Die erste stereoselektive Totalsynthese eines dimeren γ‐Lacton‐ anellierten Pyranonaphthochinons: (+)‐γ‐Actinorhodin

Abstract

Uns gelang die erste Totalsynthese von einem isomerenreinen dimeren g-Lacton-anellierten Pyranonaphthochinon, (+ +)-g-Actinorhodin. Unsere elf Stufen umfassende Synthese nutzt zwei Mal ein Paar peri-ständiger Methoxygruppen als Mediatoren einer ungewçhnlichen Selektivitätssteuerung durche inen weit entfernten Brom-oder Iodsubstituenten. Dessen Sperrigkeit gaben die Methoxygruppen an die beiden Naphthalinpositionen weiter,a nd enen wir Ar-S E -Reaktionen vornahmen. Das ermçglichte bei einer Kernbromierung eine perfekte Regiokontrolle und bei einer Oxa-Pictet-Spengler-Cyclisierung die gewünschte Diastereokontrolle.Die Absolutkonfiguration unseres Zielmoleküls legte die Sharpless-Dihydroxylierung eines b,g-ungesättigten Esters fest, der einer Heck-Kupplung entstammte.S ie ergab den g-Hydroxylactonteil eines Bromnaphthalins,d er als Substrat der Oxa-Pictet-Spengler-Reaktion fungierte.Z um g-Actinorhodingerüst führte eine dimerisierende Suzuki-Kupplung.Abbildung 1. Natürliche und synthetische g-Lacton-anellierte Pyranonaphthochinone.[*] Dipl.-Chem.M .Neumeyer,Prof. Dr.R.B r ückner

Stereoselective Total Synthesis of the Dimeric Naphthoquinonopyrano-γ-lactone (−)-Crisamicin A: Introducing the Dimerization Site by a Late-Stage Hartwig Borylation

“…Neumeyer from our group achieved it in 11 steps. 21 A second stereoselective synthesis in the field is due to K. Suzuki et al, who attained the related compound (+)-actinorhodin (4 10 ) in 20 steps recently. 22 From the information in the introductory paragraph, the absence of γlactone moieties 23 lets compound 4 look like a hydrogenolysis product of compound 3, though.…”

“…It also entailed the hope of being useful beyond this specific objective. The ensuing retrosynthetic simplifications are akin to our approach to (+)-γ-actinorhodin: 21 (1) The tetracyclic building block 6 should stem from an oxa-Pictet−Spengler cyclization of the hydroxylactone 7; 27 as often 28 its steric course was hardly predictable. (2) The hydroxylactone 7 should arise by an asymmetric Sharpless dihydroxylation/in situ lactonization from a trans-configurated β,γ-unsaturated ester 8.…”

“…BF 3 •OEt 2 ); the less volatile the ester, the higher its yield (78% for the benzyl ester 12b). Their partner in the Heck couplings, the bromonaphthalene 9, stemmed from a known bromination of 1,4,5-trimethoxynaphthalene (10), 44 which, in turn, was at hand from an earlier execution 21 of a known 31 five-step synthesis.…”

“…Gratifyingly, it was separable from Ph 3 PO by column chromatography using pentane/acetone as an eluent. 57 In CH 2 Cl 2 , the ether functions of compound 16 were cleaved smoothly with AlCl 3 21,58 (→ 67% 5 59 ) but unselectively with BCl 3 58,60 (→ 5 + a structurally similar contaminant, which was inseparable). The 1 H NMR spectrum (500.10 MHz, CDCl 3 , CD 2 Cl 2 ) and 13 C NMR spectrum (125.75 MHz, CDCl 3 , CD 2 Cl 2 ) of our totally synthetic (−)-crisamicin A (5) matched their precedents from isolated (−)-crisamicin A (5 8,13 ).…”