The chiral C-alkylation described in this patent uses a chiral phase-transfer catalyst has a methyl group on the nitrogen and this is not common for the Maruoka-type azepinium chiral quats. The reaction proceeds well with only 0.5 mole% of the chiral phase-transfer catalyst. This is an unusually low amount relative to other chiral PTC reactions.
As always, chiral PTC reactions are performed in a non-polar solvent to push the reactants and catalyst together into a tighter configuration to enhance chiral recognition.
After the first C-alkylation, the “second alkylating agent” is intramolecular and rearranges. It is interesting that high ee is achieved.
It should be noted that the ester is not hydrolyzed under these PTC conditions. Indeed, phase-transfer catalysis excels in protecting water-sensitive and base-sensitive from aqueous base.
A small amount of the wrong diastereomers is formed (about 3% using the catalyst shown above in Example 12) and is selectively converted into a seven membered diene ring containing a nitrogen, by heating. This facilitates separation from the desired product.
If your company can benefit from improved process performance, now contact Marc Halpern of PTC Organics Inc. to explore achieving low-cost high-performance green chemistry using phase-transfer catalysis in the shortest development time.
About Marc Halpern
Dr. Halpern is founder and president of PTC Organics, Inc., the only company dedicated exclusively to developing low-cost high-performance green chemistry processes for the manufacture of organic chemicals using Phase Transfer Catalysis. Dr. Halpern has innovated PTC breakthroughs for pharmaceuticals, agrochemicals, petrochemicals, monomers, polymers, flavors & fragrances, dyes & pigments and solvents. Dr. Halpern has provided PTC services on-site at more than 260 industrial process R&D departments in 37 countries and has helped chemical companies save > $200 million. Dr. Halpern co-authored five books including the best-selling “Phase-Transfer Catalysis: Fundamentals, Applications and Industrial Perspectives” and has presented the 2-day course “Practical Phase-Transfer Catalysis” at 50 locations in the US, Europe and Asia.
Dr. Halpern founded the journal “Industrial Phase-Transfer Catalysis” and “The PTC Tip of the Month” enjoyed by 2,100 qualified subscribers, now beyond 130 issues. In 2014, Dr. Halpern is celebrating his 30th year in the chemical industry, including serving as a process chemist at Dow Chemical, a supervisor of process chemistry at ICI, Director of R&D at Sybron Chemicals and founder and president of PTC Organics Inc. (15 years) and PTC Communications Inc. (20 years). Dr. Halpern also co-founded PTC Interface Inc. in 1989 and PTC Value Recovery Inc. in 1999. His academic breakthroughs include the PTC pKa Guidelines, the q-value for quat accessibility and he has achieved industrial PTC breakthroughs for a dozen strong base reactions as well as esterifications, transesterifications, epoxidations and chloromethylations plus contributed to more than 100 other industrial PTC process development projects.
Dr. Halpern has dedicated his adult life to his family and to phase-transfer catalysis (in that order!).
