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CarbaMic acid, N-[(1S)-3-Methyl-1-[[(2R)-2-Methyl-2-oxiranyl]carbonyl]butyl]-, 1,1-dimethylethyl ester, also known as tert-Butyl ((S)-4-Methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate, is a chemical compound that serves as an intermediate in the synthesis of Carfilzomib (C183460). Carfilzomib is a second-generation proteasome inhibitor with significant pharmaceutical applications.

247068-82-2

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  • CarbaMic acid, N-[(1S)-3-Methyl-1-[[(2R)-2-Methyl-2-oxiranyl]carbonyl]butyl]-, 1,1-diMethylethyl ester/manufacturer

    Cas No: 247068-82-2

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  • High purity [(1S)-3-Methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl]carbamic acid 1,1-dimethylethyl ester CAS No.:247068-82-2

    Cas No: 247068-82-2

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  • tert-Butyl N-[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]-carbamate

    Cas No: 247068-82-2

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247068-82-2 Usage

Uses

Used in Pharmaceutical Industry:
CarbaMic acid, N-[(1S)-3-Methyl-1-[[(2R)-2-Methyl-2-oxiranyl]carbonyl]butyl]-, 1,1-dimethylethyl ester is used as an intermediate compound for the production of Carfilzomib, a second-generation proteasome inhibitor. Carfilzomib is utilized for the treatment of relapsed and refractory multiple myeloma, a type of blood cancer. Its role in the pharmaceutical industry is crucial, as it contributes to the development of effective cancer therapies.
In the context of cancer treatment, Carfilzomib works by inhibiting the activity of the proteasome, a cellular enzyme responsible for breaking down proteins. This inhibition leads to the accumulation of proteins within cancer cells, ultimately resulting in cell death. The use of CarbaMic acid, N-[(1S)-3-Methyl-1-[[(2R)-2-Methyl-2-oxiranyl]carbonyl]butyl]-, 1,1-dimethylethyl ester as an intermediate in the synthesis of Carfilzomib highlights its importance in the development of innovative cancer treatments.

Check Digit Verification of cas no

The CAS Registry Mumber 247068-82-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 2,4,7,0,6 and 8 respectively; the second part has 2 digits, 8 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 247068-82:
(8*2)+(7*4)+(6*7)+(5*0)+(4*6)+(3*8)+(2*8)+(1*2)=152
152 % 10 = 2
So 247068-82-2 is a valid CAS Registry Number.

247068-82-2SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 12, 2017

Revision Date: Aug 12, 2017

1.Identification

1.1 GHS Product identifier

Product name tert-butyl N-[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]carbamate

1.2 Other means of identification

Product number -
Other names Boc-L-leucine epoxyketone

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:247068-82-2 SDS

247068-82-2Synthetic route

tert-butyl {(1S,2S)-1-hydroxy-4-methyl-1-[(R)-2-methyloxiran-2-yl]pentan-2-yl}carbamate

tert-butyl {(1S,2S)-1-hydroxy-4-methyl-1-[(R)-2-methyloxiran-2-yl]pentan-2-yl}carbamate

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
With sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃; Green chemistry;91%
With sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃; Cooling with ice;83.3%
With Dess-Martin periodane In dichloromethane at 0℃; for 3h; Dess-Martin Oxidation; Inert atmosphere;46%
With sodium hypochlorite; 2-azatricyclo[3.3.1.13,7]decan-2-ol; sodium hydrogencarbonate In water; toluene at 0℃; for 5h;5.96 g
With Dess-Martin periodane In dichloromethane at 20℃;
tert-butyl [(1S)-3-methyl-1-(2-methylpropyl)-2-oxobut-3-en-1-yl]carbamate
247068-81-1

tert-butyl [(1S)-3-methyl-1-(2-methylpropyl)-2-oxobut-3-en-1-yl]carbamate

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
With (R)-La-BINOL; triphenylphosphine; tert-butyl alcohol In toluene at 20℃; for 0.5h; Solvent;85%
With dihydrogen peroxide; benzonitrile; N-ethyl-N,N-diisopropylamine In methanol at 0℃;57%
With tetramethyl ammoniumhydroxide; urea hydrogen peroxide adduct In methanol; benzonitrile at -10℃; for 20h; Reagent/catalyst; Solvent; Inert atmosphere; stereoselective reaction;40%
tert-butyl ((R)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate

tert-butyl ((R)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tert-butyl methyl ether at 20℃; for 12h;84%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tert-butyl methyl ether at 20℃; for 24h; Reagent/catalyst; Inert atmosphere; Large scale; diastereoselective reaction;79%
tert-butyl N-[(2S)-1-(-2-methyloxirane-2-yl)-1-hydroxy-4-methylpentan-2-yl]carbamate
1609959-47-8

tert-butyl N-[(2S)-1-(-2-methyloxirane-2-yl)-1-hydroxy-4-methylpentan-2-yl]carbamate

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
With Dess-Martin periodane In dichloromethane at 0℃; for 10h; Inert atmosphere;52%
With Dess-Martin periodane In dichloromethane at 0 - 20℃; Inert atmosphere;
With Dess-Martin periodane In acetonitrile at 0 - 30℃; for 3h;4.5 g
tert-butyl [(1S)-3-methyl-1-(2-methylpropyl)-2-oxobut-3-en-1-yl]carbamate
247068-81-1

tert-butyl [(1S)-3-methyl-1-(2-methylpropyl)-2-oxobut-3-en-1-yl]carbamate

A

tert-butyl ((S)-4-methyl-1-((S)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate

tert-butyl ((S)-4-methyl-1-((S)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate

B

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
With dihydrogen peroxide; benzonitrile; N-ethyl-N,N-diisopropylamine at 0 - 4℃; for 43h; Alkaline aqueous solution;A 28%
B 48%
With i-PrEtN; dihydrogen peroxide In methanol; water; benzonitrile at 0 - 4℃; for 43h; Yield given; Yields of byproduct given;
Stage #1: tert-butyl [(1S)-3-methyl-1-(2-methylpropyl)-2-oxobut-3-en-1-yl]carbamate With C28H34F6MnN6O6S2; acetic acid In acetonitrile for 0.0833333h; Inert atmosphere;
Stage #2: With dihydrogen peroxide In acetonitrile at -20℃; for 2h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;
di-tert-butyl dicarbonate
24424-99-5

di-tert-butyl dicarbonate

(S)-2-amino-4-methyl-1-((R)-2-methyloxiran-2-yl)pentan-1-one trifluoroacetic acid salt

(S)-2-amino-4-methyl-1-((R)-2-methyloxiran-2-yl)pentan-1-one trifluoroacetic acid salt

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
With triethylamine In dichloromethane at 0 - 20℃; for 13h;39%
(1-isobutyl-3-methyl-2-oxo-but-3-enyl)carbamic acid tert-butyl ester
1186298-17-8

(1-isobutyl-3-methyl-2-oxo-but-3-enyl)carbamic acid tert-butyl ester

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
With 1,1,1-trifluoro-2-propanone; sodium hydrogencarbonate In water; acetonitrile at -10℃; Inert atmosphere;38%
N-(tert-butoxycarbonyl)-L-leucine-N'-methoxy-N'-methylamide
87694-50-6

N-(tert-butoxycarbonyl)-L-leucine-N'-methoxy-N'-methylamide

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 92 percent / diethyl ether / 2.5 h / -78 °C
2: H2O2, i-PrEtN / benzonitrile; H2O; methanol / 43 h / 0 - 4 °C
View Scheme
Multi-step reaction with 2 steps
1: tetrahydrofuran / 6 h / 0 °C / Inert atmosphere
2: potassium peroxymonosulfate; 1,1,1-trifluoro-2-propanone; sodium hydrogencarbonate / water; acetonitrile / Inert atmosphere
View Scheme
Multi-step reaction with 2 steps
1.1: tetrahydrofuran / 6 h / 0 - 25 °C
2.1: sodium hydrogencarbonate
2.2: trifluoroacetone
2.3: 1 h / -10 °C
View Scheme
N-tert-butoxycarbonyl-L-leucine
13139-15-6

N-tert-butoxycarbonyl-L-leucine

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine / dichloromethane / 3 h / 25 °C / Inert atmosphere
2: tetrahydrofuran / 6 h / 0 °C / Inert atmosphere
3: potassium peroxymonosulfate; 1,1,1-trifluoro-2-propanone; sodium hydrogencarbonate / water; acetonitrile / Inert atmosphere
View Scheme
Multi-step reaction with 3 steps
1.1: triethylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
1.2: 3 h / 25 °C
2.1: tetrahydrofuran / 6 h / 0 - 25 °C
3.1: sodium hydrogencarbonate
3.2: trifluoroacetone
3.3: 1 h / -10 °C
View Scheme
Multi-step reaction with 3 steps
1.1: isobutyl chloroformate; 4-methyl-morpholine / dichloromethane / -10 - 20 °C
2.1: tert.-butyl lithium / tetrahydrofuran; hexane / 1 h / -78 °C / Inert atmosphere
2.2: Inert atmosphere
3.1: N-ethyl-N,N-diisopropylamine; dihydrogen peroxide / methanol / 2 h
View Scheme
tert-butyl N-[(4S)-3-hydroxy-2,6-dimethylhept-1-en-4-yl]carbamate
1609959-45-6

tert-butyl N-[(4S)-3-hydroxy-2,6-dimethylhept-1-en-4-yl]carbamate

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3 h / 0 °C
2: Dess-Martin periodane / dichloromethane / 0 - 20 °C / Inert atmosphere
View Scheme
Multi-step reaction with 2 steps
1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 0 - 30 °C
2: Dess-Martin periodane / acetonitrile / 3 h / 0 - 30 °C
View Scheme
Multi-step reaction with 2 steps
1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3 h / 0 °C
2: Dess-Martin periodane / dichloromethane / 10 h / 0 °C / Inert atmosphere
View Scheme
tert-butyl ((3R,4S)-3-hydroxy-2,6-dimethylhept-1-en-4-yl)carbamate

tert-butyl ((3R,4S)-3-hydroxy-2,6-dimethylhept-1-en-4-yl)carbamate

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: bis(acetylacetonate)oxovanadium; tert.-butylhydroperoxide / dichloromethane / 1 h / 0 °C / Inert atmosphere
2: Dess-Martin periodane / dichloromethane / 3 h / 0 °C / Inert atmosphere
View Scheme
Multi-step reaction with 2 steps
1: vanadium trisacetylacetonate; tert.-butylhydroperoxide / dichloromethane / 1 h / 0 - 20 °C / Inert atmosphere; Green chemistry
2: N-ethyl-N,N-diisopropylamine; sulfur trioxide pyridine complex / dimethyl sulfoxide / 20 °C / Green chemistry
View Scheme
Multi-step reaction with 2 steps
1: bis(acetylacetonate)oxovanadium; tert.-butylhydroperoxide / dichloromethane / 0 °C / Inert atmosphere
2: N-ethyl-N,N-diisopropylamine; sulfur trioxide pyridine complex / dimethyl sulfoxide / 20 °C / Cooling with ice
View Scheme
Multi-step reaction with 2 steps
1: bis(acetylacetonate)oxovanadium; tert.-butylhydroperoxide / dichloromethane / 2 h / 0 °C
2: Dess-Martin periodane / dichloromethane / 20 °C
View Scheme
(1-isobutyl-2-oxobutyl)carbamic acid tert-butyl ester

(1-isobutyl-2-oxobutyl)carbamic acid tert-butyl ester

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: piperdinium acetate; piperidine / tetrahydrofuran / 8 h / 68 °C / Green chemistry
2: aluminum isopropoxide; isopropyl alcohol / toluene / 50 °C / Green chemistry
3: vanadium trisacetylacetonate; tert.-butylhydroperoxide / dichloromethane / 1 h / 0 - 20 °C / Inert atmosphere; Green chemistry
4: N-ethyl-N,N-diisopropylamine; sulfur trioxide pyridine complex / dimethyl sulfoxide / 20 °C / Green chemistry
View Scheme
Multi-step reaction with 4 steps
1: piperidine; piperidinyl acetate / tetrahydrofuran / 3 h / Reflux
2: aluminum isopropoxide / toluene; isopropyl alcohol / 20 - 50 °C
3: bis(acetylacetonate)oxovanadium; tert.-butylhydroperoxide / dichloromethane / 0 °C / Inert atmosphere
4: N-ethyl-N,N-diisopropylamine; sulfur trioxide pyridine complex / dimethyl sulfoxide / 20 °C / Cooling with ice
View Scheme
Multi-step reaction with 4 steps
1: piperdinium acetate; piperidine / tetrahydrofuran / 12 h / 68 °C
2: aluminum isopropoxide; isopropyl alcohol / toluene / 3 h / 50 °C
3: tert.-butylhydroperoxide; tris(acetylacetonato)vanadium(III) / dichloromethane / 12 h / 0 - 20 °C
4: N-ethyl-N,N-diisopropylamine; sulfur trioxide pyridine complex / dimethyl sulfoxide / 6 h
View Scheme
N-tert-butoxycarbonyl-L-leucine
13139-15-6

N-tert-butoxycarbonyl-L-leucine

A

tert-butyl ((S)-4-methyl-1-((S)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate

tert-butyl ((S)-4-methyl-1-((S)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate

B

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: isobutyl chloroformate; 4-methyl-morpholine; triethylamine / dichloromethane / -20 - 20 °C / Inert atmosphere
2: tetrahydrofuran / 6 h / 0 - 5 °C / Inert atmosphere
3: sodium hypochlorite; pyridine / water / 2 h / -5 - 0 °C
View Scheme
Multi-step reaction with 3 steps
1.1: Trimethylacetic acid / Isopropyl acetate / -10 - 0 °C
1.2: -10 - 25 °C
2.1: isopropylmagnesium chloride; magnesium / tetrahydrofuran; n-heptane / 3 h / -10 - 42 °C / Inert atmosphere
3.1: acetic acid; dihydrogen peroxide; C28H34F6MnN6O6S2 / acetonitrile / 2 h / -20 °C
View Scheme
N-(tert-butoxycarbonyl)-L-leucine-N'-methoxy-N'-methylamide
87694-50-6

N-(tert-butoxycarbonyl)-L-leucine-N'-methoxy-N'-methylamide

A

tert-butyl ((S)-4-methyl-1-((S)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate

tert-butyl ((S)-4-methyl-1-((S)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate

B

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: tetrahydrofuran / 6 h / 0 - 5 °C / Inert atmosphere
2: sodium hypochlorite; pyridine / water / 2 h / -5 - 0 °C
View Scheme
tert-butyl N-[(2S)-1-(-2-methyloxirane-2-yl)-1-hydroxy-4-methylpentan-2-yl]carbamate
1609959-47-8

tert-butyl N-[(2S)-1-(-2-methyloxirane-2-yl)-1-hydroxy-4-methylpentan-2-yl]carbamate

A

tert-butyl ((S)-4-methyl-1-((S)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate

tert-butyl ((S)-4-methyl-1-((S)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate

B

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
With Dess-Martin periodane In acetonitrile at 5 - 20℃; Inert atmosphere;
L-leucine
61-90-5

L-leucine

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1.1: sodium hydroxide / water / 20 h / 25 - 30 °C
2.1: 4-methyl-morpholine; chloroformic acid ethyl ester / dichloromethane / 0.33 h / -15 - -10 °C / Inert atmosphere
2.2: 2 h / -15 - -10 °C
3.1: magnesium; iodine / tetrahydrofuran / 2.5 h / 50 - 55 °C / Inert atmosphere
3.2: 8.25 h / 0 - 30 °C
4.1: potassium carbonate; benzonitrile; dihydrogen peroxide / methanol / 6 h / 25 - 30 °C
View Scheme
di-tert-butyl dicarbonate
24424-99-5

di-tert-butyl dicarbonate

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1.1: sodium hydroxide / water / 20 h / 25 - 30 °C
2.1: 4-methyl-morpholine; chloroformic acid ethyl ester / dichloromethane / 0.33 h / -15 - -10 °C / Inert atmosphere
2.2: 2 h / -15 - -10 °C
3.1: magnesium; iodine / tetrahydrofuran / 2.5 h / 50 - 55 °C / Inert atmosphere
3.2: 8.25 h / 0 - 30 °C
4.1: potassium carbonate; benzonitrile; dihydrogen peroxide / methanol / 6 h / 25 - 30 °C
View Scheme
tert-butyl [(1S)-3-methyl-1-(2-methylpropyl)-2-oxobut-3-en-1-yl]carbamate
247068-81-1

tert-butyl [(1S)-3-methyl-1-(2-methylpropyl)-2-oxobut-3-en-1-yl]carbamate

A

tert-butyl [(1R)-3-methyl-1-[[(2S)-2-methyloxiran-2-yl]carbonyl]butyl]carbamate

tert-butyl [(1R)-3-methyl-1-[[(2S)-2-methyloxiran-2-yl]carbonyl]butyl]carbamate

B

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
With dihydrogen peroxide; potassium hydroxide; N-(4-iodobenzyl)cinchoninium bromide at 0 - 4℃; Catalytic behavior; Reagent/catalyst; Temperature; Overall yield = 97 %; Overall yield = 131 g; Optical yield = 84 %ee;
N-Boc-D-Leu
16937-99-8

N-Boc-D-Leu

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran; tert-butyl methyl ether / 1 h / 0 - 5 °C
1.2: 1 h / 0 - 10 °C
2.1: 2-bromoprop-1-ene; magnesium / tetrahydrofuran / 0 - 50 °C / Inert atmosphere
3.1: acetic acid; dihydrogen peroxide / acetonitrile; water / 2 h / -20 - -10 °C
4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / tert-butyl methyl ether / 12 h / 20 °C
View Scheme
Multi-step reaction with 5 steps
1: tert-butyl methyl ether / 1.42 h / 0 - 5 °C / Inert atmosphere; Large scale
2: tert-butyl methyl ether / 1.5 h / 0 - 10 °C / Inert atmosphere; Large scale
3: magnesium; iodine / tetrahydrofuran; 2-methyltetrahydrofuran / 26 h / 40 - 45 °C / Inert atmosphere; Flow reactor; Large scale
4: dihydrogen peroxide; acetic acid; C30H36F6MnN6O6S2 / acetonitrile; water / 3.5 h / -20 - -15 °C / Inert atmosphere; Large scale
5: 1,8-diazabicyclo[5.4.0]undec-7-ene / tert-butyl methyl ether / 24 h / 20 °C / Inert atmosphere; Large scale
View Scheme
(R)-tert-butyl (4-methyl-1-morpholino-1-oxopentan-2-yl)carbamate

(R)-tert-butyl (4-methyl-1-morpholino-1-oxopentan-2-yl)carbamate

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: 2-bromoprop-1-ene; magnesium / tetrahydrofuran / 0 - 50 °C / Inert atmosphere
2: acetic acid; dihydrogen peroxide / acetonitrile; water / 2 h / -20 - -10 °C
3: 1,8-diazabicyclo[5.4.0]undec-7-ene / tert-butyl methyl ether / 12 h / 20 °C
View Scheme
Multi-step reaction with 3 steps
1: magnesium; iodine / tetrahydrofuran; 2-methyltetrahydrofuran / 26 h / 40 - 45 °C / Inert atmosphere; Flow reactor; Large scale
2: dihydrogen peroxide; acetic acid; C30H36F6MnN6O6S2 / acetonitrile; water / 3.5 h / -20 - -15 °C / Inert atmosphere; Large scale
3: 1,8-diazabicyclo[5.4.0]undec-7-ene / tert-butyl methyl ether / 24 h / 20 °C / Inert atmosphere; Large scale
View Scheme
(R)-tert-butyl (2,6-dimethyl-3-oxohept-1-en-4-yl)carbamate

(R)-tert-butyl (2,6-dimethyl-3-oxohept-1-en-4-yl)carbamate

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: acetic acid; dihydrogen peroxide / acetonitrile; water / 2 h / -20 - -10 °C
2: 1,8-diazabicyclo[5.4.0]undec-7-ene / tert-butyl methyl ether / 12 h / 20 °C
View Scheme
(S)-tert-butyl (4-methyl-1-morpholino-1-oxopentan-2-yl)carbamate
173899-64-4

(S)-tert-butyl (4-methyl-1-morpholino-1-oxopentan-2-yl)carbamate

A

tert-butyl ((S)-4-methyl-1-((S)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate

tert-butyl ((S)-4-methyl-1-((S)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate

B

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: isopropylmagnesium chloride; magnesium / tetrahydrofuran; n-heptane / 3 h / -10 - 42 °C / Inert atmosphere
2: acetic acid; dihydrogen peroxide; C28H34F6MnN6O6S2 / acetonitrile / 2 h / -20 °C
View Scheme
C14H27NO3

C14H27NO3

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: tert.-butylhydroperoxide; tris(acetylacetonato)vanadium(III) / dichloromethane / 12 h / 0 - 20 °C
2: N-ethyl-N,N-diisopropylamine; sulfur trioxide pyridine complex / dimethyl sulfoxide / 6 h
View Scheme
C14H27NO4

C14H27NO4

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
With sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide for 6h;
Boc-Leu-Cl
338972-00-2

Boc-Leu-Cl

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: triethylamine / isopropyl alcohol
2: tetrahydrofuran / 19 h / -10 - 25 °C / Inert atmosphere; Large scale
3: sodium hypochlorite; pyridine / water / 4.75 h / -15 - -5 °C
View Scheme
[(R)-1-(Imidazole-1-carbonyl)-3-methyl-butyl]-carbamic acid tert-butyl ester
54430-65-8

[(R)-1-(Imidazole-1-carbonyl)-3-methyl-butyl]-carbamic acid tert-butyl ester

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: tert-butyl methyl ether / 1.5 h / 0 - 10 °C / Inert atmosphere; Large scale
2: magnesium; iodine / tetrahydrofuran; 2-methyltetrahydrofuran / 26 h / 40 - 45 °C / Inert atmosphere; Flow reactor; Large scale
3: dihydrogen peroxide; acetic acid; C30H36F6MnN6O6S2 / acetonitrile; water / 3.5 h / -20 - -15 °C / Inert atmosphere; Large scale
4: 1,8-diazabicyclo[5.4.0]undec-7-ene / tert-butyl methyl ether / 24 h / 20 °C / Inert atmosphere; Large scale
View Scheme
heptafluorobutyric Acid
375-22-4

heptafluorobutyric Acid

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

C9H17NO2*C4HF7O2

C9H17NO2*C4HF7O2

Conditions
ConditionsYield
In dichloromethane at 0 - 23℃; for 2h; Inert atmosphere;94%
trifluoroacetic acid
76-05-1

trifluoroacetic acid

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

(S)-2-amino-4-methyl-1-((R)-2-methyloxiran-2-yl)pentan-1-one trifluoroacetic acid salt

(S)-2-amino-4-methyl-1-((R)-2-methyloxiran-2-yl)pentan-1-one trifluoroacetic acid salt

Conditions
ConditionsYield
In dichloromethane at 20℃; for 4h;88%
With trifluoroacetic acid
In dichloromethane for 0.5h; Inert atmosphere;
4-chlorobenzoyl chloride
586-75-4

4-chlorobenzoyl chloride

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

C16H20BrNO3
1373929-36-2

C16H20BrNO3

Conditions
ConditionsYield
Stage #1: tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate With trifluoroacetic acid In dichloromethane at 25℃; for 1.5h;
Stage #2: 4-chlorobenzoyl chloride With N-ethyl-N,N-diisopropylamine In chloroform at 25℃; for 16h;
61%
tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

trichloroacetic acid
76-03-9

trichloroacetic acid

(S)-2-amino-4-methyl-1-((R)-2-methyloxiran-2-yl)pentan-1-one trichloroacetic acid salt

(S)-2-amino-4-methyl-1-((R)-2-methyloxiran-2-yl)pentan-1-one trichloroacetic acid salt

Conditions
ConditionsYield
In n-heptane; dichloromethane; tert-butyl methyl ether at 0 - 20℃; Inert atmosphere;36%
C17H31N3O5

C17H31N3O5

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

C26H46N4O6
1418206-49-1

C26H46N4O6

Conditions
ConditionsYield
Stage #1: tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate With trifluoroacetic acid In dichloromethane at 25℃; for 1h;
Stage #2: C17H31N3O5 With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 25℃; for 12h;
23%
trifluoroacetic acid
76-05-1

trifluoroacetic acid

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

C10H17NO4*C2HF3O2

C10H17NO4*C2HF3O2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

C51H88N6O8

C51H88N6O8

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 130 mg / PyBOP; DiPEA / CH2Cl2; dimethylformamide / 3 h
View Scheme
tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

C59H103N7O10

C59H103N7O10

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 27.3 percent / BOP; DiPEA / dimethylformamide / 3 h
View Scheme
tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

C55H95N7O10

C55H95N7O10

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: 27.3 percent / BOP; DiPEA / dimethylformamide / 3 h
2: 91 percent / TFA / CH2Cl2 / 0.5 h
View Scheme
tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

C23H28N4O4

C23H28N4O4

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 8.6 mg / BOP; DiPEA / CH2Cl2 / 1 h
View Scheme
tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

benzyl ((S)-4-methyl-1-(((S)-4-methyl-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxopentan-2-yl) amino)-1-oxopentan-2-yl)carbamate

benzyl ((S)-4-methyl-1-(((S)-4-methyl-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxopentan-2-yl) amino)-1-oxopentan-2-yl)carbamate

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 18.7 mg / PyBOP; DiPEA / CH2Cl2 / 1 h
View Scheme
tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

(2S)-2-amino-4-methyl-1-[(2R)-2-methyloxiran-2-yl]pentan-1-one
247068-84-4

(2S)-2-amino-4-methyl-1-[(2R)-2-methyloxiran-2-yl]pentan-1-one

Conditions
ConditionsYield
With trifluoroacetic acid at 20℃; for 0.0333333 - 0.333333h;
With trifluoroacetic acid In dichloromethane at 25℃; for 1.5h; Inert atmosphere;
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 1h;
tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

C16H20BrNO3
1373929-36-2

C16H20BrNO3

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: trifluoroacetic acid / dichloromethane / 1.5 h / 25 °C / Inert atmosphere
2: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 25 °C / Inert atmosphere
View Scheme
tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Carmaphycin A
1374216-80-4

Carmaphycin A

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: trifluoroacetic acid / dichloromethane / 1.5 h / 25 °C / Inert atmosphere
2: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 h / 25 °C / Inert atmosphere
View Scheme
tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

Carmaphycin B
1374216-81-5

Carmaphycin B

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: trifluoroacetic acid / dichloromethane / 1.5 h / 25 °C / Inert atmosphere
2: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 15 h / 25 °C / Inert atmosphere
View Scheme
tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

C40H53N5O7S
1545468-56-1

C40H53N5O7S

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: dichloromethane
2: N-ethyl-N,N-diisopropylamine; DEPBT / dichloromethane / 2 h
View Scheme
tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

C44H61N7O8
1545469-05-3

C44H61N7O8

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: dichloromethane
2: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C
3: dichloromethane / 4 h / 20 °C
4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C
View Scheme
tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

C42H55N5O8S
1545468-57-2

C42H55N5O8S

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: dichloromethane
2: N-ethyl-N,N-diisopropylamine; DEPBT / dichloromethane / 2 h
3: pyridine / 20 °C
View Scheme
tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

C44H60N6O8S
1545468-58-3

C44H60N6O8S

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: dichloromethane
2: N-ethyl-N,N-diisopropylamine; DEPBT / dichloromethane / 2 h
3: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C
View Scheme
tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

C37H58N6O9
1545468-59-4

C37H58N6O9

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1.1: dichloromethane
2.1: N-ethyl-N,N-diisopropylamine; DEPBT / dichloromethane / 0.5 h
2.2: 20 °C
3.1: sodium hydride / tetrahydrofuran / 0.5 h / 20 °C
3.2: 6 h / 20 °C
View Scheme
tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate
247068-82-2

tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)carbamate

C43H58N6O8S
1545468-60-7

C43H58N6O8S

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1.1: dichloromethane
2.1: DEPBT / dichloromethane / 2 h / 0 °C
2.2: 0 - 20 °C
View Scheme

247068-82-2Downstream Products

247068-82-2Relevant articles and documents

Bioinspired manganese complexes catalyzed epoxidation for the synthesis of the epoxyketone fragment of carfilzomib

Qiu, Bin,Xia, Chungu,Sun, Wei

, p. 698 - 701 (2019)

We report herein an efficient catalytic epoxidation reaction for the synthesis of epoxyketone (tert-butyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate), which is an important synthetic intermediate of carfilzomib. A series of bioinspired manganese complexes bearing N4 ligands are carefully investigated in the epoxidation of enone precursor with H2O2 as oxidant in the presence of carboxylic acid (e.g., acetic acid).

Continuous Process Improvement in the Manufacture of Carfilzomib, Part 2: An Improved Process for Synthesis of the Epoxyketone Warhead

Beaver, Matthew G.,Shi, Xianqing,Riedel, Jan,Patel, Parth,Zeng, Alicia,Corbett, Michael T.,Robinson, Jo Anna,Parsons, Andrew T.,Cui, Sheng,Baucom, Kyle,Lovette, Michael A.,I?ten, El?in,Brown, Derek B.,Allian, Ayman,Flick, Tawnya G.,Chen, Wendy,Yang, Ning,Walker, Shawn D.

, p. 490 - 499 (2020)

The development and kilogram-scale demonstration of an improved process for the synthesis of the epoxyketone warhead of carfilzomib is described. Critical to the success of this process was: (1) development of a scalable asymmetric epoxidation protocol; (2) identification of a crystalline intermediate with improved physical properties for isolation; (3) discovery and optimization of epimerization conditions to set the target stereochemistry; and (4) introduction of a seeded-bed coaddition crystallization to facilitate isolation of the final low-melting target. The results of kilogram-scale demonstration runs are shared, including details of a continuous process for the safe execution of an exothermic Barbier-type Grignard process.

Asymmetric Epoxidation of Olefins Catalyzed by Substituted Aminobenzimidazole Manganese Complexes Derived from L-Proline

Lin, Jin,Sun, Wei,Tian, Jing,Xia, Chungu,Zhang, Jisheng

supporting information, (2021/11/16)

A family of manganese complexes [Mn(Rpeb)(OTf)2] (peb=1-(1-ethyl-1H-benzo[d]imidazol-2-yl)-N-((1-((1-ethyl-1H-benzo[d]imidazol-2-yl)methyl) pyrrolidin-2-yl)methyl)-N-methylmethanamine)) derived from L-proline has been synthesized and characterized, where R refers to the group at the diamine backbone. X-ray crystallographic analyses indicate that all the manganese complexes [Mn(Rpeb)(OTf)2] exhibit cis-α topology. These types of complexes are shown to catalyze the asymmetric epoxidation of olefins employing H2O2 as a terminal oxidant with up to 96% ee. Obviously, the R group of the diamine backbone can influence the catalytic activity and enantioselectivity in the asymmetric epoxidation of olefins. In particular, Mn(i-Prpeb)(OTf)2 bearing an isopropyl arm, cannot catalyze the epoxidation reaction with H2O2 as the oxidant. However, when PhI(OAc)2 is used as the oxidant instead, all the manganese complexes including Mn(i-Prpeb)(OTf)2 can promote the epoxidation reactions efficiently. Taken together, these results indicate that isopropyl substitution on the Rpeb ligand inhibits the formation of active Mn(V)-oxo species in the H2O2/carboxylic acid system via an acid-assisted pathway.

Macrocyclic Immunoproteasome Inhibitors as a Potential Therapy for Alzheimer's Disease

Lee, Min Jae,Bhattarai, Deepak,Jang, Hyeryung,Baek, Ahreum,Yeo, In Jun,Lee, Seongsoo,Miller, Zachary,Lee, Sukyeong,Hong, Jin Tae,Kim, Dong-Eun,Lee, Wooin,Kim, Kyung Bo

, p. 10934 - 10950 (2021/08/20)

Previously, we reported that immunoproteasome (iP)-targeting linear peptide epoxyketones improve cognitive function in mouse models of Alzheimer's disease (AD) in a manner independent of amyloid β. However, these compounds' clinical prospect for AD is limited due to potential issues, such as poor brain penetration and metabolic instability. Here, we report the development of iP-selective macrocyclic peptide epoxyketones prepared by a ring-closing metathesis reaction between two terminal alkenes attached at the P2 and P3/P4 positions of linear counterparts. We show that a lead macrocyclic compound DB-60 (20) effectively inhibits the catalytic activity of iP in ABCB1-overexpressing cells (IC50: 105 nM) and has metabolic stability superior to its linear counterpart. DB-60 (20) also lowered the serum levels of IL-1α and ameliorated cognitive deficits in Tg2576 mice. The results collectively suggest that macrocyclic peptide epoxyketones have improved CNS drug properties than their linear counterparts and offer promising potential as an AD drug candidate.

Preparation method of carfilzomib

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Paragraph 0019-0046, (2020/09/21)

The invention relates to a preparation method of carfilzomib, which comprises the following steps of: by using a compound represented by a formula I as an intermediate, carrying out deprotection, andreacting with a compound represented by a formula IV to prepare carfilzomib. The preparation method of the compound shown in the formula I comprises the following steps of: taking hydrogen peroxide asan oxidizing agent, and preparing a carfilzomib intermediate, namely the compound shown in the formula I, through selective epoxidation of a chiral organic catalyst. The preparation method disclosedby the invention is simple in reaction condition, simple and convenient to operate, good in asymmetric selectivity, good in yield, high in purity and suitable for industrial production.

Continuous Process Improvement in the Manufacture of Carfilzomib, Part 1: Process Understanding and Improvements in the Commercial Route to Prepare the Epoxyketone Warhead

Dornan, Peter K.,Anthoine, Travis,Beaver, Matthew G.,Cheng, Guilong Charles,Cohen, Dawn E.,Cui, Sheng,Lake, William E.,Langille, Neil F.,Lucas, Susan P.,Patel, Jenil,Powazinik, William,Roberts, Scott W.,Scardino, Chris,Tucker, John L.,Spada, Simone,Zeng, Alicia,Walker, Shawn D.

, p. 481 - 489 (2020/04/10)

Epoxyketone 4 is an isolated intermediate in the manufacturing route to the commercial proteasome inhibitor carfilzomib (Kyprolis). Commercial process development and optimization efforts toward the preparation of epoxyketone 4 highlighted several opportunities for process improvement. In this article, three case studies are presented that demonstrate how a detailed understanding of the reaction mechanism led to improvements that increased the overall robustness of the process. In the first case study, the mechanism of racemization of an α-chiral enone was investigated, resulting in the development of an improved aqueous workup procedure. Next, the stability of a bleach/pyridine mixture used for the step 3 epoxidation reaction was studied, leading to the identification of pyridine as a key raw material and improved reaction conditions and control strategy to meet the conversion target. Finally, oxidized butylated hydroxytoluene (oBHT) was identified as an impurity arising from the use of BHT-stabilized tetrahydrofuran in steps preceding the oxidation. The process understanding obtained from these investigations led to the implementation of process improvements that improved the robustness of the process. The development of a second-generation route to 4 is the subject of part 2 in this series (DOI: 10.1021/acs.oprd.0c00052).

LMP2 Inhibitors as a Potential Treatment for Alzheimer's Disease

Bhattarai, Deepak,Lee, Min Jae,Baek, Ahruem,Yeo, In Jun,Miller, Zachary,Baek, Yu Mi,Lee, Sukyeong,Kim, Dong-Eun,Hong, Jin Tae,Kim, Kyung Bo

, p. 3763 - 3783 (2020/04/30)

The immunoproteasome (iP), an inducible proteasome variant harboring three immunosubunits, low molecular mass polypeptide-2 (LMP2), multicatalytic endopeptidase complex subunit-1, and low molecular mass polypeptide-7 (LMP7), is involved in multiple facets of inflammatory responses. We recently reported that YU102, a dual inhibitor of the iP subunit LMP2 and the constitutive proteasome catalytic subunit β1, ameliorates cognitive impairments in mouse models of Alzheimer's disease (AD) independently of amyloid deposits. To investigate whether inhibition of LMP2 is sufficient to improve the cognitive functions of AD mice, here we prepared 37 YU102 analogues and identified a potent LMP2 inhibitor DB-310 (28) (IC50: 80.6 nM) with improved selectivity and permeability in cells overexpressing ABCB1 transporters. We show that DB-310 induces suppression of IL-1α production in microglia cells and improves cognitive functions in the Tg2576 transgenic mouse model of AD. This study supports that inhibition of LMP2 is a promising therapeutic strategy for treatment of AD.

Preparation and biological evaluation of soluble tetrapeptide epoxyketone proteasome inhibitors

Lei, Meng,Zhang, Haoyang,Miao, Hang,Du, Xiao,Zhou, Hui,Wang, Jia,Wang, Xueyuan,Feng, Huayun,Shi, Jingmiao,Liu, Zhaogang,Shen, Jian,Zhu, Yongqiang

, p. 4151 - 4162 (2019/08/07)

A series of novel tetrapeptidyl epoxyketone inhibitors of 20S proteasome was designed and synthesized. To fully understand the SAR, various groups at R1, R2, R3, R4 and R5 positions, including aromatic and aliphatic substituents were designed, synthesized and biologically assayed. Based on the enzymatic results, seven compounds were selected to evaluate their cellular activities and soluble compound 36 showed strong potency against human multiple myeloma (MM) cell lines. Microsomal stability results indicated that compound 36 was more stable in mice, rat and human microsomes than marketed carfilzomib. The in vivo activities of this compound were evaluated with the xenograft mice models of MM cell lines ARH77 and RPMI-8226 with luciferase expression and the T/C value of the two models were 49.5% and 37.6%, respectively. To evaluate the potential cardiovascular toxicity, inhibition of hERG ion channel in HEK293 cells by compound 36 and carfilzomib was carried out. The results indicated that 36 had no binding affinity for the hERG ion channel while carfilzomib could bind it with IC50 of 92.1 μM.

Exploration of the carmaphycins as payloads in antibody drug conjugate anticancer agents

Almaliti, Jehad,Miller, Bailey,Pietraszkiewicz, Halina,Glukhov, Evgenia,Naman, C. Benjamin,Kline, Toni,Hanson, Jeffrey,Li, Xiaofan,Zhou, Sihong,Valeriote, Frederick A.,Gerwick, William H.

, p. 416 - 432 (2018/10/31)

Antibody–drug conjugates (ADCs) represent a new dimension of anticancer chemotherapeutics, with warheads to date generally involving either antitubulin or DNA-directed agents to achieve low-to sub-nanomolar potency. However, other potent cytotoxins working by different pharmacological mechanisms are under investigation, such as α,β-epoxyketone based proteasome inhibitors. These proteasome active agents are an emerging class of anticancer drug that possesses ultra-potent cytotoxicity to some cancer cell lines. The carmaphycins are representatives of this latter class that we isolated and characterized from a marine cyanobacterium, and these as well as several synthetic analogues exhibit this level of potency. In the current work, we investigated the use of these highly potent cytotoxic compounds as warheads in the design of novel ADCs. We designed and synthesized a library of carmaphycin B analogues that contain amine handles, enabling their attachment to an antibody linker. The basicity of these incorporated amine handles was shown to strongly affect their cytotoxic properties. Linear amines resulted in the greatest reduction in cytotoxicity whereas less basic aromatic amines retained potent activity as demonstrated by a 4-sulfonylaniline derivative. These investigations resulted in identifying the P2 residue in the carmaphycins as the most suitable site for linker attachment point, and hence, we synthesized a highly potent analogue of carmaphycin B that contained a 4-sulfonylaniline handle as an attachment point for the linker antibody.

Covalent docking modelling-based discovery of tripeptidyl epoxyketone proteasome inhibitors composed of aliphatic-heterocycles

Dong, Xiao-Wu,Zhang, Jian-Kang,Xu, Lei,Che, Jin-Xin,Cheng, Gang,Hu, Xiao-Bei,Sheng, Li,Gao, An-Hui,Li, Jia,Liu, Tao,Hu, Yong-Zhou,Zhou, Yu-Bo

supporting information, p. 602 - 614 (2019/01/11)

The potential of specific proteasome inhibitors to act as anti-cancer agents has attracted intensive investigations. The proteasome can be covalently inhibited by epoxyketone derivatives via a two-step reaction. Several computational approaches have been developed to mimic the covalent binding event. Compound 1 composed of a six-membered heterocyclic ring was designed by using covalent docking. With a possible different binding mode from the clinical compound Carfilzomib, it occupied the S5 pocket of 20S proteasome and showed favorable inhibitory activity. Subsequently optimization and evaluation were taken place. Among these compounds, 11h demonstrated extraordinary in vitro inhibitory activity and selectivity, and good in vivo proteasome inhibitory activity, a favorable pharmacokinetic profile and xenograft tumor inhibition. The possible binding pattern of compound 11h against proteasome was further fully explored via calculations, providing a theoretical basis for finding potent proteasome inhibitors.

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