Ferrier Glycosylation Mediated by the TEMPO Oxoammonium Cation.

The TEMPO oxoammonium cation has been proven to be both an efficient oxidizing reagent and an electrophilic substrate frequently found in organic reactions. Here, we report that this versatile chemical reagent can also be used as an efficient promoter for C- and N-glycosylation reactions through a Ferrier rearrangement with moderate to high yields. This unprecedented reactivity is explained in terms of a Lewis acid activation of glycal by TEMPO forming a type of glycal-TEMPO mesomeric structure, which occurs through an extended vinylogous hyperconjugation toward the π* orbital [LP → π*, π* → σ*, and LP → π*].

β-Alkenylation of Saturated -Heterocycles via a C(sp)-O Bond Wittig-like Olefination.

Although the C-H functionalization of -heterocycles is, in fact, an easy chemical transformation, the C-H functionalization is, on the contrary, a quite difficult chemical process. Here, we present a two-step protocol that allows the ready conversion of pyrrolidines, piperidines, and an azepane into their corresponding 3--alkenyl lactams via the transient formation of 3-alkoxyamino lactams followed by a Wittig-like C(sp)-O bond olefination with stabilized ylides from phosphonium salts mediated by -BuOK. Additionally, as a proof of the synthetic effectiveness of this novel methodology, the first synthesis of the natural product callylactam A was achieved through a TiCl-catalyzed double bond isomerization of a 3--alkenyl 2-piperidone to its isomer.

En Route to Furan-Fused Naphthopyrones: Formal Synthesis of the (+)-Lasionectrin and Its C12-Epimer.

Despite the vast presence of the furan-fused naphthopyrone (FFN) skeleton in many bioactive natural products, such as lasionectrin, at present, a general approach to FFNs has not been developed yet. For that reason, a simple and straightforward synthetic approach consisting of a sequential procedure of a Diels-Alder reaction between 1,3-dimethoxy-benzocyclobutenol and furan-fused-α,β-unsaturated-δ-lactones (via an ο-quinodimethane intermediate ) followed by an oxidative aromatization of the corresponding Diels-Alder adduct is reported. Subsequently, the formal synthesis of the (+)-lasionectrin and its C12-epimer was achieved, the latter in only six steps.

Accelerated Dimerization of α,β-Unsaturated D--Hexofurano-5-ulose Derivatives through Asynchronous Hetero-Diels-Alder Reaction.

While some hetero-Diels-Alder (HDA) reactions are accelerated by either carbonyl or phosphate groups attached directly to the heterodiene moiety, the alkyl or aryl groups, on the other hand, have minimal influence. However, in this article, we demonstrate that aryl groups have a significant effect on the spontaneous dimerization reaction of α,β-unsaturated D-xylo-hexofurano-5-ulose derivatives to their respective pyrano adducts via intermolecular HDA reaction. Experimental and computational studies provide strong evidence that dimerization follows the Woodward-Katz two-stage mechanism reaction (asynchronous process), from which the aryl/aryl π-stacking interaction is mainly responsible for the rate-determining step (RDS) and electrostatic interaction for the second bond formation.

Stereoselective Synthesis and Antiallodynic Activity of 3-Hydroxylated Paroxetines.

The design, stereoselective synthesis and in vivo antiallodynic activity of four novel paroxetine analogs, named 3-hydroxy paroxetines (3HPXs), is reported herein. Among the novel synthesized compounds, three showed an antiallodynic effect, while (R,R)-3HPX was found to be 2.5 times more bioactive than (-)-paroxetine itself in neuropathic rats.

Transition-Metal-Free Multiple Functionalization of Piperidines to 4-Substituted and 3,4-Disubstituted 2-Piperidinones.

Remote and multiple functionalization of piperidines without the use of transition-metal catalysts and elaborate directing groups is one of the major challenges in organic synthesis. Herein is reported an unprecedented two-step protocol that enables the multiple functionalization of piperidines to either 4-substituted or trans-3,4-disubstituted 2-piperidones. First, by exploiting the duality of TEMPO reactivity, which under oxidative and thermal conditions fluctuates between cationic and persistent-radical form, a novel multiple C(sp )-H oxidation of piperidines to α,β-unsaturated 2-piperidones was developed.

Transition-Metal-Free Deconstructive Lactamization of Piperidines.

One of the major challenges in organic synthesis is the activation or deconstructive functionalization of unreactive C(sp )-C(sp ) bonds, which requires using transition or precious metal catalysts. We present here an alternative: the deconstructive lactamization of piperidines without using transition metal catalysts. To this end, we use 3-alkoxyamino-2-piperidones, which were prepared from piperidines through a dual C(sp )-H oxidation, as transitory intermediates.

Selective, Catalytic, and Dual C(sp)-H Oxidation of Piperazines and Morpholines under Transition-Metal-Free Conditions.

By using cheap and innocuous reagents, such as NaClO, NaOCl, and catalytic amounts of TEMPO, a new environmentally friendly protocol for the selective and catalytic TEMPO C(sp)-H oxidation of piperazines and morpholines to 2,3-diketopiperazines (2,3-DKP) and 3-morpholinones (3-MPs), respectively, has been developed. This novel direct access to 2,3-DKP from piperazines provides significant advantages over the traditional N-monoacylation/intramolecular C-N cyclization procedure. Additionally, by modulating the amounts of TEMPO, 2-alkoxyamino-3-morpholinone can be prepared from morpholine derivatives, which would enable further functionalization at the C2 position of the morpholine skeleton.

The direct and highly diastereoselective synthesis of 3,4-epoxy-2-piperidones. Application to the total synthesis and absolute configurational assignment of 3α,4α-epoxy-5β-pipermethystine.

The substrate-controlled asymmetric total synthesis and absolute configurational assignment of biologically active 3α,4α-epoxy-5β-pipermethystine, a minor component in the aerial parts of kava, has been achieved by featuring, as a key step, the environmentally friendly and direct synthesis of 2,3-epoxyamides from allyl amines. By using the chiron approach, first a carbohydrate-derived dehydropiperidine was prepared and subjected to a stereoselective tandem C-H/C[double bond, length as m-dash]C oxidation reaction. In this attempt, the required α,α-trans-epoxy-2-piperidone skeleton of the kava metabolite precursor was not achieved, although the tandem oxidation was highly stereoselective.

Transition Metal-Free Selective Double sp(3) C-H Oxidation of Cyclic Amines to 3-Alkoxyamine Lactams.

The first chemical method for selective dual sp(3) C-H functionalization at the alpha-and beta positions of cyclic amines to their corresponding 3-alkoxyamine lactams is reported. Unlike traditional Cα-H oxidation of amines to amides mediated by transition metals, the present protocol, which involves the use of NaClO2/TEMPO/NaClO in either aqueous or organic solvent, not only allows the Cα-H oxidation but also the subsequent functionalization of the unreactive β-methylene group in an unprecedented tandem fashion and using environmentally friendly reactants.

Synthesis of the Enantiomers of Tedanalactam and the First Total Synthesis and Configurational Assignment of (+)-Piplaroxide.

Highlighting the recently established methodology for the direct synthesis of glycidic amides from tertiary allyl amines, the synthesis of the enantiomers of tedanalactam were completed in two steps from the corresponding chiral dihydropiperidine. Additionally, the (+)- and (-)-enantiomers of piplaroxide were obtained from their respective tedanalactam precursor, and the absolute configuration of the naturally occurring (+)-piplaroxide was determined. The present approach represents not only the shortest synthesis of (-)-tedanalactam but also the first total synthesis of (+)-piplaroxide, a repellent against the leafcutter ant Atta cephalotes.

The Stabilizing Role of the Intramolecular C-H···O Hydrogen Bond in Cyclic Amides Derived From α-Methylbenzylamine.

A series of five-, six-, seven-, and eight-membered lactams containing the chiral auxiliary α-methylbenzylamine were structurally analyzed and further studied by DFT calculations with the purpose to examine with detail the previously detected intramolecular C-H···O hydrogen-bonding interaction formed between the hydrogen atom of the α-methylbenzylamine and the carbonyl group of the cyclic amide. The main objective was to establish whether its presence does have a tangible relevance in their spatial arrangement in solution and in the solid state or is a simple and not stabilizing interaction.

Total synthesis of cephalosporolide E via a tandem radical/polar crossover reaction. The use of the radical cations under nonoxidative conditions in total synthesis.

The present work reports the first example of the use of the chemistry of radical cations under nonoxidative conditions in total synthesis. Using a late-stage tandem radical/polar crossover reaction, a highly stereoselective total synthesis of cephalosporolide E (which is typically obtained admixed with cephalosporolide F) was accomplished. The reaction of a phthalimido derivative with triphenyltin radical in refluxing toluene engenders a contact ion-pair (radical cation) that leads, in the first instance, to the cephalosporolide F, which is transformed into the cephalosporolide E via a stereocontrolled spiroketal isomerization promoted by the diphenylphosphate acid that is formed during the tandem transformation.

Further evidence on the favorable role of the anomeric effect on the cleavage of HepDirect and cyclophosphamide prodrugs.

On the basis of previous conformational and configurational studies of 4-aryl-substituted cyclophosph(on)ates derived from d-xylofuranose derivatives, wherein it was proposed that the anomeric effect is involved in the spontaneous isomerization of the P atom and the C4 carbon, and consequently, this unusual behavior was associated with the cleavage of the HepDirect prodrugs. We synthesized an analogous series of 2-amino-2-oxo-1,3,2-dioxaphosphorinanes and performed a conformational and configurational analysis in solution and the solid state followed by an examination of their mutagenic activity. The results showed that the 2-amino-2-oxo-1,3,2-dioxaphosphorinanes with the largest mutagenic activity contain either a 4-methoxyphenyl or 4-fluorophenyl group at C4 carbon and presented a major chair conformation, which is prone to weaken the C4-O3 bond via the anomeric effect and facilitates the cleavage for the release of the biologically active metabolite.

β-Oxygen effect in the Barton-McCombie deoxygenation reaction: further experimental and theoretical findings.

The chemistry of (S)-methyl xanthates derived from xylo- and ribo-furanose derivatives in the presence of the stannyl radical is investigated. Xanthate derived from β-xylo-furanose affords exclusively a deoxygenated product; whereas, under the same reaction conditions, the α-ribo-furanose xanthate derivative produces quantitatively a hemithioacetal compound. We reasoned that in the case of the β-xylo-furanose derivative, a favorable β-oxygen effect in the Barton-McCombie deoxygenation reaction is operating where, according to theoretical calculations, unusual molecular orbital interactions (and not strain, as previously proposed) are present.

Direct chemical method for preparing 2,3-epoxyamides using sodium chlorite.

A direct method for preparing 2,3-epoxyamides from tertiary allylamines via a tandem C-H oxidation/double bond epoxidation using sodium chlorite is reported. Apparently, the reaction course consists of two steps: (i) allylic oxidation of the starting allylamine to corresponding unsaturated allylamide with sodium chlorite followed by (ii) epoxidation of the allylamide to the 2,3-epoxyamide mediated by hypochlorite ion, which is formed in situ by reduction of sodium chlorite. The reaction conditions tolerate the presence of free hydroxyl groups and typical functional groups such as TBS, aryl, alkyl, allyl, acetyl, and benzyl groups; however, when an activated aromatic ring (e.

High 1,3-trans stereoselectivity in nucleophilic substitution at the anomeric position and β-fragmentation of the primary alkoxyl radical in 3-amino-3-deoxy-ribofuranose derivatives: application to the synthesis of 2-epi-(-)-jaspine B.

The high inverse stereoselectivity in the nucleophilic substitution at the anomeric position of 3-amino-3-deoxy-ribofuranose derivatives is reported. This unprecedented stereoselectivity is explained in terms of preferential nucleophilic attack on the "inside face" of the respective five-membered ring oxocarbenium ion that orients pseudoequatorially to the benzylamine group placed at the C-3 position. In addition, an unusual β-fragmentation of a primary alkoxyl radical generated from its corresponding N-phthalimide derivative was achieved, and thus taking advantages of both reactions, the total synthesis of 2-epi-(-)-jaspine B was completed.

On the existence of the chair conformation in six-membered ring phosphates bearing an aryl group axially oriented at the C4 position: cyclic nucleotides as model compounds for cyclic phosph(on)ate and phosphoramide prodrugs.

A series of cyclic nucleotide analogues to HepDirect prodrugs were prepared by a three-component reaction of protected thymine, phosphoryl chloride, and 5-aryl-alpha-D-xylofuranoses derivatives. One of the cyclic nucleotides showed NMR data that suggest a predominant twisted conformation; however, in spite of having an aryl group at the C4 position within the crystal lattice, the cyclic nucleotide had a chair conformation with the aryl group axially oriented. By analyzing the unprecedented X-ray structure, it was observed that the oxygen atom from the phoshoryl group (P=O) is found in close proximity to the o-hydrogen atom of the aryl group (2.

5-Fluoro-1-[(4S,5R)-5-(2-hydroxy-ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]pyrimidine-2,4(1H,3H)-dione.

In the title compound, C(11)H(15)FN(2)O(5), the five-membered ring has an envelope conformation, while the six-membered ring is essentially planar, with a maximum deviation of 0.032 (2) Å from the mean plane. The crystal packing is stabilized by inter-molecular N-H⋯O and O-H⋯O hydrogen bonds, generating a layer structure parallel to (001).

Six-membered ring phosphates and phosphonates as model compounds for cyclic phosphate prodrugs: is the anomeric effect involved in the selective and spontaneous cleavage of cyclic phosphate prodrugs?

In recent years, several six-membered ring phosph(on)ates and phosphonamides have been reported as potent prodrugs against liver diseases such as hepatitis B and C and also as antitumor agents. Apparently, the success for their biological activity depends on the selective cleavage of the C4-O3 bond within the respective P-heterocyclic ring. Empirical observations have suggested that the group attached to the C4 position (aryl or pyridyl group) is responsible for the selective cleavage.

Beneficial effect of internal hydrogen bonding interactions on the beta-fragmentation of primary alkoxyl radicals. Two-step conversion of D-xylo- and D-ribofuranoses into L-threose and D-erythrose, respectively.

Primary alkoxyl free radicals were generated from their readily synthesized N-phthalimido derivatives under reductive conditions. Primary alkoxyl radicals derived from their corresponding xylo- and ribofuranose derivatives underwent, exclusively, an unusual beta-fragmentation affording L-threose and D-erythrose derivatives, respectively. This occurs because the alkoxyl radical is capable of achieving an internal hydrogen-bonding interaction leading to a stable six-membered ring intramolecular hydrogen-bonded structure.

Determination of the enantiomeric excess of chiral carboxylic acids by 31P NMR with phosphorylated derivatizing agents from C2-symmetrical diamines containing the (S)-alpha-phenylethyl group.

The use of P(III) and P(V) organophosphorus derivatizing agents prepared from C(2) symmetrical (1R,2R)- and (1S,2S)-trans-N,N'-bis-[(S)-alpha-phenylethyl]-cyclohexane-1,2-diamines 1 and 2, as well as (1R,2R)- and (1S,2S)-trans-N,N'-bis-[(S)-alpha-phenylethyl]-4-cyclohexene-1,2-diamines 3 and 4 for the determination of enantiomeric composition of chiral carboxylic acids by (31)P NMR, is described.

Nucleophilic substitution at the anomeric position of 1,2-O-isopropylidenefuranose derivatives. A novel stereoselective synthesis of cyclic phosphates analogous to cAMP.

1,2-O-Isopropylidenefuranose derivatives were treated with various nucleophiles in the presence of either BF(3).OEt(2) or trimethylsilyl trifluoromethanesulfonate (TMSOTf) leading to substitution products in a regio- and stereoselective manner. In particular, nucleophilic substitution of 1,2-O-isopropylidenefuranose derivatives when treated with allyltrimethylsilane was controlled by steric and electronic factors (similar to Woerpel's stereoelectronic model).

Intramolecular hydrogen bonding (P=O--H) stabilizes the chair conformation of six-membered ring phosphates.

[reaction: see text] Six-membered cyclic phosphates (2-phenoxy-2-oxo-1,3,2-dioxaphosphorinanes) bearing an internal protected or unprotected hydroxyl group were designed, synthesized, and studied by NMR and computational methods. Selective opening of O-isopropylidene-protected 1,2-diols at the primary site was achieved with either triethylsilane or trimethylallylsilane in the presence of BF3.OEt2.