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A library of sphingolipid analogues is designed and tested as inhibitors against mammalian and fungal sphingolipid enzymes. The synthesis of sphingolipid analogues is based on the nucleophilic ring-opening reactions of N-activated aziridine derivatives with thiols, β-thioglycosyl thiols, phosphorothioates, phosphates, and amines to afford compounds having different lipid backbones and substituents representative of the naturally occurring sphingolipid families. The screening on mammalian sphingomyelin synthase (SMS) and glucosylceramide synthase (GCS) and yeast inositol phosphorylceramide synthase (IPCS) enzymes identified several inhibitors of GCS and IPCS, but no inhibition of SMS was observed among the tested compounds.

The reaction of vinyl bromides bearing distal olefin or acetylene functionalities with tetracarbonylnickel in the presence of alcohols and triethylamine results in the formation of exo-methylene cyclic esters in a regioselective process. High influence of the bulkiness of the alcohol is found.

A diastereoselective and mild cyclization−quenching process based on the treatment of nitrogen-tethered halodienes with stoichiometric Ni(COD)2 is described. The success of this methodology relies on the presence of a distal amino group capable of coordinating with the metal in the transient vinyl or alkylnickel species, thus controlling the diastereoselectivity of the cyclization step and preventing Ni−H β-elimination prior to the quenching. In general, better results are obtained in cyclizations taking place via a 5-exo-trig process, and a diversity of mono- and bicyclic nitrogenated systems are afforded in high yields by the proper choice of starting halodienes and quenching reagents. The presence of 2,2‘-bipyridine as a ligand results in an acceleration of the process, and in some cases, higher diastereoselectivities and/or supression of the Ni−H β-elimination are observed.

Alkynylalkoxycarbene metal complexes react readily with tetraalkoxyethylenes to give the corresponding [2 + 2] cycloadducts in high yields. From these adducts the title compounds were obtained by DMSO oxidation and final hydrolysis of the acetal groups.

The extension of the Ni(CO) 4 promoted carbonylative cycloaddition of acetylenes and allyl halides to the 5–8 membered 3-halocycloolefins leads efficiently to the formation of the corresponding 4–5 fused 2-cyclopentenones with high regio and stereoselectivities.

The reaction of 1-bromomethyl-1-cycloalkenes and acetylenes in the presence of tetracarbonylnickel affords moderate to good yields of spirocyclopentenones in a regio and stereoselective process.

The title carbonylative cycloaddition of five- to eight-member ring 3-halo- and 1-(halomethyl)cycloalkenes with different acetylenes was studied. From moderate to good yields of ring-fused and spiro cyclopentenone derivatives were obtained, especially in the reaction with acctylenes bearing electron-withdrawing substituents by propa selection of the reaction conditions to avoid the acetylene polyinsertion and/or other side reactions from the organonickel intamediates

The addition of different nucleophilic compounds (aliphatic and aromatic alcohols, thiols and phosphines) to alkynylalkoxycarbene complexes has been studied. The reaction with smaller nucleophiles proceeds readily and regioselectively at the β-carbene position. With more substituted nucleophiles the reaction rate slowed down considerably. Addition of a catalytic amount of DBU (1,8-di-azabicyclo[5.4.0]undec-7-ene]) speeded up the reaction and improved the E/Z ratio.

Stereoselective syn addition of allyl bromide to acetylenes catalysed by palladium (II) bromide results in the formation of 1-bromo-1,4-dienes which were further converted to cyclopentenones through a Ni(CO)4 promoted carbonylation-cyclization process. Four CC bonds are formed by this two step sequence, leading to 2,3-substituted 5-methoxycarbonylmethylcyclopentenones 1. Application of this procedure to 2-butyne affords cyclopentenone 1c, an immediate precursor of the antibiotic methylenomicyn B.

The [Ni(CO) 4 ]-mediated carbonylative cycloaddition of alkynes and allyl halides first reported by Chiusoli, has been reviewed, extended and optimized for application to cyclopentenone synthesis. An insight into the reaction mechanism is also given to explain the results obtained, in particular the regio- and stereo-chemistry of the process.

Reaction of different vinyl bromides ( 1a–3a ), bearing phenyl substituted alkenyloxyalkyl groups, with Ni(CO) 4 affords the corresponding substituted cyclic ethers 1b–3b in moderate to good yields and high diastereoselectivity. In the cyclization of 1a , the stereoselectivity of the process can be reversed by the use of additives, such as KOAc, TlOAc, Cs 2 CO 3 , and KOCOCF 3 .

An asymmetric approach to the Ni(CO) 4 induced alkyne-allyl halide cyclization-carbonylation process by the use of homochiral acetylenic sulfoxides to afford enantiopure [5+8] fused and spiro cyclopentenones is reported.

Different approaches to the asymmetric synthesis of cyclopentenones by means of the Ni(CO) 4 -promoted alkyne-allyl halide cyclization-carbonylation are reported. The use of acetylenic sulfoxides 1 has proved effective for the synthesis of acyclic, fused [5+8], and spiro [5+5], [5+7], and [5+8] cyclopentenones, whereas placement of the aryl sulfoxide on the allylic system failed to afford any cycloadduct. Homochiral fused [5+8], and spiro [5+7] and [5+8] cyclopentenones have been obtained by this methodology. Finally, a modest enantioselectivity was observed when different homochiral α-substituted carboxylates were used as ligands in our reaction system.

The nickel promoted tandem cyclization-quenching of tethered aminobromodienes has been extended to the synthesis of 2,3,4-trisubstituted pyrrolidines. By a judicious choice of substituents on the starting aminohalodiene, the diastereoselectivity of the process can be efficiently controlled. When a chiral auxiliary on the nitrogen atom is used, enantiomerically enriched pyrrolidines can be obtained after removal of the auxiliary.

The reaction of 2-haloethylidenecycloalkanes (ring size: 5, 6, 7, 8) with either methyl-2-butynoate or 2-butynyl methyl ether and Ni(CO)4 in methanol affords mainly two type of bicyclic compounds: 5-cycloalkenylidenecyclopent-2-enones and 5-(1-cycloalkenyl)cyclopent-2-enones. The origin for the diversion of the process towards elimination instead of alkoxycarbonylation is interpreted as the result of the mutual conformation of the two rings in the intermediates favouring either elimination through enol formation or syn β-elimination. In this last case, the terminating step can proceed in two different modes, namely, intraannularly or interannularly. While for the acetylenic ester, the product from interannular elimination is exclusive or predominant regardless of the ring size of the starting halide, for the 2-butynyl methyl ether, the product distribution is found to strongly depend on the nature of the allyl component. Thus, in this case, intraannular elimination is exclusively found in the reaction of the cyclopentylidene halide, while products from interannular elimination are produced in the reaction of the eight-member homologue. Mixtures of the two types of compound are formed from the cyclic 6 and 7 allyl halides.

A catalytic version of the intramolecular Ni-promoted tandem cyclization-cyanation process is described. Generally, the reaction leads to mixtures of cyclic and open chain adducts in moderate to good yields. The presence of external bidendate nitrogen ligands, although not essential for the reaction outcome, provides stability to the catalytic system.

A simple, efficient, and diastereoselective zinc-promoted allylation of aldehydes with enantiopure (SS)-3-chloro-2-(p-tolylsulfinyl)-1-propene [(SS)-1] under aqueous Barbier conditions is described. The observed diastereoselectivity can be explained via an acyclic antiperiplanar transition state model.

A comparative study on the allylation of aldehydes with enantiopure ( S S )-2-( p -tolylsulfonyl)-prop-2-en-1-ol ( S S )- 1a and the corresponding chloride ( S S )- 1b under two different reaction systems is reported. In general, better yields were obtained from chloride ( S S )- 1b , whereas higher diastereoinduction was observed from alcohol ( S S )- 1a . The sense of diastereoinduction is the same in both systems and the stereochemistry of the major diastereomer has been determined. Moreover, the configurational stability of the sulfoxide group on the resulting sulfinyl homoallylic alcohols 3 has been proven in each reaction system, which demonstrates the efficiency of the sulfoxide group as chiral auxiliary in these allylation processes. Finally, as an example of the synthetic potential of the resulting adducts, a total synthesis of natural enantioenriched ( S )-nicotine from sulfinylalcohol 3h is reported.

A simple solution-phase protocol for the synthesis of ceramide analogues from easily accessible enantiopure scaffolds is disclosed. The method relies on the use of nucleophilic thiolates or phenoxides and appropriate supported reagents or scavengers to give the target compounds in good overall yields. The method is easily adaptable to combinatorial protocols and also amenable to automated processes for the generation of small-to-medium-sized libraries for further screening.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

A straightforward approach for the synthesis of a new series of amino phosphates structurally related to sphingosine‐1‐phosphate is described. The commercial availability of the required starting building blocks, the reduced number of steps, and the ease of purification of the intermediate and final compounds make the approach amenable to combinatorial protocols.

A versatile method for the synthesis of carbamates from an ‘in-situ’ generated polymer-supported chloroformate resin is presented. BTC (bis-trichloromethyl carbonate) is used as phosgene equivalent to afford a supported chloroformate, which, by sequential ‘one-pot’ reaction with a variety of alcohols and amines, furnishes the corresponding carbamates in high yields and purities.