Total Syntheses of Cylindrocyclophanes Exemplifying the Power of Transition-Metal Catalysis in Natural-Product Synthesis

Abstract

Cylindrocyclophanes are a class of naturally occurring 22-membered macrocycles with a unique architecture and interesting physical, chemical, and biological properties. This comprehensive account summarizes progress in various synthetic approaches to these compounds during the last twenty years, thereby emphasizing the key steps for establishing the [7,7]-paracyclophane scaffold, as well as alternative approaches to the construction of its stereocenters. Many of these syntheses highlight the power of transition-metal catalysis for natural-product synthesis. Furthermore, the unraveling of the biosynthesis to these natural products in Cylindrospermum licheniforme is discussed.1 Introduction2 Biosynthesis3 Smith’s Synthesis of (–)-Cylindrocyclophanes A and F4 Hoye’s Synthesis of (–)-Cylindrocyclophane A5 Iwabuchi’s Syntheses of (–)-Cylindrocyclophane A and (+)-Cylindrocyclophane A6 Nicolaou’s Synthesis of (–)-Cylindrocyclophanes A and F7 Breit’s Synthesis of (–)-Cylindrocyclophane F8 Conclusion

Chemoenzymatic Synthesis of Cylindrocyclophanes A and F and Merocyclophanes A and D

“…Their unique molecular architectures, combined with their diverse biological activities, have inspired synthetic chemists to prepare them in laboratories. Until now, the total chemical synthesis of cylindrocyclophanes A ( 1 ) and F ( 2 ) has been achieved by two general strategies [4] . The groups of Smith, Iwabuchi, and Breit employed cross metathesis/ring‐closing metathesis (CM/RCM) dimerization to construct the paracyclophane framework [5] .…”

“…Until now, the total chemical synthesis of cylindrocyclophanes A (1) and F (2) has been achieved by two general strategies. [4] The groups of Smith, Iwabuchi, and Breit employed cross metathesis/ring-closing metathesis (CM/RCM) dimerization to construct the paracyclophane framework. [5] The Hoye group and the Nicolaou group used Horner-Wadsworth-Emmons olefination and Ramberg-Bäcklund olefination to establish macrocyclic scaffolds, respectively.…”

Structural Basis for the Friedel–Crafts Alkylation in Cylindrocyclophane Biosynthesis

“…They feature an all-carbon 22-membered [7.7]­paracyclophane scaffold and possess a variety of biological activities, including antifungal, antibacterial, and cytotoxic activities. Several elegant strategies have been developed toward chemical synthesis of cylindrocyclophanes, − whereas their biosynthetic machinery has intrigued scientists for many years. , Recently Balskus and co-workers identified the biosynthetic gene cluster of cylindrocyclophane in C. licheniforme ATCC 29412 and deciphered the biosynthetic pathway for cylindrocyclophane F ( 3 ). − CylK, the key enzyme that catalyzes the dimerization and cyclization of compound 1 to form the [7.7]­paracyclophane scaffold was identified and characterized (Figure b) . CylK is the first enzyme discovered to catalyze the Friedel–Crafts alkylation reaction of an aromatic ring with an alkyl halide.…”

“…6,7,8,11,12 ) have all their sixcoordination from the carbonyl groups or the carboxylate oxygen atoms of the D/E side chains. The bindings of Ca 9 and Ca 10 are associated with two relatively long β2 i −β3 i loops, L2 (residues 393−413) in blade 3 and L3 (residues 459−472) in blade 4, respectively.…”

Structural Basis for the Friedel-Crafts Alkylation in Cylindrocyclophane Biosynthesis

“…11 They feature an all-carbon 22-membered [7.7]paracyclophane scaffold and possess a variety of biological activities, including antifungal, antibacterial, and cytotoxic activities. Several elegant strategies have been developed toward chemical synthesis of cylindrocyclophanes, [12][13][14][15][16][17][18][19] whereas their biosynthetic machinery has intrigued scientists for many years. 20,21 Recently Balskus and co-workers identified the biosynthetic gene cluster of cylindrocyclophane in C. licheniforme ATCC 29412 and deciphered the biosynthetic pathway for cylindrocyclophane F (3).…”