A facile protocol for N-Cbz protection of amines in PEG-600

正An efficient and eco-friendly protocol for the chemoselective N-benzyloxycarbonylation of amines was described.The reaction of amines with benzyl chloroformate(Cbz-Cl) in the presence of PEG-600 at room temperature afforded the corresponding N-Cbz derivatives in excellent yields.The method is applicable to the N-Cbz protection of aliphatic(acyclic and cyclic) and aromatic amines.     

Facile synthesis of optically active imidazole derivatives

Five optically active imidazole derivatives have been synthesized via a facile 4-step reaction sequence starting from commercially available and inexpensive N-Cbz amino acids. While microwave assisted condensation was unsuccessful, the condensation of the corresponding alpha-bromoketones with formamidine acetate in liquid ammonia was revealed to be a useful method for the synthesis of such imidazole derivatives. The derivatives thus prepared are structurally-related to histamine.     

First practical protection of alpha-amino acids as N,N-benzyloxycarbamoyl derivatives

The consecutive treatment of N-Cbz amino protected compounds with LiHMDS and CbzCl provides a practical method for the preparation of N,N-benzyloxycarbamoyl (N,N-di-Cbz) derivatives in good yield. When alpha-amino acids are used the protection occurs without racemization. The method is compatible with a wide range of other functional and protecting groups. The procedure is also valid for the synthesis of mixed N,N-carbamoyl derivatives.     

Access to NH-aziridine-2-carboxamides through Davidsen acylimidodicarbonate activation

Acylimidodicarbonates obtained from aziridine-2-carboxamides through Davidsen bis-Boc activation react with amine nucleophiles under mild conditions to form tertiary aziridine-2-carboxylic acid amides. NH aziridine-2-carboxylic acid amides were obtained by hydrogenolythic deprotection of N-Cbz derivatives.     

Pd/C-catalyzed chemoselective hydrogenation in the presence of a phenolic MPM protective group using pyridine as a catalyst poison

Employment of a Pd/C-pyridine combination as a catalyst is a very useful method for the selective removal (hydrogenolysis) of phenolic O-benzyl, N-Cbz and benzyl ester protective groups and for the selective hydrogenation of nitro and olefin functions of phenol derivatives protected with the MPM group. These discriminatory results are apparently attributable to the effect of pyridine. The MPM group could be extensively applied to chemoselective hydrogenation as a protective group for phenolic hydroxyl functions.     

Enantioselective total synthesis of (+)-azimine and (+)-carpaine

[reaction: see text] The enantioselective total syntheses of (+)-azimine and (+)-carpaine have been developed, starting with (S)-1,2,4-butanetriol as a single source of chirality. The key common feature in these syntheses involves stereoselective intramolecular hetero-Diels-Alder reaction of an acylnitroso compound. The critical macrocyclic dilactonization of the N-Cbz derivatives of azimic acid and carpamic acid was efficiently achieved by using the Yamguchi macrocyclization conditions.     

N-carbamate protected alpha-amidoalkyl-p-tolylsulfones: convenient substrates in the aza-Morita-Baylis-Hillman reaction

An efficient and practical one-pot approach to aza-Morita-Baylis-Hillman adducts has been developed. The reaction occurs between N-Boc or N-Cbz imines, generated in situ from stable and easy to handle N-Boc or N-Cbz protected alpha-amidoalkyl-p-tolylsulfones, and electron-deficient alkenes in the presence of DABCO. The presented procedure eliminates the use of the relatively unstable N-carbamate imines prior to the coupling reaction. The reaction is limited to alpha-amidosulfones derived from aromatic and heteroaromatic aldehydes.     

Organocatalytic asymmetric Mannich reactions with N-Boc and N-Cbz protected alpha-amido sulfones (Boc: tert-butoxycarbonyl, Cbz: benzyloxycarbonyl)

Different malonates and beta-ketoesters can react with N-tert-butoxycarbonyl- (N-Boc) and N-benzyloxycarbonyl- (N-Cbz) protected alpha-amido sulfones in an organocatalytic asymmetric Mannich-type reaction. The reaction makes use of a simple and easily obtained phase-transfer catalyst and proceeds under very mild and user-friendly conditions. The optimised protocol avoids the preparation and the isolation of the relatively unstable N-Boc and N-Cbz imines that are generated in situ from the bench-stable alpha-amido sulfones. The corresponding Mannich bases are generally obtained in good yields and enantioselectivities, and can be readily transformed into key compounds, such as optically active beta3-amino acids in one easy step. Enantioenriched N-Boc and N-Cbz protected beta-amino acids that are suitable for peptide synthesis are also available from the Mannich adducts through simple manipulations. Control experiments showed the dual role of the enolate-catalyst ion pair in this reaction, as well as the crucial role of the presence of water to achieve high enantioselectivities.     

Alpha-N-acetylmannosamine (ManNAc) synthesis via rhodium(II)-catalyzed oxidative cyclization of glucal 3-carbamates

[reaction: see text] Glucal 3-carbamates 1 and 7 underwent oxidative cyclization with iodobenzene diacetate or iodosobenzene in the presence of Rh2(OAc)4, providing mannosamine 2-N,3-O-oxazolidinones. With iodosobenzene, incorporation of 4-penten-1-ol provided a readily separable anomeric mixture of n-pentenyl glycosides, with the anomers exhibiting pronounced differences in reactivity as glycosyl donors. N-acylation of the sugar oxazolidinones led to alpha-selective glycosyl donors for the elaboration of various 2-mannosamine frameworks. Alternatively, the anomeric n-pentenyl glycosides of N-Cbz 2-mannosamine oxazolidinones were converted separately to oxazolidinone-opened derivatives 28alpha and 28beta. These served as stereoconvergent glycosyl donors, and the alpha-linked products were readily advanced to a variety of N-acetylmannosamine (ManNAc) frameworks, using an intramolecular O-->N acetyl transfer as the final step.     

A mild and convenient synthesis of N-carbobenzyloxy ketimines

N-Carbobenzyloxy (Cbz) ketimines were prepared conveniently from N-Cbz amines by oxidation with N-tert-butylbenzenesulfinimidoyl chloride.     

Stereoselective aldol additions catalyzed by dihydroxyacetone phosphate-dependent aldolases in emulsion systems: preparation and structural characterization of linear and cyclic iminopolyols from aminoaldehydes

The potential of dihydroxyacetone phosphate (DHAP)-dependent aldolases to catalyze stereoselective aldol additions is, in many instances, limited by the solubility of the acceptor aldehyde in aqueous/co-solvent mixtures. Herein, we demonstrate the efficiency of emulsion systems as reaction media for the class I fructose-1,6-bisphosphate aldolase (RAMA) and class II recombinant rhamnulose-1-phosphate aldolase from E. coli (RhuA)-catalyzed aldol addition between DHAP and N-benzyloxycarbonyl (N-Cbz) aminoaldehydes. The use of emulsions improved the RAMA-catalyzed aldol conversions by three to tenfold relative to those in conventional DMF/water mixtures. RhuA was more reactive than RAMA towards the N-Cbz aminoaldehydes regardless of the reaction medium. With (S)- or (R)-Cbz-alaninal, RAMA exhibited preference for the R enantiomer, while RhuA had no enantiomeric discrimination. The linear N-Cbz aminopolyols thus obtained were submitted to catalytic intramolecular reductive amination to afford the corresponding iminocyclitols. This reaction was diastereoselective in all cases examined; the face selectivity was controlled by the stereochemistry of the newly formed hydroxyl group originating from the aldehyde. Characterization of the resulting iminocyclitols allowed the assessment of the diastereoselectivity of the enzymatic aldol reactions with respect to the N-protected aminoaldehyde. RAMA formed single diastereoisomers from N-Cbz-glycinal and from both enantiomers of N-Cbz-alaninal, while 14 % of the epimeric product was observed from N-Cbz-3-aminopropanal. Diastereoselectivity from RhuA was lower than that observed from RAMA. Interestingly, a single diastereoisomer was formed from (S)-Cbz-alaninal, whereas only a 34 % diastereomeric excess was observed from its enantiomer (i.e., (R)-Cbz-alaninal).     

Serine hydroxymethyl transferase from Streptococcus thermophilus and L-threonine aldolase from Escherichia coli as stereocomplementary biocatalysts for the synthesis of beta-hydroxy-alpha,omega-diamino acid derivatives

A novel serine hydroxymethyl transferase from Streptococcus thermophilus (SHMT) and a L-threonine aldolase from Escherichia coli (LTA) were used as stereocomplementary biocatalysts for the aldol addition of glycine to N-Cbz amino aldehydes and benzyloxyacetaldehyde (Cbz=benzyloxycarbonyl). Both threonine aldolases were classified as low-specific L-allo-threonine aldolases, and by manipulating reaction parameters, such as temperature, glycine concentration, and reaction media, SHMT yielded exclusively L-erythro diastereomers in 34-60 % conversion, whereas LTA gave L-threo diastereomers in 30:70 to 16:84 diastereomeric ratios and with 40-68 % conversion to product. SHMT is among the most stereoselective L-threonine aldolases described. This is due, among other things, to its activity-temperature dependence: at 4 degrees C SHMT has high synthetic activity but negligible retroaldol activity on L-threonine. Thus, the kinetic L-erythro isomer was largely favored and the reactions were virtually irreversible, highly stereoselective, and in turn, gave excellent conversion. It was also found that treatment of the prepared N-Cbz-gamma-amino-beta-hydroxy-alpha-amino acid derivatives with potassium hydroxide (1 m) resulted in the spontaneous formation of 2-oxazolidinone derivatives of the beta-hydroxyl and gamma-amino groups in quantitative yield. This reaction might be useful for further chemical manipulations of the products.     

A facile direct anti-selective catalytic asymmetric Mannich reaction of aldehydes with preformed N-Boc and N-Cbz imines

Anti-selective Mannich reactions of N-Boc and N-Cbz protected imines with unmodified aldehydes proceeded smoothly under the catalysis of a secondary amine-thiourea catalyst, which led to high yields (70%-95%) and excellent enantioselectivity (up to 96 : 4 dr and >99% ee) under conventional organic synthetic operations.     

Convergent and stereoselective synthesis of iminosugar-containing Galf and UDP-Galf mimicks: evaluation as inhibitors of UDP-Gal mutase

The synthesis of a UDP-Galf analog incorporating a 1,4-dideoxy-1,4-imino-d-galactitol skeleton alpha-linked to UMP by a 3C-tether and of a series of related pyrrolidine galactofuranose mimicks is reported. These compounds were obtained by way of the highly stereoselective reaction of silylated nucleophiles with a N-Cbz glucofuranosylamine which afforded the corresponding open-chain product with a 1,2-syn stereochemistry, as predicted from pionneering studies from Kobayashi. Cyclization of these intermediates afforded alpha-C-glycosides of imino-galactofuranose carrying various functional groups in the aglycone. Further elaboration of the alpha-C-allyl substituted derivative by cross-metathesis with a uridin-5'-yl vinylphosphonate provided, after deprotection, the desired original UDP-Galf mimicks. Cleavage of the benzyl ether protecting groups in the iminosugar component using BCl3 proved critical to the success of the synthetic plan. Several of the new 1,4-dideoxy-1,4-imino-d-galactitol derivatives were evaluated as inhibitors of UGM (UDP-galactopyranose mutase) from Escherichia coli; however, none of them exhibited less than mM activities toward this enzyme which catalyzes a crucial step of the biosynthesis of galactofuranose-containing bacterial cell-surface glycans.     

First stereocontrolled synthesis of (S)-cleonin and related cyclopropyl-substituted amino acids

[reaction: see text]. Enantiomerically pure (S)-cleonin, a key component of the antitumor antibiotic cleomycin, was prepared starting from (R)-serine. The Kulinkovich cyclopropanation of the methyl ester of N-Cbz serine acetonide gave the hydroxycyclopropyl moiety. The amino alcohol region was further oxidized to amino acid. The Kulinkovich cyclopropanation allowed also the preparation of other non-natural substituted cyclopropylglycines.     

Fischer indole synthesis in low melting mixtures

Functionalized indoles are synthezised under mild conditions in a tartaric acid-dimethylurea melt. The melt serves as the solvent and as the catalyst. Under these reaction conditions, sensitive functional groups such as N-Boc, N-Cbz, or azides are stable, and indolenines are obtained regioselectively in excellent yields. The practical use of the method is demonstrated in the synthesis of the hormone melatonin.     

Pd/C-catalyzed chemoselective hydrogenation in the presence of diphenylsulfide

[Structure: see text] A Pd/C-catalyzed chemoselective hydrogenation using diphenylsulfide as a catalyst poison has been developed. This methodology selectively hydrogenates olefin and acetylene functionalities without hydrogenolysis of aromatic carbonyls and halogens, benzyl esters, and N-Cbz protective groups.     

Direct enantio- and diastereoselective Mannich reactions of malonate and beta-keto esters with N-Boc and N-Cbz aldimines catalysed by a bifunctional cinchonine derivative

A highly enantioselective Mannich reaction between malonate esters and N-Boc and N-Cbz aldimines, catalysed by a bifunctional cinchonine derivative, has been developed; extension of this methodology to encompass the use of 2-substituted-1,3-dicarbonyl nucleophiles allows the formation of adjacent stereocentres, one of which is quaternary, in high relative and absolute stereocontrol.     

Total synthesis of the alkaloids martinelline and martinellic acid via a hetero Diels-Alder multicomponent coupling reaction

[reaction: see text] A concise synthesis of the guanidine alkaloids, (+/-)-martinelline and (+/-)-martinellic acid, using a protic acid catalyzed 2:1 hetero Diels-Alder coupling reaction between N-Cbz 2-pyrroline and methyl 4-aminobenzoate, is described. Protic acid catalysis, rather than Lewis acid catalysis, was necessary to achieve the desired sense of diastereocontrol in the coupling reaction.     

Solid-phase synthesis of 1,3-azole-based peptides and peptidomimetics

[reaction: see text] We report highly efficient two-step procedures for the synthesis of 1,3-oxazole-, thiazole-, and imidazole-containing peptides on solid phase from dipeptides composed of C-terminal threonine, serine, cysteine, or diaminopropionic acid by using different cyclodehydration procedures followed or preceded by oxidation. The methods are compatible with Fmoc solid-phase peptide synthesis conditions and with N-Fmoc, N-Boc, N-Cbz, and N-Alloc protecting groups.