Total Synthesis of (−)‐Cylindrocyclophane F: A Yardstick for Probing New Catalytic C−C Bond‐Forming Methodologies

Abstract

A short and efficient total synthesis of the C -symmetric (-)-cylindrocyclophane F is presented, using a cross olefin metathesis dimerization strategy for construction of the [7,7]-paracyclophane macrocycle. The synthesis of the dimerization building block includes a Pd-catalyzed sp -sp Negishi cross coupling of a sterically hindered Zn-reagent with an aromatic triflate, an enantiospecific Zn-catalyzed sp -sp cross coupling of an α-hydroxy ester triflate with a Grignard reagent and the application of an enantioselective Rh-catalyzed C-allylation of an electron rich arene.

Rhodium-Catalyzed Allylation Reactions

“…In 2018, the Breit group reported the convergent total synthesis of the C 2 -symmetric (-)-cylindrocyclophane F using ZnCl 2 -catalyzed cross coupling of an -hydroxy ester triflate and enantioselective Rh-catalyzed aryl allylation as the key steps (Scheme 85). 118 The coupling partner 283 was prepared by enantiospecific Zn-catalyzed Csp 3 -Csp 3 crosscoupling of -hydroxy ester triflate with Grignard reagent followed by reduction of tert-butyl ester 282 and iodination. Enantioselective Rh-catalyzed allylation of 284 with allylic carbonate 285 afforded desired aryl allylic product 286 in 87% yield and 91% ee, where (S,S)-DIOP ligand was M. B. Thoke, Q. Kang…”

Divergent Synthesis of Novel Cylindrocyclophanes that Inhibit Methicillin‐Resistant Staphylococcus aureus (MRSA)

“…We hoped to make use of a domino cross-metathesis-ring-closing metathesis cascade as the pivotal ring-forming step based on recent syntheses that have employed similar head-to-tail cyclodimersations to good effect. [26][27][28][29][30]34] From here, we felt that this common intermediate would be accessible from commercial materials in just a few steps (Scheme 1). This head-to-tail cyclodimerisation would enable the study of a homologous series of symmetrical [m.n]cylindrocyclophanes through variation of the chain length installed during synthesis.…”

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

“…As a result of our interest in probing some recently developed stereoselective and catalytic C-C bond-forming reactions in total synthesis, we became interested in the total synthesis of (-)-cylindrocyclophane F (6). 10 We surmised that the C 2 -symmetric [7,7]-paracyclophane framework might be best constructed by means of Smith's CM/RCM strategy from two identical building blocks, but using different bond disconnections between positions 5 and 6 and between 18 and 19. Thus, our synthesis plan traced back to the dimerization substrate 75.…”

“…4 Their unique structure garnered attention from more than five groups who worked on developing various total syntheses of (-)-cylindrocyclophanes A (1) and F (6). [5][6][7][8][9][10] Diverse synthetic methodologies have been utilized either for the installation of the [7,7]-paracyclophane scaffold or for the construction of its various stereocenters. Among these, transition-metal-catalysis-based methods, in particular, permitted the concise construction of these compounds.…”