A total synthesis of the glucosidase inhibitor cyclophellitol, using the “naked
sugar” method [201, 202, 216], is based on the S N 2 ring opening of the oxa bridge
of the polysubstituted 7-oxanorbornane [217] (Scheme 28). ZnI 2 - or ZnBr 2 -
catalyzed Diels–Alder reaction of furan with (À)-1-cyanovinyl (1S)-camphanate
[218] or (À)-1-cyanovinyl (1R,5S,7R)-3-ethyl-2-oxo-6,8-dioxa- 3-azabicyclo
[3.2.1]octane-7-exo-carboxylate [219] (RADO(Et)–O(NC)C¼CH 2 ) derived from
(R,R)-tartaric acid and pyruvonitrile, and recrystallization provides the diastereomerically pure cycloadducts (+)-170 and (+)-171, respectively. The other
diastereoisomeric cycloadducts are recycled into (+)-170 and (+)-171 via retroDiels–Alder reactions on heating (reversibility of the furan Diels–Alder reactions).
Pure enantiomers (À)-170 and (À)-171 are obtained with the same ease using (+)-1cyanovinyl (1R)-camphanate and (+)-cyanovinyl (1S,5R,7R)-3-ethyl-2-oxo-6,8dioxa-3-azabicyclo[3.2.1]octane-7-exo-carboxylate (SADO(Et)–O–(NC)C¼CH 2 ),
respectively. Saponification of (+)-170 (or (+)-171) and treatment with formalin
to displace the cyanohydrins furnish enantiomerically pure 7-oxabicyclo[2.2.1]
hept-5-en-2-one, (+)-172, and allow the recovery of the chiral auxiliaries [(1S)camphanic acid, RADO(Et)-OH]. Similarly, enone (À)-172 is derived from
(À)-170 and (À)-171. The six enantiomerically pure 7-oxanorbornenes (+)- and
(À)-170, (+)- and (À)-171, and (+)- and (À)-172 are coined “naked sugars” because
O
O
HO
OBn
Bn
O
O
OBn
O
O
OBn
HO
O
OBn
O
O
OBn
TBSO
OTBS
OH
OBn
O
TBSO
OH
O
CN
OR*
O
1) ZnBr 2
O
O
O
NC
OR"
O
O
RN
O
O
X
RADO(R)-X
O
O
NR
O
O
X
SADO(R)-X
OH
HO
Br
HO
OH
OH
OH
O
HO
OH
OH
OH
HO
OH
HO
O
HSO 3 F
OR*
NC
+
176
177
178
Cyclophellitol
(+)-170 R* = (1S)-camphanoyl, (41%)
(+)-171 R* = RADO(Et), (43%)
1) MeONa/MeOH
2) H 2 CO/H 2 O
+ recovery of R*OH
(-)-172
(-)-170 R" = (1R)-camphanoyl
(-)-171 R" = SADO(Et)
from (R,R)-tartaric acid from (S,S)-tartaric acid
(+)-172
TBSCl/imidazole, 0
o
C
(S N 2)
mCBBA: 3-ClC 6 H 4 CO 3 H
TBS: (t-Bu)Me 2 Si
1) BnOTMS
2) mCPBA
(+)-172
173
174
(-)-175
1) CH 2 O
TiCl 4
2) NaBH 4
HBr
AcOH
MeONa
MeOH
2) Recryst.
90-95%
65%
(3steps)
85%
69%
90%
Scheme 28 Total synthesis of cyclophellitol applying the “naked sugar” method, i.e., starting
form enantiomerically pure 7-oxabicyclo[2.2.1]hept-5-ene-2-one
168
A.J. Moreno-Vargas and P. Vogel
sugar” method [201, 202, 216], is based on the S N 2 ring opening of the oxa bridge
of the polysubstituted 7-oxanorbornane [217] (Scheme 28). ZnI 2 - or ZnBr 2 -
catalyzed Diels–Alder reaction of furan with (À)-1-cyanovinyl (1S)-camphanate
[218] or (À)-1-cyanovinyl (1R,5S,7R)-3-ethyl-2-oxo-6,8-dioxa- 3-azabicyclo
[3.2.1]octane-7-exo-carboxylate [219] (RADO(Et)–O(NC)C¼CH 2 ) derived from
(R,R)-tartaric acid and pyruvonitrile, and recrystallization provides the diastereomerically pure cycloadducts (+)-170 and (+)-171, respectively. The other
diastereoisomeric cycloadducts are recycled into (+)-170 and (+)-171 via retroDiels–Alder reactions on heating (reversibility of the furan Diels–Alder reactions).
Pure enantiomers (À)-170 and (À)-171 are obtained with the same ease using (+)-1cyanovinyl (1R)-camphanate and (+)-cyanovinyl (1S,5R,7R)-3-ethyl-2-oxo-6,8dioxa-3-azabicyclo[3.2.1]octane-7-exo-carboxylate (SADO(Et)–O–(NC)C¼CH 2 ),
respectively. Saponification of (+)-170 (or (+)-171) and treatment with formalin
to displace the cyanohydrins furnish enantiomerically pure 7-oxabicyclo[2.2.1]
hept-5-en-2-one, (+)-172, and allow the recovery of the chiral auxiliaries [(1S)camphanic acid, RADO(Et)-OH]. Similarly, enone (À)-172 is derived from
(À)-170 and (À)-171. The six enantiomerically pure 7-oxanorbornenes (+)- and
(À)-170, (+)- and (À)-171, and (+)- and (À)-172 are coined “naked sugars” because
O
O
HO
OBn
Bn
O
O
OBn
O
O
OBn
HO
O
OBn
O
O
OBn
TBSO
OTBS
OH
OBn
O
TBSO
OH
O
CN
OR*
O
1) ZnBr 2
O
O
O
NC
OR"
O
O
RN
O
O
X
RADO(R)-X
O
O
NR
O
O
X
SADO(R)-X
OH
HO
Br
HO
OH
OH
OH
O
HO
OH
OH
OH
HO
OH
HO
O
HSO 3 F
OR*
NC
+
176
177
178
Cyclophellitol
(+)-170 R* = (1S)-camphanoyl, (41%)
(+)-171 R* = RADO(Et), (43%)
1) MeONa/MeOH
2) H 2 CO/H 2 O
+ recovery of R*OH
(-)-172
(-)-170 R" = (1R)-camphanoyl
(-)-171 R" = SADO(Et)
from (R,R)-tartaric acid from (S,S)-tartaric acid
(+)-172
TBSCl/imidazole, 0
o
C
(S N 2)
mCBBA: 3-ClC 6 H 4 CO 3 H
TBS: (t-Bu)Me 2 Si
1) BnOTMS
2) mCPBA
(+)-172
173
174
(-)-175
1) CH 2 O
TiCl 4
2) NaBH 4
HBr
AcOH
MeONa
MeOH
2) Recryst.
90-95%
65%
(3steps)
85%
69%
90%
Scheme 28 Total synthesis of cyclophellitol applying the “naked sugar” method, i.e., starting
form enantiomerically pure 7-oxabicyclo[2.2.1]hept-5-ene-2-one
168
A.J. Moreno-Vargas and P. Vogel