The Organosulfur Chemistry of the Genus AZZium - Implications for the Organic Chemistry of Sulfur By Eric Block” A Cook’s tour is presented of the organosulfur chemistry of the genus Allium, as represented, inter alia, by garlic (Allium sativum L.) and onion (Allium cepa L.). We report on the biosyn- thesis of the S-alk(en)yl-L-cysteineS-oxides (aroma and flavor precursors) in intact plants and on how upon cutting or crushing the plants these precursors are cleaved by allinase enzymes, giving sulfenic acids-highly reactive organosulfur intermediates. In garlic, 2-propenesulfenic acid gives allicin, a thiosulfinate with antibiotic properties, while in onion I-propenesulfenic acid rearranges to the sulfine (2)-propanethial S-oxide, the lachrymatory factor (LF) of onion. Highlights of onion chemistry include the assignment of stereochemistry to the LF and determination of the mechanism of its dimerization; the isolation, characterization, and syn- thesis of thiosulfinates which most closely duplicate the taste and aroma of the freshly cut bulb, and additional unusual compounds such as zwiebelanes (dithiabicyclo(2.1.llhexanes), a bis- sulfine (a 1,4-butanedithial S,Y-dioxide), antithrombotic and antiasthmatic cepaenes (a- sulfinyl disulfides), and vic-disulfoxides. Especially noteworthy in the chemistry of garlic are the discovery of ajoene, a potent antithrombotic agent from garlic, and the elucidation of the unique sequence of reactions that occur when diallyl disulfide, which is present in steam-dis- tilled garlic oil, is heated. Reaction mechanisms under discussion include [3,3]-and [2,3]-sigma- tropic rearrangements involving sulfur (e.g. sulfoxide-accelerated thio- and dithio-Claisen rearrangements) and cycloadditions involving thiocarbonyl systems. In view of the culinary importance of alliaceous plants as well as the unique history of their use in folk medicine, this survey concludes with a discussion of the physiological activity of the components of these plants: cancer prevention, antimicrobial activity, insect and animal attractive/repulsive activ- ity, olfactory-gustatory-lachrymatory properties, effect on lipid metabolism, platelet aggrega- tion inhibitory activity and properties associated with ajoene. And naturally, comments about onion and garlic induced bad breath and heartburn may not be overlooked. 1. Introduction counterpart in the complex chemistry of this and other allia- ceous plants, representing a microcosm of the field of We remember the fish which we did eat in Egypt, organosulfur chemistry. More specifically, Allium chemistry the cucumbers, melons, leeks, onions and garlic! presents us with examples of sulfur compounds with striking Num. 11 :4-6 physiological activity as well as culinary appeal, reactive organosulfur intermediates with unusual bonding, challeng- What is more familiar and pleasant to the senses than ing analytical problems, compounds with chirality at sulfur freshly chopped or sauted garlic, sliced or boiled onions, and other stereochemical features related to the presence of steaming leeks, finely diced chives, crisp raw scallions, or the sulfur, novel organosulfur heterocycles with notable spectro- delicate shallot? The scents of these commonplace plants scopic properties, redox reactions involving sulfur, as well as brings back memories of mother’s kitchen, a favorite restau- processes involving sulfur radicals, sulfur stabilized carbo- rant or even a walk through a meadow rich with the aroma cations, pericyclic reactions, noteworthy rearrangements, of wild onions. The adjectives applied to these plants, zesty, and reactions of utility in synthetic organic chemistry.“] lusty, assertive, piquant, and distinctive, and even the botan- For twenty-five years I have been exploring the organosul- ical name Allium, derived from the Celtic word “all”, which fur chemistry of the genus Allium, as represented by garlic means pungent, betray the presence of a host of remarkable (Allium sativum L.), onion (Allium cepa L.), leek (Allium flavorants and odorants all having in common one element, ampeloprasum L. var. porrum), scallion (Allium fistulosum), sulfur. Many of these flavorful sulfur compounds contain shallot (Allium ascalonicum auct.), great-headed (“ele- the ally1 group, which in turn gets its name from Allium. It phant”) garlic (Allium ainpeloprasum L. var. holmense), wild is the presence of these organosulfur compounds, more than garlic (Allium ursinum), chive (Allium schoenoprasum L.), any other attribute, that defines the character of this extraor- and Chinese chive (Allium tuberosum L.) (Fig. 1). When I dinary genus. The great American poet Carl Sanburg said: began this study, much outstanding research had already “Life itself is like an onion; it has a bewildering number of been done in this area, e.g. as summarized in a review article layers. You peel them ofJ one by one, and sometimes you cry. I’ by Nobel Laureate Arturi Virtanen.[’I As my research pro- The “bewildering number of layers” of the onion has its ceeded it became clear that there were still significant puzzles remaining to be solved, that these most common plants [“I Professor E. Block could teach us much about sulfur chemistry, and that the Department of Chemistry State University of New York at Albany compounds and mixtures produced when these plants are cut Albany, NY 12222 (USA) display an even broader range of biological activities than Angenz. Chem. Int. Ed. Ennl. 1992, 3f,1135-1178 0 VCH Verlagsgeselischafi mbH, W-6940 Weinheim, 1992 0570-0833/92/0909-1135 $3.50+ .25/0 1135 earlier suspected. While extracts and potions of garlic and ity could be demonstrated by addition of water to the insol- onion have been used for millennia in folk medicine, com- uble residue. When, however, a small quantity (1 mgmL-’) mercial products derived from these plants are now enjoying of fresh garlic powder was added to the alcohol insoluble growing popular use in many countries. Furthermore, re- fraction in water (20 mgmL-‘), the activity of the treated sponding to epidemiological evidence that lower cancer risks sample was shown to be equal to that of the original untreat- are associated with increased consumption of alliaceous ed powder. The 95 % ethanol treatment has inactivated the plants, health organizations have recently targeted garlic and enzyme required for cleavage of the precursor and addition onion as prime candidates for “designer foods” programs, of a small quantity of fresh enzyme brought about the usual programs to develop new foods that will help prevent cells cleavage. from becoming cancerous. For all of these reasons a detailed Since a strict definition of “essential oil” is “a volatile exploration of the organosulfur chemistry of the genus Alli- substance contained in certain aromatic plants that imparts um seemed justified as well as timely. This review summa- distinctive odor to the plant” and since the volatile sub- rizes progress in this field both in my own and other labora- stances of the Allium spp. are not found in the plant but torie~.[~’ result from disrupting the plant cells, it is preferable to de- scribe the process leading to a particular Allium-derived product, e.g. “steam volatile components” or “head space vo~ati~es”.[’~ 2. Organosulfur Compounds of Intact Plants Well loved he garleek, oynons, and eek lekes, 2.1. Sulfur Amino Acids Secondary Metabolites and for to drynken strong wyn, reed as blood. in Alliurn spp. “Canterbury Tales” Geoffrey Chaucer (1342-1400) Let onion atoms lurk within the bowl and, scarce suspected, animate the whole. The earliest reports concerning the isolation of organic “Recipe for Salad”, compounds from garlic (1844,1892) and onion by Wertheim Sydney Smith (1771-1845) (1844) and Semmler (1892) in Germany identified diallyl sulfidet4] (corrected in 1892 to the dis~lfide[~])and a Garlic, onion and other members of the Allium spp. con- propenyl propyl dis~lfide[~]as the principal components of tain I - 5 % dry weight of nonprotein sulfur amino acid sec- the distilled oils (“atherische Ole’’) of garlic and onion, re- ondary metabolites. Pioneering studies in the 1940s by Stoll spectively. In the 1940s it became apparent that these and and Seebeck in Basel demonstrated that the stable precursor other volatile sulfur compounds were secondary compounds of Cavallito’s antibacterial principle of garlic 1 is (+)-S-2- formed by enzymatic action on precursors in the intact bulb. propenyl-L-cysteine S-oxide (2, ‘‘alliin”).[81In the intact cell, Thus, in 1945, Cavallito et al. in Rennselaer, New York, re- 2 and related S-alk(en)yl-L-cysteineS-oxides (aroma and fla- ported that when garlic cloves were frozen in dry ice, pulver- vor precursors) are located in the cytoplasm and the C-S ized, and extracted with acetone, “the acetone extracts upon lyase enzyme allinase in the vacuole.[g1Disruption of the cell evaporation yielded only minute quantities of residue and no results in release of allinase and subsequent a$-elimination sulfides, indicating the absence of free sulfides in the plant. of the S-oxides, ultimately affording volatile and odorous The [white] garlic powder had practically no odor, but upon low molecular weight organosulfur compounds such as 1 addition of small quantities of water, the typical odor was (Scheme I). Four sulfoxides occur in Allium spp.: S-2- detected and the antibacterial principle (1) could be extract- propenyl-, S-(E)-1-propenyl-, S-methyl- and S-propyl-L- ed and isolated. This demonstrates that neither 1 nor the ally1 cysteine S-oxides (2,5-7 respectively). Onions contain 5-7 sulfides found in “Essential Oil of Garlic” are present as such while garlic contains 2, 5, and 6.[10-131The distinctive fla- in whole garlic. When the powder was heated to reflux for vors of the various Allium spp. reflect the varying amounts thirty minutes with a small volume of 95 YOethanol, no activ- of compounds 2,5-7, particularly of 5 (“isoalliin”), which is Eric Block, born in 1942 in New York City, studied chemistry at Queens College of the City University of New York. He received his Ph.D.