Fernando Sartillo-Piscil

Diastereoselective synthesis of 1,2-O-isopropylidene-1,6-dioxaspiro[4,4]nonane applying the methodology of generation of radical cations under non-oxidizing conditions

Abstract We report the stereoselective synthesis of an optically pure spiroketal via an intramolecular tandem hydrogen abstraction reaction promoted by an alkoxy radical. Expanding the use of alkene radical cation under non-oxidizing conditions in the synthetic scenario.

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.

Conformational analysis of cyclic phosphates derived from 5-C′ substituted 1,2-O-isopropylidene-α-d-xylofuranose derivatives

Abstract Twelve 2-phenoxy-2-oxo-1,3,2-dioxaphosphorinanes fused with a 1,2-O-isopropylidene-α- d -xylofuranose moiety in cis orientation and substituted at the C′5 position were prepared in two steps from commercially available diacetone-α- d -glucose. Their conformations, and configurations were determined by 1H and 31P NMR and X-ray crystallographic techniques. Both, chair–twisted–chair and chair–boat equilibria were observed in solution. We observed that the strong anisotropic shielding effect of the benzene ring in the phenoxy group generates an upfield shift of the H1 hydrogen atom, when the cyclic phosphates adopt a boat conformation. This is due to a relative cis-orientation of the P-phenoxy group and the H1 proton of the 1,2-O-isopropylidene-α- d -xylofuranose moiety. Therefore, the configuration of the phosphorus center (SP or RP) can be determined by 1H NMR spectroscopy. Interestingly, the crystal structure of one of the cyclic phosphates exhibits two independent molecules in the asymmetric unit, one with a chair and the other one with a boat conformation.

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.g., sesamol) is present in the substrate, the use of a scavenger is necessary.

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. In this regard, we show in the present work that the configuration at the P-atom, the conformation of the P-heterocyclic ring, and particularly, the anomeric effect are involved in the spontaneous and selective cleavage of the C4-O3 bond in cyclic phosph(on)ates. We arrived at this assumption based on the conformational and configurational study of simple model phosphates and phosphonates, where it was observed that the spontaneous conversion of unstable six-membered ring phosphates to their most stable six-membered ring phosphate (4d, 6d and 7d to 5d), by a selective C4-O3 bond cleavage, depends on both: the stereochemistry of the aryl group at C4 and the electronic nature of the substituent attached to the P-atom. Thus, we postulated that the anomeric effect weakens the C4-O3 bond within the 1,3,2-dioxaphosphorinane ring, favoring thus their selective cleavage and spontaneous conversion, similarly to the proposed mechanistic mode of action of six-membered ring P-heterocyclic prodrugs.

A short and practical synthesis of two Hagen's gland lactones.

A seven-step total synthesis of Hagens gland lactones 1 and 2 starting from 1,2-O-isopropylidene-alpha-D-xylofuranose 3 is reported. The success of this short and practical synthesis depends on the use of two key reactions: a stereoselective nucleophilic substitution at the anomeric position of 5 and 6, which allowed the construction of the gamma-lactone ring, and an alkyl substitution reaction on tosylated compound 4, which permitted the carbon chain elongation of the tetrahydrofuran ring appendage at C-6.

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 (2.51 A), suggesting thus an attractive nonbonding electrostatic interaction, which might be the driving force that overcomes the steric diaxial interactions imposed by the aryl group. Theoretical studies (NBO) for two model compounds showed that there are indeed interactions between filled (donor) Lewis-type NBOs and empty (acceptor) non-Lewis NBOs corresponding to the nO-->sigma*(C-H) interaction. Additionally, conversion of a diastereomeric mixture of cyclic nucleotides into the more stable diastereomeric cyclic nucleotide was observed and explained by spontaneous isomerization in the phosphorinane ring. This finding supports the recently established hypothesis for the mode of action of prodrug cleavage, for which the anomeric effect plays an important role.

Novel ring-opening of epoxides and oxetanes with POCl3 or PCl3 in the presence of DMAP

Abstract Efficient synthesis of chlorohydrins by cleavage of oxiranes and oxetanes using POCl 3 or PCl 3 in the presence of DMAP (4- N , N- dimethylaminopyridine) has been studied.

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.

Transition Metal-Free Selective Double sp3 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.