Synthetic Applications of Lithiated N-Boc Allylic Amines as Asymmetric Homoenolate Equivalents

Abstract

Lithiation of N-(Boc)-N-(p-methoxyphenyl) allylic amines in the presence of (-)-sparteine provides asymmetric homoenolate equivalents which react with electrophiles to provide highly enantioenriched enecarbamates. Acidic hydrolysis of the enecarbamates can provide the corresponding beta-substituted aldehydes. A synthetic sequence that involves a stereocontrolled intramolecular nitrone-olefin dipolar cycloaddition has been developed for the preparation of enantioenriched 2-formyl-4-phenyl-1-aminocyclopentanes from one beta-allyl-substituted aldehyde. Further manipulations allow access to an enantioenriched beta-lactam. In another synthetic sequence, transmetalation of the lithiated intermediates and reactions with aldehyde electrophiles can be controlled to afford highly enantioenriched anti homoaldol products. Use of an anti aldehyde homoaldol product as the chiral electrophile in an iterative reaction provides a double homoaldol product containing four stereogenic centers with high diastereoselectivity and enantioselectivity. Reaction pathways are proposed to account for the observed products.

Structure–Activity Studies of N‐Butyl‐1‐deoxynojirimycin (NB‐DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2

“…An intramolecular 1,3‐dipolar cycloaddition of the crude oxime 31 in toluene at reflux furnished cis ‐fused isoxazolidine 32 . The N − O bond was cleaved with activated zinc under acidic aqueous conditions to provide amine 33 . The direct reductive alkylation reaction of free amine 33 with butyraldehyde and nonyl aldehyde was low yielding and the reaction products were difficult to purify.…”

“…[42] Treatmentofaldehyde 30 with hydroxylamine hydrochloride in warm methanol in the presence of sodiumb icarbonate provided the corresponding oxime 31 as am ixture of E and Z isomers. An intramolecular 1,3-dipolar cycloaddition [43,44] of the crude oxime 31 in toluenea tr eflux furnished cis-fused isoxazolidine 32.T he NÀO bond was cleaved with activated zinc under acidic aqueous conditions [45] to provide amine 33.T he direct reductive alkylation reaction of free amine 33 with butyraldehyde and nonyl aldehydew as low yieldinga nd the reaction products were difficult to purify. Better yields and only mono-alkylated products were obtained when the HCl salt of 33 (Et 3 Nw as used to neutralize the reaction medium) was used, providing improved yields (49!73 % and 41!70 %, respectively) of 34 a and 34 b.S ubsequently, compounds 34 c-34 d were prepared using the same protocol.…”

Synthesis, Structure, and Solution Studies of Lithiated Allylic Phosphines and Phosphine Oxides

“…In recent years, we have studied alkali metal allylic amide systems − owing to the simple building block having a significant role in accessing many valuable N-containing compounds such as β-amino acids and β-lactams, , chiral β-branched esters, chiral 1,2 diamines, and peptide isosteres . Our ongoing interest in allylic amide systems and their applications has led us to delve into the phosphorus derivatives exploiting both oxidation states, where P­(V) is air-stable over the P­(III) analogues.…”

An insight into the synthesis of novel aryl-substituted alicyclic β-amino acid derivatives through substrate-directed palladium-catalysed regio- and stereoselective cross-coupling

“…One synthetic access route to aryl-substituted cyclic b-amino acids is based on the intramolecular dipolar cycloaddition of a nitrone (derived from a phenyl-substituted unsaturated aldehyde) to an olenic function, followed by isoxazolidine ring opening and hydroxymethyl group oxidation. 5 The rhodium-catalysed conjugate addition of organoborons to unsaturated cyanoesters followed by ring closure is another method for the construction of arylated cycloalkane b-amino acids, 6 while cerium(IV)-catalysed sequential three-component reactions of alkylamines, b-oxoesters and aryl ketones (chalcones) lead to polysubstituted b-amino acids with a phenyl substituent attached to the cyclohexane ring. 7 Lithium amide conjugate addition to veor six-membered phenyl-substituted a,b-unsaturated esters furnishes the corresponding phenyl-substituted b-amino acids.…”