title: Conformationally constrained beta-amino acid derivatives by intramolecular [2 + 2]-photocycloaddition of a tetronic acid amide and subsequent lactone ring opening.
abstract: [reaction: see text] The N-Boc-protected N-3-alkenyltetronic acid amides 9 and 12 were prepared from tetronic acid bromide (7) and the corresponding amines 6 and 10 by nucleophilic substitution and subsequent acylation in 71% and 39% overall yield. They underwent an intramolecular [2 + 2]-photocycloaddition upon direct irradiation (lambda = 254 nm) to yield diastereoselectively the strained lactones 15 (76%) and 16 (91%) with a 2-azabicyclo[3.2.0]heptane core. In attempts to defunctionalize the 1-hydroxymethyl substituent of the 2-azabicyclo[3.2.0]heptane skeleton, lactone 15 was converted into mesylate 18 (74% overall yield). Intermolecular substitution reactions on this mesylate, however, proceeded sluggishly or failed completely. Lactone 15 could be opened reductively (Dibal-H) or by substitution with benzylamine to the N-Boc-protected 2-azabicyclo[3.2.0]heptanes 21 (71%) and 22 (81%). Conformationally constrained beta-amino acid derivatives were obtained by quantitative N-Boc deprotection of photocycloaddition product 15, followed by N-functionalization and subsequent lactone ring opening. The N-functionalization was conducted by acylation (to 24-26), alkylation (to 27), tosylation (to 28), and isocyanate addition (to 30). The reactions proceeded in yields of 70-84%. Lactone ring opening reactions were conducted with amines to establish the suitability of this process for library synthesis. As an example, the tripeptide 38 was obtained from photocycloaddition product 15 in an overall yield of 51%.
authors.affiliation: Lehrstuhl für Organische Chemie I, Technische Universität München, D-85747 Garching, Germany.
authors.forename: Birte
authors.initials: B
authors.lastname: Basler
authors.forename: Oliver
authors.initials: O
authors.lastname: Schuster
authors.forename: Thorsten
authors.initials: T
authors.lastname: Bach
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000528:radiation effects; D000596:Amino Acids / Q000737:chemistry* / Q000528:radiation effects; D003500:Cyclization; D005663:Furans / Q000737:chemistry* / Q000528:radiation effects; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000528:radiation effects; D008968:Molecular Conformation; D010777:Photochemistry; D013237:Stereoisomerism; D014466:Ultraviolet Rays
chemical_list: D000577:Amides; D000596:Amino Acids; D005663:Furans; D007783:Lactones; C003422:tetronic acid