113400-36-5

Basic information

• Product Name: BOC-L-PYROGLUTAMIC ACID BENZYL ESTER
• Synonyms: BOC-L-PYROGLUTAMIC ACID BENZYL ESTER;(2R)-5-Oxo-1,2-pyrrolidinedicarboxylic acid 1-(tert-butyl) 2-(phenylmethyl) ester;Boc-PyroglutaMic acid. Benzyl ester;Boc-Pyr-Obzl;(S)-2-Benzyl 1-tert-butyl 5-oxopyrrolidine-1,2-dicarboxylate;Benzyl (S)-1-Boc-5-oxopyrrolidine-2-carboxylate, 98%;1,2-Pyrrolidinedicarboxylic acid, 5-oxo-, 1-(1,1-diMethylethyl)2-(phenylMethyl) ester, (S)-;2-O-benzyl 1-O-tert-butyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate
• CAS NO: 113400-36-5
• Molecular Formula: C₁₇H₂₁NO₅
• Molecular Weight: 319
• Mol File: 113400-36-5.mol
• Article Data: 27

Chemical Properties

• Melting Point: 69-70 °C
• Boiling Point: 464.947 °C at 760 mmHg
• Flash Point: 234.991 °C
• Appearance: White/Powder
• Density: 1.219
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.542
• Storage Temp.: 2-8°C
• PKA: -4.32±0.40(Predicted)
• CAS DataBase Reference: BOC-L-PYROGLUTAMIC ACID BENZYL ESTER(CAS DataBase Reference)
• NIST Chemistry Reference: BOC-L-PYROGLUTAMIC ACID BENZYL ESTER(113400-36-5)
• EPA Substance Registry System: BOC-L-PYROGLUTAMIC ACID BENZYL ESTER(113400-36-5)

Safety Data

• Hazardous Substances Data: 113400-36-5(Hazardous Substances Data)

Usage

General Description

BOC-L-Pyroglutamic acid benzyl ester is a chemical compound that is used in the synthesis of peptides and pharmaceuticals. It is a derivative of pyroglutamic acid, a cyclic derivative of glutamic acid, and has a benzyl ester group attached to it. BOC-L-PYROGLUTAMIC ACID BENZYL ESTER is commonly utilized as a protecting group in peptide synthesis to prevent unwanted reactions during the assembly of peptides. It is also used as a building block in the production of various pharmaceuticals and bioactive compounds. BOC-L-Pyroglutamic acid benzyl ester is an important chemical for the pharmaceutical and biotechnology industries.

InChI:InChI=1/C17H21NO5/c1-17(2,3)23-16(21)18-13(9-10-14(18)19)15(20)22-11-12-7-5-4-6-8-12/h4-8,13H,9-11H2,1-3H3/t13-/m0/s1

Synthetic route

di-tert-butyl dicarbonate (24424-99-5) + benzyl (L)-pyroglutamate (94885-52-6) → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
With dmap In dichloromethane at 0 - 20℃;	98%
With dmap; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 3h;	90%
With dmap; triethylamine In dichloromethane at 0 - 23℃; for 17h; Inert atmosphere;	90%

di-tert-butyl dicarbonate (24424-99-5) + L-glutamic acid dibenzyl ester hydrochloride (4561-10-8) → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In toluene at 30 - 95℃; for 9h; Solvent; Temperature; Concentration;	94.6%

L-Pyroglutamic acid (98-79-3) → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
	94%
Multi-step reaction with 2 steps 1: Et3N / tetrahydrofuran / 120 h / Heating 2: 9.0 g / Et3N; 4-(dimethylamino)pyridine / CH2Cl2 / 384 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: 85 percent / TEA / acetone 2: 73 percent / DMAP / acetonitrile View Scheme

(2S,4S)-4-((R)-3-Methyl-1,1-dioxo-2,3-dihydro-1H-1λ6-benzo[d]isothiazol-3-yl)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (135347-23-8) → 3-methylbenzo[d]isothiazole-1,1-dioxide (34989-82-7) + benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
With lithium hexamethyldisilazane In tetrahydrofuran 1.) -78 deg C, 30 min, 2.) -78 deg C -> room temperature, 2 h;	A 40% B 38%

methylmagnesium bromide (75-16-1) + (S)-2-tert-Butoxycarbonylamino-5-isobutoxycarbonyloxy-5-oxo-pentanoic acid benzyl ester → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) + benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-oxohexanoate (113400-46-7)

Conditions	Yield
In tetrahydrofuran; toluene at -78℃; for 0.75h; Yield given. Yields of byproduct given;

(S)-2-tert-Butoxycarbonylamino-5-isobutoxycarbonyloxy-5-oxo-pentanoic acid benzyl ester → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) + benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-oxohexanoate (113400-46-7)

Conditions	Yield
With methylmagnesium bromide In tetrahydrofuran; toluene at -78℃; for 0.75h; Yield given. Yields of byproduct given;

benzyl chloride (100-44-7) → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: Et3N / tetrahydrofuran / 120 h / Heating 2: 9.0 g / Et3N; 4-(dimethylamino)pyridine / CH2Cl2 / 384 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 120 h / 70 °C 2: triethylamine; dmap / dichloromethane / 16 h / 20 °C / Cooling with ice View Scheme
Multi-step reaction with 2 steps 1: triethylamine / acetone / 24 °C / Reflux; Inert atmosphere 2: dmap / dichloromethane / Inert atmosphere View Scheme

benzyl chloride (100-44-7) + N,N-diethyl-glycine-<4-hydroxy-anilide> → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 85 percent / TEA / acetone 2: 73 percent / DMAP / acetonitrile View Scheme

benzyl bromide (100-39-0) + (1R,2R)-O-Merrifield bound N-(2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2'-phenylacetamide → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: N,N-diisopropylethylamine / CH2Cl2 / 5 h / Heating 2: 37.5 g / 4-dimethylaminopyridine / acetonitrile / 3 h / 25 °C View Scheme

benzyl bromide (100-39-0) + XOOC-CH2-COOX → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 88 percent / Et3N / acetone / 24 h / 20 °C 2: 90 percent / DIEA; DMAP / dimethylformamide / 3 h / 20 °C View Scheme

L-Pyroglutamic acid (98-79-3) + Fmoc-Pro-Rink amide-MBHA resin → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 88 percent / Et3N / acetone / 24 h / 20 °C 2: 90 percent / DIEA; DMAP / dimethylformamide / 3 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: 90 percent / SOCl2; DMF / 20 °C 2: 98 percent / dimethylaminopyridine / CH2Cl2 / 0 - 20 °C View Scheme

benzyl alcohol (100-51-6) + BocNH-C(=NBoc)-SCH2-terminated resin → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / SOCl2; DMF / 20 °C 2: 98 percent / dimethylaminopyridine / CH2Cl2 / 0 - 20 °C View Scheme

benzyl alcohol (100-51-6) + NaCpW(CO)3 → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 96 percent / SOCl2 / 0 - 20 °C 2: Et3N; DMAP View Scheme

benzyl bromide (100-39-0) + t-BuOCOCH2-X → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: DIEA / CH2Cl2 / Heating 2: 9.56 g / DMAP; Et3N / acetonitrile / 20 °C View Scheme

Boc-Glu-OBn (30924-93-7) → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 4-methylmorpholine / CH2Cl2 / 0.25 h / 0 °C 2: tetrahydrofuran; toluene / 0.75 h / -78 °C View Scheme
Multi-step reaction with 2 steps 1: 4-methylmorpholine / CH2Cl2 / 0.25 h / 0 °C 2: methylmagnesium bromide / tetrahydrofuran; toluene / 0.75 h / -78 °C View Scheme

benzyl chloride (100-44-7) + sodium-compound of 1-cyclopentyl-ethanone → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: NEt3 / tetrahydrofuran / 120 h / Heating 2: NEt3 / CH2Cl2 View Scheme

benzyl chloride (100-44-7) + hydroxylamine hydrochloride → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 85 percent / triethylamine / acetone / 168 h / Heating 2: 75 percent / DMAP / acetonitrile / 1.) 0 deg C, 2 h, 2.) r.t., overnight View Scheme

tert-butyldicarbonate (34619-03-9) + benzyl (L)-pyroglutamate (94885-52-6) → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
With dmap In dichloromethane at 20℃; for 4h;

benzyl alcohol (100-51-6) → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: thionyl chloride / N,N-dimethyl-formamide / 0 - 20 °C 2: dmap / dichloromethane / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: thionyl chloride / 16 h / 0 - 23 °C / Inert atmosphere 2: dmap; triethylamine / dichloromethane / 17 h / 0 - 23 °C / Inert atmosphere View Scheme

benzyl chloride (100-44-7) + L-Pyroglutamic acid (98-79-3) → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; potassium iodide / toluene / 80 °C 2: 4-pyrrolidin-1-ylpyridine / 50 °C View Scheme

benzyl bromide (100-39-0) → benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / acetone / 16 h / Reflux 2: dmap; triethylamine / dichloromethane / 16 h / 50 °C / Inert atmosphere View Scheme

trimethylsulfoxonium iodide (1774-47-6) + benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → benzyl (2S)-2-((tert-butoxycarbonyl)amino)-6-(dimethyl(oxo)-λ6-sulfanylidene)-5-oxohexanoate

Conditions	Yield
Stage #1: trimethylsulfoxonium iodide With potassium tert-butylate In tetrahydrofuran; dimethyl sulfoxide at 20℃; for 1h; Stage #2: benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate In tetrahydrofuran; dimethyl sulfoxide at -10℃;	100%
With potassium carbonate In dimethyl sulfoxide at 50℃; for 23h; Temperature; Reagent/catalyst; Solvent;	96%
Stage #1: trimethylsulfoxonium iodide With potassium tert-butylate In tetrahydrofuran; dimethyl sulfoxide at 20℃; Stage #2: benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate In tetrahydrofuran; dimethyl sulfoxide at -12℃;
Stage #1: trimethylsulfoxonium iodide With potassium tert-butylate; dimethyl sulfoxide In tetrahydrofuran at 25℃; for 1h; Large scale; Industrial scale; Stage #2: benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate In tetrahydrofuran at -12℃; Large scale; Industrial scale;
Stage #1: trimethylsulfoxonium iodide With potassium tert-butylate In tetrahydrofuran; dimethyl sulfoxide at 25℃; for 2h; Stage #2: benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate In tetrahydrofuran; dimethyl sulfoxide at 0 - 10℃; for 8h;

benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → benzyl (2S)-N-tert-butoxycarbonyl-5-hydroxypyrrolidine-2-carboxylate (331949-29-2)

Conditions	Yield
With lithium triethylborohydride In tetrahydrofuran at -78℃; for 2h;	99%
With lithium triethylborohydride In tetrahydrofuran at -78℃; for 0.5h;	95%
With lithium triethylborohydride In tetrahydrofuran at -78℃; for 2h;	88%
With diisobutylaluminium hydride In tetrahydrofuran at -78℃;	70%
With lithium triethylborohydride In tetrahydrofuran at -78℃;

benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → L-N-t-butoxycarbonylpyroglutamic acid (53100-44-0)

Conditions	Yield
With hydrogen; palladium on activated charcoal In ethyl acetate for 120h; Ambient temperature;	98%
With hydrogen; 10percent Pd/C In ethyl acetate under 2280.15 Torr; for 1h;	98%
With hydrogen; palladium on activated charcoal In methanol for 6h;	93%

methanol (67-56-1) + benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → benzyl (2S)-N-tert-butoxycarbonyl-5-methoxypyrrolidine-2-carboxylate (331949-31-6)

Conditions	Yield
Stage #1: benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate With diisobutylaluminium hydride In tetrahydrofuran at -78℃; Stage #2: methanol With toluene-4-sulfonic acid In tetrahydrofuran at 20℃; Further stages.;	95%
Stage #1: benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate With lithium triethylborohydride In tetrahydrofuran at -78℃; Inert atmosphere; Stage #2: With dihydrogen peroxide In tetrahydrofuran; water at -78 - 20℃; Inert atmosphere; Stage #3: methanol With toluene-4-sulfonic acid In water at 20℃; Inert atmosphere; chemoselective reaction;	86%

2-bromo-1,4-difluorobenzene (399-94-0) + benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → C23H25F2NO5

Conditions	Yield
Stage #1: 2-bromo-1,4-difluorobenzene With isopropylmagnesium chloride In tetrahydrofuran at 0℃; for 2h; Stage #2: benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate In tetrahydrofuran at 0℃; for 4h;	93%

hexenylmagnesium bromide (32359-01-6) + benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → (S)-2-tert-Butoxycarbonylamino-5-oxo-undec-6-ynoic acid benzyl ester (113400-48-9)

Conditions	Yield
In tetrahydrofuran at -40℃; for 2h;	92%

benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → (S)-2-[N-(tert-butoxycarbonyl)amino]-5-hydroxypentanoic acid benzyl ester (91229-97-9)

Conditions	Yield
With sodium tetrahydroborate; potassium dihydrogenphosphate In methanol; water at 0℃; for 1.5h; Reduction;	92%
With sodium tetrahydroborate; water In tetrahydrofuran at 0 - 23℃; for 2h; Inert atmosphere;	49%
With sodium tetrahydroborate; potassium dihydrogenphosphate In methanol; water at 0℃; for 2h;	12%

methyllithium (917-54-4) + benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-oxohexanoate (113400-46-7)

Conditions	Yield
In tetrahydrofuran; diethyl ether at -78 - 20℃; for 2h; Inert atmosphere;	91%

di-tert-butyl dicarbonate (24424-99-5) + benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → tert-butyl (S)-N-tert-butoxycarbonylpyroglutamate (91229-91-3)

Conditions	Yield
Stage #1: benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate With hydrogen; palladium on activated charcoal In ethyl acetate Stage #2: di-tert-butyl dicarbonate With dmap; TEA In acetonitrile Further stages.;	83%
With dmap; hydrogen; triethylamine 2.) CH3CN; Multistep reaction;

vinyl magnesium bromide (1826-67-1) + benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → 2-tert-butoxycarbonylamino-5-oxo-hept-6-enoic acid benzyl ester (113400-37-6)

Conditions	Yield
In tetrahydrofuran at -40℃; for 2h;	82%

methyl magnesium iodide (917-64-6) + benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-oxohexanoate (113400-46-7)

Conditions	Yield
In tetrahydrofuran at -40℃; for 2h;	78%

benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) + phenyllithium (591-51-5) → (S)-2-tert-Butoxycarbonylamino-5-oxo-5-phenyl-pentanoic acid benzyl ester (148626-26-0)

Conditions	Yield
In tetrahydrofuran at -40℃; for 2h;	77%

benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) + dimethyl methane phosphonate (756-79-6) → (2S)-α-benzyl 2-N-(tert-butyloxycarbonyl)amino-5-oxo-6-(dimethylphosphonyl)hexanoate (270585-72-3)

Conditions	Yield
Stage #1: dimethyl methane phosphonate With n-butyllithium In toluene at -78℃; for 0.333333h; Metallation; Stage #2: benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate In toluene at -78 - 20℃; Addition; Further stages.;	74%

benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) + diazomethyl-trimethyl-silane (18107-18-1) → (S)-2-tert-Butoxycarbonylamino-6-diazo-5-oxo-hexanoic acid benzyl ester (208519-99-7)

Conditions	Yield
With n-butyllithium In tetrahydrofuran; hexane at -105 - -100℃; for 0.166667h;	71%

benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) + allylmagnesium bromide (1730-25-2) → (S)-2-tert-Butoxycarbonylamino-5-oxo-oct-7-enoic acid benzyl ester (113400-47-8)

Conditions	Yield
In tetrahydrofuran at -40℃; for 2h;	70%

benzyl bromide (100-39-0) + benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → 2-benzyl 1-(tert-butyl) (2S)-4-benzyl-5-oxo-1,2-pyrrolidinedicarboxylate (1243255-28-8)

Conditions	Yield
Stage #1: benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.08333h; Inert atmosphere; Stage #2: benzyl bromide In tetrahydrofuran at -78℃; for 16.05h; Inert atmosphere; stereoselective reaction;	69%

(trifluoromethyl)trimethylsilane (81290-20-2) + benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → N-Boc-5-trifluoromethyl-5-trimethylsilyloxy-L-proline benzyl ester

Conditions	Yield
With cesium fluoride In tetrahydrofuran at 0℃; for 2h; Inert atmosphere;	66%

eschenmoser's salt (33797-51-2) + benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → (S)-4,4-Bis-dimethylaminomethyl-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (159829-96-6)

Conditions	Yield
With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.666667h;	65%

benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) + methyl iodide (74-88-4) → (2S,4R)-4-methyl-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester

Conditions	Yield
Stage #1: benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate With lithium hexamethyldisilazane In tetrahydrofuran at -80℃; for 0.5h; Stage #2: methyl iodide In tetrahydrofuran at -80 - 20℃;	64.9%

benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → benzyl (L)-pyroglutamate (94885-52-6)

Conditions	Yield
With trimethylaluminum In dichloromethane Ambient temperature;	64%

4-but-1-enylmagnesium bromide (7103-09-5) + benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → (S)-2-tert-butoxycarbonylamino-5-oxo-non-8-enoic acid benzyl ester (1282532-98-2)

Conditions	Yield
Stage #1: 4-but-1-enylmagnesium bromide; benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate In tetrahydrofuran at -40℃; for 3h; Stage #2: With ammonium chloride In tetrahydrofuran; water	62%
Stage #1: 4-but-1-enylmagnesium bromide; benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate In tetrahydrofuran at -40℃; for 3h; Stage #2: With water; ammonium chloride In tetrahydrofuran	62%

benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) + methyl chloroformate (79-22-1) → 5-oxo-pyrrolidine-1,2,4-tricarboxylic acid 2-benzyl ester 1-tert-butyl ester 4-methyl ester

Conditions	Yield
Stage #1: benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 2h; Stage #2: methyl chloroformate In tetrahydrofuran at -78℃; for 3h;	60%

benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) + prenyl bromide (870-63-3) → 2-benzyl 1-(tert-butyl) (2S)-4-(3-methyl-2-butenyl)-5-oxo-1,2-pyrrolidinedicarboxylate (1243255-29-9)

Conditions	Yield
Stage #1: benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.08333h; Inert atmosphere; Stage #2: prenyl bromide In tetrahydrofuran at -78℃; for 16.05h; Inert atmosphere; stereoselective reaction;	60%

1-(4-bromophenyl)-1-propen-3-yl bromide (96090-12-9, 124854-99-5) + benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → benzyl (2S,4R,E)-N-BOC-4-(4-bromocinnamyl)pyroglutamate + benzyl (2S,4S,E)-N-BOC-4-(4-bromocinnamyl)pyroglutamate

Conditions	Yield
Stage #1: benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Activation; Stage #2: 1-(4-bromophenyl)-1-propen-3-yl bromide In tetrahydrofuran at -78℃; for 2h; Alkylation;	A 58% B n/a
Stage #1: benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Substitution; Stage #2: 1-(4-bromophenyl)-1-propen-3-yl bromide In tetrahydrofuran at -78℃; for 2h; Alkylation;	A 58% B n/a

benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → benzyl (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-5-oxopyrrolidine-2-carboxylate (116857-24-0)

Conditions	Yield
Stage #1: benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Stage #2: With N-(benzenesulfonyl)-3-phenyloxaziridine In tetrahydrofuran at -78℃; for 0.75h; Stage #3: With camphor-10-sulfonic acid; water In tetrahydrofuran at -78 - 20℃; stereoselective reaction;	55%
With 2-toluenesulfonyl-3-phenyloxazolidine; lithium hexamethyldisilazane 1.) THF, -78 deg C; Yield given. Multistep reaction;

methyl 2-(bromomethyl)propenoate (4224-69-5) + benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → benzyl (2S,4S)-N-tert-butoxycarbonyl-4-(2-carboxymethylprop-2-enyl)pyroglutamate + benzyl (2S,4R)-N-tert-butoxycarbonyl-4-(2-carboxymethylprop-2-enyl)pyroglutamate

Conditions	Yield
With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 2h; Yields of byproduct given;	A 54% B n/a
With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 2h; Yield given; Yields of byproduct given. Title compound not separated from byproducts;

lithium hexamethydisilylazide + benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) + Cinnamyl bromide (4392-24-9) → Boc-4(R)-(3-phenylpropyl)proline (220424-73-7)

Conditions	Yield
With ammonium chloride In tetrahydrofuran	54%

Upstream product

• 60555-57-9 benzyl 5-oxopyrrolidine-2-carboxylate 
• 24424-99-5 di-tert-butyl dicarbonate 
• 100-39-0 benzyl bromide 
• 149-87-1 Pyroglutamic acid 
• 4561-10-8 L-glutamic acid dibenzyl ester hydrochloride 
• 100-44-7 benzyl chloride 
• 98-79-3 L-Pyroglutamic acid 
• 100-51-6 benzyl alcohol 
• 34619-03-9 tert-butyldicarbonate 
• 94885-52-6 benzyl (L)-pyroglutamate 
• 30924-93-7 Boc-Glu-OBn 
• 75-16-1 methylmagnesium bromide 
• 135347-23-8 (2S,4S)-4-((R)-3-Methyl-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester 
• 7087-68-5 N-ethyl-N,N-diisopropylamine 

Downstream Products

• 113400-48-9 (S)-2-tert-Butoxycarbonylamino-5-oxo-undec-6-ynoic acid benzyl ester 
• 135347-23-8 (2S,4S)-4-((R)-3-Methyl-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester 
• 135347-24-9 (2S,4S)-4-((S)-3-Methyl-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester 
• 91229-91-3 tert-butyl (S)-N-tert-butoxycarbonylpyroglutamate 
• 132245-80-8 2-tert-Butoxycarbonylamino-pentanedioic acid 5-allyl ester 1-benzyl ester 
• 53100-44-0 L-N-t-butoxycarbonylpyroglutamic acid 
• 91229-97-9 (S)-2-[N-(tert-butoxycarbonyl)amino]-5-hydroxypentanoic acid benzyl ester 
• 270585-72-3 (2S)-α-benzyl 2-N-(tert-butyloxycarbonyl)amino-5-oxo-6-(dimethylphosphonyl)hexanoate 
• 861657-83-2 2-benzyl 1,4-di-t-butyl 5-oxo-1,2,4-pyrrolidinetricarboxylate 
• 61543-21-3 (S)-benzyl 5-amino-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate 
• 938075-90-2 N-((S)-1-(1,1-dimethylethoxycarbonyl)-5-oxopyrrolidine-2-carbonyl)-L-valine phenylmethyl ester 

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