Alpha Lipoic AcidThe Ultimate Antioxidant

Identity & Structure• “Thioctic acid”• “Lipolate”• (For you IUPAC nerdies): (R/S)-5-(1,2-

dithiolan-3-yl)pentanoic acid

R-AlphaLipoic Acid

S-AlphaLipoic Acid

Dihydro-Lipoic Acid

Alpha Lipoic Acid. University of Maryland Medical Center. https://umm.edu/health/ medical/altmed/supplement/alphalipoic-acid.Maldonado-Rojas, W.; Olivero-Verbel, J.; Ortega-Zuniga, C.; J. Braz. Chem.

Soc. 2011, 22(12), 2250-2259.

Function: Antioxidant• “The Ultimate Antioxidant”• Both water- and fat- soluble• Multiple radical-fighting powers

Antioxidant

Scavenger

ChelateAntioxid

ant

Directly Removes

Free Radicals

Inhibits Free Rad. Generatio

n

Re-enables

Used Antioxidan

ts

ROS MetalRecycler

Rochette, L.; Ghibu, S.; Richard, C.; Zeller, M.; Cottin, Y.; Vergely, C. Molecular Nutrition and Food Research. 2013, 57(1), 114-125. Lipoic Acid. Linus Pauling Institute. Oregon State University. http://lpi.oregonstate.edu/

infocenter/othernuts/la/index.html#safety (accessed March 2, 2014).

R-Alpha Lipoic Acid

Lysine Residue

Function: Enzyme Cofactor• Biologically active R- enantiomer binds to

a specific lysine residue.• Example: Stimulation of glucose

metabolism via insulin-signaling pathway.• Effective treatment for type 2

Diabetes.

Lipoic Acid. Linus Pauling Institute. Oregon State University. http://lpi.oregonstate.edu/ infocenter/othernuts/la/index.html#safety. Ziegler D. Treatments in Endocrinology. 2004, 3(3), 173-189.

Eat all the vitamins!

Recommended Amounts• No established dosage

recommendations or upper limit.• No adverse side effects.• Generally, 20-50 mg daily for

antioxidant support.

Alpha Lipoic Acid. University of Maryland Medical Center. https://umm.edu/health/ medical/altmed/supplement/alphalipoic-acid.

Characterization: IR• Broad 3000 cm-1 peak: Carboxylic

Acid• Strong 1700 cm-1 peak: Ring Moiety• Higher than typical aromatic.

SBDS-1H NMR 399.65 MHz. AIST:RIO-DB Spectral Database. http://sdbs.db.aist.go.jp/sdbs/cgi-bin/direct_frame_disp.cgi?sdbsno=52043.

Characterization: H-NMR• 10 Peaks• Splitting indicates hydrocarbon chain.• Group of peaks above 3 consistent

with sulfur.

SBDS-1H NMR 399.65 MHz. AIST:RIO-DB Spectral Database. http://sdbs.db.aist.go.jp/sdbs/cgi-bin/direct_frame_disp.cgi?sdbsno=52043.

Characterization: C-NMR• Shifting Downfield• Carbon 1 with carboxylic acid• Carbons 2, 3, and 4 adjacent to

sulfur atoms

SBDS-1H NMR 399.65 MHz. AIST:RIO-DB Spectral Database. http://sdbs.db.aist.go.jp/sdbs/cgi-bin/direct_frame_disp.cgi?sdbsno=52043.

Characterization: UV/Vis• Absorbance due to Carboxylic Acid• UV range• 203 nm, 302 nm

Goti, P.; Savsani, J.; Patel, P. International Journal of Pharmacy and Pharmaceutical Sciences, 2012, 4, 519-522.

Subhash P.; Kale, Ramesh R.; Pasupathy, K.; Synlett, 2005, 1129-1132.Kim, Hyeon Jin; Kwon, Seung-Ryong; Kim, Kyuwon; Electrochemistry Communications, 2012, v20, 52-55.

Synthesis Methods• Fairly simple compound, Variety of

sources.• Easier to synthesize than to extract.• Method 1:• Octanoic Acid

• Reflux with Potassium Permanganate• Ethanol solvent• 8 Hours

Subhash P.; Kale, Ramesh R.; Pasupathy, K.; Synlett, 2005, 1129-1132.Kim, Hyeon Jin; Kwon, Seung-Ryong; Kim, Kyuwon; Electrochemistry Communications, 2012, v20, 52-55.

Synthesis Methods• Method 2:• Tosylhydrazone Degenerations

• Reflux with NaOH• Highly complex• Many byproducts

Synthesis Methods• Method 3: (BEST!)• Substitute octanoic acid using Na2S

to form thiols• Bu4N+Br- catalyst in methanol to

form sulfur ring• Hydrolyze to carboxylic acidEtO

Cl

Cl

O

EtO

SH

SH

O

Na2S, S, H2O

EtO

S

O

S

Bu4N+Br-, MeOH

HO

S

O

S

NaOH, HCl, H2O

Thank You!Alpha Lipoic Acid