Octalone synthesis

The 5-oxohexanal 27 is prepared by the following three-step procedure (1) 1,2-addition of allylmagnesium bromide to an a, / -unsaturated aldehyde to give the 3-hydroxy-1,5-diene 25, (2) oxy-Cope rearrangement of 25 to give 26, and (3) palladium catalyzed oxidation to afford 27. The method was applied to the synthesis of A -2-octalone (28), which is difficult to prepare by the Robinson annulation[25]. 

Alkene acylation may be used in the synthesis of cyclic products by appropriately selecting the alkene and the acid derivative. When a,P-unsaturated acid halides react with cycloalkenes, the intermediate undergoes cyclization to yield octalones and indanones 112... 

A Dieckmann reaction of 7 and enol etherification provided trans-octalone 6 in 90% yield. An additional 10% of the transposed /3-ethoxy -enone 24 was also isolated. Compound 24 could easily be removed chromatographically (the first chromatography of the synthesis) and could be isomerized back to the 9 1 mixture in favor of 6 by resubjection to the etherification conditions. Compound 7 had three different CC Et groups, yet only the one adjacent to the CN group was attacked by the nascent ketone enolate. This selectivity, attributed to the effect of the powerfully electron-withdrawing CN group, was expected, as it was observed previously in the preparation of 3c.3 The selectivity of the enol ether formation was also expected from previous work. 

Another highlight of the period under review is the report of the total synthesis of the tricyclic alkaloid fawcettimine (22) (Scheme 2).9 Lewis-acid-catalysed Diels-Alder addition of butadiene to 2-allyl-5-methylcyclohex-2-enone provided the ds-octalone (23), which was modified as indicated to give the dialdehyde (24). After considerable experimentation, conditions were defined which led to regioselective ring-closure in the desired direction. The unsaturated aldehyde was treated directly with the Wadsworth-Emmons reagent to provide... 

The first enantiospecific total synthesis of (-)-PF1092A, B and C (10- 12) is based on the SnCLf- promoted cyclization of an a-keto methyl sulfone and dimethyl acetal followed by a Stork annulation which gives the octalone core (3) (Scheme 1). 

A new short and elegant total synthesis of ( )-luciduline, utilizing a novel intramolecular addition of an N-alkenyl-nitrone to a double bond, has been reported4 and is summarized in Scheme 1. The cis-octalone (9), along with some of... 

A similar [4 + 2] cycloaddition across the a, -positions has been observed in the reaction of isophorone dienamines with electrophilic alkenes (vide infra), and a similar ring opening has been postulated in the reaction of methyl vinyl ketone with dienamines in aprotic media (Section VII.C). Confirmatory evidence for the role of the C-3 methyl group in the above reaction was obtained from reaction of 8-methyl-A 1,8a-2-octalone dienamine with methyl acrylate only the /Talkylated product was obtained in protic and aprotic solvents14. The reaction of dienamines with electrophilic alkenes is discussed further in the section on carbocyclic synthesis (Section VII.C). 

Under conditions not favoring dehydration alternative hydrolytic pathways predominate.233 Thus, if the carbinolamine derived from compound (101) is treated with aqueous base, the main product is the octalone (102).234 This annelation clearly has great potential in synthesis, and it has already been exploited in, for example, the construction of the AB ring system of steroids (Stork and McMurry235 see also Ohashi236). 

Three independent syntheses of fukinone (335) have been published. In the first of these, Piers and Smillie ° converted the octalone (336), which they had previously used in connection with their synthesis of aristolone, into (337) by treatment with ethyl formate followed by catalytic reduction. Dehydrogenation of (337) with 2,3-dichloro-5,6-dicyanobenzoquinone and subsequent oxidation and esterification yielded (338). This keto-ester was converted into fukinone (335) by hydrogenation followed by methylation of the enolate ester and dehydration of the resultant keto-alcohol (339). Torrence and Finder have also completed the synthesis of fukinone using the octalone (336) as the key intermediate. 

The continued fascination chemists possess with asymmetric synthesis provides the basis for the next four procedures. The synthesis of (R)-(-)-10-METHYL-l(9)-OCTALONE-2 is a nice demonstration of an asymmetric Michael addition by a chiral imine followed by an aldol—in short an asymmetric Robinson annulation. The asymmetric glycolization to STILBENE DIOL (R,R-l,2-DIPHENYL-I,2-ETHANEDIOL) represents an olefin oxidation using catalytic alkaloids in tandem with osmium tetroxide. As reagents for a variety of asymmetric alkylations, the preparation of 2-CYANO-6-PHENYLOXAZOLOPIPERIDINK is pavscnicd as well as another route to... 

A third example of synthesis of a cis-A -3-octalone is the reaction of (1) with 2-methylcylohexenone (8). 

The use of a-silylated vinyl ketone is another approach to overcome drawbacks of the standard Robinson annulation conditions such as polymerization of the vinyl ketone. The a-silylated vinyl ketones are stable and can undergo Michael addition in standard aprotic conditions (conditions that induces polymerization for vinyl ketones), as well as protic conditions. Synthesis of the octalone 21 can be used as an example of this variation. The silylated ketone 20 reacts with lithium enolate 13 (generated by methyllithium from its corresponding enol silyl ether in THE) in /-butyl... 

Sato and co-workers in 1991 showed the utilization of organotin triflate as the Lewis acid catalyst for the Michael addition step. Synthesis of octalone 30 is a good example in which silyl enol ether of cyclohexanone and MVK (1.3 1 ratio) reacts in DCM in the presence of 0.05 equivalent of Bu2Sn(OTf)2 at -78 C. After alkylation was complete, sodium methoxide in methanol was added, and the mixture was stirred at room temperature to give 30 in an excellent 89% yield. ... 

The conjugate addition of enolate anions to activated 3-trimethylsilyl-3-buten-2-one helped solve another long-standing problem in organic synthesis by permitting the annulation reaction to be carried out in aprotic solvents under conditions where enolate equilibration is avoided. The annulation of thermodynamically unstable lithium enolates with MVK, where equilibration to the more stable enolate occurs prior to Michael addition, often yields a mixture of stractmal isomers. For exan le, Boeckman successfully employed 3-trimethylsilyl-3-buten-2-one in a Robinson annulation sequence (eq 2). Thus treatment of cyclohexenone with lithium dimethylcuprate in diethyl ether and then with 3-trimethylsilyl-3-buten-2-one gives the desired Michael adduct, which is converted into the functionalized octalone in 52% overall yield. ... 

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