Regioselective O-Sulfonylation of N,N-Bis(2-hydroxyalkyl)tosylamides as a Synthetic Key Step to Enantiopure Morpholines.

The synthesis of enantiopure 2,6-disubstituted morpholines was realized through sequential ring opening of two different optically pure oxiranes by a tosylamide, under solid-liquid phase-transfer catalysis (SL-PTC) conditions, mono-O-sulfonylation of the resulting tosylamido-2,2'-diol, and cyclization to the morpholine. The crucial step, the regioselective formation of the monosulfonate, was controlled by taking advantage of the different stereo, electronic, and coordination properties of the oxirane-derived side chains in the diol backbone. As an application of this protocol, a new morpholine-3-carboxamide was synthesized starting from threonine.

Memory of chirality approach to the enantiodivergent synthesis of chiral benzo[d]sultams.

The "memory of chirality" stereodivergent synthesis of polyfluorobenzo[d]sultams has been developed. The interest of this protocol resides in the possibility of using the chirality of a starting sulfonamide single enantiomer to synthesize the target sultams in both absolute configurations, by using different base systems, under homogeneous conditions.

Diastereoselective protocols for the synthesis of 2,3-trans- and 2,3-cis-6-methoxy-morpholine-2-carboxylic acid derivatives.

Two diastereoselective and straightforward protocols for the high-yielding synthesis of 2,3-trans- and 2,3-cis-6-methoxy-3-substituted morpholine-2-carboxylic esters were realized in few steps, through the condensation between 5,6-diethoxy-5,6-dimethyl-1,4-dioxan-2-one and an appropriate imine, which is the key reaction to control the C2-C3 relative stereochemistry, followed by a methanolysis/ring-closure tandem reaction sequence. In particular, 2,3-trans-morpholines derive from the R*,S*-product of the acid condensation of N-functionalized alkylimines with the silylketene acetal of the above lactone, whereas 2,3-cis-morpholines derive from the R*,R*-product of basic condensation of an N-tosylimines with the lactone.

Highly stereoselective intramolecular alpha-arylation of self-stabilized non-racemic enolates: synthesis of alpha-quaternary alpha-amino acid derivatives.

The 'one-pot' stereoselective conversion of N-(4-nitrobenzene)sulfonyl-alpha-amino acid tert-butyl esters into the corresponding N-alkyl-alpha-(4-nitrophenyl)-alpha-amino esters has been realized through N-alkylation of the starting amido esters, followed by N-C(alpha) migration of the p-nitrophenyl group and the loss of sulfur dioxide; the asymmetric induction is determined by an intermediate non-racemic enolate, without the need of an external source of chirality.

Complementary heterogeneous/homogeneous protocols for the synthesis of densely functionalized benzo[d]sultams: C-C bond formation by intramolecular nucleophilic aromatic fluorine displacement.

Polyfunctionalized benzo[d]sultams 7 and 8, which contain an alpha-amino acid unit, have been synthesized from the corresponding open chain (pentafluorobenzene)sulfonamides 4 by complementary solid-liquid phase transfer catalysis (SL-PTC) and homogeneous protocols. The cyclization step proceeds through the intramolecular nucleophilic displacement of an aromatic fluorine atom.