (up to ee or de > 98%) using a lipase-catalyzed acetylation of hemiacetals that in certain cases afforded deoxy sugar derivatives in the form of aldehydes. The stereochemistry of the reactions was determined by the NMR spectra of mandelic acid derivatives.     

Analysis of amide bond formation with an alpha-hydroxy-beta-amino acid derivative, 3-amino-2-hydroxy-4-phenylbutanoic acid, as an acyl component: byproduction of homobislactone

In the synthesis of peptidomimetics containing alpha-hydroxy-beta-amino acid, the coupling of this N(beta)-protected beta-amino acid with amine components was generally performed without the protection of its alpha-hydroxyl group. However, the formation of dipeptides in low yield was often observed when sterically hindered amine components were used. Boc-Apns-OH [Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid, allophenylnorstatine] (6), which is one of such beta-amino acid derivatives, is intensively employed as a core structure in the development of HIV-1 protease inhibitors. There have been no precise studies, to date, that have examined amide bond formation with alpha-hydroxy-beta-amino acid derivatives as an acyl component. To determine the cause of this low-yield reaction, we studied the amide bond formation focusing on the activation step of N(beta)-protected alpha-hydroxy-beta-amino acid by using a model coupling reaction between 6 and H-Dmt-OR [Dmt: (R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid] (7). A significant amount of homobislactone 9 was formed through the activation of the carboxyl group of 6 to the benzotriazole-type active esters such as OBt and OAt. In addition, this homobislactone formation was markedly increased in the presence of a catalytic amount of a base, which exhibited good correlation with the low yield of the amide bond formation, suggesting that homobislactone formation is one major reason for the low yield of the amide bond formation. Moreover, homobislactones were also formed in other derivatives of the N(beta)-protected alpha-hydroxy-beta-amino acid, suggesting a common feature of this type of amino acids. The use of a strong activation method like EDC--HOAt without base addition enhanced amide bond formation, although a small amount of homobislactone may be formed during the coupling reaction.     

Synthesis of new 3,3-dimethoxyazetidine-2-carboxylic acid derivatives

Cyclization of γ-amino-α-bromocarboxylic esters resulted in an efficient synthesis of new 3,3-dimethoxyazetidine-2-carboxylates, that is, methyl N-t-butyl-3,3-dimethoxyazetidine-2-carboxylic ester and 3,3-dimethoxyazetidine-2-carboxylic acid, or 3-bromo-4,4-dimethoxypyrrolidin-2-ones, depending on the substituent at nitrogen. Reduction of the 3,3-dimethoxyazetidine-2-carboxylates gave the corresponding 3,3-dimethoxy-2-(hydroxymethyl)azetidines. These novel cyclic amino acid derivatives, available on multigram scale, have a suitably protected carbonyl function at the 3-position, which enables further functionalization.     

Additions to non-activated alkenes: Recent advances

Non-activated olefins represent one of the most explored platform in organic synthesis affording new and useful compounds with several biological applications, among others. The typical reactivity of these compounds is the addition-type reactions. A plethora of transformations and studies were reported in the literature by many research groups. The focus of this review is to organize and describe the most recent synthetic transformations of non-activated alkenes in organic synthesis. Therefore, it is divided into five sections corresponding to each type of the products obtained: synthesis of fluoro-, chloro- and bromo-compounds; synthesis of alkyl/vinyl/aryl/heteroaryl compounds; synthesis of phospho/sulfur/silyl/cyano-compounds; synthesis of amine/amide/oxygenated compounds and synthesis of other functionalized compounds.     

Simple, chemoselective, and diastereoselective Reformatsky-type synthesis of α-bromo-α-fluoro-β-lactams

The chemoselective and diastereoselective synthesis of syn-α-bromo-α-fluoro-β-lactams was achieved using the diethylzinc-mediated Reformatsky-type reaction of ethyl dibromofluoroacetate with imines. The reaction led to diastereomerically pure β-lactams in good to moderate yields (up to 78% yield) with only small amounts of aziridine derivatives. Noncyclized 3-amino-2-bromo-2-fluoro carboxylic esters, usual Reformatsky adducts, were not formed. In contrast, reactions carried out under typical Reformatsky conditions using zinc metal were poorly chemoselective, leading to mixtures of β-lactams and aziridine derivatives.     

A concise synthesis of glycosyl-α-amino acid derivatives via homologation of dialdoses into bromo uronic acids and esters

The synthesis of the compounds of the title involves three steps from dialdoses. The reaction between potassium dibromoacetonitrile carbanion and protected dialdoses provides corresponding β-bromo-α-ketonitriles that are easily transformed into α-bromo esters by treatment with methanol or isopropanol or α-bromo acids by treatment with t-BuOH. Substitution of the bromine by sodium azide onto these last compounds and subsequent catalytic hydrogenation of the azide group afford the targeted glycosyl-α-amino acid derivatives. This methodology represents the most rapid access to the key α-amino acid moiety of polyoxins.     

Synthesis of gem-diamino derivatives on solid support

Anchoring of an α-amino-acid amide residue by its amine function to a carbamate resin followed by primary amide Hofmann rearrangement led to a gem-diamino residue linked to the resin. The generated primary amine could be acylated with various carboxylic compounds offering a large variety of molecules. Furthermore, this new solid-phase strategy allowed a reliable synthesis of a gem-diamino monomeric residue which could not be easily obtained in solution due to the limited stability of monocarbamate-protected gem-diaminoalkyl derivatives.