ATP Lit Seminar5

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


Ph I

Cl

Cl

(dichloroiodo)benzene10-I-3

pseudo-trigonal bipyramidal

Ph I

Ph

Cl-

diphenyliodonium chloride8-I-2

pseudo-tetrahedral

Outline

• Background



• 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.


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%


Ar

R1H

R2

95% MeOH R1Ar

R2

OPhI(OH)OTs


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


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.


R1

R2R3

R PhIO (2.2 equiv), HBF4 (2.2 equiv)

CH2Cl2-HFIP-H2O (9:3:1), rtO

R3

R+ O

R1

R2


OO

79%

O

O

Me

76%

O

OPh

80%

O

O

F3C

71%

O

F3C

67%

O

O2N61%

O

OMe

53%

OnC11H23

54%


• 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


• Suggests that an epoxidation precedes cleavage


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


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


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


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


• 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



• 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


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


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


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


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


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


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


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


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


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


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


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


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

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