Asymmetric reduction using

chiral catalyst

PPh2
FYI Only
RuCl2
PPh2

3
si face attack
CH3 H CH3
H2
OH OH
2 Ru(BINAP)Cl2
1 96% e.e.

Noyori and Knowles shared Nobel Prize with Sharpless in Chemistry, 2001
 Stoichiometric Chiral Reagents

Herbert C Brown
Nobel Prize 1979
Died 2004

FYI Only
Prochirality

Trigonal carbons, that are not stereogenic centres but can

be made into them, are prochirl.
• Each face can be assigned a label based on the CIP rules
• If the molecule is chiral, the faces are said to be diastereotopic.
• If the molecule is achiral, the faces are enantiotopic.
Clockwise
A face is labeled re if, when looking at that
face, the substituents at the trigonal atom are
arranged in decreasing Cahn-Ingold-Prelog
priority order in a clockwise order. 1
3
A face is labeled si if the priorities decrease in
counter-clockwise order. 2

* But the designation of the resulting chiral

center as S or R depends on the priority of the
incoming group.
Diastereoselective reactions

Si-face attack by PhMgBr is preferred

Si-face attack by H- is preferred

 Cram Model (1952) Felkin-Anh Model (1968, 77)
(Chelate-controlled) (Nonchelate-controlled)
Largest group will be away from carbonyl & Nu- will Largest group RL will be perpendicular to the carbonyl
attack from the smallest substituent side & Nu- will attack antiperiplanar to RL.

Bürgi–Dunitz
angle
Chelate vs nonchelate products
Addition of Grignard Reagent
(Chelate-controlled product)
Diastereoselective/Enantioselective Aldol Reactions
Zimmerman-Traxler TS Model (1957)
"six-membered transition states having a chair conformation."
 Z-enolate
Aldehyde from top

Aldehyde from bottom

 Evans Aldol Reaction
Z-enolate

Chiral auxiliary - Oxazolidinone

prepared from L-Valine in 3 steps

Zimmerman-Traxler TS Model
Si-face attack on aldehyde
 Control of enolate stereochemistry FYI Only
HC Brown et. al., J. Am. Chem. Soc. 1989, 111, 3441; J. Org. Chem. 1993, 58, 147.

Stereoselective Enolization- Elaiolide: Paterson, Lombert, Allerton

Org. Lett. 1999, 1, 19.
Diastereoselective Diels-Alder reaction

Diastereoselective alkylation
Enantioselective alkylation using a chiral auxiliary
 Conformation

The term “conformation” is used to denote

any one of the infinite number of
momentary arrangements of the atoms in
space that result from rotation about single
bonds.
The simplest molecule for which one may discuss rotation around a
carbon-carbon single bond is ethane. As the methyl groups rotate with
respect to each other, their hydrogen atoms become alternately
staggered and eclipsed.

The potential energy of the molecule varies with the angle of rotation
between two designated hydrogen atoms on adjacent carbons. This
angle is called “dihedral angle” (or, “torsion angle”).

2.9 kcal/mol
 (skew) (trans)

Gauche butane type interaction (van der Waals repulsive interaction)

Conformation and physical properties

Dipole moments

µ2 = Nantiµanti2 + Ngaucheµgauche2
Conformation and physical properties

Hydrogen Bonding
 Pro-R and pro-S
If two identical substituents are attached to a sp3-hybridized atom, the
descriptors pro-R and pro-S are used to distinguish between the two.

Promoting the pro-R substituent to higher priority than the other identical
substituent results in an R chirality center at the original sp3-hybridized
atom, and analogously for the pro-S substituent.

NMR spectra of such molecules

often show nonequivalence of
these protons appearing at
different chemical shifts.
 Determination of dihedral angle using NMR
Karplus equation

Martin Karplus
Nobel Prize in Chemistry 2013

Graph of the Karplus relation JHH vs (ø)

What is the dihedral angle between H1 and H2?
 Conformational Energy

18.0

15.0

12.0

9.0
-180 -135 -90 -45 0 45 90 135 180
H(5)-C(1)-C(2)-H(6)(degrees)
 Axial Chirality - in which a molecule does not possess a stereogenic
center, but an axis of chirality with restricted rotation leading to isomers
that are non-superimposable mirror images (Atropisomerism)

S R
Optically active adamantoids (Axial Chirality)

Optically active spiranes (Central Chirality)

 Helicenes
[n]Helicenes structures possess n angularly (ortho) annelated (fused) aromatic
rings, in which the steric repulsion of terminal rings force distortion from planarity,
leading to helical π-conjugated structures.

Longest helicene with 14

benzene rings

R-[7]-helicene S-[7]-helicene
Right-handed (P) Left-handed (M)
 Conformation in cyclohexane

CHAIR CHAIR
Stable conformations of some other six-membered rings

Half-chair is stabilized Boat form is stabilized

Stable conformations of some other six-membered rings

Twist
 Substituted cyclohexanes

Axial substitution
is destabilized due
to 1,3-diaxial
interactions

Axial substituents are also more

hindered, and are generally less
reactive:

Plus 0.9 kcal/mol for 1 gauche interaction

Dimethylcyclohexanes

Newman projection of cyclohexane

 1,3-cis more stable that 1,3-trans

1,4-trans more stable that 1,4-cis

 Axial H shows resonance at higher field than
equatorial H

Using 1H NMR chemical shift values, one can calculate K to be approx 5

corresponding to approx 83.3% equatorial product (-ΔG = 0.9 kcal/mol).
J. Org. Chem. 2015; pp 8134–8141
Why cis-decalin is higher in energy than trans-decalin?
Best examples of 6-membered rings are hexose or
pentose sugars in pyranose form. The most stable is
glucose that has all equatorial hydroxyl groups – β or α
anomeric sugars.
Coupling constant for anomeric H will tell us which
anomer it is.

hexose

pentose
 There are lots of
eclipsing strain in Conformations in cyclopentane
the planar form,
although there is
no angle strain.
Planar Reduction in
eclipsing strain

Further reduction in
eclipsing strain
One envelope to other

FYI Only
 Puckering of ribose sugar rings plays an import role in the
overall 3D structures of nucleic acids and their functions
While RNA has
predominantly the
C3’- endo conformation,
DNA may adjust and is
able to take on both
conformations.
 Cyclobutane Conformations

FYI Only