cyclized product 164 in reasonable yield. Intriguingly, changing the substitution
pattern of the linear precursor modified the mode of cyclization. Thus, treatment of
4-allylcoumarin under identical reaction conditions gave the 8-exo cyclized product
160, a result that has to be explained mechanistically [134].
Kumar et al. and Waldman et al. reported the preparation of benzoxocines by
using an Au(I)-catalyzed 8-endo-dig cyclization (Scheme 33) [135]. Treatment of
propargyl ether 165 with an in situ generated cationic Au(I) species yielded
benzoxocine 166. This reaction presumably proceeds through the initial formation
of the gold–alkyne complex 167, followed by an 8-endo-dig cyclization to generate
168 which led to the observed product 166.
2.2.3 Alkylation of Anion
As the previously described approaches, intramolecular enolate alkylation has not
found widespread use for the preparation of medium-ring ethers, except for a few
eight- and nine-membered ring ethers.
Kim et al. have developed an intramolecular amide enolate alkylation as a key
step for the syntheses of several natural products, such as cladiellin diterpene [136],
and laurencin [59]. These authors found that the cyclization of (E)-allylic chloride
amides through an S N 2
0 pathway furnishes tetrahydropyrans such as 170
(Scheme 34), but when the corresponding (Z )-allylic chloride was employed,
Δ
4 -oxocine 171 was found to be the major product from an S N 2 pathway with
only a minor amount of the expected S N 2
0 product 170. This result highlighted the
key role played by the alkene geometry in directing the course of the cyclization.
Kim et al. used this strategy to achieve the first total synthesis of (E)-cladiellin
and a variety of 2,11-cyclized cembranoids [137]. Enolization of highly
functionalized amide 172 with LiHMDS cleanly afforded the nine-membered ring
ether 173 (Scheme 35), presumably through a lithium-chelated (E)-enolate.
Scheme 33 Au(I)-mediated formation of benzoxocines
Synthesis of Eight- to Ten-Membered Ring Ethers
347
pattern of the linear precursor modified the mode of cyclization. Thus, treatment of
4-allylcoumarin under identical reaction conditions gave the 8-exo cyclized product
160, a result that has to be explained mechanistically [134].
Kumar et al. and Waldman et al. reported the preparation of benzoxocines by
using an Au(I)-catalyzed 8-endo-dig cyclization (Scheme 33) [135]. Treatment of
propargyl ether 165 with an in situ generated cationic Au(I) species yielded
benzoxocine 166. This reaction presumably proceeds through the initial formation
of the gold–alkyne complex 167, followed by an 8-endo-dig cyclization to generate
168 which led to the observed product 166.
2.2.3 Alkylation of Anion
As the previously described approaches, intramolecular enolate alkylation has not
found widespread use for the preparation of medium-ring ethers, except for a few
eight- and nine-membered ring ethers.
Kim et al. have developed an intramolecular amide enolate alkylation as a key
step for the syntheses of several natural products, such as cladiellin diterpene [136],
and laurencin [59]. These authors found that the cyclization of (E)-allylic chloride
amides through an S N 2
0 pathway furnishes tetrahydropyrans such as 170
(Scheme 34), but when the corresponding (Z )-allylic chloride was employed,
Δ
4 -oxocine 171 was found to be the major product from an S N 2 pathway with
only a minor amount of the expected S N 2
0 product 170. This result highlighted the
key role played by the alkene geometry in directing the course of the cyclization.
Kim et al. used this strategy to achieve the first total synthesis of (E)-cladiellin
and a variety of 2,11-cyclized cembranoids [137]. Enolization of highly
functionalized amide 172 with LiHMDS cleanly afforded the nine-membered ring
ether 173 (Scheme 35), presumably through a lithium-chelated (E)-enolate.
Scheme 33 Au(I)-mediated formation of benzoxocines
Synthesis of Eight- to Ten-Membered Ring Ethers
347