cyclopropanes in total synthesis - uni-konstanz.de · 2017. 3. 24. · julia–bruylants...
TRANSCRIPT
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Gaich-Group Seminar
Erik Stempel22.01.2013
Cyclopropanes in Total Synthesis
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Gaich-Group SeminarErik Stempel Ba
sic
2
Cyclopropane-based Strategies (I)■ formal cycloaddition strategies
■ ring-opening strategies
EDG EWG
X YEDG EWG
Z Y X
EDG EWG
EDG EWG
X Y
X Y Z
[3+2]
[3+3]
[4+3]
R[4+3]
DVCPR R
EDG EWGtransition metal five- to eight-
membered rings
EDG EWG
EDG EWG
Nu
EDG EWG
E
EDG EWG
Nu–
E+
radical-initiatedring opening
■ Tang, P.; Qin, Y. Synthesis 2012, 44, 2969.■ DVCPR = divinylcyclopropane rearrangement
9
-
Gaich-Group SeminarErik Stempel Ba
sicCyclopropane-based Strategies (II)
■ ring-opening strategies (cont.)
■ ring-opening-cyclization strategies
3■ Tang, P.; Qin, Y. Synthesis 2012, 44, 2969.
CO2Et
CO2Et
Buchnerreaction
R
ringexpansion
R
ringcleavage
or or
EDG EWG EDG EWGNuNu
EWGEDG EWGEDG EE
RR R
R
or
or
radicalcyclization
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Gaich-Group SeminarErik Stempel Ba
sic
■ Wong, H.N.C. Chem. Rev. 1989, 89, 165.
Cyclopropanes: Thermal Ring Fission■ Cyclopropyl Carbene Rearrangement
(1958)
■ Cyclopropylmethyl Carbene Rearr. (1960)
■ Vinylcyclopropyl Rearr. (1960)
■ Divinylcyclopropane Rearr. (1960)
■ Thermal isomerization of cyclopropane (1922)
4
–40 °C 195 °C
∆ H migrationBr Br
R R'
Mg
R R'
R'
R1 2 3
12 13 14
54
6 7 8
9 11 10
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■ FREUND–GUSTAVSON Cyclopropane Synthesis
■ CIAMICIAN-DENNSTEDT Cyclopropanation
■ SIMMONS–SMITH Cyclopropanation
Gaich-Group SeminarErik Stempel Ba
sicCyclopropane Reactions (I)
5
BrBr Zn2 R X 2 Na° R RWURTZ Reaction
■ Freund, A. Monatsh. 1882, 3, 625.■ Gustavson, G. J. Prakt. Chem. 1887, 36, 300.
■ Ciamician, G.; Dennstedt, N. Chem. Ber. 1881, 14, 1153.
■ Simmons, H.E.; Smith, R.D. J. Am. Chem. Soc. 1958, 80, 5323■ Furukawa, J. Tetrahedron 1968, 24, 53■ Simmons, H.E. Org. React. 1973, 20, 1
R2
R1 R4
R3 EtZnCH2IR2R1 R4
R3
IEtZn
R2R1 R4
R3
‡
– EtZnI
Ph CHCl350% NaOH Ph
H
Cl
ClNH CHCl3
50% NaOHNH
ClCl
N
Cl
15 16
17 18 1920 21 22
23 24 25
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Gaich-Group SeminarErik Stempel Ba
sic
■ MIRC = Michael initiated ring closure
Cyclopropane Reactions (II)■ MIRC
■ COREY–CHAYKOVSKY Cyclopropanation
■ MOUSSERON–FRAISSE–McCOY Cyclopropanation
■ HASSNER–GHERA–LITTLE MIRC Reaction
6
EWGSO
SO EWG
■ Johnson, A. J, Am. Chem. Soc. 1961, 83, 417.■ Corey, E.J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
O O
PhCOCH2Br
Base, rt. O O
BrO
Ph
O O
COPh
■ Fraisse, J. Bull. Soc. Chim. Fr. 1957, 986.■ McCoy, L.L. J. Am. Chem. Soc. 1958, 80, 6568.■ Mousseron, M. Compt. Rendu. 1959, 248, 887.
■ Ghera, E. Tet. Lett. 1979, 20, 4603.■ Little, R.D. Tet. Lett. 1980, 21, 2609.■ Hassner, A.; Ghera, E. Tet. Lett. 1990, 31, 3653.
Br CO2EtbasePh
SO2Ph PhO2S
Bn
CO2Et
26 27 28
29 30 31
32 33 34
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Gaich-Group SeminarErik Stempel Me
dium
■ Fischer, E.O. Chem. Ber. 1967, 100, 2445.■ Pfau, A.S.; Plattner, P.A. Helv. Chim. Acta 1939, 22, 202.
Cyclopropane Reactions (III)■ KISHNER Cyclopropane Synthesis
■ Carbenes■ Cyclopropanation via metal carbenes (metal-free = PFAU–PLATTNER Cyclopropanation)
■ SEYFERTH Dihalocarbene Reagent SEYFERTH-GILBERT Diazoalkane Reagent
7
R1
O R2
R3N2H4
– H2O N NH
R1 R2
R3N N
R1 R2
R3∆ R1 R2
R3R2R1
R3– N2
pyrazoline
■ Kishner, N. J. Russ. Phys. Chem. Soc. 1912, 43, 1132.
RR'O
O
N2
Rh, Cu, Pd, … RCO2R'
Et
Et
PhHgCF3 , NaI
PhH, ∆ Et Et
F F(MeO)2P
N2
OCu
P(OMe)2
O
■ Seyferth, D. J. Am. Chem. Soc. 1965, 87, 681.■ Seyferth, D. J. Am. Chem. Soc. 1967, 89, 959.
■ Seyferth, D. J. Am. Chem. Soc. 1967, 89, 4811.■ Seyferth, D. J. Org. Chem. 1971, 36, 128.
35 (36) 37 38 39
40 41 42
43 44 45 46 47
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Gaich-Group SeminarErik Stempel
Adva
nced
■ VCPR = vinylcyclopropane rearrangement
Cyclopropane Reactions (IV)■ BOGER Thermal Cycloadditions
■ BRANDI–GUARNA Spirocyclopropane Rearr.
■ DOERING–LaFLAMME Allene Synthesis / SKATTEBØL Vinylhalocyclopropane Rearr.
8
O O80 °C O O O O CO2CH2Ph
CO2MePh
OR
OR
MeO2C PhPhH2CO2C
O
OPh
PhH2CO2CMeO2CVCPR
■ Boger, D.L. J. Am. Chem. Soc. 1984, 106, 805.■ Boger, D.L. Tet. Lett. 1984, 25, 5611.
N OPh
1,3-CA ON
Ph∆
HN Ph
O
CHBr3KOtBu
Br Br Mg (Doering)1. PhHgCBr3 ,1. PhH, ∆2. MeLi,2. Et2O, 20 °C
RLi (Skattebøl)
■ Brandi, A.; Guarna, A. J. Chem. Soc. Comm. 1985, 1518.■ Brandi, A.; Guarna, A. Tet. Lett. 1986, 27, 1727.■ Brandi, A.; Guarna, A. J. Org. Chem. 1988, 53, 2426.
■ Doering, W.v.E. J. Am. Chem. Soc. 1954, 76, 6162.■ LaFlamme, P.M. Tetrahedron 1958, 2, 1975.■ Skattebøl, L. Tet. Lett. 1961, 2, 167.
48 49
50
51 52
53 54 55 56
57 58 59
60 61 62
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Gaich-Group SeminarErik Stempel
Adva
nced
Cyclopropane Reactions (V)■ CLOKE–WILSON Cyclopropyl Ketone Rearrangement
■ FELDMAN Vinylcyclopentane Synthesis
9
PhNH 180 °C
Cloke (1929) NH
Ph
O 400 °CWilson (1947) O
p-MeOPh CO2Et
OAl2O3–CHCl3
OAr
CO2Et
NH
Ph HCl, 60 °C
H+H2N
Ph
N
Ph
BnO
CO2Me
Ph2S2 , AIBN
PhH, hν
CO2Me
BnO
R PhSPhS R
A BPhS R
H H
AB
R
A B– PhS
■ Cloke, J.B. J. Am. Chem. Soc. 1929, 51, 1174.■ Wilson, C.L. J. Am .Chem. Soc. 1947, 69, 3002.
■ Feldman, K.S. J. Am. Chem. Soc. 1986, 108, 1328.■ Feldman, K.S. J. Am. Chem. Soc. 1988, 110, 3300.■ Feldman, K.S. J. Am. Chem. Soc. 1989, 111, 4878.
63 64
6566 67
68 69
7170
72 73 74
75 76
77
78 79
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Gaich-Group SeminarErik Stempel
Adva
nced
Cyclopropane Reactions (VI)■ JULIA–BRUYLANTS Cyclopropyl Carbinol Rearrangement
■ WENDER Homologous Diels–Alder Reaction
10
R
RhL3Cl
RhL2Cl
– L
RRhL2Cl
– L
+ L
RRhLCl
RhL2Cl – L+ L
R RhLCl R RhLCl
RhLCl
R
RhLCl
R
R
R
R
OHH+
Br
50% HBr BrO
HBr Br
OH
■ Bruylants, P. Bull. Acad. Royal. Belg. 1928, 14, 140.■ Julia, M. Bull. Soc. Chim. Fr. 1960, 1072.
■ Sarel, S.; Breuer, E. J. Am. Chem. Soc. 1959, 81, 6522.■ Wender, P.A. J. Am. Chem. Soc. 1995, 117, 4720.
80 81 82 83
84 85 86
87 88
89
90
91
92
84
93
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Gaich-Group SeminarErik Stempel
Adva
nced
Cyclopropane Reactions (VII)■ KULINKOVICH Hydroxycyclopropanation
■ SREBNIK–QUNTAR Cyclopropyl Phosphonates
11
nBu P(O)(OEt)2
Cp2ZrCl2,2 eq. EtMgBr
ZrCp2
nBu P(O)(OEt)2 2 eq. AlCl3 nBu P(O)(OEt)2
■ Quntar, A.; Srebnik, M. J. Organomet. Chem. 2005, 690, 2504.■ Quantar, A.; Srenbnik, M. J. Org. Chem. 2006, 71, 730.■ Srebnik, M.; Quantar, A. Org. Prepar. Proced. Int. 2008, 40, 505.
Ti(OiPr)42 EtMgBr Ti(OiPr)2Ph
O OEt
Ph
(iPrO)2Ti
(iPrO)2Ti O OEt
PhPh
O
EtOAc
Ti(OiPr)2EtO
(iPrO)2Ti– EtH
Ph
BrMgO
Ph
HO EtMgBr
H2O
C4H9 CO2Me
2.0 eq. EtMgBr,0.1 eq. Ti(OiPr)4
C4H9 OHCO2Me
nBuMgCl,(iOPr)3TiCl OH
H
■ Kulinkovich, O.G. Zh. Org. Khim. 1989, 25, 2245.
■ Kulinkovich, O.G. Synthesis 1991, 234.
■ Kulinkovich, O.G. Mendeleev Comm. 1993, 230.
94 95 96 97
98 99 100 102
103
104
105106
107 108 109
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Gaich-Group SeminarErik Stempel
Nat
. Pro
d.
Cyclopropane Containing Natural Products
12
H
HO
O
(+)-isovelleral
H
H
(±)-sesquicarene
O
(±)-sabinone
HH
HO2C
echinopine A
ON
NH
O
OO
OH OH
HN
4
FR–900848
O
HN
U–106305
O
OHOH
HO2CH H
OH H
(+)-ambruticin S
PhHN
OC7H15
(±)-grenadamide
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Gaich-Group SeminarErik Stempel Ex
curs
us
■ Wessjohann, L.A. Chem. Rev. 2003, 103, 1625.
Biosynthesis of Cyclopropane Rings■ Homoallyl cation ring closure.
■ Reaction of a cation with an enzyme-activated α-methyl group.
■ Methyl transfer from SAM.
■ Reaction with a homoconjugated double-bond (also via radicals).
■ Internal nucleophilic substitution (SNi)
■ several more
13
H
Enz B
R
HO
H
EnzB R
HO
SAd
NH2
CO2
H EnzB
COOH
OOH from hydroperoxide-lyase
H EnzB
COOH
O
H
SAd
CO2H
N RN
CO2H
R
X
Nu Nu
110 111
112 113
114
115 117
118
120119
121 122
124123
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Gaich-Group SeminarErik Stempel
Nat
. Pro
d.
■ Falck, J.R. J. Am. Chem. Soc. 1996, 118, 6096.
FR–900848 (Falck, 1996)
14
Bu3Sn OH Bu3Sn OTBDPS
a) (S,S)-Dioxaborolane,a) Et2Zn, CH2I2 , CH2Cl2 ,a) 23 °C, 14 h.
b) TBDPSCl, imid., DMF,b) 23 °C, 24 h.
86%, 90% ee
c) sBuLi, THF, –40 °C, 1 h;c) [ICuPBu3]4 (0.125 eq.),c) –78 °C, 1 h; O2 , –78 °C, 6 h. OTBDPS
TBDPSO
d) TBAF (0.95 eq.), THF, 23 °C, 2 h.e) RuCl3/NaIO4 , CCl4/MeCN/H2O,e) (1:1:1.5), 23 °C, 1.5 h.
66%
CO2HTBDPSO
f) 2-Mercaptopyridine N-oxide,f) DCC, DMAP, BrCCl3 , 23 °C,f) 4 h, then hν, 0 °C, 1.5 h.
g) tBuLi, THF, –78 °C, 1 h;c) [ICuPBu3]4 (0.125 eq.),c) –78 °C, 1 h; O2 , –78 °C, 3 h.
ROOR'
58%
R = R' = TBDPSR = H, R' = TBDPS d)
i) TPAP (5%), NMO, 4 Å MS,i) DCM, 23 °C, 20 min.j) XXX, nBuLi, THF, –78 °C, 0.5 h.
43%
OTBDPS
SO2Ph
73%, 98% ee
R OH
O
OB
CONMe2
CONMe2
nBu
Et2Zn, CH2I2 , DCMR OH
OH1. PhSH, PMe3/ADDP2. AcOOH
87%
SO2Ph nBuLi, Me3SiCl
83%
SO2Ph
SiMe3
N
O
NN
O
N
ADDP
125 126127
128129
130
131
132
133
134 135 136
136
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Gaich-Group SeminarErik Stempel
Nat
. Pro
d.
FR–900848 (Falck, 1996)
15■ Falck, J.R. J. Am. Chem. Soc. 1996, 118, 6096.■ The Horeau Principle, http://stoltz.caltech.edu/litmtg/mechclub/2008/JAELit06.pdf
■ Key features: - Charette–Juteau asymmetric cyclopropanation
- Dimerization strategy
- Horeau amplification principle
OTBDPS
SO2Ph
j) Li, naphthalene, THF, –78 °C, 0.1 h.k) TBAF (excess), THF, 23 °C, 2 h.l) TPAP (5%), NMO, 4 Å MS,l) DCM, 23 °C, 20 min.
61%
O
O
O NO2
(EtO)2PO O
OEt
m) XXX, LiN(TMS)2 , THF, m) –78 °C to 23 °C, 3 h.n) LiOH, MeOH/H2O, 23 °C, 48 h.o) DCC, DMAP, 4-nitrophenol,o) DCM, 23 °C, 24 h.
62%
N
NH
O
OO
OH OH
HO1. acetone, H+2. HN3 , ADDP/Me3P
85%
N
NH
O
OO
O O
N31. H+2. Rh/C, H2
85%
N
NH
O
OO
OH OH
H2N
ON
NH
O
OO
OH OH
HN
4
p) XXX,p) DMF,p) 23 °C,p) 3 h.
FR–900848
130 137
138
139
139
140 141 142
142,
http://stoltz.caltech.edu/litmtg/mechclub/2008/JAELit06.pdfhttp://stoltz.caltech.edu/litmtg/mechclub/2008/JAELit06.pdf
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Gaich-Group SeminarErik Stempel
Nat
. Pro
d.
■ Barrett, A. J. Am. Chem. Soc. 1996, 118, 7863.
U–106305 (Barrett, 1996)
16
■ Key feature: Charette–Juteau asymmetric cyclopropanation
143 144 145
146147148
149 150 151
152
132 132
132
132
HOOH HO
OHZn(CH2I)2 , DMES,S–
91%, 81% ee
1. DMP2. Ph3P=CHCO2Et
96%,99% ee after
recrystallization
CO2EtEtO2C
HOOHOHOH
HO
OTBS HO
O
O
HN
1. DiBAL2. Zn(CH2I)2 , DME2. S,S–
82%
HO3
1. DMP2. Ph3P=CHCO2Et3. DiBAL
Zn(CH2I)2,S,S–
TBSCl, imid.58%
HO5
79%91%
OTBS1. (E)-(MeO)2P(O)CH2CH=CHCO2Et2. DiBAL
84% 5HO
OTBS
5
Zn(CH2I)2,S,S–
72%
1. N-phenylthio1. succinimide, PBu32. Raney nickel3. TBAF4. DMP
Cl– Ph3P+CH2CONHCH2iBu
38%
95%
U–106305
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Gaich-Group SeminarErik Stempel
Nat
. Pro
d.
■ de Groot, A. J. Org. Chem. 2001, 66, 2350.
(+)–Isovelleral (de Groot, 2001)
■ Key step: magnesium mediated tandem rearrangement–cyclopropanation reaction
17
OTBS
CrO3, pyr.
83 %
OTBS
O
steps
OMs
O
TMSI, HDMS
OMs
TMSO
HDMS, MgI2
H H
H
HTMSO
H
HOTMS
I
H
HO
H
HO
RhCl3 ,K2CO3
82% over 2 steps
Tf2NPh,KHMDS
H
HTfO
O3 , thenNaBH4
H
HTfO
HO
Pd(OAc),CO, PPh3 ,Et3N
H
H
O
O
1. DiBAL2. Swern
H
HO
O
(+)-isovelleral
153 154 155156
157158159160
161 162 163
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Gaich-Group SeminarErik Stempel
Nat
. Pro
d.
■ Carreira, E. Chem. Eur. J. 2006, 12, 8208.
(+)-Strychnofoline (Carreira, 2006)
18
NBn
BnO O
N
OTBDPS
NBoc
OTBDPS
TMSOTf,Et3N
MgI2
55%(2 steps) NBn
BnO O
N
H
TBDPSO
1. OsO4 , NMO2. NaIO43. TsOH, CH(OMe)3
80%NBn
BnO O
N
H
TBDPSO
O O
NBn
BnO O
N
HO
1. TBAF2. IBX3. tBuOK, Ph3PMeBr4. HCl, acetone
62%
NH
HO O
N
HMeN
H
HN
1. N-methyltryptamine,1. AcOH2. Na, NH3
53%
(+)-strychnofoline
NBn
O
NBn
OMgI
N
R
NBn
O
N
R
MgI NBn
O
N
R
I
MgI2
N
OTBDPS
O
ON
OTBDPS
O
OSi
NBn
BnO O
N
OTBDPS
NBoc
OTBDPS
TMSOTf,Et3N
MgI2
55%(2 steps) NBn
BnO O
N
H
TBDPSO
1. OsO4 , NMO2. NaIO43. TsOH, CH(OMe)3
80%NBn
BnO O
N
H
TBDPSO
O O
NBn
BnO O
N
HO
1. TBAF2. IBX3. tBuOK, Ph3PMeBr4. HCl, acetone
62%
NH
HO O
N
HMeN
H
HN
1. N-methyltryptamine,1. AcOH2. Na, NH3
53%
(+)-strychnofoline
NBn
O
NBn
OMgI
N
R
NBn
O
N
R
MgI NBn
O
N
R
I
MgI2
N
OTBDPS
O
ON
OTBDPS
O
OSi
NBn
BnO O
N
OTBDPS
NBoc
OTBDPS
TMSOTf,Et3N
MgI2
55%(2 steps) NBn
BnO O
N
H
TBDPSO
1. OsO4 , NMO2. NaIO43. TsOH, CH(OMe)3
80%NBn
BnO O
N
H
TBDPSO
O O
NBn
BnO O
N
HO
1. TBAF2. IBX3. tBuOK, Ph3PMeBr4. HCl, acetone
62%
NH
HO O
N
HMeN
H
HN
1. N-methyltryptamine,1. AcOH2. Na, NH3
53%
(+)-strychnofoline
NBn
O
NBn
OMgI
N
R
NBn
O
N
R
MgI NBn
O
N
R
I
MgI2
N
OTBDPS
O
ON
OTBDPS
O
OSi
NBn
BnO O
N
OTBDPS
NBoc
OTBDPS
TMSOTf,Et3N
MgI2
55%(2 steps) NBn
BnO O
N
H
TBDPSO
1. OsO4 , NMO2. NaIO43. TsOH, CH(OMe)3
80%NBn
BnO O
N
H
TBDPSO
O O
NBn
BnO O
N
HO
1. TBAF2. IBX3. tBuOK, Ph3PMeBr4. HCl, acetone
62%
NH
HO O
N
HMeN
H
HN
1. N-methyltryptamine,1. AcOH2. Na, NH3
53%
(+)-strychnofoline
NBn
O
NBn
OMgI
N
R
NBn
O
N
R
MgI NBn
O
N
R
I
MgI2
N
OTBDPS
O
ON
OTBDPS
O
OSi
NBn
BnO O
N
OTBDPS
NBoc
OTBDPS
TMSOTf,Et3N
MgI2
55%(2 steps) NBn
BnO O
N
H
TBDPSO
1. OsO4 , NMO2. NaIO43. TsOH, CH(OMe)3
80%NBn
BnO O
N
H
TBDPSO
O O
NBn
BnO O
N
HO
1. TBAF2. IBX3. tBuOK, Ph3PMeBr4. HCl, acetone
62%
NH
HO O
N
HMeN
H
HN
1. N-methyltryptamine,1. AcOH2. Na, NH3
53%
(+)-strychnofoline
NBn
O
NBn
OMgI
N
R
NBn
O
N
R
MgI NBn
O
N
R
I
MgI2
N
OTBDPS
O
ON
OTBDPS
O
OSi
NBn
BnO O
N
OTBDPS
NBoc
OTBDPS
TMSOTf,Et3N
MgI2
55%(2 steps) NBn
BnO O
N
H
TBDPSO
1. OsO4 , NMO2. NaIO43. TsOH, CH(OMe)3
80%NBn
BnO O
N
H
TBDPSO
O O
NBn
BnO O
N
HO
1. TBAF2. IBX3. tBuOK, Ph3PMeBr4. HCl, acetone
62%
NH
HO O
N
HMeN
H
HN
1. N-methyltryptamine,1. AcOH2. Na, NH3
53%
(+)-strychnofoline
NBn
O
NBn
OMgI
N
R
NBn
O
N
R
MgI NBn
O
N
R
I
MgI2
N
OTBDPS
O
ON
OTBDPS
O
OSi
NBn
BnO O
N
OTBDPS
NBoc
OTBDPS
TMSOTf,Et3N
MgI2
55%(2 steps) NBn
BnO O
N
H
TBDPSO
1. OsO4 , NMO2. NaIO43. TsOH, CH(OMe)3
80%NBn
BnO O
N
H
TBDPSO
O O
NBn
BnO O
N
HO
1. TBAF2. IBX3. tBuOK, Ph3PMeBr4. HCl, acetone
62%
NH
HO O
N
HMeN
H
HN
1. N-methyltryptamine,1. AcOH2. Na, NH3
53%
(+)-strychnofoline
NBn
O
NBn
OMgI
N
R
NBn
O
N
R
MgI NBn
O
N
R
I
MgI2
N
OTBDPS
O
ON
OTBDPS
O
OSi
NBn
BnO O
N
OTBDPS
NBoc
OTBDPS
TMSOTf,Et3N
MgI2
55%(2 steps) NBn
BnO O
N
H
TBDPSO
1. OsO4 , NMO2. NaIO43. TsOH, CH(OMe)3
80%NBn
BnO O
N
H
TBDPSO
O O
NBn
BnO O
N
HO
1. TBAF2. IBX3. tBuOK, Ph3PMeBr4. HCl, acetone
62%
NH
HO O
N
HMeN
H
HN
1. N-methyltryptamine,1. AcOH2. Na, NH3
53%
(+)-strychnofoline
NBn
O
NBn
OMgI
N
R
NBn
O
N
R
MgI NBn
O
N
R
I
MgI2
N
OTBDPS
O
ON
OTBDPS
O
OSi
164
165
166
167 168
169
170
171
172 173 174
165175
166
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Gaich-Group SeminarErik Stempel
Nat
. Pro
d.
■ Wang, Z. Angew. Chem. Int. Ed. 2010, 49, 3215.■ Wang, Z. Tetrahedron 2010, 66, 5671.■ Mulzer, J. Angew. Chem. Int. Ed. 2007, 46, 8074.
Examples for [3+2] Cycloaddition
■ Key features: formal [3+2] cycloaddition of a cyclopropane with a ketone
19
CO2Me
CO2Me
OMe
1. Me3S(O)I, NaH2. OsO4 , NaIO4
O
CO2MeCO2Me
OMe OMe82%
Sc(OTf)3
87%
[3+2]O
CO2MeCO2Me
OMe79%
O
CO2Me
LiCl,wet DMSO,160 “C
Njardasons's and Mulzer'smethods
O
O
O
OO
NH
OH
OH
O
OH
Nicolaou's keyintermediate
(±)-platensimycin
OMe
CO2H
O
O
OMe
O
1a. SOCl21b. TMSCHN21c. TFA
59%
1. MeMgI2. NBS, (BzO)2 ,2. NaOMe3. Ir cat., H24. HIO3 ⋅ DMSO
30%
Mulzer's synthesis of the core
176 177 178 179
180180
181
182
183
184 185
MeO
OO 1. N2=C(CO2Me)2 ,1. Rh2(esp)22. 1 M HCl
73% MeO
OCO2Me
CO2Me 54%
1. Sc(OTf)32. LiCl, wet DMSO, 160 °C3. LiOH, MeOH, H2O4. Barton decarboxylation O
MeO
(±)-bruguierol A
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Gaich-Group SeminarErik Stempel
Nat
. Pro
d.
■ Fürstner, A. Chem. Commun. 2004, 2546.■ Fürstner, A. J. Am Chem. Soc. 2004, 126, 8654.
Organometallic Rearrangements■ (±)-Sesquicarene (Fürstner, 2004)
■ Key feature: Au-catalyzed cycloisomerization
■ (±)-Sabinone (Fürstner, 2004)
20
geranylacetone
O O
MgBr1.2. Ac2O, Et3N, DMAP
94%O
AuCl3(5 mol-%)
95%HO
OAu
AuOAcOAc
H
HO
H
H
O
O
Au
LiAlH4
64%
1. L–Selectride2. PPh3 , DEAD
65%
H
H(±)-sesquicarene
O TMS
BF3 ⋅ Et2O
OH
PtCl2 , 60 °C
OHPt
OH
Pt
H
50%78%
1,2–H shift
O
(±)-sabinone
Pt
(186) 187 188 189
190191192
193 194 195 196
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Gaich-Group SeminarErik Stempel
Nat
. Pro
d.
■ Chen, Y.-K. Org. Lett. 2011, 13, 5724.■ Trost, B. M. J. Am. Chem. Soc. 2011, 133, 4766.
Echinopines A and B (Chen, 2011)
21
NO2
OTBS HTBSO
NO2
Pd(OAc)2 ,PPh3
HTBSO
NO2
73%
H OTBS
H
NO2
H OTBS
H
OH
H
1. oNO2C6H4SO2NHNH22. tBuOK, oxone,2. Na2HPO4
73%
H OTBS
H
O
HO
1. LDA, PhSeBr,1. then H2O22. NaOH, H2O2
47%
H OH
HH
O
TsNHNH2 ,TFA, then HCl
H
HH
1. DMP2. WittigH
HH
H
OH
nBuLi,(CH2O)n
86% 48% 95%
HH
OHC
Ph3PRu
Ph3P
Cp
Cl
CSA, In(OTf)3
32%
HH
HO2C
NaClO2
TMSCHN2 (92%)
94%
echinopine A
OH
Ph3PRu
Ph3P
Cp
Cl
(5 mol-%)
CSA (3 mol-%),In(OTf)3 (5 mol-%),
THF, 60 °C
ORu
ORucyclopropanationO
echinopine B
Trost's one-pot redox isomerization/cyclopropanation
HH
MeO2C
197198 199
200
201202203204
205
206207
209208
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Gaich-Group SeminarErik Stempel
Nat
. Pro
d.
■ Banwell, M.G. Tetrahedron 2010, 66, 7807.■ Banwell, M.G. Tetrahedeon 2011, 67, 8348.
(–)-Connatusin A and B (Banwell, 2011)
■ Key features: oxa-di-π-methane rearrangement for the formation of a cyclopropane ring + reductive ring-opening process.
22
HO O
O steps
OBz
OAcOacetophenone, hν
acetone, 18 °C
BzOO
H
HAcO
HO
H
HAcOH
O
H
HAcO
LiHMDS, MeI
SmI2 , MeOH
81%
HO
H
HAcOH
O
H
HAcO
LiHMDS,Me2N=CH2I
71%
nBu3SnH, AIBN
nBu3SnH, AIBN
80%
98%
NMe2O
O
H
O
H
HAcO
H
O
H
HAcOO
O
OH
OH
H
HHO
O
H
HHOHO
OH
O
X
hν
X X X
Di–π–methane rearrangement (X = CH2) / Oxa-di–π–methane rearrangement (X = O)
(–)-connatusin A
(–)-connatusin B
210 211212 213
214215216
217218219
220 221 222 223
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Gaich-Group SeminarErik Stempel
Nat
. Pro
d.
■ Fukuyama, T. Pure & Appl. Chem 1997, 69, 501.■ Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39, 4073.■ Fukuyama, T. Chem. Lett. 2002, 31,α 122.
(+)-Gelsemine (Fukuyama, 1997)
23
N
CO2MeHMe2SiO N
O O
ClBn
steps
TESO
CHO
CO2MeTESO
NH
I
O
4-iodooxindole,piperidine
CO2MeO
NH
I
O
1. TBAF2. CrO33. PhMe, ∆
72%
HNO
I
OH
HMeO2C
NH
O
MeO2C
O
I
MOMN
O
O
O
PhN
HO
NC
Me
steps
1. oNO2C6H4SeCN,1. PBu32. mCPBA,2. then TEA
MOMN
O
O
O
PhNO
Me
steps
OMe
HNO
(+)-gelsemine
R1
CN
NR3
R2
mCPBAR1
CN
NR3
R2
OPolonovsky-type
elimination
R1
CN
NR3
R2
OH–
R1CN
NR3
R2
HO
– HCN R1 N
R3
R2
O
Tandem Grieco elimination – conversion of α-aminonitriles to amides
224 225 226
227 228
229230231232
233 234 235 236 237
-
Thanks for your attention.
Questions?