N-Boc Deprotection Research Articles

Synthesis of cyclopropene analogues of ceramide and their effect on dihydroceramide desaturase.

The synthesis of several analogues of the N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide (GT11), the first reported inhibitor of dihydroceramide desaturase, as well as their effects on this enzyme, are described. Modifications of the parent structure include variations on the cyclopropene ring, the N-acyl chain length, the configuration of the stereocenters, and the hydroxyl group at C1. The key intermediates for the synthesis are the products resulting from the addition of suitable organolithium compounds to either Garner's aldehyde or its enantiomer. The final products are obtained by TMSTf-induced cleavage of the protecting groups and N-acylation, both under specific conditions. An alternative method for N-Boc deprotection is also reported that allows us to obtain the cyclopropene analogue of sphingosine 12a, which can be transformed into GT11 upon acylation. The procedure consists of the conversion of the Garner aldehyde addition products into the bicyclic dihydrooxazolo[3,4,0]oxazol-3-ones 19 by transesterification in basic medium of the tert-butyl group with the hydroxyl function at C3. Mild cleavage of the N,O-isopropylidene cyclic acetal present in 19 affords the oxazolidin-2-one 20, which gives 12a upon saponification. Furthermore, compound 20 is also the key intermediate in the synthesis of the terminal deoxy, methoxy, and fluoro derivatives 9, 10, and 11, respectively. Determination of dihydroceramide desaturase activity in vitro showed that GT11 was a competitive inhibitor (Ki = 6 microM) and that its analogues with N-hexanoyl (6) and N-decanoyl (7) moieties inhibited the enzyme with similar potencies (IC50 = 13 and 31 microM, respectively). No decrease in dihydroceramide desaturase activity was observed with any of the other compounds tested.

Coupling Reactions of α‐(N‐Carbamoyl)alkylcuprates with Enol Triflates Derived from Cyclic β‐Keto Esters: A Facile Approach to γ‐Carbamoyl‐α,β‐enoates.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of (.+‐.)‐Isoretronecanol, (.+‐.)‐Curassanecine, (.+‐.)‐Heliotridane, (.+‐.)‐Tashiromine and (.+‐.)‐5‐Epitashiromine via α‐(N‐Carbamoyl)alkylcuprate Chemistry.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Coupling reactions of alpha-(N-carbamoyl)alkylcuprates with enol triflates derived from cyclic beta-keto esters: A facile approach to gamma-carbamoyl-alpha,beta-enoates.

alpha-(N-Carbamoylalkyl)cuprates couple with enol triflates derived from carbocyclic and heterocyclic (i.e., piperidinones) beta-keto esters. Product yields are higher with the alkyl(cyano)cuprates [i.e., RCu(CN)Li, 56-93%] than with the dialkylcuprate reagents (i.e., R(2)CuLi.LiCN). An enol nonaflate works as well as the corresponding enol triflate. A facile synthetic route to gamma-amino alpha,beta-enoates not readily prepared from gamma-keto-alpha,beta-enoates is thus established. The gamma-amino-alpha,beta-enoates, available via N-Boc deprotection, can be cyclized to annulated pyrrolin-2-ones.

Synthesis of (±)-isoretronecanol, (±)-curassanecine, (±)-heliotridane, (±)-tashiromine and (±)-5-epitashiromine via α-( N-carbamoyl)alkylcuprate chemistry

Vinylation of N-Boc-2-pyrrolidinylcuprate reagents with functionalized vinyl iodides followed by N-Boc deprotection and cyclization affords 1-methylidine pyrrolizidine and indolizidine carbon skeletons. Functional group manipulation of the exo-cyclic olefin provides direct synthetic entries to the pyrrolizidine alkaloids (±)-isoretronecanol, (±)-curassanecine, (±)-heliotridane or the indolizidine alkaloids (±)-tashiromine and (±)-epitashiromine. This synthetic approach to pyrrolizidine and indolizidine alkaloids requires masking of the tertiary amine during functional group interconversions involving the alkene functionality.

α-(N-Carbamoyl)alkylcuprate Chemistry in the Synthesis of Nitrogen Heterocycles

The conjugate adducts obtained via coupling of alpha-(N-carbamoyl)alkylcuprates with alpha,beta-ynoates, alpha-allenyl esters, or alpha.beta-enoates or enimides undergo N-Boc deprotection and cyclization onto the ester functionality upon treatment with PhOH/TMSCl, catecholboron bromide, or trimethylsilyl triflate. This two-pot sequence provides synthetic routes to 4-alkylidinepyrrolidine-2-ones, 4-alkylidinepyrrolizidin-2-ones, and 4-alkylidineindolizidin-2-ones via allenyl esters; pyrrolin-2-ones, tetrahydropyrrolizin-2-ones, and tetrahydroindolizin-2-ones via alpha/beta-ynoates; pyrrolidin-2-ones, pyrrolizidin-2-ones, and indolizidin-2-ones via alpha,beta-enoates or alpha.beta-enimides. The reluctance of gamma-carbamoyl-alpha,beta-enoates to undergo E/Z isomerization requires the use of (Z)-beta-iodo-alpha,beta-enoates readily prepared by the addition of HI to the alkynyl esters for the efficient preparation of pyrrolinones, tetrahydropyrrolizinones, and tetrahydroindolizinones. Utilization of omega-functionalized alpha,eta-ynoates or beta-iodo-alpha,beta-enoates allows for cyclization onto the omega-functionality providing for a synthetic route to quinolizidines.

A mild and selective method for N-Boc deprotection

A new mild method to remove N- tert-butyloxycarbonyl groups using TBAF in refluxing THF is reported. In all cases, the corresponding N-free products are obtained in good yields. The reactions are selective for acid- and base-sensitive groups, such as tert-butyl and alkyl esters, aldehydes.

Synthesis of 3-pyrrolines, annulated 3-pyrrolines, and pyrroles from alpha-amino allenes.

Alpha-amino allenes, readily prepared from reaction of alpha-(N-carbamoyl)alkylcuprates with propargyl substrates followed by N-Boc deprotection, are converted in high yields to pyrrolines with AgNO(3). Palladium-catalyzed cyclization of amino allenes affords either the pyrroline or the pyrrole depending on reaction conditions and provides for introduction of an aryl substituent at the C-3 position of the pyrroline or pyrrole. Enantioenriched pyrrolines are readily prepared from scalemic propargyl alcohols. [reaction: see text]

A Method for Selective N-Boc Deprotection on Wang Resin

A Method for Selective N-Boc Deprotection on Wang Resin

A convenient route to N-alkyl-2-tributylstannyl-pyrrolidines involving reductive amination

A new and convenient method for the formation of N-alkyl-2-tributylstannyl-pyrrolidines from N-Boc-2-tributylstannyl-pyrrolidine has been developed. The procedure uses N-Boc deprotection, followed by rapid base wash and reductive amination with an aldehyde and NaBH 3CN in nitromethane.