jo0515226_si_002.cif (19.14 kB)
Conformationally Constrained β-Amino Acid Derivatives by Intramolecular [2 + 2]-Photocycloaddition of a Tetronic Acid Amide and Subsequent Lactone Ring Opening
dataset
posted on 2005-11-25, 00:00 authored by Birte Basler, Oliver Schuster, Thorsten BachThe 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 (λ = 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 β-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%.
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amines 6tetronic acid bromideLactone 15acid derivativesazabicyclonucleophilic substitutionfunctionalizationacylationisocyanate addition254 nmlactone ring openingphotocycloaddition product 15Subsequent Lactone Ringlactone 15Intermolecular substitution reactionsBoc deprotectionmesylatetripeptide 38library synthesisConformationally
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