The design and implementation of cascade reactions is a challenging facet of organic chemistry, yet one that can impart striking novelty, elegance, and efficiency to synthetic strategies. The application of cascade reactions to natural products synthesis represents a particularly demanding task, but the results can be both stunning and instructive. This Review highlights selected examples of cascade reactions in total synthesis, with particular emphasis on recent applications therein. The examples discussed herein illustrate the power of these processes in the construction of complex molecules and underscore their future potential in chemical synthesis.

Cascade reactions in total synthesis.

beta-Peptides: from structure to function.

The preparation of urea by Wöhler constituted a landmark achievement in organic chemistry, and it laid the ground for the early days of target-oriented organic synthesis.1 Since then, significant progress has been achieved in this discipline; many powerful single bond forming reactions and asymmetric variants have been developed. These discoveries have paved the way for the stereoselective assembly of complex organic molecules, a task deemed inconceivable by early practitioners. A great many strategies were invented by chemists in order to facilitate the synthesis of complex natural products.2 One avenue in emulating nature’s efficiency would * To whom correspondence should be addressed. E-mail: dennis.hall@ ualberta.ca. † Novartis Institute for Biomedical Research. ‡ Department of Chemistry, University of Alberta. Chem. Rev. 2009, 109, 4439–4486 4439

Natural product synthesis using multicomponent reaction strategies.

Synthetic helical polymers: conformation and function.

10.2. Synthesis of Other -Amino Acid Derivatives 3676 10.2.1. Synthesis of -Amino Ketones 3676 10.2.2. Synthesis of -Amino Nitriles 3679 10.2.3. Synthesis of -Amino Phosphinates 3680 10.2.4. Synthesis of -Amino Sulfonates 3681 11. Synthesis of 1,2-Amino Alcohols 3681 11.1. 1,2-Addition to R-Alkoxy Imines 3681 11.2. 1,2-Addition of R-Substituted Organometallic Reagents to N-tert-Butanesulfinyl Imines 3687 * E-mail: jellman@berkeley.edu. † These authors contributed equally to this work. Chem. Rev. 2010, 110, 3600–3740 3600

Synthesis and Applications of tert-Butanesulfinamide

Enantiomerically pure beta-amino acid derivs. with the side-chains of Ala, Val, and Leu in the 2- or 3-position (β2- and β3-amino acids, resp.), as well as with substituents in both the 2- and 3-positions (β2,3-amino acids, of like-configuration) were prepd. and incorporated into β-hexa-, β-hepta-, and β-dodecapeptides. The new and some of the previously prepd. beta-peptides showed NH/ND exchange rates (in MeOH at room temp.) with tau1/2 ? 60 days, unrivaled by short-chain alpha-peptides. All beta-peptides were designed to be able to attain the previously described 31-helical structure. CD measurements, indicating a new secondary structure of certain beta-peptides constructed of beta2- and beta3-amino acids, were confirmed by detailed NMR soln.-structure anal. A beta2-heptapeptide and a beta2,3-hexapeptide have the 31-helical structure, while to a beta2/beta3-hexapeptide with alternating substitution pattern H-(beta2-Xaa-beta3-Xaa)3-OH a novel, unusual helical structure (in (D5)pyridine and in CD3OH) was assigned, with a central 10-membered and 2 terminal 12-membered H-bonded rings, and with C:O and N-H bonds pointing alternatively up and down along the axis of the helix. Thus, two types of beta-peptide turns were identified in soln. Hydrophobic interactions of and hindrance to solvent accessibility by the aliph. side-chains are discussed as possible factors influencing the relative stability of the two types of helixes.

β2- and β3-Peptides with Proteinaceous Side Chains: Synthesis and solution structures of constitutional isomers, a novel helical secondary structure and the influence of solvation and hydrophobic interactions on folding

With 71 refs., this review presents various aspects of beta-peptides (oligomers of beta-amino acids): synthesis, structure detn. by NMR and CD, thermal stability properties, helical and beta-pleated secondary structures, peptide folding, biol. and pharmacokinetic activities.

β‐Peptides: Twisting and Turning

-amino-acid residue of likeconfiguration!) adopts a ten-membered-ring conformation for ca 5% of the simulation time, while the central section of the b-peptide C adopts a 14-membered-ring conformation for ca 3% of the time, according to this computational analysis Further experimental and theoretical work will be necessary to find out to which extent the components (H-bonded rings) and the entire helical secondary structures of b-peptides contribute to the observed Cotton effects

http://bioinf.uab.es/xavier/papers/helvchimacta_83-34.pdf

Structure and Conformation of β-Oligopeptide Derivatives with Simple Proteinogenic Side Chains: Circular Dichroism and Molecular Dynamics Investigations

A remarkably short (four steps, 31% overall yield) enantioselective synthesis of the structurally unique C2-symmetric tetracyclic triterpene (+)-α-onocerin (1) has been developed. The brevity of this mechanism depends on the assembly of four fragments (two molecules of a chiral epoxy ketone and two molecules of vinyllithium) to generate the chiral bis-epoxide 4 in one step, and on the efficient formation of all four carbocyclic rings in one step by cation−olefin tetracyclization. New and general methodology for the conversion of vinyl tert-butyldimethylsilyl ethers to vinyl triflates with retention of E or Z olefinic geometry also was utilized in the synthesis of 1. A short enantioselective synthesis of a non-C2-symmetric diastereomer of 1 is also described which uses the new methodology.

Total synthesis of (+)-α-onocerin in four steps via four-component coupling and tetracyclization steps

The structural properties of four mixed β-peptides with alternating β2/β3- or β3/β2-sequences have been analyzed by two-dimensional homonuclear 1H-NMR- and CD spectroscopic measurements. All four β-peptides fold into (P)-helices with twelve- and ten-membered H-bonded rings (Figs. 3–6). CD Spectra (Fig. 2) of the mixed β3/β2-hexapeptide 4a and β3/β2-nonapeptide 5a, indicating that peptides of this type also adopt the 12/10-helical conformation, were confirmed by NMR structural analysis. For the deprotected β3/β2-nonapeptide 5d, NOEs not consistent with the 10/12 helix have been observed, showing that the stability of the helix decreases upon N-terminal deprotection. From the NMR structures obtained, an idealized helical-wheel representation was generated (Fig. 7), which will be used for the design of further 12/10 or 10/12 helices.

Juerg V. Schreiber

Papers

β2- and β3-Peptides with Proteinaceous Side Chains: Synthesis and solution structures of constitutional isomers, a novel helical secondary structure and the influence of solvation and hydrophobic interactions on folding

β‐Peptides: Twisting and Turning

Structure and Conformation of β-Oligopeptide Derivatives with Simple Proteinogenic Side Chains: Circular Dichroism and Molecular Dynamics Investigations

Total synthesis of (+)-α-onocerin in four steps via four-component coupling and tetracyclization steps

Mixed β2/β3-Hexapeptides and β2/β3-Nonapeptides Folding to (P)-Helices with Alternating Twelve- and Ten-Membered Hydrogen-Bonded Rings