Erick&M.&Carreira& - chemie.uni-konstanz.de€¦ · OBz O O TsO OMOM f. Ac2O, pyr, DMAP; then TBAF...

Erick M. Carreira Gaich Group Seminar Birte Schröder 13.01.14

Prof. Erick M. Carreira

•  Born in Havana, Cuba (1963) •  EducaFon;

–  B. Sc.: University of Illinois at Urbana Champaign (1984) under supervision of Prof. Sco) E. Denmark –  PhD.: Harvard University (1990) under supervision of Prof. David A. Evans –  PostDoc: California InsFtute of Technology under supervision of Prof. Peter Dervan –  Associate professor: California InsFtute of Technology (1996) –  Full professor: California InsFtute of Technology (1997)

ETH Zürich (1998-‐now) •  Former member: JusFn Du Bois, Teshik P. Yoon, Karl Gademann, Nicolai

Cramer, Tobias Ri\er, Corey Stephenson

2


Research Interest: •  Asymmetric synthesis by organometallic chemistry •  Total synthesis •  Medicinal chemistry

3

Methodology

4

O

O

H tBu

hv ∗∗

O

∗∗ ∗∗

O

tBu

Ar

Ar

R

or [M]

Ar CF3

Ar

R

CF3

or

NBn

O N

R2

R1+

cat. MgI2

NBn

O

NR1

R2

XY

+[Ir]

XY

H

R+

X

R R

Zn(OT)2

∗∗

R

X

RR

R

OHX = OR; NH2; NHR; SR; ...

∗∗ R

X

[Ir]

Photochemistry

Cyclopropana2on

Ring expansion

Nitrile oxide cycloaddi2on

Terminal alkyne addi2on

Branched allylic alcohol subs2tu2on

... and many others...

Methodology -‐ Photochemistry

a.  Intramolecular [2+2] cycloaddiFon of 1,2-‐disubsFtuted allenes with enones and enoates

5

-‐ use of opFcally acFve allenes (89-‐92%ee) -‐ asymmetric inducFon through the allene fragment (83-‐100%)

Carreira et al. JACS 1994, 116, 6622-‐6630

O

O

H tBu

hv∗∗

O

∗∗ ∗∗

O

tBu

∗∗

O

∗∗ ∗∗

O

O[O]

1 2 3

a.  Intramolecular [2+2] PhotocycloaddiFon of 1,2-‐DisubsFtuted Allenes with Enones and Enoates

6 Carreira et al. JACS 1994, 116, 6622-‐6630


O

O

tBu

H O

hv

88%OO

O

tBu

H

92% ee92% ee

O

O

tBu

H O

hv

90%OO

O

tBu

H

92% ee92% ee

TIPSOTIPSO

10 11

12 13

O

H tBu

hv

O

O

HO

tBu

O

HO tBu

+

91% ee 92% ee

O

H tBu

hv

O

O

HO

tBu

O

HO tBu

+

78% ee 74% ee

89%

72%

92% ee

89% ee

4 5 6

7 8 9

b. Asymmetric [2+2] PhotocycloaddiFon with an Allenylsilane

7

•  TMS group is used as a removable stereochemical controlling group

Carreira et al. JACS 1997, 119, 2597-‐2605

Scope: •  X = O, NBoc •  5-‐ and 6-‐membered rings •  Coumarin derivates (X= O, S)


O

X

H TMS

hv

O

X

TMS

Me3SiF

H O

X

H

TBAF/HOAc

14 15 16

O

O

H TMS

O

H TMS

H

kf

krO

SiMe3H

O

O

O

TMS H

kc

14 17 18 19

c. Stereospecific 1,5-‐Hydrogen-‐Atom Transfer

8 c. Carreira et al. JACS 1997, 119, 2597-‐2605 d. Tet. Le\. 1997, 38, 5579-‐5582


d. PhotocycloaddiFon/FragmentaFon ReacFon of Dioxinones

O

O

O

OO

tBu

H

Ph

Ph O

O

O

OO

Ph

Ph

tBuH

H

H

O

O

O

OO

Ph

Ph

H

H

tBu

1,4 - diradical

hv 1,5 H shift

20 21 22

O O OMe Me

OR O

OO O

MeMe

R O

O

R

CO2Me

O O OMe Me

OR

OO O

MeMe

O

R

O

O

R

CO2Me

hv

hv

MeOH/K2CO30°C

MeOH/K2CO30°C

23 24 25

26 27 28

a. Trifluoromethyl-‐subsFtuted Cyclopropanes and Cyclopropenes

9 Carreira et al. Angew. Chem. Int. Ed. 2010, 49, 938 Carreira et al. Angew. Chem. Int. Ed. 2010, 49, 4294

Methodology – Cyclopropanes

Reac:vity of Cyclopropenes

CF3

Ph

CF3

PhPd/CaCO3

H2

Me

Me

Pd(OAc)2p-Br-C6H4NO2K2CO3

BuLi,PhCHO

CF3

Ph

OH

Ph CF3

Ph

NO2

H

Ph

CF3

Me

Me

97%

93%78%

90%

Diels-‐Alder reacEon

reducEon

Heck coupling

lithiaEon and trapping

R2

R1

R1

Ar

F3C NH2 HCl

or

+

[Fe(TPP)Cl] (3mol%)DMAP (10 mol%)NaNO2 (1.8 eq.)

NaOAc (20 mol%)H2SO4 (10 mol%)H2O, r.t., 14 h

R1Ar

CF3Rh2(esp)4 (2.5 mol%)NaNO2 (2.4 eq.)

NaOAc (20 mol%)H2SO4 (10 mol%)H2O, r.t., 14 h

CF3

R1 R2

29

30

31

32 33

c. Iron-‐catalyzed CyclopropanaFons

10


Carreira et al. Org. Le\. 2012, 14, 2162-‐2183.

Carreira et al. Org. Le\. 2011, 13, 3080-‐3081.

b. Iron-‐catalyzed PreparaFon of Vinyl-‐and Alkynylcyclopropanes

RFe-catalyst

ClH3N CF3R

R CF3

CF3

R

10 examples52-95 %R = Aryl

35

36

29

37

38

R

COOEt

NH3Cl+

Fe-catalyst

NaNO2/AcOHH2O

COOEtR 10 examples

55-79 %6:1 - 10:1 dr

39 40 41

11

Methodology -‐Cyclopropanes

Carreira et al. Org. Le\. 2012, 14, 1900-‐1901

d. PreparaFon of Trifluoromethyl-‐subsFtuted Aziridines

•  Good yields, good diastereoselecFvity •  cis-‐subsFtuted aziridine is major product •  DeprotecFon w/ CAN gives the free aziridine

N2

CF3+

R

O

NPMB

BF*OEt2 NPMB

CF3R

O

in situ generated

9 examples47-73 %R = Aryl11:1 - 19:1 cis/trans

42 43 44

e. Trifluoroethyl-‐subsFtuted Ketones from Aldehydes and Cyclohexanones

12 Carreira et al. Angew. Chem. Int. Ed. 2011, 50, 9085.


MechanisFc studies:

in situ generaEon F3C NH2 HCl

1) NaNO2, 1 h, 0°C, CH2Cl2/H2O (30:1) N2

CF3

ZrCl4, RCHO-78°c, 45 min, CH2Cl2/H2O (30:1)

O

RCF3

ZrCl4, cyclic ketone-78°c, 45 min, CH2Cl2/H2O (30:1)

O CF3

R

29 42

45

46

N2

CF3

O

HR+

ZrCl4R

CF3

N2

Cl4ZrO H

R= alkylHydride migration

R= arylAryl migration

O

RCF3

O

HCF3

R

N2

CF3O

CF3

R

F3C

42 47 48

49

50 51

Ring expansion of Cyclopropanes by Aldimines

13 Carreira et al. Angew. Chem. Int. Ed. 1999, 38, 3186

Methodology – Ring expansion

NBn

O

NBn

OMg

NR1

R2

INBn

O

N

R2

R1

NBn

OMg

I

INBn

O

IN

R2

R1

A

B C

PotenFal mechanisFc pathways leading to the formaFon of the pyrrolidine ring:

NBn

O N

R2

R1+

cat. MgI2

NBn

O

NR1

R2

68-98%<98:2 d.r. N

Bn

O

NR1

R2

+

R1 = alkyl, allyl, Bu, TsR2 = alkyl, Ar, furyl

52 53 54 55

Methodology – Ring expansion

14

ApplicaFons in Total Synthesis

1) (+)-‐SpirotryprostaFn B

2) Strychnofoline

Carreira et al. Angew. Chem. Int. Ed. 1999, 38, 3186. Carreira et al. J. Am. Chem. Soc. 2005, 127, 11505. Carreira et al. Angew. Chem. Int. Ed. 2003, 42, 694.

NNHN

O

OH

(+)-Spirotryprostatin B

PGN

HO

O NH

O

NPG

R1

R2 R3

+NH

O N

R1

PG+

R2 R3

56 57 58 59 60

NBn

OHO

N

HMeN

HN

H

H

NBn

OBnO

N

H

OTBDPSN

TBDPSONBn

O+

BnO

Strychnofoline

61 62 63 64


Research Interest: •  Asymmetric synthesis by organometallic chemistry •  Total synthesis •  Medicinal chemistry

15

Total Synthesis

16

NBn

OHO

N

HMeN

HN

H

H

Strychnofoline

HO

Me

OAc

CO2MeN

(+)-daphmanidin E

NNHN

O

OH

(+)-Spirotryprostatin B

MeMe

OCl

MeCl

Gomerone C

NO

O

H i-Pr

Me

Me

(-‐) Dendrobine

17

Total Synthesis of Strychnofoline

Carreira et al. Angew. Chem. Int. Ed. 2012, 51, 3436-‐3439

Key features: •  Ring expansion of a spiro-‐[cyclopropan-‐1,3‘-‐

oxindole] and a cyclic imine

SyntheFc Approach:

N

TBDPSONBn

OBnO

HN

HN

+ +

63 64 65

NBn

OHO

N

HMeN

HN

H

H

61

Strychnofoline

NBoc

TBDPSO

Oa. i) PhSeCl, LHMDS, THF, -78°C ii) H2O2, EtOac, rt

NBoc

TBDPSO

O

b. CuBr*SMe2. allyl MgCl, TMSCl

c. i) DiBAl-H ii) HCl (aq.)

NBoc

TBDPSO

d. TMSOTf, NEt3N

TBDPSO66 67 68 63

Strychnofoline

18 Carreira et al. Angew. Chem. Int. Ed. 2012, 51, 3436-‐3439

N

TBDPSO

NBn

O+e. MgI2, THF

BnONBn

OBnO

N

H

f. NMO, OsO4, H2O, dioxane, tBuOH, rt

g. NaIO4, H2O, dioxane, tBuOH, rth. pTsOH, MeOH, CH(OMe)3

ring expansion

OTBDPS

63 64 69

NBn

OBnO

N

H

OTBDPS

CH(OMe)2

i. TBAFj. IBX, DMSOk. tBuOK. Ph3PMeBr

NBn

OBnO

N

H CH(OMe)2NBn

OBnO

N

H CHO

l. 10 % HCl (aq)

707172

Strychnofoline


NBn

O

N

H CHO

m. N-Methyltryptamine, AcOH, tol, refl.

NBn

OBnO

N

HMeN

HN

H

H

n. Na, NH3, THF,tBuOH, -78 to -45°C

73 74

NH

OHO

N

HMeN

HN

H

H

Strychnofoline 61

Total Synthesis of (+)-‐ Daphmanidin E

20

Retrosynthe2c plan

Key features: •  Readily available building block which features two

quaternary centers and the bicyclo[2.2.2]octane skeleton

•  Two Claisen rearrangements •  Late-‐stage cobalt-‐catalyzed Heck coupling


one-‐pot reacFon from diethyl succinate

HO

Me

OAc

CO2MeN

(+)-daphmanidin E

RX

OO

PGO

PGO

PGHN

MeClaisen rearrangement

late-stage alkylHeck coupling

O

OCO2Et

EtO2C

75 76 77

21

(+)-‐ Daphmanidin E


O

OCO2Et

EtO2C

a. 1,3-propandiol, pTsOH, 88%b. KHMDS, 2-(NTf2)*pyr, 87%

OTfCO2Et

EtO2COO

c. C3H5OSitBuPh2, 9-BBN, [Pd2(dba)3]/CHCl3 (2mol%), AsPh3 (16mol%), K3PO4, DMF/THF/H2O, 45%

CO2Et

EtO2COO

OTBDPS

d. BH3*SMe2, THF, rt, then NaBO3*4H2O; DiBAl 72%e. pTsOH (5mol%), acetone; then BzCl, pyr, DMAP, 95%

OTBDPS

O

OBzO

O

TsO

OMOM

f. Ac2O, pyr, DMAP; then TBAF 86%

OTBDPS

O

OBzO

O

OMOM

OTBDPS

O

OBzO

O

OMOM

g. 155°C, nonane, d.r. = 10:1, 86%

HH

Claisen rearrangement

77 78 79

808182

22



L1

PPh2

N

Me MeMe

NEt2

O

OBn

OTBDPS

O

OBzO

O

OMOMHH

h. KHMDS, [18]crown-6, allyl bromide, 83%i. o-xylene, 165°C, 40%

OTBDPS

O

OBzO

OOMOMH

O

OBzO

OOMOMH

AcO

m. CeCl3, oxalic acid, 98%n. Me3S/imidazole; then MOMCl, DiPEA; TBAF, THF, rt 90%o. DMP, 99%

O

OBzH OMOMH

AcO

O

MOMO

p. MeNO2 ,NH4OAc, 75 °C, 77%

O

OBzOMOMH

AcO

MOMO

O2N

Henry condensation

q. ZnMe2, [Cu(OTf)]2, L1, 0°C, d.r =1:5,90% comb. yield

O

OBzOMOMH

AcO

MOMO

BocHN

r. Zn, aq NH4Cl,EtOH, 40°c; Boc2O,EtOH, rt, 85%

Me

Claisen rearrangement

j. 9-BBN, THF, rt; then NaBO3*4 H2O, 60%k. Ac2O, pyr, DMAP, CH2Cl2, rt; TBAF*3H2O, THF, rt, 86%l. 2-NO-C6H4SeCN, PBu3, THF, rt; H2O2, pH 7 buffer, CH2Cl2, rt, 94%

Grieco's protocol

82 83 84

858687

23



stoichiometric

110 mol% catalyst, sunlamp, 60°C, MeCN

catalytic25 mol% catalyst, 1.5 eq iPr2NEt,blue LED, 23°C, MeCN

Key step: Late-‐stage cobalt-‐catalyzed alkyl-‐Heck cycliza2on

s. O3, PPh3, CH2Cl2, -78°C; NaBH(OAc)3, AcOH, THF, rt, 72%t. MsCl, Et3N, CH2Cl2, 0°C; NaI, acetone, 76%u. DBU, PhMe, rt, 92%

O

OBzOMOMH

AcO

MOMO

BocHN

Me

87I

O

OBz

O

AcO

MOMO

BocHN

Me

O

AcO

MOMO

BocHN

Me

Co

SnPh3

N

N

N

Me

MeN

N

Me

Me

O

OBz88 89

90

24



Endgame

O

AcO

MOMO

BocHN

Me

O

OBz

a. K2CO3, MeOH, 0°C, 77%b. PCC, CH2Cl2, rt. 92%c. Bn2NH*CF3CO2H (1:1), PhH, 50°C, 77% after 1 recycle

O

MOMO

BocHN

Me

OBz

OH d. NaCN, AcOH, MnO2, MeOH, rt;

K2CO3, MeOH, 45°C; Ac2O, iPr2NEt, DMAP, CH2Cl2, rt

79% over three steps

O

MOMO

BocHN

Me

OAc

CO2Me

e. CF3CO2H, CH2Cl2, rt; NH4Cl, EtOH, 75°C, 56%

MOMO

Me

OAc

CO2MeNf. Ph2BBr, CH2Cl2,

-25°c, 76%

HO

Me

OAc

CO2MeN

(+)-daphmanidin E

89 91 92

9375

25

Total Synthesis of Gomerone C


Retrosynthe2c plan

Key features: •  Diels-‐Alder cycloaddiFon •  γ-‐SelecFve oxidaFon •  α-ChlorinaFon •  HydrochlorinaFon •  Late-‐stage Conia-‐ene reacFon

MeMe

OClO

MeCl

Conia-ene reaction

hydrochlorination

MeMe

TMS

OCl

OTBS

selective oxidation

α-chlorination

H

MeMe O

Me

O

Diels-Aldercycloaddition

Gomerone C

94 95 96

26

Gomerone C


Me

Me OMe

TBSO

+

a. Me2AlCl (20 mol%)tol/CH2Cl2 (2:1). -15 °C.

then 0°C, 24h, 69%

H

MeMe O

Me

TBSO b. F3CCO2H, CH2Cl2 rt. 2h, 89%

c. 2-methyl-2-ethyl-1,3-dioxolane, TsOH*H2O (25 mol%)ethylene glycol (12 mol%), rt, 45min, 95%

H

MeMe O

Me

O

O

97 98 99 100

d. phosphazene base P2tBu (3.0 equiv.), F9C4SO2F, DMF,-10°C to rt for 2h; then rt, 24h

e. i) nBuLi, THF, -78°C to rt, 40min;ii) BF3*OEt, -78°C, 10miniii) DMF (3.3 equiv.), 60min, 78%f. Pd/C (10mol%), H2, (1atm), EtOAc, 2h, 84%

g. dimethyl-1-diazo-2-oxopropylphosphonate, K2CO3, MeOH, 88%h. nBuLi, TMSCl, -78°C to rt; then 0.1 M aq. HCl, 92%

H

MeMe

TMS

O

102

H

MeMe

O

O

101O

H

27

Gomerone C


H

MeMe

TMS

O

102

i. LDA, THF, -78°C; then PhS(=N-tBu)Cl, 94%

j. TBSOTf, 2,6-lutidine, DCM, 0°Ck. CrO3, 3,5-dimethylpyrazole, DCM, -20°C, 20min

66% over two steps

l. KN(SiMe3)2 (2 eq.) TBSCl (2 eq.), THF, -78°C to rt

m. Bu4NCl3 (2.4 eq.), DCM, -78°C to rt,

51% over two steps

MeMe

TMS

OCl

OTBS n. (MeCN)[(2-biphenyl)di-tert-butylphosphine]Au SbF6, acetone, 45°C, 6h, 65%

MeMe

OCl d. HCl (gas), SnCl4, DCM,

sealed tube, -78°C to rt,5h, 67%

MeMe

OCl

MeClConia-ene reaction

w/ Echavarren's cat.

Gomerone C

O O

104 105 94

MeMe

TMS

OO

28

Total Synthesis of (-‐)-‐Dendrobine


Strategy for the construc2on of the core of (-‐)-‐dendrobine

NO

O

H i-Pr

Me

MeC10-N bond formationreduction lactonization

MeO2C

MeMe

O

NMe

Me

R

Stereoselective protonation

Enamineconjugateaddition

Me

MeO2C

MeMe

OHC 3

O

Cascade sequence

106 107 108

(-‐)-‐Dendrobine


MeTBDPSO

MeO2C OTBS

MeMe

4

112

k. HF*pyrl. PCC, celite

74% over 5 steps

Me

MeO2C

MeMe

OHC 3

O

107

m. BnMeNHn. H2. Pd/C

68%MeO2C

MeMe

O

NH

Me

H

113

h. TEMPO, PhI(OAc)2

i. iPr2NLi, TMSClj. Me3SiCHN2, benzene, MeOH

EtO2C

Me Me

OO Me

Me

a. LiAlH4b. PhCOCl, DMAP, NEt3c. AcOH

d. TBSCl, DMAP, imid.e. HF*pyrf. (COCl)2, Me2SO, NEt3

iPr

OOTBS Li

(CH2)4OTBDPS

g. EtMgBriPr

TBSO

OBz OH OHOTBDPS

4

60% over 6 steps

81%d.r. (anti/syn) = 2.2 : 1

109 110 111

SyntheFc Approach



(-‐) dendrobine

MeO2C

MeMe

O

NH

Me

H

113

o. PHT, DMAP, THF, rt.

63% MeO2C

MeMe

O

N

Me

H

Br

MeO2C

MeMe

O

NH

Me

H

Br

114 115

MeO2C

MeMe

OMe

NMe

116

p. NaBH4, iPrOH

65%

NO

O

H i-Pr

Me

Me

106

Supplementary Slides

32

Daphmanidin ResoluFon via diastereomeric hydrazones

Supplementary Slides

33

Daphmanidin Comins reagent

34

MeMe

TMS

OCl

OTBS n. (MeCN)[(2-biphenyl)di-tert-butylphosphine]Au SbF6, acetone, 45°C, 6h, 65%

MeMe

OClO

MeMe

TMS

OCl

OTBS

[Au]

MeMe

OClO

[Au]

TMS

Gomerone C

Mechanism of Conia-‐ene reacFon:

Erick&M.&Carreira& - chemie.uni-konstanz.de€¦ · OBz O O TsO OMOM f. Ac2O, pyr, DMAP; then TBAF...

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Transcript of Erick&M.&Carreira& - chemie.uni-konstanz.de€¦ · OBz O O TsO OMOM f. Ac2O, pyr, DMAP; then TBAF...