A-Onocerin synthesis

The coupling of carboxylic acids has been profitably used in natural product synthesis. Kolbe electrolysis of 8 is part of a (-j-)-a-onocerin synthesis [36], the electrolysis of 9 afforded a dimer with two quaternary carbon atoms [37], and 2,6,10,15,19,23-hexamethyltetracontane has been synthesized from 10 [38]. Cyclo-propylcarboxylic acids, e.g. 11 [39] and 12 [40], could be coupled to bicyclopropyl compounds others led to allylic compounds via ring opening of an intermediate carbenium ion. The dimerization of half-esters of diacids is also of industrial interest, because in this way l, -diesters are easily accessible [41]. 

Similarly, efficient tetracyclization (MeAlCl2-promoted) of the bis-allylic silane/ bis-epoxide 97 constitutes the key step in the synthesis of (+)-a-onocerin. In this case, because of the presence of the bis-allylic silane group, a double bis-annula-tion occurs, with the formation of the ethylene-bridge linked bis-decalin system present in the target compound (Scheme 8.26) [46],... 

A good example of the simplicity and power of the chemistry to rapidly construct complex systems is provided by the Kolbe dimerization of (55) as the key step of a total synthesis of the triterpene (+)-Q -onocerin (57 Scheme 14) [33], Thus, oxidation of (+)-hydroxy keto acid (55) in methanol containing a trace of sodium methoxide and at a temperature of 50 C, followed by acylation and chromatography, provided (+)-diacetoxydione (56) in a 40% yield. 

A more complicated example, in which the presence of symmetry reduces the problem of creating eight chiral centres to only four, is the case of (+)-a-onocerine (8), the synthesis of which [15] was performed by coupling of the two enantiomerically pure C 5 units (7, X = COOH), with the correct stereochemistry, in order to prevent the formation of the unnatural meso form d,l + l,d) (Scheme 4.2). 

As part of the total synthesis of the triterpene (+)-a-onocerin, one of the first total syntheses in which RuO played a key role, a diphenylethyleneacetoxyketone was oxidised to the corresponding acetoxyketoacid by RuO /aq. Na(10yacetone. Aromatic ring oxidation was also involved (cf. 3.3.1 below) [219]. An oxidative cyclisation of a 1,5-diene to a diol by RuCl3/Na(10 )/wet SiO /THF formed part of the synthesis of the antitumour agent cw-solamin [220]. 

Scheme 12.10. Synthesis of a-onocerin using butyldimethylsilyl, THF = tetrahydrofuran, a three-component nucleophilic addition/Brook Tf = trifluoromethanesulfonyl, DME = 1,2-rearrangement/alkylation on acylsilanes, by dimethoxyethane, TMS = trimethylsilyl, Corey and co-workers [33]. TBS = t- TBAF = n-tetrabutylammonium fluoride.

One step in the production of (5), a key intermediate in a synthesis of the tetracyclic triterpene a-onocerin, involved allylic oxidation of the a,)3-unsaturated ester (1). This was accomplished with Se02 in boiling acetic acid.18b The unsaturated hydroxy lactone produced (2) was next to be converted into the saturated keto acid (5), presumably by a stepwise process. However, the Israeli investigators were pleas-... 

After Stork etaL 123) had carried out the total synthesis of a a-onocerin (68), Tsuda and Hattori 124) in 1967 succeeded in converting (68) to hydroxyhopanone (69) via gammaceran-3-on-21-ol (70) (see Chart 16). 

In the absence of carbonyl compounds, allylic bromides treated with Cp2TiCl underwent the expected dimerization process, which has been exploited for the synthesis of symmetrical terpenoids such as squalene and [1-onocerin [82]. In contrast, non-allylic olefinic iodoethers and a-bromo carbonyl compounds underwent 5-exo cyclization to the corresponding tetrahy-drofuran derivatives [83,84]. 

The radicals may dimerize, participate in mixed coupling between two different radicals, or undergo cyclization. Each of these avenues is illustrated by the examples discussed next. Simple dimerization allows retrosynthetic disconnections to be made at any symmetrical carbon-carbon bond in a target molecule, and has been used in, for example, the synthesis of onocerin (13) [5], a- and )6-oconceradiene (14 and 15) [6], and pentacyclosqualene (16) [6,7]. The use of a mixed Kolbe oxidation allows disconnections to be made at nonsymmetrically substituted sites. A host of natural products have been generated using the latter protocol including, for example, brevicomin (21) [8], looplure (29) [9], and disparlure (35) [10] [note Scheme 2, Eq. (6), and Scheme 3]. 

A good example of the simplicity of the operation is provided by Stork s total synthesis of the complex triterpene (+)-o -onocerin (13) [5]. In tliis instance, the (+)-hydroxy keto acid 11 was oxidized in a methanol solution containing a trace of sodium methoxide at 0.1 A and 50 V, at a temperature of 50" C. Following acetylation with acetic anhydride/pyridine and chromatography, the (+)-diacetoxydione 12 was isolated in a 40% yield. 

If the retrosynthesis of a target compound leads to two symmetrical fragments, the Kolbe electrolysis is a favorable method for its synthesis. For example, the dimerization of L or LI is the key step in the synthesis of pentacyclosqualene [192] and of or-onocerin [193], respectively. Similarly, the precursor of a perhydrophenanthrene has been synthesized [194a]. 

The total synthesis of (+)- -onocerin via four-component coupling and tetracyclization steps was achieved in the laboratory of E.J. Corey. The farnesyl acetate-derived acyl silane was treated with vinyllithium, which brought about the stereospecific formation of a (Z)-silyl enol ether as a result of a spontaneous Brook rearrangement. In the same pot, the solution of I2 was added to obtain the desired diepoxide via oxidative dimerization. 

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