Samarium(II) Iodide Mediated Sequential Reactions Bowman/Lit. seminar.pdf · Sequential Reactions...
Transcript of 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
Curran, D. P.; Totleben, M. J. Journal of the American Chemical Society 1992, 114, 6050-8.
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
Curran, D. P.; Totleben, M. J. Journal of the American Chemical Society 1992, 114, 6050-8.
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%
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
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
Radical Cyclization/Carbonyl Addition
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
THF, t-BuOH, rt88% (17:1)
OH
Me
O
THF, t-BuOH, rt66% (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 % 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
Molander, G. A.; McKie, J. A. Journal of Organic Chemistry 1992, 57, 3132-9.
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.
Intramolecular Nucleophilic AcylSubstitution/Intramolecular Barbier Cyclization
• 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
Molander, G. A.; Harris, C. R. Journal of the American Chemical Society 1995, 117, 3705-16.
Intramolecular Nucleophilic AcylSubstitution/Intramolecular Barbier Cyclization
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.)
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
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
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
OI
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/KetylOlefin Coupling
MeO
OO
IO
O
HOSmI2
THF, HMPA 0 °C to rt
67%
MeO
O
O
IO
HOSmI2
THF, HMPA 0 °C to rt65% (11:1)
CO2EtO
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
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956.
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
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1998, 63, 812-816.
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
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/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
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 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
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 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
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1998, 63, 4374-4380.
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
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
OSm(III)
1.) SmI2
2.) MeOH
HO
HOMe
RMe
SmI2
• Complete selectivity was achieved through chelation of the ketyloxygen and the hydroxyl group
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956.
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
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956.
Domino Epoxide Ring Opening/KetylOlefin Coupling Reactions
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
Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956.
Domino Epoxide Ring Opening/KetylOlefin 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
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.
Epoxide Fragmentation/Tandem Radical Cyclizations
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
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
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
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
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
Molander, G. A.; Del Pozo Losada, C. Tetrahedron 1998, 54, 5819-5832.
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 -
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
IOH
MsO83%
NaOMe, MeOH
Reflux, 2 h88%
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
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
Molander Gary, A.; Brown Giles, A.; Storch de Gracia, I. Journal of Organic Chemistry 2002, 67, 3459-63.
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
Molander Gary, A.; Brown Giles, A.; Storch de Gracia, I. Journal of Organic Chemistry 2002, 67, 3459-63.
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
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''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.
Insertion of Isocyanides into Organic Halides Preparation of α-Hydroxy Ketones
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.
Insertion of Isocyanides into Organic Halides Preparation of α-Hydroxy Ketones
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%
Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. Journal of Organic Chemistry 1993, 58, 1458-65.
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%
Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. Journal of Organic Chemistry 1993, 58, 1458-65.
Insertion of Isocyanides into Organic Halides Preparation of α-Hydroxy Ketones
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%
Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. Journal of Organic Chemistry 1993, 58, 1458-65.
Insertion of Isocyanides into Organic Halides Preparation of α-Hydroxy Ketones
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%
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 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.
Synthesis of Vicinal Di- and Tri-Carbonyl Compounds
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
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
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%
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 °C70%
N
O
O
N
2.5 eq. SmI2, HMPA
2 eq. Phenol, 23 °C73%
N
H
O
O
OH
NO
CO2Me2.5 eq. SmI2
2 eq. Phenol, 23 °C73%
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.
Cyclizations of Indole Derivatives
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
Gross, S.; Reissig, H.-U. Organic Letters 2003, 5, 4305-4307.
Cyclizations of Indole Derivatives
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%
Gross, S.; Reissig, H.-U. Organic Letters 2003, 5, 4305-4307.
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
Synthesis of Phomoidrides
O
OO
O
OO
O
HOO
Poses several challenges
Synthesis of Phomoidrides
O
OO
O
OO
O
HOO
Poses several challenges• Bridgehead olefin contained in a [4.3.1] bicyclic framework
Synthesis of Phomoidrides
O
OO
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
OO
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
OO
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 coreat stereogenic centers
Synthesis of Phomoidrides
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