Synthesis of the octahydronaphthalene core of nahuoic acid A via a B(C₆F₅)₃-catalyzed intramolecular Diels–Alder (IMDA) reaction

Abstract

Model tetraenal 9b underwent intramolecular Diels-Alder cycloaddition in CHCl at -10 °C under catalysis by the bulky Lewis acid B(CF) to deliver as major components the cis-fused angularly-methylated octahydronaphthalene products, which are formed through the alternative exo orientations of the reacting moieties. One of these diastereomers features the relative and absolute configuration present in the core of nahuoic acid A, a natural product that acts as a cofactor-competitive inhibitor of the lysine methyl transferase SETD8. By contrast, catalysis of the reaction by MeAlCl at -40 °C selectively afforded the trans-fused isomer resulting from the Re-endo orientation.

Total synthesis of nahuoic acid A via a putative biogenetic intramolecular Diels–Alder (IMDA) reaction

“…While our efforts to synthesize nahuoic acid A (1a) were in progress, 19 the total synthesis of nahuoic acid Ci (1c, Scheme 2) was reported. 5 The cis-octahydronaphthalene fragment 9 was secured by intermolecular Diels-Alder cycloaddition reaction of components 5 and 6 promoted by enantiopure TADDOLderived titanium complex 7 to afford intermediate 8, followed by functional group interconversion and generation of additional stereocenters.…”

“…25a,b Members of natural [4+2]cyclases 25c-d including enzymes involved in inverse electrondemand Diels-Alder reactions, 25e have been identified in Nature, in some cases as part of enzymatic cascade reactions that generate further biosynthetic complexity. 25f-i We have already reported 19 the synthesis of functionalized tetraenal 25 and tetraenoates 26-27 (Scheme 4), which are shorter unsaturated analogues of pentaenoate 12 (Scheme 3) as model systems to test the feasibility of the IMDA tactic 22 to reach 1a. The IMDA reaction of tetraenal 25 led, under both purely thermal and Lewis acid-promoted IMDA reaction conditions, to the octahydronaphthalenes as mixtures of two cis-octahydronaphthalenes and a trans-diastereoisomer, thus confirming the formation of products through both exo approaches and through one of the putative endo alternatives, the latter being of lower energy.…”

“…The IMDA reaction of tetraenal 25 led, under both purely thermal and Lewis acid-promoted IMDA reaction conditions, to the octahydronaphthalenes as mixtures of two cis-octahydronaphthalenes and a trans-diastereoisomer, thus confirming the formation of products through both exo approaches and through one of the putative endo alternatives, the latter being of lower energy. 19 We wish to report herein the full account of our synthesis of nahuoic acid A (1a) based on the putative biogenetic proposal using the corresponding pentaenals related to 12 (Scheme 3), which required the contruction of the entire unsaturated acyclic skeleton in a highly diastereo-and enantioselective fashion.…”

“…For the preparation of functionalized tetraenes 25, 26 and 27 (Scheme 4) containing the acyclic skeletons required for the IMDA reaction, 19 a Suzuki-Miyaura cross-coupling 23 27 In addition, model pentaenals 34a and 34b were constructed by unsaturated chain extension of iodotrienal 19. 19 The Horner-Wadsworth-Emmons (HWE) reaction 28 of 19 19 with the corresponding anions of phosphonates 30a and 30b, generated with n-BuLi and DMPU in THF, afforded conjugated dienoates 31a and 31b, respectively (Scheme 4). Whereas the reaction with phosphonate 30a afforded a 5 :1 E/Z mixture of isomers of 31a in 77% yield, using the methyl-substituted analogue 30b both the isomer ratio (10:1) of pentaenoates 31b and the yield of the HWE reaction (89%) were higher.…”

“…Exhaustive NMR studies suggested structure 37 (Scheme 5) for the octahydronaphthalene diastereoisomer obtained in the IMDA reaction, which was further confirmed by X-Ray difraction analysis. 19 This compound must likely originate from the Re-endo orientation of the dienophile fragment relative to the reacting diene in non-conjugated tetraenal 25. . ).…”