samarium(ii) iodide mediated cyclizations in natural evans.rc.fas. ii) iodide mediated cyclizations...

Samarium(II) Iodide Mediated Cyclizations in Natural Product SynthesisThe Kagan Reagent Part II

An Evans Group Afternoon SeminarKeith Fandrick

Seminar outline:-Introduction and Background-Intramolecular Barbier Reaction-Intramolecular Reformatsky Reaction-Radical Alkene and Alkyne Cyclizations-Carbonyl-Alkene Reductive Cyclizations-Intramolecular Pinacol Couplings-Intramolecular Reductive Couplings of Carbonyls and Hydrazones-Total Synthetic endeavors utilizing mutiple SmI2 cyclizations

Primary ReferencesProcter, D. J. Chem. Rev. 2004, 3371.Krief, A. Chem. Rev. 1999, 745.Molander, G. Chem. Rev. 1996, 307.Molander, G. Chem. Rev. 1992, 29.Curran, D. R. Synlett 1992, 943. Rajapakse, H. Evans Group Seminar 1998

SmI2 Discovery and BackgroundIntroduction

-Samarium diiodide was first reported by Kagan in 1977. Kagan reported the preliminary deoxygenation of epoxides and sulfoxides, chemoselective reduction of aldehydes in the presence of ketones, dehalogenations, and couplings between ketones and alkyl halides. (Kagan, H. B. Nouv. J. Chim. 1977, 5. Kagan, H. B. J. Am. Chem. Soc. 1980, 2693)

-Samarium diiodide is the subject of >20 reviews and >850 publications.

-Samarium diiodide is commercially available as an anhydrous powder (5g, $185) or as a 0.1 M solution in THF (100mL, $32). (Aldrich catalog 2003-2004)

-Samarium diiodide can be prepared from Sm metal and CH2I2, ICH2CH2I, or I2.

-Reactions are generally performed with an excess of samarium diiodide, degassed reagents and solvents, and in dry THF containing an antioxidant.

-Catalytic amounts of SmI2 can be used with the addition of mischmetall (alloy of lanthanides [La 33%, Ce 50%, Nd 12%, Pr 4%, Sm and other lanthanides 1%] to regenerate SmI2. The use of catalytic amounts of Sm(II) and mischmetall is more cost effective. The alloy is unreactive to carbonyls and simple to use.

-The normal work-up usually requires acidic conditions. However, Rochelle's salt and potassium carbonate can be used for acid sensitive substrates. (Little D. J. Org. Chem. 1996, 3240)

-THF appears to be the proton source for the termination of radical cascades. If a second reduction with additional equivalent of SmI2 occurs the proton source is generally the alcoholic co-solvent. (Curran D. P. J. Am. Chem. Soc. 1988, 5046)

-Samarium diiodide chemoselectively reduces: organic halides, carbonyls, -hetero-sustituted carbonyls, cyclopropyl ketones, epoxides, amine oxides, sulfoxides, phosphine oxides, sulfones, sulfonates, nitro, nitroso, and azo compounds, allyl acetates, and isoxazoles.

Krief, A. Chem. Rev. 1999, 745.

-2.25

-2

-1.75

-1.5

-1.25

-10 1 2 3 4 5 6 7

Equiv of HMPA relative to Samarium Diiodide

Oxi

datio

n Po

tent

ial

SmI2 Reduction Potential

-Samarium diiodide is a polyvalent single electron reducing agent.

-The reduction potential (Eo) of Sm+2/Sm+3

in water is -1.55 V compared to Nao/Na+1 of -2.77 V.

-The reduction potential of SmI2 can be increased by the addition of HMPA, and LiBror LiCl.

-The addition of transition metal increasesthe rate of several SmI2 reactions.(Kagan, H. B. Synlett 1996, 633)

-Changes in protic solvents can alterthe rates of SmI2 mediated reactions andin some cases alter the mechanism.

-Visible light increases the reduction potentialof SmI2. (Ogawa, A. J. Am. Chem. Soc. 1997, 2745)

Krief, A. Chem. Rev. 1999, 745.

UV-vis spectrum of SmI2 in THF

Effects on the Eo of SmI2 with HMPA

SmI2 Barbier Reaction Basic Mechanism

Sm

I

I

HMPA

HMPA

HMPA

HMPAOuter Sphere

ETR-I+ Sm

I

I

HMPA

HMPA

HMPA

HMPA+ R

+ SmI

I

HMPA

HMPA

HMPA

HMPA

Outer Sphere ETSm

I

I

HMPA

HMPA

HMPA

HMPA+ R

+-

Sm

R

I

HMPA

HMPA

HMPA

HMPASm

I

I

HMPA

HMPA

R

HMPAorR' R'

O

R' R'R

OSmInHMPAm

H+R' R'R

OH

-Reduction of the ketone followed by substitution of alkyl-halide with ketyl-radical ruled out by Kagan, because the use of chiral alkyl-halides leads to racemic products.

-The replacemed of HMPA with LiBr predominately leads to the Pinacol product via inner sphere electron transport/reduction of the ketone via formation of SmBr2.

-Replacement of HMPA with HMDS leads to the formation of [Sm(HMDS)2]2, which has a redox potential inbetween SmI2 and [Sm(HMPA)6]I2. [Sm(HMDS)2]2 reacts faster with alkyl halides and ketones via change in mechanism towards an inner sphere ET process.

Molander, G. J. Am. Chem. Soc. 1987, 6556. Curran, D. P. Synlett 1992, 943.Flowers, R. A. Org. Lett. 1999, 2133.Flowers, R. A. J. Am. Chem. Soc. 2000, 7718.Flowers, R. A. J. Am. Chem. Soc. 2002, 6895. Flowers, R. A. J. Am. Chem. Soc. 2002, 14663.Flowers, R. A. J. Am. Chem. Soc. 2004, 6891.

Intramolecular SmI2 Barbier ReactionsBasic Mechanism

Me

Me O

Me

I

Me

Me O

Me Me

Me O

MeMe

Me O

Me

Me

Me O

Me

I2Sm

Me

Me

Me

OSmI2

Me

Me

Me

OH

Me

Me O

Me

SmI2

Me

Me

Me

OSmI2

Me

Me

Me

OH

SmI2

SmI2KSm

KC

SmI2

H+

H+

H+

Reactions performed with 2 equiv of SmI2 and 20 equiv of HMPA

SmI2 (M) A B C D0.010.030.050.07

64%42%27%20%

21%42%55%59%

11%11%13%15%

4%5%5%6%

A

B

C

Me

MeO

Me

D Curran, D. P. Tetrahedron 1997, 9023Krief, A. Chem. Rev. 1999, 745Molander, G. A. J. Org. Chem. 1991, 4112

H

Me

Intramolecular SmI2 Barbier ReactionsEunicellin and Muscone

O

O

I

Me

Me SmI2, THF-78 oC to rt

O

MeOH

O

AcO

AcO Me

OAc

OAcMeMeMe

CH2

Eunicellin

Hoffman, M. R. Tetrahedron 1997, 4331

88% Single Diastereomer

SmI2, HMPATHF

1) HgO, I2 PhH, hv, O oC 59%2) Bu3SnH-AIBN PhH, hv, 82%

O

Me

90% Single Diatereomer(+/-) Muscone

Suginome, H. Tetrahedron 1987, 3963

O

I

Me Me

OHH

H

MeMe

Intramolecular SmI2 Barbier ReactionsPolyoxypeptin A

NTs

I Me O

ORNTs

OHMe

ORNTs

MeOH

ORSmI2 +

R Yield A:BTBDPSTrH

76%45%75%

13:8731:6997:3

THF, HMPA

HNN

N

N

N

NH HN

O

Me

O

O

N

O

OMeO

OH

H

H

MeOH

Pr

H

iPrH

Me

HO

OH H

Me

H

OHO O

OH

Polyoxypeptin A

OSmI2O

H

N H

I

OSmI2O

H

H

Me

N

I

TsTs

Favored Disfavored

Hamada, Y. Tetrahedron Letters 2002, 4695Procter D. Chem. Rev. 2004, 3371

Hamada's Explanation

OO

Sm(III)(HMPA)n

N

I

Ts

H

O

Me

N

I

Ts

OP Sm(III)(HMPA)n

HH

Procter's Explanation

-Mechanism might proceed through a bis-radical stucture

A B

Intramolecular SmI2 Barbier CyclizationsSynthetic Studies Towards Variecolin

Molander, G. Org. Lett. 2001, 2257For increased reaction rates with NiI2 see: Kagan, H. Synlett 1996, 633For increasing reducing ability of SmI2 with visible light see: Ogawa A. J. Am. Chem. Soc. 1997, 2745

OMe

I

O

Cl+

SmI2, cat. NiI2THF, 72% OH

OMe

Cl

1:1 Mixture of diastereomers due to racemic starting

materials RuCl3, NaIO4MeCN, CCl4, H2O

65%

OCl

O

H

H

H

O

HO SmI2, NiI2hv, THF

H

Me

MeH

H

H

MeOHC

O

Me

Me

63%

Variecolin

Model of Intermediate A

A

OSmInTHFm

SmI2 Reformatsky reactionsBasic Mechanism

OBr

O

O

MePh

2 equiv SmI2THF, -78 oC

O

Me

SmI2 Intramolecular Reformatsky reactions(+/-) Paeoniflorigenin and Paeoniflorin

O

O

OH OTIPS

H

Me

Cl

NC

Slow Additionof SmI2 (7 equiv)

THF, -45 oC10h

O

OTIPS

NC

HO

O

MeO

OH

HO

HOO

MeO

OH

O

HO

O

OHHO

HOHO

Paeoniflorin Paeoniflorigenin

Chem 3D w/ MM2 energy minimization

Corey, E. J. J. Am. Chem. Soc. 1993, 8871

93% Single Diastereomer

-Product of the cyclization is base sensitive. Retro-Aldol is observed upon treatment of product with Et3N.

O

SmI2 Intramolecular Reformatsky reactionsUridine Derivatives

Matsuda A. J. Org. Chem. 1997, 1368

O N

OTBSO

O

O

N

O

OEt

SmI2THF O

N

OTBS

N

O

OEt

OOH

H

OBr

O N

OTBS

N

O

OEt

OH

OH

H2N

O

Uridine Derivatives

O

O

O

I3Sm

-Substrate is Base sensitive

-Uridine Derivatives have been shown to be potent antitumor agents bothin vitro and in vivo

Base

OTBS

Conditions Product Yieldsrt w/ Znrt0 oC-78 oC-78 oC w/ HMPA

A

C 22%A 71%A 75%A 90%A 76%, B 11%

O N

OTBSO

AcO

N

O

OEt

NH

N

O

OEt

B C

Product Distribution Plausible Tra