“Free of Base” Sulfa-Michael Addition for Novel o-Carboranyl-DL-Cysteine Synthesis

Abstract

The sulfa-Michael addition reaction was applied for the two-step synthesis of o-carboranyl cysteine 1-HOOCCH(NH2)CH2S-1,2-C2B10H11 from the trimethylammonium salt of 1-mercapto-o-carborane and methyl 2-acetamidoacrylate. To avoid the decapitation of o-carborane into its nido-form, the “free of base” method under mild conditions in a system of two immiscible solvents toluene-H2O was developed. The replacement of H2O by 2H2O resulted in carboranyl-cysteine containing a deuterium label at the α-position of the amino acid 1-HOOCCD(NH2)CH2S-1,2-C2B10H11. The structure of the protected o-carboranyl cysteine was determined by single-crystal X-ray diffraction. The obtained compounds can be considered as potential agents for the Boron Neutron Capture Therapy of cancer.

Synthesis of Charge-Compensated nido-Carboranyl Derivatives of Sulfur-Containing Amino Acids and Biotin

“…A separate group of carborane derivatives of ( S )-amino acids is represented by compounds in which the boron polyhedral fragment is attached to a sulfur atom. Synthesis of carborane-containing derivatives of ( RS )-cysteine ( 1a,b ), ( S )-homocysteine ( 2 ), and cysteine homologues ( 3a – c , 4a – c ) as well as amino acids containing a mercaptododecaborane residue ( 5 – 7 ) ,, (Figure ) is commonly based on the alkylation of the corresponding carboranyl thiols and dodecaboranyl thiols, in which the B–S bond is already present. The introduction of ( o -carboran-1-yl)­phenyl substituent at the thiol groups of cysteine and cysteine-containing peptides using a bis -sulfonated biarylphosphine-ligated Pd reagent has been reported .…”

Carborane: Dedicated to the Work of Professor Alan Welch

“…The recent synthesis and biological evaluation of m-carboranyl-cysteine as an agent for boron neutron capture therapy inspired the group to synthesize the analogue based on readily available 1-mercapto-o-carborane. The synthesis was optimised by using the "free of base" method [2].…”