The 8-hexapeptide (H-8-HVal-8-HAla-8-HLeu)2-OH (2) was prepared from the component L-8-amino acids by conventional peptide synthesis, including fragment coupling. A cyclo-8-tri-and a cyclo-8-hexapeptide were also prepared. The 8-amino acids were obtained from a-amino acids by Amdf-Eisfert homologation. All reactions leading to the 8-peptides occur smoothly and in high yields. The 8-peptides were characterized by their CD and NMR spectra (COSY, ROESY, TOCSY, and NOE-restricted modelling), and by an X-ray crystal-structure analysis. 8-Sheet-type structures (in the solid state) and a compact, left-handed or ( M ) 3 , helix of 5-A pitch (in solution) were discovered. Comparison with the analogous secondary structures of a-peptides shows fundamental differences, the most surprising one at this point being the greater stability of$peptide helices. There are structural relationships of 8-peptides with oligomers of 8-hydroxyalkanoic acids, and dissimilarities between the two classes of compounds are a demonstration of the power of H-bonding. Thep-hexapeptide 2 is stable to cleavage by pepsin at pH 2 in H 2 0 for at least 60 h at 37", while the corresponding a-peptide H-(Val-Ala-Leu),-OH is cleaved instantaneously under these conditions. The implication of the described results are discussed.Peptides and proteins are molecules central to life on our planet. When proteinogenic or ribosomal, they consist of a-amino acids linked together by amide bonds. We have recently embarked on a project aimed at the synthesis of oligomers from /?-amino acids (P-peptides), in order to be able to compare the structures and the properties of these unnatural peptide analogs with those of the natural products. Another point which attracted our interest in the /?-oligopeptides is their resemblance with poly(/?-hydroxyalkanoates) (PHA), an ubiquitous class of biopolymers which have been the subject of research in our group for many years [ 11.

Preparation and screening of twenty new ligands, all analogs of a, a, a :oc '-tetraaryl-1,3-dioxolane-4,5dimethanol (TADDOL), for the Ti-catalyzed asymmetric addition of methyltri(isopropoxy)titanium and diethylzinc to benzaldehyde are described. These ligands have the dioxolane ring of the TADDOL's replaced by cyclobutane, cyclopentane, cyclohexene, cyclohexane, bicyclo[2.2. llheptene and -heptane and hicyclo[2.2.2]octene and -octane moieties; several have H-atoms or alkyl groups in place of the aryl groups, and nine of them have C2 symmetry. X-Ray crystallography and molecular mechanics are used to analyze the structure of the ligands, and two structural features appear to correlate with selectivity: i) the torsion angle for the chelating 0-atom and the ortho-C-atom of the axial Ph group (a small, ca. 19", angle is optimum, Fig.8) and i i ) the 'degree of perpendicularity' of the axial Ph group (Fig.9). Competition experiments indicate that TADDOL l a catalyzes both the methyltitanium and diethylzinc additions 2 50 limes faster than the related dioxolane analogs 12a, 12c, and 12e (Scheme 7), indicating that both axial and equatorial aryl groups (see Footnote 6 ) are necessary for ligand-accelerated catalysis of these reactions. A refined mechanistic hypothesis is presented (Fig. 10) to explain the selectivities observed for these new ligands. Our analysis suggests that a combination of structural features appear necessary for good catalytic efliciency and high selectivity. These features, especially the rather subtle conformational effects, appear to be optimized (among the ligands tested) in the TADDOL's.Introduction. -The stereoselective addition of organometallics to the heterotopic faces of a carbonyl group has been the subject of intense study for over forty years, ever since Curtin [l], Cram [2], and Prelog [3] first began rationalizing the selective addition of nucleophiles to diastereotopic faces of aldehydes and ketones. Of particular interest has been the gradual development of theories regarding the factors that are responsible for facial selectivity. E.g., following Cram's original postulate, notable contributions to the theory were made over the years by Karahatsos [4], Felkin [5], Dunitz [6], Anh [7], and Heathcock [8] and coworkers, among others. ') 2, 3, 4, ')Visiting Professor (1993)(1994) from the

The linear oligo-P-peptides derived from P-homoalanine -0Bn is presented. The cyclic derivatives were found to be (H-P-HAla-OH) have been prepared by Arndt-Eistert ho-highly insoluble (m.p. >3OO0C with decomposition) and the mologation of Boc-alanine and subsequent peptide coupling effect of lithium salts on their solubility, particularly with reprocedures. Cyclisation via pentafluorophenyl esters resulted spect to obtaining NMR data, is discussed. The CD spectra in the formation of the cyclic 0-peptides in remarkably high of the cyclo-P-tetrapeptides are presented and these give an yields. The X-ray crystal structure analysis of Boc-(P-HAla)2 indication that "nanotube-like" structures may be present.The synthesis and applications of enantiomerically pure p-amino acids have now become areas of rapidly increasing intere~tl~.~]. Within these areas, we have begun a range of projects concerned with the synthesis and structural characteristics of P-peptides -the peptides derived entirely from P-amino acids. In recent work, we have demonstrated the initially surprising fact that short chain oligomers of P-peptides form distinct secondary structures -the hexapeptide H-(P-HVal-P-HAla-P-HL~u)~-OH has been shown to exist as a left-handed (or M> 31 helix in solution[4] and a study of related heptapeptide~1~1 has given us an insight into the prerequisites for formation of such helical structures. Most recently, we have synthesised P-peptides bearing asubstituents and have begun to investigate the secondary structures of these peptides[61.Other work in our group has, for many years, focused on the poly(hydroxya1kanoate) family [7,8], with the use of poly-(R)-3-hydroxybutanoate [P(3-HB)] A in a wide variety of fields being of particular interest. These fields include its use as a source of chiral synthetic C4 building blocks and its possible role as a component in a natural, non-proteinaceous ion channel. Consideration of all our previous work in these fields led to the obvious idea of investigating the amide analogues of [P(3-HB)] oligomers A, D, the P-peptide oligomers B, C, E derived entirely from P-homoalanine. Furthermore, we have already commented on the conflicting opinions, within the literature, as to the likely structures of P-peptide~[~?~] and taking these reports, the work[l01 of Goodman et al. specifically related to poly [(S>-P-aminobutanoic acid], the very recent work" l ] of Gellman and coworkers, and our recent work into account, an investigation into the structure of these P-HAla peptides is also of interest. We now report the synthesis of both linear and cyclic Ppeptides derived entirely from either P-homoalanine (H-P- HAla-OH) or N-methyl-P-homoalanine (H-NMe-PHAla-OH) and our initial investigations into their structural characteristics. SynthesisIn our previous ~o r k [ '~-'~l , we have made use of the Arndt-Eistert homologation of an a-amino acid for the

X-Ray diffraction analyses of the fully protected peptides Boc-[(S)-Iva],-OMe (n = 3, 4 , 6) reveal two independent molecules in the asymmetric unit. The structures of these can be described as fi-turns or 310 helices (depending on the length of the oligopeptide) of alternating screw sense (M and P ) in a head to tail alignment. This structure is stabilized by hydrogen bonds between the N-H(l) of the (M)-helix and the O=C(o-1) of the (P)-helix and the N-H(2) (M) and the ester carbonyl group (P). Low temperature 'H-NMR spectra of the hexamer in CDZCl2 solution show two interchanging species in a ratio of 4 : l ; NOESY experiments prove that these are the two helical conformers found in the crystal ( P : M , 4 : l ) . The NOESY spectrum at -90°C indicates the pairing of ( P ) and (M) helices. Thermodynamic and kinetic parameters for the helix transformation P @ M (unfolding/folding) are presented.

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