2 O1–C2 THP-Forming Processes
Of the numerous connections for the construction of THP rings, O1–C2 bond
formation has proven to be an efficient, stereochemically predictable, and reliable
approach. Such methods encompass S N 2 and S N 1 nucleophilic addition, conjugate
addition, metal-promoted, and dehydrative cyclizations as represented in Scheme 1.
This section will only cover those processes that produce tetrahydropyrans
(Scheme 1, Eqs. 1–4). As such, the common O1–C2 closure by dehydration of
δ-hydroxy ketones to give dihydropyrans will not be discussed (Scheme 1, Eq. 5).
The goal of this section is to highlight methods used for the stereoselective construction of tetrahydropyrans in the context of complex natural product synthesis.
2.1 Conjugate Addition
Conjugate addition has found widespread use in organic synthesis and, not surprisingly, in the construction of oxygen-containing heterocycles [13]. As shown in
Scheme 2, intramolecular nucleophilic hydroxyl attack onto the electron-deficient
β-carbon of an α,β-unsaturated carbonyl system proceeds through an exo (or endo)
ring closure to provide the corresponding tetrahydropyran. The most common mode
of ring closure involves 6-exo-trig cyclization of α,β-unsaturated hydroxy ketones
or esters. Cyclization can be carried out under Brønsted basic or acidic conditions.
Under basic conditions, 2,6-trans THPs are kinetically favored at low temperatures
(À78
C) and short reaction times, whereas 2,6-cis THPs are thermodynamically
favored at higher temperatures and longer reaction times. The stereoselectivity
observed for base-mediated reactions has been described by the difference in
energy and HOMO/LUMO orbital overlap between the s-cis (TS-A, lower energy,
better orbital overlap) and s-trans (TS-B, higher energy, decreased orbital overlap)
TS conformations (Scheme 2, Eq. 1) [14–18]. Under acidic conditions, the transition state (TS-D) leading to the thermodynamic 2,6-cis disubstituted pyran is now
kinetically favored based on a frontier molecular orbital (FMO) theory argument
(Scheme 2, Eq. 2). Inspection of the FMO coefficients of the allylic cationic species
and the orbital overlap with the oxygen lone pair indicates greater stereoelectronic
stabilization in TS-D than TS-C [13, 19]. These arguments validate the observed
selectivity for simple 2,6-substituted tetrahydropyrans, but the stereochemical
outcome of more complex THPs requires conformational analysis of the resultant
heterocycle.
Paterson et al. reported perhaps the simplest intramolecular oxyanion conjugate
addition in the synthesis of the C1–C15 fragment of swinholide A [20, 21]. This
particular cyclization constitutes one of the first examples of the less common endo
conjugate addition to a dihydropyran. Cyclization of 13 under Lewis acid/Brønsted
basic conditions provided the racemic dihydropyrone 14 in good yield (61 %)
(Scheme 3). Attempts at reaction optimization by changing solvent had little effect,
46
M.A. Perry et al.
Of the numerous connections for the construction of THP rings, O1–C2 bond
formation has proven to be an efficient, stereochemically predictable, and reliable
approach. Such methods encompass S N 2 and S N 1 nucleophilic addition, conjugate
addition, metal-promoted, and dehydrative cyclizations as represented in Scheme 1.
This section will only cover those processes that produce tetrahydropyrans
(Scheme 1, Eqs. 1–4). As such, the common O1–C2 closure by dehydration of
δ-hydroxy ketones to give dihydropyrans will not be discussed (Scheme 1, Eq. 5).
The goal of this section is to highlight methods used for the stereoselective construction of tetrahydropyrans in the context of complex natural product synthesis.
2.1 Conjugate Addition
Conjugate addition has found widespread use in organic synthesis and, not surprisingly, in the construction of oxygen-containing heterocycles [13]. As shown in
Scheme 2, intramolecular nucleophilic hydroxyl attack onto the electron-deficient
β-carbon of an α,β-unsaturated carbonyl system proceeds through an exo (or endo)
ring closure to provide the corresponding tetrahydropyran. The most common mode
of ring closure involves 6-exo-trig cyclization of α,β-unsaturated hydroxy ketones
or esters. Cyclization can be carried out under Brønsted basic or acidic conditions.
Under basic conditions, 2,6-trans THPs are kinetically favored at low temperatures
(À78
C) and short reaction times, whereas 2,6-cis THPs are thermodynamically
favored at higher temperatures and longer reaction times. The stereoselectivity
observed for base-mediated reactions has been described by the difference in
energy and HOMO/LUMO orbital overlap between the s-cis (TS-A, lower energy,
better orbital overlap) and s-trans (TS-B, higher energy, decreased orbital overlap)
TS conformations (Scheme 2, Eq. 1) [14–18]. Under acidic conditions, the transition state (TS-D) leading to the thermodynamic 2,6-cis disubstituted pyran is now
kinetically favored based on a frontier molecular orbital (FMO) theory argument
(Scheme 2, Eq. 2). Inspection of the FMO coefficients of the allylic cationic species
and the orbital overlap with the oxygen lone pair indicates greater stereoelectronic
stabilization in TS-D than TS-C [13, 19]. These arguments validate the observed
selectivity for simple 2,6-substituted tetrahydropyrans, but the stereochemical
outcome of more complex THPs requires conformational analysis of the resultant
heterocycle.
Paterson et al. reported perhaps the simplest intramolecular oxyanion conjugate
addition in the synthesis of the C1–C15 fragment of swinholide A [20, 21]. This
particular cyclization constitutes one of the first examples of the less common endo
conjugate addition to a dihydropyran. Cyclization of 13 under Lewis acid/Brønsted
basic conditions provided the racemic dihydropyrone 14 in good yield (61 %)
(Scheme 3). Attempts at reaction optimization by changing solvent had little effect,
46
M.A. Perry et al.