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Hirsutene and Δ9(12) –Capnellene
D. P. Curran (1986)
Presenter: Mehdi Moemeni
Back Ground of Radical Structure
Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757–771.
C
In a modern context the first organic free radical identifiedwas triphenylmethyl radical. This species was discovered byMoses Gomberg in 1900 at the University of Michigan.
Radical Reactions
Smith, M. B.; March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York:Wiley, ISBN 0-471-72091-7
Radical chain reactions have three distinct phases:1) initiation, 2) propagation, and 3) termination.
Initiation(heat or light)
Propagation
X2 2X
RH + X R + XH
R + X2 RX + X
Termination
R + X RX
Baldwin’s Rules
YZ
X
YZ
X
YZ
X
YZ
X
YZ
X
YZ
X
Exo-Tet Endo-Tet Exo-Trig Endo-Trig
Exo-Dig Endo-Dig
- Tetrahedral for sp3 carbon- Trigonal for sp2 carbon- Digonal for sp carbon
Baldwin J. E. J. Chem. Soc., Chem. Commun. 1976, 18, 734.
n-Bu3SnH
PhCO3t-Buh, (62%)
6-exo-trig
radicalcyclization
O
H Br
O
H
O
H
n-Bu3SnH
OO
Ketoneolefination
SativeneCopacamphene stereoisomeric ratio of 4 to 5 (2:3)
1 2 3
45
Bakuzis, P.; Campos, O.O.S.; Bakuzis, M. L.F. J. Org. Chem. 1976, 41, 3261.
Radical Reactions Examples
Radical Reactions in Examples
Stork, G.; Sher, P.M.; Chen, H. L. J. Am. Chem. Soc. 1986, 108, 6384.
O
TBSO
I
OEt n-Bu3SnCl (0.1 equiv.),NaCNBH3 (2.0 equiv.),hTHF, 25 °C
C5H11
O
SiMe3
O
TBSO
OEt
5-exo-trig
radical cyclization
O
TBSO
OEt
intermoleculartrapping
O
TBSO
OEt
C5H11
O
SiMe3
n-Bu3SnH
O
TBSO
OEt
C5H11
O
SiMe3140 °C,
Brook Rearrangement
O
TBSO
OEt
C5H11
Me3SiO
2-(trimethylsilyl)-1-octen-3-one(7equiv.)
CO2H
HO
HO
HO H
H
H
6 7 8
91011
(+) prostaglandin F2
Radical Reactions in Examples
Keck, G.E.; Yates, J.B. J. Org. Chem. 1982, 47, 3590;Keck, G.E.; Enholm, E.J.; Yates, J.B.; Wiley, M.R. Tetrahedron 1985, 41, 4079.
N
OOH
N
O
O
Br
N- bromosuccinimide
CH2Cl2, 0°C (83%)
N
O
O
BrSn n-Bu3
(2.0 equiv)
AIBN (cat.)PhH, reflux
(88%)
ON
O
intermoleculartrapping
ON
O
Sn n-Bu3(-n-Bu3Sn )-elliminationO
N
O
13 14 15
1617
NC NN CN
AIBN: 2,2’-azobisisobutyronitrile
Radical Reactions in Examples
Barton, D.H.R.; Beaton, J.M.; Geller, L.E.; Pechet, M. M. J. Am. Chem. Soc. 1960, 82, 2640;Barton, D. H. R.; Beaton, J.M.; Geller, L.E.; Pechet, M.M. ibid. 1961, 83, 4076.Barton, D. H. R. Pure & Appl. Chem. 1968, 16, 1;Barton, D. H. R. Aldrichimica Acta 1990, 23, 3.
OH ClNO(nitrosyl chloride)
HONO h
HO H-atom
abstraction
OH
NO(nitric oxide)
OHN O
tautomerizationOHN OH
H3OOH OO
OH
18 19 20 21
222325 24
Radical Reactions in Examples
Barton, D.H.R.; Beaton, J.M. J. Am. Chem. Soc. 1960, 82, 2641;Barton, D. H. R.; Beaton, J.M. ibid. 1961, 83, 4083.
HOH
H H
H
O
OAcO
corticosterone acetate
CINO
pyr., 25 °C
OH
H H
H
O
OAcO
NO
(-NO)hPhCH3, 32°C(nitrite ester photolysis)
OH
H H
H
O
OAcO
HOH
H H
H
O
OAcO
H-atom abstraction
2627
2829
Radical Reactions in Examples
OH
H H
H
O
OAcO
HOH
H H
H
O
OAcO
H-atom abstraction
HOH
H H
H
O
OAcONO
tautomerization HOH
H H
H
O
OAcON
OH
O
H
H H
H
O
OAcOHO
(20% yield from SM)HNO2nitrous acid
NO
aldostrone 21-acetate
2829
3031
Barton, D.H.R.; Beaton, J.M. J. Am. Chem. Soc. 1960, 82, 2641;Barton, D. H. R.; Beaton, J.M. ibid. 1961, 83, 4083.
Back Ground of Hirsutene
In 1947, Heatley and co-workers reported that (+)-hirsutic acid produced by the filamentousfungus Stereum hirsutum. This is derived, in vivo, from the (+)-hirsutene.
- First total synthesis : Nozoe, S; Tetrahedron Lett. 1976, 17, 195
- First total synthesis by Radical Reactions: Curran, D. P.; Rakiewicz, D. M. J. Am. Chem.Soc. 1985, 107, 1448Tetrahedron 1985, 41, 3943
- First Asymmetric total synthesis: Hua, D. H.; Sinai-Zingde, G,; Venkataraman, S.J. Am. Chem. Soc., 1985, 107, 4088.
H
H H
Hirsutene (a linear triquinane)
Capnellene is a naturally occurring hydrocarbon derived from Capnella imbricata, a species ofsoft coral. Capnellene derivatives and hirsutenes, demonstrate antibacterial and antitumorproperties with pharmacological potential.
- First total synthesis: Paquette, L; J. Am. Chem. Soc. 1985, 107, 1448.
- First total synthesis by Radical Reactions : Curran, D.P.; Chen, M. H. Tetrahedron Lett. 1985,26,4991.
- First Asymmetric total synthesis: Meyers, A; Bienz,S; J. Org. Chem., 1990, 55,791.
Capnellene (a linear triquinane)
Back Ground of Capnellene
Back Ground
Dennis Patrick CurranProfessor at University of Pittsburgh
Well known for work in the interface of radical chemistry and organic synthesis
H
H H
Hirsutene
Retrosynthetic Analysis and Strategy
Curran, D. P.; Rakiewicz, D. M. J. Am. Chem. Soc. 1985, 107, 1448Curran, D. P.; Rakiewicz, D. M. Tetrahedron 1985, 41, 3943
H
H Hhirsutene
H
H H
5-exo-dig
radicalcyclization H H
H
5-exo-trigradicalcyclization
H HH
I
H
C-C bondformation
SN2
lactoneopening
OO
H
THPO M
32
3334
35
36trans disubstituted cyclopentene
Total Synthesis
O1- NaBH4, CeCl3(Luche reduction)
2- Ac2O, Et3N
OAcLDA, THF, -78°C
Then t-BuMe2SiClHMPA
O
OTBS
[3,3]CH3Cl, reflux
(Ireland ester enolateClaisen rearrangement)
O
OTBSH
PhSeCl, CH2Cl2, -78°C
Phenylseleno lactonizationO
PhSe
O
H2O2
THF(62% from 37)
O
OH
HH
SePh
O
37 38 39
4041
42
Curran, D. P.; Rakiewicz, D. M. J. Am. Chem. Soc. 1985, 107, 1448Curran, D. P.; Rakiewicz, D. M. Tetrahedron 1985, 41, 3943
Total Synthesis
O
OH
HH
SePh
O
(Selenoxidesyn-elimination)
OO
H
THPO Br
Li naphthalenide, THF, -78°C(organolithium formation)
then CuBr SMe2(organocuprate formation)then 43(50-75%)
CO2H
HH
THPO
1. PPTS, EtOH2. LiAlH4(64% overall)
HH
HO
OH
1. (Tf)2OPyrCH2Cl2, -10°C
2. n-Bu4NIPhH, reflux(64% overall)
HH
I
I
HH
I 1. Me3Si Li(1.0 equiv)THF, 0°C
2. CsF(78% overall)
42
43
44
45
464748
Curran, D. P.; Rakiewicz, D. M. J. Am. Chem. Soc. 1985, 107, 1448Curran, D. P.; Rakiewicz, D. M. Tetrahedron 1985, 41, 3943
Reductive Litiation
Freeman. J. Org. Chem. 1980, 45, 1294.
Br OTHPLi
LiBrNaphtalenide
OTHP
Li
OTHPLi
O
OH
CO2H
HH
THPO
45
Single regio and stereo isomer
Total Synthesis
I
HH
n-Bu3SnH, AIBN (cat)
PhHreflux (80%)
HH
5-exo-trig
radical cyclizationHH
H
5-exo-digradical cyclization
HH
Hn-Bu3SnH
HH
H
()-hirsutene
48 49 50
51
Curran, D. P.; Rakiewicz, D. M. J. Am. Chem. Soc. 1985, 107, 1448Curran, D. P.; Rakiewicz, D. M. Tetrahedron 1985, 41, 3943
NC NN CN
AIBN: 2,2’-azobisisobutyronitrile
Capnellene
Retrosynthetic Analysis and Strategy
H
H H H
CO2HX
H H
H
OO
H
H
52 53
5455
Capnellene
5-exo-dig
radicalcyclization
5-exo-trig
radicalcyclization
Curran, D.P.; Chen, M. H. Tetrahedron Lett. 1985, 26,4991
Total Synthesis
Curran, D.P.; Chen, M. H. Tetrahedron Lett. 1985, 26,4991
O()- norbornenone
Baeyer- villigeroxidation
OO
acid-catalyzedrearrangement
OH
H
O
MeMgBrCuBr.SMe2THF, -20°C
H
CO2H
Iodolactonization
I2OH
H
O
IDBU,THF, 25°C
(66% from 147)
OH
H
O
56 57
585960
Acid catalyzed rearrangement
O
O
H
O
OH
HH
H
O
OH
H
O
H
H
O
Total Synthesis
OO MgBr
CuBr.SMe2, THF, -20°C
(SN2 anti lactone opening)
O O
H
CO2HLiAlH4
(80% from 150)
O O
H
OH
1. MeSO2Cl2. NaI3. Li.H2N(CH2)2NH2
DMSO, 25°C(43% from 152)
O O
H
1. CrO3. aq. H2SO4, (CH3)2CO2. CH2N2( 70% overall)
H
CO2Me1. MeMgBr (excess)
2. Me3SiBr(90% overall)H
Br
OH
H
O
60 6162
636465
Jones oxidatio
Curran, D.P.; Chen, M. H. Tetrahedron Lett. 1985, 26,4991
Total Synthesis
Br
H
n-Bu3SnH, AIBN(cat.)
PhH80°C (80% GC yield) H
5-exo-trig
radicalcyclization H
H H
5-exo-digradicalcyclization
H
H Hn-Bu3SnH
H
H H
)-9(12)-Capnellene
65 66 67
68
Curran, D.P.; Chen, M. H. Tetrahedron Lett. 1985, 26,4991
Conclusion
Through the application of radical chemistry, valuable functional group transformationsand challenging carbon-carbon bond construction can be achieved under usually mildreaction condition.
Radical reactions are powerful, one-pot strategies for the synthesis of complexpolycyclic molecules.
Carbon-centered radicals are also highly reactive intermediates that add to carbon-carbon π bonds via early, reactant-like transition states.
Tandem or sequential radical cyclizations can offer exceedingly concise solutions tochallenging problems in organic synthesis.