complex spiroacetal natural product scaffolds, as well as the drive to develop and
improve existing methods. A number of recently reported methods for the synthesis
of spiroacetals are discussed, including their application in the synthesis of natural
products containing the spiroacetal scaffold.
Keywords [3+2]-cycloaddition • [4+2]-cycloaddition • Anionic homo-Fries
rearrangement • Benzannulated • Chiral phosphoric acids • Cyclopropane ring
opening • Dehydrative spirocyclization • DIHMA • Electrophilic cyclization •
Enol ether • Epoxide ring opening • Ferrier rearrangement • Furan oxidation •
Hydroalkoxylation • Intramolecular hydrogen abstraction • o-quinone methide •
Oxa-Michael • Oxonium ion • Oxymercuration • RCM • Rearrangement • Reductive cyclization • Spiroacetal • Spirocyclization • Transition metal catalysis •
Wacker cyclization
1 Introduction
The selective and efficient synthesis of spiroacetals has attracted much attention in
the synthetic community [1–9] both because of the synthetic challenge of complex
spiroacetal natural products, as well as the drive to develop and improve existing
methods. This review aims to cover recent reports (2008 onwards) of methods for
the synthesis of spiroacetals and their application in natural product synthesis.
1.1 Stereochemistry of Spiroacetals and the Anomeric Effect
The stereochemistry of spiroacetals (both synthetic and naturally occurring) can
largely be divided into two categories—the so-called anomeric or axial/axial
conformers, and non-anomeric or axial/equatorial conformers. In 6,6-spiroacetals,
four possible conformations exist (Fig. 1a–2d) with varying relative stabilities,
which are interchangeable via ring flipping [2].
Most naturally occurring spiroacetals have a doubly anomeric configuration,
representing the lowest energy conformer, where both acetal oxygen atoms are
axial with respect to each other. Such an arrangement has been calculated to
contribute an estimated 2.4 kcal/mol decrease in energy per axial substituent in
6,6-spiroacetals [10]. The anomeric effect, as this is known, is thought to be due to
overlap of the axial nonbonding orbital of the acetal oxygen atom with the C–X
antibonding σ* orbital of the electronegative substituent (in the case of spiroacetals,
the C–O σ* orbital, Fig. 1) [11–14]. Where the electronegative substituent is in the
equatorial position (i.e., 1b), this overlap is not possible. The conformers are also
occasionally referred to as the “thermodynamic” and “contra-thermodynamic”
isomers; however, as there are cases where the doubly anomeric conformer is not
the most thermodynamically favored this terminology can become confusing.
190
M.A. Brimble and L.A. Stubbing
improve existing methods. A number of recently reported methods for the synthesis
of spiroacetals are discussed, including their application in the synthesis of natural
products containing the spiroacetal scaffold.
Keywords [3+2]-cycloaddition • [4+2]-cycloaddition • Anionic homo-Fries
rearrangement • Benzannulated • Chiral phosphoric acids • Cyclopropane ring
opening • Dehydrative spirocyclization • DIHMA • Electrophilic cyclization •
Enol ether • Epoxide ring opening • Ferrier rearrangement • Furan oxidation •
Hydroalkoxylation • Intramolecular hydrogen abstraction • o-quinone methide •
Oxa-Michael • Oxonium ion • Oxymercuration • RCM • Rearrangement • Reductive cyclization • Spiroacetal • Spirocyclization • Transition metal catalysis •
Wacker cyclization
1 Introduction
The selective and efficient synthesis of spiroacetals has attracted much attention in
the synthetic community [1–9] both because of the synthetic challenge of complex
spiroacetal natural products, as well as the drive to develop and improve existing
methods. This review aims to cover recent reports (2008 onwards) of methods for
the synthesis of spiroacetals and their application in natural product synthesis.
1.1 Stereochemistry of Spiroacetals and the Anomeric Effect
The stereochemistry of spiroacetals (both synthetic and naturally occurring) can
largely be divided into two categories—the so-called anomeric or axial/axial
conformers, and non-anomeric or axial/equatorial conformers. In 6,6-spiroacetals,
four possible conformations exist (Fig. 1a–2d) with varying relative stabilities,
which are interchangeable via ring flipping [2].
Most naturally occurring spiroacetals have a doubly anomeric configuration,
representing the lowest energy conformer, where both acetal oxygen atoms are
axial with respect to each other. Such an arrangement has been calculated to
contribute an estimated 2.4 kcal/mol decrease in energy per axial substituent in
6,6-spiroacetals [10]. The anomeric effect, as this is known, is thought to be due to
overlap of the axial nonbonding orbital of the acetal oxygen atom with the C–X
antibonding σ* orbital of the electronegative substituent (in the case of spiroacetals,
the C–O σ* orbital, Fig. 1) [11–14]. Where the electronegative substituent is in the
equatorial position (i.e., 1b), this overlap is not possible. The conformers are also
occasionally referred to as the “thermodynamic” and “contra-thermodynamic”
isomers; however, as there are cases where the doubly anomeric conformer is not
the most thermodynamically favored this terminology can become confusing.
190
M.A. Brimble and L.A. Stubbing