Tuesday, April 10, 2012

N-de(alpha-methyl)benzylation in presence of carbon-carbon double bonds in the synthesis of (+)-Pseudodistomin D


Amine as alpha methyl benzyl: Stephen Davies' group at Oxford used the (S)-N-alpha-methylbenzyl group to attach the (S)-N-allyl-N-alpha-methyl-benzylamide on a conjugated ester stereoselectively (>99% ee).  After subsequent Grubb's metathesis to create a 6-membered ring, they removed the chiral auxiliary (i.e alpha-methylbenzyl group) by hydrogenation using Pd(OH)2/C as the catalyst in methanol at 50 C.  Along similar lines, they attached the (S)-N-allyl-N-alpha-methyl-paramethoxybenzylamine group on the same conjugated ester stereoselectively (>90% ee).  This time, the chiral auxilliary (i.e alpha-methyl-paramethoxybenzyl group) was removed by using formic acid and triethylsilane, which also kept the isolated carbon-carbon double bonds intact.
Installation: (S)-alpha-methyl-paramethoxybenzylamine (>99% ee) is commercially available.
Survived: Grubbs
Removal: H2, Pd(OH)2/C;  also used HCOOH/Et3SiH

Reference: Organic Letters, 2012, 14, 1672-1675

The attack of lithium (S)-alpha-methyl-paramethoxybenzylamine on a conjugated ester creates the first stereocenter, which is then used to direct the next two sterocenters via a iodolactonization reaction.  However, there is a ~ 10% drop in stereoselectivity between using  (S)-alpha-methyl-paramethoxybenzylamine (ee = 90%) and (S)-alpha-methyl-benzylamine (ee =99%) - this difference is not explained and is carried throughout the synthesis.  After the iodolactonization step, a epoxide is formed which is then regioselectively (3:1 ratio) opened by NaN3 (in presence of NH4Cl in DMSO at 80 C).  The azide is reduced to the corresponding amine using Staudinger conditions - abeit with polymer supported PPh3 to ease the purification.