4298-08-2

Basic information

• Product Name: L-Proline, 3-hydroxy-,(3S)-
• Synonyms: L-Proline,3-hydroxy-, trans-;Proline, 3-hydroxy-, L-trans- (8CI);(2S,3S)-(-)-3-Hydroxy-L-proline;(2S,3S)-3-Hydroxyproline;trans-3-Hydroxy-L-proline;trans-3-Hydroxyproline
• CAS NO: 4298-08-2
• Molecular Formula: C₅H₉NO₃
• Molecular Weight: 131.1299
• Product Categories: Heterocycles;Pyrrolidine series
• Mol File: 4298-08-2.mol
• Article Data: 27

Chemical Properties

• Melting Point: 235 °C
• Boiling Point: 355.233 °C at 760 mmHg
• Flash Point: 168.639 °C
• Appearance: White to light beige powder
• Density: 1.395g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.54
• Storage Temp.: under inert gas (nitrogen or Argon) at 2–8 °C
• PKA: 2.03±0.40(Predicted)
• CAS DataBase Reference: L-Proline, 3-hydroxy-,(3S)-(CAS DataBase Reference)
• NIST Chemistry Reference: L-Proline, 3-hydroxy-,(3S)-(4298-08-2)
• EPA Substance Registry System: L-Proline, 3-hydroxy-,(3S)-(4298-08-2)

Safety Data

• Safety Statements: 22-24/25
• WGK Germany: 3
• F: 10
• Hazardous Substances Data: 4298-08-2(Hazardous Substances Data)

Usage

Chemical Properties

White to light beige powder

Uses

trans-3-Hydroxyproline, is a versatile building block, used in the synthesis of various pharmaceutical and biologically active compounds. It is used as an intermediate in the synthesis of ferrocene-hydroxyproline amino acid conjugates.

InChI:InChI=1/C5H9NO3/c7-3-1-2-6-4(3)5(8)9/h3-4,6-7H,1-2H2,(H,8,9)/t3-,4-/m0/s1

Synthetic route

(2S,3S)-N-benzyl-2-hydroxyproline (312583-31-6) → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
With hydrogen; palladium on activated charcoal In methanol at 20℃; for 13h;	98%

(S,S)-2-(tert-butoxycarbonyl)-3-acetoxypyrrolidine → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
With hydrogenchloride In water at 20℃; for 16h;	89%

(2S,3S)-3-hydroxy-pyrrolidine-2-carboxylic acid methyl ester hydrochloride → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
With potassium hydroxide In methanol; water Ambient temperature;	88%

Potassium; (2S,3S)-2-amino-3-hydroxy-5,5-dimethoxy-pentanoate (120789-99-3) → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
With hydrogen; trifluoroacetic acid; platinum(IV) oxide In ethanol; water for 15h; Ambient temperature;	87%

(S,S)-N-(1)-(tert-butoxycarbonyl)-2-(tert-butoxycarbonyl)-3-hydroxypyrrolidine → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
With hydrogenchloride In water at 20℃; for 16h;	87%

(2S,3S)-1-(tert-butoxycarbonyl)-3-(tert-butyldimethylsiloxy)pyrrolidine-2-carboxylic acid (156045-82-8) → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
With hydrogenchloride In ethanol for 3h; Inert atmosphere; Reflux;	80%
With hydrogenchloride for 3h; Heating;	70%

FR901469 hydrochloride → threo-β-hydroxy-L-glutamic acid (threo-L-BHGA) (6208-98-6) + (R)-β-hydroxypalmitic acid (928-17-6, 2398-34-7, 83780-74-9, 20595-04-4) + trans-3-hydroxy-L-proline (4298-08-2) + 4R-4-hydroxyproline (51-35-4)

Conditions	Yield
With hydrogenchloride at 110℃; for 16h;	A 14.7 mg B 19 mg C 14.2 mg D 15.6 mg

(2S,3S)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-2-carboxylic acid methyl ester → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
With Dowex 50W-X8; water In tetrahydrofuran Heating;	0.14 g

L-proline (147-85-3) → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
With α-ketoglutaric acid; iron(II) sulfate; ascorbic acid; Aeromonas caviae In water at 25℃; for 24h; pH=7; Enzymatic reaction;

(2R,3S)-1-Benzyl-3-hydroxy-pyrrolidine-2-carbonitrile → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 83 percent / aq. hydrochloric acid / 8 h / 45 - 50 °C 2: 98 percent / H2 / Pd-C / methanol / 13 h / 20 °C View Scheme

methyl (2S,3S)-3-hydroxy-2-[(9-phenyl-9-fluorenyl)-amino]-4-pentenoate (404369-20-6) → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 98 percent / imidazole / dimethylformamide / 12 h / 20 °C 2.1: BH3*SMe2 / tetrahydrofuran / 10 h / 20 °C 2.2: 70 percent / NaOH; aq. H2O2 / tetrahydrofuran 3.1: 87 percent / MsCl; Et3N / tetrahydrofuran / 3 h / 0 °C 4.1: H2 / Pd/C / methanol / 3 h / 60 °C 5.1: 0.14 g / Dowex 50W-X8; H2O / tetrahydrofuran / Heating View Scheme

(2S,3S)-1-Allyl-3-hydroxy-pyrrolidine-2-carboxylic acid amide → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: Amberlyst 15 / 65 °C 2: 70 percent / 1.) Pd(dba)2, Dppb, mercaptobenzoic acid, 2.) 1M HCl / tetrahydrofuran / Ambient temperature 3: 88 percent / KOH / methanol; H2O / Ambient temperature View Scheme

(2S,3S)-1-Allyl-3-hydroxy-pyrrolidine-2-carboxylic acid methyl ester (213131-33-0) → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 70 percent / 1.) Pd(dba)2, Dppb, mercaptobenzoic acid, 2.) 1M HCl / tetrahydrofuran / Ambient temperature 2: 88 percent / KOH / methanol; H2O / Ambient temperature View Scheme

(2R,3S)-1-Allyl-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-2-carbonitrile (213131-29-4) → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: HCl / methanol / -20 °C 2: Amberlyst 15 / 65 °C 3: 70 percent / 1.) Pd(dba)2, Dppb, mercaptobenzoic acid, 2.) 1M HCl / tetrahydrofuran / Ambient temperature 4: 88 percent / KOH / methanol; H2O / Ambient temperature View Scheme

(3R,7aS)-3-phenyl-3,7a-dihydro-1H-pyrrolo[1,2-c]oxazol-5-one (134107-65-6) → trans-3-hydroxy-L-proline (4298-08-2)

Conditions

Yield

Multi-step reaction with 7 steps 1: 63 percent / t-BuOOH, n-Bu4NF, K2CO3 / dimethylformamide; 2,2,4-trimethyl-pentane; tetrahydrofuran / 2 h 2: 79 percent / aluminum amalgam, NaHCO3 (half sat.) / ethanol; acetone / 2 h 3: 74 percent / imidazole / dimethylformamide / 6 h / 40 °C 4: 1.) BH3*SMe, 2.) TMEDA / 1.) THF, 70 deg C, 2 h, 2.) THF, Et2O, RT, 6 h 5: 80 percent / H2 / 10percent Pd/C / methanol / 3 h / 15001.2 Torr 6: 51 percent / NaIO4, RuCl3 / acetonitrile; CCl4; H2O / 1.5 h / Ambient temperature 7: 70 percent / 6 M aq. HCl / 3 h / Heating View Scheme

(3R,7aS)-3-phenyl-tetrahydro-pyrrolo[1,2-c]oxazol-5-one (103201-79-2) → trans-3-hydroxy-L-proline (4298-08-2)

Conditions

Yield

Multi-step reaction with 9 steps 1: 1.) n-BuLi, hexamethyldisilazane / 1.) THF, -78 deg C, 30 min, 2.) THF, -78 deg C, 2 h 2: 30percent aq. H2O2 / ethyl acetate / 0.67 h / 0 - 22 °C 3: 63 percent / t-BuOOH, n-Bu4NF, K2CO3 / dimethylformamide; 2,2,4-trimethyl-pentane; tetrahydrofuran / 2 h 4: 79 percent / aluminum amalgam, NaHCO3 (half sat.) / ethanol; acetone / 2 h 5: 74 percent / imidazole / dimethylformamide / 6 h / 40 °C 6: 1.) BH3*SMe, 2.) TMEDA / 1.) THF, 70 deg C, 2 h, 2.) THF, Et2O, RT, 6 h 7: 80 percent / H2 / 10percent Pd/C / methanol / 3 h / 15001.2 Torr 8: 51 percent / NaIO4, RuCl3 / acetonitrile; CCl4; H2O / 1.5 h / Ambient temperature 9: 70 percent / 6 M aq. HCl / 3 h / Heating View Scheme

bicyclic (2R,5R,6R)-6-hydroxy-2-phenyl-3-oxa-1-azabicyclo<3.3.0>octan-8-one (156045-79-3) → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: 74 percent / imidazole / dimethylformamide / 6 h / 40 °C 2: 1.) BH3*SMe, 2.) TMEDA / 1.) THF, 70 deg C, 2 h, 2.) THF, Et2O, RT, 6 h 3: 80 percent / H2 / 10percent Pd/C / methanol / 3 h / 15001.2 Torr 4: 51 percent / NaIO4, RuCl3 / acetonitrile; CCl4; H2O / 1.5 h / Ambient temperature 5: 70 percent / 6 M aq. HCl / 3 h / Heating View Scheme

(2R,3S)-1-benzyl-3-tert-butyldimethylsilyloxy-2-hydroxymethylpyrrolidine (156045-81-7) → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 80 percent / H2 / 10percent Pd/C / methanol / 3 h / 15001.2 Torr 2: 51 percent / NaIO4, RuCl3 / acetonitrile; CCl4; H2O / 1.5 h / Ambient temperature 3: 70 percent / 6 M aq. HCl / 3 h / Heating View Scheme

tert-butyl (2R,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)pyrrolidine-1-carboxylate (156129-73-6) → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 51 percent / NaIO4, RuCl3 / acetonitrile; CCl4; H2O / 1.5 h / Ambient temperature 2: 70 percent / 6 M aq. HCl / 3 h / Heating View Scheme

(2R,5R,6S)-6-tert-butyldimethylsiloxy-3-oxa-2-phenyl-1-azabicyclo<3.3.0>octane-8-one (156045-80-6) → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) BH3*SMe, 2.) TMEDA / 1.) THF, 70 deg C, 2 h, 2.) THF, Et2O, RT, 6 h 2: 80 percent / H2 / 10percent Pd/C / methanol / 3 h / 15001.2 Torr 3: 51 percent / NaIO4, RuCl3 / acetonitrile; CCl4; H2O / 1.5 h / Ambient temperature 4: 70 percent / 6 M aq. HCl / 3 h / Heating View Scheme

(3R,7aS)-3-phenyl-6-(phenylselanyl)tetrahydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one → trans-3-hydroxy-L-proline (4298-08-2)

Conditions

Yield

Multi-step reaction with 8 steps 1: 30percent aq. H2O2 / ethyl acetate / 0.67 h / 0 - 22 °C 2: 63 percent / t-BuOOH, n-Bu4NF, K2CO3 / dimethylformamide; 2,2,4-trimethyl-pentane; tetrahydrofuran / 2 h 3: 79 percent / aluminum amalgam, NaHCO3 (half sat.) / ethanol; acetone / 2 h 4: 74 percent / imidazole / dimethylformamide / 6 h / 40 °C 5: 1.) BH3*SMe, 2.) TMEDA / 1.) THF, 70 deg C, 2 h, 2.) THF, Et2O, RT, 6 h 6: 80 percent / H2 / 10percent Pd/C / methanol / 3 h / 15001.2 Torr 7: 51 percent / NaIO4, RuCl3 / acetonitrile; CCl4; H2O / 1.5 h / Ambient temperature 8: 70 percent / 6 M aq. HCl / 3 h / Heating View Scheme

(2R,5R,6R,7R)-6,7-epoxy-2-phenyl-3-oxa-1-aza-bicyclo<3.3.0>octane-8-one (154631-82-0) → trans-3-hydroxy-L-proline (4298-08-2)

Conditions

Yield

Multi-step reaction with 6 steps 1: 79 percent / aluminum amalgam, NaHCO3 (half sat.) / ethanol; acetone / 2 h 2: 74 percent / imidazole / dimethylformamide / 6 h / 40 °C 3: 1.) BH3*SMe, 2.) TMEDA / 1.) THF, 70 deg C, 2 h, 2.) THF, Et2O, RT, 6 h 4: 80 percent / H2 / 10percent Pd/C / methanol / 3 h / 15001.2 Torr 5: 51 percent / NaIO4, RuCl3 / acetonitrile; CCl4; H2O / 1.5 h / Ambient temperature 6: 70 percent / 6 M aq. HCl / 3 h / Heating View Scheme

C51H89N11O18 → L-erythro-3-amino-butane-1,2,4-triol (736129-34-3) + L-serin (56-45-1) + L-threonine (72-19-5) + L-arginine (74-79-3) + 2-(S)-amino-3-(R)-hydroxysuccinic acid (7298-98-8) + trans-3-hydroxy-L-proline (4298-08-2) + L-proline (147-85-3) + (R)-3-hydroxy-13-methyltetradecanoic acid (221695-92-7)

Conditions	Yield
With hydrogenchloride; water for 20h; Reflux;

...Expand

C51H89N11O18 → L-serin (56-45-1) + L-threonine (72-19-5) + (2S,3S)-3-amino-2,4-dihydroxy-butyric acid (29621-86-1) + L-arginine (74-79-3) + 2-amino-2-deoxy-L-erythronic acid (21768-43-4) + trans-3-hydroxy-L-proline (4298-08-2) + L-proline (147-85-3) + (R)-3-hydroxy-13-methyltetradecanoic acid (221695-92-7)

Conditions	Yield
With hydrogenchloride; water for 20h; Reflux;

...Expand

tripropeptin C → L-serin (56-45-1) + L-threonine (72-19-5) + L-arginine (74-79-3) + L-threo-3-hydroxyaspartic acid (1186-90-9, 1860-87-3, 4294-45-5, 5174-55-0, 5753-30-0, 6532-76-9, 7298-98-8, 7298-99-9, 16417-36-0, 71653-06-0, 81601-40-3) + 2-(S)-amino-3-(R)-hydroxysuccinic acid (7298-98-8) + trans-3-hydroxy-L-proline (4298-08-2) + L-proline (147-85-3) + (R)-3-hydroxy-13-methyltetradecanoic acid (221695-92-7)

Conditions	Yield
With hydrogenchloride; water for 20h; Reflux;

...Expand

L-proline (147-85-3) → trans-3-hydroxy-L-proline (4298-08-2) + 4R-4-hydroxyproline (51-35-4)

Conditions	Yield
With His-tagged eukaryotic α-ketoglutarate/FeII-dependent proline hydroxylase F from Glarea lozoyensis ATCC 74030; ascorbate; α-ketoglutarate; iron(II) sulfate In aq. buffer at 20℃; for 1h; pH=6; Kinetics; Enzymatic reaction; stereoselective reaction;

(S,S)-N-(1)-benzyl-2-(tert-butoxycarbonyl)-3-acetoxypyrrolidine-2-carboxylate → trans-3-hydroxy-L-proline (4298-08-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 25% Pd(OH)2/C; acetic acid / methanol; water / 20 °C / 3800.26 Torr 2: hydrogenchloride / water / 16 h / 20 °C View Scheme

di-tert-butyl dicarbonate (24424-99-5) + trans-3-hydroxy-L-proline (4298-08-2) → (2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (187039-57-2)

Conditions	Yield
With sodium hydroxide In tetrahydrofuran at 20℃;	100%
With sodium hydroxide In tetrahydrofuran; water	100%
With sodium hydroxide In tetrahydrofuran	92%

methanol (67-56-1) + trans-3-hydroxy-L-proline (4298-08-2) → (2S,3S)-methyl 3-hydroxypyrrolidine-2-carboxylate (496841-04-4)

Conditions	Yield
With thionyl chloride	100%
With thionyl chloride
With hydrogenchloride

methanol (67-56-1) + trans-3-hydroxy-L-proline (4298-08-2) → (2S,3S)-3-hydroxy-pyrrolidine-2-carboxylic acid methyl ester hydrochloride

Conditions	Yield
With thionyl chloride at 0 - 20℃;	100%
With hydrogenchloride at 0 - 20℃;	99%
With thionyl chloride at 0℃; for 16h;	99%

(fluorenylmethoxy)carbonyl chloride (28920-43-6) + trans-3-hydroxy-L-proline (4298-08-2) → (2S,3S)-(3-hydroxy)pyrrolidine-1,2-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (296774-32-8)

Conditions	Yield
With sodium hydrogencarbonate In 1,4-dioxane at 0 - 20℃; for 9h;	98%
With sodium hydrogencarbonate In 1,4-dioxane at 0 - 20℃; for 9h;	98%
With sodium carbonate In 1,4-dioxane; water at 0 - 20℃; for 3h;	59%
With sodium carbonate In 1,4-dioxane; water at 0 - 20℃; for 3h;	59.2%
With sodium hydrogencarbonate In 1,4-dioxane; water at 4 - 20℃; for 10h;	58%

methanol (67-56-1) + di-tert-butyl dicarbonate (24424-99-5) + trans-3-hydroxy-L-proline (4298-08-2) → (2S,3S)-1-tert-butyl-2-methyl 3-hydroxypyrrolidine-1,2-dicarboxylate (184046-78-4)

Conditions	Yield
Stage #1: methanol; trans-3-hydroxy-L-proline With thionyl chloride at 0 - 20℃; for 16h; Stage #2: di-tert-butyl dicarbonate With triethylamine In dichloromethane at 20℃; for 2h;	96%

di-tert-butyl dicarbonate (24424-99-5) + benzyl bromide (100-39-0) + trans-3-hydroxy-L-proline (4298-08-2) → 2-benzyl 1-(tert-butyl) (2S,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate (330945-07-8)

Conditions	Yield
Stage #1: di-tert-butyl dicarbonate; trans-3-hydroxy-L-proline With sodium hydroxide; water In tetrahydrofuran at 20℃; for 19h; Stage #2: With hydrogenchloride In tetrahydrofuran; water Stage #3: benzyl bromide With hydrogenchloride; potassium hydrogencarbonate more than 3 stages;	91%

methanol (67-56-1) + trans-3-hydroxy-L-proline (4298-08-2) → methyl (3S)-3-hydroxy-L-prolinate hydrochloride

Conditions	Yield
With acetyl chloride at 0 - 65℃; for 6h;	91%

2-(tert-Butoxycarbonyloxyimino)-2-phenylacetonitrile (58632-95-4) + trans-3-hydroxy-L-proline (4298-08-2) → (2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (187039-57-2)

Conditions	Yield
With triethylamine In 1,4-dioxane; methanol; water at 20℃; for 4h;	88%
With sodium hydroxide In 1,4-dioxane; water at 0℃; for 12h;

N-Fmoc L-Phe (35661-40-6) + trans-3-hydroxy-L-proline (4298-08-2) → (2S,3S)-1-[(S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-phenyl-propionyl]-3-hydroxy-pyrrolidine-2-carboxylic acid (847978-88-5)

Conditions	Yield
Stage #1: N-Fmoc L-Phe With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 4h; Stage #2: trans-3-hydroxy-L-proline With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃;	88%

trans-3-hydroxy-L-proline (4298-08-2) + benzyl chloroformate (501-53-1) → (2S,3S)-1-((benzyloxy)carbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (62182-54-1)

Conditions	Yield
With sodium hydrogencarbonate In water for 20h;	78%
With N-ethyl-N,N-diisopropylamine In water; N,N-dimethyl-formamide at 0 - 20℃;
With sodium hydrogencarbonate

tert-butyldicarbonate (34619-03-9) + trans-3-hydroxy-L-proline (4298-08-2) → (2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (187039-57-2)

Conditions	Yield
With sodium hydrogencarbonate In water for 24h;	75%

trans-3-hydroxy-L-proline (4298-08-2) + toluene-4-sulfonic acid (104-15-4) + isobutene (115-11-7) → 3(S)-tert-butoxy-L-proline tert-butyl ester tosylate

Conditions	Yield
In dichloromethane at -78 - 20℃; for 72h;	72%

methanol (67-56-1) + trityl chloride (76-83-5) + trans-3-hydroxy-L-proline (4298-08-2) → (2S,3S)-1-(triphenylmethyl)-3-hydroxyproline methyl ester (401909-57-7)

Conditions	Yield
Stage #1: methanol; trans-3-hydroxy-L-proline With thionyl chloride Stage #2: trityl chloride With triethylamine In dichloromethane at 0 - 20℃;	72%

trans-3-hydroxy-L-proline (4298-08-2) + isobutene (115-11-7) → trans-3-tert-butoxy-L-proline

Conditions	Yield
Stage #1: trans-3-hydroxy-L-proline; isobutene With toluene-4-sulfonic acid In dichloromethane at -78 - 20℃; for 72h; Stage #2: With sodium hydroxide In dichloromethane; water at 0℃; for 4h; Stage #3: With hydrogenchloride In dichloromethane; water at 0℃; for 0.5h;	69%

trans-3-hydroxy-L-proline (4298-08-2) + 1H,2H,4H-thieno[2,3-d][1,3]oxazine-2,4-dione (103979-54-0) → (8S,8aS)-8-hydroxy-6,7,8,8a-tetrahydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine-4,9(10H)-dione (1140528-76-2)

Conditions	Yield
In water Reflux; regioselective reaction;	35%

trans-3-hydroxy-L-proline (4298-08-2) + 2-aminobenzaldehyde (529-23-7) → 1,2,3,3a,4,9-hexahydro-pyrrolo[2,1-b]quinazolin-3-ol (55727-58-7)

Conditions	Yield
In butan-1-ol at 150℃; for 0.25h; Microwave irradiation; Sealed tube; regioselective reaction;	11%

3,5-dichlorobenzensulfonyl chloride (705-21-5) + trans-3-hydroxy-L-proline (4298-08-2) → (2S,3S)-1-(3,5-Dichloro-benzenesulfonyl)-3-hydroxy-pyrrolidine-2-carboxylic acid (425403-87-8)

Conditions	Yield
With sodium carbonate In water at 20℃;

trans-3-hydroxy-L-proline (4298-08-2) → (2S,3R)-N-tert-Butyloxycarbonyl-3-benzoyloxy-2-pyrrolidinecarboxylic Acid Methyl Ester (496841-07-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / PPh3; DEAD / tetrahydrofuran / 9 h / 0 - 20 °C View Scheme

trans-3-hydroxy-L-proline (4298-08-2) → (2S,3S)-N-tert-butyloxycarbonyl-3-(tert-butyldimethylsilyloxy)-2-pyrrolidinecarboxylic acid methyl ester (850003-05-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 99 percent / HCl / 0 - 20 °C 2: 80 percent / Et3N / CH2Cl2 / 0 - 20 °C 3: 90 percent / i-Pr2NEt / DMAP / CH2Cl2 / 48 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: acetyl chloride / 6 h / 0 - 65 °C 2: sodium hydrogencarbonate / tetrahydrofuran; water / 0 - 20 °C 3: 1H-imidazole / N,N-dimethyl-formamide / 3.5 h View Scheme
Multi-step reaction with 3 steps 1: acetyl chloride / 20 h / 0 - 65 °C 2: sodium hydrogencarbonate / tetrahydrofuran / 10 h / 0 - 20 °C 3: 1H-imidazole / N,N-dimethyl-formamide / 4 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: acetyl chloride / 0 - 65 °C / Cooling with ice bath; Inert atmosphere 2: sodium hydrogencarbonate / tetrahydrofuran; water / 0 - 20 °C / Inert atmosphere; Cooling with ice bath 3: 1H-imidazole / N,N-dimethyl-formamide / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: hydrogenchloride / 6.17 h / 0 - 20 °C 2: triethylamine / dichloromethane / 0 - 20 °C 3: 1H-imidazole / dichloromethane / 20 °C View Scheme

Upstream product

• 125787-20-4 cis-(3R)-(tert-butyldimethylsilyloxy)-2-cyano-1-methoxycarbonyl-3-pyrrolidine 
• 161993-49-3 (2S,3R)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-2-carboxylic acid 
• 147214-63-9 cyclothialidine 
• 1262015-07-5 (2S,3R)-N-(benzyloxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid 
• 156045-82-8 (2S,3S)-1-(tert-butoxycarbonyl)-3-(tert-butyldimethylsiloxy)pyrrolidine-2-carboxylic acid 
• 166383-69-3 (2R,3R)-1-t-Butoxycarbonyl-2-benzyloxymethyl-3-hydroxypyrrolidine 
• 166383-82-0 (2R,3R)-2-Benzyloxymethyl-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester 
• 174541-85-6 (4R,5R)-4-Benzyloxymethyl-5-(2-chloro-ethyl)-oxazolidin-2-one 
• 153805-41-5 methyl (4R,5R)-4-(benzyloxy)methyl-2-oxo-5-oxazolidineacetate 
• 153805-45-9 (4R,5R)-4-(benzyloxy)methyl-5-(2-hydroxyethyl)-2-oxo-oxazolidine 
• 186132-96-7 (2S,3R)-1-[(tert-butoxy)carbonyl]-3-hydroxypyrrolidine-2-carboxylic acid 
• 123287-88-7 (2S,3R)-tert-butyl 3-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate 
• 147-85-3 L-proline 
• 154631-82-0 (2R,5R,6R,7R)-6,7-epoxy-2-phenyl-3-oxa-1-aza-bicyclo<3.3.0>octane-8-one 

Downstream Products

• 187039-57-2 (2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid 
• 865110-90-3 N-[(3-cyanobenzene)sulfonyl]-(3S)-hydroxy-(L)-proline methyl ester 
• 95341-65-4 (2S,3S,4R)-3,4-dihydroxy-L-proline 
• 1374647-72-9 tert-butyl [(2R,3R)-2-(azidomethyl)-1-benzylpyrrolidin-3-yl]carbamate 
• 850003-11-1 (7R,7aR)-7-amino-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one 
• 850003-10-0 (7R,7aR)-7-azido-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one 
• 850003-07-5 1-(4-{[(2R,3S)-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-2-ylmethyl]-amino}-phenyl)-1H-pyridin-2-one 
• 850003-08-6 (7S,7aR)-7-(tert-butyl-dimethyl-silanyloxy)-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one 
• 850000-85-0 5-chloro-thiophene-2-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide 
• 850003-06-4 (2R,3S)-3-(tert-butyl-dimethyl-silanyloxy)-2-{[4-(2-oxo-2H-pyridin-1-yl)-phenylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester 
• 1024021-36-0 tert-butyl [(2S,3R)-1-Benzyl-2-(hydroxymethyl)pyrrolidin-3-yl]carbamate 
• 1374647-71-8 methyl (2S,3R)-3-azido-1-benzylpyrrolidine-2-carboxylate 
• 1374647-70-7 (2R,3S)-2-(azidomethyl)-1-benzyl-3-(tert-butyldiphenylsilyloxy)pyrrolidine 
• 1374647-68-3 [(2R,3S)-1-benzyl-3-(tert-butyldiphenylsilyloxy)pyrrolidin-2-yl]methanol 

Relevant articles and documents

Microbial screening in hydroxylation of l-proline

Microbial screening of 250 wild type strains resulted in identification of five strains with the activity of prolyl hydroxylase. All five strains hydroxylated regioselectively and enantioselectively l-proline into 4(R)-trans-hydroxy-l-proline 1. The best conversions were obtained with a wild type of Aeromonas caviae. 3-Hydroxylase activity was not detected.

Total Synthesis of 3(S)-Carboxy-4(S)-hydroxy-2,3,4,5-tetrahydropyridazine, an Unusual Amino Acid Constituent of Luzopeptin A

The enantiospecific synthesis of 3(S)-carboxy-4(S)-hydroxy-2,3,4,5-tetrahydropyridazine (2), a novel constituent of the antibiotic antitumor agent luzopeptin A is described.Structural corroboration of the synthetic compound is based on three points.The 13C NMR spectrum of synthetic 2 was compared with that of a similar degradation product of luzopeptin.The 1H NMR spectrum of 2 was compared with that of the synthetic cis isomer.Finally, the synthetic methodology developed for the synthesis of 2 was applied to the synthesis of the known L-trans-3-hydroxyproline.

Modular Chemoenzymatic Synthesis of GE81112 B1 and Related Analogues Enables Elucidation of Its Key Pharmacophores

The GE81112 complex has garnered much interest due to its broad antimicrobial properties and unique ability to inhibit bacterial translation initiation. Herein we report the use of a chemoenzymatic strategy to complete the first total synthesis of GE81112 B1. By pairing iron and α-ketoglutarate dependent hydroxylases found in GE81112 biosynthesis with traditional synthetic methodology, we were able to access the natural product in 11 steps (longest linear sequence). Following this strategy, 10 GE81112 B1 analogues were synthesized, allowing for identification of its key pharmacophores. A key feature of our medicinal chemistry effort is the incorporation of additional biocatalytic hydroxylations in modular analogue synthesis to rapidly enable exploration of relevant chemical space.

Preparation method of cis-3-hydroxyl-L-proline

The invention provides a preparation method of cis-3-hydroxyl-L-proline. The preparation method comprises the following steps of using the industrially produced L-serine as the starting raw material,introducing a second chiral center into the nucleophilic addition reaction of aldehyde via an ortho chiral induction format, and separating the product and an isomer by a column separating method; constructing an intermediate of which the carbon number is the same with the carbon number of a target product through the hydroxyl protection and the hydroboration-oxidizing reaction, constructing a five-elemental ring of the proline via the cyclization reaction in molecules, and removing the protective radicals, so as to obtain the cis-3-hydroxyl-L-proline. The cis-3-hydroxyl-L-proline prepared bythe preparation method has the advantages that the chemical purity and optical purity are high; the whole technology is simple and is easy to implement, the cost is low, the expensive or hypertoxic raw material or reagent is not used, and the cis-3-hydroxyl-L-proline is suitable for kilogram-level production; the higher implementing value and social and economic benefits are realized.