Handout 1B: Synthesis of Amino Acids

2 Important Keys of Synthesizing Amino Acids

• incorporating the amino and carboxyl groups in the appropriate positions

• incorporating the appropriate chiralirty

Ester Hydrolysis: Basic

• can occur in acidic or basic conditions

• saponification (basic): stable species are hydroxide, alkoxide, alcohol and water

  • any O atom should be neutral of have formal charge of -1

  • ultimate product is RCO₂^-, unless there’s an acid workup

  • not reversible, since the carboxylate is non electrophilic w.r.t alkoxide

Ester Hydrolysis: Acidic Conditions

• reversible

• ester must be protonated first to make it electrophilic enough to react w/ water

• nucleophile is water

Gabriel Synthesis

• involves addition of potassium phthalimide to diethyl-2-bromomalonate (phthalimide allows for a single addition)

  • the ensuing diester is hydrolyzed to the diacid, then decarboxylated then further hydrolyzed

  • the imide is hydrolyzed to yield an amine, diacid and phthalic acid

• Gabriel synthesis yields a racemic product: the tautomerization following the decarboxylation entails protonation at the ⍺-carbon, which will occur 50:50 from each side

Hydrolysis of Phthalimide

Enantiospecific Process

• a starting enantiomer gives predominantly one enantiomeric product; the other starting enantiomer will give the other enantiomeric product

Chiral Auxiliary

• homochiral (one enantiomer) helper molecule that is incorporated into an achiral molecule of interest

• helps it achieve a stereoselective process and then revmoed, leaving a chiral molecule that is not racemic

• we use (1R, 2S)-2-amino-1,2-diphenylethanol for enantiospecific amino acid synthesis

• 1st step: an SN2 reaction b/w the amine (more nucleophilic than the alcohol) and the ⍺-bromoester yields an intermediate that quickly cyclizes to a six-membered ring

  • the low nucleophilicity of the alcohol is compensated by the intramolecularity of the reaction

• a weak based mops up the acid produced and thus helps convert the remaining starting material from an ammonium to an amine

2nd Step

• protects the amine as a carbamate (t-Boc)

• the carbamate is not nucleophilic

3rd Step

• NaHMDS is a strong base that is sterically hinderedl it will pull off any acidic proton, but is a poor nucleophile

• the deprotonation (3rd step) is not stereoselective, the less hindered proton may be removed preferentially, but the ensuing anion inverts rapidly

• this anion will react from the face opposite that of the large phenyls, which block the electrophile from coming in from the top

• this key step is a diastereoselective reaction, and ultimately after completion of all steps, leads to an enantioselective process

Final Steps

• TFA removes the Box group and hydrogenolysis of the benzylamine and benzyl ester readily break the benzyl C-N and C-O bonds

Enantioselective A.A Synthesis using a Chiral Auxiliary