cyclic ether 59 in 87 % yield. Similarly, diene 60 smoothly underwent a RCM with
the second-generation Grubbs catalyst 11 to give the cyclic ether 61 in 53 % yield.
Chattopadhyay et al. combined [76, 77] a Claisen rearrangement with a RCM for
the synthesis of a range of carbocycles and heterocycles. Thus, 8-allyl-7-hydroxy4-methylcoumarin (63), obtained by using a Claisen rearrangement of 7-allyloxy-4methylcoumarin (62) (Scheme 11), was alkylated with butenyl bromide to install
the diene, producing 64. When compound 64 was treated with Grubbs catalyst 9,
the oxocinocoumarin 65 was obtained. Similarly, several other oxepino- and
oxocinocoumarins were analogously prepared. The study was later extended to
the preparation of oxepine and oxocine-annulated 2-quinolones [78].
The heliannuols are a promising group of phenolic allelochemicals isolated from
Helianthus annuus that exhibit useful biological activity [79]. The benzooxocin
ring system present within these molecules has induced synthetic activity using
RCM for their preparation. Snieckus and Stefinovic first reported [80] that the
diallylated benzene derivative 66 (Scheme 12), prepared by using their directedmetallation protocol, when treated with catalyst 9 followed by a catalytic hydrogenation of 67 provided (Æ)-helianane. Shishido et al. reported [81] an
enantioselective total synthesis of (À)-heliannuol A 73 (Scheme 13), the most active
member of the family [82]. Diene 70 was prepared in a sequence of ten steps in
which the stereogenic center at C7 was set by an enzymatic desymmetrization of the
prochiral diol 68. Compound 69 was obtained in 78 % enantiomeric excess, which
was increased to 100 % by recrystallization. RCM of diene 70, induced by catalyst
11, provided oxocin derivative 71 in an impressive yield of 88 %. The high yield for
this cyclization is probably due to the conformational constraints induced by both
the benzene ring and the geminal dimethyl group [83]. Compound 71 was then
elaborated into the natural product through a selective epoxidation.
At this point, and to highlight the potential of the metathesis strategy for the
synthesis of medium-sized oxacycles, it should be mentioned that two structurally
related families of natural products, although lactones, have been successfully
synthesized by RCM. Recently, a sequential Evans–Tishchenko and RCM developed
by Aird et al. [84] was used to access the functionalized eight-membered ring core of
octalactins, highly functionalized compounds produced by an actinomycete collected
Scheme 11 Combination of the Claisen rearrangement with RCM for the preparation of mediumsized ethers
Synthesis of Eight- to Ten-Membered Ring Ethers
331
the second-generation Grubbs catalyst 11 to give the cyclic ether 61 in 53 % yield.
Chattopadhyay et al. combined [76, 77] a Claisen rearrangement with a RCM for
the synthesis of a range of carbocycles and heterocycles. Thus, 8-allyl-7-hydroxy4-methylcoumarin (63), obtained by using a Claisen rearrangement of 7-allyloxy-4methylcoumarin (62) (Scheme 11), was alkylated with butenyl bromide to install
the diene, producing 64. When compound 64 was treated with Grubbs catalyst 9,
the oxocinocoumarin 65 was obtained. Similarly, several other oxepino- and
oxocinocoumarins were analogously prepared. The study was later extended to
the preparation of oxepine and oxocine-annulated 2-quinolones [78].
The heliannuols are a promising group of phenolic allelochemicals isolated from
Helianthus annuus that exhibit useful biological activity [79]. The benzooxocin
ring system present within these molecules has induced synthetic activity using
RCM for their preparation. Snieckus and Stefinovic first reported [80] that the
diallylated benzene derivative 66 (Scheme 12), prepared by using their directedmetallation protocol, when treated with catalyst 9 followed by a catalytic hydrogenation of 67 provided (Æ)-helianane. Shishido et al. reported [81] an
enantioselective total synthesis of (À)-heliannuol A 73 (Scheme 13), the most active
member of the family [82]. Diene 70 was prepared in a sequence of ten steps in
which the stereogenic center at C7 was set by an enzymatic desymmetrization of the
prochiral diol 68. Compound 69 was obtained in 78 % enantiomeric excess, which
was increased to 100 % by recrystallization. RCM of diene 70, induced by catalyst
11, provided oxocin derivative 71 in an impressive yield of 88 %. The high yield for
this cyclization is probably due to the conformational constraints induced by both
the benzene ring and the geminal dimethyl group [83]. Compound 71 was then
elaborated into the natural product through a selective epoxidation.
At this point, and to highlight the potential of the metathesis strategy for the
synthesis of medium-sized oxacycles, it should be mentioned that two structurally
related families of natural products, although lactones, have been successfully
synthesized by RCM. Recently, a sequential Evans–Tishchenko and RCM developed
by Aird et al. [84] was used to access the functionalized eight-membered ring core of
octalactins, highly functionalized compounds produced by an actinomycete collected
Scheme 11 Combination of the Claisen rearrangement with RCM for the preparation of mediumsized ethers
Synthesis of Eight- to Ten-Membered Ring Ethers
331