Facile Synthesis of trans-S-1-Propenyl-L-Cysteine Sulfoxide (Isoalliin) in Onions (Allium cepa) (2011)

Scheme 1 Allium species such as onions (Allium cepa) and garlic (Allium sativum) contain a variety of sulfur compounds which exhibit significant biological activities including anticarcinogenic, antitumorigenic, antimutagenic, antimicrobial, immunomodulatory, cardiovascular-protective, and antioxidant effects. Several S-alk(en)yl-L-cystein sulfoxides have been reported to be present in genus Allium in the form of nonprotein sulfur amino acids. Trans-S-1-propenyl-L-cystein sulfoxide (isoalliin, 1) has been isolated from onions, 8 and it has been shown to be the precursor of the lachrymatory properties of Allium cepa by the action of the enzyme alliinase on the conversion of odorless trans-S-1-propenyl-L-cystein sulfoxide into the corresponding volatile thiosulfinate. Quantification of S-alk(en)yl-L-cystein sulfoxides is an important issue in Allium research. The unusual amino acid transS-1-propenyl-L-cystein sulfoxide (1) is in demand in the field of Allium chemistry including metabolism and biological studies, and serves as a standard for determination of S-alk(en)yl-Lcystein sulfoxides. Herein, we describe the facile synthesis of trans-S-1-propenyl-L-cystein sulfoxide in three steps. The synthesis of trans-S-1-propenyl-L-cystein sulfoxide (1) was reported by three research groups. Nishimura and co-workers performed the isomerization of a terminal triple bond (ethyl prop-2-ynyl sulfide) to ethyl prop-1-ynyl sulfide and the subsequent reductive coupling with alkyl chloride as key reaction steps. Parry and Sood reported the synthesis of compound 1 in five steps without presenting a detail experimental description. They also used the isomerization of a terminal triple bond (benzyl prop-2-ynyl sulfide) to benzyl prop-1-ynyl sulfide in the scheme of synthesis of 1. Namyslo and Stanitzek utilized palladium-catalyzed coupling of a thiol with alkenyl bromide and completed the synthesis of compound 1 in five steps. Our synthesis started with the formation of vinylsulfide 3 from the commercially available (E)-1-bromo-1-propene (2), which by treatment with t-BuLi and the successive addition of dibenzyl disulfide afforded (E)-1-(benzylthio)-1-propen (3) (Scheme 1). The isomerically pure trans-(1-propen) compound 3 was obtained providing the characteristic large NMR coupling of the trans-olefinic protons (J = 15.0 Hz). Reductive cleavage of a C-S bond in compound 3 by Na in liquid NH3 followed by addition of 3-chloro-L-alanine hydrochloride gave trans-S-1-propenyl-L-cystein (4). Finally, the oxidation of sulfide 4 by aqueous hydrogen peroxide provided sulfoxide 1 in a quantitative yield. Compound 1 was obtained as a mixture of two diastereomers with a new formed sulfur chiral center. The structure of 1 was confirmed by a comparision with those in the literature. In summary, a natural amino acid, trans-S-1-propenyl-Lcystein sulfoxide (1) was synthesized from (E)-1-bromo-1-propene in a concise way, via the sequential (i) the formation of vinylsulfide from lithiated propene and disulfide, (ii) reductive cleavage/alkylation of vinylsulfide, (iii) sulfide oxidation to sulfoxide. This compound is widely used as a reference for studies on Allium chemistry including biosynthesis of S-alkenylL-cystein sulfoxides, metabolism studies and biological investigations.