2.3 Alkene-Mediated Cyclizations
Electrophile-activated alkene additions are a common chemical transformation of
carbon–carbon double bonds. This section will review some of the more common
methods encountered in the context of macrolide natural product synthesis. Typically, THP formation occurs by a 6-exo-trig cyclization of δ-hydroxy alkenes in the
presence of an appropriate metal salt. Activation of the π-system occurs through
reversible formation of a π-complex or an onium intermediate that leads to the
heterocycle by attack of the pendant oxygen nucleophile [43]. The stereochemical
outcome of the cyclization is dictated by the nucleophilic attack occurring on the
face opposite electrophilic π-complexation (Scheme 20). Facial discrimination of
the alkene can therefore be achieved through either substrate control (chiral
directing-group coordination) or chiral metal reagent/catalyst.
Metal-activated alkene additions can be classified as stoichiometric or catalytic
processes. Stoichiometric processes for THP synthesis typically involve the use of
mercury(II) salts and to a lesser extent iodo and seleno reagents. The progress of
intramolecular oxymercuration is determined by the stability of the cationic intermediates. Product stereochemistry is under substrate control and usually leads to
the thermodynamically more stable THP product. Catalytic variations generally
involve palladium complexes [44], but other transition metals are becoming more
common (e.g., Pt [45], Ag [46], Sn [47], Ce [48]). The oxidation state of Pd
determines the catalyst reactivity. Palladium(0) complexes are nucleophilic and
participate in tetrahydropyran synthesis through π-allyl cation intermediates,
whereas Pd(II) complexes possess electrophilic character and progress through a
reversible π-complex.
Masamune et al. reported on an oxymercuration approach to the synthesis of the
B ring of bryostatin 1 (Scheme 21) [49]. Mercury acetate-mediated cyclization of
63 followed by acetylation of the C7 alcohol allowed for oxidative cleavage of the
organomercurial intermediate to give a 1:1 diastereomeric mixture of 4-methylene
THP 64 in good yield (64 % over three steps). The lack of diastereoselection can be
attributed to the absence of a chelating directing group near the reacting alkene
center.
Leighton et al. described an effective and mild palladium-catalyzed tandem
alkene addition/carbonylation procedure in the synthesis of leucascandrolide A
[50]. Intramolecular alkoxycarbonylation of diol 65 under Semmelhack conditions
proceeded efficiently to provide the desired 2,6-cis-tetrahydropyran 66 in 75 %
yield with a dr of >10:1 (Scheme 22). Reaction optimization showed that use of
benzonitrile as a cosolvent leads to cleaner and more efficient reactions. The
functional group tolerance and chemoselectivity of the reaction simplified the
protecting group strategy.
Fettes and Carreira were the first to describe the use of a selenium-based reagent
to effect alkoxymetallation of an alkene to give a 2,6-trans tetrahydropyran in the
total synthesis of leucascandrolide A [22]. Various electrophiles (I 2 , IBr, and
Hg(OAc) 2 ) gave disappointing levels of diastereoselectivity (1:1), whereas
56
M.A. Perry et al.
Electrophile-activated alkene additions are a common chemical transformation of
carbon–carbon double bonds. This section will review some of the more common
methods encountered in the context of macrolide natural product synthesis. Typically, THP formation occurs by a 6-exo-trig cyclization of δ-hydroxy alkenes in the
presence of an appropriate metal salt. Activation of the π-system occurs through
reversible formation of a π-complex or an onium intermediate that leads to the
heterocycle by attack of the pendant oxygen nucleophile [43]. The stereochemical
outcome of the cyclization is dictated by the nucleophilic attack occurring on the
face opposite electrophilic π-complexation (Scheme 20). Facial discrimination of
the alkene can therefore be achieved through either substrate control (chiral
directing-group coordination) or chiral metal reagent/catalyst.
Metal-activated alkene additions can be classified as stoichiometric or catalytic
processes. Stoichiometric processes for THP synthesis typically involve the use of
mercury(II) salts and to a lesser extent iodo and seleno reagents. The progress of
intramolecular oxymercuration is determined by the stability of the cationic intermediates. Product stereochemistry is under substrate control and usually leads to
the thermodynamically more stable THP product. Catalytic variations generally
involve palladium complexes [44], but other transition metals are becoming more
common (e.g., Pt [45], Ag [46], Sn [47], Ce [48]). The oxidation state of Pd
determines the catalyst reactivity. Palladium(0) complexes are nucleophilic and
participate in tetrahydropyran synthesis through π-allyl cation intermediates,
whereas Pd(II) complexes possess electrophilic character and progress through a
reversible π-complex.
Masamune et al. reported on an oxymercuration approach to the synthesis of the
B ring of bryostatin 1 (Scheme 21) [49]. Mercury acetate-mediated cyclization of
63 followed by acetylation of the C7 alcohol allowed for oxidative cleavage of the
organomercurial intermediate to give a 1:1 diastereomeric mixture of 4-methylene
THP 64 in good yield (64 % over three steps). The lack of diastereoselection can be
attributed to the absence of a chelating directing group near the reacting alkene
center.
Leighton et al. described an effective and mild palladium-catalyzed tandem
alkene addition/carbonylation procedure in the synthesis of leucascandrolide A
[50]. Intramolecular alkoxycarbonylation of diol 65 under Semmelhack conditions
proceeded efficiently to provide the desired 2,6-cis-tetrahydropyran 66 in 75 %
yield with a dr of >10:1 (Scheme 22). Reaction optimization showed that use of
benzonitrile as a cosolvent leads to cleaner and more efficient reactions. The
functional group tolerance and chemoselectivity of the reaction simplified the
protecting group strategy.
Fettes and Carreira were the first to describe the use of a selenium-based reagent
to effect alkoxymetallation of an alkene to give a 2,6-trans tetrahydropyran in the
total synthesis of leucascandrolide A [22]. Various electrophiles (I 2 , IBr, and
Hg(OAc) 2 ) gave disappointing levels of diastereoselectivity (1:1), whereas
56
M.A. Perry et al.