Cram’s Chelation Model

 When a metal atom is used in a chemical reaction, they affect the

stereochemical outcome of the reaction due to chelation, which is when the

metal atom coordinates to other atoms in the molecule, especially atoms like

oxygen and gives only one stereoisomer

 If the ketone contains a α-group such as -OH, -NH2 and O-CH3 which is able

to coordinate with the metallic part of the reagent to form a five-membered

ring.

 The nucleophile preferentially approaches the electrophilic carbon from the

side of CH3.

 If the chelating group is Li, the cyclic model predicts the same

stereochemistry as the open chain model, but if it is CH 3 or Ph opposite

stereochemistry follows.

 Asymmetric induction through chelate model is usually high.

Felkin-Anh Model

 In this model, two reactive conformations (Structure 1 and Structure 2) have

been considered in which either the largest (R L) or the most electron-

withdrawing group (which provides the greatest σ* - π* overlap with the

carbonyl π* orbital) at Cα is placed at right angle to the C=O double bond.

 Between the two, the first with R M opposing C=O and RS gauche to R is

usually preferred.

 The non-bonded interactions which involve R’ and RS (rather than R’ and RM

as in Structure 2) are thus minimized.

 The model predicts the same stereochemistry as Cram's but provides a more

quantitative assessment of 1,2-asymmetric induction.

 A third conformation (Structure 3) may make some contribution but is

generally ignored (unfavorable steric interactions).

(Structure - 1) (Structure - 2) (Structure - 3)

Cyclophanes

 The compounds in which two benzene rings are joined by methylene bridges

on either side between para positions and show atropisomerisms. Such

compounds are known as paracyclophanes.

 Paracyclophane with m = n = 2 is optically stable.

 In the case of unsymmetrically substituted paracyclophanes, the presence of

even one substituent (COOH group) in any of the benzene rings makes the

structure chiral with a plane of symmetry.

 If the COOH group is replaced by the amino group and by chlorine and

hydroxyl, the optical activity is retained.

 The absolute configuration of a paracyclophane, whose optical activity is due

to the chirality of the paracyclophane structure and an asymmetric centre in

the side chain (R = CH2–CHOH–CH3), is given below.

  Paracyclophanes having sulphur-containing bridges are also known.

 Cyclophanes having bridges in meta position are called metacyclophanes and

such cyclophanes can exist in optically active forms.

 Some paracyclophanes contain only one aromatic ring and an aliphatic bridge

in the para position. Some examples of such compounds are given below.

 The presence of substituents in the benzene ring or in the bridge makes such

paracyclophanes chiral.

SAMP/RAMP as Chiral Auxiliaries

  The Enders SAMP/RAMP hydrazone alkylation reaction is an asymmetric

carbon-carbon bond formation reaction facilitated by pyrrolidine chiral

auxiliaries.

 This method is usually a three-step sequence,

1. The first step is to form the hydrazone between (S)-1-amino-2-

methoxymethylpyrrolidine (SAMP) or (R)-1-amino-2-

methoxymethylpyrrolidine (RAMP) and a ketone or aldehyde.

2. Afterwards, the hydrazone is deprotonated by lithium diisopropylamide

(LDA) to form an azaenolate, which reacts with alkyl halides or other

suitable electrophiles to give alkylated hydrazone species with the

simultaneous generation of a new chiral center.

3. Finally, the alkylated ketone or aldehyde can be regenerated by ozonolysis

or hydrolysis.

 This reaction is a useful technique for asymmetric α-alkylation of ketones and

aldehydes, which are common synthetic intermediates for medicinally

interesting natural products and other related organic compounds.

Mechanism
  The Enders SAMP/RAMP hydrazone alkylation begins with the synthesis of

the hydrazone from a N,N-dialkylhydrazine and a ketone or aldehyde.

 The hydrazone is then deprotonated on the α-carbon position by a strong

base, such as lithium diisopropylamide (LDA), leading to the formation of a

resonance stabilized anion - an azaenolate.

 This anion is a very good nucleophile and readily attacks electrophiles, such

as alkyl halides, to generate alkylated hydrazones with simultaneous creation

of a new chiral center at the α-carbon.

Applications

1. Synthesis of zaragozic acid A

The chiral hydrazone is formed through Enders' hydrazone alkylation

reaction. The subsequent ozonolysis and Wittig reaction led to the formation of

zaragozic acid A, which is a potent medicine for coronary heart disease.

2. Synthesis of denticulatin A and B

 An allyl iodide reacts with the azaenolate to give a chiral hydrocarbon chain.

The ketone was transformed after several steps into denticulatin A and B -

polypropionate.

3. Synthesis of the derivative of arteannuin

(-)-C10-demethyl arteannuin B is a structural analog of the antimalarial

artemisinin. The alkylated hydrazone is obtained through the Enders' alkylation

reaction. This intermediate was then elaborated into (-)-C10-demethyl arteannuin B.

4. Synthesis of epothilone A

Epothilone A and B are the effective anticancer drugs. Ender's alkylation

reaction was utilized the synthesis to install the stereogenic center at C8.