4.5 Radical Reactions
4.5.1 Free Radical Cyclisation
Nowadays, radical cyclisation is still an ongoing domain. Instead of the standard
anionic and cationic processes, the radical reactions can be carried out on a wide
array of substrates without extensive use of protecting groups. Nevertheless, the
selective formation of seven-membered rings is not a favourable process according
to Baldwin’s rules, and hydrogen atom abstraction usually takes place, decreasing
the efficiency and attractiveness for this radical process.
Regarding the total synthesis of ciguatoxin (Scheme 55), the G oxepane ring was
constructed from 143 according to a 7-exo-trig process leading to a secondary
radical, stabilised by the presence of an electron-withdrawing group. To avoid
extensive oligomerisation, the reaction was conducted under highly diluted conditions with complete stereocontrol and with an impressive 85 % yield [79].
7-Endo-trig cyclisations have been also considered to prepare new topoisomerase inhibitors from 3-aryl-isoquinolines (Scheme 56) [80]. Thus, in the case of 146,
the high regioselectivity allowing the formation of 148 could be easily explained by
the stability of the intermediate (secondary radical α to an oxygen atom) before the
reduction with tributylstannyl hydride.
A fruitful 1,2-radical rearrangement has been also reported to convert 2-(9Hxanthenyl)malonate monoester 149 into dibenzo[b]oxepin 150. The process
required the use of manganese(III) triacetate as a single-electron transfer (SET)
oxidant. The primary and highly stabilised radical could then undergo a ring
O
O
H
200 °C, 2 h
Benzene
(0.01 M)
BHT
O
O
CO 2 Me
O
O
CO 2 Me
142 (46%)
141 (35%)
140
O
H
139
m-CPBA
CH 2 Cl 2
93%
CO 2 Me
CO 2 Me
+
Scheme 54 Thermal electrocyclic ring-opening of bicyclo[2.1.0]oxaheptane 140
TBSO
OH
Me
TBSO
O
Me
(COCl) 2
DMSO, CH 2 Cl 2
Et 3 N
O
Me
TBSO
1)
-60 °C
2)
138
136
137
87%
Scheme 53 Access to a seven-membered ring ether involving a Cope rearrangement
Synthesis of Seven-Membered Ring Ethers and Lactones
307
4.5.1 Free Radical Cyclisation
Nowadays, radical cyclisation is still an ongoing domain. Instead of the standard
anionic and cationic processes, the radical reactions can be carried out on a wide
array of substrates without extensive use of protecting groups. Nevertheless, the
selective formation of seven-membered rings is not a favourable process according
to Baldwin’s rules, and hydrogen atom abstraction usually takes place, decreasing
the efficiency and attractiveness for this radical process.
Regarding the total synthesis of ciguatoxin (Scheme 55), the G oxepane ring was
constructed from 143 according to a 7-exo-trig process leading to a secondary
radical, stabilised by the presence of an electron-withdrawing group. To avoid
extensive oligomerisation, the reaction was conducted under highly diluted conditions with complete stereocontrol and with an impressive 85 % yield [79].
7-Endo-trig cyclisations have been also considered to prepare new topoisomerase inhibitors from 3-aryl-isoquinolines (Scheme 56) [80]. Thus, in the case of 146,
the high regioselectivity allowing the formation of 148 could be easily explained by
the stability of the intermediate (secondary radical α to an oxygen atom) before the
reduction with tributylstannyl hydride.
A fruitful 1,2-radical rearrangement has been also reported to convert 2-(9Hxanthenyl)malonate monoester 149 into dibenzo[b]oxepin 150. The process
required the use of manganese(III) triacetate as a single-electron transfer (SET)
oxidant. The primary and highly stabilised radical could then undergo a ring
O
O
H
200 °C, 2 h
Benzene
(0.01 M)
BHT
O
O
CO 2 Me
O
O
CO 2 Me
142 (46%)
141 (35%)
140
O
H
139
m-CPBA
CH 2 Cl 2
93%
CO 2 Me
CO 2 Me
+
Scheme 54 Thermal electrocyclic ring-opening of bicyclo[2.1.0]oxaheptane 140
TBSO
OH
Me
TBSO
O
Me
(COCl) 2
DMSO, CH 2 Cl 2
Et 3 N
O
Me
TBSO
1)
-60 °C
2)
138
136
137
87%
Scheme 53 Access to a seven-membered ring ether involving a Cope rearrangement
Synthesis of Seven-Membered Ring Ethers and Lactones
307