Herein we describe a strategy for the preparation of artificial alpha-helices involving replacement of one of the main-chain hydrogen bonds with a covalent linkage. To mimic the C=O...H-N hydrogen bond as closely as possible, we envisioned a covalent bond of the type C=X-Y-N, where X and Y are two carbon atoms connected through an olefin metathesis reaction. Our results demonstrate that the replacement of a hydrogen bond between the i and i + 4 residues at the N-terminus of a short peptide with a carbon-carbon bond results in a highly stable constrained alpha-helix at physiological conditions as indicated by CD and NMR spectroscopies. The advantage of this strategy is that it allows access to short alpha-helices with strict preservation of molecular recognition surfaces required for biomolecular interactions.
We have reported a new class of artificial α-helices in which a pre-organized α-turn nucleates the helical conformation [R. N. Chapman, G. Dimartino, and P. S. Arora, J. Am. Chem. Soc., 2004, 126, 12252 and D. Wang, K. Chen, J. L. Kulp, III, and P. S. Arora, J. Am. Chem. Soc., 2006, 128, 9248]. This manuscript describes the effect of the core nucleation template on the overall helicity of the peptides and demonstrates that the macrocycle which most closely mimics the 13-membered hydrogen-bonded α-turn in canonical α-helices also affords the most stable artificial α-helix. We also investigate the stability of these synthetic helices through classical helix-coil parameters and find that the denaturation behavior of HBS α-helices agrees with the theoretical properties of a peptide with a well-defined and stable helix nucleus.
[reaction: see text] This report describes the solid-phase synthesis of hydrogen-bond surrogate-derived artificial alpha-helices by a ring-closing metathesis reaction. From a series of metathesis catalysts evaluated for the synthesis of these helices, the Hoveyda-Grubbs catalyst was found to afford high yields of the macrocycle irrespective of the peptide sequence.
Metallated haloalkenes were used to open epoxides in moderate to good yield. The homoallylic alcohols obtained underwent Swern oxidation to afford three gamma,gamma-difluorinated beta,gamma-enones, which reacted with either vinyllithium,2-lithio-2H-dihydropyran or another metallated haloalkene to afford substituted trans-1,2-divinylcyclohexanols of different degrees of stability. These intermediates underwent neutral thermal oxy-Cope rearrangements when heated in xylene in Ace tubes. The first-formed enols ketonised without loss of HF to afford a range of cyclodecenones in moderate to good yield; X-ray crystallography was used extensively for product characterisation. All substrates rearranged more rapidly than a cis/trans mixture of 1,2-divinylcyclohexanols.
A Claisen rearrangement of a partially-fluorinated system involving ring expansion occurred at an unusually low temperature, 100 °C lower than a comparable system from the literature.Paquette and co-workers showed how the Claisen rearrangement could be used to transform readily available vinylic lactones into medium-ring carbocycles during a series of landmark natural product syntheses. 1 The Tebbe reaction 2 fulfils a critical role in providing the vinyl ether component of the allyl vinyl rearrangement precursor; Scheme 1 summarises the sequence.The rearrangement step requires the use of high temperatures and some special experimental precautions; 3 after the Tebbe reaction, the allyl vinyl ether is sealed in base washed tubes to minimise decomposition through enol ether protiolysis and Paquette notes that following minimal enol ether purification, traces of the Tebbe reagent by-products may be present in the rearrangement medium. Given that aluminium reagents are indeed known to cause dramatic accelerations of [3,3]-Claisen rearrangements, 4 some assistance to the rearrangement would not be surprising, though the nature of the active Lewis acid is not clear nor is the effect large given the reaction conditions (23 h at 175 °C in Scheme 1). Double bond migration can also compete with rearrangement forming non-productive allyl vinyl ethers.We were interested to see if halogenation of the allylic fragment would accelerate the ring expansion and lower the reaction temperature. The literature suggests that g,g-difluorination accelerates [3,3]-Claisen rearrangements in some cases; 5 though the idea has not been tested fully and definitive theoretical work does not exist, a general concensus exists that the rehybridisation of an sp 2 CF 2 centre to sp 3 is favoured as geminal CF 2 -substitution destabilises the alkene. Unambiguous accelerative effects exerted in g,g-difluorinated systems have also been reported in other rearrangement systems including [2,3]-Wittigs, 6 heteroatomic [2,3]-rearrangements 7 and oxyCope 8 reactions.Stork enamine chemistry allowed the syntheses of ketoesters 2a and 2b and the addition of 1-chloro-2,2-difluoroethenyllithium 9 generated from 1-chloro-2,2,2-trifluoroethane afforded good yields of alcohol products 3a as a mixture of diastereoisomers (Scheme 2); we assume that the major product has a trans-relationship between the sidechains. 3 No lactone products were detected; what we expected was the collapse of the initial alkoxide onto the ester in at least one of the diastereoisomers. After isolating the hydroxyester, we tried to lactonise it under acidic and basic conditions but failed. Instead of hydrolysing the acid, we synthesised tert-butyl ester 3c as a mixture of diastereoisomers; a single lactone, to which we assigned structure 4a, was isolated in moderate yield after treatment of these hydroxyesters with trifluoroacetic acid in dichloromethane. Presumably, alkyl-O cleavage and carboxy protonation allows closure to the lactone; it seems less likely that the acid intercepts an ally...
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