AC SamariumIodide

Samarium(II) Iodide in Organic Synthesis
Aroop Chandra January 10th, 2013
Samarium
! Derived from Samarskite mineral in 1879 ! Atomic weight 150.36, atomic number 62, mp 1074 C, bp 1794 C ! 21 Isotopes of Sm reported so far
The Reagent and the Effect of Additives

! Preparation of samarium iodide
Kagan's method using 1,2-diidoethane 3 Sm 2 SmI3 + + 3 ICH2CH2I Sm 2 SmI3 3 SmI2
Girard, P.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693.
3 CH2=CH2
Sm
Imamoto's method using iodine 3 Sm 2 SmI3 + + 3 I2 Sm 2 SmI3 3 SmI2

Imamoto, T.; Ono, M. Chem. Lett. 1987, 501.
Sm
Concellon's method utilizing various oxidants and sonication 3 Sm + oxidants

sonication THF, 5 min
oxidants (CHI3, CH2I2, I2)
Concellon, J. M.; Bardales. E.; Huerta, M. Eur. J. Org. Chem. 2003, 1775.
SmI2
Mechanism of SmI2-Mediated Reactions

Radicals and anions from organohalides
[R-SmIII] SmI2 SmI2
H+
R-H
R-X
(X = Cl, Br, I)
[R ]
R-H
R-R
Reduction of halides: iodides > bromides > chloride

R R-X SmI2, THF rt R-H C12H25 C12H25 C12H25

a
X I Br Cl
time 6h 48 h 48 ha
yield (%) 95 82 no rxn
reaction carried out at 60 C
Inanga, J.; Ishikawa, M. Chem. Lett. 1987, 102, 1485.

R R-X SmI2, THF rt R-H C12H25 C12H25 C12H25

a
X I Br Cl
time 6h 48 h 48 ha
yield (%) 95 82 no rxn
! Effect of Lewis bases on the reduction of alkyl halides

HMPA signicantly increases the rate of reduction
R R-X SmI2, THF HMPA, rt R-H C10H21 C10H21 C10H21

a
X I Br Cl
time 5 min 10 min 8 ha
yield (%) 96 97 94
Inanga, J.; Ishikawa, M. Chem. Lett. 1987, 102, 1485.

Alternatives to HMPA
O Me N N Me Me N Me NH N Me Me
O MeO P OMe MeO N N
DMPU
TMG
TMP
DBU
! The basic cosolvents enhances the reducing ability of SmI2 in two ways:
1. Basic cosolvents dissociate SmI2 aggregates in THF 2. Basic cosolvents may perturb the electron-donating orbital of Sm(II) and raise its energy, thus increasing the Sm(II)/Sm(III) reduction potential
! A relatively large excess of these Lewis basic cosolvents are required as compared to HMPA ! None of these basic cosolvents has as high an afnity of SmI2 as HMPA

R-X
SmI2 HMPA, THF
[R ]
SmI2
[R-SmIII]
H+
R-H
(RX = primary, secondary, and tertiary halides)
Curran's rate data for the reduction of alkyl radicals to the corresponding anions
faster
primary alkyl radical SmI2 HMPA
primary alkylsamarium
k = 106 M-1S-1
secondary alkyl radical
secondary alkylsamarium
k = 105 M-1S-1
tertiary alkyl radical
tertiary alkylsamarium
k = 104 M-1S-1
slower
Curran, D. P.; Fevig, T. L.; Jasperse, C. P. Synlett. 1992, 943.

Ketyl radical anions from carbonyl groups
+
O
SmI2
R1 R2
step 1
R1
O R2
SmIIII2
step 2
R1 R2
SmIII O O III Sm
R2 R1
HO
OH R2 R2 R1
step 3
R1

+
O
SmI2
R1 R2
step 1
R1
O R2
SmIIII2
step 2
R1 R2
SmIII O O III Sm
R2 R1
HO
OH R2 R2 R1
step 3
R1
SmI2
step 4
R1 SmIII R2
SmIII O O III Sm
R2 SmIII R1
protonation
R1
OH R2

! Effect of proton donors (H2O and alcohols) in carbonyl reduction

+
O
SmI2
R1 R2
step 1
R1
O R2
SmIIII2
step 2
R1 R2
SmIII O O III Sm
R2 R1
proton donors
R1
OH R2
pinacol coupling
HO R1
OH R2 R2 R1
SmI2
step 4
R1 SmIII R2
SmIII O O III Sm
R2 SmIII R1
protonation
R1
OH R2

! Effect of Lewis basic cosolvents (HMPA) in carbonyl reduction

+
O
SmI2
R1 R2
step 1
R1
O R2
SmIIII2
step 2
R1 R2
SmIII O O III Sm
HO R2 R1
OH R2 R2 R1
step 3
R1
SmI2
step 4
R1 SmIII R2
SmIII O O III Sm
R2 SmIII R1
protonation
R1
OH R2
! Addition of HMPA increases the rate of reduction of dialkylketones by 2 order of magnitude

! The role of proximal Lewis basic functional groups in carbonyl reduction
OH
O Me
SmI2, THF MeOH, 0 C (95% yield)

SmIII
OH H O O H Me SmIII
OH Me
protonation
single diastereomer
Keck, G. E.; Wager, C. A. Org. Lett. 2000, 2, 2307.

! The role of proximal Lewis basic functional groups in carbonyl reduction
OH
O Me
SmI2, THF MeOH, 0 C (95% yield)

SmIII
OH H O O H Me SmIII
OH Me
protonation
single diastereomer
Keck, G. E.; Wager, C. A. Org. Lett. 2000, 2, 2307.
O Me
SmI2, THF
Et OEt
Me O
Et OEt
steps
Me
Me
OH CO2Et Et
-78 C, 10 min (51% yield)
IIISm
d. r. 200:1
Molander, G. A.; Kenny, C. J. Am. Chem. Soc. 1989, 111, 8236.
Carbon-Carbon Bond-forming Reactions Using SmI2
! Pinacol Coupling ! Carbonyl-alkene coupling ! Radical alkene/alkyne coupling ! Barbier and grignard reaction ! Reformatsky reaction ! Aldol-type reaction ! Fragmentation reaction ! Sequential carbon-carbon bond formation (cascade reaction) ! Modication of biomolecules

! Pinacol Coupling
Mechanistic Scenarios
SmI2
R1
SmI2
R1
R2
Path B
R2 SmI2
O R1 R2
SmI2
R1
SmI2 R2
Path A
R1 R2
SmI2 R1 O R2 SmI2
H+
R1 R2
H R1 O R2 H
ketone Path C
R1 O R1 R2 R2 O O SmI2 R1 R2
pinacol product
SmI2
Lebrun, A, Kagan, H. B. Tetrahedron Lett. 1993, 34, 2311.

! Intermolecular pinacol coupling
Asymmetric synthesis of hydrobenzoins
O (OC)3Cr H R2 R1
R1 OH
R2
R1 OH
R2
1. SmI2, THF 2. I2, CH2Cl2 (92% yield)

R2 R1 OH
+
R2 R1 OH
threo
(95 : 5)
erythro
(OC)3Cr R2
Sm O H R1 O H R1
Cr(CO)3 R2
Collin, J.; Machrouhi, F.; Nief, F. Tetrahedron. Lett. 1999, 40, 3161.

! Intramolecular pinacol coupling
Synthesis of carbocyclic monosaccharide (+)-caryose
OBn BnO O Me O
SmI2 THF, t-BuOH (64% yield)
BnO
BnO BnO BnO
O Sm(III) O H Me
OBn BnO BnO OH Me OH
OH
steps
Me Me HO CHO HO Me OH
d.r. > 23:1
(+)-caryose
Adinol. M.; Barone, G.; Iadonisi, L.; Manna, R. Tetrahedron. 1997, 53, 11767.

! Intramolecular Pinacol Coupling
Applications to complex natural products
O Me
Me O
O Me
OH Me
O Me OH Me O
Me
SmI2 THF, t-BuOH

H Me OH
steps
Me
H Me O
OH Me
-78 C (95% yield)
Me
H Me OH
OAc
single diastereomer
forskolin
Anies, C.; Pancrazi, A; Lallemand, J. -Y.; Prange, T. Bull. Soc. Chim. Fr. 1997, 134, 203.

! Intramolecular Pinacol Coupling
Applications to complex natural products
O Me
Me O
O Me
OH Me
O Me OH Me O
Me
SmI2 THF, t-BuOH

H Me OH
steps
Me
H Me O
OH Me
-78 C (95% yield)
Me
H Me OH
OAc
single diastereomer
forskolin
Anies, C.; Pancrazi, A; Lallemand, J. -Y.; Prange, T. Bull. Soc. Chim. Fr. 1997, 134, 203.
HO Me Me
Me
OMOM H
HO
Me
OMOM H
HO
Me
SmI2
H O OHC MOMO H OMOM Me
steps
Me H Me OH HO H
OH H
THF, HMPA -78 C (54% yield)
Me Me OH HO
H OMOM Me
H HO OH Me
MOMO
grayanotoxin III
Kan, T.; Hosokawa, S.; Nara, S.; Okisawa, M.; Ito, S.; Matsuda, F.; Shirahama, H. J. Org. Chem. 1994, 59, 5532.

! Carbonyl-alkene coupling
Traditional mechanism
O R X
SmI2
R
SmIII Y X Y = electron withdrawing group R
SmIII
X = alkyl, aryl, H
SmI2
OH R Y
H+
R
SmIII SmIII Y
! Intramolecular carbonyl-alkene couplings display a greater degree of tolerance in alkene components

! Intermolecular carbonyl-alkene coupling
O OSmIII O
O O OMe
EtO
SmI2 THF, i-PrOH (82% yield)
SmIIIO
Fukuzawa, S.; Nakanishi, T.; Fujinami, T.; Sakai, S. Chem. Commun. 1986, 624.

! Intermolecular carbonyl-alkene coupling
O OSmIII O
O O OMe
EtO
SmI2 THF, i-PrOH (82% yield)
SmIIIO
Fukuzawa, S.; Nakanishi, T.; Fujinami, T.; Sakai, S. Chem. Commun. 1986, 624.
Matsuda's asymmetric synthesis of !-lactone
OH Ph Me O
SmI2 THF, MeOH (74% yield)

Ph
HO
SmIII OO Ph
OH
Me
Me
O Me Me OEt O
d.r. > 99:1

Kawatsura, M.; Matsuda, F, Shrihama, H. J. Org. Chem. 1994, 59, 6900.

! Intramolecular carbonyl-alkene coupling
Applications in complex natural product synthesis
H
D
Ph O
CO2Et Me
SmI2 THF, MeOH (84% yield)
Ph O
H
D
H O
E
O O Me
d.r. > 20:1
HO Me H O
+Na-O
3SO
H Me O H H O H O H H O H Me
D
+Na-O
3SO
H H H O
E
H H H H O
O Me H OH
yessotoxin
O H Me
Me
Suzuki, K.; Nakata, T. Org. Lett. 2002, 4, 3943.

! Intramolecular carbonyl-alkene Coupling
Applications in complex natural product synthesis
H Me O
SmI2, LiBr
O Me H O O H
H O
Me O Me H SmIII O
THF, t-BuOH -78 C (54% yield)
H Me HO Me O O OH
steps
Me HO Me O O OAc CHO
maoecrystal Z single diastereomer
Cha, J. Y.; Yeoman, J. T. S.; Reisman, S. E. J. Am. Chem. Soc. 2011, 133, 14964.

! Carbonyl-arene coupling
Synthesis of highly functionalized benzannulated indolizidines
CO2Me
CO2Me
SmI2 (2 eq)
N O O Me
Me N O
OSmIII
THF, HMPA -78 C (85% yield)
SmIIIO
OMe H Me N OSmIII CO2Me H Me OH N O
Br
Gross, S.; Reissig, H. -U. Org. Lett. 2003, 5, 4305.

! Radical alkene-alkyne additions ! The addition of sp2 and sp3 carbon-centered radicals to unsaturated carbon-carbon bonds ! Halides and sulfones are the most common functional groups used as precursors to radicals ! Intermolcecular variant of this reaction has found only limited applications in organic synthesis
Traditional mechanism
kred
R-SmI2
reduction SmI2
R
X = halide, sulfone R = alkyl, alkene, aryl
radical cyclization
kcyc
R' R'-SmI2
! For successful ring closure, the unimolecular rate constant for cyclization (kcyc) should be sufciently
higher than the bimolecular rate constant for the second reduction step (kred[SmI2])

! Intramolecular radical-additions to alkene
Curran's synthesis of BCD ring-system of penitrem D
H NC I Me
H H Me
SmI2 acetone, HMPA
NC
reduction SmI2
NC H
SmI2
Me
-78 C (40% yield)
Me H
B A
Me O
F
Me H NC H
H
G
Me OH Me
C D
H
E
Me
H
OH
I
OH Me
N H
Me
penitrem D
Rivkin, A.; Nagashima, T.; Curran, D. P. J. Org. Chem. 2004, 69, 3719.

! Intramolecular radical additions to alkene
I Me
SmI2
O
Me Me n-BuO O
H2CrO4 (70% yield)

O O
Me Me
n-BuO
THF, HMPA rt, 2 h
Fukuzawa, S.; Tsuchimoto, T. Synlett. 1993, 803.

! Intramolecular radical additions to alkene
I Me
SmI2
O
Me Me n-BuO O
H2CrO4 (70% yield)

O O
Me Me
n-BuO
THF, HMPA rt, 2 h
Fukuzawa, S.; Tsuchimoto, T. Synlett. 1993, 803.
Highly functionalized cyclopentanes from sugar derived substrate

I HO CO2t-Bu
SmI2 HMPA, MeOH THF, -78 C (91% yield)
HO O O CO2t-Bu H Me
HO CO2t-Bu
O O Me Me
Me
Me
Me
d.r. 78:1
Salari, B. S. F.; Biboutou, R. K.; Bennett, S. M. Tetrahedron. 2000, 56, 6385.

! Intramolecular radical additions to alkyne
OBn Br N
OBn
SmI2, HMPA THF, 0 C (86% yield)

N
steps
N Me
OH
OH
oxirine
Aoyagi, Y.; Inariyama, T.; Arai, Y.; Tsuchida, S.; Matsuda, Y.; Kobayashi, H.; Ohta, A. Tetrahedron. 1994, 50, 13575.

! Intramolecular radical additions to alkyne
OBn Br N
OBn

N
steps
N Me
OH
OH
oxirine
Aoyagi, Y.; Inariyama, T.; Arai, Y.; Tsuchida, S.; Matsuda, Y.; Kobayashi, H.; Ohta, A. Tetrahedron. 1994, 50, 13575.
H N O Br Ph

N O
steps
Ph N
pyrrolam A
Aoyagi, Y.; Manabe, T.; Arai, Y.; Yuhara, T.; Ohta, A. Tetrahedron. 1996, 52, 869.

! Barbier and grignard reactions
alkyl halide + carbonyl compounds
add
SmI2
Barbier reaction
OH
from alkyl halides
R1
R3 R2
from carbonyl compounds
Barbier conditions should be considered for:
! allylic and benzyl halides ! alkyl halides that lead to unstable organosamariums ! alkyl halides that lead to organosamariums that can react with themselves

! Barbier and grignard reactions
alkyl halide + carbonyl compounds
alkyl halide
add
SmI2
add Grignard reaction

then carbonyl compounds
Barbier reaction
OH
from alkyl halides
R1
R3 R2
from carbonyl compounds
Barbier conditions should be considered for:
! allylic and benzyl halides ! alkyl halides that lead to unstable organosamariums ! alkyl halides that lead to organosamariums that can react with themselves

! Intermolecular Barbier and grignard reactions
Alkoxymethylation of hindered ketones
Me Me Me
SmI2 (2.0 eq)

O Me Me H Me Ph O Cl Me
Me
O SmIII O Ph H Me Me
OH
THF, rt (92% yield)
Me Me
OBn
White, J. D.; Somers, T. C. J. Am. Chem. Soc. 1987, 109, 4424.

! Intermolecular Barbier and grignard reactions
Alkoxymethylation of hindered ketones
Me Me Me
SmI2 (2.0 eq)

O Me Me H Me Ph O Cl Me
Me
O SmIII O Ph H Me Me
OH
THF, rt (92% yield)
Me Me
OBn
White, J. D.; Somers, T. C. J. Am. Chem. Soc. 1987, 109, 4424.
TBDMS O N Boc O
TBDMS
SmI2 (2.0 eq) THF, rt (58% yield)
O N OH Boc
Zheng, X.; Huang, P. -Q. Org. Lett. 2005, 7, 553.

! Intramolecular Barbier reactions
Synthesis of highly functionalized cyclopentanes
O R1 I X = OR, NR2 R1, R2 = alkyl, H Molander, G. A.; Etter, J. B.; Zinke, P. W. J. Am. Chem. Soc. 1987, 109, 453. O X
SmI2 THF, -78 C
SmIII
SmIII R1 O
H R1 O
R1
OH
O X R2
R2
R2
R2

Synthesis of highly functionalized cyclopentanes
O R1 I X = OR, NR2 R1, R2 = alkyl, H Molander, G. A.; Etter, J. B.; Zinke, P. W. J. Am. Chem. Soc. 1987, 109, 453. O X
SmI2 THF, -78 C
SmIII
SmIII R1 O
H R1 O
R1
OH
O X R2
R2
R2
R2
Br O
H O H Br
SmI2 THF, HMPA rt (68% yield)

HO
HH OH
HH
Lannoye, G.; Sambasivarao, K.; Wehrli, S.; Cook, J. M. J. Org. Chem. 1998, 53, 2327.

Organosamarium additions to esters
O I Cl OEt O
SmI2 THF, 0 C (79% yield)
Ph
I2Sm Cl
Ph
OEt
Ph
O Cl
SmI2
Ph O Ph SmI2
OH
Molander, G. A.; Mckie, J. A. J. Org. Chem. 1993, 58, 7216.

Organosamarium additions to esters
O I Cl OEt O
Ph
I2Sm Cl
Ph
OEt
Ph
O Cl
SmI2
Ph O Ph SmI2
OH
Molander, G. A.; Mckie, J. A. J. Org. Chem. 1993, 58, 7216.
Organosamarium additions to amides

O O N Bn O t-Bu
SmI2 (2 eq) THF, HMPA -78 C to rt

Cl O
O N
OH t-Bu
(95% yield)
Bn Fadel, A. Tetrahedron: Asymmetry. 1994, 5, 531.

Synthesis of larger rings
OBn Cl OBn OH HO Me H
HO Me Me MOMO H
OHC MOMO
OH
Me
vinigrol
Kito, M.; Sakai, T.; Shirahama, M.; Matsuda, F. Synlett. 1997, 219.

Synthesis of larger rings
OBn Cl OBn OH HO Me H
HO Me Me MOMO H
OHC MOMO
OH
Me
vinigrol
Kito, M.; Sakai, T.; Shirahama, M.; Matsuda, F. Synlett. 1997, 219.
Me Me Me H O H Br
Me Me CHO OMe
Me Me
Me Me
Me Me Me H O H
Me Me OH O
SmI2 THF, rt (60% yield)
Me
H O H OH OMe
TBSO Me O TBS OMe
TBSO Me O TBS OMe
HO Me HO Me O
Me
Me
Kendomycin
Lowe, J. T.; Panek, J. S. Org Lett. 2008, 10, 3813.

! Reformatsky and aldol-type reactions
aldol reaction X = OR, SR, NR2

O O R1 R3 X R2 OSmIII R1 R3 R2 O R4 R5 R1 R2 R3 OH
SmI2
R4 R5
R1 = alkyl, aryl, H, OR, NR2 X = heteroatom substituents
X = halide Reformatsky reaction
! Samarium enolate is exploited as nucleophiles ! Alkylation of Sm(III) enolates with alkyl halides is precedented

! Reformatsky reaction
O Br N Me Me
O O O Me Me Me H
SmI2 THF, -78 C (87% yield)
t-Bu
SmIII O O H N O
OH Me Me Me Me
O N
O O
Me Me
Me
single diastereomer
Fukuzawa, S.; Matsuzawa, H.; Yoshimitsu, S. -I. J. Org. Chem. 2000, 65, 1702.

O Br N Me Me
O O O Me Me Me H
t-Bu
SmIII O O H N O
OH Me Me Me Me
O N
O O
Me Me
Me
single diastereomer
Fukuzawa, S.; Matsuzawa, H.; Yoshimitsu, S. -I. J. Org. Chem. 2000, 65, 1702.
F Ph
F CO2Et CH2O

Ph
OH
CO2Et NHBoc
NHBoc
single regioisomer
Otaka, A.; Watanabe, J.; Yukimasa, A.; Sasaki, Y.; Watanabe, H.; Oishi, S.; Fuiji, N. J. Org. Chem. 2004, 69, 1634.

Double Reformatsky reaction, dimerization
Me TBDPSO TBDPSO Me Me O OMe O O n-Bu O Me H Me Me Br Me OTBS O Me Me O MeO Me Me HO O TBSO HO Me O OH Me Me H Me Me OTBDPS O Me OTBS O OH n-Bu O

O n-Bu
O OMe O
O OH O O n-Bu
Me H Me Me
acutiphycin
Moslin, R. M.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 15106.

Modied approach to acutiphycin
TBDPSO
Me OTES n-Bu O Me TESO CHO
TBDPSO
Me OTES O Me
O O
Me H Me Me Br

O
O TESO n-Bu
Me H Me HOMe
HO
Me O OH Me
steps
O OH O O n-Bu
Me H Me Me
acutiphycin

Intramolecular variant
O Br O
SmI2
O Ph O Me
Ph
O Me O
IIISm
O OH Ph Me
THF, -78 C (95% yield)
single diastereomer
Molander, G. A.; Etter, J. B.; Harring, L. S. J. Am. Chem. Soc. 1991, 113, 8036.

! Aldol-type reactions
NHBz MeO2C MeO2C N OTBDMS O OMe OHC OTBDMS N N N
OTBDMS SPh
TBDPSO
TBDPSO
OSmIII
NHBz N N O HO H O MeO2C OTBDMS OTBDPS OMe O OTBDMS N N
d. r. = 1:1

! Elimination reaction
Danishefsky's total synthesis of taxol
O O Me Me
Me Me
OTES
I2Sm O
SmI2, Ac2O
O
O Me
Me Me Me
OTES
!-elimination
O
THF, -78 C
H OH OBzOAc
H OH OBzOAc
I2Sm O AcO Me Me
Me Me
OTES Me O
O Me
Me Me
OTES Ph O BzHN OH O Me
AcO
O Me Me Me
OH
H OH OBzOAc
H OH OBzOAc
H OH OBzOAc
taxol
Masters, J. L.; Link, J. T.; Snyder, L. B.; Young, W. B.; Danishefsky, S. J. Angew. Chem. Int. Ed. 1995, 34, 1723. Danishefsky, S. J.; Masters, J. J.; Young, W. B.; Link, J. T.; Snyder, L. B.; Magee, T. B.; Jung, D. K.; Isaacs, R. C. A.; Bornmann. W. G.; Alaimo, C. A. J. Am. Chem. Soc. 1996, 118, 2843.
Sequential Carbon-Carbon Bond Formation Reactions Using SmI2

! Sequences initiated by radical cyclizations
Radical-radical sequence
I2SmO Me
Me
SmI2, HMPA t-BuOH THF, 0 C to rt (63% yield, d.r. = 10:1)
I2SmO
Me H
5-exo-trig
H O
OH I2SmO Me OH Me H H O H O O O
5-exo-dig
Me
paeonilactone A
Boffey, R. J.; Santagostino, M.; Whittingham, W. G.; Kilburn, J. D. J. Chem. Soc., Chem Commun. 1998, 1875.

Radical-radical sequence
CHO Me Me
Me O O
I2SmO
Me O O
Me Me
carbonyl-alkene cyclization
Me Me
OSmI2 H
Me O
radical-alkyne cyclization
O
OH Me Me H H H Me O O
OH Me Me H O H Me O
hyponophillin
Fevig, T. L.; Elliot, R. L.; Curran, D. P. J. Am. Chem. Soc. 1988, 110, 5064.

Radical-anionic sequence
OHC
Me
CHO
SmI2, t-BuOH THF, 0 C (90% yield)

H H O O
Me
SmIII
CHO
O Me H
OH OH
single diastereomer
Helm, M. D.; Sucunza, D.; Helliwell, M.; Procter, D. J. Tetrahedron Lett. 2009, 50, 3224.

Radical-anionic sequence
OHC
Me
CHO
SmI2, t-BuOH THF, 0 C (90% yield)

H H O O
anti-radical cyclization
Me
SmIII
CHO
O Me O H SmIII O SmIII CHO O
SmIII O O H SmIII O SmIII
chelation-controlled aldol cyclization
O Me H
OH OH Me
single diastereomer

! Sequences initiated by anionic reactions
anionic-radical sequence
I O O Cl H
SmI2 (4.0 eq) THF, HMPA (67% yield)

H
OSmIII Cl
SmIIIO
SmIIIO
SmIIIO OSmIII OH H Cl H
O H H Cl H H
Modication of Biomolecules Using SmI2

! Modication of peptides
Cbz
H N
O S Ph
N Ph
SmI2 (2.0 eq)

Ph
H N O
O N H Me Me
THF, -78 C (67% yield)
Cbz
H N
H N O
O N H Me Me
CO2Me
Ph
CO2Me
SmIII H N
O S Ph
Cbz
Hoj, B.; Skrydstrup, T. J. Am. Chem. Soc. 2003, 125, 4030.

! Modication of peptides
NHTs O BocHN O NHTrt H N O Me O CO2Me N H O H N O O N Ph O O NHTs O O H N O O O CO2Me Me
SmI2, H2O THF, -78 C (62% yield)
BocHN O NHTrt
N H
H N O
Ph
NHTs O BocHN O NHTrt N H O H N O SmIII O O N Ph O
Handen, A. M.; Lindsay, K. B.; Karaffa, J.; Skrydstrup, T. J. Am. Chem. Soc. 2006, 128, 9616.

! Modication of carbohydrates
BnO BnO OBn O SO2Ph OH OBn HO O OMe
OBn
HO
OMe
BnO BnO
OBn H OBn OH
OBn Perrin, E.; Sinay, P. Synlett. 1994, 420.

! Modication of carbohydrates
BnO BnO OBn O SO2Ph OH OBn HO O OMe BnO O SO2Ph O OBn Me O Me OBn BnO BnO BnO Me Me O Si O O SO2Ph O O OMe BnO Bn BnO BnO BnO Me Me O Si O BnO O SmIII O O OMe Bn O OMe BnO BnO Me Me O Si O O Bn O OMe BnO O OBn O OMe
n-BuLi, Me2SiCl
OBn
THF (82% yield)
BnO
Si
OBn
SmI2, benzene HMPA, 60 C
O H BnO BnO OBn O H Si Me O OBn Me
O OMe OBn
HO
HF HMPA, 60 C (50% yield, 2 steps)

BnO BnO OBn O H OBn OH
OBn
Perrin, E.; Sinay, P. Synlett. 1994, 420.
Conclusion
120 100 80
number of papers
60 40 20
1994
1996
1998
2000
2002
2004
2006
2008
2010
! Solvent rates plays a large role on reactivity and regioselectivity in SmI2 mediated reactions ! Intramolecular reactions can provide high levels of enantio - and diastereoselectivity ! There is a still a potential for the discovery of new reaction types using SmI2

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Samarium(II) Iodide in Organic Synthesis

Aroop Chandra January 10th, 2013

The Reagent and the Effect of Additives

Imamoto's method using iodine 3 Sm 2 SmI3 + + 3 I2 Sm 2 SmI3 3 SmI2

Concellon's method utilizing various oxidants and sonication 3 Sm + oxidants

Mechanism of SmI2-Mediated Reactions

[R-SmIII] SmI2 SmI2

Reduction of halides: iodides > bromides > chloride

Mechanism of SmI2-Mediated Reactions

R R-X SmI2, THF rt R-H C12H25 C12H25 C12H25

yield (%) 95 82 no rxn

reaction carried out at 60 C

Inanga, J.; Ishikawa, M. Chem. Lett. 1987, 102, 1485.

Mechanism of SmI2-Mediated Reactions

R R-X SmI2, THF rt R-H C12H25 C12H25 C12H25

yield (%) 95 82 no rxn

reaction carried out at 60 C

! Effect of Lewis bases on the reduction of alkyl halides

R R-X SmI2, THF HMPA, rt R-H C10H21 C10H21 C10H21

time 5 min 10 min 8 ha

reaction carried out at 60 C

Inanga, J.; Ishikawa, M. Chem. Lett. 1987, 102, 1485.

Mechanism of SmI2-Mediated Reactions

O MeO P OMe MeO N N

Mechanism of SmI2-Mediated Reactions

SmI2 HMPA, THF

(RX = primary, secondary, and tertiary halides)

primary alkyl radical SmI2 HMPA

secondary alkyl radical

tertiary alkyl radical

Curran, D. P.; Fevig, T. L.; Jasperse, C. P. Synlett. 1992, 943.

Mechanism of SmI2-Mediated Reactions

Mechanism of SmI2-Mediated Reactions

Mechanism of SmI2-Mediated Reactions

! Effect of proton donors (H2O and alcohols) in carbonyl reduction

Mechanism of SmI2-Mediated Reactions

! Effect of Lewis basic cosolvents (HMPA) in carbonyl reduction

! Addition of HMPA increases the rate of reduction of dialkylketones by 2 order of magnitude

Mechanism of SmI2-Mediated Reactions

! The role of proximal Lewis basic functional groups in carbonyl reduction

SmI2, THF MeOH, 0 C (95% yield)

Mechanism of SmI2-Mediated Reactions

! The role of proximal Lewis basic functional groups in carbonyl reduction

SmI2, THF MeOH, 0 C (95% yield)

-78 C, 10 min (51% yield)

Molander, G. A.; Kenny, C. J. Am. Chem. Soc. 1989, 111, 8236.

Carbon-Carbon Bond-forming Reactions Using SmI2

Carbon-Carbon Bond-forming Reactions Using SmI2

Lebrun, A, Kagan, H. B. Tetrahedron Lett. 1993, 34, 2311.

Carbon-Carbon Bond-forming Reactions Using SmI2

1. SmI2, THF 2. I2, CH2Cl2 (92% yield)

Carbon-Carbon Bond-forming Reactions Using SmI2

SmI2 THF, t-BuOH (64% yield)

BnO BnO BnO

OBn BnO BnO OH Me OH

d.r. > 23:1

Carbon-Carbon Bond-forming Reactions Using SmI2

SmI2 THF, t-BuOH

-78 C (95% yield)

Carbon-Carbon Bond-forming Reactions Using SmI2

SmI2 THF, t-BuOH

-78 C (95% yield)

THF, HMPA -78 C (54% yield)

Carbon-Carbon Bond-forming Reactions Using SmI2