6217-54-5

Usage

Uses

Used in Pharmaceutical Industry:
cis-4,7,10,13,16,19-Docosahexaenoic acid is used as a pharmaceutical ingredient for its role in several physiological and pathological processes, including neural development, cardiovascular diseases, obesity, and inflammation. It is also used in the production of specialized pro-resolving mediators (SPMs), which regulate host defense and the resolution of inflammation.
Used in Nutritional Supplements:
cis-4,7,10,13,16,19-Docosahexaenoic acid is used as a nutritional supplement to support brain health, cognitive function, and overall well-being. It is commonly found in fish oil supplements and is also commercially manufactured from microalgae, such as Crypthecodinium cohnii and Schizochytrium.
Used in Food Industry:
cis-4,7,10,13,16,19-Docosahexaenoic acid is used as a food additive to enrich products with omega-3 fatty acids, which are essential for maintaining a healthy diet and supporting various bodily functions.
Used in Cosmetics Industry:
cis-4,7,10,13,16,19-Docosahexaenoic acid is used in cosmetics and skincare products for its beneficial effects on skin health, including moisturization and anti-inflammatory properties.
Used in Research and Development:
cis-4,7,10,13,16,19-Docosahexaenoic acid is used as a research compound in the development of new drugs and therapies targeting various health conditions, as well as in studies investigating the role of omega-3 fatty acids in human health and disease.

Biosynthesis of DHA

ALA is an essential fatty acid. It is synthesised in plants and in many lower organisms and is found in the human diet mainly as a component of green leaves, some nuts, seeds and vegetable oils, and foods made from or containing those ingredients. There is a metabolic pathway that links ALA to DHA. This pathway involves a series of enzyme-catalysed elongation and desaturation reactions. Elongation enzymes, called elongases, add pairs of carbon atoms to the growing acyl chain, in this case converting an 18-carbon fatty acid into a 22-carbon one, while desaturase enzymes insert double bonds into the acyl chain, in this case converting a fatty acid with 3 double bonds in its acyl chain into one with 6 double bonds. These reactions occur predominantly within the endoplasmic reticulum. The pathway is believed to mainly occur within the liver, but there is some evidence that other tissues, including brain and testis, have high expression of the genes encoding the relevant enzymes.

Biological Activity

Endogenous omega-3 fatty acid. Acts as a selective retinoid X receptor (RXR) agonist that displays no activity at RAR, thyroid hormone receptor or the vitamin D receptor (VDR). Activates all three RXR isoforms. Also shown to inhibit A β 1-42 fibrillation and toxicity in vitro .

Biochem/physiol Actions

Docosahexaenoic acid, DHA, is an omega-3 polyunsaturated fatty acid with 22 carbons and six double bonds, the first double bond occuring at position three from the methyl terminus (22:6 n-3). DHA is a component of lipid membranes and the myelin sheath. DHA also serves as a precursor for signaling molecules such as prostaglandins and eicosanoids.

Purification Methods

Its solubility in CHCl3 is 5%. It has been purified from fish oil by GLC using Ar as mobile phase and EGA as stationary phase with an ionisation detector [UV: Stoffel & Ahrens J Lipid Res 1 139 1959], and via the ester by evaporative "molecular" distillation using a 'continuous molecular still' at 10-4 mm with the highest temperature being 110o and a total contact time with the hot surface being 60sec [Farmer & van den Heuvel J Chem Soc 427 1938]. The methyl ester has b 208-211o/2mm, d4 0.9398, 20 1.5035. nD With Br2 it forms a dodecabromide m ca
240o(dec). Also, the acid was converted to the methyl ester and purified through a three-stage molecular still [as described by Sutton Chem Ind (London) 11383 1953] at 96o, and the rate was adjusted so that one-third of the material was removed each cycle of three distillations. The distillate (numbered 4) (13g) was dissolved in EtOH (100mL containing 8g of KOH) at -70o and set aside for 4hours at 30o with occasional shaking under a vacuum. Water (100mL) was added and the solution was extracted with pentane, washed with HCl, dried (MgSO4), filtered and evaporated to give a clear oil (11.5g) m -44.5o to -44.1o. In the catalytic hydrogenation of the oil six mols of H2 are absorbed and docosanoic acid (behenic acid) is produced with m 79.0-79.3o undepressed with an authentic sample (see docosanoic acid below) [Whitcutt Biochem J 67 60 1957]. [Beilstein 2 IV 1812.]

InChI:InChI=1/C22H32O2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-20-21-22(23)24/h3-4,6-7,9-10,12-13,15-16,18-19H,2,5,8,11,14,17,20-21H2,1H3,(H,23,24)/b4-3+,7-6+,10-9+,13-12+,16-15+,19-18-

Synthetic route

all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate (81926-94-5) → docosahexaenoic acid (6217-54-5)

Conditions	Yield
With ethylenediaminetetraacetic acid; edetate disodium In ethanol; water at 60 - 65℃; for 2h;	98%
With sodium hydroxide; edetate disodium In ethanol at 65℃;	98%
Stage #1: all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate With water; sodium hydroxide In methanol at 20℃; for 1.5h; Stage #2: With hydrogenchloride In methanol; water Cooling with ice;	91%

docosahexaenoic acid ethyl ester → docosahexaenoic acid (6217-54-5)

Conditions	Yield
With lithium hydroxide monohydrate In ethanol; water at 60℃; for 1h; Inert atmosphere;	94%

all-cis-4,7,10,13,16,19-docosahexaenoic acid methyl ester (2566-90-7) → docosahexaenoic acid (6217-54-5)

Conditions	Yield
With lithium hydroxide In tetrahydrofuran; water	92%
Stage #1: all-cis-4,7,10,13,16,19-docosahexaenoic acid methyl ester With water; lithium hydroxide In tetrahydrofuran at 0 - 20℃; for 12h; Stage #2: With citric acid In water at 0℃; pH=~ 4;

all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate (81926-94-5) + serinol (534-03-2) → docosahexaenoic acid (6217-54-5) + (4Z,7Z,10Z,13Z,16Z,19Z)-N-(1,3-dihydroxypropan-2-yl)docosa-4,7,10,13,16,19-hexaenamide

Conditions	Yield
With Novozym 435 lipase on resin In acetone at 35℃; for 4h; Green chemistry; Enzymatic reaction;	A n/a B 87%

3-Amino-1,2-propanediol (616-30-8, 13552-31-3) + all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate (81926-94-5) → docosahexaenoic acid (6217-54-5) + (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2,3-dihydroxypropyl)docosa-4,7,10,13,16,19-hexaenamide (1048012-06-1)

Conditions	Yield
With Novozym 435 lipase on resin In acetone at 35℃; for 8h; Green chemistry; Enzymatic reaction;	A n/a B 80%

all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate (81926-94-5) + ethanolamine (141-43-5) → docosahexaenoic acid (6217-54-5) + N-docosahexaenoylethanolamine (162758-94-3)

Conditions	Yield
With Novozym 435 lipase on resin In acetone at 35℃; for 8h; Green chemistry; Enzymatic reaction;	A n/a B 75%

(R)-2-aminopropan-1-ol (35320-23-1) + all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate (81926-94-5) → docosahexaenoic acid (6217-54-5) + (4Z,7Z,10Z,13Z,16Z,19Z)-N-((R)-1-hydroxypropan-2-yl)docosa-4,7,10,13,16,19-hexaenamide (1282618-08-9)

Conditions	Yield
With Novozym 435 lipase on resin In acetone at 35℃; for 8h; Green chemistry; Enzymatic reaction;	A n/a B 70%

all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate (81926-94-5) + (R)-3-amino-1,2-propanediol (66211-46-9) → docosahexaenoic acid (6217-54-5) + C25H39NO3

Conditions	Yield
With Novozym 435 lipase on resin In acetone at 35℃; for 8h; Green chemistry; Enzymatic reaction;	A n/a B 70%

(S)-3-Amino-1,2-propanediol (61278-21-5) + all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate (81926-94-5) → docosahexaenoic acid (6217-54-5) + C25H39NO3

Conditions	Yield
With Novozym 435 lipase on resin In acetone at 35℃; for 8h; Green chemistry; Enzymatic reaction;	A n/a B 65%

all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate (81926-94-5) + ethylenediamine (107-15-3) → docosahexaenoic acid (6217-54-5) + (4Z,7Z,10Z,13Z, 16Z,19Z)docosa-4,7,10,13,16,19-hexaenoic acid [2-((4Z,7Z,10Z,13Z, 16Z,19Z)docosa-4,7,10,13,16,19-hexaenoylamino)ethyl]amide (1333067-15-4)

Conditions	Yield
With Novozym 435 lipase on resin In acetone at 35℃; for 8h; Green chemistry; Enzymatic reaction;	A n/a B 60%

serin (302-84-1) + all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate (81926-94-5) → docosahexaenoic acid (6217-54-5) + C25H37NO4

Conditions	Yield
With Novozym 435 lipase on resin In acetone at 35℃; for 8h; Green chemistry; Enzymatic reaction;	A n/a B 55%

all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate (81926-94-5) + 1,3-Diamino-2-hydroxypropane (616-29-5) → docosahexaenoic acid (6217-54-5) + C25H40N2O2 + C47H70N2O3

Conditions	Yield
With Novozym 435 lipase on resin In acetone at 35℃; for 8h; Green chemistry; Enzymatic reaction;	A n/a B 48% C 38%

C25H40O2Si → docosahexaenoic acid (6217-54-5)

Conditions	Yield
With sodium thiosulfate In water Yield given;

(Z)-3-Hexen-1-ol (928-96-1) → docosahexaenoic acid (6217-54-5)

Conditions

Yield

Multi-step reaction with 9 steps 1: pyridine, Ph3PBr2 / acetonitrile / 0 °C 2: acetonitrile / 24 h / Heating 3: 56 percent / NaN(SiMe3)2 / tetrahydrofuran / 1.) room temperature, 2.) -90 deg C 4: 100 percent / H+ / tetrahydrofuran 5: 86 percent / LiAlH4 / tetrahydrofuran / -70 °C 6: 94 percent / CBr4, Ph3P / CH2Cl2 / 1.) 0 deg C, 15 min, 2.) room temperature, 1 h 7: 95 percent / acetonitrile / Heating 8: 76 percent / NaN(SiMe3)2 / tetrahydrofuran / -80 °C 9: 92 percent / LiOH / tetrahydrofuran; H2O View Scheme

1-bromo-3-hexene (84254-20-6) → docosahexaenoic acid (6217-54-5)

Conditions

Yield

Multi-step reaction with 8 steps 1: acetonitrile / 24 h / Heating 2: 56 percent / NaN(SiMe3)2 / tetrahydrofuran / 1.) room temperature, 2.) -90 deg C 3: 100 percent / H+ / tetrahydrofuran 4: 86 percent / LiAlH4 / tetrahydrofuran / -70 °C 5: 94 percent / CBr4, Ph3P / CH2Cl2 / 1.) 0 deg C, 15 min, 2.) room temperature, 1 h 6: 95 percent / acetonitrile / Heating 7: 76 percent / NaN(SiMe3)2 / tetrahydrofuran / -80 °C 8: 92 percent / LiOH / tetrahydrofuran; H2O View Scheme

(3Z,6Z,9Z)-dodecatrien-1-ol (81345-02-0) → docosahexaenoic acid (6217-54-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: 94 percent / CBr4, Ph3P / CH2Cl2 / 1.) 0 deg C, 15 min, 2.) room temperature, 1 h 2: 95 percent / acetonitrile / Heating 3: 76 percent / NaN(SiMe3)2 / tetrahydrofuran / -80 °C 4: 92 percent / LiOH / tetrahydrofuran; H2O View Scheme

(3Z)-3-hexenyltriphenylphosphonium bromide (21676-05-1) → docosahexaenoic acid (6217-54-5)

Conditions

Yield

Multi-step reaction with 7 steps 1: 56 percent / NaN(SiMe3)2 / tetrahydrofuran / 1.) room temperature, 2.) -90 deg C 2: 100 percent / H+ / tetrahydrofuran 3: 86 percent / LiAlH4 / tetrahydrofuran / -70 °C 4: 94 percent / CBr4, Ph3P / CH2Cl2 / 1.) 0 deg C, 15 min, 2.) room temperature, 1 h 5: 95 percent / acetonitrile / Heating 6: 76 percent / NaN(SiMe3)2 / tetrahydrofuran / -80 °C 7: 92 percent / LiOH / tetrahydrofuran; H2O View Scheme

(Z)-6,6-diisopropoxyhex-3-en-1-al (162758-88-5) → docosahexaenoic acid (6217-54-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: 51 percent / NaN(SiMe3)2 / tetrahydrofuran / 1.) room temperature, 2.) -90 deg C 2: H+ / tetrahydrofuran 3: 76 percent / NaN(SiMe3)2 / tetrahydrofuran / -80 °C 4: 92 percent / LiOH / tetrahydrofuran; H2O View Scheme

(Z,Z,Z)-1-bromododeca-3,6,9-triene (169900-26-9) → docosahexaenoic acid (6217-54-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 95 percent / acetonitrile / Heating 2: 76 percent / NaN(SiMe3)2 / tetrahydrofuran / -80 °C 3: 92 percent / LiOH / tetrahydrofuran; H2O View Scheme

(Z,Z,Z)-dodeca-3,6,9-trien-1-al (169900-23-6) → docosahexaenoic acid (6217-54-5)

Conditions	Yield
Multi-step reaction with 5 steps 1: 86 percent / LiAlH4 / tetrahydrofuran / -70 °C 2: 94 percent / CBr4, Ph3P / CH2Cl2 / 1.) 0 deg C, 15 min, 2.) room temperature, 1 h 3: 95 percent / acetonitrile / Heating 4: 76 percent / NaN(SiMe3)2 / tetrahydrofuran / -80 °C 5: 92 percent / LiOH / tetrahydrofuran; H2O View Scheme

(Z,Z)-10-oxodeca-4,7-dienoic acid methyl ester (169900-28-1) → docosahexaenoic acid (6217-54-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 76 percent / NaN(SiMe3)2 / tetrahydrofuran / -80 °C 2: 92 percent / LiOH / tetrahydrofuran; H2O View Scheme

(Z,Z,Z)-1,1-diisopropoxydodeca-3,6,9-triene (169900-22-5) → docosahexaenoic acid (6217-54-5)

Conditions	Yield
Multi-step reaction with 6 steps 1: 100 percent / H+ / tetrahydrofuran 2: 86 percent / LiAlH4 / tetrahydrofuran / -70 °C 3: 94 percent / CBr4, Ph3P / CH2Cl2 / 1.) 0 deg C, 15 min, 2.) room temperature, 1 h 4: 95 percent / acetonitrile / Heating 5: 76 percent / NaN(SiMe3)2 / tetrahydrofuran / -80 °C 6: 92 percent / LiOH / tetrahydrofuran; H2O View Scheme

(Z,Z)-10,10-diisopropoxydeca-4,7-dienoic acid methyl ester (169900-25-8) → docosahexaenoic acid (6217-54-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: H+ / tetrahydrofuran 2: 76 percent / NaN(SiMe3)2 / tetrahydrofuran / -80 °C 3: 92 percent / LiOH / tetrahydrofuran; H2O View Scheme

(Z,Z,Z)-dodeca-3,6,9-trienyltriphenylphosphonium bromide → docosahexaenoic acid (6217-54-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 76 percent / NaN(SiMe3)2 / tetrahydrofuran / -80 °C 2: 92 percent / LiOH / tetrahydrofuran; H2O View Scheme

5-((3Z,6Z,9Z,12Z,15Z)-1-iodooctadeca-3,6,9,12,15-pentaenyl)dihydro-2(3H)-furanone (78144-19-1) → docosahexaenoic acid (6217-54-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium iodide / acetonitrile / 1 h / 23 °C 2: sodium thiosulfate / H2O View Scheme

all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate (81926-94-5) + eicosapentaenoic acid ethyl ester (86227-47-6) → all cis-5,8,11,14,17-eicosapentaenoic acid (10417-94-4) + docosahexaenoic acid (6217-54-5)

Conditions	Yield
Stage #1: all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate; eicosapentaenoic acid ethyl ester With water; sodium hydroxide In methanol at 20℃; for 1.5h; Stage #2: With hydrogenchloride In water Cooling with ice;

D-glucose (50-99-7) → docosahexaenoic acid (6217-54-5)

Conditions	Yield
Stage #1: D-glucose; Labyrinthulae strain mh313 microorganism In water at 28℃; for 96h; pH=6.0; Enzymatic reaction; Stage #2: With hydrogenchloride; methanol Product distribution / selectivity;

carbon dioxide (124-38-9) → docosahexaenoic acid (6217-54-5)

Conditions	Yield
With Nannochloropsis Gaditana Microbiological reaction; Photolysis; Large scale;

all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate (81926-94-5) + glycerol (56-81-5) → docosahexaenoic acid (6217-54-5) + (4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenoic acid 2,3-dihydroxy-propyl ester + 1,3-didocosahexaenoylglycerol

Conditions	Yield
With Novozyme 435 immobilized on polystyrene at 35℃; for 24h; Solvent; Green chemistry; Enzymatic reaction;

diazomethane (186581-53-3, 908094-01-9) + docosahexaenoic acid (6217-54-5) → all-cis-4,7,10,13,16,19-docosahexaenoic acid methyl ester (2566-90-7)

Conditions	Yield
In diethyl ether	100%

docosahexaenoic acid (6217-54-5) → (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyl chloride (98776-99-9)

Conditions	Yield
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 2h;	100%
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 2h; Cooling with ice;	100%
With oxalyl dichloride In chloroform for 2h;

docosahexaenoic acid (6217-54-5) → (±)-19,20-epoxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (895127-62-5)

Conditions	Yield
With human recombinant cytochrome P450 1A1 Enzymatic reaction; stereoselective reaction;	100%
With MS-PPOH

all cis-5,8,11,14,17-eicosapentaenoic acid (10417-94-4) + docosahexaenoic acid (6217-54-5) + magnesium bis(lysinate) trihydrate → magnesium Bis-Lysinate Mono-EPA Mono-DHA dihydrate

Conditions	Yield
With Tocopherol In methanol; ethyl acetate at 50℃; for 0.333333h; Inert atmosphere;	100%

docosahexaenoic acid (6217-54-5) + 1-t-Butoxycarbonylpiperazine (57260-71-6) → tert-butyl 4-(4Z,7Z,10Z,13Z,16Z, 19Z)-docosa-4,7,10,13,16,19-hexaenoylpiperazine-1-carboxylate (1204318-13-7)

Conditions	Yield
With triethylamine; HATU In acetonitrile at 20℃; for 16h;	99%

docosahexaenoic acid (6217-54-5) + 1,2-di-O-palmitoyl-sn-glycerol (6076-30-8) → 1-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyl)-2,3-dihexadecanoyl-sn-glycerol

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Steglich Esterification;	99%

docosahexaenoic acid (6217-54-5) + (2R)-1,2-bis-O-stearylglycerol (1429-59-0) → 1-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyl)-2,3-dioctadecanoyl-sn-glycerol

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Steglich Esterification;	99%

docosahexaenoic acid (6217-54-5) + taxol (33069-62-4) → [3H]-Docosahexaenoic acid-Paclitaxel

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 1 - 2h;	98%
With dmap; dacarbazine In dichloromethane at 20℃;

docosahexaenoic acid (6217-54-5) + calcium bis(lysinate) monohydrate → calcium bis-lysinate bis-DHA

Conditions	Yield
In methanol at 50℃; Inert atmosphere;	98%

docosahexaenoic acid (6217-54-5) → 5-((3Z,6Z,9Z,12Z,15Z)-1-iodooctadeca-3,6,9,12,15-pentaenyl)dihydro-2(3H)-furanone (78144-19-1)

Conditions	Yield
With hydrogen iodide; iodine; potassium hydrogencarbonate In ethanol at 0 - 4℃; for 18h; Inert atmosphere; Darkness;	97%
With 2,6-dimethylpyridine; iodine In dichloromethane at 0℃; for 15h; Inert atmosphere; Cooling with ice;	96%
With iodine; potassium hydrogencarbonate; potassium iodide In tetrahydrofuran; water for 48h; Ambient temperature;	95%

docosahexaenoic acid (6217-54-5) + glycine ethyl ester hydrochloride (5680-79-5) → methyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)acetate

Conditions	Yield
Stage #1: docosahexaenoic acid; glycine ethyl ester hydrochloride With dmap; triethylamine In dichloromethane at 20℃; for 0.0833333h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Inert atmosphere;	97%
With benzotriazol-1-ol; 1,2-dichloro-ethane; triethylamine In dichloromethane at 20℃; for 18h;	55%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 18h;	55%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 18h;	55%

docosahexaenoic acid (6217-54-5) + L-valyl-L-lysine (22677-62-9) → L-valyl-L-lysine DHA salt

Conditions	Yield
With Tocopherol In ethanol; ethyl acetate at 60℃;	97%

docosahexaenoic acid (6217-54-5) + ethanolamine (141-43-5) → N-docosahexaenoylethanolamine (162758-94-3)

Conditions	Yield
Stage #1: docosahexaenoic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 0.5h; Stage #2: ethanolamine In dichloromethane for 12h;	96%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Inert atmosphere;	92%
With Novozym 435, consisting of immobilized Candida antarctica lipase B In acetonitrile at 40℃; for 15h; Enzymatic reaction;	20%

docosahexaenoic acid (6217-54-5) + magnesium bis-lysinate monohydrate → magnesium bis-lysinate bis-DHA dihydrate

Conditions	Yield
With Tocopherol In methanol; ethyl acetate at 50℃; for 0.333333h; Inert atmosphere;	96%

docosahexaenoic acid (6217-54-5) → (4Z,7Z,10Z,13Z,16Z,19Z)-N-hydroxydocosa-4,7,10,13,16,19-hexaenamide (89017-02-7)

Conditions	Yield
Stage #1: docosahexaenoic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 0.5h; Stage #2: With hydroxylamine In dichloromethane for 12h;	96%

docosahexaenoic acid (6217-54-5) → (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamide

Conditions	Yield
Stage #1: docosahexaenoic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 0.5h; Stage #2: With ammonia In dichloromethane for 12h;	96%

pyrrolidine (123-75-1) + docosahexaenoic acid (6217-54-5) → (4Z,7Z,10Z,13Z,16Z,19Z)-1-(pyrrolidin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one

Conditions	Yield
Stage #1: docosahexaenoic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 0.5h; Stage #2: pyrrolidine In dichloromethane for 12h;	96%

piperidine (110-89-4) + docosahexaenoic acid (6217-54-5) → (4Z,7Z,10Z,13Z,16Z,19Z)-1-(piperidin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one

Conditions	Yield
Stage #1: docosahexaenoic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 0.5h; Stage #2: piperidine In dichloromethane for 12h;	96%

morpholine (110-91-8) + docosahexaenoic acid (6217-54-5) → (4Z,7Z,10Z,13Z,16Z,19Z)-1-morpholinodocosa-4,7,10,13,16,19-hexaen-1-one

Conditions	Yield
Stage #1: docosahexaenoic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 0.5h; Stage #2: morpholine In dichloromethane for 12h;	96%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Inert atmosphere;

1-methyl-piperazine (109-01-3) + docosahexaenoic acid (6217-54-5) → (4Z,7Z,10Z,13Z,16Z,19Z)-1-(4-methylpiperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one

Conditions	Yield
Stage #1: docosahexaenoic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 0.5h; Stage #2: 1-methyl-piperazine In dichloromethane for 12h;	96%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Inert atmosphere;

docosahexaenoic acid (6217-54-5) + benzylamine (100-46-9) → (4Z,7Z,10Z,13Z,16Z,19Z)-N-benzyldocosa-4,7,10,13,16,19-hexaenamide

Conditions	Yield
Stage #1: docosahexaenoic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 0.5h; Stage #2: benzylamine In dichloromethane for 12h;	96%

docosahexaenoic acid (6217-54-5) + rac-methylbenzylamine (618-36-0) → (4Z,7Z,10Z,13Z,16Z,19Z)-N-(1-phenylethyl)docosa-4,7,10,13,16,19-hexaenamide

Conditions	Yield
Stage #1: docosahexaenoic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 0.5h; Stage #2: rac-methylbenzylamine In dichloromethane for 12h;	96%

docosahexaenoic acid (6217-54-5) + (R)-1-phenyl-ethyl-amine (3886-69-9) → (4Z,7Z,10Z,13Z,16Z,19Z)-N-((S)-1-phenylethyl)docosa-4,7,10,13,16,19-hexaenamide

Conditions	Yield
Stage #1: docosahexaenoic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 0.5h; Stage #2: (R)-1-phenyl-ethyl-amine In dichloromethane for 12h;	96%

docosahexaenoic acid (6217-54-5) + (S)-1-phenyl-ethylamine (2627-86-3) → (4Z,7Z,10Z,13Z,16Z,19Z)-N-((R)-1-phenylethyl)docosa-4,7,10,13,16,19-hexaenamide

Conditions	Yield
Stage #1: docosahexaenoic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 0.5h; Stage #2: (S)-1-phenyl-ethylamine In dichloromethane for 12h;	96%

docosahexaenoic acid (6217-54-5) + 1,3-dilauroylglycerol (539-93-5) → 1,3-dilauroyl-2-docosahexaenoylglycerol

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 15h;	95%
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 80h;	25%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h;

docosahexaenoic acid (6217-54-5) + glycerol 1,3-dimyristate (7770-09-4) → (4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenoic acid 2-tetradecanoyloxy-1-tetradecanoyloxymethyl-ethyl ester

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 15h;	95%

docosahexaenoic acid (6217-54-5) + methyl (2S)-2-amino-3-hydroxypropanoate hydrochloride (5680-80-8) → N-docasahexanoyl-L-serine methyl ester

Conditions	Yield
With triethylamine; carbonochloridic acid, butyl ester In tetrahydrofuran; methanol; acetonitrile at 20℃; for 2h;	95%

docosahexaenoic acid (6217-54-5) + (R)-1-O-octadecyl-3-decanoyl-sn-glycerol (1278408-35-7) → (R)-1-O-octadecyl-2-docosahexaenoyl-3-decanoyl-sn-glycerol (1278408-81-3)

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 15h; Inert atmosphere;	95%

Upstream product

• 2566-90-7 all-cis-4,7,10,13,16,19-docosahexaenoic acid methyl ester 
• 928-96-1 (Z)-3-Hexen-1-ol 
• 84254-20-6 1-bromo-3-hexene 
• 169900-26-9 (Z,Z,Z)-1-bromododeca-3,6,9-triene 
• 169900-23-6 (Z,Z,Z)-dodeca-3,6,9-trien-1-al 
• 169900-28-1 (Z,Z)-10-oxodeca-4,7-dienoic acid methyl ester 
• 169900-25-8 (Z,Z)-10,10-diisopropoxydeca-4,7-dienoic acid methyl ester 
• 78144-19-1 5-[(3Z,6Z,9Z,12Z,15Z)-1-iodooctadeca-3,6,9,12,15-pentaenyl]dihydro-2(3H)-furanone 
• 81926-94-5 all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate 
• 86227-47-6 eicosapentaenoic acid ethyl ester 
• 534-03-2 serinol 
• 66211-46-9 (R)-3-amino-1,2-propanediol 
• 141-43-5 ethanolamine 
• 616-30-8 3-Amino-1,2-propanediol 

Downstream Products

• 2566-90-7 all-cis-4,7,10,13,16,19-docosahexaenoic acid methyl ester 
• 78144-19-1 5-[(3Z,6Z,9Z,12Z,15Z)-1-iodooctadeca-3,6,9,12,15-pentaenyl]dihydro-2(3H)-furanone 
• 105-54-4 butanoic acid ethyl ester 
• 124596-98-1 triglyceride of docosahexaenoic acid 
• 140670-40-2 (4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenoic acid 2,3-dihydroxy-propyl ester 
• 98776-99-9 (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyl chloride 
• 946524-43-2 4,7,10,13,16,19-docosahexaenoyl ethanolamide-d4 
• 89-84-9 2',4'-dihydroxy-4-acetophenone 
• 1139-83-9 urolithin B 
• 480-66-0 2,4,6-trihydroxyacetophenone 
• 1143-70-0 urolithin B 
• 118-93-4 o-hydroxyacetophenone 
• 123673-33-6 17(S)-hydroperoxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid 
• 90780-53-3 13-HDHA 

Relevant academic research and scientific papers

Synthesis of all-Z-1,6,9,12,15-octadecapenten-3-one, a vinyl ketone polyunsaturated marine natural product isolated from callysponga sp

The synthesis of the marine natural product 1,6Z,9Z,12Z,15Z- octadecapentaen- 3-one (1) has been achieved by two different routes starting from the ethyl esters of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively. Using EPA ethyl ester as starting material the polyunsaturated vinyl ketone lipid 1 was obtained in 17% overall yield.

Antioxidative Properties and Chemical Changes of Quercetin in Fish Oil: Quercetin Reacts with Free Fatty Acids to Form Its Ester Derivatives

In this research, we studied the antioxidative properties and chemical changes of quercetin in fish oil during accelerated storage at 60 °C for 5 days. Gas chromatography (GC) analysis showed that quercetin inhibited aldehyde formation and unsaturated fatty acid oxidation in fish oil significantly; however, the inhibitory effects decreased gradually with prolonged heating time. Moreover, quercetin was consumed with increasing heating time. Some new phenolic derivatives were discovered in the fish oil with quercetin, with their structures fully elucidated by LC-MS/MS and comparison with newly synthesized ones (characterized by MS and NMR spectroscopy). Based on their chemical structures, we proposed that quercetin reacted with EPA and DHA to form the corresponding quercetin fatty acid esters in fish oil. In addition, the newly formed quercetin-3-O-eicosapentaenoate and quercetin-3-O-docosahexaenoate showed weaker DPPH and ABTS radical cation scavenging activity but much improved lipophilicity, higher cell membrane affinity, and hence enhanced cellular antioxidant activity compared with the parent quercetin. Overall, quercetin could be used as a safe dietary polyphenol to inhibit lipid oxidation. The newly formed quercetin-polyunsaturated fatty acid esters may render improved bioactivity to humans, which needs further investigation.

PROCESSES IN THE PREPARATION OF POLYUNSATURATED KETONE COMPOUNDS

A process comprising the following steps: a-i) treating a polyunsaturated ester with a base in a solvent of lower alcohol and water to form the corresponding polyunsaturated acid; a-ii) treating the product from step a-i), especially the crude product, with a halolactonization agent in the solvent of lower alcohol and water, to form the corresponding polyunsaturated halolactone; and a-iii) treating the product from step a-ii), especially the crude product, with a reagent in the solvent of lower alcohol and water to convert the polyunsaturated halolactone to the corresponding polyunsaturated epoxide lower alkyl ester.

Fatty Acid Cysteamine Conjugates as Novel and Potent Autophagy Activators That Enhance the Correction of Misfolded F508del-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

A depressed autophagy has previously been reported in cystic fibrosis patients with the common F508del-CFTR mutation. This report describes the synthesis and preliminary biological characterization of a novel series of autophagy activators involving fatty acid cysteamine conjugates. These molecular entities were synthesized by first covalently linking cysteamine to docosahexaenoic acid. The resulting conjugate 1 synergistically activated autophagy in primary homozygous F508del-CFTR human bronchial epithelial (hBE) cells at submicromolar concentrations. When conjugate 1 was used in combination with the corrector lumacaftor and the potentiator ivacaftor, it showed an additive effect, as measured by the increase in the chloride current in a functional assay. In order to obtain a more stable form for oral dosing, the sulfhydryl group in conjugate 1 was converted into a functionalized disulfide moiety. The resulting conjugate 5 is orally bioavailable in the mouse, rat, and dog and allows a sustained delivery of the biologically active conjugate 1.

PROCESS FOR THE PREPARATION OF A POLYUNSATURATED KETONE COMPOUND

The invention relates to the manufacture of certain polyunsaturated compounds employing a particular application of the Mitsonobu reaction in the presence of at least one anti-oxidant. We have found a method of making a pharmaceutically-acccptable polyunsaturated ester or thioester compound directly, which can ultimately be converted to the advantageous ketone compounds, in which unwanted oxidation and cis/trans isomerization are substantially reduced or eliminated using particular Mitsonobu chemistry.

One-pot synthesis of polyunsaturated fatty acid amides with anti-proliferative properties

A one-pot environmentally friendly transamidation of ω-3 fatty acid ethyl esters to amides and mono- or diacylglycerols was investigated via the use of a polymer-supported lipase. The method was used to synthesize a library of fatty acid monoglyceryl esters and amides. These new derivatives were found to have potent growth inhibition effects against A549 lung cancer cells.

PROCEDURE FOR THE OBTAINMENT OF FATTY ACIDS OF PHARMACOLOGICAL AND NUTRITIONAL INTEREST

This invention refers to a procedure for obtaining fatty acids of pharmacological and nutritional interest that comprises the steps of feeding a gas comprising CO2 into a reactor that contains a culture that comprises at least one species of microalgae capable of photosynthesis, the process of photosynthesis by the species of microalgae from the CO2 supplied, producing a biomass that contains a general formula (I) compound: extraction of the general formula (I) compound from the biomass obtained and concentration and/or purification of this compound.

METHOD FOR THE SYNTHESIS OF DHA

A method for preparing docosahexaenoic acid (DHA). The method comprises coupling a compound represented by Formula I with a compound represented by Formula II followed by partial hydrogenation to obtain a compound represented by Formula III. The compound represented by Formula III acts as a DHA precursor and thus can be hydrolysed to obtain DHA. Novel starting materials represented by Formula I and Formula II, and synthetic routes for preparing the same are also provided.

Concise syntheses of three ω-3 polyunsaturated fatty acids

The synthesis of the three ω-3 polyunsaturated fatty acids, eicosatetraenoic acid (3), docosapentaenoic acid (4), and stearidonic acid (5) has been achieved using eicosapentaenoic acid or docosahexaenoic acid as the starting materials.

Chemoenzymatic synthesis of a focused library of enantiopure structured 1-O-alkyl-2,3-diacyl-sn-glycerol type ether lipids

A highly efficient two-step chemoenzymatic synthesis of enantiopure structured ether lipids of the 1-O-alkyl-2,3-diacyl-sn-glycerol type has been developed. Chimyl, batyl and selachyl alcohols possessing pure saturated fatty acid (SFA) attached to the sn-3 position and pure EPA and DHA attached to the sn-2 position were obtained under full regiocontrol. This was offered by mild conditions and a highly efficient lipase that operated at room temperature. High-resolution 1H NMR spectroscopy was used to monitor the progress of the reactions and to evaluate the full regiocontrol of the reactions involved by keeping track of all prospective adducts involved in these reactions. This was extended to preparation of a focused library of eight monoacyl intermediate adducts for all even-numbered SFA ranging from C2-C16 and the corresponding EPA and DHA structured diacyl glycerol ethers (DAGE) products for chimyl, batyl and selachyl alcohols, the total of 72 compounds.