Diastereoselective Synthesis of the HIV Protease Inhibitor Darunavir and Related Derivatives via a Titanium Tetrachloride-Mediated Asymmetric Glycolate Aldol Addition Reaction.

Darunavir is a potent HIV protease inhibitor that has been established as an effective tool in the fight against the progression of HIV/AIDS in the global community. The successful application of this drug has spurred the development of derivatives wherein strategic regions (e.g.

Diastereoselective and Enantioselective Synthesis of α--Methoxyphenoxy-β-Lactones: Dependence on the Stereoelectronic Properties of the β-Hydroxy-α--Methoxyphenoxycarboxylic Acid Precursors.

Treatment of β-hydroxy-α--methoxyphenoxy carboxylic acids derived from the asymmetric glycolate aldol addition reaction with -nitrobenzenesulfonyl chloride yielded divergent results depending on the nature of the β-substituent of the carboxylic acid. Substrates bearing either alkyl substituents (R = --butyl, --octyl, -benzyl, isopropyl, --butyl) or aryl systems bearing electron-withdrawing substituents (R = --CHCl, --CHBr, --CHNO) yielded β-lactones. In contrast, α--methoxyphenoxy-β-hydroxycarboxylic acids bearing electron-donating aryl groups or the sterically demanding 2-naphthyl group formed ()-alkenes.

(5S)-4-(2,2-Dimethyl-prop-yl)-5-isopropyl-1,3,4-oxadiazinan-2-one.

The title compound, C(11)H(22)N(2)O(2), has one chiral center and packs in the monoclinic space group P2(1). The asymmetric unit has five crystallographically independent mol-ecules, four of which engage in inter-molecular N-H⋯O hydrogen bonding.

(6S)-2-tert-Butyl-6-[(4S,5R)-3,4-dimethyl-5-phenyloxazolidin-2-yl]phenol.

The title compound, C(21)H(27)NO(2), exhibits hydrogen bonding between the phenolic H atom and the heterocyclic N atom. The absolute configuration of the mol-ecule is known from the synthetic procedure.

(6S)-2,4-Di-tert-butyl-6-[(4S,5R)-3-iso-propyl-4-methyl-5-phenyloxazolidin-2-yl]phenol.

The title oxazolidine compound, C(27)H(39)NO(2), was synthesized from N-isopropyl-norephedrine. The dihedral angle between the aromatic rings is 70.33 (5)°.

(6R)-2-tert-Butyl-6-[(4R,5S)-3-isopropyl-4-methyl-5-phenyl-oxazolidin-2-yl]phenol.

In the title compound, C(23)H(31)NO(2), the lone pair on the nitro-gen atom is oriented to facilitate intra-molecular hydrogen bonding with the hydr-oxy group residing on the phenyl substituent. The five-membered ring adopts an envelope confornmation with the O atom at the flap. The absolute stereochemistry was verified by measurement of optical activity using a digital polarimeter.

Beta-amino alcohol derived beta-hydroxy- and beta-(o-diphenylphosphino)benzoyloxy(o-diphenylphosphino)benzamides: an ester-amide ligand structural model for the palladium-catalyzed allylic alkylation reaction.

A commercially available collection of beta-amino alcohols have been converted to their corresponding beta-hydroxy- and beta-(o-diphenylphosphino)benzoyloxy(o-diphenylphosphino)benzamides 11a-f and 12a-f and have been employed in the Tsuji-Trost asymmetric alkylation reaction with 1,3-diphenylpropenyl acetate. With the exception of ligands 11b and 11f, the beta-hydroxybenzoyloxy(o-diphenylphosphino)benzamide ligands 11a-f primarily afforded the (R)-enantiomer of the product. In contrast, the bis(phosphine) ligands 12a-f consistently afforded the (S)-enantiomer.

(5S,6R)-5-Methyl-6-phenyl-4-propyl-1,3,4-oxadiazinane-2-thione.

The title mol-ecule, C(13)H(18)N(2)OS, is an oxadiazinanthione derived from (1R,2S)-norephedrine. There are two molecules in the asymmetric. Both adopt roughly half-chair conformations; however, the 5-position carbon orients out of opposite faces of the oxadiazinanthiones plane in the two molecules.

(5R,6S)-4-Isopropyl-5-methyl-6-phenyl-3-propanoyl-2H-1,3,4-oxadiazinan-2-one.

The title compound, C(16)H(22)N(2)O(3), was synthesized during the course of a study on (1R,2S)-norephedrine-derived 1,3,4-oxadiazinan-2-ones. The conformation adopted by the isopropyl group is pseudo-axial relative to the oxadiazinan core. The allylic strain contributes to this conformational arrangement.

(5S,6S)-4,5-Dimethyl-3-methyl-acryloyl-6-phenyl-1,3,4-oxadiazinan-2-one.

The title compound, C(15)H(18)N(2)O(3), is an example of an oxadiazinan-2-one with significant inter-action between the N(3)-acyl and N(4)-methyl groups. These steric inter-actions result in a large torsion angle between the two carbonyl groups, not present with acyl substituents with less steric demand.

(4R,5S)-5-Benzyl-4-isopropyl-1,3,4-oxadiazinan-2-one.

The title compound, C(13)H(18)N(2)O(2), is an N(4)-isopropyl-l-phenyl-alanine-based oxadiazinanone. Although the two mol-ecules in the asymmetric unit are oriented appropriately for hydrogen bonding, the distance between the donor and acceptor atoms is large enough to support only weak, if any, hydrogen bonding. The absolute configuration is known based on the known starting compounds in the synthetic procedure.

Toward the development of a structurally novel class of chiral auxiliaries. Conformational properties of the aldol adducts of oxadiazinones: observation of unusual shielding effects.

Asymmetric aldol reactions were conducted with the titanium enolate of N(3)-hydrocinnamoyl-3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one to afford aldol adducts 5a-j. The dominant product of the asymmetric aldol reaction was the non-Evans syn adduct as determined by (1)H NMR spectroscopy and X-ray crystallography. When evaluating the (1)H NMR spectra of adducts 5a-j, a highly shielded signal with an average chemical shift of 0.

Intramolecular chiral relay at stereogenic nitrogen. Synthesis and application of a new chiral auxiliary derived from (1R,2S)-norephedrine and acetone.

(1R,2S)-Norephedrine has been employed in the synthesis of a novel 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one via reductive alkylation with acetone, N-nitrosation, reduction, and cyclization. The oxadiazinone was treated with either propionyl chloride or 3-thiophenylpropionyl chloride to afford the corresponding N(3)-acylated oxadiazinones 9a and 9b, respectively. X-ray crystallographic analysis of the N(3)-thiophenylpropionyl oxadiazinone 9b revealed that the C(2)-urethane carbonyl and the N(3)-carbonyl are arranged in an anti-periplanar conformation.

Conformational studies of N(3)-substituted [1,3,4]-oxadiazinan-2-ones.

Pseudoephedrine-based [1,3,4]-oxadiazinan-2-ones acylated at the N(3)-position with either acetyl (2a), propionyl (2b), or phenylacetyl (2c) substituents are known to undergo conformational changes that are observable by (13)C NMR spectroscopy. The conformational properties of new [1,3,4]-oxadiazinan-2-one derivatives 2d-k are examined by X-ray crystallography and variable-temperature (13)C NMR spectroscopy and further evaluated by semiempirical AM1 calculations. The collected data reveal that the conformational changes of the overall ring system are dependent upon the stereoelectronic factors of the N(3)-substituent.

Toward the development of a structurally novel class of chiral auxiliaries: diastereoselective aldol reactions of a (1R,2S)-ephedrine-based 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one.

[reaction: see text] Asymmetric aldol addition reactions have been conducted with (1R,2S)-ephedrine-derived 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one (2). Diastereoselectivities range from 75:25 to 99:1 for the formation of the crude non-Evans syn adducts 8a-h. The facial selectivity of the enolate is directed by the stereogenic N(4)-methyl substituent.