The exploitation of ring strain as a driving force to facilitate chemical reactions is a well-appreciated principle in organic chemistry. The most prominent and most frequently used compound classes in this respect are oxiranes and cyclopropanes. For rather a long time, cyclobutanes lagged behind these three-membered-ring compounds in their development as reactive substrates, but during the past decade an increasing number of useful reactions of four-membered-ring substrates have emerged. This Minireview examines corresponding catalytic reactions ranging from Lewis or Brønsted acid catalyzed processes to enzymatic reactions. The main focus is placed on transition-metal-catalyzed C-C bond-insertion and β-carbon-elimination processes, which enable exciting downstream reactions that deliver versatile building blocks.

The search for new pharmaceutically relevant lead structures still has a focus on natural products. [1] In particular, cytotoxic compounds isolated from marine sources display a rich structural diversity.[2] However, the often highly potent compounds frequently lack selectivity for cancer cells over nontransformed wild-type cells. Largazole (1), which was recently isolated in scarce amounts by Luesch and co-workers from cyanobacteria of the genus Symploca, appears to be an exception to this pattern.[3] The growth-inhibitory activity of 1 is considerably higher for cancer cell lines (GI 50 = 7.7 nm) than for the corresponding nontransformed cells (GI 50 = 122 nm).[3] This excellent property makes 1 an important synthetic target. A synthesis should provide enough material for further biological studies to establish the biological profile of 1 in more detail and to determine the mode of action of 1 and the origin of its observed growth-inhibition selectivity.The structure of largazole (1) consists of several uncommon structural motifs, such as a 4-methylthiazoline unit, which, in analogy to didehydromirabazole, [4] is fused linearly to a thiazole ring, and a sensitive thioester moiety. We chose a synthetic approach that would enable the late-stage preparation of different analogues from a common precursor. This aim is reflected in our retrosynthetic strategy (Scheme 1): We planned to assemble 1 by a cross-metathesis reaction between the alkene 2 a [5] and the cyclic core in the form of the cyclic terminal alkene 13 (see Scheme 3), which in turn should be accessible from the fragments 3 and 4 through the formation of two amide bonds.The synthesis of fragment 3 started with an enzymatic resolution of alcohol 5 with Amano lipase PS to provide acetate 6 with excellent enantioselectivity (Scheme 2).[6] The subsequent hydrolysis of 6 required very mild conditions, as elimination to the conjugated diene occurs as a competing reaction. This side reaction was mitigated by the use of potassium carbonate in methanol. The optically pure allylic alcohol (S)-5 obtained in this way in 82 % yield was esterified with Fmoc-l-valine to give the amine fragment 3 after cleavage of the Fmoc group with piperidine.The cyano-substituted thiazole 10 [7] was prepared in four steps in an overall yield of 39 % from N-Boc-aminoacetonitrile (7) and cysteine methyl ester hydrochloride (8). Basecatalyzed condensation gave the thiazoline, which was oxidized directly to the thiazole with bromotrichloromethane.Scheme 1. Retrosynthesis of largazole (1). Boc = tert-butoxycarbonyl.

A rhodium-catalyzed enantioselective insertion into the C-C bond of tert-cyclobutanols and subsequent proto-demetalation provides access to methyl substituted quaternary stereogenic centers in excellent yields and enantioselectivities. The reaction was used for a synthesis of (S)-4-ethyl-4-methyl-octane, the simplest saturated hydrocarbon with a quaternary stereogenic center.

Activation of otherwise inert bonds has significant potential in the design of efficient and synthetically useful transformations. While general catalytic carbon-carbon single bond activations are still in their infancy, this emerging area examines recent developments in the activation of strained rings, focusing on enantioselective reactions.

The catalytic activation of C-C bonds bears significant ecological and economical advantages. In this account we describe our results for an enantioselective C-C activation of symmetrically substituted tert-cyclobutanols. Subsequent downstream reactions of the obtained alkylrhodium intermediate give rise to a wide range of synthetically versatile products bearing all-carbon quaternary stereogenic centers with excellent enantioselectivities. Intramolecular Bond-Activation Reactions 3.1 Aromatic C(sp 2 )-H Activations 3.2 Aromatic C(sp 2 )-SiR 3 Activations 3.3 1,3-Shift Reactions, C(sp 3