The tandem Ru-catalyzed alkene–alkyne coupling/conjugate addition sequence
occurred in modest yield (34 %) yet showed remarkable chemoselectivity and
functional group tolerance (80 % brsm) (Scheme 66).
5.2 Summary
These representative examples demonstrate the usefulness of HDA reactions for
THP synthesis in the context of complex natural products. Both chiral auxiliary and
asymmetric catalysis methods offer a reliable way to construct 6-membered oxygen
heterocycles in high yield and stereoselectivity. The chiral auxiliary approach
benefits from the wide array of available chiral auxiliaries as well as a number of
ways to stereoselectively install chiral moieties contained within the natural product.
Removal of the auxiliary imposes additional synthetic considerations. The strength
of the asymmetric catalysis tactic comes from the ability to generate chiral products
from achiral substrates with high levels of stereocontrol. While these approaches
produce DHP rings, there are several methods available for their transformation to
highly substituted THP products making HDA an attractive method.
6 C2 Functionalization of Lactols and Lactones
Functionalization of lactols or lactones is a useful method for introducing substitution at the C2 position of tetrahydropyran rings [122]. Retrosynthetically, this
transformation can be envisioned as arising from a Lewis acid-mediated alkylation
of an oxocarbenium ion by an organometallic nucleophile (Scheme 67, Eq. 1). The
stereochemical outcome of the reaction is predicted by axial attack of the nucleophile on the half-chair conformation of oxocarbenium ion 252, to provide kinetically favored 2,6-trans THP 253 (Scheme 67, Eq. 2) [123]. The electronics of the
newly formed side chain must be taken into account when considering such
disconnections. For example, side chains bearing an electron-withdrawing group
(EWG) can sufficiently lower the pK a of the hydrogen on C2. As a result, C2
isomerization can occur through acid- or base-catalyzed mechanisms leading to the
thermodynamically favored 2,6-cis-254 (Scheme 67, Eq. 3) [124]. Another minor
drawback is that substrate functionality must be tolerant of Lewis acids. Despite
these small concerns, such lactone/lactol functionalization strategies for THP
synthesis remain useful due to the number of methods to access lactols and lactones,
the mild reaction conditions, predictive stereochemical outcomes, and high yields.
Lactol 257 (or 259) is commonly accessed by the spontaneous closure of alcohol
256 (or 258) on an aldehyde (or ketone) six atoms away (Scheme 68, Eq. 1–2)
[125]. Note that lactols derived from ketones can lead to a 2,6-cis arrangement for R
and R
0 using a hydride nucleophile in the presence of a Lewis acid. α-Alkoxy ether
260 is typically synthesized by ozonolysis of the 5-alken-1-ol 7 followed by
treatment with dimethyl sulfide and aqueous acid (Scheme 68, Eq. 3). Lactone
Synthesis of Saturated Tetrahydropyrans
85
occurred in modest yield (34 %) yet showed remarkable chemoselectivity and
functional group tolerance (80 % brsm) (Scheme 66).
5.2 Summary
These representative examples demonstrate the usefulness of HDA reactions for
THP synthesis in the context of complex natural products. Both chiral auxiliary and
asymmetric catalysis methods offer a reliable way to construct 6-membered oxygen
heterocycles in high yield and stereoselectivity. The chiral auxiliary approach
benefits from the wide array of available chiral auxiliaries as well as a number of
ways to stereoselectively install chiral moieties contained within the natural product.
Removal of the auxiliary imposes additional synthetic considerations. The strength
of the asymmetric catalysis tactic comes from the ability to generate chiral products
from achiral substrates with high levels of stereocontrol. While these approaches
produce DHP rings, there are several methods available for their transformation to
highly substituted THP products making HDA an attractive method.
6 C2 Functionalization of Lactols and Lactones
Functionalization of lactols or lactones is a useful method for introducing substitution at the C2 position of tetrahydropyran rings [122]. Retrosynthetically, this
transformation can be envisioned as arising from a Lewis acid-mediated alkylation
of an oxocarbenium ion by an organometallic nucleophile (Scheme 67, Eq. 1). The
stereochemical outcome of the reaction is predicted by axial attack of the nucleophile on the half-chair conformation of oxocarbenium ion 252, to provide kinetically favored 2,6-trans THP 253 (Scheme 67, Eq. 2) [123]. The electronics of the
newly formed side chain must be taken into account when considering such
disconnections. For example, side chains bearing an electron-withdrawing group
(EWG) can sufficiently lower the pK a of the hydrogen on C2. As a result, C2
isomerization can occur through acid- or base-catalyzed mechanisms leading to the
thermodynamically favored 2,6-cis-254 (Scheme 67, Eq. 3) [124]. Another minor
drawback is that substrate functionality must be tolerant of Lewis acids. Despite
these small concerns, such lactone/lactol functionalization strategies for THP
synthesis remain useful due to the number of methods to access lactols and lactones,
the mild reaction conditions, predictive stereochemical outcomes, and high yields.
Lactol 257 (or 259) is commonly accessed by the spontaneous closure of alcohol
256 (or 258) on an aldehyde (or ketone) six atoms away (Scheme 68, Eq. 1–2)
[125]. Note that lactols derived from ketones can lead to a 2,6-cis arrangement for R
and R
0 using a hydride nucleophile in the presence of a Lewis acid. α-Alkoxy ether
260 is typically synthesized by ozonolysis of the 5-alken-1-ol 7 followed by
treatment with dimethyl sulfide and aqueous acid (Scheme 68, Eq. 3). Lactone
Synthesis of Saturated Tetrahydropyrans
85