ring opening of bicyclic oxanorbornenes as well as the application of these methods
to the generation of tetrahydrofuran-containing natural products.
Keywords [3+2]-Cycloaddition • Acetal • Allylsilane • Cobalt • Cyclization •
Furan • Grubbs catalyst • Hemiacetal • Iodoether • Manganese • Michael addition •
Osmium • Osmium tetroxide • Oxanorbornene • Oxidative cyclization • Palladium •
Permanganate • Prins • Prins-pinacol • Ring-closing • Ring-opening • ROM/CM •
ROM/RCM • Ruthenium • Ruthenium tetroxide • Tetrahydrofuran
1 Introduction
Substituted tetrahydrofurans have been popular targets for synthetic chemists. This
is due to both the challenges associated with the synthesis of substituted heterocycles
and the presence of tetrahydrofuran rings in natural and non natural targets including
lignans [1], nucleosides [2], annonaceous acetogenins, and macrolides [3, 4]. This
chapter covers the important advances that have been made in this area from the
period 2005 to 2012 with a focus on some of the newer technologies including
oxidative cyclizations, [3+2]-cycloadditions, and the fragmentation of bicyclic ring
systems (for a review that covers the period up to 2005, see [5]).
2 Nucleophilic Additions to Acetals and Hemiacetals
The addition of nucleophiles to cyclic acetals and hemiacetals is an effective
method of building tetrahydrofurans. These reactions give tetrahydrofurans from
readily available starting materials and generally proceed with high diastereoselectivity that is generally predictable using Woerpel’s model where the stereochemical outcome is explained using stereoelectronic effects [6]. In this model the
nucleophile adds from the “inside” of the favored envelope conformer due to
developing eclipsed interactions with the corresponding “outside” approach (see 3)
(Scheme 1).
Hong and coworkers have taken advantage of hemiacetal reductions to synthesize lignan natural products. In the course of their studies, they discovered that the
relative stereochemistry of the products that come from the activation and reduction
of hemiketal 4 was dependent upon the conditions used to carry out the reaction
(Scheme 2) [7]. Namely, they found that 2,5-cis-tetrahydrofuran isomer 5, as
needed for the synthesis of (–)-futokadsurin A and (–)-veraguensin, came from
the rapid NaBH 3 CN reduction of the intermediate oxocarbenium ion that comes
2
J.D. Rainier
to the generation of tetrahydrofuran-containing natural products.
Keywords [3+2]-Cycloaddition • Acetal • Allylsilane • Cobalt • Cyclization •
Furan • Grubbs catalyst • Hemiacetal • Iodoether • Manganese • Michael addition •
Osmium • Osmium tetroxide • Oxanorbornene • Oxidative cyclization • Palladium •
Permanganate • Prins • Prins-pinacol • Ring-closing • Ring-opening • ROM/CM •
ROM/RCM • Ruthenium • Ruthenium tetroxide • Tetrahydrofuran
1 Introduction
Substituted tetrahydrofurans have been popular targets for synthetic chemists. This
is due to both the challenges associated with the synthesis of substituted heterocycles
and the presence of tetrahydrofuran rings in natural and non natural targets including
lignans [1], nucleosides [2], annonaceous acetogenins, and macrolides [3, 4]. This
chapter covers the important advances that have been made in this area from the
period 2005 to 2012 with a focus on some of the newer technologies including
oxidative cyclizations, [3+2]-cycloadditions, and the fragmentation of bicyclic ring
systems (for a review that covers the period up to 2005, see [5]).
2 Nucleophilic Additions to Acetals and Hemiacetals
The addition of nucleophiles to cyclic acetals and hemiacetals is an effective
method of building tetrahydrofurans. These reactions give tetrahydrofurans from
readily available starting materials and generally proceed with high diastereoselectivity that is generally predictable using Woerpel’s model where the stereochemical outcome is explained using stereoelectronic effects [6]. In this model the
nucleophile adds from the “inside” of the favored envelope conformer due to
developing eclipsed interactions with the corresponding “outside” approach (see 3)
(Scheme 1).
Hong and coworkers have taken advantage of hemiacetal reductions to synthesize lignan natural products. In the course of their studies, they discovered that the
relative stereochemistry of the products that come from the activation and reduction
of hemiketal 4 was dependent upon the conditions used to carry out the reaction
(Scheme 2) [7]. Namely, they found that 2,5-cis-tetrahydrofuran isomer 5, as
needed for the synthesis of (–)-futokadsurin A and (–)-veraguensin, came from
the rapid NaBH 3 CN reduction of the intermediate oxocarbenium ion that comes
2
J.D. Rainier