5.1 Acid-Induced Ethereal Bridge Nucleophilic
Displacements
At 25
C aqueous HCl converts the parent 7-oxanorbornane 1 into trans-4-chlorocyclohexan-1-ol, and on heating both trans- and cis-1,4-dichlorocyclohexane are
formed [210]. With aqueous HBr, 1 was transformed to trans-4-bromocyclohexanol
[211]. Oxanorbornane 1 reacts with dinitrogen pentoxide in CH 2 Cl 2 giving exclusively trans-cyclohexa-1,4-diyl dinitrate [212].
Ogawa et al. [213] have prepared the carba analogues of pyranoses (Scheme 27)
by H 2 SO 4 -induced acetolysis of 7-oxanorbornane 166 derived from the
enantiomerically pure 7-oxanorbornene (À)-164 (ee > 99 %). This compound is
obtained by Diels–Alder reaction of furan and acrylic acid. Resolution of the
cycloadduct so-obtained uses recrystallization of diastereoisomeric amides derived
from (+)-(R)-α-methylbenzylamine. Stereoselective epoxidation of (À)-164 generates an intermediate exo-epoxide that undergoes lactonization into (+)-165 in
formic acid at 70
C. Reduction of the latter with LiAlH 4 furnishes a diol that is
acetylated into triacetate 166. In H 2 SO 4 /Ac 2 O 166 undergoes two competitive
reactions. In one of them, a direct S N 2 attack of acetic acid onto the least sterically
hindered bridgehead center produces β-D-carba-glucopyranose peracetate, (+)-167.
The other reaction is an S N 1 process with the participation of an endo acetoxy group
leading to cationic intermediate 168 and finally to the peracetate of α-D-carbagalactopyranose, (+)-169.
When 166 is reacted with HBr in AcOH, products of S N 1 acetolysis are not
observed; direct S N 2 reactions of bromide anion are highly favored. This generates
dibromides that have been converted into pent-N,O-acetate of (+)-validamine
[214]. Ogawa and Takagahi have prepared (+)-pipoxide starting with bromine
addition to (À)-164 and through a multistep synthesis involving HBr reaction of a
7-oxanorbornane intermediate [215].
Scheme 27 Ogawa et al.’s synthesis of enantiomerically pure carba-pyranoses
Synthesis of 7-Oxabicyclo[2.2.1]heptane and Derivatives
167
Displacements
At 25
C aqueous HCl converts the parent 7-oxanorbornane 1 into trans-4-chlorocyclohexan-1-ol, and on heating both trans- and cis-1,4-dichlorocyclohexane are
formed [210]. With aqueous HBr, 1 was transformed to trans-4-bromocyclohexanol
[211]. Oxanorbornane 1 reacts with dinitrogen pentoxide in CH 2 Cl 2 giving exclusively trans-cyclohexa-1,4-diyl dinitrate [212].
Ogawa et al. [213] have prepared the carba analogues of pyranoses (Scheme 27)
by H 2 SO 4 -induced acetolysis of 7-oxanorbornane 166 derived from the
enantiomerically pure 7-oxanorbornene (À)-164 (ee > 99 %). This compound is
obtained by Diels–Alder reaction of furan and acrylic acid. Resolution of the
cycloadduct so-obtained uses recrystallization of diastereoisomeric amides derived
from (+)-(R)-α-methylbenzylamine. Stereoselective epoxidation of (À)-164 generates an intermediate exo-epoxide that undergoes lactonization into (+)-165 in
formic acid at 70
C. Reduction of the latter with LiAlH 4 furnishes a diol that is
acetylated into triacetate 166. In H 2 SO 4 /Ac 2 O 166 undergoes two competitive
reactions. In one of them, a direct S N 2 attack of acetic acid onto the least sterically
hindered bridgehead center produces β-D-carba-glucopyranose peracetate, (+)-167.
The other reaction is an S N 1 process with the participation of an endo acetoxy group
leading to cationic intermediate 168 and finally to the peracetate of α-D-carbagalactopyranose, (+)-169.
When 166 is reacted with HBr in AcOH, products of S N 1 acetolysis are not
observed; direct S N 2 reactions of bromide anion are highly favored. This generates
dibromides that have been converted into pent-N,O-acetate of (+)-validamine
[214]. Ogawa and Takagahi have prepared (+)-pipoxide starting with bromine
addition to (À)-164 and through a multistep synthesis involving HBr reaction of a
7-oxanorbornane intermediate [215].
Scheme 27 Ogawa et al.’s synthesis of enantiomerically pure carba-pyranoses
Synthesis of 7-Oxabicyclo[2.2.1]heptane and Derivatives
167