cyclopropanes in total synthesis - uni-konstanz.de · 2017. 3. 24. · julia–bruylants...

Gaich-Group Seminar

Erik Stempel22.01.2013

Cyclopropanes in Total Synthesis

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


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


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

■ FREUND–GUSTAVSON Cyclopropane Synthesis

■ CIAMICIAN-DENNSTEDT Cyclopropanation

■ SIMMONS–SMITH Cyclopropanation


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


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

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

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


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


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


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


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

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


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


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


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


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


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


80%NBn

BnO O

N

H

TBDPSO

O O

NBn

BnO O

N

HO


62%

NH

HO O

N

HMeN

H

HN


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


80%NBn

BnO O

N

H

TBDPSO

O O

NBn

BnO O

N

HO


62%

NH

HO O

N

HMeN

H

HN


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


80%NBn

BnO O

N

H

TBDPSO

O O

NBn

BnO O

N

HO


62%

NH

HO O

N

HMeN

H

HN


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


80%NBn

BnO O

N

H

TBDPSO

O O

NBn

BnO O

N

HO


62%

NH

HO O

N

HMeN

H

HN


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


80%NBn

BnO O

N

H

TBDPSO

O O

NBn

BnO O

N

HO


62%

NH

HO O

N

HMeN

H

HN


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


80%NBn

BnO O

N

H

TBDPSO

O O

NBn

BnO O

N

HO


62%

NH

HO O

N

HMeN

H

HN


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


80%NBn

BnO O

N

H

TBDPSO

O O

NBn

BnO O

N

HO


62%

NH

HO O

N

HMeN

H

HN


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


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


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


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


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


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.

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cyclopropanes in total synthesis - uni-konstanz.de · 2017. 3. 24. · julia–bruylants...

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