Kopecky and Rychnovsky also targeted leucascandrolide A to demonstrate their
Mukaiyama Aldol-Prins (MAP) method (Scheme 38) [78]. The MAP reaction
generates an oxocarbenium intermediate from an enol ether and an aldehyde,
which is capable of undergoing a Prins cyclization with the pendant allylsilane.
Aldehyde 278 (from Scheme 73, Eq. 1) in the presence of enol ether 142 and boron
trifluoride etherate underwent the MAP cascade without incident. The reaction
mixture was treated with sodium borohydride to reduce any of the unreacted
aldehyde and simplify purification. Desired alcohol 143 was then isolated in
78 % yield as a 5.5:1 mixture of diastereomers.
While use of Lewis or Brønsted acids is the most common way to generate the
requisite oxocarbenium ion for a Prins cyclization, single electron pathways offer
an attractive alternative. The mild, functional group tolerant conditions of electron
transfer initiated cyclization (ETIC) method pioneered by Floreancig and
coworkers were highlighted in their synthesis of leucascandrolide A [80]. Oxidative
benzylic carbon–carbon bond cleavage of ether 144 was achieved by treatment with
ceric ammonium nitrate to give oxocarbenium ion 145 (Scheme 39). Subsequent
attack of the enol acetate through a chair-like transition state led to
2,6-tetrahydropyran-4-one 146 (68 % yield as a single diastereomer).
Indium Lewis acids have garnered attention due to their mild reactivity and air
and water stability. Both Li et al. and Chan and Loh have shown that In(III)
complexes are suitable Lewis acids for Prins cyclizations [81, 82]. These reports
prompted Loh and coworkers to embark on a synthesis of (+)-SCH 351488 that
utilized this strategy (Scheme 40) [83]. Condensation of homoallylic alcohol 147
and aldehyde 148 in the presence of indium tribromide and TMSBr gave 4-bromo
THP 149 in 65 % overall yield as an inconsequential mixture of diastereomers
(2,4-cis/2,4-trans ¼ 75:25). Complete retention of the homoallylic alcohol stereochemistry is responsible for the key 2,6-cis relationship in the product. Initial
attempts to apply these same conditions to the B ring resulted in acetonide
deprotection and no THP formation. Subsequent optimization revealed that indium
triflate and TMSCl were competent additives to effect cyclization. Careful temperature control was required to suppress an undesired Prins side reaction. The
combination of homoallylic alcohol 150 and aldehyde 151 in the presence of the
appropriate Lewis acids at À78
C, followed by warming to –40
C for 4 h, led to
the desired monomer precursor 152 in 42 % yield.
Rychnovsky et al. used their MAP strategy to construct the A ring of (+)-SCH
351488, while the B ring was constructed using a reductive acetylation/Prins
cyclization protocol (Scheme 41) [84]. Use of enol ether 153 and aldehyde 154 in
the presence of titanium tetrabromide afforded the ring-closed product with the
appended side chain. The resulting bromide was reduced under radical conditions,
and SEM protection of the alcohol gave advanced alkene 155 in 55 % yield over
three steps. The B ring was constructed using α-acetoxy ether 156, derived from
reductive acetylation of the corresponding ester, as a Prins precursor. Treatment of
156 with tin tetrabromide led to THP formation. Reduction of the bromide and
acidic removal of the silyl moiety afforded 2,6-cis THP alcohol 157 in 55 % yield
over two steps. These examples demonstrate the utility of masked oxocarbenium
ions (aldehyde equivalents) in expanding the scope of this method.
Synthesis of Saturated Tetrahydropyrans
67
Mukaiyama Aldol-Prins (MAP) method (Scheme 38) [78]. The MAP reaction
generates an oxocarbenium intermediate from an enol ether and an aldehyde,
which is capable of undergoing a Prins cyclization with the pendant allylsilane.
Aldehyde 278 (from Scheme 73, Eq. 1) in the presence of enol ether 142 and boron
trifluoride etherate underwent the MAP cascade without incident. The reaction
mixture was treated with sodium borohydride to reduce any of the unreacted
aldehyde and simplify purification. Desired alcohol 143 was then isolated in
78 % yield as a 5.5:1 mixture of diastereomers.
While use of Lewis or Brønsted acids is the most common way to generate the
requisite oxocarbenium ion for a Prins cyclization, single electron pathways offer
an attractive alternative. The mild, functional group tolerant conditions of electron
transfer initiated cyclization (ETIC) method pioneered by Floreancig and
coworkers were highlighted in their synthesis of leucascandrolide A [80]. Oxidative
benzylic carbon–carbon bond cleavage of ether 144 was achieved by treatment with
ceric ammonium nitrate to give oxocarbenium ion 145 (Scheme 39). Subsequent
attack of the enol acetate through a chair-like transition state led to
2,6-tetrahydropyran-4-one 146 (68 % yield as a single diastereomer).
Indium Lewis acids have garnered attention due to their mild reactivity and air
and water stability. Both Li et al. and Chan and Loh have shown that In(III)
complexes are suitable Lewis acids for Prins cyclizations [81, 82]. These reports
prompted Loh and coworkers to embark on a synthesis of (+)-SCH 351488 that
utilized this strategy (Scheme 40) [83]. Condensation of homoallylic alcohol 147
and aldehyde 148 in the presence of indium tribromide and TMSBr gave 4-bromo
THP 149 in 65 % overall yield as an inconsequential mixture of diastereomers
(2,4-cis/2,4-trans ¼ 75:25). Complete retention of the homoallylic alcohol stereochemistry is responsible for the key 2,6-cis relationship in the product. Initial
attempts to apply these same conditions to the B ring resulted in acetonide
deprotection and no THP formation. Subsequent optimization revealed that indium
triflate and TMSCl were competent additives to effect cyclization. Careful temperature control was required to suppress an undesired Prins side reaction. The
combination of homoallylic alcohol 150 and aldehyde 151 in the presence of the
appropriate Lewis acids at À78
C, followed by warming to –40
C for 4 h, led to
the desired monomer precursor 152 in 42 % yield.
Rychnovsky et al. used their MAP strategy to construct the A ring of (+)-SCH
351488, while the B ring was constructed using a reductive acetylation/Prins
cyclization protocol (Scheme 41) [84]. Use of enol ether 153 and aldehyde 154 in
the presence of titanium tetrabromide afforded the ring-closed product with the
appended side chain. The resulting bromide was reduced under radical conditions,
and SEM protection of the alcohol gave advanced alkene 155 in 55 % yield over
three steps. The B ring was constructed using α-acetoxy ether 156, derived from
reductive acetylation of the corresponding ester, as a Prins precursor. Treatment of
156 with tin tetrabromide led to THP formation. Reduction of the bromide and
acidic removal of the silyl moiety afforded 2,6-cis THP alcohol 157 in 55 % yield
over two steps. These examples demonstrate the utility of masked oxocarbenium
ions (aldehyde equivalents) in expanding the scope of this method.
Synthesis of Saturated Tetrahydropyrans
67