Grandisol synthesis

You saw in Chapter 21 how carbonyls form enolates when they are treated with base. On p. 528, you met nitriles doing something very similar, and the first step of the grandisol synthesis is the reaction of the enolate of a nitrile with an electrophile—an alkyl bromide. 

Methylcyclobutenyltrimethylsilane undergoes Friedel-Crafts acylation affording the 2-methyl-l-acetylcyclobutene [67223-99-8] which was an intermediate in the synthesis of grandisol [26532-22-9] (176). 

Scheme 21. The Barton reaction in Magnus s synthesis of grandisol (117).

Scheme 54 summarizes Font s synthesis of (+)-grandisol (36), the male pheromone of the cotton boll weevil (Anthonomus grandis) [80]. The key-step is the double [2+2] photocycloaddition of ethylene to bis(a,(3-butenohde) A to give B, which yielded C after glycol cleavage. The recently identified pheromone of the oleander scale (Aspidiotus nerii) possesses a structure similar to that of grandisol (Scheme 54), and its synthesis was reported by Ducrot [81 ] and also by Guerrero [82,83]. 

An example of the application of the metallacycle reaction to the synthesis of natural products is given by the synthesis of an intermediate for grandisol starting with isoprene (example 11, Table I). 

Electrocyclic closure of butadiene units encased within cycloheptane rings has been used to obtain bicyclo[3.2.0]heptene systems (Scheme 5)12. For example, irradiation of eucarvone 21 led to the formation of adduct 22 in 52% yield via a disrotatory ring closure123. This adduct was used as a key intermediate in the synthesis of the pheromone grandisol, 23, which proceeded in 20% overall yield from 22. In their synthesis of a-lumicolchicine. Chapman and coworkers utilized a photochemically initiated four-electron disrotatory photocyclization of colchicine to produce /Murnicolchicine 24a and its /-isomer 24b in a 2 1 ratio12b. These adducts were then converted, in a second photochemical step, to the anti head-to-head dimer a-lumicolchicine 25. 

Though the triplet sensitized photolysis of isoprene (159) does, as noted above, produce a complex mixture of products, one of these adducts has been used in the context of complex molecule synthesis (equation 5)71. Cyclobutane 160, which was formed in ca 20% yield by the benzophenone sensitized photolysis of 159, could be easily transformed into fragrantolol, 161, an isomer of grandisol isolated from the roots of the Artemisia fragrans, by simple hydroboration/oxidation of the less hindered double bond. 

Cyclobutane.—Grandisol syntheses have been re viewed,and Trost s full paper on grandisol and fragranol synthesis (Vol. 6, pp. 21, 22) has been published. 

Nickel(0)-catalyzed dimerization of isoprene (3 2-methylbuta-l.3-diene) has been used as the key step in the synthesis of (+)-grandisol (8), a male boll weevil pheromone. It is interesting to note that the cyclobutane 4 was formed by unsymmetrical and head-to-head cyclodimerization and that cycloadduets 5-7 were also formed in this transformation.9... 

Intramolecular cycloaddition of chiral ketene 3 has been successfully employed in the synthesis of both ( + )- and ( —)-grandisol, the principal pheromone of the boll weevil.14 Although a mixture of diastereomers 4 A and 4B is obtained, the products are optically pure. 

The ketene iminium salt cycloaddition route has been used to prepare a key intermediate 7 for the synthesis of grandisol.10... 

The photoaddition of the pyran-2-one (330) to ethylene to give the adduct (331) has been employed in a synthesis of grandisol,274 and the cyclobutane derivatives (332 and 333) were obtained on irradiation of the pyran-4-one (334) in 2-methylpropene.275 Photocycloadditions of dehydroacetic acid276 and 2,4-dioxo-3,3-dimethyl-2,3-dihydropyran277 have also been described, and the synthetically useful addition of 2,2,6-trimethyl-1,3-dioxolenone (335) to 2,3-dimethylbut-2-ene has been reported.278... 

The use of these cyclobutano sugars has been developed for the synthesis of natural products such as grandisol [47]. Both enantiomers of this pheromone are available by 2 + 2 photoaddition of ethylene to methyl hex-2-enopyranosid-4 ulose 44. After further manipulations, ( + ) and (—) grandisol (45, 46) are synthesized following Scheme 21. 

Stork, G. Cohen, J. F. Ring size in epoxynitrile cyclization. A general synthesis of functionally substituted cyclobutanes. Application to ( )-grandisol. /. Am. Chem. Soc. 1974, 96, 5270-5272. 

Babler, J. H. Base-promoted cyclization of a d-chloro ester application to the total synthesis of ( )-grandisol. Tetrahedron Lett. 1975, 2045-2048. 

The cyclohexenone 13 was needed for a synthesis of the boll weevil hormone grandisol. Disconnection with Robinson annelation (chapter 21) in mind gives the rather unstable looking enone 15. No doubt a Mannich method could be used (16 R = NR2) but any leaving group X in 16 will do. 

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