1,1-dioxonaphtho[1,2-b]thiophene-2-methyloxycarbonyl (alpha-Nsmoc) and 3,3-dioxonaphtho[2,1-b]thiophene-2-methyloxycarbonyl (beta-Nsmoc) amino-protecting groups.
Of the three theoretically possible, Bsmoc-related, naphthothiophene sulfone-based amino-protecting groups, the two most readily available derivatives, the alpha- and beta-Nsmoc analogues, have been examined as substitutes for the Bsmoc residue in cases where the latter lead to oily protected amino acids or amino acid fluorides. All of the naphtho systems gave easily handled solid amino acid derivatives. The intermediate sulfone alcohol 11 used as the key reagent for introduction of the alpha-Nsmoc protecting group was readily made from alpha-tetralone (Scheme 1). The corresponding beta-analogue 17 was made similarly on a small scale, but due to the high cost of beta-tetralone, an alternate route involving reaction of rhodanine with alpha-naphthaldehyde was used for large-scale work (Scheme 2). All proteinogenic amino acids were converted to their alpha- and beta-Nsmoc derivatives. Deblocking studies showed that the reactivity toward deblocking by piperidine followed the order alpha-Nsmoc > Bsmoc > beta-Nsmoc. 1H NMR experiments showed that deblocking of the two new systems was mechanistically similar to that previously established for the Bsmoc derivative in that the reaction is initiated by Michael addition to the beta-carbon atom of the alpha,beta-unsaturated sulfone system. Application of alpha- and beta-Nsmoc amino acids to the solid-phase synthesis of two model peptides was examined. An advantage of the alpha-Nsmoc system over the long-known Bsmoc system proved to be the milder conditions needed for the deblocking step relative to the Bsmoc case, which is itself more readily deblocked than the classic Fmoc analogue.
Carpino
Louis A
LA
Department of Chemistry, University of Massachusetts, Amherst, MA 01003, USA. carpino@chem.umass.edu
Abdel-Maksoud
Adel Ali
AA
Ionescu
Dumitru
D
Mansour
E M E
EM
Zewail
Mohamed A
MA
D000438:Alcohols; D000596:Amino Acids / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D009281:Naphthalenes / Q000138:chemical synthesis*; D010880:Piperidines / Q000737:chemistry; D013876:Thiophenes / Q000138:chemical synthesis*
C518836:1,1-dioxonaphtho(1,2-b)thiophene-2-methyloxycarbonyl; D000438:Alcohols; D000596:Amino Acids; D007202:Indicators and Reagents; D009281:Naphthalenes; D010880:Piperidines; D013876:Thiophenes