enantioselective total synthesis of (+)-gliocladin c and (+)-gliocladine c
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Enantioselective Total Synthesis of (+)-Gliocladin C and (+)-Gliocladine C. 石枫 2011-7-9. Larry E. Overman, Org. Lett., 2007, 9, 339 Larry E. Overman, J. Am. Chem. Soc. 2011,133, 6549. (+)-Gliocladine C. (+)-Gliocladin C. They were isolated from fungal secondary metabolites. - PowerPoint PPT PresentationTRANSCRIPT
Enantioselective Total Synthesis of (+)-Gliocladin C and (+)-Gliocladine C
石枫2011-7-9
Larry E. Overman, Org. Lett., 2007, 9, 339Larry E. Overman, J. Am. Chem. Soc. 2011,133, 6549
(+)-Gliocladine C
NH
N
NMe
O
O
HO
HMe
HN
S
S
They were isolated from fungal secondary metabolites.
They showed a wide range of bioactivities.
(+)-Gliocladin C
NH
N
NMe
O
OH
HN
O
Enantioselective Total Synthesis of (+)-Gliocladin C
Larry E. Overman, Org. Lett., 2007, 9, 339
NH
N
NMe
O
OH
HN
O
(+)-Gliocladin C
cyclizaztionNH
HN
N
OMe
H
NHMe
O
O O
OEtNBn
BnN
NBoc
OH
H
OH
cyclization
Mukaiyama aldol reaction
NBn
OTBDMS
NBn
N
O
OHCBoc
+NBn
O
BnN
O O
NH2 NBn
O
BnN
N
O
Boc
OH
N
O
O
H
C7H7SO2NHNH2
N
O
NNSO2C7H7
HH
OH
N
O
N
H
N
SO2
C7H7
N
O
N2
H
BnBr
EtOH/KOH aq.
Sythesis of starting material from isatine:
J. Am. Chem. Soc. 1958, 80, 2257
Muthusamy, S. J. Chem. Soc., Chem. Commun. 2002, 824
N
O
N2
Bn
NBn
Rh(OAc)4
NBn
O
NBnTBDMS-OTf
Et3N, CH2Cl2, rt(>99%) (87%) N
Bn
OTBDMS
NBn
Overman, L. E. Org. Lett. 2005, 7, 2795
NBn
OTBDMS
NBnN
O
OHCBoc
BF3.Et2ODTBMPCH2Cl2, -78oC(75-89%)
NBn
O
BnN
N
O
Boc
OH
(ds~80:1)
TBDMS: t-butyl dimethyl silyl
DTBMP: 2,6-di-tert-butyl-4-methylpyridine(to prevent desilylation of the siloxy nucleophile)
Nt-Bu
t-Bu
Mukaiyama aldol reaction
(a) 3M HCl, MeOH, rt(b) 2,2-dimethoxypropane, CSA, benzene, 60oC
(85% for 2 steps)
CSA: 樟脑磺酸
O SO3H
NBn
O
BnN
O O
NH2
LiAlH4, THF, rt
SiO2, MeOH, rt(93%)
NBn
BnN
NH
OO
H
TMSOTf, i-Pr2EtN
CH2Cl2, rt (91%)
NBn
BnN
NH
O
H
OTMS
Rychnovsky’s method
NBn
BnN
NH
O
H
OTMS(a) (Boc)2O, Na2CO3, THF-H2O, rt
(b) (CO2H)2, MeOH, rt(71% for 2 steps)
NBn
BnN
NBoc
OH
H
OH
(a) NaH; TBDMSCl, CH2Cl2, rt (96%)(b) NaH; MeI, 0oC to rt (77%)
(c) TBAF (1equi), THF, rt (92%)
NBn
BnN
NBoc
OMe
H
OH
TBDMSCl: t-Bu Si
Me
Me
Cl
TBAF: FBu4N
(a) Dess-Martin, pyridine,CH2Cl2, rt(b) NaClO2, NaH2PO4, 2-methyl-2-butene, THF-H2O, rt
(c) MeNH2.HCl, BOP,CH2Cl2, rt (60% for 3 steps)
BOP: benzotriazole-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate
P
N
N
NO
NN
N
P-FF
F
FF
F
NBn
BnN
NBoc
OMe
H
NHMe
O TMSIMeCN, rt
(65%)
NBn
BnN
NH
OMe
H
NHMe
ONa, NH3,t-BuOH, THF
-78oC (87%)
NH
HN
NH
OMe
H
NHMe
O
ClCOCO2Et,Et3N,CH2Cl2, rt
(87%)
NH
HN
N
OMe
H
NHMe
O
O O
OEt
(TMS)2NH, 140oCsealed tube
(73%)
Mulliez, M.; Royer, J. Tetrahedron 1984, 40, 5143
Mulliez’s methodNH
N
NMe
O
OH
HN
O
(+)-Gliocladin C
From isatine to (+)-Gliocladin C: 21 steps, ~4% overall yield.
next
Mukaiyama aldol reaction:
Pioneer work: Mukaiyama, T., Chem. Lett. 1973, 1011; Mukaiyama, T., J. Am. Chem. Soc. 1974, 96, 7503
R1 H
O+
OSiMe3
R3R2
Lewis acid or Lewis base(stochiometric, substochiometric,or catalytic)
aqueous work-upR1 R3
O
R2
OH
R1 R3
O
R2
OH
anti-diastereomer syn-diastereomer
+
R2 is small. R2 is large.
R1 H
O MX4
-X R1 H
OX3M
O
R3R2
SiMe3X
+ -Me3SiX
R1 R3
O
R2
O
X3M aqueous
work-up
R1 R3
O
R2
OH
Mechanism:
back
MeO OMe H MeO OMe
HO
Me
OHHO
OH
OOMe
-MeOH
-MeOH
H OH
O
-H
O
O
Mechanism:
NBn
O
BnN
O O
NH2
LiAlH4, THF, rt SiO2, MeOH, rt
NBn
OH
BnN
O O
NH2
NBn
O
BnN
O O
NH2
LAH
NBn
BnN
O O
NH2
NBn
BnN
NH
OO
H
Mechanism:
back
Rychnovsky’s method:
Scott D. Rychnovsky, J. Am. Chem. Soc. 1994,116,1753
OTBS
CH3
O O O O O O O O
CH3TESOTf,i-Pr2NEt
110oC
OTES
O
CH3
Mechanism:
O
O
SiMe3TfO
O
O
SiMe3
H N(i-Pr)2Et
O
O
SiMe3 back
P
N
N
NO
NN
N
P-FF
F
FF
F
PN N
N
ON
NN
O
O
O
O
P
N
N
N
NH2
Me
NHMe
O
The action of BOP:
The action of TMSI:
N O
O
I
-CO2
-t-BuI
NH
back
NH
N
NMe
O
O
HO
HMe
HN
S
S
sulfur substitution
dihydroxylation
nucleophilic additiohn
NH
N
NMe
O
OH
HN
O
(+)-Gliocladin C
NP
PN
CHO
OMe
N
NMe
O
OR'
O+
NP
PN
OR
O
Enantioselective Total Synthesis of (+)-Gliocladine C
Larry E. Overman, J. Am. Chem. Soc. 2011,133, 6549
cyclization
NBoc
BocN
O
H
NH
HN
O
OH
(a) TFA, Et3SiH, CH2Cl2, rt
(b) i)(Boc)2O, 15mol% DMAP, CH2Cl2, rt ii) MeOH 68% two steps
O
OCl CCl3
Et3N, THF, 0oC97%
NBoc
BocN
OO
OCCl3
NBoc
BocN
O
O
O
CCl3
98:2 er
O
OCl CCl3
Et3N, THF, 40oC
10mol% (S)-(-)-4-pyrrolidinopyrindinyl(pentamethylcyclopentadienyl) iron
88%, 98:2 er
5mol% (S)-(-)-4-pyrrolidinopyrindinyl(pentamethylcyclopentadienyl) iron
THF, rt96%, 98:2 er
Steglich-type rearrangement
NBoc
BocN
O
O
O
CCl3
98:2 er
(a) NaBH4, MeOH, 0oC (81%)
(b) HC(OMe)3, 10mol% PPTS,MeOH, 65oC (83%, 1.2:1 dr)
NBoc
BocN
OMe
O
O
CCl3
(a) LiBH4-MeOH, Et2O, rt to 40oC
(b) Dess Martin periodinane,pyridine, CH2Cl2, rt (95%)
NBoc
BocN
CHO
OMe
PPTS: pyridinium p-toluenesulfonate Dess Martin periodinane (DMP):
OI
O
AcO OAcOAc
Soai reduction
Soai reduction: LiBH4-MeOH (Esters, lactones, and epoxides)
Soai, K.; Ookawa, A. J. Org. Chem. 1986, 51, 4000
NBoc
BocN
CHO
OMe
N
NMe
O
OMe
O
(a)LDA, THF, -78 oC
(b) -78 oC
(c) AcOH, -78 oC to rt (75%) NBoc
BocN
OMeN
NMeO
O
OMe
BF3.Et2O, CH2Cl2,
-78oC to -40oC (80%)
NBoc
BocN
N
H
NMe
O
O
ONeat, 175oC
89%
NH
HN
N
H
NMe
O
O
O
(+)-Gliocladin C
Sc(OTf)3, MeCN, 0oC to rt60%
NBoc
BocN
N
H
NMe
O
O
O(a) MeMgCl, THF, -78oC (86%, 9:1 dr).
(b)TBSOTf, DMAP, Et3N, DMF, rt (94%, 3:2 dr).
NBoc
BocN
N
H
NMe
OOTBS
O
Me
epimer: major/minor=3:2
NBoc
BocN
N
H
NMe
OOTBS
O
Me
OHOH Ac2O, DMAP,CH2Cl2, rt
93%
AD-Mix-, H2NSO2Me, K2OsO4.2H2O,
(DHQ)2PHAL, t-BuOH/H2O/acetone, rt
82%, >14:1 dr NBoc
BocN
N
H
NMe
OOTBS
O
Me
AcOAcO
major minor
OsO4/NMO 1:1 20:1
AD-Mix- 14:1 20:1
AD-Mix- 5:1 20:1
NMO: N-甲基吗啉氧化物
NOO
Sharpless asymmetric dihydroxylation
NBoc
BocN
N
H
NMe
OOTBS
O
Me
AcOAcO (a) H2S, BF3.Et2O,CH2Cl2, -78oC to rt
(b) O2, MeOH/EtOAc, rt 62%
NH
N
NMe
O
O
AcO
HMe
HN
S
S
La(OTf)3, MeOH,40oC
75%
From isatine to (+)-Gliocladin C: 10 steps, 11% overall yield.
From precursor of (+)-Gliocladin C to (+)-Gliocladine C: 6 steps, 29% yield.
NH
N
NMe
O
O
HO
HMe
HN
S
S
(+)-Gliocladine C
Org. Lett., 2007, 9, 5267.
Mechanism of acid-promoted ionic reduction:
NH
HN
O
H
NH
HN
O
O
H
H
NH
N
O
H
H SiEt3
OH H
NBoc
BocN
NBoc
BocN
OMeN
NMeO
O
OMeBF3 N
Boc
BocN
N
NMeO
O
ON
H
NMe
O
O
O
Me
MeO
Mechanism of ring-closing:
back
back
N O
R2 OCOR3
R1
+Py
N O
R2 O
R1
N
X
COR3
I
II
-PyN O
R2O
R1
R3OC
III
-Py
N O
R2 O
R1COR3
IV
Steglich-type rearrangement:
Pioneer work: Steglich, W. Tetrahedron Lett. 1970, 11, 4727
O
Ph
OOR
O DMAP
CH2Cl2,rtO
Ph
O
OR
O
Black, T. H. J. Chem. Soc. Chem. Commun. 1986, 1524
Catalytic enantioselective Steglich-type rearrangement :
N
N
FePh Ph
Ph
PhPh
O
R1
OOR
O 5% cat.
CH2Cl2,35oC O
R1
O
OR
O
NR2
R1
OOR
O 5% cat.
CH2Cl2,35oC NR2
R1
O
OR
O
R3 R3
up to 94%, 99%ee
R2R2
up to 95%, 97%ee
cat.
Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 3921
N
N H
OAcCPh3 P
MeMeH
H
Me
t-Bu
t-Bu
Vedejs, E. J. Am. Chem. Soc. 2003, 125, 4166
Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368;
Mechanism of Steglich-type rearrangement:
NO
R1
Ar
O OR2
O
Nu
NO
R1
Ar
O
OR2
O
Nu
-Nu
NO
R1
Ar
O
R2O
O
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Sharpless asymmetric dihydroxylation (SAD):
Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 4263
Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968
R1
R2
R3
R4
R1-4 = H, alkyl, aryl
chiral ligand (catalytic)oxidant (stoichiometric)OsO4 (catalytic)
organic solvent / water(AD-mix or AD-mix)
HO OH
R2 R4
R1 R3
orHO OH
R1 R3R2 R4
RS
RL
RM
H
NW NE
SW SE
"OH HO"-face AD-mix
"OH HO"-face AD-mix
Empirical model:
(DHQ)2PHAL (DHQD)2PHAL
AD-mix : (DHQ)2PHAL+K2OsO2(OH)4+K3Fe(CN)6
AD-mix: (DHQD)2PHAL+K2OsO2(OH)4+K3Fe(CN)6
N
MeO
ONNN
H
Et
H
N
OMe
O
N
HH
Et
N
OMe
ON N N
HH
N
MeO
O
NH
H
Et Et
Mechanism of SAD :
Os
O
OO
O
-L+L
Os
OO
O
O
L
+ alkene
concerted [3+2]mechanism Os
O
O
O
O
L
R1R2R3
R4
O
OsO
R1
R3
R2
R4O
O L
osmium(VI)glycolate
stoichiometricoxidant
O
OsO
R1
R3
R2
R4O
O O
H2O
HO OH
R1
R3R2R4
+ alkene
stepwise [2+2]mechanism
Os
OO
O O
R1
R2R3
R4osmaoetane
Os
OO
OO
R1
R2R3
R4L
+Lrearrangement
start here
Synthetic applications of SAD :
O CO2t-Bu
OsO4, (DHQ)2-AQN,K3Fe(CN)6,K2CO3,t-BuOH/H2O 0oC, 3days
O CO2t-Bu
HOOH
HO
OH
45
7
steps
O COOH
HOOH
HO
OH
45
7OH
3-Deoxy-D-manno-2-octulosonic acid
OBn
BnO
OH
OBn
(E)
(Z)
(a) AD-mix , 1mol% OsO4,5mol%(DHQD)2PHAL,CH3SO2NH2(2equi),K2S2O8 (2equi),t-BuOH/H2O (1:1)0oC to rt, 4days
(b) 1mol% OsO4,5mol%(DHQD)2PHAL,NMO(2equi),acetone/H2O (5:1)(45%, 76% ee)
OBnBnO
OH
OBn
OH
OH
OH
OH34
56
steps
OO Ph
OAcOR
O
HOOCHOOC
OHCOOH
34
56
(+)-Zaragozic acid C
Armstrong, A. J. Org. Chem. 2000, 65,7020
Burke, S. D. Org. Lett. 1999, 1, 71.
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Mechanism of sulfur substitution:
NBoc
BocN
N
H
NMe
OOTBS
O
Me
AcO O
O BF3
BF3
NBoc
BocN
N
H
NMe
OOTBS
O
Me
AcO
BF3
H2S
H2S
NH
N
NMe
O
O
AcO
HMe
HNSH
SH
O2
MeOH/EtOAc, rt
NH
N
NMe
O
O
AcO
HMe
HN
S
S
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