Reactions in Strong Acids. II.¹ New Concept in Amino Acid Chemistry: C-Derivatization of Amino Acids²

Protein oxidation and peroxidation

“…Thus hydrogen atom abstraction occurs preferentially adjacent to the–OH groups of Ser and Thr [ 37 ]. In contrast the protonated side-chain amine of Lys disfavours attacks at C-6, with abstraction occurring predominantly at C-4 and C-5 [ 33 , 34 , 38 , 39 ]. In each case, these reactions generate carbon-centred radicals whose fate is discussed below.…”

Synthesis of Halogenated α‐Amino Acids

“…Interestingly, Kollonitsch discovered that by varying the reaction conditions, chlorination could be directed predominantly to C-3 or C-4. For the synthesis of 3-chloroglutamic acid, the parent amino acid was irradiated with chlorosulfuric acid (6 M), whilst starting with glutamic anhydride in 3 M chlorosulfuric acid, 4-chloroglutamic acid was the major product [31]. An alternative approach to introduce a chloride at C-3 of glutamate was reported by Iwasaki et al in which 3-hydroxy-D,L-glutamic acid diethyl ester was treated with PCl 5 in CHCl 3 [82].…”

“…However, photochlorination of L-lysine in concentrated HCl was found to be both regio-and stereoselective, giving the erythro product, (2S,4S)-4-chlorolysine in 74% yield, which was then converted to g-hydroxy-L-lysine using silver nitrate and used in the synthesis of threo-g-hydroxyhomo-L-arginine [31,85].…”

“…Reaction of the alkenes with chlorine gave allyl chlorides 49, 50, and 51 in modest yields (28-37% In the 1960s, Kollonitsch et al described the radical chlorination of a series of a-amino acids under acidic conditions giving b-and g-chlorinated products [31]. It was shown that irradiation of L-isoleucine in either trifluoroacetic acid (TFA) or 50% sulfuric acid in the presence of chlorine gave the L-5-chloroisoleucine which was not purified but treated directly with base to give a concise synthesis of trans-L-3-methylproline in 33% yield [32].…”

Reflections on Process Research II

“…Over the years, Janos Kollonitsch, who began his Merck career in Process Research but then moved into Medicinal Chemistry, had developed a program of photohalogenation of medicinally important substrates in strong acid media to provide unusual and new halogenated analogs of the substrates. 5 Initially, the focus was on chlorination, but even 30 years ago the potential of fluorine in bioactive molecules was recognized. Janos and his co-workers developed a photofluorination protocol wherein substrates were dissolved in liquid HF at À78 C and photofluorinated employing trifluoromethylhypofluorite (CF 3 OF) and unfiltered UV light from a 1000-W high-pressure Hg/Xe lamp.…”