THP derivatives 290 that contain the pendant oxygen functionality required to
construct the B ring contained in the natural products. In all cases, the products are
obtained in high yields and good diastereoselectivities (72–93 %, dr ¼ 84:16 to
dr ¼ 100:0).
6.3 Summary
Lactols and α-alkoxy ethers have proven to be useful intermediates for the synthesis
of THP-containing natural products. These representative examples demonstrate
that while most commonly used to access 2,6-trans motifs, careful substrate design
and judicious choice of nucleophile also allows for the synthesis of 2,6-cis THP
rings. The mild conditions for these functional group tolerant transformations allow
for rapid construction of complex fragments in good yield and with high levels of
predictable diastereoselectivity. In addition, the variety of methods for synthesizing
lactols and lactones increases the overall utility of such approaches.
7 Conclusion
The examples described herein demonstrate the variety, efficiency, reliability, and
stereofidelity of THP-forming processes in complex natural product synthesis over
the last few decades. The seemingly straightforward construction of
tetrahydropyrans through O1–C2 bond formation includes methods ranging from
the long-standing S N 2/S N 1 and oxa-Michael-based cyclizations to the more recent
transition metal-catalyzed reactions. The recent developments in epoxide-opening
cyclizations allow for selective formation of THPs over the more favored THFs as
well as the ability to construct fused tetrahydropyran units simultaneously by a
cascade sequence. The less obvious C2–C3 bond-forming processes include the
venerable Prins cyclization, Petasis–Ferrier rearrangement, and Panek annulation
strategies. The reliability of the Prins in the formation of 2,6-cis THP rings and the
ability to trap various nucleophiles at the C4 position have made this transformation
a cornerstone in THP synthesis. Similarly, the Petasis–Ferrier method provides
access to 2,6-cis-tetrahydropyran-4-ones, with the added advantages of increased
THP substitution patterns and the C4 ketone for further functionalization. Panek
annulation provides either 2,6-cis or 2,6-trans DHP rings that can be rapidly
converted to highly functionalized THPs but require careful substrate selection.
Only upon the advent of alkene metathesis was the C3–C4 disconnection made
practical. The RCM strategy benefits from the variety of asymmetric methods to
install allylic and homoallylic alcohols (Class 1) and/or the synthetic handles
afforded in the unsaturated lactone products for further functionalization (Class 2).
The improvement in asymmetric hetero-Diels–Alder reactions, due to the development of chiral organocatalytic and Lewis acid-catalyzed procedures, has provided
Synthesis of Saturated Tetrahydropyrans
91
construct the B ring contained in the natural products. In all cases, the products are
obtained in high yields and good diastereoselectivities (72–93 %, dr ¼ 84:16 to
dr ¼ 100:0).
6.3 Summary
Lactols and α-alkoxy ethers have proven to be useful intermediates for the synthesis
of THP-containing natural products. These representative examples demonstrate
that while most commonly used to access 2,6-trans motifs, careful substrate design
and judicious choice of nucleophile also allows for the synthesis of 2,6-cis THP
rings. The mild conditions for these functional group tolerant transformations allow
for rapid construction of complex fragments in good yield and with high levels of
predictable diastereoselectivity. In addition, the variety of methods for synthesizing
lactols and lactones increases the overall utility of such approaches.
7 Conclusion
The examples described herein demonstrate the variety, efficiency, reliability, and
stereofidelity of THP-forming processes in complex natural product synthesis over
the last few decades. The seemingly straightforward construction of
tetrahydropyrans through O1–C2 bond formation includes methods ranging from
the long-standing S N 2/S N 1 and oxa-Michael-based cyclizations to the more recent
transition metal-catalyzed reactions. The recent developments in epoxide-opening
cyclizations allow for selective formation of THPs over the more favored THFs as
well as the ability to construct fused tetrahydropyran units simultaneously by a
cascade sequence. The less obvious C2–C3 bond-forming processes include the
venerable Prins cyclization, Petasis–Ferrier rearrangement, and Panek annulation
strategies. The reliability of the Prins in the formation of 2,6-cis THP rings and the
ability to trap various nucleophiles at the C4 position have made this transformation
a cornerstone in THP synthesis. Similarly, the Petasis–Ferrier method provides
access to 2,6-cis-tetrahydropyran-4-ones, with the added advantages of increased
THP substitution patterns and the C4 ketone for further functionalization. Panek
annulation provides either 2,6-cis or 2,6-trans DHP rings that can be rapidly
converted to highly functionalized THPs but require careful substrate selection.
Only upon the advent of alkene metathesis was the C3–C4 disconnection made
practical. The RCM strategy benefits from the variety of asymmetric methods to
install allylic and homoallylic alcohols (Class 1) and/or the synthetic handles
afforded in the unsaturated lactone products for further functionalization (Class 2).
The improvement in asymmetric hetero-Diels–Alder reactions, due to the development of chiral organocatalytic and Lewis acid-catalyzed procedures, has provided
Synthesis of Saturated Tetrahydropyrans
91