Samarium(II) Iodide Mediated Sequential Reactions Roy Bowman January 16, 2004.

Samarium(II) Iodide MediatedSequential Reactions

Roy Bowman

January 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

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

• Typically generated and utilized in situ

• Most stable as Sm(III)

Sm I2THF(dry)

23 °C, 2 hSmI2

3 Sm 2 CHI3THF(dry)

Sonication, 5 min 3 SmI2 HC CH

SmTHF(dry)

0 °C to 23 °C, 2 hSmI2I I H2C CH2

Samarium(II) Iodide

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

OH

OSmI2, 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 OH5

99%

Reduction of Carbonyl Derivatives BrTHF, rt, 20 min

2

82%

Coupling of Organic Halides

Alkylations by Allyl Halides

O

BrTHF, rt, 20 min

SmI2

OH

71%

SmI2

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

Ability to promote both one and two electron processes

• Radical/Anionic

• Anionic/Radical

• Anionic/Anionic

• Radical/Radical

I SmI2

SmI2 Sm(III)

Cyclization SmI2

Sm(III)

Organosamarium

A

B

Organosamarium

E+

E+

E

E

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

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

• Unclear how carbonyl addition proceeded

• Barbier or Grignard type reaction?

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)

O

H+

R

OH

Samarium Grignard


Formation of Organosamarium

I

O

SmI2

AcetophenoneO

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



I

O

R R

O2.2 SmI2

HMPA/THF

25 °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/THF

25 °C

O

E

E+

Electrophile Product Yield

I2

PhSSPh

O

I

O

SPh

PhSeSePhO

SePh

69%

65%

72%

Electrophile Product Yield

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

R2

R1

MeOD

HO CO2RR''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/THF

25 °C

Me OEt

O O

R1 R2

O HO CO2EtMe MeHO

R2

R1

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)

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

• Facile cyclization was achieved with unactivated ketones

Radical Cyclization/ Nucleophilic Addition

O HO MeMe

SmI2, HMPA

THF, t-BuOH, rt

86% (150:1)

O

THF, t-BuOH, rt

91% (36:1)

HO MeMe

O

THF, t-BuOH, rt

90% (150:1)

HO

H

Me

O

THF, t-BuOH, rt

92% (93:5:2)

HO

H

Me

O

THF, t-BuOH, rt

89% (150:1)

HO

H

Me

O

THF, t-BuOH, rt

85% (2:1:1)

HO

H

Me

O

THF, t-BuOH, rt

88% (17:1)

OH

Me

O

THF, t-BuOH, rt

66% (17:1)

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 % YieldElectrophile Product % Yield

HO MeOH

O

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 Acyl Substitution/Intramolecular Barbier Cyclization

O

OI

2 SmI2O

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)

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

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


• Ability to sequence formation of the organosamarium species 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

OH

90%

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

O

I 2 SmI2 EtO

O

OSm(III)

O

O

SmI2

O

O

Sm(III)

O

OCH2Sm(III)1.) SmI2

2.) H3O+

O

OHCH3

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

• Provides access to bi- and tricyclic furans an pyrans

Nucleophilic Acyl Substitution/Ketyl Olefin Coupling

EtO

O

I

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

O

I

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/Ketyl Olefin Coupling


MeO

OO

IO

O

HOSmI2


67%

MeO

O

O

IO

HOSmI2


65% (11:1)

CO2Et

O

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

-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)

O

O OHOH

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

OOH

HO

85% (6:1)

O

O

HOH

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/Alkenyl Transfer Reactions

R1O O

R2

O R3R4

X

2 SmI2R1O O

O R3R4R2

Sm(III)

NASO

O

R2

R4 R3O

O

R2

R4 R3SmI2

Sm(III)

SmI2Ketyl-Olefin Coupling

O

H

O R4

R3

R2

Sm(III)

Sm(III)

-Elimination or

Protonation

HO

R2

H

OH

R3

R4

O

H

HO R4

R3

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 B

1 Me Me/H H/Me Cl 73 -

2 Me Et/H H/Et Cl 71 <5

3 Me Et/H H/Et I 77 <5

4 t-Bu i-Pr H I 70 23

5 t-Bu H i-Pr I 69 25

6 Me i-Pr H Cl 62 14-23

7 Me H i-Pr Cl 60-70 14-23


Nucleophilic Acyl Transfer/Alkenyl Transfer Reactions

EtO

O

O

BrHO

OH

EtO

O

O

BrHO

OH

OCO2Et

Br

OH OH

O

Br

O

HO

OH

OH

H

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

O

Sm(III)

1.) SmI2

2.) MeOH

HO

HOMe

RMe

SmI2


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

Domino Epoxide Ring Opening/Ketyl Olefin 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 R

Me

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

O

1.) SmI2

2.) MeOH

O

O

Sm(III)

O O

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

Sm(III)

SmI2

MeOH

O OH

SmI2

HOO

Radical

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

OH

n

m

OH

HO

nm

1 2 3H

Entry m n T (°C) Cis/trans Ratio 3

%Yield 2

% Yield 3

1 2 1 0 5/1 - 72

2 2 1 -20 4/1 - 70

3 1 1 0 18/1 - 61

4 1 1 -20 37/1 - 60

5 1 2 0 3/1 43 22

6 1 2 rt 3/1 40 27

7 2 2 0 2/1 67 14

8 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

OHHO OH

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

MeO

O

O

OR O

O

HOR

R=H

R=CO2Et

77% (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/Grob Fragmentation

O

OMs

I

2 SmI2 OSm(III)

OMs

Grob

Fragmentation

O

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

• 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

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

I

OH

MsO83%

NaOMe, MeOH

Reflux, 2 h

88%

O

7.)

8.)

9.)


Reformatsky/Nucleophilic Acyl Substitution

O O

RI

I

O

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.


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 initial Reformatsky reaction

• Selectivity results from highly organized transition state



Entry Substrate Product % Yield

Me

O O

Cl

Br

O

OHO

Me

HO

391

Me

O O

I

I

O

OHO

Me

HO

902

Me

O OI

O

I

O

MeHO

HO

3 76

t-Bu

O O

I

I

O

4OHO

t-Bu

HO

84

t-Bu

O OI

O

I5

O

t-BuHO

HO

76



Entry Substrate Product % Yield

Ph

O O

I

I

O

OHO

Ph

HO

6 70

Ph

O OI

O

I7 63O

PhHO

HO

Et

O O

I

I

O

OHO

Et

HO

8 70 (32:1)

Et

O O

I

I

O

OHO

Et

HO

9 58 (8:1)

O

I

O

O

IOHO

HO

10 85

O O

O

I

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''OSm(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 -Hydroxy Ketones

R1-X2 eq. SmI2

R1 Sm(III)

Xy

NC N

R1

XySm(III) R2 R3

O

R1OH

N

R2 R3

Xy

(-iminoalkyl)samarium(III)

H+

R1OH

O

R2 R3

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.

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

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

• Compatibility with a variety of functional groups under mild conditions


Entry R-X Electrophile Product Yield

Et Br

Et Br

Et Br

Et Br

EtCHO

tBuCHO

O

O

N

Xy

OH

Et

N

Xy

OH

tBu

N

Xy

OH

N

Xy

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

N

Xy

OH

t-Bu Br

O

t-Bu

N

Xy

H

Bn Br

O

Bn

N

Xy

OH

Br

O N

Xy

OH

CH2 Br9

O

CH29

N

Xy

OH

5.)

6.)

7.)

8.)

9.)

99%

99%

37%

74%

81%


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

BnO BrN

Xy

OH99%

O OBr

O O

N

Xy

Et Et

OH

TMSOBr

TMSO

N

Xy

OH

PivOI

PivO

N

Xy

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

BnO

N

Xy

BnO

N

Xy

BnO

N

Xy

BnO

N

Xy

Et

OH

OH

OH

OH

14.)

15.)

16.)

17.)

86%

99%

99%

70%



Entry Imine Method Product Yield

Et

N

Xy

OH Et

OOH

N

Xy

OHO

OH

BnO

N

Xy

Et

OAcBnO

O

Et

OAc

BnO

N

Xy

OH

BnO

OOH

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 BrXy

NC

2 eq. SmI2

THF-HMPA

N

C

Xy

R

SmI2 N

C

Xy

R

SmI2

XyN

CR

SmI2

CN

Xy

XyN

CR

SmI2

CN

Xy

RE

N

Xy

N

Xy

Xy

NC

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.


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

EtCHO

0 °C, 12 h

cyclohexanone

0 °C, 12 h

Entry Alkyl Halide Method Product Yield



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

N

Xy

N

Xy

OHH2SO4, H2O, MeOH

65 °C, 8 hEt

O

O

OH

Et OMe

N

Xy

N

Xy

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 °C

70%

N

O

O

N

2.5 eq. SmI2, HMPA


73%

N

H

O

O

OH

N

O

CO2Me2.5 eq. SmI2


73%

N

H OH

CO2Me

1.)

2.)

3.)

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

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

• The intermediate organosamarium species can be trapped by electrophiles


SmI2 Sm(III) N OSm(III)

N

ON

O

N

OSm(III)HSmI2N

OSm(III)H

Sm(III)

1.) Electrophile

2.) H+N

OHH

E


• High degree of diastereoselectivity comes from ordered transition state



N

CO2Me

O2.5 eq. SmI2

THF, 23 °C

Br

N

CO2Me

O

O

OTBS

O

I2.5 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

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

O

O

SmI2, HMPA

t-BuOH, THF, 0 °C

HO

O

HOO

O

O

H

Paeonilactone B

7 Steps

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

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)

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

Sm(III)O

Me

RO

Me

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

Synthesis of (±) Hypnophilin

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

OOH

O

O

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 cyclopentene forms the triquinane core for Hypnophilin and Coriolin

Synthesis of (±) HypnophilinO

O

O1.3 SmI2

THF/HMPA

0 °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

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

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

Synthesis of Phomoidrides

O

O

O

O

OHOH

O

O

O

O

O

O

O

O

O

O

O

O

OHOH

OO

O

O

O

O

O

O

O

O

OHOHO

O

HOO

HOO

Phomoidride A Phomoidride B

Phomoidride C Phomoidride D

John Wood, Unpublished Results, webpage

• 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


O

O

O

O

OO

O

HOO

Poses several challenges


O

O

O

O

OO

O

HOO


• Bridgehead olefin contained in a [4.3.1] bicyclic framework


O

O

O

O

OO

O

HOO



• Stereogenic all carbon quaternary center


O

O

O

O

OO

O

HOO




• Potentially hydrolytically labile maleic anhydride moiety


O

O

O

O

OO

O

HOO




• Potentially hydrolytically labile maleic anhydride moiety

• Two olefinic side chains attached to the phomoidride core at stereogenic centers


O

O OOEt

O

CO2EtEtO2C

O

O

O

OOEt

O

CO2EtEtO2C

O

OOEt

EtO2C

O

CO2Et

O

OOEt

EtO2C

O

CO2Et

O

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 shown

utility in natural product synthesis

Acknowledgements

Dr. Jeff Johnson

Johnson Group

Samarium(II) Iodide Mediated Sequential Reactions Roy Bowman January 16, 2004.

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