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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