samarium(ii) iodide mediated sequential reactions bowman/lit. seminar.pdf · sequential reactions...

Samarium(II) Iodide MediatedSequential Reactions

Roy BowmanJanuary 16, 2004

Sequential Reactions

• Multiple bonds formed in a one pot process

• No need to collect and purify intermediates

• Access to elaborate products

• Although conceptually attractive, design of sequential reactions can be overwhelming

• Cationic, anionic, radical, pericyclic, carbenoid, and transition metal catalyzed sequential processes have been realized

Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321-3354.

Samarium(II) Iodide

Sm I2THF(dry)23 °C, 2 h

SmI2

3 Sm 2 CHI3THF(dry)

Sonication, 5 min 3 SmI2 HC CH

SmTHF(dry)

0 °C to 23 °C, 2 hSmI2I I H2C CH2

• Typically generated and utilized in situ

• Most stable as Sm(III)

Totleben, M. J.; Curran, D. P.; Wipf, P. Journal of Organic Chemistry 1992, 57, 1740-4. Concellon, J. M.; Rodriguez-Solla, H.; Bardales, E.; Huerta, M. European Journal of Organic Chemistry 2003, 1775-1778

Samarium(II) Iodide

OH

O SmI2, MeOH

THF, rt, 24 h OH

O

Reduction of Conjugated Double Bonds

OSmI2, t-BuOH

THF, 60 °C, 2 h

98%

95%

Deoxygenation Reactions of Epoxides

Me H

O

5

SmI2, MeOH

THF, rt, 24 h Me OH599%

Reduction of Carbonyl Derivatives BrTHF, rt, 20 min

2

82%

Coupling of Organic Halides

Alkylations by Allyl Halides

OBr

THF, rt, 20 minSmI2

OH

71%

SmI2

Girard, P.; Namy, J. L.; Kagan, H. B. Journal of the American Chemical Society 1980, 102, 2693-8.

Samarium(II) Iodide

Promotes several individual reactions important in synthesis:

- Radical Cyclizations - Ketyl-Olefin Coupling

- Pinacolic Coupling - Barbier Type Reactions

- Aldol Type Reactions - Reformatsky Type Reactions

- Conjugate Additions - Nucleophilic Acyl Substitutions

-Cycloadditions

Samarium(II) Iodide

I SmI2

SmI2 Sm(III)

Cyclization SmI2

Sm(III)

Organosamarium

A

B

Organosamarium

E+

E+

E

E

Ability to promote both one and two electron processes

• Radical/Anionic

• Anionic/Radical

• Anionic/Anionic

• Radical/Radical

Reactivity

Reactivity can be manipulated using:

• Co-solvents: HMPA, TMG, DBU

• Additives: Ni(II), Fe(III)

• Irradiation of the reaction mixture

• Allows for highly selective and efficient sequential reactions to be effective

Molander, G. A.; McKie, J. A. Journal of Organic Chemistry 1992, 57, 3132-9.Cabri, W.; Candiani, I.; Colombo, M.; Franzoi, L.; Bedeschi, A. Tetrahedron Letters 1995, 36, 949-52.

Ogawa, A.; Sumino, Y.; Nanke, T.; Ohya, S.; Sonoda, N.; Hirao, T. Journal of the American Chemical Society 1997, 119, 2745-2746.

Machrouhi, F.; Hamann, B.; Namy, J. L.; Kagan, H. B. Synlett 1996, 633-634.

Radical Cyclization/Carbonyl Addition

I

O

SmI2

O O O

OH

PhPh

O

• Unclear how carbonyl addition proceeded

• Barbier or Grignard type reaction?

Curran, D. P.; Totleben, M. J. Journal of the American Chemical Society 1992, 114, 6050-8.

Formation of Organosamarium

R XO SmI2 H+

R

OH

SmI2 SmI2

R

O Sm(III)

R

OSm(III)

H+

Samarium Barbier

(Ketyl)

R XSmI2

RSmI2

R Sm(III)

OH+

R

OH

Samarium Grignard


Formation of Organosamarium

I

O

SmI2

Acetophenone O

OH

Ph

Sm-Barbier Sm-Grignard

< 20% 89%

Samarium-Barbier Conditions:Addition of O-Allyl-iodobenzene and acetophenone to a THF solution containing Samarium diiodide and HMPA

Samarium-Grignard Conditions:Iodobenzene was added to a solution of SmI2/HMPA after; 5 minutes acetophenone was added


Radical Cyclization/Carbonyl AdditionI

OR R

O2.2 SmI2

HMPA/THF25 °C

O

HO

RR

Ketone % Yield

3-pentanone 69

4-heptanone 81

cyclopentanone 68

cyclohexanone 65

2-methylcyclohexanone 70

4-t-butylcyclohexanone 67

Molander, G. A.; Harring, L. S. Journal of Organic Chemistry 1990, 55, 6171-6.

Radical Cyclization/Carbonyl AdditionI

O 2.2 SmI2

HMPA/THF25 °C

O

EE+

Electrophile Product Yield Electrophile Product Yield

I2

PhSSPh

O

I

O

SPh

PhSeSePhO

SePh

69%

65%

72%

Bu3SnI

PhNCO

(i-PrCO)2O

O

SnBu3

O

O

O

i-Pr

O

NHPh

82%

65%

55%



R'

O O

ORR''

SmI2R'

O O

ORR''

Sm(III)

OO

ORR' R''

H2C

Sm(III)

SmI2

OO

ORR' R''

Sm(III)

Sm(III)

R1 R2

OHO CO2R

R''R'HO

R2R1

MeODHO CO2R

R''R'

D

Molander, G. A.; Kenny, C. Journal of Organic Chemistry 1991, 56, 1439-45.

• Pendent ester activates ketone

•Control of three stereocenters

• Forming radical is trans to ketyl oxygen


2.2 SmI2

HMPA/THF25 °C

Me OEt

O O

R1 R2

O HO CO2EtMe MeHO

R2R1

Entry Ketone % Yield d.r.

1 Acetone 79 31:1

2 3-Pentanone 73 65:1

3 Diisopropyl ketone 32 >200:1

4 Cyclohexanone 58 200:1

5 Cyclopentanone 65 60:1

6 2-Methylcyclohexanone 75 1:1

7 4-t-Butylcyclohexanone 61 10:1

Molander, G. A.; Kenny, C. Journal of Organic Chemistry 1991, 56, 1439-45.

Radical Cyclization/Nucleophilic Addition

R

OSmI2

R

OSm(III) Ketyl-Olefin

Cyclization

O Me

SmI2

O Me Sm(III)E+HO Me E

Sm(III)

Sm(III)

• Facile cyclization was achieved with unactivated ketones

Molander, G. A.; McKie, J. A. Journal of Organic Chemistry 1992, 57, 3132-9.

Radical Cyclization/ Nucleophilic Addition

O HO MeMeSmI2, HMPA

THF, t-BuOH, rt86% (150:1)

O

THF, t-BuOH, rt91% (36:1)

HO MeMe

O

THF, t-BuOH, rt90% (150:1)

HO

H

Me

O

THF, t-BuOH, rt92% (93:5:2)

HO

H

Me

O

THF, t-BuOH, rt89% (150:1)

HO

H

Me

O

THF, t-BuOH, rt85% (2:1:1)

HO

H

Me

O


OH

Me

O


OH

Me

SmI2, HMPA

SmI2, HMPA

SmI2, HMPA

SmI2, HMPA

SmI2, HMPA

SmI2, HMPA

SmI2, HMPA

1.)

2.)

3.)

4.)

5.)

6.)

7.)

8.)


Radical Cyclization/ Nucleophilic Addition

Me

OSmI2, HMPA

THF,t-BuOH, rt

MeHOElectrophile

E

Electrophile Product % Yield Electrophile Product % YieldHO Me

OHO

80

PhCHOHO Me

Ph

OH

Ac2O

Ac2O

AcO Me

HO Me

O

O

83 (3:1)

85

74

(5 eq., rt, 6 h)

(2 eq., 0 °C, 15 min)

(PhS)2

O2

CO2

H2C NMe

Me

HO Me

S

HO Me

HO Me

CO2H

HO Me

OH

Ph

NMe2

77

69 (15:1)

73

65


Intramolecular Nucleophilic AcylSubstitution/Intramolecular Barbier Cyclization

O

OI2 SmI2

O

O

Cl

Sm(III) O

Cl

OSm(III)

2 SmI2

O

O

Sm(III)

Sm(III)

H3O+OH

OH

O Cl

O Sm(III)

O

O Sm(III)

Sm(III)

• Provides access to a variety of bi- and tri-cyclic ring systems

Molander, G. A.; Harris, C. R. Journal of the American Chemical Society 1995, 117, 3705-16.


• Ability to sequence formation of the organosamariumspecies so carbon-carbon bonds may be directed

• Alkyl halides are reduced in the order I > Br > Cl

• Sequences where order is unimportant are performed with diiodides

• Sequenced reactions in which side chain reaction order is significant are performed with alkyl iodide/alkyl chloride substrates



O

O

I

I OH

OH83%

O

OI

I

OH

OH90%

EtO OEt

O O

I I

OH

CO2Et64%

TBSO

CO2Et

Br

BrTBSO OH

84%

O

OI

I

O

OI

I

SmI2, HMPA

THF, 0 °C

SmI2, HMPA

THF, 0 °C

OH

OH

OH

OH

SmI2, HMPA

THF, 0 °C

97%

91%

SmI2

THF, 0 °C

SmI2, HMPA

THF, 0 °C

SmI2, HMPA

THF, 0 °C

1.)

2.)

3.)

4.)

5.)

6.)


Nucleophilic Acyl Substitution/Ketyl Olefin Coupling for Preparation of Oxygen Heterocycles

EtO

O

OI 2 SmI2 EtO

O

OSm(III)

OO

SmI2

OO

Sm(III)

O

OCH2Sm(III)1.) SmI2

2.) H3O+O

OHCH3

• Provides access to bi- and tricyclic furans an pyrans

Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956.

Nucleophilic Acyl Substitution/KetylOlefin Coupling

EtO

OI

OEtO

O

O

EtO

O

O

EtO

O

O

I

I

SmI2

THF, HMPA 0 °C to rt

O

HO

67%

O

SmI2


SmI2


SmI2


OH

83%

O

OH

I O

OH

76 (7.3:1)

67%

EtO

OI

O TMS

SmI2

THF, HMPA 0 °C to rt O

HOTMS

55%

EtO

O

I

OBr

SmI2


O

HO

69%

1.)

2.)

3.)

4.)

5.)

6.)


Nucleophilic Acyl Substitution/KetylOlefin Coupling

MeO

OO

IO

O

HOSmI2


67%

MeO

O

O

IO

HOSmI2

THF, HMPA 0 °C to rt65% (11:1)

CO2EtO

Ph

I

SmI2


OOH

Ph

56%

O

O

I

O

Ph

SmI2


O

HO

OH

Ph

54%

O

Ph

OI

O

SmI2


HO

PhOH

54%

O

MeO

OO

I

O

TMS

SmI2


O

HO

TMS

TMS

68%

7.)

8.)

9.)

10.)

11.)

12.)

TMS


Ketyl-Olefin Coupling/β-Elimination

O

OSmI2

O

H

OSm(III) SmI2

β-Elimination

H3O+

O

OH

H

HO

OH

• Result is net addition of an alkenyl moiety to a carbonyl group

• Complementary to traditional alkylation techniques


Ketyl-Olefin Coupling/β-Elimination

O

O

HO

H

OH

n nn=1

n=3

50% (50:1)

71% (4:1)

OO OH

OH

77% (2.7:1)

O

O

HO

OH

nn n=1 92% (>100:1)

n=2 93% (>100:1)

n=3 74% (>100:1)O

O

HO

OH74% (>100:1)

O

O OH

HO

85% (6:1)

O

O

H OH

OH83% (5:1:1:1)

THF/HMPA/ 23 °C

THF/HMPA/60 °C

THF/HMPA/ 23 °C

THF/HMPA/60 °CTHF/HMPA/60 °C



1.)

2.)

3.)

4.)

5.)

6.)

SmI2

SmI2

SmI2

SmI2

SmI2

SmI2


Nucleophilic Acyl Substitution/AlkenylTransfer Reactions

R1O OR2

O R3R4

X

2 SmI2R1O O

O R3R4R2

Sm(III)

NASO

OR2

R4 R3O

OR2

R4 R3SmI2

Sm(III)

SmI2Ketyl-Olefin Coupling

O

H

O R4R3

R2

Sm(III)

Sm(III)

β-Elimination or

Protonation

HO

R2

H

OH

R3R4

O

H

HO R4R3

R2

+

A B

• Provides cyclic products from acyclic starting materials


Nucleophilic Acyl Transfer/Alkenyl Transfer Reactions

R1O

O

O

X

R3 R2 HO

H

OH

R2R3

O

H

HO

R2

H

R3SmI2

THF, HMPA, rt

A B

Entry R1 R2 R3 X %Yield A %Yield B1 Me Me/H H/Me Cl 73 -2 Me Et/H H/Et Cl 71 <53 Me Et/H H/Et I 77 <54 t-Bu i-Pr H I 70 235 t-Bu H i-Pr I 69 256 Me i-Pr H Cl 62 14-237 Me H i-Pr Cl 60-70 14-23


Nucleophilic Acyl Transfer/AlkenylTransfer Reactions

EtO

O

OBr HO

OH

EtO

O

OBr

HO

OH

OCO2Et

Br

OH OH

OBr

OHO

OH

OHH

OH

74%

69%

76%

80%

SmI2

THF, HMPA, 23 °C

SmI2

SmI2

SmI2

1.)

2.)

3.)

4.)

THF, HMPA, 23 °C

THF, HMPA, 23 °C

THF, HMPA, 23 °C


Epoxide Ring Opening/Ketyl Olefin Coupling

R

O

O

SmI2R

O

O

Sm(III)

R

O OSm(III)

SmI2

MeOH R

O OH

HOO

R

Sm(III)HO

R

OSm(III)

1.) SmI2

2.) MeOH

HO

HOMe

RMe

SmI2

• Complete selectivity was achieved through chelation of the ketyloxygen and the hydroxyl group


Domino Epoxide Ring Opening/KetylOlefin Coupling Reactions

R

O

O

6 SmI2/HMPA

THF, MeOH, 0 °CHO

HOMe

HO

HO

MeMe

MeR R

R

O OH

R

OH OH

1 2 3 4 5

Entry R %Yield 2 + 3(Ratio 2:3)

%Yield 4 %Yield 5 Reaction Time (min)

1 Me 88 (12:1) - - 15

2 Et 86 (10:1) - - 20

3 i-Pr 72 (10:1) - - 20

4 t-Bu 10 (7:1) - 47 60

5 Ph - 16 45 20



R

O

O

6 SmI2/HMPA

THF, MeOH, 0 °C R

O OH

R

OH OH

HO

HO RMe

Me

HO

HO

MeR

R6 7 8 9 10

Entry R %Yield 7+8(ratio 7:8)

%Yield 9 %Yield 10 Time (min)

1 Me 61 (>100:1) - - 10

2 Et 65 (100:1) - - 15

3 i-Pr 66 (50:1) - - 20

4 t-Bu 81 (2:1) - - 30

5 Ph - 53 24 15



R2

O

OR1

6 SmI2/HMPA

THF, MeOH, 0 °C HO

HO

HO

HO

MeMe

R2 R2

R1 R1

11 12 13

Entry R1 R2 T(°C) %Yield 12+13(ratio 12:13)

1 CO2Et Me -78 85 (>50:1)2 Ph Me -78 82 (2.6:1)3 Ph Me 23 °C 79 (1:1.6)4 Ph Me 0 76 (1:1)5 Ph Me -20 78 (1.5:1)


Epoxide Fragmentation/Tandem Radical Cyclizations

O

O1.) SmI2

2.) MeOH

O

O

Sm(III)

O O

Sm(III)Sm(III) Sm(III)

Sm(III)

SmI2

MeOH

O OH

SmI2

HOORadical

Cyclization

HOO

Radical

Cyclization

OHO

1.) SmI2

2.) MeOH

OHOH

HH H

Molander, G. A.; Del Pozo Losada, C. Tetrahedron 1998, 54, 5819-5832.


O

On m

6 SmI2/HMPA

THF/MeOH HO

OHn

m

OHHO

nm

1 2 3H

Entry m n T (°C) Cis/trans Ratio 3

%Yield 2

% Yield 3

1 2 1 0 5/1 - 722 2 1 -20 4/1 - 703 1 1 0 18/1 - 614 1 1 -20 37/1 - 605 1 2 0 3/1 43 226 1 2 rt 3/1 40 277 2 2 0 2/1 67 148 2 2 rt 2/1 56 26



O

PhO

6 SmI2, HMPA

THF, MeOH, 0 °C HO

HO

Ph

OH

H

HO

Ph18% 55% (1.6:1)

O

O HO

OH HO OH

H12% (5:1) 55% (3.6:1)

MeO

O

O

OR O

O

HOR

R=H

R=CO2Et77% (10:1)77% (18:1)

O

TMSO

HO OH

TMS

64% (7:1)

O

OPh

HO OH

Ph

Silica Gel

Ph

HO

62%

1.)

2.)

3.)

4.)

5.)6 SmI2, HMPA

THF, MeOH, 0 °C

6 SmI2, HMPA

THF, MeOH, 0 °C

6 SmI2, HMPA

THF, MeOH, 0 °C

6 SmI2, HMPA

THF, MeOH, 0 °C


Intramolecular Barbier Cyclization/GrobFragmentation

O

OMs

I

2 SmI2 OSm(III)

OMs

Grob

Fragmentation

O

• Stereospecific with regard to the leaving group

•Stereochemistry of the alkoxide plays no role in the stereochemistry of the fragmentation

•Fragmentation proceeds under mild conditions

Molander, G. A.; Le Huerou, Y.; Brown, G. A. Journal of Organic Chemistry 2001, 66, 4511-4516.

Ring Expansion by Grob Fragmentation Mediated by SmI2

O

X

OMs

O

mm

nn

2.5 SmI2, 2% NiI2

THF, rt

Entry X n m Ring Size Yield

1 Cl 2 0 8 -

2 I 1 1 8 69

3 I 1 2 9 42

4 I 2 1 9 86

5 I 2 2 10 51

6 I 2 4 12 -


Ring Expansion by Grob Fragmentation Mediated by SmI2

O

I

OMs

2.5 SmI2, 2% NiI2

THF, rt

O

91%

OI

OMs

2.5 SmI2, 2% NiI2

THF, rt

2.5 SmI2, 2% NiI2

THF, rt

O

92%

O

OMs

IOH

MsO83%

NaOMe, MeOH

Reflux, 2 h88%

O

7.)

8.)

9.)


Reformatsky/Nucleophilic Acyl Substitution

O O

RI

IO

2 SmI2 O

O

RO I

2 SmI2Sm(III) O

O

ROSm(III) Sm(III)

O

O

RSm(III)

Sm(III)

O

H3O+O

HO

RHO

• Provides an efficient route to functionalized 8 and 9 membered carbocycles

Molander Gary, A.; Brown Giles, A.; Storch de Gracia, I. Journal of Organic Chemistry 2002, 67, 3459-63.

Reformatsky/Nucleophilic Acyl Substitution

OR1

OO Sm(III)

R2

H O O

R1

R2

OH

O O

HO

R2

R1

O

OO

R1

R2

H

Sm(III)

A

B

• Diastereoselectivity of sequential process originates in the initialReformatsky reaction

• Selectivity results from highly organized transition state


Reformatsky/Nucleophilic Acyl SubstitutionEntry Substrate Product % Yield

Me

O OCl

BrO

OHOMe

HO

391

Me

O OI

IO

OHOMe

HO

902

Me

O OI

O

I

O

MeHO

HO

3 76

t-Bu

O OI

IO

4OHO

t-Bu

HO

84

t-Bu

O OI

O

I5O

t-BuHO

HO

76


Reformatsky/Nucleophilic Acyl SubstitutionEntry Substrate Product % Yield

Ph

O OI

IO

OHOPh

HO

6 70

Ph

O OI

O

I7 63O

PhHO

HO

Et

O OI

IO

OHOEt

HO

8 70 (32:1)

Et

O OI

IO

OHOEt

HO

9 58 (8:1)

OI

O

OI

OHO

HO

10 85

O O

OI

11 69OHO

HO

I


Transformation of Carbohydrate Derivatives into Cyclopentanols

O

I

R'

R''O ORSmI2 O

R'

R''O ORSmI2 O

R'

R''O OR

Sm(III)

O

R'

R''O

SmI2

O

R'

R''O Sm(III)Sm(III)

Sm(III)

R'

R''O OSmI2Sm(III)

R'

R''O O

R'

CH3

R''O OH H+

Grove, J. J. C.; Holzapfel, C. W.; Williams, D. B. G. Tetrahedron Letters 1996, 37, 5817-5820.

Transformation of Carbohydrate Derivatives into Cyclopentanols

O

I

R''O

R'

ORSmI2 O

R'

R''O SmI2

Me

R'

R''O OH

Entry R R’ R’’ Yield (%)

1 Ac OAc Ac 70

2 Ac OPiv Piv 72

3 Ac OBn Bn 76

4 Ph H Piv 72

5 Ph H Bn 71

Grove, J. J. C.; Holzapfel, C. W.; Williams, D. B. G. Tetrahedron Letters 1996, 37, 5817-5820.

Insertion of Isocyanides into Organic Halides Preparation of α-Hydroxy Ketones

R1-X2 eq. SmI2

R1 Sm(III)

XyNC N

R1

XySm(III) R2 R3

O

R1OH

N

R2 R3

Xy

(α-iminoalkyl)samarium(III)

H+

R1OH

O

R2 R3

• Facile synthesis of α-hydroxy ketones by samarium mediated coupling of organic halides , 2,6-xylyl isocyanide, and carbonyl compounds

• α-Addition of organosamarium to isocyanide forms an (α-iminoalkyl)samariumcomplex which can act as an acyl anion equivalent

• Compatibility with a variety of functional groups under mild conditions

Murakami, M.; Kawano, T.; Ito, Y. Journal of the American Chemical Society 1990, 112, 2437-9.Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. Journal of Organic Chemistry 1993, 58, 1458-65.


Entry R-X Electrophile Product Yield

Et Br

Et Br

Et Br

Et Br

EtCHO

tBuCHO

O

O

NXy

OH

Et

NXy

OHtBu

NXy

OH

NXy

OH

1.)

2.)

3.)

4.)

75%

94%

99%

94%

Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. Journal of Organic Chemistry 1993, 58, 1458-65.


Entry R-X Ketone Product Yield

i-Pr Br

O

i-Pr

NXy

OH

t-Bu Br

O

t-Bu

NXy

H

Bn Br

O

Bn

NXy

OH

Br

O NXy

OH

CH2 Br9

O

CH29

NXy

OH

5.)

6.)

7.)

8.)

9.)

99%

99%

37%

74%

81%


Insertion of Isocyanides into Organic Halides Preparation of α-Hydroxy KetonesEntry R-X Electrophile Product Yield

BnO BrNXy

OH99%

O OBr

O O

NXy

Et Et

OH

TMSOBr

TMSO

NXy

OH

PivOI

PivO

NXy

Et

OH

Et

Et Et

O

Et Et

O

O

O

10.)

11.)

12.)

13.)

97%

99%

73%



Entry R-X Electrophile Product Yield

BnO Cl

BnO Cl

BnO Cl

BnO Cl

EtCHO

O

O

O

BnONXy

BnONXy

BnONXy

BnONXy

Et

OH

OH

OH

OH

14.)

15.)

16.)

17.)

86%

99%

99%

70%



Entry Imine Method Product Yield

Et

NXy

OH Et

OOH

NXy

OHO

OH

BnONXy

Et

OAcBnO

O

Et

OAc

BnONXy

OH

BnOO

OH

1 % H2SO4, MeOH, H2O, 23 °C

1 % H2SO4, MeOH, H2O, 23 °C

0.1% HCl, C6H6, MeOH, H2O, 23 °C

0.1% HCl, C6H6, MeOH, H2O, 23 °C

18.)

19.)

20.)

21.)

70%

81%

81%

71%


Synthesis of Vicinal Di- and Tri-Carbonyl Compounds

R BrXyNC

2 eq. SmI2

THF-HMPA

NC

Xy

RSmI2 N

C

Xy

RSmI2

XyNC

R

SmI2

CN

Xy

XyNC

R

SmI2

CN

Xy

RE

NXy

NXy

XyNC

E+H2SO4

MeOH/H2O65 °C

RE

O

O

Murakami, M.; Masuda, H.; Kawano, T.; Nakamura, H.; Ito, Y. Journal of Organic Chemistry 1991, 56, 1-2.


Entry Alkyl Halide Method Product Yield

Et Br

i-Pr Br

n-Bu Br

Et Br

1.)

2.)

3.)

4.)

EtH

N

N

Xy

Xy

i-PrH

N

N

Xy

Xy

n-Bu

N

N

Xy

Xy

Et

N

N

Xy

Xy

90%

60%

70%

77%

OH

OH

Et

H2O

0 °C, 15 min

H2O

0 °C, 15 min

EtCHO0 °C, 12 h

cyclohexanone

0 °C, 12 h



Entry Alkyl Halide Electrophile Product Yield

6.)

7.)

8.)

Et Br

Et Br

Et Br

EtOAc

EtCO2Me

MeOCO2Me

Et

N

N

Xy

Xy

Et

N

N

Xy

Xy

O

O

Et

Et

N

N

Xy

Xy

O

Me

OMe

83%

79%

63%



Et

NXy

NXy

OH H2SO4, H2O, MeOH

65 °C, 8 hEt

O

O

OH

Et OMe

NXy

NXy

O H2SO4, H2O, MeOH

65 °C, 8 hEt OMe

O

O

ONH2H2N NN

Et CO2Me

75%

71%


Cyclizations of Indole Derivatives

N

H OH2.5 eq. SmI2, HMPA

2 eq. Phenol, 23 °C70%

N

O

O

N

2.5 eq. SmI2, HMPA


N

H

O

O

OH

NO

CO2Me2.5 eq. SmI2


N

H OHCO2Me

1.)

2.)

3.)

• Indole derivatives can act as accepter units for intramolecular coupling of ketyls

• The intermediate organosamarium species can be trapped by electrophiles

Gross, S.; Reissig, H.-U. Organic Letters 2003, 5, 4305-4307.


SmI2 Sm(III) N OSm(III)

NO

NO

NOSm(III)HSmI2

NOSm(III)H

Sm(III)

1.) Electrophile

2.) H+NOH

HE

• High degree of diastereoselectivity comes from ordered transition state



N

CO2Me

O2.5 eq. SmI2

THF, 23 °CBr

N

CO2Me

O

O

OTBS

O

I 2.5 eq. SmI2

THF, 23 °C

N

CO2Me

O

O

2.5 eq. SmI2

THF, 23 °C

N

O

OHHCO2Me

53%

N

O

OHHCO2Me

OTBS

N

O

HOH

MeO2C

4.)

5.)

6.)Cl

76%

65%


Cascade Radical Cyclizations: Synthesis of Paeonilactone B

O

O

SmI2, HMPA

t-BuOH, THF, 0 °C

HO

O

HOO

OO

H

Paeonilactone B

7 Steps

• Initiated by ketyl radical cyclization onto a methylene cyclopropanewith subsequent endo ring opening

Boffey, R. J.; Santagostino, M.; Kilburn, J. D.; Whittingham, W. G. Chemical Communications (Cambridge) 1998, 1875-1876.

Cascade Radical Cyclizations: Synthesis of Paeonilactone B

O

O

H

SmI2

OH

OSm(III)O

O

O

OO

O

Sm(III)

Sm(III)Sm(III)

1.) SmI2

2.) t-BuOHO

HO

63% (10:1)

Sm(III)O

MeRO

Me

H• Stereochemistry set in initial cyclization which proceeds through a chair-like transition state

Boffey, R. J.; Santagostino, M.; Kilburn, J. D.; Whittingham, W. G. Chemical Communications (Cambridge) 1998, 1875-1876.

Synthesis of (±) Hypnophilin

OOH

OO

H

H

(±)-Coriolin

O

O

H

H

(±)-Hypnophilin

OH

OH

O

H

HOH O

O

OO

O

• Radical cyclizations can construct multiple five-membered rings in a controllable fashion

•Tandem radical cyclizations about a cyclopenteneforms the triquinane core for Hypnophilin and Coriolin

Fevig, T. L.; Elliott, R. L.; Curran, D. P. Journal of the American Chemical Society 1988, 110, 5064-7.

Synthesis of (±) HypnophilinO

O

O1.3 SmI2

THF/HMPA0 °C

H

HOH

O

OpTSA

AcetoneH

HOH

O

O

O

O

Sm(III)

H

HOSm(III)

O

O

H

HO

O

OSm(III)

63%

4 Steps

H

HOH

O

O(±)-Hypnophilin

• Product isolated as a 10:1 mixture ofproduct and reduced aldehyde

Fevig, T. L.; Elliott, R. L.; Curran, D. P. Journal of the American Chemical Society 1988, 110, 5064-7.

Synthesis of Phomoidrides

O

OO

O

OHOH

OO

O

OO

O

OO

O

OO

O

OHOH

OO

O

OO

O

OO

O

O

OHOHO

O

HOO

HOO

Phomoidride A Phomoidride B

Phomoidride C Phomoidride D

• A and B isolated in 1995 at Pfizer• Later the two related congeners,C and D, were isolated and found

to be epimers of A and B

John Wood, Unpublished Results, webpage


O

OO

O

OO

O

HOO

Poses several challenges


O

OO

O

OO

O

HOO

Poses several challenges• Bridgehead olefin contained in a [4.3.1] bicyclic framework


O

OO

O

OO

O

HOO


• Stereogenic all carbon quaternary center


O

OO

O

OO

O

HOO



• Potentially hydrolytically labile maleic anhydride moiety


O

OO

O

OO

O

HOO



• Potentially hydrolytically labile maleic anhydride moiety

• Two olefinic side chains attached to the phomoidride coreat stereogenic centers


O

O OOEt

O

CO2EtEtO2C

OO

O

OOEt

O

CO2EtEtO2C

O

OOEt

EtO2C

O

CO2Et

O

OOEt

EtO2C

O

CO2EtO

OO

OEt

OO

O

EtO2CCO2Et

SmI2

THF

97%

Br

1.) SmI2

2.) H+

• Efficient method for construction of the isotwistane core

John Wood, Unpublished Results, Webpage

Summary

• Mild conditions, tolerant to functionality

• Reactivity can be manipulated allowing each step in the sequence to be tuned

• Capable of driving sequential reactions

• Highly diastereoselective resulting from highly organized transition states

• Sequential radical cyclization mediated by SmI2 have shownutility in natural product synthesis

Acknowledgements

Dr. Jeff Johnson

Johnson Group

samarium(ii) iodide mediated sequential reactions bowman/lit. seminar.pdf · sequential reactions...

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