Total synthesis of polycarbocyclic sesquiterpenes: A survey of novel methods and reactions

Limonoids are highly oxygenated C13α-triterpenes and common secondary metabolites. Several hundred congeners have been isolated to date. The first total synthesis of (±)-limonin, the flagship congener of the limonoids, is now reported and features 1) a tandem radical cyclization generating the BCD ring system with the C13α configuration that is essential to the limonoids and a Robinson annulation to construct the limonoid androstane framework, 2) a singlet-oxygen cycloaddition and a Baeyer–Villiger oxidation to synthesize the highly oxidized D ring, and 3) a Suarez reaction to construct the unique AA′ ring system.

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Total Synthesis of Limonin

Diels−Alder reactions of labile and readily dimerizing masked o-benzoquinones, i.e., substituted 6,6-dimethoxy-2,4-cyclohexadienones with electron-deficient dienophiles that resulted in the development of an efficient and reliable one-pot method for the preparation of highly functionalized bicyclo[2.2.2]octenones, are described. Oxidation of 2-methoxyphenols 8, 9, 11, 13, and 14 with (diacetoxy)iodobenzene in methanol afforded the corresponding masked o-benzoquinones 1, 2, 4, 6, and 7, which are not stable enough to be isolated and are found to dimerize under reaction conditions in a highly regio- and stereoselective manner to provide the Diels−Alder dimers 22, 23, 25, 27, and 28 respectively. On the other hand, masked o-benzoquinones 3 and 5, derived from phenols 10 and 12, respectively, were found to be quite labile and provided a complex mixture of products. However, masked o-benzoquinones 1−7, when generated in the presence of dienophiles such as methyl acrylate, methyl methacrylate, and methyl vinyl ...

Generation, Stability, Dimerization, and Diels−Alder Reactions of Masked o-Benzoquinones. Synthesis of Substituted Bicyclo[2.2.2]octenones from 2-Methoxyphenols

2.6. Radical Reactions 5932 2.6.1. Radical Halogenation 5932 2.6.2. Ring-Opening and Expansion 5932 2.6.3. Miscellaneous 5934 2.7. Ring-Opening and Ring Expansion 5934 2.7.1. Cyclic Acetals 5934 2.7.2. Epoxides 5934 2.7.3. Cycloalkanes 5935 2.7.4. Ozonides 5937 2.7.5. Ring Expansion 5938 2.8. Ring Closure and Contraction 5939 2.8.1. Ring Closure 5939 2.8.2. Ring Contraction 5943 2.8.3. Ring Rearrangements 5943 2.9. Oxidation 5943 2.9.1. Oxidation of Halogenated Alcohols 5943 2.9.2. Oxidation of Olefins 5945 2.10. Pericyclic Reactions 5945 2.10.1. Cycloadditions 5945 2.10.2. Sigmatropic Rearrangements 5945 3. Synthesis of γ-Halo Ketones and Aldehydes 5946 3.1. Nucleophilic Substitution 5946 3.1.1. Enolate Alkylation 5946 3.1.2. Conversion of an Alcohol or Ether into an Alkyl Halide 5947

Synthesis of β-, γ-, δ-, ..., ω-halogenated ketones and aldehydes.

A four step synthesis of Seychellene (1) is described. Intramolecular Diels-Alder reaction of dienon 2 furnished the tricyclic ketones 3 and 4 in good yield. Hydrogenation of 3 gave 5 and 6. The higher reactivity of 6 with methyllithium compared to 5 allowed the selective preparation of 8, which, on subsequent acid-catalyzed rearrangment afforded Seychellen in 57,5% yield. In an analogues manner epi-Seychellene was synthetized via the intermediates 5 and 7.

Synthese von (±) Seychellen†

Total synthesis of dl-siccanin and dl-siccanochromene E

The total synthesis of (±)-seychellene (4,7,8-trimethyl-11-methylenetricyclo[5.3.1.03,8]undecane)(I) from2,3-di-methylcyclohex-2-en-1-one (XIV) is described. The ketone (XIV) was converted into 2-methyl-2-(3-methyl-5-iodopentyl)-3-methylenecyclohexan-1-one (XV), which gave 2-methyl-2-(3-methyl-5-iodopentyl)-3-bromo-methylcyclohexa-3,5-dien-1-one (XIX) with N-bromosuccinimide. Treatment of bromo-ketone (XIX) with chromium(II) chloride followed by acid gave 2,3-dimethyl-2-(3-methyl-5-iodopentyl)cyclohexa-3,5-dien-1-one (XXI). 2,3-Dimethyl-2-(3-methyl-5-dimethylaminopentyl)cyclohexa-3,5-dien-1-one (XXII) was obtained from the dienone (XXI) and was oxidised; pyrolysis of the resulting N-oxide yielded 4,7,8-trimethyltricyclo-[5.3.1.03,8]undec-9-en-11-one (VII). The adduct (VII) was hydrogenated to (±)-norseychellanone (4,7,8-trimethyltricyclo[5.3.1.03,8]undecan-11 -one), whose transformation into (±)-seychellene is known.

Total synthesis of (±)-seychellene

Pyrolysis of the N-oxide of 6-(5-dimethylamino-3-methylpentyl)-5,6-dimethylcyclohexa-2,4-dienone gives a tricyclic ketone which on hydrogenation yields racemic norseychellanone.

Synthesis of racemic seychellene based upon intramolecular Diels–Alder addition of a cyclohexadienone derivative

The stereoselective synthesis of dl -siccanin (1) and dl -siccano-chromene E (2) has been described. Acid isomerization of nonconjugated octalone 11a, derived from known octalone 5, stereoselectively provided cis-fused octalone 12, from which cis -drimane aldehyde 31 was obtained. After condensation of 31 with lithio-orcinol dimethyl ether, the product 32 was treated with pyridinium chloride to give tetrahydrofuran 33 whose complete stereostructure was unambiguously established by an X-ray crystal analysis. While cyclization of monophenol 34, obtained by partial demethylation of 33, with sulfuric acid afforded siccanochromene E methyl ether (35), reaction of 34 with Lewis acid gave siccanin methyl ether (36) along with 35. In the latter cyclization, the formation of 36 was demonstrated to occur from initially formed 35. Finally, demethylation of 35 and 36 provided 2 and 1, respectively. A novel tetrahydrofuran formation by a neighboring participation, which was observed in hydroxy ketone 24 and diol 32, are also discussed.

Narihiko Fukamiya

Papers

Total synthesis of dl-siccanin and dl-siccanochromene E

Total synthesis of (±)-seychellene

Synthesis of racemic seychellene based upon intramolecular Diels–Alder addition of a cyclohexadienone derivative

Total Synthesis of dl-Siccanin and dl-Siccanochromene E.