hydrogen autotransfer” methodology, a · 2014-01-16 · hydrogen autotransfer methodology...

“Hydrogen Autotransfer” methodology, a

powerful tool for the atom economical

construction of C-C and C-N bonds

Jicheng Zhang

09/25/13

OutlineOutline

• Total Synthesis of 6-Deoxyerythronolide B

• Carbonyl allylation and crotylation

• Synthesis of pyrroles

• C-alkylation, N-alkylation

•Conclusion

• Introduction

• Construction of C-C and C-N bonds

Hydrogen Autotransfer MethodologyHydrogen Autotransfer Methodology

Catalyst Hydrogen

taken

Hydrogen

given

Overall transformation

The hydrogen autotransfer process is a type of domino reaction.

a powerful tool for the construction of C−C and C−N bonds using alcohols :

• only water is generated as byproduct

• hazardous alkylating agents (alkyl halides) can be avoided Tietze, L. F. et al., Angew. Chem. Int. Ed. 1993, 105, 137. Pellissiser, H.et al., Tetrahedron. 2006, 62, 1619.

Sheldon, R. A. et al., Chem Ind. (London). 1992, 903.

Environmental AwarenessEnvironmental Awareness

atom efficiency:

Green chemistry metrics:

• Effective mass yield

• Carbon efficiency

• Atom efficiency

Sheldon, R. A. et al., Green Chem. 2007, 9, 1237.

Sheldon, R. A. et al., Chem Ind. (London). 1992, 903.

Taguchi, K. et al., J. Am. Chem. Soc. 2004, 126, 72

atom efficiency (%) = yield (%) × ∑ (equiv × Mw)i + ∑ (equiv × Mw)j

Mw of final product i = reagents,

j = catalysts and additives

• Reaction mass efficiency

• Environmental (E) factor

Enolates reaction with alkyl halides:

Hydrogen autotransfer process:

Alcohols as ElectrophilesAlcohols as Electrophiles

ideal electrophilic agents:

• low-molecular-weight leaving group

• minimum environmental impact of this group

How can alcohols be electrophiles?

H2O is the only waste material.

Deuterium-labelling experiments:

N-alkylation of amines:

Martinez, R. et al., Tetrahedron Lett. 2005, 46, 3683.

Okimoto, Y. et al., J. Am. Chem. Soc. 2002, 124, 1590.

--Alkylation of Ketones with Alkyl HalidesAlkylation of Ketones with Alkyl Halides

one of the most used methods is the coupling of enolate derivatives with alkyl halides.

• regioselective formation of enolates

• toxicity issue with some alkyl halides

great disadvantages:

Hydrogen autotransfer process:

complete regioselectivity :

Ketones:

Alcohols: Sakaguchi, S. et al., J. Org. Chem. 2001, 66, 4710.

Okimoto, Y. et al., J. Am. Chem. Soc. 2002, 124, 1590.

Taguchi, K. et al., J. Am. Chem. Soc. 2004, 126, 72

d’Angelo, J. et. al., Tetrahedron. 1976, 32, 2979

NN--Alkylation of Amines Alkylation of Amines

The alkylation reaction of amines is typically achieved by reaction with an alkyl halide.

• overalkylation

Secondary amines:

Hydrogen autotransfer process:

Hamid, S. A. et al., J. Am. Chem. Soc. 2009, 131, 1766.

Saidi, O. et al., Chem.Commun.. 2010, 46, 1541.

Tertiary Tertiary AAmines mines PPreparation reparation

tertiary amines prepared by secondary amines:

cyclic amines: acyclic amines:

ammonium salts:

Hamid, S. A. et al., J. Am. Chem. Soc. 2009, 131, 1766.

Yamaguchi, R. et al., Org. Lett. 2008, 10, 181.

Enantioselective Carbonyl AllylationEnantioselective Carbonyl Allylation

• Total Synthesis of 6-Deoxyerythronolide B

• Enantioselective carbonyl allylation

• Synthesis of pyrroles

• C-alkylation, N-alkylation

•Conclusion

• Introduction

• Construction of C-C and C-N bonds

• Carbonyl crotylation

Prevailing Protocols Rely On Prevailing Protocols Rely On

Allyl Metal ReagentsAllyl Metal Reagents The first Enantioselective Carbonyl Allylation:

other allyl metal reagents:

disadvantages: • stoichiometric byproducts generation

• multistep syntheses of ally metal reagents

• failed for small aliphatic groups

Catalytic Enantioselective ProtocolsCatalytic Enantioselective Protocols

the first highly enantioselective catalytic carbonyl allylations:

stoichiometric quantities of tin byproducts

highly moisture sensitive

Nozaki-Hiyama-Kishi reaction:

• stoichiometric quantities of metallic reductants such as SnCl2, or Et2Zn

Hargaden, G. C. et al., Adv. Synth. Catal. 2007, 349, 2407.

Allyl Metal Reagents Can Be Allyl Metal Reagents Can Be

Avoided Based on HAAvoided Based on HA A transfer hydrogenative carbonyl allylation method has been established based on hydrogen autotransfer

process

(R)-BINAP is for benzylic alcohols

Kim, S. I. et al., J. Am. Chem. Soc. 2008, 130, 14891.

OrthoOrtho--Cyclometalated ComplexCyclometalated Complex

effect of m-nitrobenzoic acid: X-Ray analysis of iridium complex:

iridium complex as a catalyticaly relevant entity: stereoinduction:

Benincori, T. et al., J. Org. Chem. 2000, 65, 2043.

Davis, D. L. et al., J. Am. Chem. Soc. 2002, 128, 4210.

Shimizu, H. et. al., Tetrahedron. 2005, 61, 5405.

Stereoselective Synthesis of the Stereoselective Synthesis of the

Marcolactone Core of (+)Marcolactone Core of (+)--NeopeltolideNeopeltolide Retrosynthesis:

transfer hydrogenative method:

Raghavan, S. et al., Org. Lett. 2012, 14, 2346.

Chen, W. et al., Eur. J. Org. Chem. 2005, 1665.

Ouellet, S. G. J. Am. Chem. Soc. 2005, 127, 32.

asymmetric allylboration:

DiastereoDiastereo-- and Enantioselective and Enantioselective

Carbonyl CrotylationCarbonyl Crotylation

• Total Synthesis of 6-Deoxyerythronolide B

• Carbonyl allylation

• Synthesis of pyrroles

• C-alkylation, N-alkylation

•Conclusion

• Introduction

• Construction of C-C and C-N bonds

• Diastereo- and Enantioselective

Carbonyl Crotylation

Indirect Stereoselective Carbonyl CrotylationIndirect Stereoselective Carbonyl Crotylation

the first generally highly diastereo- and enantioselective solution:

Ti-crotyl reagents:

multiple manipulations and multiple preformed organometallics are required

Si-crotyl reagents:

Hafner, A. et al., J. Am. Chem. Soc. 1992, 114, 2321.

Kim, H. et al., J. Am. Chem. Soc. 2011, 133, 6517.

--Methyl Allyl Acetate Mediated Methyl Allyl Acetate Mediated

antianti--Diastereoselective CrotylationDiastereoselective Crotylation

the first-generation iridium catalytic system:

• poor anti-diastereoselectivities

a second-generation ortho-cyclometallated iridium catalytic system:

Kim, S. I. et al., J. Am. Chem. Soc. 2009, 131, 2514.

m-nitrobenzoic acids screening: loading of acetate, concentration, and temperature :

Sun, X. et al., J. Org. Chem. 2008, 73, 1143.

Kim, I. S. J. Am. Chem. Soc. 2008, 130, 6340.

Chirally Modified Catalysts ScreeningChirally Modified Catalysts Screening

Zhang, Z. et al,. J. Org. Chem. 2000, 65, 6223.

diphosphines ligands:

ligand rigidity:

Kitamura, M. et al., Tetrahedron. Lett. 1991, 32, 4163.

Anger, D. J. et. al., Tetrahedron Asymmetry. 1997, 8, 3327.

A Range of A Range of Benzylic and Aliphatic AlcoholsBenzylic and Aliphatic Alcohols

Hafner, A. et al., J. Am. Chem. Soc. 1992, 114, 2321.

Kim, H. et al., J. Am. Chem. Soc. 2011, 133, 6517.

Carbonyl Carbonyl synsyn--CrotylationCrotylation

ruthenium-catalyzed processes:

Zbieg, R. J. et al., J. Am. Chem. Soc. 2011, 133, 10582.

proposed Catalytic Mechanism:

stereochemical model:

Crotylation via ButadieneCrotylation via Butadiene

Butadiene is a product of petroleum cracking and is produced about 12 × 106 metric tons annually

acid-base reaction of H2Ru(CO)(PPh3)3 and HX:

acids:

Zbieg, R. J. et al., Science. 2012, 336, 324.

Liao, S. et al., Angew. Chem. Int. Ed. 2010, 49, 628.

Inversion of DiastereoInversion of Diastereo-- and Enantioselectivityand Enantioselectivity

McInturff, L. R. et al., J. Am. Chem. Soc. 2012, 134, 20628.

Saito, T. et al., Adv. Synth. Catal. 2001, 133, 1141.

Structure of Ru(CO)(OAc)(TADDOL-phosphate)[(S)-SEGPHOS]

as Determined by single-crystal XRD analysis.

XX--ray Diffraction Analysis of ray Diffraction Analysis of

Ruthenium ComplexRuthenium Complex

X-Ray diffraction analysis: hydrometalation of the s-cis conformer

of butadiene:

syn: TADDOL-derivatives, kinetically preferred, (Z)-σ-allyl

anti: BINOL-derivatives, thermodynamically, (E)-σ-allyl

Zbieg, R. J. et al., Science. 2012, 336, 324.

Murakami, M. et al., Organometallics. 1999,18, 1326.

X = phosphate counterion

Proposed Mechanism for Proposed Mechanism for

Crotylation of ButadieneCrotylation of Butadiene syn-diastereo- and Enantioselectivity:

Xue, P. et al., Organometallics. 2004, 23, 4735.

Murakami, M. et al., Organometallics. 1999,18, 1326.

Regioselective Synthesis of PyrrolesRegioselective Synthesis of Pyrroles

• Total Synthesis of 6-Deoxyerythronolide B

• Carbonyl allylation and crotylation

• Regioselective Synthesis of Pyrroles

• C-alkylation, N-alkylation

•Conclusion

• Introduction

• Construction of C-C and C-N bonds

aryl ketones: alkyl ketones:

α-functionalized ketones :

lower yield :

• bulky 2,3-disubstituted diols

• weak nucleophiles

Aryl, Alkyl, and Aryl, Alkyl, and --Functionalized KetonesFunctionalized Ketones

Zhang, M. et al., J. Am. Chem. Soc. 2013, 135, 11384.

Benzylic KetoneBenzylic Ketones s and Ammoniaand Ammonia

N-nonsubstituted pyrroles:

benzylic ketones:

Brand, J. P. et al., J. Angew. Chem., Int. Ed.. 2009, 48, 9346.

Insight into the Possible MechanismInsight into the Possible Mechanism

Deuterium-labeling experiments:

No amino alcohol or amino

ketone intermediates

No deuterated product: dehydrogenation of the diol might be the rate-determining step.

Raghavan, S. et al., Angew. Chem., Int. Ed.. 2011, 50. 86.

Pigen, D. et al., Angew.Chem., Int. Ed. 2010, 49, 8130.

Proposed Reaction PathwaysProposed Reaction Pathways

Raghavan, S. et al., Angew. Chem., Int. Ed.. 2011, 50. 86.

Pigen, D. et al., Angew. Chem., Int. Ed. 2010, 49, 8130.

Ghosh, A. et al., Angew. Chem., Int. Ed 2004, 43. 1918.

Total Synthesis of 6Total Synthesis of 6--Deoxyerythronolide BDeoxyerythronolide B

• Total Synthesis of 6-Deoxyerythronolide B

• Carbonyl allylation and crotylation

• Synthesis of pyrroles

• C-alkylation, N-alkylation

•Conclusion

• Introduction

• Construction of C-C and C-N bonds

Total Synthesis of 6Total Synthesis of 6--Deoxyerythronolide B Deoxyerythronolide B

Erythromycin A is the first macrolide antibiotic.

the erythromycins tied to the evolution of synthetic organic chemistry:

• great impact on human medicine

• complex stereochemical relationships

C−C Bond-FormingTransfer Hydrogenation:

• two different methods for alcohol CH-crotylation

• 14 steps (longest linear sequence), 20 total steps

Gao, X. et al., J. Am. Chem. Soc. 2013, 135, 4223.

RetrosynthesisRetrosynthesis

fragment A:

fragment B:

Xuan, R. et al., J. Org. Chem. 2008, 73, 1456.

Gao, X. et al., J. Am. Chem. Soc, 2011, 336, 324.

The Synthesis of Fragment AThe Synthesis of Fragment A

Ru-catalyzed syn-crotylation of n-propanol:

fragment A prepared in 6 steps from propanol and butadiene:

McInturff, E. L. et al., J. Am. Chem. Soc. 2012, 336, 324.

Micoine, K. et al., J. Am. Chem. Soc. 2010, 132, 14064.

Evans Evans synsyn--aldol reactionaldol reaction

one step with Ru-catalyzed syn-crotylation:

six steps using evans syn-aldol reaction:

Michael, T. C. et al., J. Org. Chem. 2001, 66, 894.

Tokuyama, H. et al., Synthesis. 2009, 474.

The Synthesis of Fragment BThe Synthesis of Fragment B

anti-diastereo- and enantioselective Ir-catalyzed double crotylation:

fragment B prepared in eight steps:

Travis, B. R. et al., J. Am. Chem. Soc, 2002, 124, 3824.

White, J. D. et al., J. Org. Chem. 1994, 59, 3347.

Union of Fragment A and Fragment BUnion of Fragment A and Fragment B

Inanaga, T. et al., Chem. Soc, Jpn 1979, 52, 1989.

Freeman, P. K. et al., J. Org. Chem. 2002, 67, 5015.

Xuan, R. et al., J. Org. Chem. 2008, 73, 1456.

ConclusionsConclusions

C-alkylation:

• regioselective enolates can

be avoid

• high atom efficiency

N-alkylation:

• circumvent overalkylation problem

• water is the only waste material

carbonyl allylation:

• avoid allyl metal reagents

• high yield and excellent ee for

both aliphatic and benzyl alcohols

anti-crotylation:

• -methyl allyl acetate works for different

types of alcohols.

• butadiene not efficient for aliphatic alcohols

syn-crotylation:

• good yield and excellent ee for

both aliphatic and benzyl alcohols

• 2-silylbutadiene not commercially

availabe

pyrroles:

• low yield with large substituted diols

• high regioselectivity with unsymmetrical

diols

• Prof. Huang

• Group members

• All my other friends

• You

AcknowledgementAcknowledgement

Zhaojun, Weizhun, Issac, Hovig, Herbert, Steve, Qian,

Berm, Peng, Zeren, Mehdi.