total synthesis of welwitindolinone alkaloids
DESCRIPTION
Total synthesis of Welwitindolinone Alkaloids. Guochang Gong Group. In 1994, Moore reported the isolation of welwitindolinone alkaloids from a series of marines and terrestrial cyanobacteria. Moore et al, JACS , 1994 , 116 , 9935-9942. - PowerPoint PPT PresentationTRANSCRIPT
Total synthesis of Welwitindolinone Alkaloids
Guochang
Gong Group
NR
OO
MeMe
HMe
Cl
SCN
Welwitindolinone B isothiocyanateR=H, Me
NMe
OO
MeMe
HMe
Cl
RH
N-Methylweltindolinone CR= NCS, NC
NMe
OO
MeMe
HMe
Cl
R
H
OH
3-hydroxy-N-methylwelwitindolinone CR= NCS, NC
NMe
OO
MeMe
HMe
O
CN
H
O
N-Methylwelwitindolinone Disonitrile
NH
MeMeO
H
Cl
Me
CN
Welwitindolinone Aisonitrile
NH
H
ClMeCN
H
Fischerindole G
In 1994, Moore reported the isolation of welwitindolinone alkaloids froma series of marines and terrestrial cyanobacteria.
Moore et al, JACS, 1994, 116, 9935-9942
total synthesis of Welwitindolinone A isonitrile and Fischerindole G,see: Baran et al, JACS, 2005,127,15394-15396 Wood et al, JACS, 2006,128, 1448-1449 JACS, 2008,130,2087-2100
Konopelshi, OL, 2001, 3, 3001-3004
NMe
OMeMeOCN
H
Rawal, OL, 2005, 7, 3421-3424
NBoc
OMeOOC
TBDMSO
NMe
OSimpkins, OL, 2005, 7, 4087-4089
NMe
OO
MeMeHO
HWood, JACS, 1999, 121, 6326-6327
NMe
OO
MeMe
HMeMe
HH
Garg, OL, 2009, 11, 2349-2351
NMe
OMeMe
H
H
O
Martin, OL, 2010, 12, 2492-2495
NMe
OO
MeMe
H
MeOOCH
O
Rawal, OL, 2011, 13, 3214-3217
NMe
MeMeOCN
RO
RO
H
R= TBS
Funk, OL, 2006, 8, 2643-2645
Rawal retrosynthetic analysis
NMe
OO
MeMe
HMe
O
CN
H
O
NMe
OO
MeMe
HMe
O
SCN
X
OH
NMe
OMeMe
HMe
TBSO
OHC
X
NMe
OMeMe
HMe
OTBSX
BrHO
H
NMe
MeMe
BrOTBS
Me
MeOH
O
+
HO
N-Methylwelwitindolinone Disonitrile
NMe
OO
MeMe
HMe
O
CN
H
O
N-Methylwelwitindolinone Disonitrile
OTBS
Me
O
+
OTBS
Me
OMeH
OOHC
Me
OTBS
O
Me1, CuBr, Me2S, MgBr
-78oC, THF, than TFEF
2, Me2SO4, K2CO3, DMF
50%, 2 steps15: 1
NMe
Me
MeBr HO
NMe
BrO
Me MeMgBr, 0oC, THF
TFEF O OF
F
F:
Zayia's reagent
OHHOOC
HOOH
OH
D-(-)-Quinic Acid
cas: 77-95-2
TCL, 25g 560
dry HCl, acetone
25oC
78%
OH
OO
O
O
LiAlH4 ,THF
87%
OH
OOHO
HO
NaIO4
66%O
OHO
O
MsCl,Et3N
DCM
83%O
O
OH2, Pd(OH)2/C
50 psi
76% OO
O
DBU, TBSCl, C6H6, reflux
87%OTBS
O
Me2CuLi,TMSCl
OTBS
O
DDQ, HMDS
OTBS
OTMS
rf: JOC, 1986, 51, 2332-2342
rf: JOC, 1989,54, 3738-3740
rf: JOC, 2007, 72, 6885-6890
50% 2 steps
HMDS
SiHN Si
DBU, toluene
OH
O
49%
OTBS
Me
OMeH
O
Zayia, OL, 1999, 1, 989-991
CuBr, Me2S, MgBr
-78oC, THF
OTBS
O
MeOTBS
Me
OH
H
O
O OF
F
FOTBS
Me
OMgBr
R
OR'
1, 1.1eq LDA, Et2O, -78oC2, Zayia's reagent, -78oC3, H+,-78oC
R
O
R'
OH
O O OH
75%
O79%
O OH
O
Me
MeOTMS
O
Me
OH
MeO
OHC
83%
60%
OTBS
Me
MeO
H
O
KHMDS, TMSCl
-78oC, THF
OTBS
Me
MeO
H
OTMS
NMe
MeMe
Br HO
TMSOTf, -40oC, THFThen, aq HClO4
78% 2 stepsNMe
OMeMe
HMe
OTBS
BrHO
H
Pd(OAc)2 (30 mol%)PtBu3 (30 mol %)KHMDS, 80oC, toluene
NMe
OMeMe
HMe
TBSO
OHC
73%
1, HF, DCM2, DMP, DCM
91%, 2 steps
NMe
OMeMe
HMe
O
OHC
KHMDS, NBS-78oC, THF
91%
NMe
OMeMe
HMe
OTBS
BrHO
HPd(OAc)2 (30 mol%)PtBu3 (30 mol %)KHMDS, 80oC, toluene
NMe
OMeMe
HMe
TBSO
OHC
73%
O
R''R R'
H + ArBrPdL2
Base
O
R''R R'
Ar
ArBrPd(O)
PdAr
Br
O
R''R R'
H
+ Base
O
R''RR'
Pd Ar
O
R''R R'
Ar
O
R'' RR'
PdAr
Buchwald, JACS, 1997, 119, 11108-11109Hartwig, JACS, 1997, 119, 12382-12383Buchwald, JACS, 1998, 120,1918-1919Hartwig, JACS, 1999, 121, 1473-1478
NMe
OMeMe
HMe
O
OHC
BrDMDO, acetoneNaHCO3
41%
NMe
OO
MeMe
HMe
O
OHC
H
ONH2OH*HClPy, 45oC, MeOH
94%
NMe
OO
MeMe
HMe
O H
O
NHO
NCS, DMF; then 0oC THF, NEt3
NMe
OO
MeMe
HMe
O
SCN
H
O
NH
NH
S 65%
MeNP OPh
110oC, toluene 54% N
Me
OO
MeMe
HMe
O
CN
H
O
N-Methylwelwitindolinone Disonitrile
Rawal et al, JACS, 2011, 133, 5798-5801
NMe
OO
MeMe
HMe
O H
O
NHO
NCS, DMF; then 0oC THF, NEt3
NMe
OO
MeMe
HMe
O
SCN
H
O
NH
NH
S
65%
R
NOH NCS
R
N OH
Cl
thiourea
Et3N R
N
S
O
NH2
NH2 rtR-NCS
R
N
S
O
NH2
NH2
-H2N NH2
O
Ryu, TL, 1993, 34, 8283-8284Kim, TL, 1997, 38, 1597-1598
NMe
OO
MeMe
HMe
O
SCN
H
O
MeNP OPh
110oC, toluene 54% N
Me
OO
MeMe
HMe
O
CN
H
O
N-Methylwelwitindolinone Disonitrile
R-NCX +MeN
P OPhR-NC +
NP OPh
XMe
X= OX= S
RN
CX N
POPh
Me
RN
C-X N+
POPh
MeX
PO
N
NR
Me
Ph NP OPh
XMe
R-NC
+
Mukaiyama et al, Bull. Chem. Soc. Jpn. 1965, 38, 858-859
NMe
OO
MeMe
HMe
Cl
SCNH
Electrophilic chlorination
NMe
OMeMe
HMe
N
OHC
NH2
NMe
OMeMe
HMe
O
OHC
Rawal retrosynthetic analysis
NMe
OO
MeMe
HMe
Cl
SCNH
NMe
OO
MeMe
HMe
Cl
CNH
NMe
OO
MeMe
HMe
Cl
SCNOH
N-Methylweltindolinone C-NCS N-Methylweltindolinone C-NC 3-hydroxy-N-methylwelwitindolinone C
NMe
OMeMe
HMe
O
OHC
THF/EtOH, 0oC
89%NMe
O
MeMe
HMe
O
HO
N2H4, AcOH
EtOH, 70oC
NMe
OMeMe
HMe
N
HO
NMe
OMeMe
HMe
Cl
HO
NH2
NCS
Pyridine61% 2 steps
MMPPTFA, AcOH
72%NMe
OMeMe
HMe
Cl
HOO
H
Dess-martinperiodinane, NaHCO3
DCM99%
NMe
O
MeMe
HMe
Cl
OHC
OH
NH2OH*HCl, pyridine MeOH, 45oC
97%
NMe
OMeMe
HMe
Cl
OH
NHO
NCS, DMF, THF, 40oC
then Et3N, 23oC
N
NH
SH83%
NMe
OO
MeMe
HMe
Cl
SCNH
N-Methylweltindolinone C-NCS
(Dr= 4.4: 1 )
1.1 equivNaBH(OMe)3
COOH
O
OO-
2
Mg2+ 6H2O*
MMPP
NMe
OMeMe
HMe
O
HO
N2H4, AcOH
EtOH, 70oC
NMe
OMeMe
HMe
N
HO
NMe
OMeMe
HMe
Cl
HO
NH2
NCS
Pyridine61% 2 steps
NNH2
NCS NNH
ClN+
N-
-HCl
N+N
Cl+Cl
H Cl
O NN2H4NH2
NCSCl
NCS
Chem. Phram. Bull. 1963, 684-685Chem. Phram. Bull. 1963, 1413-1417
NMe
OMeMe
HMe
O
OHC
HOOH
4 A mol, toluene
100oC
57% NMe
OMeMe
HMe
O
O
O
(not observed)NMe
OMeMe
H
OH
O
H
NMe
OMeMe
HMe
O
OHC Cope
NMe
MeO
CHO
O
NMe
MeO
CHO
OH
rearomatization
NMe
MeO
O
O
H
NMe
OOH
Me
OH
NMe
OOH
Me
O
Aldol
NMe
OMeMe
H
OH
O
H
E-olefin to Z-olefin
NMe
OO
MeMe
HMe
Cl
SCNH
MeNP OPh
110oC, toluene
65% NMe
OO
MeMe
HMe
Cl
CNH
N-Methylweltindolinone C-NC
KHMDS, THF, -78oC
thenPh NSO2Ph
O
67 %
NMe
OO
MeMe
HMe
Cl
SCNOH
3-hydroxy-N-methylwelwitindolinone C
Rawal, JACS, 2012, 134, 1392-1395
Garg retrosynthetic analysis
NMe
OO
MeMe
HMe
Cl
SCNH
NMe
OMeMe
HMe
H
Cl
OH
NMe
OMeMe
HMe
H
RO
OR
Me
O
NMe
Br
OR
Me
O
Me
NMe
Me
H
OR
Me
O
NMe
Br+
OPiv
Me
O
Me
Me
MeO
Me
s-carvone
1, K2CO3, MeOH, 60oC
2, I2, MeOH, 23oC
NMe
Br
OH
Me
O
Me
NMe
Br Me
HTBSCl, imidazoleDMAP, Bu4NI
DMF, 100oC
54% 2 steps
90%
OTBS
Me
O
Me
NMe
Br Me
H NaNH2 (10.5 equiv)t-BuOH (3.5 equiv)
THF, 23oC
NMe
OMeMe
HMe
H
TBSO
+
OTBSMe
O Me
NMe
Me
H
2.5 : 1
46%
Cas:2240-16-8 25mL 556
Chem.pharm.bull.1994, 42, 1393-1398JOC. 1978, 43, 2057-2059
OPiv
Me
O
Me
Me
MeO
Me
s-carvone
MeO
Me
LiAlH4 MeOPiv
Me
PivCl
Pyridine
PivCl =O
Cl
CrO3Me
OPiv
MeO
NaOMe
MeOH
MeOPiv
Me
MeO
NH
N
MgBr
CuBr
Me
OPiv
Me
MeO
MeOPiv
Me
CrO3Me
OPiv
MeONH
N
NH N+ CrO3
N NCrO OH
OH
: NH+NCr
HO
O-O
N NCrHO
OHO
H
:O
N NS
SO
O
O
OF
FF
F FF
comins' reagent
NMe
OMeMe
HMe
H
TBSO
1, TBAF, THF, 60oC
2, Dess-Martin,DCM,23oC
95% 2 steps NMe
OMeMe
HMe
H
O1, KHMDS, THF, -78oC comins's reagent
2, (Me3Sn)2, Pd(PPh3)4 LiCl, dioxane, 110oC
74% 2 steps NMe
OMeMe
HMe
H
Me3Sn
CuCl2, dioxane23-80 oC75%
NMe
OMeMe
HMe
H
Cl
NBS, 0oC, DCM HCl, 80oC, EtOH
89%, 2 stepsNMe
OMeMe
HMe
H
Cl
OH
NMe
OMeMe
HMe
H
Cl
Br
NMe
OMeMe
HMe
H
Cl
OH
1, i-Bu2AlH,DCM, -78oC
2, Cl3CC(O)NCO DCM, 0--23oC K2CO3, MeOH
86% 2steps NMe
MeMe
OH
Me Cl
HH
OO
H2N
AgOTf, PhI(OAc)2bathophenanthroline
CH3CN, 82oC
33%
25%
NMe
MeMe
OH
Me Cl
H
OO
HN1, Ba(OH)2* 8H2O H2O, dioxane,110oC
2, IBX, TFA DMSO, 23oC
48% 2 steps NMe
OMeMe
HMeH2N
Cl
OH
N O O N
S
DMAP, DCE, 90oC
NMe
OMeMe
HMeSCN
Cl
OH
N-Methylweltindolinone C-NCS
Garg et al, JACS, 2011, 133, 15797-15799
bathophenanthroline
NN
NMe
OMeMe
HMe
H
Cl
OH
1, LiEt3B-D,THF,-78--0oC
2, Cl3CC(O)NCO DCM, 0--23oC K2CO3, MeOH
100% 2steps NMe
MeMe
OH
Me Cl
HH
OO
H2N
D
NMe
MeMe
OH
Me Cl
HH
OO
H2N
R
AgOTf, PhI(OAc)2bathophenanthroline
CH3CN, 82oC+
NMe
OMeMe
HMe
H
Cl
OH
NMe
MeMe
OH
Me Cl
H
OO
HN
R
R= H 33% 25%
R=D 60% 8%
NMe
MeMe
OH
Me Cl
H
OO
HN
D1, Ba(OH)2* 8H2O H2O, dioxane,110oC
2,Dess-martin, TFA DCM, 23oC
66% 2 steps NMe
OMeMe
HMeH2N
Cl
OH
1,HCO2H, Ac2O THF, 0--23oC
2, Burgess reagent THF, Benzene, rt
100% NMe
OO
MeMe
HMe
Cl
CNH
N-Methylweltindolinone C-CN
NMe
OO
MeMe
HMe
Cl
CNH
NaH, airTHF, 23oC
NMe
OO
MeMe
HMe
Cl
CNOH
NMe
OO
MeMe
HMe
Cl
SCNH
NaH, airTHF, 23oC
47%
48%
NMe
OO
MeMe
HMe
Cl
SCNOH
3-hydroxy-N-methylwelwitindolinone C-NCS
3-hydroxy-N-methylwelwitindolinone C-NC
Garg et al, JACS, 2012, 134, 1396-1399
O N
OS
O
ON+
Burgess reagent