atp lit seminar5
TRANSCRIPT
Hypervalent Iodine Reagents in Organic Synthesis
Andrew T. Parsons
March 23, 2007
Outline
• Background
• Iodine(III) reagents
• Iodine(V) reagents
• Conclusions
Hypervalent Iodine: An Introduction
Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523-2584.
• Hypervalent iodine: Species that exceed eight electrons in the valence shell, typically IIII and IV
– Can accommodate up to 12 valence electrons:
– Species with 10 valence electrons are more common:
I(OAc)2 I(OCOCF3)2 IOTs
HO
OI
AcO
O
OAcOAc
Dess-Martin periodinane
Hypervalent Iodine: A Brief History
• Both Iodine(III) and (V) compounds were first prepared by Willgerodt in 1886 and 1900, respectively
• Iodine(III) compounds are referred to as λ3-iodanes• Iodine(V) compounds are referred to as λ5-iodanes,
periodanes, or periodinanes
Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123-1178.
ICl2 IO O
iodoxybenzene:(caution: explosive)
(dichloroiodo)benzene
Structural Characteristics• λ3-iodanes:
• λ5-iodanes:
IO
AcO
OAc
OAc
OI
O-
OHO O
o-iodoxybenzoic acid10-I-4
pseudo-trigonal bipyramidal
Dess-Martin periodinane12-I-5
pseudo-octahedral
Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123-1178.
Ph I
Cl
Cl
(dichloroiodo)benzene10-I-3
pseudo-trigonal bipyramidal
Ph I
Ph
Cl-
diphenyliodonium chloride8-I-2
pseudo-tetrahedral
Outline
• Background
• Iodine(III) reagents
• Iodine(V) reagents
• Conclusions
Preparation of IIII Reagents• Most reagents are prepared directly from iodobenzene:
Varvoglis, A. Tetrahedron 1997, 53, 1179-1255.
I
I(OAc)2
Ac2O, H2O2
CF3CO2HI(OCOCF3)2H2O
IO
TsOH, H2O
I(OH)OTs
Cl2ICl2
HBF4, H2O
PhIOHBF4
Reactions of Iodine(III) Compounds
• Reactivity is driven by the electrophilic nature of IIII
– Typical reactions proceed through an initial nucleophilic attack of the iodine center:
– PhIX is an excellent leaving group, and therefore subsequent substitutions and reductive eliminations are prevalent
IX
XINu
X
+ X-
-Nu
INu
X
-R
PhI + X-
Nu R
Reactions of Iodine(III) Compounds: Oxygenations
Reactions of Iodine(III) Compounds: Oxygenations
• Iodosylbenzene, PhIO:– Useful for a number of different oxidations– Exists as a polymer, which is activated through depolymerization when treated with alcoholic solvents and base
– Can also be activated in the presence of a Lewis acid or Br - catalyst
– The active IIII species, PhI(OMe)2, can also be generated from PhI(OAc)2
(PhIO)nMeOH
IPh
OH
OMe
MeOHIPh
OMe
OMe
H2O+
Moriarty, R. M.; Hu, H.; Gupta, S. C. Tetrahedron Lett. 1981, 22, 1283. Moriarty, R. M. J. Org. Chem. 2005, 70, 2893-2903.
Oxidations with Iodosylbenzene
• Useful in the α-hydroxylation of ketones
• α-Hydroxylation of ketones can be carried out using CrO3, typically with higher yields
• PhIO is a non-toxic alternative to CrVI
Ar Me
O (PhIO)n
MeOH, KOH10 C
ArOH
OMeMeO
Moriarty, R. M.; Gupta, S. C.; Hu, H.; Berenschot, D. R.; White, K. B. J. Am. Chem. Soc. 1981, 103, 686-688.Moriarty, R. M.; Hu, H.; Gupta, S. C. Tetrahedron Lett. 1981, 22, 1283.
Oxidations with Iodosylbenzene
Moriarty, R. M.; Hu, H.; Gupta, S. C. Tetrahedron Lett. 1981, 22, 1283.
Ar Me
O (PhIO)nMeOH, KOH Ar
OHOMeMeO H+
Ar
O
OH
O
OH
O
OHO
OH
O
OH
Me MeO F60% 45% 50% 70%
O
OH
Cl
O
OH
Br
O
OH
I
O
OH
O2N63% 70% 71% 48%
Mechanism of α-Hydroxylation
Moriarty, R. M. J. Org. Chem. 2005, 70, 2893-2903.
R1 R2O -OMe
R1 R2O
R1 R2O
I PhMeO
R1 R2
I PhMeO
OMeO-OMe
R1
R2
OMeO-OMe
R1 R2
OH
OMeMeO
PhI + -OMe
I Ph
OMe
OMe
Applications in Total Synthesis• Synthesis of (-)-Xialenon
• Carrying out this transformation using a Rubottom oxidation provided a dr of 3:1
TBSO
O 1. PhI(OAc)2KOH, MeOH
2. 10% H2SO470%, over 2 steps TBSO
O
OHTBAF
HO
O
OH
dr = 7:1 (-)-Xialenon
Hodgson, D. M.; Galano, J.-M.; Christlieb, M. Tetrahedron 2003, 59, 9719-9728.Rubottom, G.M.; Gruber, J.M. J. Org. Chem. 1978, 43, 1599-1602
Catalytic α-Acetoxylation of Ketones
R
O
R
O
OAc
PhI (0.10 equiv),mCPBA (2.0 equiv) BF3OEt2 (3 equiv)
AcOH-H2O, rt
O
46%
OAc
O
OAc
F55%
Ph
O
OAc
Me
58%
Ph
O
OAc
O
OEt
49%
OAc
O
63%
Ph
O
OAc
58%
R1 R1
Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamoto, K. J. Am. Chem. Soc. 2005, 127, 12244-12245.
Catalytic Cycle
PhI
[PhI(III)]
R
O
IPh
OAc
AcOH
R
O
OAc
R
OH
R
O
MeH+
mCPBA
mCBA
AcOH +
BF3OEt2
Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamoto, K. J. Am. Chem. Soc. 2005, 127, 12244-12245.
Oxidative Rearrangements of Aryl Alkenes
• Koser’s reagent induces an oxidative rearrangement of aryl alkenes to afford α-aryl ketones
Ar
R1H
R2
95% MeOH R1Ar
R2
OPhI(OH)OTs
Justik, M. W.; Koser, G. F. Tetrahedron Lett. 2004, 45, 6159-6163.
Oxidative Rearrangements of Aryl Alkenes
O
Me
Me
Me
O
84% 89%
O
Me
MeO
92%
O
Me
NC
82%
O
Me
59%
F3C
O
85%
Ph
O
84%
Ph
O
Me
70%
Justik, M. W.; Koser, G. F. Tetrahedron Lett. 2004, 45, 6159-6163.
Ar
R1H
R2
95% MeOH R1Ar
R2
OPhI(OH)OTs
Oxidative Rearrangements of Aryl Alkenes
R1
Ar
R2IPh
OH
OTs
Ar
R1
R2
IPh
HO
Ar
R1
R2
IPh OMe
HH
OMe
R1R2
ArH
MeOH, H2OOMe
R1R2
ArH OMe
TsOH, H2OR1
O
Ar
R2
PhI
H2O-OTs
MeOH
Justik, M. W.; Koser, G. F. Tetrahedron Lett. 2004, 45, 6159-6163.
Oxidative Cleavage of Alkenes
• Works well for electron-rich olefins• Reaction times typically 0.5-5 h• Safer than ozonolysis, cheaper than transition-metal
reagents
R1
R2R3
R PhIO (2.2 equiv), HBF4 (2.2 equiv)
CH2Cl2-HFIP-H2O (9:3:1), rtO
R3
R+ O
R1
R2
Miyamoto, K.; Tada, N.; Ochiai, M. J. Am. Chem. Soc. 2007, 129, 2772-2773.
Oxidative Cleavage of Alkenes
R1
R2R3
R PhIO (2.2 equiv), HBF4 (2.2 equiv)
CH2Cl2-HFIP-H2O (9:3:1), rtO
R3
R+ O
R1
R2
Miyamoto, K.; Tada, N.; Ochiai, M. J. Am. Chem. Soc. 2007, 129, 2772-2773.
OO
79%
O
O
Me
76%
O
OPh
80%
O
O
F3C
71%
O
F3C
67%
O
O2N61%
O
OMe
53%
OnC11H23
54%
Oxidative Cleavage of Alkenes
• Suggests that an epoxidation precedes cleavage
Miyamoto, K.; Tada, N.; Ochiai, M. J. Am. Chem. Soc. 2007, 129, 2772-2773.Moriarty, R. M.; Gupta, S. C.; Hu, H.; Berenschot, D. R.; White, K. B. J. Am. Chem. Soc. 1981, 103, 686-688.
PhIO (2.2 equiv), HBF4 (2.2 equiv)
CH2Cl2-HFIP-H2O (9:3:1), rt25 h
O+
O
39% 34%
O2N O2NO2N
Oxidative Cleavage of Alkenes
• Suggests that an epoxidation precedes cleavage
Miyamoto, K.; Tada, N.; Ochiai, M. J. Am. Chem. Soc. 2007, 129, 2772-2773.
OPhIO (1.1 equiv), HBF4 (1.1 equiv)
CH2Cl2-HFIP-H2O (9:3:1), rt88%
OO2N O2N
PhIO (2.2 equiv), HBF4 (2.2 equiv)
CH2Cl2-HFIP-H2O (9:3:1), rt25 h
O+
O
39% 34%
O2N O2NO2N
Reactions of Iodine(III) Compounds: Oxidation of Phenols
• Previously:
OH
PhIX2
O
NuR R
Nu
typically PhIX2 = PhI(OAc)2 or PhI(OCOCF3)2
Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123-1178.
Application to Spirocyclizations• Tether a nucleophile to the phenol:
• Possible applications in natural product synthesis
OH
Y NuH
PHIX2
solvent
O
Y Nu
Spirocyclization of Phenols: Early Studies
OH
YHO
PhI(OCOCF3)2
O
YO
O
O
59%
O
OO
O
80%
O
O
O
86%
K2CO3, CH3CN0 C to rt, 10 min
Tamura, Y.; Yakura, T.; Haruta, J.-I.; Kita, Y. J. Org. Chem. 1987, 52, 3927-3930.
Mechanism
O
O
O
O
O
O
IPh
F3COCO
OCOCF3 OCOCF3, PhI
O
O
O
PhI(OCOCF3)2
Tamura, Y.; Yakura, T.; Haruta, J.-I.; Kita, Y. J. Org. Chem. 1987, 52, 3927-3930.
Current Standard: Catalytic Spirocyclizations
Dohi, T.; Maruyama, A.; Yoshimura, M.; Morimoto, K.; Tohma, H.; Kita, Y. Angew. Chem. Int. Ed. 2005, 44, 6192-6196.
OH
O
O
OArI(OCOCF3)2 (0.05 equiv)
mCPBA (1.5 equiv)CF3CO2H (1.0 equiv)
CH2Cl2, rtHO2C
O
O
O
Br
O
O
O
Me
O
O
O
Me O
O
O
Me
O
O
O
Br Br
Me O
O
O
Br Me
Me
66% 76% 73% 77% 91% 80%
R R
Catalytic Cycle
Dohi, T.; Maruyama, A.; Yoshimura, M.; Morimoto, K.; Tohma, H.; Kita, Y. Angew. Chem. Int. Ed. 2005, 44, 6192-6196.
Ar-IIII
Ar-ImCPBA
mCBA
OH
CO2H
O
O
O
ArI(OCOCF3)2
Applications in Total Synthesis• Synthesis of Aranorosin:
OH
HN
CO2H
Cbz
PhI(OAc)2
MeOH, 0 C O
OHNCbz
O
40%NH
OO
O
O
OOH
HO
Aranorosln
Wipf, P.; Kim, Y.; Fritch, P. C. J. Org. Chem. 1993, 58, 7195-7203.
PhI(OCOCF3)2-Promoted Formation of Lactols
Kita, Y.; Matsuda, S.; Fujii, E.; Horai, M.; Hata, K.; Fujioka, H. Angew. Chem. Int. Ed. 2005, 44, 5857-5860.
O
R1
R
PhI(OCOCF3)2 (1.0 equiv)
H2O:CH3CN (1:4)0 C to rt
OH
n
O
R
OH
n
R1 O
or ORO
HO
n
if R1 = H
PhI(OCOCF3)2-Promoted Formation of Lactols
Kita, Y.; Matsuda, S.; Fujii, E.; Horai, M.; Hata, K.; Fujioka, H. Angew. Chem. Int. Ed. 2005, 44, 5857-5860.
O
R1
R
PhI(OCOCF3)2 (1.0 equiv)
H2O:CH3CN (1:4)0 C to rt
OH
n
O
R
OH
n
R1 O
or ORO
HO
n
if R1 = H
O
O
OH
49%
O
O
OH
66%
OO
Et
HO
74%
OO
Ph
HOO
OMe
HO
72% 65%
Applications in Total Synthesis• Synthesis of (+)-Tanikolide
O
C11H23
OH
C11H23
O
PhI(OCOCF3)2
H2O72%
OO
C11H23
HO
2 steps
O O
OH
C11H23
(+)-Tanikolide
Kita, Y.; Matsuda, S.; Fujii, E.; Horai, M.; Hata, K.; Fujioka, H. Angew. Chem. Int. Ed. 2005, 44, 5857-5860.
Applications in Total Synthesis
OH
R
O
HOCOCF3
O
R
O
I
OCOCF3Ph
OH2
HOCOCF3OH2
R
HO
OI
O
Ph
PhI
HO
R
O
O
OO
R
HO
PhI(OCOCF3)2
Kita, Y.; Matsuda, S.; Fujii, E.; Horai, M.; Hata, K.; Fujioka, H. Angew. Chem. Int. Ed. 2005, 44, 5857-5860.
• Synthesis of (+)-Tanikolide
Carbon-Carbon Bond Forming Reactions
Carbon-Carbon Bond Forming Reactions: Cyclizations with PhI(OCOR)2
• PhI(OCOR)2 reagents have been shown to promote attack by carbon nucleophiles:
NH
O
O
PhI(OCOCF3)2
CF3CH2OHNH
O
O
ORO
Kita, Y.; Takada, T.; Ibaraki, M.; Gyoten, M.; Mihara, S.; Fujita, S.; Tohma, H. J. Org. Chem. 1996, 61, 223-227.
C-C Bond Forming Cyclizations
HOCOCF3
PhI(OCOCF3)2
NH
O
O
HO
N
O
O
HO
IPh OCOCF3
PhI, HOCOCF3
N
O
O
O H
NH
O
O
O
74%
Kita, Y.; Takada, T.; Ibaraki, M.; Gyoten, M.; Mihara, S.; Fujita, S.; Tohma, H. J. Org. Chem. 1996, 61, 223-227.
Applications in Total Synthesis• Synthesis of (±)-Stepharine
N
OH
MeO
MeOO
CF3
N
O
MeO
MeOO
CF3
IOAc
Ph
N
O
MeO
MeO
O
CF3
NaBH4NH
O
MeO
MeO
90%
(±)-Stepharine
PhI(OAc)2
TFE, 0 C
PhI, -OAc
Honda, T.; Shigehisa, H. Org. Lett. 2006, 8, 657-659.
C-C Bond Forming Reactions: C-H Activation
Kalyani, D.; Deprez, N.; Desai, L. V.; Sanford, M.S. J. Am. Chem. Soc. 2005, 127, 7330-7331.
Deprez, N.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972-4973.
N N
Ph
R R
R2R1
[Ph2I]BF4 (1.1-2.5 equiv)Pd(OAc)2 (0.05 equiv)
Solvent, 100 C
R NR1
O
R NR1
O
R2
[Ph2I]BF4 (1.1-2.5 equiv)Pd(OAc)2 (0.05 equiv)
Solvent, 100 C
NH
NH
[Ph2I]BF4 (1-3.0 equiv)IMesPd(OAc)2 (0.05 equiv)
AcOH, rt
Ph
R2
R R
C-C Bond Forming Reactions: C-H Activation
NMe
Ph
75%
N
Ph CHO
51%
NO
O
Ph
83%
N
O
Ph
83%
OMe
HNMe
O
Cl
Ph
67%
NH
PhNH
Ph
AcO
81% 71%
NH
Ph
69%
Kalyani, D.; Deprez, N.; Desai, L. V.; Sanford, M.S. J. Am. Chem. Soc. 2005, 127, 7330-7331.Deprez, N.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972-4973.
Mechanism of C-H Activation
N
PdNC X
PhI
HXPdX2
2
PdNC X
Ph
X
PdX2
2
N
Ph
NCPh
[Ph2I]X
Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300-2301.Kalyani, D.; Deprez, N.; Desai, L. V.; Sanford, M.S. J. Am. Chem. Soc. 2005, 127, 7330-7331.
Outline
• Background
• Iodine(III) reagents
• Iodine(V) reagents
• Conclusions
Preparation of IV Reagents
Boeckman, Jr., R.K.; Shao, P.; Mullins, J.J. Org. Synth. 2000, 77, 141-152. Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537-4538.
I
O
OHOxone, H2O
I
O
O
OHO
o-Iodoxybenzoic acid(IBX)
Ac2O, AcOH I
O
O
OAcAcO OAc
Dess-Martin periodinane(DMP)
70 C, 3 h 85 C to rt72%81%
• Caution: There have been reports of violent explosions occurring upon heating of these reagents to >200 °C
Oxidations of Alcohols: A Brief Overview
• DMP and IBX have been widely used for the mild oxidation of alcohols to ketones and aldehydes:
Zoller, T.; Breuilles, P.; Uguen, D. Tetrahedron Lett. 1999, 40, 6253-6256.Myers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.; Kwon, S. Tetrahedron Lett. 2000, 41, 1359-1362.Smith, A.B., III; Kanoh, N.; Ishiyama, H.; Minakawa, N.; Rainier, J.D.; Hartz, R.A.; Cho, Y.S.; Moser, W.H.J. Am. Chem. Soc. 2003, 125, 8228-8237.
HONHFmoc
R
DMP, CH2Cl2-H2O, rt
99% ee
>90%O
NHFmoc
R99% ee
Swern: >95% (50% ee)TEMPO: >80 % (95% ee)
OHR1
R
OR1
RIBX
DMSO, rt86-100%
O
HO
MeMe
O
O
MeMe
DMP
CH2Cl2, rt
Dehydrogenation of Saturated Aldehydes and Ketones with IBX
R
OIBX (2.0-3.0 equiv)
R
O
R1 R1DMSO
Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596-7597.
Dehydrogenation of Saturated Aldehydes and Ketones with IBX
R
OIBX (2.0-3.0 equiv)
R
O
R1 R1DMSO, 65-85 C
Me
O
85%
O
TIPS
H
H85%
NO
84%
O
83%
O
O
68%
O
58%
Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596-7597.
Mechanism of Dehydrogenation by IBX
• Single electron transfer is likely operative:
Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem. Soc. 2002, 124, 2245-2258.
R
HO
R1
I
O
O
OHO
I
O
O
OHO
HO
R
R1
I
O
O
OHOHO
R
R1 H
H2O +
R
O
R1
OI
O
OH
I
O
O
OHOHO
R
R1 H
IBA
Applications in Total Synthesis
• Efforts toward the synthesis of Phomoidride B
O
OH
H
TBSO
O
MeO
OOMe
O
OH
H
TBSO
O
MeO
OOMe
IBXDMSO-Tol80 C, 3 h
52%
CO2MeMeO2C O
H
O
OO
HO2C
H
O
R
R
OO
Phomoidride B
Ohmori, N. J. Chem. Soc., Perkin Trans. 1 2002, 755-767.
Tandem Conjugate Addition/Dehydrogenation with IBX
Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T.Angew. Chem. Int. Ed. 2002, 41, 996-1000.
N
O
MeO
IBXMPO =O
I
O
O OH
CuBrSMe2, RMgX;then TMEDA, TMSCl
O
n
OTMS
nR
IBXMPO (2 equiv)in DMSO, rt
O
nR
THF, -78 to -25 C
not isolated
Tandem Conjugate Addition/Dehydrogenation with IBX
Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T.Angew. Chem. Int. Ed. 2002, 41, 996-1000.
1. CuBrSMe2, RMgX;then TMEDA, TMSCl
THF, -78 to -25 C
2. IBXMPO (2 equiv)in DMSO, rt.
O O O O
OO
I
O O
NC
90% 97% 94%
47%
98% 98%
O
n
O
nR
Cyclization of N-Aryl Amides Carbamates, and Ureas Using IBX
Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A. J. Am. Chem. Soc. 2002, 124, 2233-2244.
HN X
ONX
O
Me
R
R
IBX (4.0 equiv)
THF:DMSO (10:1)90 C
where X = CH2, O, NR
Cyclization of N-Aryl Amides and Carbamates Using IBX
Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A. J. Am. Chem. Soc. 2002, 124, 2233-2244.
HN X
ONX
O
Me
R
R
IBX (4.0 equiv)
THF:DMSO (10:1)90 C
N
O
Me
86%
N
O
H H Br
86%
NO
O
Me
HH
72%
NO
O
Ph Ph
76%
NN
O
Ph
Me
84%
NCO2Me
OPh
93%
Mechanism
NH
O
IBXSET N
O
H
H+
N
O
N
O
N
O
HN
Me
O
5-exo-trig
Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A. J. Am. Chem. Soc. 2002, 124, 2233-2244.
Oxidation of Carboxamides to Nitriles
O
NH2R
IBX (2.5 equiv)Et4N+ Br- (2.5 equiv)
CH3CN, 60 CR CN + CO2
Bhalerao, D. S.; Mahajan, U. S.; Chaudhari, K. H.; Akamanchi, K. G. J. Org. Chem. 2007, 72, 662-665.
Oxidation of Carboxamides to Nitriles
Bhalerao, D. S.; Mahajan, U. S.; Chaudhari, K. H.; Akamanchi, K. G. J. Org. Chem. 2007, 72, 662-665.
CN
O2N
CN
CNS CN
MeO
MeO
CN
75% 85% 95% 72% 80% 60%
CN
O
O
NH2R
IBX (2.5 equiv)Et4N+ Br- (2.5 equiv)
CH3CN, 60 CR CN + CO2
Proposed Mechanism
Bhalerao, D. S.; Mahajan, U. S.; Chaudhari, K. H.; Akamanchi, K. G. J. Org. Chem. 2007, 72, 662-665.
OI
OHO
O
Br
OI OH
O
O
Br
H2NR
O
NR
O
H
Br
OI
O
O
+
O
N
C
R
OI
O
HO
OI
O
O
O
NH
R
H
HN RR CN
CO2
I
CO2H
+
IBX
H2O
Conclusions
• Hypervalent Iodine compounds are versatile reagents that can promote a number of different transformations
• Alternative to toxic metal reagents
• Disadvantages: – Enantioselective transformations are largely
elusive– Safety concerns with some reagents
Acknowledgements
Cory BauchAshley BermanMary Robert NahmJustin PotnickRebecca Duenes
Matthew CampbellShanina SandersAndy SatterfieldSteve GreszlerChris Tarr
The Johnson Research Group:
Prof. Jeff Johnson
Greg BoyceGeanna MinDan SchmittMike SladeAustin Smith
Mechanism of Tandem Conjugate Addition/Dehydrogenation with IBX
Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T.Angew. Chem. Int. Ed. 2002, 41, 996-1000.
N
O
MeO
O
I
O
O OH
R
R1
OX
N
O
MeO
O
I
O
O O
R
R1
XOH
SETN
O
MeO
O
I
O
O O
R
R1
N
O
MeO
O
I
O
O O
R
HR1
NO
MeO
OI
O
HO
+
R
O
R1
Mechanism of THF Activation
OI
O
O OH
O
H2O
OI
O
OO
SETO
I
O
OO
OI
O
OO
H
NAr
O
OI
O
OO
OI
O
OOO
I
O
OH
+O
Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A. J. Am. Chem. Soc. 2002, 124, 2233-2244.
Support of a SET Mechanism in IBX Mediated Dehydrogenations
Ph
Ph
HO
IBX
Ph
Ph
HO
IO
O
HO
OH Ph
Ph
O
Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem. Soc. 2002, 124, 2245-2258.
• Hammet analysis shows the reaction is only slightly dependent on the electronics of aryl-containing substrates (ρ= -.75, σp
+)
Support of a SET Mechanism in IBX Mediated Cyclizations
Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A. J. Am. Chem. Soc. 2002, 124, 2233-2244.
Ph
HN
O
Et
1. SET
2. 5-exo-trig N
O
Et
N
O
Et
Ph
N
O
Et
SET
N
O
Et
N
O
Et
-Hrearomatization
N
O
Et
Support of a SET Mechanism in IBX Mediated Cyclizations
N
O
PhSBu3SnH
AIBN (cat.)
NO
H
H
Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A. J. Am. Chem. Soc. 2002, 124, 2233-2244.
Nomenclature• Hypervalent compounds are characterized according to
the Martin-Arduengo designation, N-X-L, where:– Number of valence electrons, N– Identity of the hypervalent atom, X– Number of ligands, L
• For example, (diacetoxyiodo)benzene:
I(OAc)2
(diacetoxyiodo)benzene10-I-3
Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123-1178.
Oxygenation of Silyl Enol Ethers
• Typically assisted by a Lewis acid catalyst
• Similar reactions can be carried out using Tl(lll)– Highly toxic– Tl(III) is approximately three times more expensive
than I(III)
R
OTMS PhIO, BF3OEt2, ROH
R
O
OR
Moriarty, R. M.; Duncan, M. P.; Prakash, O. J. Chem. Soc. Perkin Trans. 1 1987, 1781-1784.
Hydroxylation of Silyl Enol Ethers
O
OH
O
OHO
OH
O
OH
O
OH
Me Cl O2N
Me
OO
OH
O
OH
O
OH
65% 72% 68% 70%
74% 78% 80% 83%
R
OTMS PhIO, BF3OEt2, H2O
R
O
OH0 C, 4h
Moriarty, R. M.; Duncan, M. P.; Prakash, O. J. Chem. Soc. Perkin Trans. 1 1987, 1781-1784.
Mechanism of Hydroxylation
• Similarly to the α-hydroxylation of ketones, the reaction initiates through a nucleophilic attack at I(III)
• A second nucleophilic attack on the I(III) bearing followed by elimination affords PhI and the product
R1
OR3Si I Ph
OBF3
R3SiF
R1
O
IOBF2
Ph
OH2
R1 OH
O
+ PhI
+H + -OBF2
Moriarty, R. M.; Duncan, M. P.; Prakash, O. J. Chem. Soc. Perkin Trans. 1 1987, 1781-1784.
Progress Towards Asymmetric α-Hydroxylation of Ketones
NN
O O
Mn
tBu tBu
Cl tButBu
R
SiR2Me2
R1 R1
O
R
OH
1. 1 (7 mol %), PhIO (1.5 equiv)PPNO (0.3 equiv), CH2Cl2
2. HCl, MeOH
S,S-1
Adam, W.; Fell, R. T.; Stegmann, V. R.; Saha-Moller, C. R. J. Am. Chem. Soc. 1998, 120, 708-714.
• Reaction is hampered by low conversion• Only modest enantioselectivity obtained
Progress Towards Asymmetric α-Hydroxylation of Ketones
Adam, W.; Fell, R. T.; Mock-Knoblauch, C.; Saha-Moller, C. R. Tetrahedron Lett. 1996, 37, 6531-6534.Adam, W.; Fell, R. T.; Stegmann, V. R.; Saha-Moller, C. R. J. Am. Chem. Soc. 1998, 120, 708-714.
Et
O
Ph
OH
Me
O
Ph
OH
Me
O
SEt
OH
81% (56% ee) 81% (60% ee) 35% (18% ee)
Ph
O
Me
OH
92% (39% ee)
Ph
O
Me
OH
54% (67% ee)
When SiR3 = TMS
When SiR3 = TBS
(R,R-1)
(R,R-1)
(S,S-1)(S,S-1)(S,S-1)
NN
O O
Mn
tBu tBu
Cl tButBu
1
α-Oxygenation of Silyl Enol Ethers• In a similar fashion, other oxygen nucleophiles can be employed:
PhIO, TMSOTf
Ph
OSiR3
Ph
O
OTfCH2Cl2, -78 C to rt
70%
Moriarty, R. M.; Epa, W. R.; Penmasta, R.; Awasthi, A. K. Tetrahedron Lett. 1989, 30, 667-669.
• Synthesis of (±)-Cephalotaxine
Yasuda, S.; Yamada, T.; Hanoaka, M. Tetrahedron Lett. 1986, 27, 2023-2026.
NOO
(PhIO)nMeOH, KOH
N O
HO
MeO
MeO
N
HO
MeO
OO
H H H
(±)-Cephalotaxine
NH
OO OO
2 stepsOH
O