Hydrogen-Mediated C-C Coupling Beyond Hydroformylation: Michael J. Krische

Formation of C-C Bonds via Catalytic

Hydrogenation and Transfer HydrogenationProfessor Michael J. Krische University of Texas at Austin

BASF – 150th Anniversary CelebrationChicago, Illinois; June 22-24, 2015

Victor Grignard, C. R. Acad. Sci. 1900, 130, 1322.

1912

Paul Sabatier, C. R. Acad. Sci. 1896, 1240.

The Haber-Bosch Reaction

N2 + 3 H2 → NH3 100 M Tons/Yr

12% of GMP Reactions are Hydrogenations

Only 3% are Oxidations

Asymmetric H2: > 50% Chiral Compounds Made Industrially

Notwithstanding Biocatalysis/Resolution

OPRD 2005, 9, 253CE&N 9/05, 2005

Victor Grignard, C. R. Acad. Sci. 1900, 130, 1322.

1912

Paul Sabatier, C. R. Acad. Sci. 1896, 1240.

Largest Volume Application of Enantioselective Catalysis (1996, Metolachlor)

Victor Grignard, C. R. Acad. Sci. 1900, 130, 1322.

1912

Paul Sabatier, C. R. Acad. Sci. 1896, 1240.

Victor Grignard, C. R. Acad. Sci. 1900, 130, 1322.

Hydrogen-Mediated Carbonyl Addition

Hydrogenation: > 10% of GMP Reactions

Paul Sabatier, C. R. Acad. Sci. 1896, 1240.

1912

Victor Grignard, C. R. Acad. Sci. 1900, 130, 1322.

1912

Otto Roelen – Hydroformylation, 1938

Hydrogen-Mediated Carbonyl Addition

Hydrogenation: > 10% of GMP Reactions

Reviews: Angew. Chem. Int. Ed. 2009, 48, 34; Top. Organomet. Chem. 2011, 43, 107.

J. Am. Chem. Soc. 2008, 2747

X-Ray Crystal StructureRhL2(cod)

JACS 2008, 2747

X-Ray Crystal StructureRhL2*(cod)

JACS 2008, 2747

JACS 2006, 17051; Org. Lett. 2006, 5657; JACS 2008, 12592.

Oppolzer JACS 1993, 1593; Wipf JOC 1998, 6454

Reactants M.W. = C13H16O

Product M.W. = C13H18O

H2

Ni-Catalyzed Alkyne-Carbonyl Reductive Coupling: Montgomery JACS 1997, 6098; Jamison JACS 2003, 3442.

JACS 2007, 12644.

JACS 2007, 12644.

JACS 2005, 11269.

JACS 2006, 16448.

Angew. Chem. Int. Ed. 2006, 6885

H2

H2

C=O Addition via ReactantREDOX Pairs

C=N Addition via ReactantREDOX Pairs

Metal Price

01/2014-01/2015*Pt Pd Rh Ir Ru

$$ / Ounce 1,381 809 1,175 555 64

$$ / Mole 9,503 3,037 4,265 3,763 228

http://www.platinum.matthey.com

Merck Process Tetrahedron Asymm. 2003, 3581

JACS 2007, 15134; JACS 2011, 1141

ACIE 2015, 5465

JACS 2009, 5054; Org. Lett. 2010, 2514.JACS 2009, 5054; Org. Lett. 2010, 2514.

JACS 2009, 5054; Org. Lett. 2010, 2514.

JACS 2015, 3161

JACS 2015, 3161

2015 – Submitted for Publication

JACS 2015, 1798

JACS 2009, 10366; Nature Chem. 2011, 287; ACIE 2011, 5687; Chem. Sci. 2013, 1876.

Angew. Chem. Int. Ed. 2015, In Press; Submitted for Publication

Angew. Chem. Int. Ed. 2012, 2972

Angew. Chem. Int. Ed. 2012, 7830

Polyketide Natural Products: Commercial Medicines From Soil Bacteria

Polyketide Natural Products: Commercial Medicines From Soil Bacteria

Review: Nat. Prod. Rep. 2014, 31, 504

Review: Nat. Prod. Rep. 2014, 31, 504

Polyketide Natural Products: Commercial Medicines From Soil Bacteria

Redox-Triggered C-C Coupling of Dienes

Classical Crotylation: Brown JACS 1983, 2092

JACS 2008, 6338; JACS 2008, 14120.

JACS 2008, 6338; JACS 2008, 14120.

Redox-Triggered C-C Coupling of Dienes

Science 2012, 336, 324; JACS 2012, 20628.

Science 2012, 336, 324; JACS 2012, 20628.

Science 2012, 336, 324; JACS 2012, 20628.

Science 2012, 336, 324; JACS 2012, 20628.

Science 2012, 336, 324; JACS 2012, 20628; Computation - Houk JACS 2015 In Press.

X-Ray Crystal Structure

Science 2012, 336, 324; JACS 2012, 20628 ; Computation - Houk JACS 2015 In Press.

X-Ray Crystal Structure

Science 2012, 336, 324; JACS 2012, 20628.

Tsuji-Trost Reaction

Redox-Triggered Carbonyl Addition

Hartwig ACIE 2008, 1928

JACS 2008, 6340JACS 2008, 14891.

JACS 2008, 6340JACS 2008, 14891.

JACS 2008, 6340; JACS 2008, 14891. JOC 2011, 2350.

JACS 2008, 6340; JACS 2008, 14891. Org. Lett. 2012, 6302.

JACS 2008, 6340; JACS 2008, 14891. Org. Lett. 2012, 6302.

Angew. Chem. Int. Ed. 2013, 3195; Chem. Eur. J. 2014, 13382.

Recovery and Recycling of Catalyst

1st Run

2nd Run

3rd Run

JACS 2014, 8911

JACS 2014, 8911

JACS 2012, 11100; ACIE 2011, 3493; ACIE 2011, 4173

Review: Angew. Chem. Int. Ed. 2014, 9142

ACIE 2009, 5018; JACS 2010, 15559

The Horeau Principle: Tetrahedron 1973, 1055

ACIE 2009, 5018; JACS 2010, 15559

ACIE 2009, 5018; JACS 2010, 15559

Prior Syntheses (LLS)45 Steps (Mori)31 Steps (Rychnovsky )29 Steps (Evans)

20 Steps (LLS) JACS 2010, 15559

JACS 2011, 12795

JACS 2011, 12795

JACS 2011, 12795

Prior Syntheses35 Steps (Danishefsky)

28 Steps (Cossy)22 Steps (Leighton)

38 Steps (Miyashita)49 Steps (Guindon) JACS 2015, In Press

13 StereocentersNow

13 Steps

Over 18 Total Syntheses (1979-2015)

JACS 2013, 4223

6-Deoxyerythronolide BMasamune (26 Steps)Danishefsky (39 Steps)

Evans (23 Steps), White (23 Steps)JACS 2013, 4223

6-Deoxyerythronolide BMasamune (26 Steps)Danishefsky (39 Steps)

Evans (23 Steps), White (23 Steps)JACS 2013, 4223

Org. Lett. 2006, 891; Org. Lett. 2009, 3108;JACS 2011, 13876; JACS 2014, 9142.

Org. Lett. 2006, 891; Org. Lett. 2009, 3108;JACS 2011, 13876; JACS 2014, 9142.

JACS 2011, 13876; JACS 2014, 9142.

Review - Nat. Prod. Rep. 2014, 504.

Review - Nat. Prod. Rep. 2014, 504.

Victor Grignard, C. R. Acad. Sci. 1900 , 130, 1322.

Paul Sabatier, C. R. Acad. Sci. 1896, 1240.

Hydrogen-Mediated Carbonyl Addition

Reviews - Nat. Prod. Rep. 2014, 504; Angew. Chem. Int. Ed. 2014, 9142

1912

Victor Grignard, C. R. Acad. Sci. 1900 , 130, 1322.

Paul Sabatier, C. R. Acad. Sci. 1896, 1240.

Hydrogen-Mediated Carbonyl Addition

Reviews - Nat. Prod. Rep. 2014, 504; Angew. Chem. Int. Ed. 2014, 9142

1912

February 7, 2015