74892-81-2

Basic information

• Product Name: (2R,4R)-4-Methylpiperidine-2-carboxylic acid
• Synonyms: (2R,4R)-4-METHYLPIPERIDINE-2-CARBOXYLIC ACID;(2R,4R)-4-Methylpipecolinic acid;2-Piperidinecarboxylic acid, 4-methyl-, (2R,4R)-
• CAS NO: 74892-81-2
• Molecular Formula: C₇H₁₃NO₂
• Molecular Weight: 143.18
• EINECS: 1312995-182-4
• Mol File: 74892-81-2.mol
• Article Data: 8

Chemical Properties

• Boiling Point: 267 ºC
• Flash Point: 115 ºC
• Appearance: /
• Density: 1.062
• Vapor Pressure: 0.0024mmHg at 25°C
• Refractive Index: 1.464
• Storage Temp.: 2-8°C(protect from light)
• PKA: 2.48±0.40(Predicted)
• CAS DataBase Reference: (2R,4R)-4-Methylpiperidine-2-carboxylic acid(CAS DataBase Reference)
• NIST Chemistry Reference: (2R,4R)-4-Methylpiperidine-2-carboxylic acid(74892-81-2)
• EPA Substance Registry System: (2R,4R)-4-Methylpiperidine-2-carboxylic acid(74892-81-2)

Safety Data

• Hazardous Substances Data: 74892-81-2(Hazardous Substances Data)

Usage

General Description

"(2R,4R)-4-Methylpiperidine-2-carboxylic acid is a chemical compound classified as a non-proteinogenic alpha amino acid, meaning it is not directly incorporated into proteins during the process of protein synthesis. Its chemical structure contains a piperidine ring, a common feature in many alkaloids and pharmaceuticals, and a functional carboxylic acid group. This chemical compound is chiral, showcasing two stereocenters, which further results in its four different isomeric forms. Despite being mainly used in research settings, its specific applications and properties are largely dependent on the stereochemistry of the individual isomers. Furthermore, the safety and potential health effects of this chemical are yet to be thoroughly studied.

InChI:InChI=1/C7H13NO2/c1-5-2-3-8-6(4-5)7(9)10/h5-6,8H,2-4H2,1H3,(H,9,10)/t5-,6-/m1/s1

Synthetic route

(4R,8R,10R)-8-methyl-4-phenylhexahydropyrido[2,1-c][1,4]oxazin-1-one → (2R-trans)-4-Methyl-2-piperidinecarboxylic acid (74892-81-2)

Conditions	Yield
With hydrogen; palladium dihydroxide In ethanol	98%
With hydrogen; palladium dihydroxide In ethanol for 2h;	98%

C22H25NO2 → (2R-trans)-4-Methyl-2-piperidinecarboxylic acid (74892-81-2)

Conditions	Yield
Stage #1: C22H25NO2 With hydrogen; [Rh(NBD)(PPh3)2]PF6 In ethanol at 50℃; under 760.051 Torr; for 4h; Stage #2: With palladium hydroxide, 20 wt% on carbon; hydrogen In ethanol; water at 23℃; under 760.051 Torr; for 5h;	86%

(2R,4S)-2-amino-6-methoxy-4-methyl-6-oxohexanoic acid → (2R-trans)-4-Methyl-2-piperidinecarboxylic acid (74892-81-2)

Conditions	Yield
With potassium borohydride In water at 1 - 60℃; for 3.5h;	83.1%

(2R,4R)-N-(tert-butoxycarbonyl)-4-methylpipecolic acid (154002-73-0) → (2R-trans)-4-Methyl-2-piperidinecarboxylic acid (74892-81-2)

Conditions	Yield
With hydrogenchloride In methanol at 20℃; for 2h;	74%

C10H19NO2 → (2R-trans)-4-Methyl-2-piperidinecarboxylic acid (74892-81-2)

Conditions

Yield

Multi-step reaction with 7 steps 1: NaHCO3 / methanol / 16 h / 60 °C 2: NaIO4 / tetrahydrofuran; H2O / 2 h / 20 °C 3: 27 g / NaBH4 / methanol / 0.5 h / 0 °C 4: 79 percent / 1st generation Grubbs catalyst / CH2Cl2 / 16 h / 20 °C 5: H2 / PtO2*H2O / ethyl acetate / 16 h / 2250.23 Torr 6: 63 percent / NaClO; NaClO2; sodoum phosphate buffer / TEMPO; bleach / acetonitrile; H2O / 18 h / 35 °C / pH 6.7 7: 74 percent / aq. HCl / methanol / 2 h / 20 °C View Scheme

(2R,3R)-N-allyl-N-(tert-butoxycarbonyl)-3-amino-5-methyl-5-hexen-1,2-diol → (2R-trans)-4-Methyl-2-piperidinecarboxylic acid (74892-81-2)

Conditions

Yield

Multi-step reaction with 6 steps 1: NaIO4 / tetrahydrofuran; H2O / 2 h / 20 °C 2: 27 g / NaBH4 / methanol / 0.5 h / 0 °C 3: 79 percent / 1st generation Grubbs catalyst / CH2Cl2 / 16 h / 20 °C 4: H2 / PtO2*H2O / ethyl acetate / 16 h / 2250.23 Torr 5: 63 percent / NaClO; NaClO2; sodoum phosphate buffer / TEMPO; bleach / acetonitrile; H2O / 18 h / 35 °C / pH 6.7 6: 74 percent / aq. HCl / methanol / 2 h / 20 °C View Scheme

(+)-(2R)-N-allyl-N-(tert-butoxycarbonyl)-2-amino-4-methyl-4-pentenaldehyde → (2R-trans)-4-Methyl-2-piperidinecarboxylic acid (74892-81-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: 27 g / NaBH4 / methanol / 0.5 h / 0 °C 2: 79 percent / 1st generation Grubbs catalyst / CH2Cl2 / 16 h / 20 °C 3: H2 / PtO2*H2O / ethyl acetate / 16 h / 2250.23 Torr 4: 63 percent / NaClO; NaClO2; sodoum phosphate buffer / TEMPO; bleach / acetonitrile; H2O / 18 h / 35 °C / pH 6.7 5: 74 percent / aq. HCl / methanol / 2 h / 20 °C View Scheme

(2R)-N-allyl-N-(tert-butoxycarbonyl)-2-amino-4-methyl-4-penten-1-ol (954379-06-7) → (2R-trans)-4-Methyl-2-piperidinecarboxylic acid (74892-81-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 79 percent / 1st generation Grubbs catalyst / CH2Cl2 / 16 h / 20 °C 2: H2 / PtO2*H2O / ethyl acetate / 16 h / 2250.23 Torr 3: 63 percent / NaClO; NaClO2; sodoum phosphate buffer / TEMPO; bleach / acetonitrile; H2O / 18 h / 35 °C / pH 6.7 4: 74 percent / aq. HCl / methanol / 2 h / 20 °C View Scheme

(N-(tert-butoxycarbonyl)-(6R)-1,2,3,6-tetrahydro-4-methylpyridine-2-yl)methanol (954379-07-8) → (2R-trans)-4-Methyl-2-piperidinecarboxylic acid (74892-81-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: H2 / PtO2*H2O / ethyl acetate / 16 h / 2250.23 Torr 2: 63 percent / NaClO; NaClO2; sodoum phosphate buffer / TEMPO; bleach / acetonitrile; H2O / 18 h / 35 °C / pH 6.7 3: 74 percent / aq. HCl / methanol / 2 h / 20 °C View Scheme

(N-(tert-butoxycarbonyl)-(2R,4R)-4-methylpiperidine-2-yl)methanol (173369-02-3) → (2R-trans)-4-Methyl-2-piperidinecarboxylic acid (74892-81-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 63 percent / NaClO; NaClO2; sodoum phosphate buffer / TEMPO; bleach / acetonitrile; H2O / 18 h / 35 °C / pH 6.7 2: 74 percent / aq. HCl / methanol / 2 h / 20 °C View Scheme

((2S,3S)-3-(2-methylallyl)oxiran-2-yl)methanol (954378-99-5) → (2R-trans)-4-Methyl-2-piperidinecarboxylic acid (74892-81-2)

Conditions

Yield

Multi-step reaction with 8 steps 1: LiClO4 / 16 h / 40 °C 2: NaHCO3 / methanol / 16 h / 60 °C 3: NaIO4 / tetrahydrofuran; H2O / 2 h / 20 °C 4: 27 g / NaBH4 / methanol / 0.5 h / 0 °C 5: 79 percent / 1st generation Grubbs catalyst / CH2Cl2 / 16 h / 20 °C 6: H2 / PtO2*H2O / ethyl acetate / 16 h / 2250.23 Torr 7: 63 percent / NaClO; NaClO2; sodoum phosphate buffer / TEMPO; bleach / acetonitrile; H2O / 18 h / 35 °C / pH 6.7 8: 74 percent / aq. HCl / methanol / 2 h / 20 °C View Scheme

(4R,10R)-8-methylene-4-phenyloctahydropyrido[2,1-c][1,4]oxazin-1-ol (194796-77-5) → (2R-trans)-4-Methyl-2-piperidinecarboxylic acid (74892-81-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 85 percent / DMSO; (COCl)2; Et3N / CH2Cl2 / 1.5 h / -50 - 20 °C 2: 74 percent / H2 / PtO2 / ethyl acetate / 0.25 h 3: 98 percent / H2 / Pd(OH)2 / ethanol / 2 h View Scheme
Multi-step reaction with 3 steps 1: 85 percent / (COCl)2, DMSO, Et3N / -50 - 0 °C 2: H2 / PtO2 / ethyl acetate 3: 98 percent / H2 / Pd(OH)2 / ethanol View Scheme

(4R,9aR)-8-methylene-4-phenyl-hexahydropyrido[2,1-c][1,4]oxazin-1-one (194796-78-6) → (2R-trans)-4-Methyl-2-piperidinecarboxylic acid (74892-81-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 74 percent / H2 / PtO2 / ethyl acetate / 0.25 h 2: 98 percent / H2 / Pd(OH)2 / ethanol / 2 h View Scheme
Multi-step reaction with 2 steps 1: H2 / PtO2 / ethyl acetate 2: 98 percent / H2 / Pd(OH)2 / ethanol View Scheme

(R)-3-methyl-γ-butyrolactone (65284-00-6) → (2R-trans)-4-Methyl-2-piperidinecarboxylic acid (74892-81-2)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: methanol / 5 h / 80 °C 2.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 1 h / -60 °C / Inert atmosphere 2.2: 0.5 h / -60 - 20 °C 3.1: ethanolamine / water / 6.5 h / 60 - 80 °C 4.1: sodium hydroxide / 2.5 h / Reflux 5.1: pyrrole aldehyde / water / 24 h / 37 °C / pH 8 6.1: sulfuric acid / 3 h / 0 - 20 °C 7.1: potassium borohydride / water / 3.5 h / 1 - 60 °C View Scheme

(S)-methyl-3-hydroxy-2-methylpropanoate (147915-53-5) → (2R-trans)-4-Methyl-2-piperidinecarboxylic acid (74892-81-2)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 1 h / -60 °C / Inert atmosphere 1.2: 0.5 h / -60 - 20 °C 2.1: ethanolamine / water / 6.5 h / 60 - 80 °C 3.1: sodium hydroxide / 2.5 h / Reflux 4.1: pyrrole aldehyde / water / 24 h / 37 °C / pH 8 5.1: sulfuric acid / 3 h / 0 - 20 °C 6.1: potassium borohydride / water / 3.5 h / 1 - 60 °C View Scheme

(R)-3-Methyl-4-oxo-butyric acid methyl ester (125137-08-8) → (2R-trans)-4-Methyl-2-piperidinecarboxylic acid (74892-81-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: ethanolamine / water / 6.5 h / 60 - 80 °C 2: sodium hydroxide / 2.5 h / Reflux 3: pyrrole aldehyde / water / 24 h / 37 °C / pH 8 4: sulfuric acid / 3 h / 0 - 20 °C 5: potassium borohydride / water / 3.5 h / 1 - 60 °C View Scheme

Upstream product

• 125137-08-8 (R)-3-Methyl-4-oxo-butyric acid methyl ester 
• 147915-53-5 (S)-methyl-3-hydroxy-2-methylpropanoate 
• 65284-00-6 (R)-3-methyl-γ-butyrolactone 
• 194796-78-6 (4R,9aR)-8-methylene-4-phenyl-hexahydropyrido[2,1-c][1,4]oxazin-1-one 
• 194796-77-5 (4R,10R)-8-methylene-4-phenyloctahydropyrido[2,1-c][1,4]oxazin-1-ol 
• 954378-99-5 ((2S,3S)-3-(2-methylallyl)oxiran-2-yl)methanol 
• 173369-02-3 (N-(tert-butoxycarbonyl)-(2R,4R)-4-methylpiperidine-2-yl)methanol 
• 954379-07-8 (N-(tert-butoxycarbonyl)-(6R)-1,2,3,6-tetrahydro-4-methylpyridine-2-yl)methanol 
• 954379-06-7 (2R)-N-allyl-N-(tert-butoxycarbonyl)-2-amino-4-methyl-4-penten-1-ol 
• 154002-73-0 (2R,4R)-N-(tert-butoxycarbonyl)-4-methylpipecolic acid 
• 1620-76-4 2-Cyano-4-methylpyridin 
• 1003-67-4 4-methylpyridine-1-oxide 
• 123811-83-6 (+/-)-cis-Boc-4-methylpipecolinic acid 
• 123811-73-4 4-Methyl-pyridine-2-carboxylic acid; hydrochloride 

Downstream Products

• 610786-78-2 (2R,4R)-1,4-dimethylpiperidine-2-carboxylic acid 
• 123811-83-6 (+/-)-cis-Boc-4-methylpipecolinic acid 

Relevant articles and documents

A Concise, Enantiospecific Total Synthesis of Chilocorine C Fueled by a Reductive Cyclization/Mannich Reaction Cascade

Among defensive alkaloids isolated from ladybugs, the heterodimeric member chilocorine C possesses an alluring monomeric unit that combines quinolizidine and indolizidine substructures. Indeed, the overall stereochemical disposition of its ring fusions is distinct from those of related natural products. Herein we show that a carefully orchestrated sequence with several chemoselective transformations, including a designed cascade that accomplishes nine distinct chemical reactions in one-pot, can smoothly forge that domain and ultimately enable a 15-step, 11-pot enantiospecific synthesis of the natural product. Mechanistic studies, density functional theory calculations, and the delineation of several other unsuccessful approaches highlight its unique elements.

Enantioselective synthesis of trans-4-methylpipecolic acid

(Chemical Equation Presented) An asymmetric synthesis for the preparation of both enantiomers of trans-methylpipecolic acids is described. It is based on Sharpless epoxidation as a chirality source, regioselective ring opening with allylamine, and ring-closing metathesis to construct the piperidine ring. The stereogenic center at C-4 is set by stereoselective hydrogenation that is directed by the alcohol functionality of an intermediate and proceeds with good diastereomeric control (trans/cis 16/1). Crystallization of the Boc-protected amino acid afforded the target products with excellent chemical (98% de) and enantiomeric purity (99% ee).

Asymmetric syntheses of enantiopure 4-substituted pipecolic acid derivatives

(2R,4R)-4-Methylpipecolic acid and (2S,4R)-4-hydroxypipecolic acid, two biologically active amino acids, were synthesized using the same strategy. A third amino acid, obtained in a protected form, was also obtained in the same way. The key step of these syntheses involves an intramolecular eneiminium cyclization which occurs with complete stereoselectivity. The resulting exocyclic double bond can react in a diastereoselective way to afford pure lactones, which can then be efficiently converted into the amino acids.