samarium(ii) iodide mediated sequential reactions roy bowman january 16, 2004
TRANSCRIPT
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
Curran, D. P.; Totleben, M. J. Journal of the American Chemical Society 1992, 114, 6050-8.
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
Curran, D. P.; Totleben, M. J. Journal of the American Chemical Society 1992, 114, 6050-8.
Radical Cyclization/Carbonyl Addition
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%
Curran, D. P.; Totleben, M. J. Journal of the American Chemical Society 1992, 114, 6050-8.
Radical Cyclization/Carbonyl Addition
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
Radical Cyclization/Carbonyl Addition
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.)
Molander, G. A.; McKie, J. A. Journal of Organic Chemistry 1992, 57, 3132-9.
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
Molander, G. A.; McKie, J. A. Journal of Organic Chemistry 1992, 57, 3132-9.
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
Intramolecular Nucleophilic Acyl Substitution/Intramolecular Barbier Cyclization
• 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
Molander, G. A.; Harris, C. R. Journal of the American Chemical Society 1995, 117, 3705-16.
Intramolecular Nucleophilic Acyl Substitution/Intramolecular Barbier Cyclization
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.)
Molander, G. A.; Harris, C. R. Journal of the American Chemical Society 1995, 117, 3705-16.
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
THF, HMPA 0 °C to rt
SmI2
THF, HMPA 0 °C to rt
SmI2
THF, HMPA 0 °C to rt
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
THF, HMPA 0 °C to rt
O
HO
69%
1.)
2.)
3.)
4.)
5.)
6.)
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956.
Nucleophilic Acyl Substitution/Ketyl Olefin Coupling
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956.
MeO
OO
IO
O
HOSmI2
THF, HMPA 0 °C to rt
67%
MeO
O
O
IO
HOSmI2
THF, HMPA 0 °C to rt
65% (11:1)
CO2Et
O
Ph
I
SmI2
THF, HMPA 0 °C to rt
OOH
Ph
56%
O
O
I
O
Ph
SmI2
THF, HMPA 0 °C to rt
O
HO
OH
Ph
54%
O
Ph
OI
O
SmI2
THF, HMPA 0 °C to rt O
HO
PhOH
54%
O
MeO
OO
I
O
TMS
SmI2
THF, HMPA 0 °C to rt O
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
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1998, 63, 812-816.
• 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
THF/HMPA/60 °CTHF/HMPA/60 °C
THF/HMPA/60 °CTHF/HMPA/60 °C
1.)
2.)
3.)
4.)
5.)
6.)
SmI2
SmI2
SmI2
SmI2
SmI2
SmI2
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1998, 63, 4374-4380.
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
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1998, 63, 4374-4380.
• 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
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1998, 63, 4374-4380.
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
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1998, 63, 4374-4380.
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
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1998, 63, 4374-4380.
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
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956.
• 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
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956.
Domino Epoxide Ring Opening/Ketyl Olefin Coupling Reactions
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
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956.
Domino Epoxide Ring Opening/Ketyl Olefin Coupling Reactions
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)
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956.
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.
Epoxide Fragmentation/Tandem Radical Cyclizations
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
Molander, G. A.; Del Pozo Losada, C. Tetrahedron 1998, 54, 5819-5832.
Epoxide Fragmentation/Tandem Radical Cyclizations
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
Molander, G. A.; Del Pozo Losada, C. Tetrahedron 1998, 54, 5819-5832.
Epoxide Fragmentation/Tandem Radical Cyclizations
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
Molander, G. A.; Del Pozo Losada, C. Tetrahedron 1998, 54, 5819-5832.
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 -
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
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.)
Molander, G. A.; Le Huerou, Y.; Brown, G. A. Journal of Organic Chemistry 2001, 66, 4511-4516.
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.
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 initial Reformatsky reaction
• Selectivity results from highly organized transition state
Molander Gary, A.; Brown Giles, A.; Storch de Gracia, I. Journal of Organic Chemistry 2002, 67, 3459-63.
Reformatsky/Nucleophilic Acyl Substitution
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
Molander Gary, A.; Brown Giles, A.; Storch de Gracia, I. Journal of Organic Chemistry 2002, 67, 3459-63.
Reformatsky/Nucleophilic Acyl Substitution
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
Molander Gary, A.; Brown Giles, A.; Storch de Gracia, I. Journal of Organic Chemistry 2002, 67, 3459-63.
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
Insertion of Isocyanides into Organic Halides Preparation of -Hydroxy Ketones
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.
Insertion of Isocyanides into Organic Halides Preparation of -Hydroxy Ketones
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%
Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. Journal of Organic Chemistry 1993, 58, 1458-65.
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%
Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. Journal of Organic Chemistry 1993, 58, 1458-65.
Insertion of Isocyanides into Organic Halides Preparation of -Hydroxy Ketones
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%
Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. Journal of Organic Chemistry 1993, 58, 1458-65.
Insertion of Isocyanides into Organic Halides Preparation of -Hydroxy Ketones
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%
Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. Journal of Organic Chemistry 1993, 58, 1458-65.
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.
Synthesis of Vicinal Di- and Tri-Carbonyl Compounds
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
Murakami, M.; Masuda, H.; Kawano, T.; Nakamura, H.; Ito, Y. Journal of Organic Chemistry 1991, 56, 1-2.
Synthesis of Vicinal Di- and Tri-Carbonyl Compounds
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%
Murakami, M.; Masuda, H.; Kawano, T.; Nakamura, H.; Ito, Y. Journal of Organic Chemistry 1991, 56, 1-2.
Synthesis of Vicinal Di- and Tri-Carbonyl Compounds
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%
Murakami, M.; Masuda, H.; Kawano, T.; Nakamura, H.; Ito, Y. Journal of Organic Chemistry 1991, 56, 1-2.
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
2 eq. Phenol, 23 °C
73%
N
H
O
O
OH
N
O
CO2Me2.5 eq. SmI2
2 eq. Phenol, 23 °C
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
Cyclizations of Indole Derivatives
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
Gross, S.; Reissig, H.-U. Organic Letters 2003, 5, 4305-4307.
• High degree of diastereoselectivity comes from ordered transition state
Cyclizations of Indole Derivatives
Gross, S.; Reissig, H.-U. Organic Letters 2003, 5, 4305-4307.
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
Synthesis of Phomoidrides
O
O
O
O
OO
O
HOO
Poses several challenges
Synthesis of Phomoidrides
O
O
O
O
OO
O
HOO
Poses several challenges
• Bridgehead olefin contained in a [4.3.1] bicyclic framework
Synthesis of Phomoidrides
O
O
O
O
OO
O
HOO
Poses several challenges
• Bridgehead olefin contained in a [4.3.1] bicyclic framework
• Stereogenic all carbon quaternary center
Synthesis of Phomoidrides
O
O
O
O
OO
O
HOO
Poses several challenges
• Bridgehead olefin contained in a [4.3.1] bicyclic framework
• Stereogenic all carbon quaternary center
• Potentially hydrolytically labile maleic anhydride moiety
Synthesis of Phomoidrides
O
O
O
O
OO
O
HOO
Poses several challenges
• Bridgehead olefin contained in a [4.3.1] bicyclic framework
• Stereogenic all carbon quaternary center
• Potentially hydrolytically labile maleic anhydride moiety
• Two olefinic side chains attached to the phomoidride core at stereogenic centers
Synthesis of Phomoidrides
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