typical retrosynthetic disconnections. General mechanistic and stereochemical
considerations for each disconnection are included. The various strategies related
to THP ring formation are discussed in the context of natural product synthesis.
Keywords Etherification • Hetero-Diels–Alder • Oxocarbenium ion • Reductive
acetylation • Ring-closing metathesis • Tetrahydropyran
1 Introduction
Tetrahydropyran (THP) rings are important motifs in natural products and medicinal chemistry programs. As such, several reviews on the synthesis of THP rings
have been reported [1–3]. The focus of this review is to present the strategies for
THP synthesis in a systematic way. This chapter is divided into sections based on
the retrosynthetic disconnections typically used to construct THP rings. Each
section begins with a brief introduction of the different strategies for each disconnection and includes discussion of general mechanistic and stereochemical considerations. Finally, examples of each disconnection are given with respect to the
synthesis of a select group of natural products.
The single-bond disconnections presented in this review are O1–C2, C2–C3, and
C3–C4. A section on the synthesis of dihydropyran (DHP) rings using heteroDiels–Alder reactions is included since these products are easily reduced to THP
products. The functionalization of lactones and lactols is also included because
these methods have found widespread use in THP synthesis. Table 1 shows a
statistical snapshot of the disconnections and strategies in terms of yields presented
in this review.
Given the wealth of THP-containing natural products and reports of THP
syntheses, we decided that a small subset of natural products would be chosen to
reduce the data set to a manageable size. The natural products shown in Fig. 1 were
Table 1 Comparison of the frequency and median yields for the disconnections discussed in this
survey
Disconnection
Strategy
n
Median % yield
O1–C2
Conjugate addition
14
75
Nucleophilic substitution cyclization
10
84
Alkene-mediated cyclization
8
81
Epoxide opening
2
82
C2–C3
Prins cyclization
13
68
Petasis–Ferrier union/rearrangement
3
77
Panek annulation
4
78
C3–C4
Class 1 ring-closing metathesis
5
94
Class 2 ring-closing metathesis
3
73
Others
Hetero-Diels–Alder
8
69
Lactol reduction
4
95
Lactone reduction/reductive acetylation
13
84
44
M.A. Perry et al.
considerations for each disconnection are included. The various strategies related
to THP ring formation are discussed in the context of natural product synthesis.
Keywords Etherification • Hetero-Diels–Alder • Oxocarbenium ion • Reductive
acetylation • Ring-closing metathesis • Tetrahydropyran
1 Introduction
Tetrahydropyran (THP) rings are important motifs in natural products and medicinal chemistry programs. As such, several reviews on the synthesis of THP rings
have been reported [1–3]. The focus of this review is to present the strategies for
THP synthesis in a systematic way. This chapter is divided into sections based on
the retrosynthetic disconnections typically used to construct THP rings. Each
section begins with a brief introduction of the different strategies for each disconnection and includes discussion of general mechanistic and stereochemical considerations. Finally, examples of each disconnection are given with respect to the
synthesis of a select group of natural products.
The single-bond disconnections presented in this review are O1–C2, C2–C3, and
C3–C4. A section on the synthesis of dihydropyran (DHP) rings using heteroDiels–Alder reactions is included since these products are easily reduced to THP
products. The functionalization of lactones and lactols is also included because
these methods have found widespread use in THP synthesis. Table 1 shows a
statistical snapshot of the disconnections and strategies in terms of yields presented
in this review.
Given the wealth of THP-containing natural products and reports of THP
syntheses, we decided that a small subset of natural products would be chosen to
reduce the data set to a manageable size. The natural products shown in Fig. 1 were
Table 1 Comparison of the frequency and median yields for the disconnections discussed in this
survey
Disconnection
Strategy
n
Median % yield
O1–C2
Conjugate addition
14
75
Nucleophilic substitution cyclization
10
84
Alkene-mediated cyclization
8
81
Epoxide opening
2
82
C2–C3
Prins cyclization
13
68
Petasis–Ferrier union/rearrangement
3
77
Panek annulation
4
78
C3–C4
Class 1 ring-closing metathesis
5
94
Class 2 ring-closing metathesis
3
73
Others
Hetero-Diels–Alder
8
69
Lactol reduction
4
95
Lactone reduction/reductive acetylation
13
84
44
M.A. Perry et al.