“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.