First Stereoselective Total Synthesis of a Dimeric Naphthoquinonopyrano‐γ‐lactone: (+)‐γ‐Actinorhodin

Abstract

We have accomplished the first total synthesis of an isomerically pure naphthoquinonopyrano-γ-lactone dimer, γ-actinorhodin, in eleven steps. Two steps exploit pairs of peri-MeO groups as unusual selectivity controls. The respective MeO groups convey the steric bulk of a bromo or iodo substituent located ortho to one MeO group as steric hindrance into the vicinity of the second MeO group. This relay effect was indispensable for exerting regiocontrol in an aromatic bromination and diastereocontrol in an oxa-Pictet-Spengler cyclization. The absolute configuration of our target compound was established in an asymmetric Sharpless dihydroxylation of a β,γ-unsaturated ester, which was synthesized in a Heck coupling of a bromoiodonaphthalene with ethyl vinylacetate. The dihydroxylation provided the γ-hydroxylactone moiety of the bromonaphthalene that was used as the substrate in the oxa-Pictet-Spengler cyclization. Dimerization to the core of γ-actinorhodin occurred by two Suzuki couplings.

Controlling the Substitution Pattern of Hexasubstituted Naphthalenes by Aryne/Siloxyfuran Diels–Alder Additions: Regio‐ and Stereocontrolled Synthesis of Arizonin C1 Analogs

“…This strategy equals one, which we followed in total syntheses of the naphthoquinonopyrano-γ-lactone natural products (+)kalafungin (1a), [7c] (-)-arizonin B1 (2), [7r] (-)-arizonin C1 (3), [7s] and (+)-γ-actinorhodin. [21,22] The difference between the present syntheses and our former ones is how we prepareed the bromonaphthalene substrate of the Heck coupling. This is shown at the bottom of Scheme 2 and discussed in the next paragraph.…”

“…Each arizonin C1 analog of Figure or Scheme was prepared by an identical series of 4 late steps: 1) Heck‐coupling; 2) asymmetric dihydroxylation; 3) oxa‐Pictet–Spengler reaction; oxidation of the naphthohydroquinone (details: below). This strategy equals one, which we followed in total syntheses of the naphthoquinonopyrano‐γ‐lactone natural products (+)‐kalafungin ( 1a ),[7c] (–)‐arizonin B1 ( 2 ),[7r] (–)‐arizonin C1 ( 3 ),[7s] and (+)‐γ‐actinorhodin , . The difference between the present syntheses and our former ones is how we prepareed the bromonaphthalene substrate of the Heck coupling.…”

Total Synthesis of Actinorhodin

“…In reality, however, there are two significant distinctions: 1) the monomeric unit is enantiomeric ( ent ‐nanaomycin A is also a natural product), and 2) additional hydroxy groups at C6 and C6′ are present, conforming to binaphthazarin. Although numerous syntheses of the related monomers have been reported, the dimer synthesis is far more challenging, and the only example of a completed synthesis is the recently reported total synthesis of the kalafungin‐related, more oxidized dimer γ‐actinorhodin by Neumeyer and Brückner …”

Establishing Consensus Stereostructures for the Naphthoquinonopyrano‐γ‐lactone Natural Products (–)‐Arizonin B1 and (–)‐Arizonin C1 by Total Syntheses. Diastereocontrol of Oxa‐Pictet–Spengler Cyclizations by Protective‐Group Optimization

“…N ‐Bromosuccinimide (NBS) in N , N ‐dimethylformamide (DMF) brominates 2‐iodo‐1,4,5,8‐tetramethoxynaphthalene with perfect regioselectivity . This suggested that bromination of the naphthalene tetraether 16a could occur likewise.…”

“…Table shows eight γ‐naphthylated β‐hydroxy‐γ‐lactone substrates and details how they were carried on – with acetaldehyde or its dimethyl acetal –, giving eight different dihydropyrans, and what the respective 3a,5 trans ‐/ 3a,5 cis ‐selectivities were. Half of the substrate/product pairs stem from the current study ( 31 / 32 , 35 / 36 , and 38 / 39 ) or ( 48 / 49 ) from our total synthesis of γ‐actinorhodin . Three additional substrate/product pairs were studied by others and by ourselves ( 42 / 43 ,[10c] 44 / 45 ,[18a] and 46 / 47 ).…”