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presented by Jon ParrishSeptember 8th, 2004
Radicals in Total Synthesis
Outline
• Background
• Metal-hydride approaches to free radicals
• Organometallic/inorganic reductants
• Organometallic/inorganic oxidants
• Miscellaneous approaches to radicals
• Important radical-based synthetic methods
Background
• The first observed free radical species is attributed to Gomberg(triphenylmethyl radical) in 1900.
• The introduction of tin hydride methods for generating radicals(1970’s) increased interest in the synthetic utility of radicals.
• Researchers in free radical chemistry include: Barton, Curran,Giese, Molander (SmI2), Gansauer (Cp2TiCl), Snider (Mn(OAc)3),Newcomb, Zard, Crich, Sibi, Keck, Porter, Hart, Renaud, Murphy,Kende etc.
Features of Carbon-Centered Free Radicals
• Radicals are either planar, or slightly pyramidal with a very lowbarrier to inversion; therefore most free radicals do not retainstereochemical information.
• Radical additions to C=C bonds are typically exothermic andirreversible. Additionally, radicals are not typically associated withmetallic counterions or aggregation spheres. As such, they areuniquely capable of forming congested bonds
• In contrast to anions, radicals rarely β-eliminate allowing for radicalformation next to oxygen and nitrogen functionalities.
• Radicals are tolerant of a wide variety of functionality includingalcohols, amines, esters, etc.
• Most radical reactions involve interaction of the radical SOMO withthe olefin LUMO; therefore most radicals are considerednucleophilic
Outline
• Background
• Metal-hydride approaches to free radicals
• Organometallic/inorganic reductants
• Organometallic/inorganic oxidants
• Miscellaneous approaches to radicals
• Important radical-based synthetic methods
Metal Hydride Reductions
• Typical reaction involves homolysis of a carbon-halogen or carbon-chalcogen bond by a tin or silyl hydride and an initiator.
• The rate of the desired reaction must be faster than unwantedtermination by the metal hydride.
• Rate of hydrogen atom donation is R3SnH > (TMS)3SiH> R3GeH >R3SiH.
R
initiators
diazo compounds (i.e. AIBN, V70, etc.)
Et3B/O2
h!
Initiation: Bu3Sn-Hinitiator
Bu3Snmetal hydrides
Bu3SnH
Ph3SnH
(TMS)3SiH
Ph3GeHPropagation:
Bu3Sn+ Bu3SnX
R R'reaction
RBu3SnH
R-H + Bu3Sn (premature termination)
R-X
Termination: R'Bu3SnH
R'-H + Bu3Sn
or
Alkyl/Aryl Radicals from Tin and Silicon Hydrides
a) Bu3SnH/AIBN
b) 30% H2O2
78 %
O
O
OSi
Br
O
O
OH
HO
(-)-talaromycin
Crimmins, M. T. and O' Mahony, R. JOC 1989, 54, 1157.
(TMS)3SiH/AIBN
NMs OBn
I
N3
NOBn
NH
HMs
65 %
N OAcH
Me
N
MeOCO2MeOH
Et
(+/-)-vindoline
Murphy et al. Org Lett. 2002, 4, 443-445.
MeO MeO
R3SnH/init.
X RR
Acyl Radicals from Tin Hydrides
• Acyl radicals are considered more nucleophilic than alkyl radicals;prefer to react with electron-poor olefins
allylSnBu3/AIBN
55 %10:1 dr
pleuromutilin
Zard et al. Org. Lett. 2003, 5, 325-328.
O SePh
CO2Et
OH
CO2Et
(Bu3Sn)2/h!
85 %acanthodoral
Koreeda et al. Org. Lett. 2004, 6, 537-540.
SPhH
SO2Ar
O
SePh
SPhH
O
H
CHO
R3SnH/init.
R X
O
R
O
Miscellaneous Radicals from Tin Hydrides
MsO
THPO
NH
S
Bu3SnH/AIBN
CO2Bn
CO2Me
N
OTHP
CO2Bn
CO2Me
MsO
> 60 %(-)-vindoline
Fukuyama et al. JACS 2002, 124, 2137-2139.
N OAcH
Me
N
MeOCO2MeOH
Et
O
O
OTBS
MeO
TBSO
OTBS
OMe
H
H
(TMS)3SiH/AIBN
O
S
OTBS
MeO
TBSO
TBSO OMe
H
44 %> 95% de
O
Sherburn et al. Org. Lett. 2004, 6, 1345-1348.
O
O
MeO
MeO
OH
OMe
H
H
(-)-arctigenin
Atom Transfer Reactions
• An initially formed radical can also abstract an appropriatelydistanced group forming a second radical species that can, in turn,undergo additional chemistry.
43 %
Bu3SnH/AIBN
Naito et al. Tet. Lett. 2004, 45, 3481-3484.
N
N
O
Br
Ac
N
N
O
Ac
CO2Me
NH
N
HN
HN
NH
HN
HN
O
RO
martinelline
CO2Me
78 %
N O
Br
CO2Me
TMSBu3SnH/AIBN
BzN CO2Me
TMS
HN
N
Cl
(+/-)-epibatidine
Ikeda et al. JCS, Perkin I, 1997, 3339-3344.
Organomercury Reduction
• This older method of radical formation involves reduction of aorganomecurial to an alkyl radical.
• The mercurial hydride species is an excellent hydrogen atom donorfrequently leading to premature reduction of radical intermediates.
NaBH4
H2C=CHCN
59 %
OOOO
CN
HgOAcO
O
O
(+)-ipomeamarone
Sugimura et al. Tetrahedron 1994, 50, 11647-11658.
NaBH4R HgHR HgX R
45 %
THPOC9H19
HgBr
OH
CN
THPOC9H19OH
CNOC9H19
O
HO
(+/-)-malyngolide
NaBH4
Kozikowski et al. Organometallics 1982, 1, 675.
Outline
• Background
• Metal-hydride approaches to free radicals
• Organometallic/inorganic reductants
• Organometallic/inorganic oxidants
• Miscellaneous approaches to radicals
• Important radical-based synthetic methods
Samarium (II) Iodide
• Typically formed by the oxidation of samarium (0) with either 1,2-diiodoethane or iodine.
• Samarium (II) forms dark blue/purple solutions and is most oftenused in tetrahydrofuran.
• Reactivity can be enhanced by adding Lewis basic additives likeNMP, DMPU or HMPA (E0 for SmI2 = -0.98 V, SmI2/HMPA = -1.75V).
• see a) Procter et al. Chem. Rev. 2004, 104, 3371-3403.b) Molander et al. Chem. Rev. 1996, 96, 307-338.
SmI2Sm0
ICH2CH2I (- CH2=CH2 )
or
I2
Alkyl/Aryl Radicals from SmI2
• Single electron reduction of labile bonds with SmI2 can lead to avariety of alkyl/aryl/vinyl radical species.
• Alkyl radicals (in particular) are susceptible to further reduction toform anionic organosamarium species limiting radical reactivity.
O
OSi
OO OMe
OBn
BnO
OBn
BnOSO2Ph
OBn
O
OH
HOO OMe
OBn
BnO
OBn
BnO
OBnH
50 % for two steps
Sinay et al. Synlett. 1994, 420.
N
Br
OBn
N
OBn
SmI2/HMPA
N
OH
OH
(+/-)-oxerine
Ohta et al. Tetrahedron 1994, 50, 13575.
86 %
R X R + XSmI2
1. SmI2/HMPA
2. HF
Ketyl Radicals from SmI2
• Most aldehydes and ketones can be reduced with samarium(II)iodide to yield ketyl radical species; reduction of esters, amides ornitriles are rare
O
N
N
O
NOMe
MOM
OMe
O
NCbz
O
MeO2C
O
N
N
O
NH2
MOM
OMe
O
NCbz
HO
MeO2C
40-45%
SmI2/HMPADiazonamide A
Nicolaou et al. ACIEE
2003, 42, 1753.
R R'
O
R R'
OSmSmI2
paeonilactone B
Kilburn et al. Chem. Commun. 1998, 1875.
SmI2/HMPA
O
H
H
HO
O
O
H
H
HO
O
O
O
H
63 %
Cascade Reactions with SmI2
65 % hypnophilin
Curran et al. Tetrahedron 1985, 41, 3943-3958.
O H
O
OO
OOH
H
H H
MeOH
H
H
MeO
O
SmI2
ISmI2/HMPA
acetone
H
HOH
41 %
penitrem D
Curran et al. Org. Lett. 2003, 5, 419.
NH O
OH
OH
HOH
Titanocene (III) Chloride
• Homogenous dark-green colored reagent formed by the reduction oftitanocene dichloride (commercially available) with either zinc,aluminum or manganese. Must be used in THF!
• Cp2TiCl is a mild reductant (E0 = -0.75) selective for the formation ofα-alkoxy radicals from epoxides; it does not react with simpleorganohalides or ketones. In addition, Cp2TiCl does not appreciablyreduce radicals to organometallic anionic species.
• The radical formed from reductive opening of epoxides will reliablyform at the site producing the more stable radical (typically, themore substituted site)
• see Gansauer et al. Chem. Rev. 2000, 100, 2771-2788.
Cp2TiIV
Cl2Mn or Zn or Al
THFCp2Ti
IIICl
Titanocene(III)-mediated Cyclizations
74 %
6:1 dr methylenolactocin
Roy et al. JOC, 1998, 63, 2829-2834.
Cp2TiCl
C5H11 O
O
O
HO
C5H11O
HO
C5H11 O
O
R
O Cp2TiCl
ROTiCp2Cl
(-)-siccanin
Trost et al. JACS, ASAP.
Cp2TiCl
O
OMe
H
O
O
H
H
MeO
HOO
H
H
HO
O
60 %
Outline
• Background
• Metal-hydride approaches to free radicals
• Organometallic/inorganic reductants
• Organometallic/inorganic oxidants
• Miscellaneous approaches to radicals
• Important radical-based synthetic methods
Manganese (III) Acetate
• Mild reductant used to form radicals from β-carbonyls
R R
O O
R R
O OMn(OAc)3
Mn(OAc)3/Cu(OAc)2
O
H
H
THPO
O
Cl
CO2Me O
H
H
O
O
O
H
H
THPO
O
CO2Me
Cl
65 % estafiatin
Kim et al. JACS
1997, 119, 8391.
HO
O
O
HO
O
OHOAc
O
O
9-acetoxyfukinanolide61 %
Greene et al. JACS 1996, 118, 9992.
Mn(OAc)3
Snider, B. B. Chem. Rev. 1996, 96, 339-364.
Ceric Ammonium Nitrate
• Lanthanide alternative to manganese acetate; can be used at lowertemperatures and in more solvents.
R R
O O
R R
O O(NH4)2Ce(NO3)6
norbisabloide76 %
Mane et al. Tet. Lett. 2002, 43, 4535-4536.
CAN
O
O
O
O
H OCO2H
O
H
O
O
H
O
O
OMe
OMe
MeO
Me
OH
CAN
O
O
OMe
OMe
MeO
Me
O
O
OMe
OMe
OMe
Me
OOH OH
48 % (brsm)
O
O
OH
OH
HO
Me
O
O
OH
OH
OH
Me
OOH OH
hybocarpone
AlBr3
Nicolaou et al. JACS 2004, 126,
607-612.
Nair et al. Chem. Soc. Rev. 1997, 127-132
Aromatic Oxidation
VOF3/AgBF4
65 %
Evans et al. ACIEE 1998, 37, 2700-2704.
NH
ONH
NO2
F
Cl
OBn
OMeOMeMeO
MeHN
ONHTFA
O
NH
ONH
NO2
F
Cl
OBn
OMeOMeMeO
MeHN
O
NHTFA
O
19:1 atropselectivity
vancomycin
N
OH
OBn
OBnMe
Me
Bn
HN
OH
OH
OHMe
Me
NH
OH
OH
HO Me
Me
OMe
Me
OMe
Me
OMe
Me
1. Ag2O
2. H2, Pd/C
(+/-)-michellamines
~ 75 %
Hoye et al. JOC 1999, 64, 7184-7201.
Outline
• Background
• Metal-hydride approaches to free radicals
• Organometallic/inorganic reductants
• Organometallic/inorganic oxidants
• Miscellaneous approaches to radicals
• Important radical-based synthetic methods
Diradicals
N
N
CH3CN, reflux H H
H
H
H
(+/-)-coriolin
Little et al. JOC 1985, 52, 4649-4661
HO
OHOH
OHO
OHO
OH OH
thermal N2 extrusion 3 + 2 cyclization
isomerization
Outline
• Background
• Metal-hydride approaches to free radicals
• Organometallic/inorganic reductants
• Organometallic/inorganic oxidants
• Miscellaneous approaches to radicals
• Important radical-based synthetic methods
Intermolecular Radical Traps
• Radicals can be trapped with a variety of intermolecular reagents toadd functionality.
R
R'CCl3X
R3SnH/1,4-cyclohexadiene
RSeSeR (RSSR)
RR'R X
R SeR
R H
(R' = CN, CO2R, NO2, SO2R
P(O)(OR)2, etc.)
(X = halogen)
Barton Decarboxylation
• Method for reductive removal of carboxylic acid moiety; intermediateradical species can also be trapped before reduction.
R
O
Cl
NO
O
R
S
N
HO
SBu3SnH/AIBN
R H
Barton et al. Chem. Commun. 1983, 939.
OH
O
AcO
1. SOCl2
2. CBrCl3,
N
HO
S
Br
AcO
64 % for 3 steps
Kutner et al. Org. Process Res. Dev. 1998, 2, 290-293.
50 g scale!
Barton-McCombie Deoxygenation
• Mild method for deoxygenation of alcohol moiety (cf. sulfonatereduction with LAH); again the transient radical can also be trapped.
O O
O
O
O
OMe Me
OBn
MeOBn
H
MeOTBSBnO
BnO
Me Bu3SnH/AIBN O O
O
O
O
Me MeOBn
MeOBn
H
MeOTBSBnO
BnO
Me
75 %
S
S
towards brevetoxin B
Nicolaou et al. JACS 1997, 119, 10239-10251.
Bu3SnH/AIBNR H
Barton et al. Perkin I. 1975, 1, 1574.
R OHKH, CS2
then MeIR
O
S
S
Keck Allylation
• Mild method for functionalization of carbon-halogen bonds; worksbest with secondary halides.
(-)-tuberostemonine
Wipf et al. JACS 2002, 124, 14848-14849.
N
O
O O
O
MeH
HHPhSe
H
N
O
O O
O
MeH
HH
HallylSnPh3/AIBN
N
O
O O
O
MeH
HH
H
Me
70 %
R X
initiatorR R
allylBu3Sn+ Bu3Sn
Keck et al. JACS 1982, 104, 5829-5831.
N OBr
O
N O
O
allylSnBu3/AIBN
88 %
> 95:5 dr
NH OH
C5H11
C4H9
(+/-)-perhydrohistrionicotoxin
Keck et al. JOC 1982, 47, 3590-3591.
Self-Oxidizing Protecting Group
Bu3SnH/AIBNO
MeO2C
OH
C8H15
OTPSO
Br
O
MeO2C
OH
C8H15
OTPSO
CP-225,917
Nicolaou et al. Org. Lett. 1999, 1, 63-66.
80 %
OH
O
Ph Ph
Br
Bu3SnH/AIBN
OH
O
H
58 %
Curran et al. Synthesis 1992, 123-127.
O
Br
RBu3SnH/AIBN R O
H
OR
Curran et al. Synthesis 1992, 123-127.
Conclusions
• Radical chemistry can be a powerful, selective method for carbon-carbon bond forming reactions (particularly cyclizations).
• The mild, neutral reaction conditions and functional groupcompatibility of carbon-centered radicals lend itself well toward usein complex systems associated with natural product synthesis.
• Future work is needed to expand the number of reliable radical-based synthetic methods, particularly those of an intermolecularfashion.
Important References
• Sibi, M. P.; Renaud, R., Eds. Radicals in Organic Synthesis; Wiley-VCH: New York, 2001.
• Giese, B. Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds; Pergamon Press: Oxford, 1986.
• Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of RadicalReactions; Wiley-VCH: New York, 1996.
• Curran et al. “Radical Reactions in Natural Product Synthesis,”Chem. Rev. 1991, 91, 1237-1286.
• Curran, D. P. “Radical Addition Reactions” and “Radical CyclizationReactions and Sequential Radical Reactions” in ComprehensiveOrganic Synthesis; Trost, B. M., Fleming, I. Eds. Pergamon Press:New York, 1992.
