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. 2025 Jul 2;30(13):2841.
doi: 10.3390/molecules30132841.

Fluorinated Analogs of Organosulfur Compounds from Garlic (Allium sativum): Synthesis and Chemistry

Eric Block  1 , Benjamin Bechand  1 , Sivaji Gundala  1 , Abith Vattekkatte  1 , Kai Wang  1
Affiliations

Fluorinated Analogs of Organosulfur Compounds from Garlic (Allium sativum): Synthesis and Chemistry

Eric Block et al. Molecules. .

Abstract

We report the first syntheses-from commercially available 3-chloro-2-fluoroprop-1-ene (9)-of key garlic-derived compounds containing sp2-fluorine. We also report synthesis of fluoro-5,6-dihydrothiopyrans by trapping 2-fluorothioacrolein (15). Thus, difluoroallicin (12, S-(2-fluoro-2-propenyl) 2-fluoroprop-2-ene-1-sulfinothioate) is prepared by peracid oxidation of 1,2-bis(2-fluoro-2-propenyl)disulfane (11). S-2-Fluoro-2-propenyl-l-cysteine (2-fluorodeoxyalliin, 13), synthesized from cysteine and characterized by X-ray crystallography, is oxidized to its S-oxide, 2-fluoroalliin (22). The latter, with alliinase-containing powdered fresh garlic, gives a mixture of 12, allicin (1), and isomers of monofluoroallicin (23), indicating that 22 serves as a substrate for garlic alliinase. Upon heating, 12 generates transient 15, which dimerizes giving difluoro vinyl dithiins 6 and 7. Ethyl acrylate trapping of 15 affords 5- and 6-substituted 3-fluoro-5,6-dihydro-4H-thiopyrans (19 and 20). In 1,1,1,3,3,3-hexafluoro-2-propanol (HEFP) as solvent, 12 is converted into trifluoroajoene ((E,Z)-1-(2-fluoro-3-((2-fluoro-2-propenyl)sulfinyl)prop-1-en-1-yl)-2-(2-fluoro-2-propenyl)disulfane; 18). Liquid sulfur converts 11 to a (CH2=CFCH2)2Sn mixture (n = 4-15), characterized by UPLC-(Ag+)-coordination ion spray-mass spectrometry.

Keywords: 1,2-bis(2-fluoro-2-propenyl)disulfane; 2-fluoroalliin; 2-fluorothioacrolein; 3-fluoro-5,6-dihydro-4H-thiopyrans; ajoene; allicin; difluoroallicin; garlic; trifluoroajoene; vinyl dithiins.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Scheme 1
Scheme 1
Enzymatic formation of allicin (1) from alliin (2) by way of 2-propenesulfenic acid (3); synthesis of allicin by oxidation of diallyl disulfide (4); conversion of 1 to ajoene (8); decomposition of 1 to vinyl dithiins (6 and 7) via intramolecular elimination to thioacrolein (5). In addition to 2, garlic cloves contain methiin (MeS(O)CH2CH(NH2)CO2H) and isoalliin (MeCH=CHS(O)CH2CH(NH2)CO2H), which give rise to associated structures with methyl and 1-propenyl groups [2,3,4].
Scheme 2
Scheme 2
Synthesis of difluoroallicin (12) from 3-chloro-2-fluoroprop-1-ene (9) by way of thioacetate 10 and bis(2-fluoro-2-propenyl) disulfide (11); synthesis of S-2-fluoro-2-propenyl-l-cysteine (13) from 9; conversion of 12 to vinyl dithiins 16 and 17 via 2-fluorothioacrolein (15) with loss of 2-fluoro-2-propenesulfenic acid (14); conversion of 12 to trifluoroajoene 18; conversion of 11 to polysulfane mixture 21; conversion of 13 to (+)-S-2-fluoro-2-propenyl-l-cysteine S-oxide (2-fluoroalliin; 22).
Scheme 3
Scheme 3
Synthesis of 3-fluoro-5,6-dihydro-4H-thiopyran 19 and 20 from difluoroallicin 12.
Scheme 4
Scheme 4
Enzymatic conversion of 2-fluoroalliin 22 to a mixture of 1, 12 and 23a,b. Alliin, present in the unpurified powdered garlic, provides the C3H5 group.
Figure 1
Figure 1
Molecular structure of the l-enantiomer of fluorodeoxyalliin (13); non-hydrogen atoms are represented by thermal ellipsoids at the 50% probability level. Color coding: green = fluorine, yellow = sulfur, red = hydrogen, black = carbon.
Scheme 5
Scheme 5
Conversion of disulfide 11 to polysulfane mixture 21 through condensation with molten sulfur. Several equivalents of S8 can react, losing different numbers of sulfur atom groupings, followed by SN2′ reaction with 2-fluoroallyl sulfonium species giving polysulfane mixture 21. By other techniques, compounds containing up to 26 sulfur atoms could be observed.
Figure 2
Figure 2
UPLC (Ag+)-CIS-MS selective ion chromatogram of polysulfane mixture 21, with 4 to 15 sulfur atoms: C6H8F2S4-107Ag complex, m/z 352.7, 6.78/6.85 min (split peak due to column issues); C6H8F2S5-107Ag complex, m/z 384.7, 7.71 min; C6H8F2S6-107Ag complex, m/z 416.7, 8.41 min; C6H8F2S7-107Ag complex, m/z 448.7, 9.00 min; C6H8F2S8-107Ag complex, m/z 480.7, 9.50 min; C6H8F2S9-107Ag complex, m/z 512.6, 9.97 min; C6H8F2S10-107Ag complex, m/z 544.5, 10.38 min; C6H8F2S11-107Ag complex, m/z 576.4, 10.7 min; and C6H8F2S12-107Ag complex, m/z 608.4, 11.1 min. With additional signal amplification, other low abundance complexes could also be seen: C6H8F2S13-107Ag complex, m/z 640.3, 11.43 min; C6H8F2S14-107Ag complex, m/z 672.3, 11.73 min; C6H8F2S15-107Ag complex, m/z 704.2, 12.05 min. The insert shows molecular ions m/z 352.73 and 354.73 corresponding to C6H8F2S4-107Ag and C6H8F2S4-109Ag. The chromatogram selecting for C6H8F2Sn-109Ag complexes was very similar.
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