Stereoselective Homologation–Amination of Aldehydes by Addition of Their Nitrones to C‐2 Metalated Thiazoles—A General Entry to α‐Amino Aldehydes and Amino Sugars

Abstract

A general method for the homologation of aldehydes to a-amino aldehydes (aminohomologation) has been developed, which employs nitrones as iminium derivatives of the aldehydes. Key operations include a) the addition of a thiazole metalated at C-2 to the N-benzylnitrone derived from the aldehyde, b) the reductive dehydroxylation of the resultant thiazolyl N-benzylhydroxylamine, and c) the unmasking of the formyl group from the thiazole ring. The homologation sequence was studied by employing nitrones derived from various chiral polyalkoxy aldehydes and dialdoses. The addition of 2-lithiothiazole to these nitrones was synselective, whereas the reaction with the same nitrones precomplexed with Lewis acids was mri-selective. Hence, from each nitrone a pair of diastereoisomeric hydroxylamines was obtained. These compounds were then converted by the above sequence into a-epimeric a-amino aldehydes. Model elaborations of some of these products afforded the amino sugars D-glucosamine, D-mannosamine, D-nOJirimycin, and advanced intermediates for the synthesis of destomic acid and lincosamine.

Synthesis of Non‐Natural Aromatic α‐Amino Acids by a Heck Reaction

“…To avoid a partial reduction of the aromatic side-chain, we applied a transfer hydrogenation protocol with 1,4-cyclohexadiene and Pd(OH) 2 in refluxing ethanol in all other cases. [13] Subsequent to the desilylation with TBAF in THF, Fmoc protection of the amino group was carried out (5a-e). The final step to complete the synthesis of the amino acid building blocks 6a-d is the oxidation of the protected amino alcohols 5a-d with PDC in DMF.…”

Polyalkoxy Nitrones as Chiral Building Blocks in Asymmetric Synthesis

“…In the case of thiazole and furan, the synthetic equivalences of these heterocyclic rings with the formyl and carboxyl groups, respectively, were exploited for developing new synthetic methodologies. The conversion of (hydroxyaminomethyl)thiazoles 15 to the protected (aminomethyl)thiazoles 16 could be done by a two-step process consisting of concomitant deoxygenation and debenzylation with titanium (III) chloride and further reaction with di-tert-butyl dicarbonate in dioxane [14] (Scheme 3). Finally, transformation of the thiazole ring into a formyl group according to the described protocol [15] furnished α-amino aldehydes 17.…”

“…Since the starting nitrones (precursors of hydroxylamines 15 and 18) were prepared from the corresponding aldehydes, the overall processes outlined in Scheme 3 can be considered as stereoselective homologations with incorporation of an amino functionality into the newly generated asymmetric center. We referred to these transformations as thiazole-based aminohomologation (TBAH) [14] and furan-based aminohomologation (FBAH) [17], respectively (Scheme 4). The reactivity of polyalkoxy nitrones with hetaryl nucleophiles of synthetic utility [21] (such as furan and thiazole) made possible the total syntheses of several natural products of interest.…”

“…Deprotection of the acetonide moiety afforded the aminosugar N-acetyl-D-mannosamine 22 [14,22]. The stereocontrolled aminohomologation of aldehyde 23 led to epimeric α-amino aldehydes 24 and 24, advanced intermediates in synthesis of destomic acid and lincosamine, respectively (Scheme 6) [23].…”

“…The stereocontrolled aminohomologation of aldehyde 23 led to epimeric α-amino aldehydes 24 and 24, advanced intermediates in synthesis of destomic acid and lincosamine, respectively (Scheme 6) [23]. Similarly, aldehyde 28 was subjected to the same methodology to furnish α-aminoaldehyde 29 which was further transformed into the aza sugar D-nojirimycin (Scheme 7) [14]. The above nitrone-thiazole methodology was also applied for the synthesis of novel anomeric Cglycosyl α-amino acids by oxidation of the corresponding α-amino aldehydes with NaClO 2 in aqueous NaH 2 PO 4 [24].…”