Timeless Methods for Radical Cyclizations in Total Synthesis Patricia Zhang MacMillan Group Meeting Wednesday September 25th, 2013
Timeless Methods for Radical Cyclizations in Total Synthesis
Patricia ZhangMacMillan Group Meeting
Wednesday September 25th, 2013
Radical Cyclizations in Total Synthesis
Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757.
! A little history
! 1900: Moses Gomberg
trivalent carbon (discovery predated electronic theory)
"Ph3C" rather than "Ph3C•"
! 1929: Paneth and Hofeditz
Pb(CH3)4 Pb 4CH3•
! in rapid current of H2+
Paneth, F.; Hofeditz, W. Chem. Ber. 1929, 62, 1335.
Radical Cyclizations in Total Synthesis
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
! A change in the synthetic community's outlook on carbon radicals
! dimerization at diffusion rates! disproportionation! polymerization! extremely reactive
"Unruly & Uncontrollable"
! extremely reactive! neutral species, good for crowded bonds! inert to OH and NH! no !-elimination of OR, NR, etc.! ground state of structures good T.S. models! easy racemic synthesis of radical precursor
"Mild, Neutral and Selective"
Functional Group Transformations
Synthetic Radical Chemistry
! Kolbe oxidation! Hoffman-Loffler-Freytag! Meerwein arylation! NBS bromination! Kharasch reaction! Tin Hydride
! Giese reactions: Intermolecular Additions! Barton's thiohydroxamates: Carbon Radicals! Hart's pyrrolizidine synthesis! Stork's regio- and stereoselective syntheses! Curran's tandem syntheses
then in the 1980s.......
Radical Cyclizations in Total Synthesis
! Goal: General overview of major methods from the 1980s boom
Cyclizations organized by method of radical generation:
The Tin Hydride Method
The Fragmentation Method
The Reduction Method
The Oxidation Method
Showcase power of these methods with examples from today
Radical Cyclizations in Total Synthesis
! The Tin Hydride Method
Initiation:
Bu3SnH
N NMe
MeCN
Me
NCMe
Me Me
CNN22
!+
Me Me
CN+
Me Me
CN+ Bu3Sn
Propagation:
Bu3Sn + R-X R Bu3SnX+
R' + Bu3SnH R'-H + Bu3Sn
AIBN
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
Bu3SnH, AIBN, !
Raddition orcyclization
R X C C R' H
C C+ R'
Radical Cyclizations in Total Synthesis
! The Tin Hydride Method
Initiation:
Bu3SnH
N NMe
MeCN
Me
NCMe
Me Me
CNN22
!+
Me Me
CN+
Me Me
CN+ Bu3Sn
Propagation:
Bu3Sn + R-X R Bu3SnX+
R' + Bu3SnH R'-H + Bu3Sn
AIBN
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
Bu3SnH, AIBN, !
Raddition orcyclization
R X C C R' H
C C+ R'
Radical Cyclizations in Total Synthesis
! The Tin Hydride Method
Initiation:
Bu3SnH
N NMe
MeCN
Me
NCMe
Me Me
CNN22
!+
Me Me
CN+
Me Me
CN+ Bu3Sn
Propagation:
Bu3Sn + R-X R Bu3SnX+
R' + Bu3SnH R'-H + Bu3Sn
AIBN
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
Bu3SnH, AIBN, !
Raddition orcyclization
R X C C R' H
C C+ R'
Radical Cyclizations in Total Synthesis
! Radical cyclizations follow Baldwin's rules
Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 11 , 6513-6556.
Bu3SnH, AIBN, !
R X
C C
R
C C
Radical Cyclizations in Total Synthesis
! Radical cyclizations follow Baldwin's rules
Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 11 , 6513-6556.
Bu3SnH, AIBN, !
R X
C C
R
C C
boxed structures are allowed
Radical Cyclizations in Total Synthesis
! The Tin Hydride Method
Substrate Trends:
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
Bu3SnH, AIBN, !R X C C R' H
! Bu3SnH most commonly used reagent to conduct free-radical reactions! Overall reaction: R-X for stronger R-H, Sn-H for stronger Sn-X
! Transferability of X to Bu3Sn• is
! Reactivity of R• to Bu3SnH is
X• + Bu3Sn• Bu3Sn-X I > Br > SePh > "C(S)SMe > Cl > SPh
R• + Bu3Sn•Bu3SnH R-H+ aryl # vinyl > alkyl > allyl # benzyl
Radical Cyclizations in Total Synthesis
! The Tin Hydride Method
Substrate Trends:
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
Bu3SnH, AIBN, !R X C C R' H
! Bu3SnH most commonly used reagent to conduct free-radical reactions! Overall reaction: R-X for stronger R-H, Sn-H for stronger Sn-X
! Transferability of X to Bu3Sn• is
! Reactivity of R• to Bu3SnH is
X• + Bu3Sn• Bu3Sn-X I > Br > SePh > "C(S)SMe > Cl > SPh
R• + Bu3Sn•Bu3SnH R-H+ aryl # vinyl > alkyl > allyl # benzyl
Radical Cyclizations in Total Synthesis
! The Tin Hydride Method
Substrate Trends:
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
Bu3SnH, AIBN, !R X C C R' H
! Bu3SnH most commonly used reagent to conduct free-radical reactions! Overall reaction: R-X for stronger R-H, Sn-H for stronger Sn-X
! Transferability of X to Bu3Sn• is
! Reactivity of R• to Bu3SnH is
X• + Bu3Sn• Bu3Sn-X I > Br > SePh > "C(S)SMe > Cl > SPh
R• + Bu3Sn•Bu3SnH R-H+ aryl # vinyl > alkyl > allyl # benzyl
Radical Cyclizations in Total Synthesis
! Beckwith's rules
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
! Cyclizations containing five linking carbons or less prefers exo-mode
! Radicals add to least substituted carbon of olefin if no other geometric constraints
! Bond undergoing homolytic cleavage must lie close to the plane of the radical
! 5-Hexenyl radical ring closures are stereoselective:
1
2
34
56
2-, 4- substituted systems give trans
2-,3-, or 4- substitued systems reflects conformation preference of chair T.S.
1
23
4 5
6
12
3
4 5
6
12
3
45
6
3
12
45
6
R R
RR
Radical Cyclizations in Total Synthesis
! Beckwith's rules
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
! Cyclizations containing five linking carbons or less prefers exo-mode
! Radicals add to least substituted carbon of olefin if no other geometric constraints
! Bond undergoing homolytic cleavage must lie close to the plane of the radical
! 5-Hexenyl radical ring closures are stereoselective:
1
2
34
56
1-,3- substituted systems give cis
R
Me
R
Me
R
Me Me
R R R
Radical Cyclizations in Total Synthesis
! Beckwith's rules
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
! Cyclizations containing five linking carbons or less prefers exo-mode
! Radicals add to least substituted carbon of olefin if no other geometric constraints
! Bond undergoing homolytic cleavage must lie close to the plane of the radical
! 5-Hexenyl radical ring closures are stereoselective:
1
2
34
56
2-,4- substituted systems give cis
Me Me
Me Me
R
RR
RRR
Radical Cyclizations in Total Synthesis
! Beckwith's rules
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
! Cyclizations containing five linking carbons or less prefers exo-mode
! Radicals add to least substituted carbon of olefin if no other geometric constraints
! Bond undergoing homolytic cleavage must lie close to the plane of the radical
! 5-Hexenyl radical ring closures are stereoselective:
1
2
34
56
2-, 4- substituted systems give trans2-,3-, or 4- substitued systems reflects conformation preference of chair T.S.
1
23
4 5
6
12
3
4 5
6
12
3
45
6
3
12
45
6
R R
RR
Radical Cyclizations in Total Synthesis
! Carbacycle formation with tin hydride
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
! Cyclizations yielding 5-membered rings are fast
20x faster
+
50x faster
! High regioselectivity for 5-exo
Radical Cyclizations in Total Synthesis
! Carbacycle formation with tin hydride
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
! Cyclizations yielding 5-membered rings are fast
20x faster
+
50x faster
! High regioselectivity for 5-exo
Radical Cyclizations in Total Synthesis
! First application of tin hydride in total synthesis
Bakuzi, P.; Campos, O. O. S.; Bakuzis, M. L. F. J. Org. Chem. 1976, 41, 3261-3264.
Me
OMe
Me
Br
Me
O
Me Me
Me
O
Me Me
Me
OMe
Me
3 : 2
6-exo
62%+
Me
Me Me
Me
Me Me
sativene cocamphene
! 6-membered rings are less general than 5! diminished regioselective and stereoselectivity! more suspectible to reduction before cyclization
+
6x faster
1,5 hydrogen transfer H
H
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
Radical Cyclizations in Total Synthesis
! Stork improves the 6-exo cyclization
Stork, G.; Baine, N. H. J. Am. Chem. Soc 1982, 104 , 2323-2325.
! vinyl radicals much more reactive to cyclization
!1000x faster
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
IMe
Me OH
Me Me
Bu3SnH, UV irradiation
72%
no 7-endo product1 : 1 diastereomers
Me Me
Me
Me OH
! more suspectible to reduction and good allylic H atom abstractor! low inversion barrier for vinyl radical
MeO2C CO2Me
Me
Br
MeO2C CO2Me
Br
Me
MeO2C CO2Me
MeMe
75%
Radical Cyclizations in Total Synthesis
! Vinyl radical in the total synthesis of norseychellanone
Stork, G.; Baine, N. H. Tetrahedron Lett. 1985, 26, 5927-5930.
O
MeMe LDA
Br
Me Br
O MeMe
MeBr
O
MeMe
Me
O
MeMe
Me
85:15 !/"norseychellanone
Bu3SnHcat. AIBNirradiation
70%
H2, Pd/C
Radical Cyclizations in Total Synthesis
! Activated olefins to aid 6-endo cyclization
Ladlow, M.; Pattenden, G. Tetrahedron Lett. 1985, 26, 4413-4416.
IMe
Me
O
OMe
OMe
Me
O OMe
MeO
MeMe
Me
Bu3SnH, AIBN
PhH, 85 °C97%
1. TMSI2. Bu3SnH, AIBN
45%
O OH
MeO
MeMe
Me
EWG on "electrophile" lowers LUMO energy
O OH
MeO
MeMe
MeO
alliacolide
Me
Me
O
OMe
OMe
Me
Radical Cyclizations in Total Synthesis
! Activated olefins to aid 6-endo cyclization
Ladlow, M.; Pattenden, G. Tetrahedron Lett. 1985, 26, 4413-4416.
IMe
Me
O
OMe
OMe
Me
O OMe
MeO
MeMe
Me
Bu3SnH, AIBN
PhH, 85 °C97%
1. TMSI2. Bu3SnH, AIBN
45%
O OH
MeO
MeMe
Me
EWG on "electrophile" lowers LUMO energy
O OH
MeO
MeMe
MeO
alliacolide
Me
Me
O
OMe
OMe
Me
mCPBA
Radical Cyclizations in Total Synthesis
! Enones as radical acceptor activators
Giese, B. Angew. Chem. Int. Ed. Engl. 1983, 22, 753-764.
O
Me
O
Me
2500x faster
R C C
SOMO
LUMO
HOMO
! Empirical evidence ! Frontier orbital theory explanation
Radical Cyclizations in Total Synthesis
! The triquinane system
Curran, D.P.; Rakiewicz, D.M. J. Am. Chem. Soc. 1985, 107 , 1448.Curran, D.P.; Chen, M.-H. Tetrahedron Lett. 1985, 26, 4991.
H
Me
MeH
H
Me
hirsutene
H
H
Me
H
!9(12)-capnellene
MeMe
Me
Me H
MeMe
Me
H H
MeMe
Radical Cyclizations in Total Synthesis
! The triquinane system
Curran, D.P.; Rakiewicz, D.M. J. Am. Chem. Soc. 1985, 107 , 1448.Curran, D.P.; Chen, M.-H. Tetrahedron Lett. 1985, 26, 4991.
H
Me
MeH
H
Me
hirsutene
H
H
Me
H
!9(12)-capnellene
MeMe
Me
Me H
MeMe
Me
H H
MeMe
Radical Cyclizations in Total Synthesis
Curran, D.P.; Rakiewicz, D.M. J. Am. Chem. Soc. 1985, 107 , 1448.
H
Me
MeH
H
Me
hirsutene
MeMe
Me
H H
MeMe
Me
H H
I
Bu3SnH, AIBN (cat.)
PhH (0.02 M), reflux, 80%
Me
H H
Me
Me
H
Me
MeH
H
MeBu3SnH 5-exo-dig
5-exo-trig
Radical Cyclizations in Total Synthesis
Curran, D.P.; Rakiewicz, D.M. J. Am. Chem. Soc. 1985, 107 , 1448.
H
Me
MeH
H
Me
hirsutene
MeMe
Me
H H
MeMe
Me
H H
I
Bu3SnH, AIBN (cat.)
PhH (0.02 M), reflux, 80%
Me
H H
Me
Me
H
Me
MeH
H
MeBu3SnH 5-exo-dig
5-exo-trig
Radical Cyclizations in Total Synthesis
! 1°, 2°, and 3° alkyl radicals have similar reactivities
Curran, D.P.; Rakiewicz, D.M. J. Am. Chem. Soc. 1985, 107 , 1448.Curran, D.P.; Chen, M.-H. Tetrahedron Lett. 1985, 26, 4991.
H
Me
MeH
H
Me
hirsutene
H
H
Me
H
!9(12)-capnellene
MeMe
Me
Me H
MeMe
Me
H H
MeMe
80%
80%
Radical Cyclizations in Total Synthesis
! A common natural product for radical cyclization strategies
CO2HMe
HO
HO OHH
H
(+)-Prostaglandin F2!
Radical Cyclizations in Total Synthesis
! Stork's tandem vicinal difunctionalization strategy
Stork, G.; Sher, P. M.; Chen, H.-L. J. Am. Chem. Soc. 1986, 108 , 6384-6387.
O
TBSO
IOEt Bu3SnCl (0.1 eq.)
NaCNBH3 (2.0 eq.)h!, THF, RT
SiMe3
O
C5H11
O
TBSO
OEt
TBSO
OOEt
TBSO
O
SiMe3
O
C5H11
in situ Bu3SnH
OEt
TBSO
O
SiMe3
O
C5H11
OEt
TBSO
O
O
C5H11
OEt
1. "2. Pd(OAc)2
Giese reaction
58%
Radical Cyclizations in Total Synthesis
! Keck's attempt at PGF2!
O
TBSO
IOEt Bu3Sn
O
C5H11
PhMe, reflux
N NCN NC
TBSO
O
O
C5H11
OEt
SnBu3TBSO
O
O
C5H11
OEt
- Bu3Sn
72%
Keck, G. E.; Burnett, D. A. J. Org. Chem. 1987, 52, 2958.
Radical Cyclizations in Total Synthesis
! The fragmentation method
Keck, G. E.; Yates, J. B. J. Org. Chem. 1982, 47, 3590.
! Keck applies allylation to perhydrohistrionicotoxin synthesis
SnBu3
h!N O
O
Br 2O
N
O
ON
O
SnBu3
N O
O
- Bu3Sn
perhydrohistrionicotoxin
NH
O
Bu
Me
Radical Cyclizations in Total Synthesis
! Intramolecular Keck allylation
Danishefsky, S. J.; Panek, J. S. J. Am. Chem. Soc. 1987, 109 , 917.
N
O
MeO
MeO
SePhN
MeO
MeO
SePh
AcO SnBu3
1. Bu3SnLi2. Ac2O
Bu3SnH
N
MeO
MeO
OAc
N
MeO
MeO
O
3-demethoxyerythratidinone
88%
directed introduction of unsaturation
Radical Cyclizations in Total Synthesis
! Keck allylation for use in scholarisine A
Smith, M. W.; Snyder, S. A. J. Am. Chem. Soc. 2013, 135 , 12964-12967.
OO
Me
NN
scholarisine A
OO
NN
IC-H arylation
OO
CO2Me
ONHR
tandem vicinal difunctionalization
OO
ONHR
X
CO2Me
Radical Cyclizations in Total Synthesis
! Keck allylation for use in scholarisine A
Smith, M. W.; Snyder, S. A. J. Am. Chem. Soc. 2013, 135 , 12964-12967.
OO
Me
NN
scholarisine A
OO
NN
IC-H arylation
OO
CO2Me
ONHR
tandem vicinal difunctionalization
OO
ONHR
X
CO2Me
Radical Cyclizations in Total Synthesis
! Keck allylation for use in scholarisine A
Smith, M. W.; Snyder, S. A. J. Am. Chem. Soc. 2013, 135 , 12964-12967.
OO
CO2Me
ONHR
OO
ONHBoc
Br
CO2Me SnBu3
Et3B, PhH,75 °C, air
(3 steps)59%
OO
ONHBoc
CO2Me
OO
ONHBoc
CO2Me
OO
ONHBoc
CO2MeSnBu3
Radical Cyclizations in Total Synthesis
! Keck allylation for use in scholarisine A
Smith, M. W.; Snyder, S. A. J. Am. Chem. Soc. 2013, 135 , 12964-12967.
OO
CO2Me
ONHR
OO
ONHBoc
Br
CO2Me SnBu3
Et3B, PhH,75 °C, air
(3 steps)59%
OO
ONHBoc
CO2Me
OO
ONHBoc
CO2Me
OO
ONHBoc
CO2MeSnBu3
Radical Cyclizations in Total Synthesis
! Keck allylation for use in scholarisine A
Smith, M. W.; Snyder, S. A. J. Am. Chem. Soc. 2013, 135 , 12964-12967.
OO
Me
NN
scholarisine A
OO
NN
I Bu3SnH, ACHN, PhMe, !
OO
NN
OO
NN
H
OO
NN
OO
NN
[O]
Radical Cyclizations in Total Synthesis
! Keck allylation for use in scholarisine A
Smith, M. W.; Snyder, S. A. J. Am. Chem. Soc. 2013, 135 , 12964-12967.
OO
Me
NN
scholarisine A
OO
NN
I Bu3SnH, ACHN, PhMe, !
OO
NN
OO
NN
H
OO
NN
OO
NN
[O]
Radical Cyclizations in Total Synthesis
! Keck allylation for use in scholarisine A
Smith, M. W.; Snyder, S. A. J. Am. Chem. Soc. 2013, 135 , 12964-12967.
OO
Me
NN
scholarisine A
OO
NN
I Bu3SnH, ACHN, PhMe, !
OO
NN
OO
NN
H
OO
NN
OO
NN
[O]
Radical Cyclizations in Total Synthesis
! Keck allylation for use in scholarisine A
Smith, M. W.; Snyder, S. A. J. Am. Chem. Soc. 2013, 135 , 12964-12967.
OO
Me
NN
scholarisine A
OO
NN
I Bu3SnH, ACHN, PhMe, !
OO
NN
OO
NN
H
OO
NN
OO
NN
[O]
Radical Cyclizations in Total Synthesis
! Keck allylation for use in scholarisine A
Smith, M. W.; Snyder, S. A. J. Am. Chem. Soc. 2013, 135 , 12964-12967.
OO
Me
NN
scholarisine A
OO
NN
I Bu3SnH, ACHN, PhMe, !
OO
NN
OO
NN
H
OO
NN
OO
NN
[O]
Radical Cyclizations in Total Synthesis
! Keck allylation for use in scholarisine A
Smith, M. W.; Snyder, S. A. J. Am. Chem. Soc. 2013, 135 , 12964-12967.
OO
Me
NN
scholarisine A
OO
NN
I Bu3SnH, ACHN, PhMe, !
OO
NN
OO
NN
H
OO
NN
OO
NN
[O]
Radical Cyclizations in Total Synthesis
! Aryl radicals utilized as hydrogen atom abstractors
Smith, M. W.; Snyder, S. A. J. Am. Chem. Soc. 2013, 135 , 12964-12967.
OO
NN
I Bu3SnH, ACHN, PhMe, !
OO
NN
OO
N
18%
6%
N
Radical Cyclizations in Total Synthesis
! Parker and Fokas: (-)-morphine via radical cyclization and fragmentation
Parker, K. A.; Fokas, D. J. Am. Chem. Soc. 1992, 114 , 9688-9689.
Br
SPh
OMeONMe
Ts
HO
O
SPhNTs
Me
OH
O
SPhNTs
Me
OH
O
HO
SPh
MeO MeO
MeO
O
HO
MeO
NMe
Ts N TsMe
O
HO
MeO
HH - PhS•
nBu3SnH, AIBN
PhH, reflux
30%
5-exo-trig
6-endo-trig
fragmentation
NMe
(-)-morphine
geometric constraints prevent 5-exo
Radical Cyclizations in Total Synthesis
! Parker and Fokas: (-)-morphine via radical cyclization and fragmentation
Parker, K. A.; Fokas, D. J. Am. Chem. Soc. 1992, 114 , 9688-9689.
Br
SPh
OMeONMe
Ts
HO
O
SPhNTs
Me
OH
O
SPhNTs
Me
OH
O
HO
SPh
MeO MeO
MeO
O
HO
MeO
NMe
Ts N TsMe
O
HO
MeO
HH - PhS•
nBu3SnH, AIBN
PhH, reflux
30%
5-exo-trig
6-endo-trig
fragmentation
NMe
(-)-morphine
geometric constraints prevent 5-exo
Radical Cyclizations in Total Synthesis
! Parker and Fokas: (-)-morphine via radical cyclization and fragmentation
Parker, K. A.; Fokas, D. J. Am. Chem. Soc. 1992, 114 , 9688-9689.
Br
SPh
OMeONMe
Ts
HO
O
SPhNTs
Me
OH
O
SPhNTs
Me
OH
O
HO
SPh
MeO MeO
MeO
O
HO
MeO
NMe
Ts N TsMe
O
HO
MeO
HH - PhS•
nBu3SnH, AIBN
PhH, reflux
30%
5-exo-trig
6-endo-trig
fragmentation
NMe
(-)-morphine
geometric constraints prevent 5-exo
Radical Cyclizations in Total Synthesis
! Parker and Fokas: (-)-morphine via radical cyclization and fragmentation
Parker, K. A.; Fokas, D. J. Am. Chem. Soc. 1992, 114 , 9688-9689.
Br
SPh
OMeONMe
Ts
HO
O
SPhNTs
Me
OH
O
SPhNTs
Me
OH
O
HO
SPh
MeO MeO
MeO
O
HO
MeO
NMe
Ts N TsMe
O
HO
MeO
HH - PhS•
nBu3SnH, AIBN
PhH, reflux
30%
5-exo-trig
6-endo-trig
fragmentation
NMe
(-)-morphine
geometric constraints prevent 5-exo
Radical Cyclizations in Total Synthesis
! Parker and Fokas: (-)-morphine via radical cyclization and fragmentation
Parker, K. A.; Fokas, D. J. Am. Chem. Soc. 1992, 114 , 9688-9689.
Br
SPh
OMeONMe
Ts
HO
O
SPhNTs
Me
OH
O
SPhNTs
Me
OH
O
HO
SPh
MeO MeO
MeO
O
HO
MeO
NMe
Ts N TsMe
O
HO
MeO
HH - PhS•
nBu3SnH, AIBN
PhH, reflux
30%
5-exo-trig
6-endo-trig
fragmentation
NMe
(-)-morphine
geometric constraints prevent 5-exo
Radical Cyclizations in Total Synthesis
! Titanium(III)-induced cyclization of epoxyolefins
Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1988, 110 , 8561-8562.
O2Cp2TiCl
CO2MeMeO2C
Cp2(Cl)TiO Ti(Cl)Cp2
HO Me
CO2MeMeO2C
CO2MeMeO2C
85:15 cis:trans
68%
H3O+
Cp2(Cl)TiO
CO2MeMeO2C
Cp2(Cl)TiO
CO2MeMeO2C
Radical Cyclizations in Total Synthesis
! Titanium(III)-induced cyclization of epoxyolefins
Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1988, 110 , 8561-8562.
O2Cp2TiCl
CO2MeMeO2C
Cp2(Cl)TiO Ti(Cl)Cp2
HO Me
CO2MeMeO2C
CO2MeMeO2C
85:15 cis:trans
68%
H3O+
Cp2(Cl)TiO
CO2MeMeO2C
Cp2(Cl)TiO
CO2MeMeO2C
Radical Cyclizations in Total Synthesis
! Epoxides as !-alkoxy radical cyclization precursors
Velasco, J. et. al. J. Org. Chem. 2013, 78, 5482-5491.
N
HO
HO
N
N NH
O
NH2
EntecavirAntiviral agent against Hepatitis B
BMS patent to expire in 2015 in U.S.
OTBS OAc
O
20 mol% Cp2TiCl2, 10 mol% IrCl(CO)(PPh3)2
Mn (2 eq.), collidine, TMSCl, H2 (4 bar), THF, 4 hr. RT58% AcO
HOOTBS
Radical Cyclizations in Total Synthesis
! Epoxides as !-alkoxy radical cyclization precursors
Velasco, J. et. al. J. Org. Chem. 2013, 78, 5482-5491.
OTBS OAc
OAcO
HOOTBS
Cp2TiCl2
1/2 M 1/2 MCl2
Cp2TiCl
AcO
TBSO
OTiIIILn
AcO
LnTiIIIOOTBS
AcO
LnTiIIIOOTBS
LnTiIII
IrCl(CO)(PPh3)2, H2, collidine, TMSCl
Radical Cyclizations in Total Synthesis
! The reductive method
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
R-Xe-
R + X-R' R
R'
e-
RR'
H+
RR'
H
anionic chemistry
Radical Cyclizations in Total Synthesis
! The reductive method more commonly used to generate ketyl radicals
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
R'
R'
e-
R'
H+
R'
H
anionic chemistry
O
R R
R = H, alkyl
R R
O
RR
O
RR
SmI2 O
OH
RR
Radical Cyclizations in Total Synthesis
! The triquinane system using SmI2
Fevig, T. L.; Elliott, R. L.; Curran, D. P. J. Am. Chem. Soc. 1988, 110 , 5064-5067.
H
H
Me
hypnophilin
Me
Me H
MeMe
Me
H H
MeMe
O
O
Me
Me
OH
Radical Cyclizations in Total Synthesis
! The triquinane system using SmI2
Fevig, T. L.; Elliott, R. L.; Curran, D. P. J. Am. Chem. Soc. 1988, 110 , 5064-5067.
Me
Me
Me
Me
MeMe
H
Me
MeH
H
Me
MeMe
Me
H H
MeMe
Me
H H
O
SmI2, THF/DMPU
69%
Me
H H
Me
Me
H
Me
MeH
H
Me
O
O
OSmI2
O
O
O
O
O
O
OOSmI2
SmI2
O
OHO
Radical Cyclizations in Total Synthesis
! Kilburn's stereoselective synthesis of paeonilactone B via a SmI2 cyclization
Boffey, R. J.; Wittingham, W. G.; Kilburn, J. D. J. Chem. Soc., Perkin Trans. 1, 2001, 487-496.
OMe
OH
SmI2, HMPA, tBuOH
THF, 0 to RT63% Me
OSmIIILn
H
OH
H
Me
OSmIIILn
H
OOSmIIILn
MeH
O
10:1 diastereomers
O
O
H
H
MeHO
O
O
H
H
MeHO
HMPA thought to cooridnate to SmIII to add bulk and induce stereoselectivity
Radical Cyclizations in Total Synthesis
! SmI2 for macrocyclizations in Diazonamide A
Nicolaou, K. C. et. al. ACIEE 2003, 42, 1753.
O
N
Me
Me
Cbz O
NBn
N MOM
N
O
NOMe
SmI2, DMA
O
N
Me
Me
Cbz HO
NBn
N MOM
N
O
H2N
40-45%
NH
NH
N
O
NO
O
O
HN
MeMe
HN
O
Me Me
HO Cl
Cl
diazonamide A
Radical Cyclizations in Total Synthesis
! SmI2 for macrocyclizations in Diazonamide A
Nicolaou, K. C. et. al. ACIEE 2003, 42, 1753.
O
N
Me
Me
Cbz O
NBn
N MOM
N
O
NOMe
SmI2, DMA
O
N
Me
Me
Cbz HO
NBn
N MOM
N
O
H2N
40-45%
O
N
Me
Me
Cbz O
NBn
N MOM
N
O
NOMe
SmI2
I2Sm
Radical Cyclizations in Total Synthesis
De Mesmaeker, A. et. al. Tetrahedron Lett. 1989, 30, 6307-6310.
! Radical cyclizations in sugar chemistry
O
OBn
OBn
BnO O
O
OBn
SePhOBn
BnO O
Bu3SnH, AIBN, 90%Me
O
OBn
SO2PhOBn
BnO O
Et3B, Bu3SnH, RT, 72%
O
OBn
OBn
BnO O
MeSmI2, HMPA, 78%
O
OBn
SePhOBn
BnO NH
O
OBn
OBn
BnO NH
Me
Sinay, P. et. al. Tetrahedron Lett. 1992, 33, 8065-8068.Czernecki, S.; Ayadi, E.; Xie, J. Tetrahedron Lett. 1996, 37, 9193-9194.
Radical Cyclizations in Total Synthesis
De Mesmaeker, A. et. al. Tetrahedron Lett. 1989, 30, 6311-6314.
! Tethered alkene and alkyne radical acceptors
Stork, G.; Suh, H. S.; Kim G. J. Am. Chem. Soc. 1991, 113 , 7054-7056.
O SePh
OOMeMeO
OMe
SiMe
MePh
1. Bu3SnH, AIBN2. TBAF
73%
O
OHOMeMeO
OMePh
E:Z >20:1
O SePh
OBnOBnO
OBn
OMe
Bu3SnH, AIBN
89%
O
OBnBnO
OBn
OOMe
MeO
OBnBnO
OBnOTBDMS
OMe
Me H
Radical Cyclizations in Total Synthesis
! 9-endo cyclization for !"C-disaccharides
Xin, Y. C.; Mallet, J.-M.; Sinay, P. J. Chem. Soc., Chem. Commun. 1993, 864-865.
O
OSePhBnO
BnOBnO
SiMe Me
O
O
OBn
OBnOMe
1. Bu3SnH, AIBN2. HF, THF
40%
O
OHBnO
BnOBnO
O
OH
OMe
BnOBnO
! 8-endo cyclization for #"C-disaccharides
O
OSePhBnO
BnO OBn
SiO
Me Me
O
OBn
OBn
OMe
1. Bu3SnH, AIBN2. TBAF
45%
O
OHBnO
BnO OBn
OOBn
OMe
HO
OBn
6, 2' adduct
3, 2' adduct
Radical Cyclizations in Total Synthesis
! 5-exo SmI2 cyclization for C-disaccharides
Mazeas, D.; Skrydstrup, T.; Doumeix, O.; Beau, J.-M. Angew. Chem. Int. Ed. Engl. 1994, 33, 1383-1386.
1. SmI2, THF2. TBAF, THF3. Pd/C, H24. Ac2O, Py
48%
! no HMPA makes SmI2 weaker reductant! LUMO !* of SO2Ar lowered with 2-pyridine! less toxic conditions
O SO2PyrOSi
MeMe
O
BnOBnOOMe
OBn
OBn
BnOBnO
OOBn
BnOBnO
O
OMeAcOAcOAcO
AcO
Radical Cyclizations in Total Synthesis
Wilcox, C. S.; Gaudino, J. J. J. Am. Chem. Soc. 1986, 108 , 3104-3105.
OH
OHOHHO
HO
carba-D-fructo-furanose
MeO2CBnO OBn
Br2HC OHOBn
O
OBn
HO
BnO
OBn
commercially available
t-BuO2CBnO OBn
OBnHO
t-BuO2CHC PPh3
DCM, 92%
2:3 E:Z
MeO2CBnO OBn
OBnO
1. Me2SO, (COCl)2, NEt3, 96%2. TFA, DCM, 0 °C, 93%
1. LDA2. CH2Br23. LDA, CH2N2
78%
5 equiv. Bu3SnH, PhH, RT85%
OHOBn
BrHC
OBnOBn
MeO2C OBn
OHOBnMeO2C
BnOH
Radical Cyclizations in Total Synthesis
Wilcox, C. S.; Gaudino, J. J. J. Am. Chem. Soc. 1986, 108 , 3104-3105.
OH
OHOHHO
HO
carba-D-fructo-furanose
MeO2CBnO OBn
Br2HC OHOBn
OHO
OBnBnO
OBn
commercially available
t-BuO2CBnO OBn
OBnHO
t-BuO2CHC PPh3
DCM, 92%
2:3 E:Z
MeO2CBnO OBn
OBnO
1. Me2SO, (COCl)2, NEt3, 96%2. TFA, DCM, 0 °C, 93%
1. LDA2. CH2Br23. LDA, CH2N2
78%
5 equiv. Bu3SnH, PhH, RT85%
OHOBn
BrHC
OBnOBn
MeO2C OBn
OHOBnMeO2C
BnOH
Radical Cyclizations in Total Synthesis
Wilcox, C. S.; Gaudino, J. J. J. Am. Chem. Soc. 1986, 108 , 3104-3105.
OH
OHOHHO
HO
carba-D-fructo-furanose
MeO2CBnO OBn
Br2HC OHOBn
OHO
OBnBnO
OBn
commercially available
t-BuO2CBnO OBn
OBnHO
t-BuO2CHC PPh3
DCM, 92%
2:3 E:Z
MeO2CBnO OBn
OBnO
1. Me2SO, (COCl)2, NEt3, 96%2. TFA, DCM, 0 °C, 93%
1. LDA2. CH2Br23. LDA, CH2N2
78%
5 equiv. Bu3SnH, PhH, RT85%
OHOBn
BrHC
OBnOBn
MeO2C OBn
OHOBnMeO2C
BnOH
Radical Cyclizations in Total Synthesis
Wilcox, C. S.; Gaudino, J. J. J. Am. Chem. Soc. 1986, 108 , 3104-3105.
OH
OHOHHO
HO
carba-D-fructo-furanose
MeO2CBnO OBn
Br2HC OHOBn
OHO
OBnBnO
OBn
commercially available
t-BuO2CBnO OBn
OBnHO
t-BuO2CHC PPh3
DCM, 92%
2:3 E:Z
MeO2CBnO OBn
OBnO
1. Me2SO, (COCl)2, NEt3, 96%2. TFA, DCM, 0 °C, 93%
1. LDA2. CH2Br23. LDA, CH2N2
78%
5 equiv. Bu3SnH, PhH, RT85%
OHOBn
BrHC
OBnOBn
MeO2C OBn
OHOBnMeO2C
BnOH
Radical Cyclizations in Total Synthesis
Wilcox, C. S.; Gaudino, J. J. J. Am. Chem. Soc. 1986, 108 , 3104-3105.
OH
OHOHHO
HO
carba-D-fructo-furanose
MeO2CBnO OBn
Br2HC OHOBn
OHO
OBnBnO
OBn
commercially available
t-BuO2CBnO OBn
OBnHO
t-BuO2CHC PPh3
DCM, 92%
2:3 E:Z
MeO2CBnO OBn
OBnO
1. Me2SO, (COCl)2, NEt3, 96%2. TFA, DCM, 0 °C, 93%
1. LDA2. CH2Br23. LDA, CH2N2
78%
5 equiv. Bu3SnH, PhH, RT85%
OHOBn
BrHC
OBnOBn
MeO2C OBn
OHOBnMeO2C
BnOH
Radical Cyclizations in Total Synthesis
Wilcox, C. S.; Gaudino, J. J. J. Am. Chem. Soc. 1986, 108 , 3104-3105.
OH
OHOHHO
HO
carba-D-fructo-furanose
MeO2CBnO OBn
Br2HC OHOBn
OHO
OBnBnO
OBn
commercially available
t-BuO2CBnO OBn
OBnHO
t-BuO2CHC PPh3
DCM, 92%
2:3 E:Z
MeO2CBnO OBn
OBnO
1. Me2SO, (COCl)2, NEt3, 96%2. TFA, DCM, 0 °C, 93%
1. LDA2. CH2Br23. LDA, CH2N2
78%
5 equiv. Bu3SnH, PhH, RT85%
OHOBn
BrHC
OBnOBn
MeO2C OBn
OHOBnMeO2C
BnOH
Radical Cyclizations in Total Synthesis
Wilcox, C. S.; Gaudino, J. J. J. Am. Chem. Soc. 1986, 108 , 3104-3105.
OH
OHOHHO
HO
carba-D-fructo-furanose
MeO2CBnO OBn
Br2HC OHOBn
OHO
OBnBnO
OBn
commercially available
t-BuO2CBnO OBn
OBnHO
t-BuO2CHC PPh3
DCM, 92%
2:3 E:Z
MeO2CBnO OBn
OBnO
1. Me2SO, (COCl)2, NEt3, 96%2. TFA, DCM, 0 °C, 93%
1. LDA2. CH2Br23. LDA, CH2N2
78%
5 equiv. Bu3SnH, PhH, RT85%
OHOBn
BrHC
OBnOBn
MeO2C OBn
OHOBnMeO2C
BnOH
Radical Cyclizations in Total Synthesis
! The oxidative method
O
RH
R'
OH
RR'
M+n
-H+
O
RR'
O
RR'
R" O
RR'
R"M+n
M+n-1+
O
RR'
R" product
! Chemical oxidation
! Electrochemical oxidationKolbe electrolysis
2 R-CO2- 2 [ R-CO2•] 2 R• R-R-e- -CO2
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
Radical Cyclizations in Total Synthesis
! The oxidative method
O
RH
R'
OH
RR'
M+n
-H+
O
RR'
O
RR'
R" O
RR'
R"M+n
M+n-1+
O
RR'
R" product
! Chemical oxidation
! Electrochemical oxidationKolbe electrolysis
2 R-CO2- 2 [ R-CO2•] 2 R• R-R-e- -CO2
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
Radical Cyclizations in Total Synthesis
! The oxidative method
O
RH
R'
OH
RR'
M+n
-H+
O
RR'
O
RR'
R" O
RR'
R"M+n
M+n-1+
O
RR'
R" product
! Chemical oxidation
! Electrochemical oxidationKolbe electrolysis
2 R-CO2- 2 [ R-CO2•] 2 R• R-R-e- -CO2
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.
Radical Cyclizations in Total Synthesis
! Oxidative quadruple cyclization to prepare tetracyclic diterpenes
Snider, B.B.; Kiselgof, J. Y.; Foxman, B. M. J. Org. Chem. 1990, 112 , 4003-4008.
O
Me
MeMn(OAc)3, Cu(OAc)2
MeOH, RT, 3 h35%
Me
OMe CO2Et
Me
H
H
CO2EtMe
Me
Me CO2Et
Me O
H
H
isosteviol
Me
Me
Me
H
H
beyer-15-ene-3,9-diol
HO
HO
Radical Cyclizations in Total Synthesis
! Oxidative quadruple cyclization by Snider
Snider, B.B.; Kiselgof, J. Y.; Foxman, B. M. J. Org. Chem. 1990, 112 , 4003-4008.
O
Me
MeMn(OAc)3, Cu(OAc)2
MeOH, RT, 3 h35%
Me
OMe CO2Et
Me
H
H
CO2EtMe
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
Mn(III)Cu(II)
* only other epimer isolated
Radical Cyclizations in Total Synthesis
! Oxidative quadruple cyclization by Snider
Snider, B.B.; Kiselgof, J. Y.; Foxman, B. M. J. Org. Chem. 1990, 112 , 4003-4008.
O
Me
MeMn(OAc)3, Cu(OAc)2
MeOH, RT, 3 h35%
Me
OMe CO2Et
Me
H
H
CO2EtMe
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
Mn(III)Cu(II)
* only other epimer isolated
Radical Cyclizations in Total Synthesis
! Oxidative quadruple cyclization by Snider
Snider, B.B.; Kiselgof, J. Y.; Foxman, B. M. J. Org. Chem. 1990, 112 , 4003-4008.
O
Me
MeMn(OAc)3, Cu(OAc)2
MeOH, RT, 3 h35%
Me
OMe CO2Et
Me
H
H
CO2EtMe
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
Mn(III)Cu(II)
* only other epimer isolated
Radical Cyclizations in Total Synthesis
! Oxidative quadruple cyclization by Snider
Snider, B.B.; Kiselgof, J. Y.; Foxman, B. M. J. Org. Chem. 1990, 112 , 4003-4008.
O
Me
MeMn(OAc)3, Cu(OAc)2
MeOH, RT, 3 h35%
Me
OMe CO2Et
Me
H
H
CO2EtMe
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
Mn(III)Cu(II)
* only other epimer isolated
Radical Cyclizations in Total Synthesis
! Oxidative quadruple cyclization by Snider
Snider, B.B.; Kiselgof, J. Y.; Foxman, B. M. J. Org. Chem. 1990, 112 , 4003-4008.
O
Me
MeMn(OAc)3, Cu(OAc)2
MeOH, RT, 3 h35%
Me
OMe CO2Et
Me
H
H
CO2EtMe
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
Mn(III)Cu(II)
* only other epimer isolated
Radical Cyclizations in Total Synthesis
! Oxidative quadruple cyclization by Snider
Snider, B.B.; Kiselgof, J. Y.; Foxman, B. M. J. Org. Chem. 1990, 112 , 4003-4008.
O
Me
MeMn(OAc)3, Cu(OAc)2
MeOH, RT, 3 h35%
Me
OMe CO2Et
Me
H
H
CO2EtMe
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
O
Me
CO2Et Me Me
Mn(III)Cu(II)
* only other epimer isolated
Radical Cyclizations in Total Synthesis
OPh
O
Me
Me
HO
OH
Me
MeMe
Me
Me
Mn(OAc)3, Cu(OAc)2, AcOH, RT, 3 hrs
OMeMe O
O
HOMe
Me
Me
Me MeH
H
garcibracteatone
OO
O Me
Me
Me MeH
HO
Me
Me
Me
OO
O
Me
Me
Me
Me MeH
Me
Me
HOOO
O
HOMe
Me
Me
Me MeH
MeMe
OMeMe O
O
HOMe
Me
Me
Me MeH
H
Pepper, H. P.; Lam, H. C.; Bloch, W. M.; George, J. H. Org. Lett. 2012, 14 , 5162-5164.
Radical Cyclizations in Total Synthesis
! The oxidative method
Pepper, H. P.; Lam, H. C.; Bloch, W. M.; George, J. H. Org. Lett. 2012, 14 , 5162-5164.
OPh
O
Me
Me
HO
OH
Me
MeMe
Me
Me Mn(OAc)3, Cu(OAc)2, AcOH, RT, 3 hrs
OMeMe O
O
HOMe
Me
Me
Me MeH
H
garcibracteatone14%
OMeMe O
O
HOMe
Me
MeH
H
Me Me5-epi-garcibracteatone
8%
! 4 C-C bonds formed! no protecting groups! 5 stereocenters formed! biomimetic pathway
Radical Cyclizations in Total Synthesis
OPh
O
Me
Me
HO
OH
Me
MeMe
Me
Me
Mn(OAc)3, Cu(OAc)2, AcOH, RT, 3 hrs
OMeMe O
O
HOMe
Me
Me
Me MeH
H
garcibracteatone
OO
O Me
Me
Me MeH
HO
Me
Me
Me
OO
O
Me
Me
Me
Me MeH
Me
Me
HOOO
O
HOMe
Me
Me
Me MeH
MeMe
OMeMe O
O
HOMe
Me
Me
Me MeH
H
Pepper, H. P.; Lam, H. C.; Bloch, W. M.; George, J. H. Org. Lett. 2012, 14 , 5162-5164.
Radical Cyclizations in Total Synthesis
OPh
O
Me
Me
HO
OH
Me
MeMe
Me
Me
Mn(OAc)3, Cu(OAc)2, AcOH, RT, 3 hrs
OMeMe O
O
HOMe
Me
Me
Me MeH
H
garcibracteatone
OO
O Me
Me
Me MeH
HO
Me
Me
Me
OO
O
Me
Me
Me
Me MeH
Me
Me
HOOO
O
HOMe
Me
Me
Me MeH
MeMe
OMeMe O
O
HOMe
Me
Me
Me MeH
H
Pepper, H. P.; Lam, H. C.; Bloch, W. M.; George, J. H. Org. Lett. 2012, 14 , 5162-5164.
Radical Cyclizations in Total Synthesis
OPh
O
Me
Me
HO
OH
Me
MeMe
Me
Me
Mn(OAc)3, Cu(OAc)2, AcOH, RT, 3 hrs
OMeMe O
O
HOMe
Me
Me
Me MeH
H
garcibracteatone
OO
O Me
Me
Me MeH
HO
Me
Me
Me
OO
O
Me
Me
Me
Me MeH
Me
Me
HOOO
O
HOMe
Me
Me
Me MeH
MeMe
OMeMe O
O
HOMe
Me
Me
Me MeH
H
Pepper, H. P.; Lam, H. C.; Bloch, W. M.; George, J. H. Org. Lett. 2012, 14 , 5162-5164.
Radical Cyclizations in Total Synthesis
OPh
O
Me
Me
HO
OH
Me
MeMe
Me
Me
Mn(OAc)3, Cu(OAc)2, AcOH, RT, 3 hrs
OMeMe O
O
HOMe
Me
Me
Me MeH
H
garcibracteatone
OO
O Me
Me
Me MeH
HO
Me
Me
Me
OO
O
Me
Me
Me
Me MeH
Me
Me
HOOO
O
HOMe
Me
Me
Me MeH
MeMe
OMeMe O
O
HOMe
Me
Me
Me MeH
H
Pepper, H. P.; Lam, H. C.; Bloch, W. M.; George, J. H. Org. Lett. 2012, 14 , 5162-5164.
Radical Cyclizations in Total Synthesis
! So what is "radical" now?
! Total syntheses with radical cyclizations method in the last year:
! No photoredox radical cyclization in total synthesis yet
! Radical cyclization still primarily for carbon-carbon bond formations
! Many use fragmentation method - for functional handle after
! Total syntheses with tandem radical cyclization in the last year:
Tin Reagent: 8 reported Reduction: 6 reported Oxidation: 6 reported
Tandem: 5