4.3 Summary
These representative examples demonstrate the versatility of RCM reactions for
THP synthesis in the context of complex natural products. Both Class 1 and Class 2
substrates afford a reliable way to construct 6-membered oxygen-containing rings
in high yields. The Class 1 RCM is versatile from the standpoint of having a number
of ways to stereoselectively install the allylic and homoallylic moieties, whereas the
strength of Class 2 RCM lies in the versatile synthetic handles afforded in the
unsaturated lactone products. While neither of these reactions directly yield THP
rings, the established functionalization methods certainly make RCM an attractive
strategy. These methods will no doubt be a common strategy in the future.
5 O1–C6 and C2–C3 DHP-Forming Processes
The Diels–Alder (DA) reaction is a powerful method for the efficient and
stereoselective formation of highly functionalized six-membered rings. The pivotal
role of DA reactions in the construction of carbocyclic frameworks can be translated to the synthesis of moderately complex heterocycles [2]. The heteroDiels–Alder (HDA) reaction generally proceeds with high regio- and diastereoselectivity (setting up to 4 contiguous stereogenic centers in a single step) and
moderate to excellent yield [109]. From a retrosynthetic perspective, a THP is
assembled by bond formation at O1–C6 and C2–C3 followed by reduction of the
resultant alkene at C4–C5. For DHP synthesis, there are two modes of reactivity:
the normal-electron demand (Scheme 61, Eq. 1) and inverse-electron demand
systems (Scheme 61, Eq. 2). The normal-electron demand system uses a carbonyl
compound dienophile with a conjugated diene, whereas inverse demand systems
have an alkene dienophile and an α,β-unsaturated carbonyl as the diene.
Cycloadduct stereochemistry is dependent on transition state geometries
[110]. There are four different transition structures that arise from dienophile
orientation (endo vs. exo) and diene geometry (E- vs. Z-isomers). The examples
discussed herein concern only normal demand systems using a carbonyl and
(E)-olefin dienes and can therefore be described by the transition states (i.e.,
TS-A and TS-B) leading to 226.
There are two main HDA approaches to stereocontrolled THP synthesis. The
first uses a chiral auxiliary to direct π-facial selectivity and generally proceeds
through an endo transition state to give 2,6-cis cycloadducts. The second approach
uses coordination of a chiral Lewis acid to activate the carbonyl while directing the
approach of the diene to one face of the carbonyl dienophile. Several catalysts have
been developed for the asymmetric HDA reaction with Jacobsen’s Cr(III) complexes [111, 112] exhibiting good to excellent enantioselectivities with a variety of
substrates [113].
Synthesis of Saturated Tetrahydropyrans
81
These representative examples demonstrate the versatility of RCM reactions for
THP synthesis in the context of complex natural products. Both Class 1 and Class 2
substrates afford a reliable way to construct 6-membered oxygen-containing rings
in high yields. The Class 1 RCM is versatile from the standpoint of having a number
of ways to stereoselectively install the allylic and homoallylic moieties, whereas the
strength of Class 2 RCM lies in the versatile synthetic handles afforded in the
unsaturated lactone products. While neither of these reactions directly yield THP
rings, the established functionalization methods certainly make RCM an attractive
strategy. These methods will no doubt be a common strategy in the future.
5 O1–C6 and C2–C3 DHP-Forming Processes
The Diels–Alder (DA) reaction is a powerful method for the efficient and
stereoselective formation of highly functionalized six-membered rings. The pivotal
role of DA reactions in the construction of carbocyclic frameworks can be translated to the synthesis of moderately complex heterocycles [2]. The heteroDiels–Alder (HDA) reaction generally proceeds with high regio- and diastereoselectivity (setting up to 4 contiguous stereogenic centers in a single step) and
moderate to excellent yield [109]. From a retrosynthetic perspective, a THP is
assembled by bond formation at O1–C6 and C2–C3 followed by reduction of the
resultant alkene at C4–C5. For DHP synthesis, there are two modes of reactivity:
the normal-electron demand (Scheme 61, Eq. 1) and inverse-electron demand
systems (Scheme 61, Eq. 2). The normal-electron demand system uses a carbonyl
compound dienophile with a conjugated diene, whereas inverse demand systems
have an alkene dienophile and an α,β-unsaturated carbonyl as the diene.
Cycloadduct stereochemistry is dependent on transition state geometries
[110]. There are four different transition structures that arise from dienophile
orientation (endo vs. exo) and diene geometry (E- vs. Z-isomers). The examples
discussed herein concern only normal demand systems using a carbonyl and
(E)-olefin dienes and can therefore be described by the transition states (i.e.,
TS-A and TS-B) leading to 226.
There are two main HDA approaches to stereocontrolled THP synthesis. The
first uses a chiral auxiliary to direct π-facial selectivity and generally proceeds
through an endo transition state to give 2,6-cis cycloadducts. The second approach
uses coordination of a chiral Lewis acid to activate the carbonyl while directing the
approach of the diene to one face of the carbonyl dienophile. Several catalysts have
been developed for the asymmetric HDA reaction with Jacobsen’s Cr(III) complexes [111, 112] exhibiting good to excellent enantioselectivities with a variety of
substrates [113].
Synthesis of Saturated Tetrahydropyrans
81