A mixed lithium-cadmium amide and a combination of lithium and zinc amides were reacted with a range of ferrocenes; deprotonative mono- or dimetallation in general occurred chemoselectively at room temperature, as evidenced by subsequent quenching with iodine.

The C-linked carbo-beta-peptides, oligomers of a new class of C-linked carbo-beta3-amino acids, have been shown to generate mixed 12/10 and 10/12 helices. The design involves use of "alternating chirality" of the epimeric (at the amine center) monomers to control the stability of these helices. The observation of stable 12/10 helix in a tripeptide and 10/12 helix in a tetrapeptide is unprecedented.

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Ein neuer Dreh: Die α/β‐Hybriddipeptid‐Wiederholungseinheiten, die aus alternierenden C‐verknüpften Carbo‐β3‐aminosäuren und L‐Ala‐Resten hergestellt wurden, tendieren stark zur Bildung gemischter Helices und liefern bislang unbekannte rechtsgängige 11/9‐ und 9/11‐Helixstrukturen (siehe Bild).

Synthetic oligomers of b-amino acids, that is, b-peptides, [1] are amongst the most studied class of molecules in foldamer chemistry. Changes in their substitution pattern generate a variety of interesting structural features in these molecules, [2][3][4][5] which have thus begun to prove immensely useful in bioactive peptide mimicry.[6] Amongst the various peptide secondary structures, mixed helices are unique to b-peptides. These structures contain intertwined 12 and 10-membered Hbonded rings and are unprecedented in a-proteins. Seebach et al. [4a] were the first to demonstrate the existence of righthanded 12/10 mixed helical structures in b-peptides with alternating b 2 and b 3 residues. Kessler and co-workers [4b] have reported such structures in mixed peptides containing constrained f-sugar amino acid and b-hGly repeats. We recently reported [7] the formation of both 10/12 and 12/10 right-handed helices by b-peptides derived from C-linked carbo-b 3 -amino acids (Caa) with "alternating chirality." Although a variety of helical structures have been discovered in b-peptides, no reports have been published in this active area of research that describe left-handed mixed helices. Several natural proteins [8] have been found to contain small fragments of left-handed helices, most of which occur in or near an active or binding site and are thus likely to be of functional importance. Herein, we report the design, synthesis, and structural study of "mixed b-peptides" with right-handed and novel left-handed mixed (10/12 and 12/10) helical structures. These peptides are derived from alternating epimeric Clinked carbo-b 3 -amino acids [9] (1 or 2; Scheme 1) and b-hGly units.Our previous study revealed that Caa 1 occupies an energetically unfavorable position in the carbo-b-peptides 3 and 4, [7] although robust mixed helical structures were formed by these peptides. We envisaged a new design intended to provide more conformational freedom and relieve steric strain [10,11] through the inclusion of alternating Caa (1 or 2) and b-hGly residues. Mixed b-peptides 5-12 (5/6 and 7/8 with Caa 2 and 1 at the N terminus, respectively; 9/10 and 11/12 with b-hGly at the N terminus) were prepared by conventional procedures (1-ethyl-3(3-dimethylaminopropyl)carbodiimide, 1-hydroxy-1H-benzotriazole) and differences in the conformational behavior of the various peptides were studied. We anticipated that Caas 1 and 2 would define the conformational behavior of b-hGly in 5-12 (Scheme 1).Structural studies on these peptides were carried out by using NMR and CD spectroscopic techniques. The 1 H NMR spectra of 5 and 6 in CDCl 3 show well-resolved backbone proton signals, as well as low-field NH resonances (NH(2)-NH(3) for 5; NH(2)-NH(5) for 6), which indicate the involvement of these NH groups in H bonding. This bonding was further confirmed by solvent titration studies.[12] The coupling constants 3 J CaH/CbH of the peptides (> 10 Hz or < 5 Hz) clearly demonstrate the predominance of a single conformation about the CaÀCb bond (single q valu...

Positive and negative ion electrospray ionization (ESI) tandem mass spectral study of a new series of hybrid peptides, viz, BocN-alpha,beta-peptides and BocN-beta,alpha-peptides, synthesized from C-linked carbo-beta3-amino acids [Caa (S)] and L-Ala has been carried out. The alpha,beta-peptides have been differentiated from beta,alpha-peptides by the collision-induced dissociation (CID) of [M + H]+ and [M - H]- ions in positive and negative ion ESI-MS respectively. The fragment ion [M + H - C(CH3)3 + H]+ formed from [M + H]+ ions by the loss of 2-methyl-prop-2-ene in alpha,beta-peptides with L-Ala at the N-terminus is insignificant or totally absent for beta,alpha-peptides which have the Caa (S) at N-terminus. The fragment ion [M - H-C(CH3)3OH - HNCO]- formed from [M - H]- of beta,alpha-peptide acids is totally absent for alpha,beta-peptide acids. This has been attributed to the absence of the beta-methylene group in alpha,beta-peptides, and the participation of the beta-methylene group in the loss of HNCO in beta,alpha-peptide acids is confirmed by the deuteration experiments. The CID of [M + H-Boc + H]+ ions of these peptides also produce characteristic fragmentation. In the CID spectra of alpha,beta-peptides, the b(n)+ ions and the resulting y(n)+ ions occur at a mass difference of 243 and 71 Da corresponding to the successive losses of Caa and L-Ala, whereas a mass difference of 71 and 243 Da is observed for beta,alpha-peptides. In contrast to the CID of protonated peptides, the CID of [M - H]- ions of the alpha,beta- and beta,alpha-peptide acids do not give b(n)- ions and show abundant z(n) (-) ions. Further, a pair of diastereomeric dipeptide esters and acids have been distinguished by the CID of [M + H]+ ions. The loss of 2-methyl-prop-2-ene is more pronounced for Boc-NH-Caa(R)-D-Ala-OCH3 (21) and Boc-NH-Caa(R)-D-Ala-OH (23) with Caa (R) at the N-terminus, whereas it is totally absent for Boc-NH-Caa (S)-D-Ala-OCH3 (22) and Boc-NH-Caa(S)-D-Ala-OH (24) peptides, which have Caa (S) at the N-terminus. Thus, on the basis of our previous and present studies, we propose that the CID of [M + H]+ ions provides a simple and useful method for distinguishing the configuration of Caa (S or R) at the N-terminus of BocN-carbo beta,alpha- and beta,beta-dipeptides.

A mass spectral study of a series of new Boc-C-linked carbo-beta(3)-peptides prepared from C-linked carbo-beta(3)-amino acids (Caa) was carried out using liquid secondary ion mass spectrometry (LSIMS), electrospray ionization (ESI) and tandem mass spectrometry. Using the nomenclature of Roepstorff and Fohlman, the positive ion high- and low energy collision-induced dissociation (CID) of [M + H - Boc + H](+) ions of the peptides produce both N- and C-terminus ions, y(n) (+) and b(n) (+) ions, with high abundance and other ions of low abundance. Further, characteristic fragment ions of carbohydrate moiety are observed. In contrast to the CID of protonated peptide acids, the CID of [M - H](-) ions of the beta(3)-peptide acids do not give b(n)(-) ions and show abundant z(n)(-) and c(n) (-) ions which are insignificant in the former. Two pairs of positionally isomeric Boc-carbo-beta(3)-dipeptides were differentiated by the CID of [M + H](+) ions in LSIMS and ESIMS. The fragment ion [M + H - C(CH(3))(3) + H](+) formed from [M + H](+) by the loss of 2-methylprop-2-ene is relatively more abundant in the dipeptide Boc-NH-beta-hGly-Caa(S)-OCH(3) (14) containing the sugar moiety at the C-terminus whereas it is insignificant in Boc-NH-Caa(S)-beta-hGly-OCH(3) (13), which has the sugar moiety at the N-terminus. Similarly, two pairs of diastereomeric dipeptides were distinguished by the high- and low-energy CID of [M + H](+) ions. The loss of 2-methylprop-2-ene is more pronounced for Boc-NH-Caa(R)-beta-hGly-OCH(3) (17) and Boc-NH-Caa(R)-Caa(S)-OCH(3) (18) isomers whereas it is insignificant for Boc-NH-Caa(S)-beta-hGly-OCH(3) (13) and Boc-NH-Caa(S)-Caa(S)-OCH(3) (2) isomers. This was attributed to a favorable configuration of the carbohydrate moiety favoring the 'H' migration involved in the loss of 2-methylprop-2-ene from the [M + H](+) ions of isomers 17 and 18 compared with the unfavorable configuration of the carbohydrate moiety in isomers 13 and 2.

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