Creativity From the Chiral Pool
Part 1: Carvone
Baran Group Meeting
A useful reference
Brandon Rosen
Some Basic (Obvious) Transformations of Carvone
Enantioselective Synthesis: Natural Products From Chiral Terpenes by Tse-Lok Ho
O
H2O2, NaOH
MeOH
O
O
O
70 - 100%
H
OH
LAH, Et2O
(R)-(-)-carvone
Spearmint oil
$0.29/g
$43.56/mol
(S)-(+)-carvone
Caraway seeds
$2.58/g
$386.82/mol
70 - 100%
O
H2, Wilkinson's cat.
or H2, PtO2
82 - 100%
Industrial preparation of (-)-Carvone:
See "Fragrances and Flavors", Ullman's Encyclopedia of Industrial Chemistry.
NO
NOH
H3O+
Base
NOCl
O
O
Zn, EtOH
O
Cl
50%
O
(+)-limonene
(-)-carvone
t-BuOCl
Cl
86%
Fleming's Total Synthesis of (±)-Carvone
Fleming, Synthesis, 1979, 736.
O
AcCl, MeOH
O
1. LDA
2. TMSCl
97%
OTMS
O
DDQ
96%
TMS
73%
"The beauty of this route is the
simplicity with which functionality
has been introduced selectively on
to each side of the unsymmetrical
ketone 1".
O
BrMg
Cl
O
CuCl
85%
TiCl4
Et3N, TMSCl
87%
TMS
82%
H
O
O
OTMS
DDQ
52%
KMnO4
HO
O
CO2H
Page 1
Creativity From the Chiral Pool
Part 1: Carvone
Baran Group Meeting
An Overwhelming Sample of Carvone-Derived Syntheses
O
O
O
O
Picrotoxinin
Trost, 1999
OH
O
N
H
O
HO
HO
O
O
OH
O
H
H
OH
H
H
O
OH
Ryanodol
Deslongchamps, 1979
H
O
H
C7H15CO2
O
O
N
46%
O
OH
H
OH
H
Omphadiol
Romo, 2011
H
N
O O
HO
Platensimycin
Lee, 2009
O
N
H
Cyperolone
Kirsch, Org Lett 2012, 14, 1250.
OTIPS
O
6 steps
O
OTES
PtCl4, cod
R
OTES
O
80%
[M]
Briarellin F
Overman, 2003
Samaderine Y
Shing, 2005
Br
N
H
(N)-Methylwelwitindolinone C
Isothiocyanate
Trilobolide
Ley, 2003
HO
NaNH2
H
H
O
OH
Salsolene Oxide
Paquette, 1997
OTBS
H
13 steps
O
O
OH
O
TBSO
O
HO
N
H
Hapalindole Q
H
SCN
O
HO
HO
3 steps
Cl
O
OEt
OPiv
4. NaOMe
5. vinyl-MgBr,
CuBr•DMS
OAc O
O
O
CP-263,114 core
Yoshimitsu, 2000
H
OH
Cubitene
Lindel, 2012
O
HO
OH
H O
Guanacastepene E
Sorensen, 2006
NCS
1. LAH
2. PivCl
3. CrO3
OH
Valerianonoid A
Srikrishna, 2004
BnO
HO
O
H
Garg, JACS 2011, 133, 15797.
H
OH
O
O
(N)-Methylwelwitindolinone C Isothiocyanate
OH
O
Cyrneine A
Gademann, 2012
Peribysin E
Danishefsk, 2008
MOMO
53%
N
H
7-deacetoxyalcyonin acetate
Overman, 1995
CO2H
4 steps
O
O
AcO
Kainic Acid
Fukuyama, 2011 AcO
CHO
H
HO
CO2H
HO
H
H
LHMDS, then [Cu]
+
N
H
OH
Cyperolone
Kirsch, 2012
Hapalindole Q
Baran 2004
HO
O
O
HO
N
H
OMe
Hapalindole Q
Baran, JACS 2004, 126, 7450.
O
H
NCS
Brandon Rosen
OH
OH
CO2H
OTIPS
O
8 steps
H
O
Chinensiolide B O
Hall, 2010
HO
O
O
Cyperolone
Page 2
Creativity From the Chiral Pool
Part 1: Carvone
Baran Group Meeting
Brandon Rosen
Kainic Acid
Fukuyama, Org Lett 2011,13, 2068.
O
1. H2O2, NaOH
2. H2SO4
3. NaIO4
4. I2, KI
I
O
1. NaClO2,
NaH2PO4
O
I
CHO
Hectogram Scale
NHCO2Me
Name rxns?
"In view of the ease of the entire
operation and the use of the
readily available and inexpensive
reagents, we are convinced that
our synthetic route alone would
satisfy the global demand for (-)Kainic Acid."
Br
5 steps
HO
O
O
N
CO2Me
Kainic Acid
O
OH
OH
O
O
Corianin
7-Deacetoxyalcyonin Acetate
Picrotoxinin
Overman, JACS 1995, 117, 10391.
R3SiO
Br O
H
PPh2
O
OSiR3
OSIR3
P
P
1. t-BuLi,
9 steps
H
CHO
TMS
OMe
OH
OHC
OTIPS
O
Pd(OAc)2
Ligands
70 %
O
2. PPTS
3. Me6Sn2, [Pd]
NIS
CN
3 steps
OHC
I
1. H2
2. LDA, PhN(Tf)2
O
CO2H
BF3•OEt2
OTIPS
OH
Name rxn?
TMS
Br
MeO2C
7 steps
O
MeO2C
O
O
O
Br
3. LiCH2CN
4. C5H5NHBr3
O
O
Trost, JACS 1996, 118, 233.
Trost, JACS 1999, 121, 6131 and 6183.
1. LDA, CH2O
2. TBDMSCl
O
4 steps
CO2H
N
H
2. LHMDS, TBHP
OH
CO2t-Bu
CO2H
1. Me2NCH(OMe)2
Ac2O
O
3 steps
Picrotoxinin and Corianin
O
HO
H
O
MeO2C
O
HO
11 steps
O
2. MeOH, ∆
O
PhO P N3
OPh
O
MeO2C
O
H
Br
O
R3SiO
O
R3SiO
H
Br
H
R3SiO
O
OSiR3
OSIR3
Name rxn?
H
I
O
1. NiCl2-CrCl2
2. Ac2O
3. TBAF
Name rxn?
H
HO
H
O
AcO
OH
7-deacetoxyalcyonin acetate
Page 3
TMS
Creativity From the Chiral Pool
Part 1: Carvone
Baran Group Meeting
Briarellin F
Brandon Rosen
Guanacastepene E
Overman, JACS 2003, 125, 6650.
Sorensen, JACS 2006, 128, 7025.
1. 9-BBN, then
NaOH, H2O2
O
O
1. H2, PtO2
2. LDA, MeI
O
1. LDA, TMSCl, then
AcOH
O
2. LAH (> 20:1 d.r.)
2. TEMPO, NCS
H
OH
H
H
O
C7H15CO2
OH
CN
LHMDS
OH
O
58%
2. [Pd], (Me3Sn)2
O
O
Briarellin F
[Pd]
87%
Gademann, ACIE 2012, 51, 4071
OTBS
4 steps
TBSO
3 steps
O
O
O PMP
O
AcO
PMP
O
O
O
Name rxn?
PMP
1. SmI2
O
2. PhSeBr
3. mCPBA
175 °C
81%
O
TBSO
TBSO
O
O
hv
82%
CHO
OTBS
2. EDCI
O
1. NfF
SnMe3
HO
1. NaCN
OH
O
Cyrneine A
O
O
3. O3, then H2, Pd/C
H
O
OHC
AcO
1. PhNTf2
2. CrO3
8 steps
TBSO
O
H O
CHO
PMP
O
5 steps
OH
O
H
TBSO
3) [Pd]
O
Guanacastepene E
O
Cladantholide
1. CH2Br2, LiTMP
2. BuLi
Lee, JACS 1997, 119, 8391.
O
TBSO
HO
OTBS
3 steps
OH
1. H2O2, NaOH
2. LiCl, TFA
3) DHP, PPTS
O
Cl
OTHP
NaOMe
MeO2C
OTHP
95%
Name rxn?
O
CHO
Cyrneine A
Page 4
Creativity From the Chiral Pool
Part 1: Carvone
Baran Group Meeting
Brandon Rosen
Upial
Taschner, JACS 1985, 107, 5570.
O
O
MeO2C
3 steps
OTHP
Bu3SnH
THPO
99%
O
HO
4 steps
H
O
H
H
OMe
O
1. TsOH, MeOH
2. PCC
4 steps
HCl
70%
THPO
1. MeMgBr
2. OsO4, NaIO4
3. KOCl, MeOH
H
H
3 steps
O
OEt
Name rxn?
O
O
O
OHC
4. Swern
5. SOCl2
MeO2C
O
H
Upial
H
H
OMe
O
O
H
3. LDA, TMSCl
4. DMDO
O
H
Name rxn?
Br
EtO
4 steps
OH
Name rxn?
Omphadiol
Romo, ACIE 2011, 50, 7537.
O
O
O
Cladantholide
Thapsigargins
OTHP
H
12 steps
H
OTES
O
OH
Grubbs
OEt
O
OH
O
Thapsivillosin F
PPY+
2. TsCl, 4-PPY
O
OH
92%
2 steps
Grubbs
95%
OAc O
H
HO
OO
1. H5IO6
OMOM
TBDPSO
O
O
63%
Ley, ACIE 2003, 42, 5996
See "Steven Ley" group meeting
MeO2C
[Mn(dpm)3]
PhSiH3, O2
H
O
H
O
Br
OMOM
OH
OH
TBDPSO
H
OTES
O
3 steps
O
H
OEt
H
1. tBuLi, DIBAL
H
O
2. Et2Zn, CH2I2
Name rxn?
OH
H
Omphadiol
Page 5
Creativity From the Chiral Pool
Part 1: Carvone
Baran Group Meeting
Paquette, JACS 1997, 119, 2767.
See "Leo A. Paquette" group meeting
O
HO
TBSO
O
TBSO
AcO
Salsolene Oxide
1. H2, Pt
2. O3
Br
5 steps
CO2H
CO2Et
3. NaBH4
4. HBr, EtOH
H
(COCl)2
H
H
O
HO
OH
5 steps
O
H
Brandon Rosen
O
O
H
OMe
H
H
H
O
O
Samaderine Y
Et3N, ∆
57%
Platensimycin
Lee, JACS 2009, 131, 8413.
O
O
O
1. SeO2
1. LAH
Bu3SnH
O
SPh
O
2. NBS
Br
O
TMSC(Li)N2
2. PCC
CHO
Br
81%
Salsolene Oxide
Samaderine Y
Shing, ACIE 2005, 44, 7981.
See "Traditional Chinese Medicine" group meeting
O
3 steps
O
1. LDA, CH2O
2. (OMe)2CMe2
O
O
TBSO
O
TBSO
MgBr
1.
O
OAc
1. TFA
2. TBSOTf
O
2. NaH, crown ether
3. Ac2O
OH
O
O
Peribysin E
Danishefsky, JACS 2008, 130, 13765
O
6 steps
H
H
7 steps
2. Pd(OAc)2
TBSO
O
TBSO
O
OAc
O
OTMS 1. EtAlCl2
PhMe, 180 °C
62%
TBSO
O
TBSO
CO2H
O O
HO
Platensimycin
3. NMO, TPAP
O
OH
H
N
O
O
TBSO
H
H
H
H
O
1. MnOAc3,
TBHP
OMe
TBSO
O
TBSO
AcO
O
2. MnOAc3, ∆
H
H
H
O
1. EtAlCl2
H
O
3. Pd(OAc)2
OMe
H
O
O
OTES 2. SiO2
O
H
CHO
O
3 NaBH4, CeCl3
OH
O
TBSO
O
TBSO
O
65%
1. TBSOTf
2. TBHP, NaOH
O
3. CrO3
4. NaBH4, CeCl3
3 steps
O
O
Adduct not available through
Robinson Annulation!
Page 6
Creativity From the Chiral Pool
Part 1: Carvone
Baran Group Meeting
Brandon Rosen
Carvone-Derived Diene Ligands
1. OsO4, NaIO4
H
O
Carreira, JACS 2004, 126, 1628.
Carreira, Org Lett 2004, 6, 3873.
TMSN3
2. mCPBA
AcO
H
O
I2
~ 1:1 d.r.
OMe
O
1. NBS, MeOH
2. KOtBu
O
TESO
OTBS 3 steps
AcO
OTES
H
OTBS
89%
O
H
TiCl4
50%
HO
H
CHO
HO
1. iBuLi
1. NBS, MeOH
2. KOtBu
O
1. LDA, allylBr
2. LiNEt2, PhNTf2
3. [Pd], HCO2H
OMe
H
Ar
~ 1:1 d.r.
OMe
O
O
HCl, MeOH
OH
AcO
2. PCC
OTBS
H
2. ArZnCl, [Pd]
O
I
Suzuki
OMe
1. LDA, PhNTf2
O
80%
OH
OMe
ent-Peribysin E
Ecklonialactones A and B
Fürstner, JACS 2010, 132, 11042.
O
O
Ph
O
B
Ligand A
O
O
[Rh(C2H4)2Cl]2
Ligand A
80% ee
O
4 steps
O
Ph
O
MeO(Me)N
O
O
Name rxn? MeO P
MeO
O
N2
8 steps
H
O
O
MeO(Me)N
O
Ecklonialactone A (∆6,7)
Ecklonialactone B
Page 7
Baran Group Meeting
Creativity From the Chiral Pool
Part 1: Carvone
Some Basic (Less Obvious) Transformations of Carvone
Brandon Rosen
Do it at home!
Derive retrosyntheses of the following molecules using carvone as a starting material!
4 steps
H
HO
O
H
OH
H
OH
CO2H
Gibberellic Acid
O
O
3 steps
H
OH
OH
O
HO
HO
Dictyoxetane
O
Amphidicolin
Cafestol
I
H
H
O
HO
OH
O HO
Cyclooctatin
OH
Phorbol
H
O
3 steps
HO
OH
O
O
OMe
O
4 steps
MeO2C
OTHP
H
CO2Et
O
HO
Solanoeclepin A
N
O
H
O
Br
O HO
O
O
4 steps
H
O
Pleuromutilin
CO2H
HO
H
O
O
OH
H
OH
H
O
OHC
H
OH
H
H
CHO
HO
H
O
2 steps
OH
CO
HO
H
I
4 steps
H
O
O
O
O
Limonin
OH
O
H
HO
H
MeO2C
CO2Me
O
Nominine
OMe
H
Mandapamate
O
3 steps
O
Page 8