CHIRAL METHODOLOGY Asymmetric Reactions – Part One

What is asymmetric hydrogenation and why is it industrially important?

Adding H₂ across C=C, C=O, or C=N using chiral metal catalysts. Important due to high efficiency (TON/TOF), high ee, and industrial scalability

What variables must be optimized in asymmetric hydrogenation?

Hydrogen source, pressure, temperature, solvent, metal (Rh, Ru, Ir), and chiral ligand.

How can you make a chiral reducing agent from LiAlH₄?

Add a chiral diol and a simple alcohol (ROH) to form a chiral aluminum hydride complex for enantioselective carbonyl reduction.

What is atropisomerism and how does it create chirality?

Chirality from restricted rotation around a single bond (e.g., in biphenyls with bulky ortho substituents). Results in non-superimposable mirror images

in the example shown, which atropisomer is more expensive and why?

he (R)-enantiomer (clockwise twist) is more expensive — likely due to being the biologically active form or harder to synthesize.

What is BINAL-H and how does it achieve high enantioselectivity?

Chiral reducing agent from BINOL + AlH₃. Works via a chair-like 6-membered transition state that controls hydride delivery to one face of the carbonyl.

What causes the high selectivity in BINAL-H reductions?

n-π repulsion between the ketone’s alkyl group and BINOL’s aromatic system disfavors one transition state, favoring the other.

Name four chiral catalysts/reagents and their uses.

1. CBS reagent – ketone reduction

2. Alpine-Borane – alkyne reduction

3. Ru-BINAP-diamine – asymmetric hydrogenation (Noyori)

4. DIP-Chloride – stereoselective reduction (Brown)

How does Alpine-Borane achieve stereoselective alkyne reduction?

The bulky α-pinene group blocks one face of the alkyne, directing hydride delivery to the less hindered side

What are two methods for asymmetric imine reduction?

1. Iridium-catalyzed H₂ hydrogenation (high pressure, >99% ee)

2. Transfer hydrogenation with HCOOH/NEt₃ (no high pressure, 97% ee)

If a reaction gives 32% ee in favor of S, what is the % of R?

34% R (S = 66%, R = 50 – 16 = 34%)

Why does replacing isopropyl with phenyl increase ee?

Phenyl is larger, rigid, and engages in extra steric/electronic interactions with the catalyst, improving facial discrimination.

How can you separate enantiomers after a reaction?

1. Chiral column chromatography

2. diastereomeric salt formation,

3. kinetic resolution.

What is the stereochemical outcome of SN2 vs SN1 reactions?

SN2 = Inversion (backside attack). SN1 = Racemic mixture (carbocation intermediate).

What does the Mitsunobu reaction guarantee?

SN2 substitution with complete inversion of configuration at alcohols.

What two reagents are essential for the classic Mitsunobu reaction?

1. PPh₃ (triphenylphosphine)

2. DEAD (diethyl azodicarboxylate)

What are the byproducts of the Mitsunobu reaction and why do they matter?

O=PPh₃ (stable) and reduced DEAD. The strong P=O bond formation drives the reaction forward.

What type of nucleophile is required for Mitsunobu and why?

Acidic nucleophile (pKa < 15) so it can be deprotonated to become a good attacking Nu⁻

Give three examples of Mitsunobu nucleophiles.

Carboxylic acids (pKa ~4-5), phenols (pKa ~10), phthalimide (pKa ~8-9)

Why is the 2019 Mitsunobu advancement important for drug discovery?

Greener, safer, higher atom economy, no toxic byproducts, easier scale-up for pharmaceutical synthesis

How does chiral catalysis relate to drug safety?

One enantiomer may be therapeutic; the other may be toxic or inactive. Asymmetric synthesis ensures high ee of the active form.