3.4 Summary
C2–C3 Disconnections remain attractive retrosynthetic strategies for the construction of THP rings. Prins cyclization protocols are the predominate method for such
disconnections in the context of natural product synthesis. The wide utility and
scope of this transformation must be balanced by careful selection of substrates,
since a variety of side reactions or loss of stereochemical information is possible
(vide supra). This method has proved extremely reliable for the installation of
2,6-cis THP rings. The related Petasis–Ferrier method also provides access to
2,6-cis THP rings, with the added advantages of increased THP substitution patterns and the C4 ketone as a functional handle. Panek annulation allows rapid
access to either 2,6-cis or 2,6-trans DHP rings by judicious substrate selection (R
0
for allyl substrates and syn/anti for crotylsilanes). These DHP products can easily
be converted to THP rings through simple reduction or be elaborated further by
manipulation of the alkene moiety. Each of these methods has proven useful in
complex natural product synthesis and will continue to remain useful for
constructing THP motifs.
4 C3–C4 THP-Forming Processes
Ring-closing metathesis (RCM) is a powerful method for carbon–carbon bond
formation that is often employed in the synthesis of complex natural products
[99, 100]. Oxygen-containing heterocycles, such as tetrahydropyran (THP) rings,
can be envisioned to arise from such transformations (Scheme 53) [101]. When
considering such disconnections, the C3–C4 ring closure is preferable to the slower
and more problematic C2–C3 metathesis [102]. RCM strategies for THP synthesis
are useful due to the mild conditions, excellent functional group compatibility,
retention of stereochemical information, and high yields. The main drawback is that
stereochemistry must be installed prior to the reaction and further reduction is
necessary to reach the THP oxidation state.
There are two main classes of RCM reactions that are important in the synthesis
of THP rings (Scheme 54). Class 1 involves the ring closure of ether 199 bearing
allylic and homoallylic functionalities to afford 3,4-dihydropyrans 198, which upon
simple reduction leads to THP 202. Class 2 involves an RCM of homoallylic
acrylate substrate 203 to provide unsaturated lactone 204, which can be further
functionalized to THP 202. All of the RCM metathesis examples in this survey
utilize either the first-generation Grubbs catalyst (G-I) or the second-generation
Grubbs catalyst (G-II), shown in Fig. 2.
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M.A. Perry et al.
C2–C3 Disconnections remain attractive retrosynthetic strategies for the construction of THP rings. Prins cyclization protocols are the predominate method for such
disconnections in the context of natural product synthesis. The wide utility and
scope of this transformation must be balanced by careful selection of substrates,
since a variety of side reactions or loss of stereochemical information is possible
(vide supra). This method has proved extremely reliable for the installation of
2,6-cis THP rings. The related Petasis–Ferrier method also provides access to
2,6-cis THP rings, with the added advantages of increased THP substitution patterns and the C4 ketone as a functional handle. Panek annulation allows rapid
access to either 2,6-cis or 2,6-trans DHP rings by judicious substrate selection (R
0
for allyl substrates and syn/anti for crotylsilanes). These DHP products can easily
be converted to THP rings through simple reduction or be elaborated further by
manipulation of the alkene moiety. Each of these methods has proven useful in
complex natural product synthesis and will continue to remain useful for
constructing THP motifs.
4 C3–C4 THP-Forming Processes
Ring-closing metathesis (RCM) is a powerful method for carbon–carbon bond
formation that is often employed in the synthesis of complex natural products
[99, 100]. Oxygen-containing heterocycles, such as tetrahydropyran (THP) rings,
can be envisioned to arise from such transformations (Scheme 53) [101]. When
considering such disconnections, the C3–C4 ring closure is preferable to the slower
and more problematic C2–C3 metathesis [102]. RCM strategies for THP synthesis
are useful due to the mild conditions, excellent functional group compatibility,
retention of stereochemical information, and high yields. The main drawback is that
stereochemistry must be installed prior to the reaction and further reduction is
necessary to reach the THP oxidation state.
There are two main classes of RCM reactions that are important in the synthesis
of THP rings (Scheme 54). Class 1 involves the ring closure of ether 199 bearing
allylic and homoallylic functionalities to afford 3,4-dihydropyrans 198, which upon
simple reduction leads to THP 202. Class 2 involves an RCM of homoallylic
acrylate substrate 203 to provide unsaturated lactone 204, which can be further
functionalized to THP 202. All of the RCM metathesis examples in this survey
utilize either the first-generation Grubbs catalyst (G-I) or the second-generation
Grubbs catalyst (G-II), shown in Fig. 2.
76
M.A. Perry et al.