Asymmetric induction - need to provide chiral information consider a reaction on enantiotopic faces:

Re-face Si-face –––– O CNO CN O

H H H NC H C CN CH3 3 H3C

without chiral racemic mixture

Δ ‡ Δ ‡ information GS GR ΔΔ ‡ G 0 3.4 5.3 11.1 [kJ/mol] R:S 50:50 80:20 90:10 99:1 % ee0 608098 at 20°C with chiral

information ΔG ‡ ΔG ‡ S R one enantiomer preferentially

- chiral information often provided in reactant itself 2. 1,2-Induction

- diastereoselective reaction: one diastereomer formed preferentially - here: nucleophilic addition to a carbonyl group - 1,2: the α-C atom adjacent to the prochiral carbonyl group is a C* - the preferred face of the nucleophilic attack can be predicted

example Which of the two diastereomers is the major product?

H + CH3MgI H H Ph Ph + Ph hydrolysis O OH HO

A. Cram’s Rule (1952) (D.J. Cram, UCLA, 1987 Nobel Prize, with J.-M. Lehn and C.J. Pedersen) - simplest solution to the problem - based on steric considerations for nucleophilic attack on C=O - principle: - assume conformation with largest substituent away from O - attack from less crowded face of the ground state molecule 2. 1,2-Induction continued

- stepwise solution to the problem:

H + CH3MgI H H Ph Ph + Ph hydrolysis O OH HO - - identify the nucleophile: CH3 O - identify the appropriate conformation: Ph anti to O Ph H - draw molecule in a Newman projection and identify the least hindered face:

O O H CH3 view - CH3 this is Cram’s rule Ph H Si Ph H OH H H CH3 H C H - determine the product after hydrolysis: 3 Ph S Ph H HO - So, here attack onto the Si face gives an S configuration for an S,S diastereomer:

H + CH3MgI R H S H Ph S Ph S + Ph S hydrolysis O OH HO minor major 2. 1,2-Induction continued

- Cram’s rule is easy to apply and often leads to the correct product, but - Cram’s rule works with a fundamentally wrong assumption: - the differentiation is in ΔΔG‡, so not the ground state, but the TS is important

B. Felkin-Anh Model (1974-80) - approximation of the TS geometry - principle: - Nu attacks opposite of largest substituent - Nu attacks away from O

same example

Which of the two diastereomers is the major product?

H + CH3MgI H H Ph Ph + Ph hydrolysis O OH HO 2. 1,2-Induction continued

- stepwise solution to the problem:

H + CH3MgI H H Ph Ph + Ph hydrolysis O OH HO - - identify the nucleophile: CH3 - draw the TS in a Newman projection and identify the least hindered path:

O O O M S S M L L this is the Felkin-Anh model L S M H H H - Si from Cram’s rule Nu Nu-

OH H H3C - determine the product after hydrolysis: H C Ph H 3 Ph S H H HO - Again, here attack onto the Si face gives an S configuration for an S,S diastereomer:

H + CH3MgI R H S H Ph S Ph S + Ph S hydrolysis O OH HO minor major 2. 1,2-Induction continued

- the trajectory of attack: the Bürgi-Dunitz trajectory

O M in a π* L molecular orbital C=O S H picture: Nu-

109°

- attack onto the π*-orbital of the C=O - attack away from O