Rapid Synthesis of Boc-2′,6′-dimethyl-l-tyrosine and Derivatives and Incorporation into Opioid Peptidomimetics

Abstract

The unnatural amino acid 2',6'-dimethyl-l-tyrosine has found widespread use in the development of synthetic opioid ligands. Opioids featuring this residue at the N-terminus often display superior potency at one or more of the opioid receptor types, but the availability of the compound is hampered by its cost and difficult synthesis. We report here a short, three-step synthesis of Boc-2',6'-dimethyl-l-tyrosine (3a) utilizing a microwave-assisted Negishi coupling for the key carbon-carbon bond forming step, and employ this chemistry for the expedient synthesis of other unnatural tyrosine derivatives. Three of these derivatives (3c, 3d, 3f) have not previously been examined as Tyr(1) replacements in opioid ligands. We describe the incorporation of these tyrosine derivatives in a series of opioid peptidomimetics employing our previously reported tetrahydroquinoline (THQ) scaffold, and the binding and relative efficacy of each of the analogues at the three opioid receptor subtypes: mu (MOR), delta (DOR), and kappa (KOR).

An Effective and Safe Enkephalin Analog for Antinociception

“…We, therefore, synthesized the acid version of our lead compound KK-102, which is the corresponding acid KK-103, and evaluated its pharmaceutical properties. KK-103 was synthesized by hydrolysis of the C -terminal methyl ester of KK-102 using LiOH in tetrahydrofuran (THF)/H 2 O [ 38 , 39 ]. KK-103 showed an almost identical relative DOR binding (68 ± 2% vs. 70 ± 1%) compared to its parent compound KK-102, both of which exerted a receptor binding that was most comparable to Leu-ENK ( Table 1 ).…”

Total Synthesis of Elmenols A and B and Related Rearranged Angucyclinones

“…We envisiaged the related scheme could be used for preparation of unnatural analogs, which we would like to demonstrate by way on the example on desmethyl compound 7 ‐ H and later on Elmenol analog 4 ‐ H . On the first step we performed bromination of 7‐bromo‐1‐tetralone in α‐position according to the modified literature procedure to obtain dibromoderivative 12 , [27] followed by palladium‐catalyzed beta‐elimination [28] to give the naphthol 10 ‐ H . Then naphthalene 10 ‐ H was converted to 7 ‐ H in two steps, as described above.…”

Synthesis of C3-symmetric star-shaped molecules containing α-amino acids and dipeptides via Negishi coupling as a key step

“…Thus, commercially available L-serine ( 3 ) was treated with acetyl chloride in methanol to give methyl ester 4 , which was subjected to N -Boc protection with di- tert -butyl dicarbonate (Boc 2 O) and triethylamine in tetrahydrofuran (THF) to obtain the N -Boc-serine methyl ester ( 5 ) in 93% yield [42]. Afterwards, the protected methyl ester 5 was subjected to iodination in the presence of iodine (I 2 ), triphenylphosphane (PPh 3 ) and imidazole in CH 2 Cl 2 at 0 °C to deliver the iodo derivative 6 in 63% yield [43–44]. Finally, the iodo compound 6 was treated with freshly activated Zn in DMF at room temperature to afford the zinc insertion product 7 (Scheme 1) [43].…”

“…Afterwards, the protected methyl ester 5 was subjected to iodination in the presence of iodine (I 2 ), triphenylphosphane (PPh 3 ) and imidazole in CH 2 Cl 2 at 0 °C to deliver the iodo derivative 6 in 63% yield [43–44]. Finally, the iodo compound 6 was treated with freshly activated Zn in DMF at room temperature to afford the zinc insertion product 7 (Scheme 1) [43].…”