Although known for more than 50 years the rubromycin family still constitutes a fascinating class of antitumour antibiotics. They are characterized by a challenging molecular architecture with the central spiroketal unit as the key feature and possess highly attractive biological properties. After a short treatment of the history of their isolation, structural elucidation and biosynthesis, their biological activities will briefly be summarized. This review strongly emphasizes the synthetic efforts aimed at these complex hexacyclic spiroketals. Reactions leading to simple spiroketal model compounds are described, followed by the synthetic approaches to the fully functionalized naphthalene and isocoumarin “wings”. The coupling of these units and their transformations into more advanced spiroketals demonstrate “the state of the art” in this research field. Only Danishefsky and co‐workers have so far completed the total synthesis of a fully functionalized rubromycin derivative; however, their product heliquinomycinone (103) is still only the aglycon of the natural product heliquinomycin (7), and it was prepared as the racemic compound. All these achievements and pitfalls reveal that increased engagement of synthetic organic chemists is required to develop new methods to make rubromycins and their analogues available by a modular approach and with reasonable efficacy. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

The development of a new method for the enantioselective synthesis of disubstituted gamma-butyrolactones is reported. Based on this strategy, the total synthesis of three paraconic acids, that is (-)-roccellaric acid, (-)-nephrosteranic acid and (-)-protopraesorediosic acid, and the formal total synthesis of (-)-methylenolactocin and (-)-protolichesterinic acid is described, which are important because of their antibiotic and antitumor properties. Key steps of the synthesis are copper(I)-catalyzed asymmetric cyclopropanations of furans, highly diastereoselective Sakurai allylations, Lewis acid or Lewis base catalyzed retroaldol/lactonization cascades, and ruthenium(II)-catalyzed, intermolecular cross metathesis reactions.

Asymmetric 1,4-addition of arylboronic acids to (E)-methyl 2-cyano-3-arylpropenoates proceeded in the presence of a rhodium catalyst (3 mol %) coordinated with a chiral diene ligand, (R,R)-Ph-bod*, to give high yields of the corresponding methyl 3,3-diaryl-2-cyanopropanoates with high enantioselectivity (up to 99% ee). This catalytic asymmetric transformation was applied to the asymmetric synthesis of (R)-tolterodine.

An efficient synthesis of highly substituted naphthaldehyde derivatives 8 was required for the planned synthesis of compounds of the rubromycin family. Three different routes towards this goal were attempted. Route I started with 1,5-dihydroxynaphthalene (10), and the pentaalkoxy-substituted naphthaldehyde 17 was obtained in a straightforward sequence in moderate overall yield. Route II employed an aryne cycloaddition to generate the functionalized naphthalene skeleton. This sequence smoothly provided the bromonaphthalene derivative 19, which served as a very suitable precursor of aldehyde 24, boronic acid 25, and finally the unsymmetrically substituted hexaalkoxynaphthalene derivative 18. Unfortunately, though, the regioselective formylation of 18 to provide the desired aldehyde 8a was not possible, this key compound being obtained only in low yield. Whereas an attempted Claisen rearrangement of O-allylated derivative 30 furnished the wrong regioisomer 33, the ortho-Fries re-

Stepwise application of the Pd-catalyzed S(N)2' reaction and the desilylative S(E)2' reaction to the ambivalent 2-bromo-1-silyl-1,3-dienes provides a novel route to the highly enantioselective construction of tertiary and quaternary propargylic stereogenic centers via axially chiral allenylsilanes.