Catalytic Olefin Isomerization

1
Catalytic Olefin Isomerization

• RuHCl(PPh3)3 will hydrogenate olefins in the
  presence of H2, but it also isomerizes a-olefins
  to internal olefins through reactions of the Ru-H
  bond.

2
Catalytic Olefin Isomerization - Product
Distribution
4-centred planar transition state
3
Enantiomers and their Properties

• That 2-butanol and its mirror
• image cannot be superimposed
• shows that these are two
• different molecules
• these stereoisomers
• are enantiomers
• Chiral molecules exist as enantiomers
• due in most cases to the presence of
• an asymmetric carbon
• While the influence of chirality on biological
  activity can be pronounced, the physical
  properties of enantiomers are identical except
  for optical rotation.

4
Chiral Compounds with Differing Biological Effects
5
Diastereomers and their Properties

• Stereoisomers that are not mirror images of each
  other are called diastereomers.
• They may chiral molecules (2,3-pentanediol,
  below) but need not be, as seen for cis- and
  trans-2-butene.
• (2R, 3R) (2S, 3R)
• (2R, 3S) (2S, 3S)
• Diastereomers have different melting points,
  boiling points, refractive indices, heats of
  formation and other physical properties.
• Reaction of a racemic mixture with a single
  enantiomer generates isolable diastereomers.

6
Production/Isolation of Chiral Compounds

• Optical Purity
• where a is the specific rotation of the mixture
  and ao is that of the pure enantiomer
• Enantiomeric Excess (ee)
• Methods of producing/isolating asymmetric
  compounds
• Kinetic resolution and/or selective
  crystallization of racemates
• Fermentation
• Asymmetric transformations of prochiral compounds
• enzyme catalyzed functionalizations
• chemical hydrogenation, epoxidation, etc.

7
Catalytic Asymmetric Hydrogenation

• A leading example is the synthesis of L-dopa, an
  optically active drug generated from non-chiral
  starting materials for the treatment of
  Parkinsons disease.

Phosphine ligand of rhodium catalyst precursor
8
Catalyst Precursors for Selective Hydrogenation

• Horner and Knowles at Monsanto (1968) prepared an
  asymmetric phosphine which, when used in the
  place of PPh3 in Wilkinsons catalyst, generated
  enantioselectivity in the hydrogenation of
  prochiral olefins.
• Refinements in ligand structure
• (steric bulk and basicity)
• led to steady improvements
• in enantiomeric excess.
• Best results were observed
• for bidentate phosphines.

9
Catalyst Precursors for Selective Hydrogenation
10
Catalyst Precursors for Selective Hydrogenation

• Ruthenium-base systems have a broad
• range of utility as asymmetric catalysts.
• a,b-unsaturated carboxylic acids are
• hydrogenated in high yield and ee
• (S-Naproxen, below) as well as
• allylic alcohols.
• Note that the BINAP ligand is an
• example of a chiral, bidentate phosphine
• by virtue of it having atropisomeric forms
  (isomers that can be separated only because
  rotation about a single bond is prevented).

11
Catalyst Precursors for Selective Hydrogenation

• Organometallic compounds of the
  Schrock/Osborn-type have proven to be more
  selective hydrogenation catalysts than the
  Wilkinson derivatives
• This catalyst precursor is readily activated by
  H2 to generate a Rh(I) complex that is
  coordinated with solvent.

12
Substrate Coordination in Asymmetric
Hydrogenations

• Achieving high enantiomeric excesses seems to
  require a
• substrate that is capable of
• bidentate coordination.
• This secondary
• coordination generates
• diastereomeric adducts
• with rigid
• phosphine/
• substrate
• arrangements.
• Hydroxy, carbonyl, and
• amino, groups in an
• a-position to the double bond
• are suitable.

13
Hydrogenation of Dehydroamino Acid Derivatives
14
Hydrogenation Mechanism - Achiral Phosphines

• Mechanism of the Rh(DIPHOS) catalyzed
  hydrogenation of
• methyl-(Z)-a-acetamidocinnamate (MAC).

15
Reaction Coordinate of an Enantioselective
Synthesis

• To achieve high enantiomeric
• excess, the diastereomeric
• transition states of the rate
• determining steps must be
• substantially different in energy.
• The theoretical ee is a strong
• function of D(DG) as shown to
• the left.

16
Enantioselective Hydrogenation Mechanism
k1 k-1
k1 k-1