Green Chemistry Principle #8

Reduce Derivatives

Unnecessary derivatization (use of blocking groups, protection/deprotection, temporary modification of physical/chemical processes) should be minimized or avoided if possible, because such steps require additional reagents and can generate waste.

By Peter J. Dunn, Green Chemistry Lead, Pfizer

One of the key principles of green chemistry is to reduce the use of derivatives and protecting groups in the synthesis of target molecules. One of the best ways of doing this is the use of enzymes. Enzymes are so specific that they can often react with one site of the molecule and leave the rest of the molecule alone and hence protecting groups are often not required.

A great example of the use of enzymes to avoid protecting groups and clean up processes is the industrial synthesis of semi-synthetic antibiotics such as ampicillin and amoxicillin.

In the first industrial synthesis Penicillin G (R=H) is first protected as its silyl ester [R = Si(Me)3] then reacted with phosphorus pentachloride at -40oC to form the chlorimidate 1 subsequent hydrolysis gives the desired 6-APA from which semi-synthetic penicillins are manufactured.

Industrial Synthesis of Penicillin
(i) TMSCl then PCl5, PhNMe2, CH2Cl2, -40oC (ii) n-BuOH, -40oC, then H2O, 0oC (iii) Pen-acylase, water

This synthesis has been largely replaced by a newer enzymatic process using pen-acylase. This synthesis occurs in water at just above room temperature. The new synthesis has many advantages from a green perspective one of which is that the silyl protecting group is not required.

More than 10,000 metric tons of 6-APA is made every year and much of it by the greener enzymatic process so this is a fantastic example of Green Chemistry making a real difference.

More Resources

The Importance of Green Chemistry in Process Research and Development

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