total synthesis of (-)quinocarcin
DESCRIPTION
Total synthesis of (-)Quinocarcin. Mounuo Cheng 20091115. DX-52-1 R=CN Quinocarcinol R=H. Quinocarcin. terazomine. quinocarcinamide. quinocarcinamide. Jieping Zhu Jacs 2008,130, 7148-7152. Jieping Zhu Jacs 2008,130, 7148-7152. Catalytic enantioselective enolate alkylation under PTC. - PowerPoint PPT PresentationTRANSCRIPT
Total synthesis of (-)Quinocarcin
Mounuo Cheng20091115
Quinocarcin
DX-52-1 R=CNQuinocarcinol R=H
quinocarcinamideterazomine
N N
COOH
OO
N N
COOH
O ROH
N N
COOH
OOH
O
N N
OONH
O
NH
OH
OH
N N
COOH
OO
N N
COOH
OOH
O
N N+
O
Cbz
OBnO
BrOTIPS
N
OOBn
O
Br OH
NHCbz
OTIPS
NH
CO2CH3
OOBn
Br
OH
CHO
CHO
OBn
Ph
PhN
CO2tBu
HOOC
NHCbzOTBS
Jieping Zhu Jacs 2008,130, 7148-7152
quinocarcinamide
Jieping Zhu Jacs 2008,130, 7148-7152
OH
CHO
Ph
PhN CO2tBu
TBDMSCl, imidazole, DMF0oC to rt. overnight
NaBH4, MeOH, 0oC to rt. 1h 94% (2 steps)
Ph3P, imidazoleBr2, DCM, 0oC to rt. 1h
NBS, MeCN, 60oC96% (2 steps)
0.1cat, CsOH H2ODCM, -78oC, 24h
THF/AcOH/H2O (1:1:1)
rt, 5h, 87% (2steps)
OH
Br
NH2
CO2tBuTBAF, THF
0oC, 2h, 91%
OTBS
OH
OTBS
Br
Br
OTBS
Br
NH2
CO2tBu
NH
CO2CH3
OOBn
Br
Catalytic enantioselective enolate alkylation under PTC
Ph
PhN
CO2tBu
OTBS
Br
Br
0.1cat, CsOH H2ODCM, -78oC, 24h
OTBS
Br
N
CO2tBu
Ph
Ph
N
ON
Br
E. J. Corey Jacs, 1997, 119, 12414-12415
M. J. O Donnell Jacs, 1989, 111, 2353-2355
Ph
PhN CO2R 0.1cat, 50% aq NaOH 20eq
DCM, 25oC, 4h, ee: 66%
Br Ph
PhN CO2R N
OHN
Cl
Jieping Zhu Jacs 2008,130, 7148-7152
CHO
OBnOH
Br
NH2
CO2tBu
+4A MS, AcOH
DCM, RT, 36H, 91%
Boc2O, DIPEA, MeCNrt, 6H, 85%
Me2SO4, acetone, Ca2CO3rt, 4h, 92%
SOCl2, MeOH
reflux, 4h, 95% NH
CO2CH3
OOBn
Br
NH
CO2tBu
OHOBn
Br
NBoc
CO2tBu
OOBn
Br
Pictet-spengler
R1
R2
NH2
+R3 R4
O
HN
R2
R1
OH
R3R4
H
HN
R2
R1
O
R3R4
HH
+
N
R2
R1
R3R4
N
R2
R1
R4
R3
H NH
R1
R2
R3R4
HNH
R1
R2
R3R4
NH
CO2CH3
OOBn
Br
+ HOOC
OTBS
NHCbz HATU, HOAt, DIPEA, DMF, 71%
0oC, 8h then rt 36h
LiBH4, MeOH
Et2O, RT, 2h, 91%
Swern oxidation
94%EtSH, Hf(OTf)4
DCM, RT, 15h, 88%N
OOBn
Br
O
NCbz
OH
SEt
NNN
N
O+N
N
PF6
NNN
N
HO
Jieping Zhu Jacs 2008,130, 7148-7152HATUHOAt
N
OOBn
Br
O
NHCbz
OTBS
HO
N
OOBn
Br
O
NCbz
OTBS
OH
N
CO2CH3
OOBn
Br
O
NHCbz
OTBS
N
OOBn
Br
O
NCbz
OTBS
OH
EtSH, Hf(OTf)4
DCM, RT, 15h, 88%N
OOBn
Br
O
NCbz
OH
SEt
PhSH, Hf(OTf)4
DCM, RT, 15h, 71%
N
OOBn
Br
O
NCbz
O
EtSH, Hf(OTf)4
DCM, RT, 15h, 88% N
OOBn
Br
O
NCbz
O
N
OOBn
Br
O
NCbz
OTBS
OH
N
OOBn
Br
O
NCbz
OH
O
N
OOBn
Br
O
NCbz
OH
CN
MeOH
TMSCN
Lewisor bronsted acid
X
X
Jieping Zhu Jacs 2008,130, 7148-7152
Jieping Zhu Jacs 2008,130, 7148-7152
N
OOBn
Br
O
NCbz
OH
SEtSwern oxidation
TIPSOTf, TEA, Et2Ort, overnight, 92%(2steps)
AgBF4, THF
rt, 6h, 88%
N NCbz
CHO
OOBn
O
BrJones oxidation
Pd/C, H2, MeOH, rt, 6h
HCHO, HCO2H,NaBH3CN, RT, 2h95% (2steps)
N N
COOH
O O
Li/NH3 (liquid), THF, -33oC
then 2NHClrt, 2h, 87%
N
OOBn
Br
O
NCbz
SEt
OTIPS
N NCbz
COOH
OOBn
O
Br
N N
COOH
OOH
O
Philip Garner Jacs 1993,115, 10742-10753
N
O
O
N
Ar
OH
hvelectrocyclicring-opening
N+C-O
OAr
OHCOOHN
NO
OAr
OHCOOH exo-si
CHO
O
N
N
COOHH
O
N
NO
OAr
OH
CHO
Philip Garner Jacs 1993,115, 10742-10753
O
O
OS
SO
O
MeSCH2S(O)Me
Triton B, THF, reflux
yield 91%, E/Z 5:1
HCl Et2O
reflux, yield 72%
COOHt-BuCOCl, TEA, THF, 0oC
LiNO
O
Ph
-78oC, yield 73%
O
N
OPh
O
O
KN(TMS)2, THF, -78oCtrisyl azide; HOAc,
yield 89%
-78oC to rt
O
N
OPh
O
ON3
O
N3NaBH4 , THF-H2O, 0oC
yield 83%, 96% auxiliary
OH
O
NH2
OH10% Pd/C
EtOH, rtyield 78%
N
Ph
OHTriton B
O
NH2
OHO
OO
O
HN
OHHOOC
OAc2O, NaOAc
120oC O
NOAc
O
Oyield 80%
44%
+ O
NHAcOAc
19%
O
NOAc
O
O+
10%, TEA,
5N HCl-THF, rt
yield 76%O
NOH
O
O
MeN3, toluene
rt. yield 99%O
NOH
O
O
NN
N
O
NOH
O
O
toluene reflux 65% to the target product
hv (Hg-Pyrex)
dioxane yield 90%
N
hv(2537A)
dioxaneO
NOH N+
H-
CO
O+ N
SO2
O exo-si attack
yield 61%O
NOH
O
O
N
N
SO2
O
Philip Garner Jacs 1993,115, 10742-10753
O
NOH
O
O
N
N
SO2
O MOMCl, DIPA
DCM, yield 92%O
NMOMO
O
O
N
N
SO2
O NBS
CHCl3, hv
O
NMOMO
O
O
N
N
SO2
O
BrO
NMOMO
O
O
N
N
SO2
O
P+Ph3 Br-
Ph3P, CHCl3
56% overall
O
NMOMO
ON
N
SO2
O
KO(t)Bu, DMF
120oC
Raney-Ni (W-4)
H2 atm (1400 psi)EtOH, 65oC O
NMOMO
ON
N
SO2
O
H
yield 30~32%
Philip Garner Jacs 1993,115, 10742-10753
LiOH, THF-H2O
yield 100%O
NMOMO
ON
COOH
O
NMOMO
ON
N
SO2
O
HH
Li/NH3, THF, -33oC
NaCN, H2O (PH=7)60% overall
O
NMOMO
NCN
COOHH
DX-52-1
TMSCl + NaI
MeCN, yield 72%O
NHO
NCN
COOHH O
N
N
COOHH
AgNO3, MeOH-H2O
O
yield 94%
Philip Garner Jacs 1993,115, 10742-10753
N N
COOH
OO
N NBn
CO2CH3
OOBn
CO2CH3
AryneAnnulation
O
NH NBn
CO2CH3
CO2CH3
O
BnO
+
HN NBn
CO2CH3
O
Brian M. Stoltz Jacs 2008,130, 17270-17271
Ortheogonal synthesis of indolines and isoquinolines cia aryne annulation
TMS
OTf
+
R NH
O
CO2CH3
F-
N CO2CH3
O R1
NCO2CH3
R1O
CO2CH3
R2O
N
R2
CO2CH3
R1 = OtBuR2 = Ar, alkyl, …
Brian M. Stoltz Jacs 2008,130, 17270-17271
HNN+
O
Bn
N
SO2
O+
NMM, MeCN, -20oC
NaOMe, MeOH, 23oC
BnOCl
O
DMAP, TEA,DCM, 23oC-reflux
Y(OTf)3, MeOH
DCM, reflux, 89%+
OTf
TMSO
TBAT, THF
40oC, 60% N NBn
CO2CH3
OOBn
CO2CH3
HN NBn
CO2CH3
O
N NBn
CO2CH3
O
BnOO
NH NBn
CO2CH3
CO2CH3
O
BnO
O
NN
SiPhF
FPhPh
NMM TBAT
Brian M. Stoltz Jacs 2008,130, 17270-17271
N NBn
CO2CH3
OBnO
CO2CH3
Pd/C, H2
THF, 23oC3.3:1
NaBH3CN, conc HCl
MeOH, 0oC, 55%
toluene, 110oC
99%
aq HCHOPd(OH)2/C, H2
MeOH, 23oC 80%
LiOH H2O
THF/H2O 23oC
N N
COOH
O O
BrLi/NH3 (liquid), THF, -78oC-30oC
then1NHCl 81%(2steps)
NH NBn
CO2CH3
OOBn
CO2CH3
NH NBn
CO2CH3
OOBn
CO2CH3
H
N NBn
CO2CH3
OOBn
H
O
N N
CO2CH3
OOH
H
O
N N
CO2H
OOH
H
O
Andrew G. Myers Jacs 2005,127, 16796-16797
NFmoc
CHO
OOBn
+H2N
CN
N
TMS
O
1.Na2SO4, 2.DBU
3.HCN, 91%
ZnCl2, TMSCN
TFE, 60oC, 15h
N NH
OHOBn
CN
1, Cs2CO3, Me2SO4, 80%2. NaIO4, OsO4, 88%
3. Jones Reagent, 91
BCl3
N N
COOH
O O
AgNO3, MeOH, H2O
70%, (2steps)
NH
OOBn
NH
CN
N
TMS
O
NC
N N
COOH
OOBn
CN
N N
COOH
OOH
CN
DX-52-1
OO
Fmoc
NH
OOBn
NH
CN
N
TMS
O
NCZnCl2, TMSCN
TFE, 60oC, 15h
N
OHOBn
CN
NH
TMSCN
N
OHOBn
CN
NH
TMSCN
N
OHOBn
NH
TMS
N
OHOBn
CN
NH
TMS
CN
CNCN
44% at 1h, 61% to T 15% at 1h, 30% to T
12% at 1h, 54% to T 19% at 12h, 41% to T
N NH
OHOBn
CN
NH
OOBn
NH
CN
N
TMS
O
NC
NH
OOBn
NH
CN
N
O
NC
NH
OOBn
NH
CN
N
TMS
O
NC
NH
OOBn
NH
CN
N
O
NC
TMS
TMS
46% to T 53% to T
40% to T 45% to T
N NH
OHOBn
CN
