An Approach to Clavams and 1-Oxacephams from Hydroxy Acids

[2 + 2] Cycloaddition of chlorosulfonyl isocyanate to chiral alkyl vinyl ethers bearing a sterogenic center in the alkyl part of the ether afford the corresponding azetidin-2-ones with relatively good asymmetric induction in certain cases. Reactions were shown to depend on steric requirements of the ligands at the stereogenic center. The model that rationalizes the stereochemical outcome is based on the s-cis conformation of the vinyl ether in which the bulkiest of the ligands is situated in the plane of the double bond, and the next most demanding substituent is placed gauche to the double bond

Configurational Assignment of 5-Substituted Pyrazolidin-3-ones Using Circular Dichroism Spectroscopy

The chiroptical properties of the title compounds bearing various substituents at the N(1) and N(2) nitrogen atoms are discussed. It was found that the sign of the n−π* Cotton effect centered at about the 230−250 nm region can be correlated with the absolute configuration of the stereogenic center at C(5). It was also found that the sign of this Cotton effect is predictable by Weigang's lactam sector rule. MMX calculations, supported by X-ray measurements, showed that substituents at the nitrogen atoms significantly affect the conformation of the five-membered ring. It was additionally concluded that the conformation of the five-membered ring in 5-substituted pyrazolidin-3-ones is the sign-determining factor for an n−π* transition

Diastereoselective Synthesis of Carbapenams via Kinugasa Reaction

A facile approach to carbapenams via Kinugasa reaction between terminal copper acetylides and nonracemic cyclic nitrones derived from malic and tartaric acid is reported. The stereochemical preferences observed in these reactions are explained. The reaction provides an entry to the carbapenams basic skeleton

Diastereoselective Synthesis of Carbapenams via Kinugasa Reaction

A facile approach to carbapenams via Kinugasa reaction between terminal copper acetylides and nonracemic cyclic nitrones derived from malic and tartaric acid is reported. The stereochemical preferences observed in these reactions are explained. The reaction provides an entry to the carbapenams basic skeleton

Asymmetric Kinugasa Reaction of Cyclic Nitrones and Nonracemic Acetylenes

Kinugasa reactions between chiral acetylenes and five-membered nitrones, achiral and bearing a stereogenic center in both enantiomeric forms, proceed in moderate to good yield with high diastereoselectivity affording mostly one dominant product. The first step of the reaction is controlled by the configuration of the nitrone, whereas the protonation of intermediate enolate in the second step depends mainly on the configuration of the bridgehead carbon atom formed in the first step. In the case of the mismatched pair, the configuration at the C-6 center of the carbapenam skeleton may also be affected by the configuration of the stereogenic center in the acetylene portion

Total Synthesis of Ezetimibe, a Cholesterol Absorption Inhibitor

Ezetimibe (1), a strong β-lactamic cholesterol absorption inhibitor, was synthesized from (R)-6-(4-fluorophenyl)-5,6-dihydro-2H-pyran-2-one 7. Independent pathways were analyzed in order to select the optimal one, which involved 1,3-dipolar cycloaddition with C-(4-benzyloxyphenyl)-N-(4-fluorophenyl)-nitrone (8), intramolecular nucleophilic displacement at the benzylic position of the lactone, cleavage of the N–O bond, elimination of a water molecule, hydrogenation of the double bond, rearrangement of the six-membered lactone ring into a β-lactam moiety, and final deprotection of the phenolic hydroxyl group. Highly stereoselective Sc­(OTf)3-catalyzed 1,3-dipolar cycloaddition was the most crucial step of the synthesis. Owing to the rigid transition state of the cycloaddition, the absolute configuration of the starting lactone controlled the formation of other stereogenic centers of the final molecule 1

Approach to Monobactams and Nocardicins via Diastereoselective Kinugasa Reaction

A Kinugasa reaction between copper­(I) acetylides and cyclic nitrones derived from chiral amino alcohols and glyoxylic acid is reported. The stereochemical preferences observed in this reaction are discussed. The alkyne molecule approaches the nitrone exclusively <i>anti</i> to the large substituent next to the nitrogen atom to provide the <i>cis</i>-substituted β-lactam ring preferentially. The six-membered oxazinone ring can be opened by reduction with lithium borohydride. Deprotection of the β-lactam nitrogen atom can be achieved by lithium in liquid ammonia reduction or by CAN oxidation, depending on the substituents attached to the four-membered azetidinone ring. The adducts obtained by the Kinugasa reaction provide an attractive entry to a variety of monocyclic β-lactam structures related to monobactams and nocardicins

Total Synthesis of Ezetimibe, a Cholesterol Absorption Inhibitor

Ezetimibe (<b>1</b>), a strong β-lactamic cholesterol absorption inhibitor, was synthesized from (<i>R</i>)-6-(4-fluorophenyl)-5,6-dihydro-2<i>H</i>-pyran-2-one <b>7</b>. Independent pathways were analyzed in order to select the optimal one, which involved 1,3-dipolar cycloaddition with <i>C</i>-(4-benzyloxyphenyl)-<i>N</i>-(4-fluorophenyl)-nitrone (<b>8</b>), intramolecular nucleophilic displacement at the benzylic position of the lactone, cleavage of the N–O bond, elimination of a water molecule, hydrogenation of the double bond, rearrangement of the six-membered lactone ring into a β-lactam moiety, and final deprotection of the phenolic hydroxyl group. Highly stereoselective Sc­(OTf)₃-catalyzed 1,3-dipolar cycloaddition was the most crucial step of the synthesis. Owing to the rigid transition state of the cycloaddition, the absolute configuration of the starting lactone controlled the formation of other stereogenic centers of the final molecule <b>1</b>

Approach to Monobactams and Nocardicins via Diastereoselective Kinugasa Reaction

A Kinugasa reaction between copper­(I) acetylides and cyclic nitrones derived from chiral amino alcohols and glyoxylic acid is reported. The stereochemical preferences observed in this reaction are discussed. The alkyne molecule approaches the nitrone exclusively <i>anti</i> to the large substituent next to the nitrogen atom to provide the <i>cis</i>-substituted β-lactam ring preferentially. The six-membered oxazinone ring can be opened by reduction with lithium borohydride. Deprotection of the β-lactam nitrogen atom can be achieved by lithium in liquid ammonia reduction or by CAN oxidation, depending on the substituents attached to the four-membered azetidinone ring. The adducts obtained by the Kinugasa reaction provide an attractive entry to a variety of monocyclic β-lactam structures related to monobactams and nocardicins

Total Synthesis of Ezetimibe, a Cholesterol Absorption Inhibitor

Ezetimibe (<b>1</b>), a strong β-lactamic cholesterol absorption inhibitor, was synthesized from (<i>R</i>)-6-(4-fluorophenyl)-5,6-dihydro-2<i>H</i>-pyran-2-one <b>7</b>. Independent pathways were analyzed in order to select the optimal one, which involved 1,3-dipolar cycloaddition with <i>C</i>-(4-benzyloxyphenyl)-<i>N</i>-(4-fluorophenyl)-nitrone (<b>8</b>), intramolecular nucleophilic displacement at the benzylic position of the lactone, cleavage of the N–O bond, elimination of a water molecule, hydrogenation of the double bond, rearrangement of the six-membered lactone ring into a β-lactam moiety, and final deprotection of the phenolic hydroxyl group. Highly stereoselective Sc­(OTf)₃-catalyzed 1,3-dipolar cycloaddition was the most crucial step of the synthesis. Owing to the rigid transition state of the cycloaddition, the absolute configuration of the starting lactone controlled the formation of other stereogenic centers of the final molecule <b>1</b>