Post on 20-Aug-2018
Total Synthesis of (-)-Himandrine
Movassaghi, M.; Tjandra, M.; Qi, J.J. Am. Chem. Soc. 2009, 131, 9648-9650.
Jason M. Stevens - 07.29.2009
Galbulimima Alkaloids
2
OMeN
Me
HO
OBzCO2Me
(-)-himandrine
NHMe
HO
O
GalbulimimaAlkaloid 13
OMeN
Me
HO
OH
himgaline
Movassaghi MovassaghiSchering PloughEvansMander
Schering-PloughEvans
O
O
Me H
H H
H
N
Me
H
himbacine himbeline
O
O
Me H
H H
H
HN
Me
HMe
Hart and Kozikowski
• Isolated from the bark of Galbulimima belgraveana (New Guinea/Australia)
• Galbulimima Alkaloids have shown to be useful as antithrombotic agents and possible agents for offsetting Alzheimer’s disease
• This work is ~75% the same as for GB-13
About (-)-Himandrine
Retrosynthesis
OMeN
Me
HO
OBzCO2Me(-)-himandrine
OMeNHMe
HO
N O
OMe
O
N ON
Me
Me
NOMeMe
TBSO
OO
+
4
Retrosynthesis
OMeN
Me
HO
OBzCO2Me(-)-himandrine
OMeNHMe
HO
N O
OMe
O
N ON
Me
Me
NOMeMe
TBSO
OO
+
4
Responsible for setting everystereocenter in the molecule
Building the trans-Decalin
HO OHO
i. D-ProlinePhNOCH2Cl2, 0 oC
ii. NaBH4, MeOH
90%, 98.4% eeHO O NHPh
Zn, AcOH
EtOH
80%
Building the trans-Decalin
HO OHO
i. D-ProlinePhNOCH2Cl2, 0 oC
ii. NaBH4, MeOH
90%, 98.4% eeHO O NHPh
Zn, AcOH
EtOH
80%
O N HN
Ph
RCO2
-
Building the trans-Decalin
HO OHO
i. D-ProlinePhNOCH2Cl2, 0 oC
ii. NaBH4, MeOH
90%, 98.4% eeHO O NHPh
Zn, AcOH
EtOH
80%
O N HN
Ph
RCO2
-
Why C-O bond formation andnot C-N bond formation?
Building the trans-Decalin
O OMeHO OMe
TBSO OMeTBSO OH
TBSClimidazole, DMAP
DMF, 0 oC
94%
Me3O.BF4Proton Sponge
4Å-MS, CH2Cl2
93%
HCl
MeOH
98%
SO3.pyridine
i-Pr2NEt, DMSO
CH2Cl2
CBr4, PPh3
CH2Cl2, 0 oC
65% (2 steps)
HO OH
BrBr
OMe
Building the trans-Decalin
O OMeHO OMe
TBSO OMeTBSO OH
TBSClimidazole, DMAP
DMF, 0 oC
94%
Me3O.BF4Proton Sponge
4Å-MS, CH2Cl2
93%
HCl
MeOH
98%
SO3.pyridine
i-Pr2NEt, DMSO
CH2Cl2
CBr4, PPh3
CH2Cl2, 0 oC
65% (2 steps)
HO OH
BrBr
OMe
Why Meerwein conditions?
Building the trans-Decalin
BrBr
OMe (HO)2B
Me
OTBS
BrOMeMe
TBSOPd(PPh3)4, Tl2CO3
THF, H2O
97%
Building the trans-Decalin
BrBr
OMe (HO)2B
Me
OTBS
BrOMeMe
TBSOPd(PPh3)4, Tl2CO3
THF, H2O
97%
Why is there complete selectivity for the “E”-Br?
Building the trans-Decalin
BrBr
OMe (HO)2B
Me
OTBS
BrOMeMe
TBSOPd(PPh3)4, Tl2CO3
THF, H2O
97%
Why is there complete selectivity for the “E”-Br?
What is the role of the Tl2CO3?
Building the trans-Decalin
R Br RBr
PdCl2(dppf)
R1MgBr
RBrR R1+ +
Building the trans-Decalin
R Br RBr
PdCl2(dppf)
R1MgBr
RBrR R1+ +
Generally, E-vinyl bromides are much more reactive than Z-vinyl bromides
Building the trans-Decalin
Pd(0)
BrBr
OMe
BrPdIIBr
OMePdIIBr
OMe
Me
OTBS
BrOMeMe
TBSO
B(OH)2
Me
OTBS
HO
KOH: rel rate = 1TlOH: rel rate = 1000
(HO)2B
Me
OTBS
M-OH
If oxidative addition is the slow step then this intermediate is short lived and quickly consumed.
If transmetallation is the slow step then this intermediate is long livedand eventually decomposes
TlOH significantly accelerates thetransmetallation step thus fixingoxidative addition as the slow step
Building the trans-Decalin
CuI, K2CO3,β-lactam MeNH(CH2)2NHMe
Toluene, 120 oC
85%BrOMeMe
TBSO
NOMeMe
TBSO
O
What is this even for?
Building the trans-Decalin
NOMeMe
TBSO
O
NOMeMe
HO
O
NOMeMe
O
O
TBAF, THF
0 oC to rt
DMSO, i-Pr2NEtSO3
.pyridine
CH2Cl2
80% (2 steps)
NOMeTBSO
O
TBSOTf, NEt3
CH2Cl2, -78 oC
82%
acrolein4,5-DihydroIMES-Cl2Ru=CH(o-Oi-Pr)Ph(10 mol%)
CH2Cl2 1 h
85%N
OMeTBSO
O
O
NOMeMe
O
O
Building the trans-Decalin
TBSO
OHH
NO
H OMe
N,N-Diethylaniline
BHT, MeCN95 oC, 7 h
75%
H
NO
H OMe
OHH
H1. TiCl4 4Å-MS CH2Cl2, -78 oC
2. Martin Sulfurane benzene, rt
57% (2 steps)
NOMeTBSO
O
O
Building the trans-Decalin
TBSO
OHH
NO
H OMe
N,N-Diethylaniline
BHT, MeCN95 oC, 7 h
75%
H
NO
H OMe
OHH
H1. TiCl4 4Å-MS CH2Cl2, -78 oC
2. Martin Sulfurane benzene, rt
57% (2 steps)
NOMeTBSO
O
O
What is this for?
Building the trans-Decalin
TBSO
OHH
NO
H OMe
N,N-Diethylaniline
BHT, MeCN95 oC, 7 h
75%
H
NO
H OMe
OHH
H1. TiCl4 4Å-MS CH2Cl2, -78 oC
2. Martin Sulfurane benzene, rt
57% (2 steps)
NOMeTBSO
O
O
What is this for?
Enforces s-cis geometry
Building the trans-Decalin
TBSO
OHH
NO
H OMe
N,N-Diethylaniline
BHT, MeCN95 oC, 7 h
75%
H
NO
H OMe
OHH
H1. TiCl4 4Å-MS CH2Cl2, -78 oC
2. Martin Sulfurane benzene, rt
57% (2 steps)
NOMeTBSO
O
O
What is this for?
What is BHT for?
Enforces s-cis geometry
Building the trans-Decalin
TBSO
OHH
NO
H OMe
N,N-Diethylaniline
BHT, MeCN95 oC, 7 h
75%
H
NO
H OMe
OHH
H1. TiCl4 4Å-MS CH2Cl2, -78 oC
2. Martin Sulfurane benzene, rt
57% (2 steps)
NOMeTBSO
O
O
What is this for?
What is BHT for?
Enforces s-cis geometry
Protected carbonyl
Building the trans-Decalin
TBSO
OHH
NO
H OMe
N,N-Diethylaniline
BHT, MeCN95 oC, 7 h
75%
H
NO
H OMe
OHH
H1. TiCl4 4Å-MS CH2Cl2, -78 oC
2. Martin Sulfurane benzene, rt
57% (2 steps)
NOMeTBSO
O
O
What is this for?
What is BHT for?
Why Martin Sulfurane?
Enforces s-cis geometry
Protected carbonyl
Ph2SOC(CF3)2Ph
OC(CF3)2Ph
The Cyclohexylamine
OMe
O
N ON
Me
Me
n-BuLi, THF;CuBr.Me2S, -78 to -40 oC;enone; -78 to -10 oC; PhSH
The Cyclohexylamine
OMe
O
N ON
Me
Me
n-BuLi, THF;CuBr.Me2S, -78 to -40 oC;enone; -78 to -10 oC; PhSH OMe
NRMe
O
N O
The Cyclohexylamine
OMe
O
N ON
Me
Me
n-BuLi, THF;CuBr.Me2S, -78 to -40 oC;enone; -78 to -10 oC; PhSH OMe
NRMe
O
N O
OMeNRMe
O
N O
The Cyclohexylamine
OMe
O
N ON
Me
Me
n-BuLi, THF;CuBr.Me2S, -78 to -40 oC;enone; -78 to -10 oC; PhSH OMe
NRMe
O
N O
OMeNRMe
O
N O
OMeN
HMe
HO
N O NaBH4
EtOH, 0 oC
The Cyclohexylamine
OMe
O
N ON
Me
Me
n-BuLi, THF;CuBr.Me2S, -78 to -40 oC;enone; -78 to -10 oC; PhSH OMe
NRMe
O
N O
OMeNRMe
O
N O
OMeN
HMe
HO
N O NaBH4
EtOH, 0 oCOMe
NHMe
HO
N O
The Cyclohexylamine
OMe
O
N ON
Me
Me
n-BuLi, THF;CuBr.Me2S, -78 to -40 oC;enone; -78 to -10 oC; PhSH OMe
NRMe
O
N O
OMeNRMe
O
N O
OMeN
HMe
HO
N O NaBH4
EtOH, 0 oCOMe
NHMe
HO
N O
complete selectivity
The Cyclohexylamine
OMe
O
N ON
Me
Me
n-BuLi, THF;CuBr.Me2S, -78 to -40 oC;enone; -78 to -10 oC; PhSH OMe
NRMe
O
N O
OMeNRMe
O
N O
OMeN
HMe
HO
N O NaBH4
EtOH, 0 oCOMe
NHMe
HO
N O
complete selectivity
2-azetidinone still in placeto protect the carbonyl
PG Adjustments
CBzClK2CO3, i-PrNEt2
THF, H2O, 0 oC to rt
50% (3 steps)OMe
NCbzMe
HOTsOH.H2O
benzene
81%
O
OMeN
CbzMe
HO
N O
OMeN
HMe
HO
N O
still rockin the2-azetidinone
Installing the Methyl EsterPOCl3, DMF
CH2Cl2, 0 oC to rt
71%OMe
NCbzMe
HO
O
Installing the Methyl Ester
POCl3, DMF
CH2Cl2, 0 oC to rt
71%
OMeNZ
Me
O O
OMeN
CbzMe
HO
OH
N+
Cl
Me Me
OMeNZ
Me
HO
O
N+MeMe
H
OMeNZ
Me
O O
NMe2H
OMeNZ
Me
O O
H
B
OMeN
CbzMe
HO
O
POCl3, DMF
CH2Cl2, 0 oC to rt
71%OMe
NCbzMe
HO
O
Getting Rid of the Enol
DDQ, SiO2
MeCN, waterOMeNZ
Me
O O
OMeNZ
Me
HO
O
O
Would anyone like to suggest a mechanism?
Installing the Methyl Ester
OMeNZ
Me
HO
O
OOMe
NZ
Me
HO
O
CO2H
NaClO2, NaH2PO42-methyl-2-butene
H2O, t-BuOH OMeNZ
Me
HO
O
CO2Me
CH2N2
THF, 0 oC
61% (3 steps)
TMSIDTBMP
CH2Cl2, 0 oC
66%OMe
NH
Me
TMSO
O
CO2Me
Et3N.(HF)3
THF
90%OMe
NHMe
HO
O
CO2MeOMeNZ
Me
HO
O
CO2Me
Almost There!
OMeNHMe
HO
O
CO2Me
N-chlorosuccinimide
MeCN, 45 min
89%
Almost There!
OMeNHMe
HO
O
CO2Me OMeNHMe
HO
OHOMeO
N-chlorosuccinimide
MeCN, 45 min
89%OMe
NHMe
HO
OOMeO
Cl
OMeN
Me
HO
OE
OMeNHMe
HO
O
CO2Me
N-chlorosuccinimide
MeCN, 45 min
89%
Also of Interest
OMeNHMe
HO
OE
N-chlorosuccinimide
CH3CN
stop reaction at 10 minOMe
NMe
HO
OECl
OMeN
Me
HO
OE
OMeN
Me
HO
OE
CH3CN
SM
CH3CNOMe
NMe
HO
OE
PDT PDT
can't form dienol!
H
OMeNDMe
HO
OE
D
MeOH MeOD
cyclohexylamine iscapable deprotonatingC9 to give the dienol
Finished
OMeN
Me
HO
OEOMe
NMe
HO
OHCO2Me
H
OMeN
Me
HO
OBzCO2Me
NaBH4
EtOH, 0 oC
90%
BzCl
pyridine, 7 d
87%
Yet another completelyselective NaBH4 reduction
Conclusions
• Total synthesis completed in 27 steps.
• Proline catalyzed alpha-aldehyde oxidation provided the stereocenter that lead to the formation of all other stereocenters under substrate control.
• Demonstrated sequential cross-coupling reactions from a dibromoolefin.
• Transannular IMDA.
• Conjugate addition-Mannich reaction to incorporate the cyclohexylamine.
• NCS mediated late stage ring closure.