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Organic Chemistry
Table of Contents
Unit 26 Overview: Biomolecules: Amino Acids & Proteins
26.1 Structures of Amino Acids
26.2 Amino Acids and the Henderson–Hasselbalch Equation: Isoelectric Points
26.3 Synthesis of Amino Acids
26.4 Peptides and Proteins
26.5 Amino Acid Analysis of Peptides
26.6 Peptide Sequencing: The Edman Degradation
26.7 Peptide Synthesis
26.8 Automated Peptide Synthesis: The Merrifield Solid-Phase Method
26.9 Protein Structure
26.10 Enzymes and Coenzymes
26.11 How Do Enzymes Work? Citrate Synthase

α-Amino acids are essential building blocks of proteins. We'll explore three key methods for synthesizing these crucial compounds: the amidomalonate synthesis, reductive amination of α-keto acids, and enantioselective synthesis using chiral catalysts.

Each method offers unique advantages for creating α-amino acids. We'll examine the reaction steps, mechanisms, and stereochemical considerations involved in these synthetic approaches, providing a foundation for understanding amino acid synthesis in organic chemistry.

Synthesis of α-Amino Acids

Amidomalonate synthesis method

  • Prepares α-amino acids from diethyl acetamidomalonate
    • Amido-substituted malonic ester synthesized by reacting diethyl malonate with sodium ethoxide and ethyl acetate, then ammonia
  • Amidomalonate anion formed by deprotonation with sodium ethoxide
    • Undergoes SN2 reaction with alkyl halide (R-X) to form diethyl 2-acetamido-2-alkylmalonate
  • Hydrolysis of ester groups and decarboxylation by heating with aqueous HCl yields α-amino acid product
    • Acetyl group also hydrolyzed to reveal free amino group
  • Gabriel synthesis is another method using phthalimide as a protected form of the amino group

Reductive amination of α-keto acids

  • Synthesizes α-amino acids from α-keto acids
    • Contain carboxylic acid group and ketone group on α-carbon (pyruvic acid)
  • α-Keto acid first converted to imine by reaction with ammonia
    • Nucleophilic ammonia attacks ketone group, forming tetrahedral intermediate
    • Proton transfer and loss of water yields imine (Schiff base)
  • Imine reduced to corresponding α-amino acid using reducing agent
    • Sodium cyanoborohydride ($NaBH_3CN$) or hydrogen gas with metal catalyst
    • Hydride transfer from reducing agent to electrophilic imine carbon forms α-amino acid product (alanine)
  • Transamination is a biological process that can interconvert α-keto acids and α-amino acids

Enantioselective synthesis with chiral catalysts

  • Prepares specific enantiomer (S or R) of α-amino acid
  • Uses chiral catalyst in reductive amination of α-keto acid
    • Catalyst forms complex with imine intermediate, controlling stereochemistry of hydride transfer step
  • Example: $(S)$-2-amino-2′-hydroxy-1,1′-binaphthyl ($S$-NOBIN)
    • Complexes with imine through hydrogen bonding and π-stacking interactions
    • Orients imine for preferential hydride transfer from $Si$ face, yielding $S$ enantiomer of α-amino acid
  • Other chiral catalysts include chiral transition metal complexes (rhodium) or organocatalysts (proline)
    • Choice depends on substrate structure, desired enantioselectivity, and reaction conditions
  • Asymmetric synthesis techniques are crucial for controlling the stereochemistry of the final product

Additional Synthetic Methods and Considerations

  • Strecker synthesis: A versatile method for preparing α-amino acids from aldehydes or ketones
  • Stereochemistry plays a crucial role in amino acid synthesis, affecting biological activity and function
  • Various approaches can be employed to control the stereochemical outcome of the synthesis

Key Terms to Review (35)

Amidomalonate synthesis: Amidomalonate synthesis is a chemical process used to produce amino acids by synthesizing a compound known as amidomalonate, which then undergoes various reactions to form the desired amino acid. This method allows for the creation of amino acids with specific configurations, making it valuable in the study and production of peptides and proteins.
Schiff base: A Schiff base is a compound featuring a nitrogen atom double-bonded to a carbon atom, which is also bonded to an aryl or alkyl group but not a hydrogen atom, created by the condensation of an amine with an aldehyde or ketone. In the context of glycolysis, it plays a role in the enzymatic conversion of intermediates.
Alkyl halide: An alkyl halide is an organic compound in which one or more hydrogen atoms in an alkane (saturated hydrocarbon) have been replaced by a halogen atom (fluorine, chlorine, bromine, or iodine). This substitution results in a molecule with distinct chemical and physical properties compared to its alkane precursor.
SN2 reaction: In organic chemistry, an SN2 reaction is a type of nucleophilic substitution where a nucleophile strongly attacks an electrophilic center in one step, leading to the simultaneous displacement of a leaving group. This reaction mechanism is characterized by its bimolecular nature, involving two reacting species in the rate-determining step.
Anti stereochemistry: Anti stereochemistry describes the spatial arrangement in a chemical reaction where two substituents are positioned on opposite sides of a double bond or ring structure after the reaction. It is particularly relevant in the halogenation of alkenes, resulting in products where the added atoms are located across from each other.
Reductive amination: Reductive amination is a chemical process that combines an aldehyde or ketone with an amine in the presence of a reducing agent to form a substituted amine. This method is widely used for synthesizing primary, secondary, and tertiary amines from simpler organic molecules.
Stereochemistry: Stereochemistry is the study of the three-dimensional arrangement of atoms in molecules and how this arrangement affects the chemical and physical properties of the substance. It examines the spatial orientation of atoms and their relationship to one another, which is crucial in understanding many organic chemistry concepts.
Hydrolysis: Hydrolysis is a chemical reaction in which a compound is cleaved into smaller molecules by the addition of water. This process involves the breaking of chemical bonds through the insertion of water molecules, often resulting in the formation of new functional groups or the decomposition of larger molecules.
Alanine: Alanine is a non-essential amino acid that is commonly found in proteins. It plays a crucial role in various biochemical processes, including protein synthesis, energy production, and amino acid metabolism.
Asymmetric Synthesis: Asymmetric synthesis is a chemical reaction that produces a chiral molecule in a stereoselective manner, resulting in the formation of one enantiomer or diastereomer in excess over the other. This concept is crucial in understanding various topics in organic chemistry, including Pasteur's discovery of enantiomers, chirality at nitrogen, phosphorus, and sulfur, prochirality, chirality in nature and chiral environments, and the synthesis of amino acids.
Si face: The Si face refers to the side of a prochiral center where silicon is attached. This term is important in the context of prochirality and the synthesis of amino acids, as the Si face can influence the stereochemical outcome of reactions involving prochiral centers.
Chiral Catalysts: Chiral catalysts are enantioselective catalysts that can preferentially promote the formation of one enantiomer of a product over the other in a chemical reaction. These catalysts possess a chiral environment that allows them to interact differently with the reactants, leading to the selective formation of a desired stereoisomer.
Transamination: Transamination is a fundamental biochemical reaction in which an amino group is transferred from one organic molecule to another, typically from an amino acid to a keto acid. This process is crucial for the synthesis and catabolism of amino acids, as well as the regulation of nitrogen balance in the body.
Alkyl Halide: An alkyl halide is a type of organic compound that consists of an alkyl group (a hydrocarbon chain) bonded to a halogen atom (fluorine, chlorine, bromine, or iodine). These compounds are important intermediates in many organic reactions, including polar reactions, elimination reactions, and substitution reactions.
Sodium Ethoxide: Sodium ethoxide is an alkoxide compound with the chemical formula C₂H₅ONa. It is a strong nucleophile and base used in various organic reactions, including the preparation of alkenes, the Wittig reaction, and Claisen condensations.
Rhodium: Rhodium is a rare, silvery-white, hard, and corrosion-resistant transition metal. It is primarily used as a catalyst in various chemical processes, including the reduction of alkenes through hydrogenation and the synthesis of amino acids.
SN2 Reaction: The SN2 reaction, or bimolecular nucleophilic substitution, is a type of organic reaction where a nucleophile attacks the backside of a carbon atom bearing a leaving group, resulting in the displacement of the leaving group and the inversion of stereochemistry at the carbon center.
Imine: An imine is a functional group that consists of a carbon-nitrogen double bond, where the nitrogen is connected to a hydrogen atom and an organic substituent. Imines are important intermediates in organic synthesis and are found in various biological processes.
Decarboxylation: Decarboxylation is a chemical reaction that involves the removal of a carboxyl group (–COOH) from a molecule, typically resulting in the release of carbon dioxide (CO2). This process is important in various organic chemistry reactions and metabolic pathways.
Gabriel Synthesis: The Gabriel synthesis is a chemical reaction used to synthesize primary amines from phthalimide and an alkyl or aryl halide. It is a versatile method for the preparation of a wide range of primary amines, which are important building blocks in organic chemistry and have applications in the synthesis of various compounds, including amides, amino acids, and pharmaceuticals.
Schiff Base: A Schiff base is a functional group that consists of a carbon-nitrogen double bond, where the nitrogen atom is connected to an aryl or alkyl group rather than hydrogen. Schiff bases are formed through the condensation reaction between a primary amine and an aldehyde or ketone, and they play important roles in various biological processes.
Reductive Amination: Reductive amination is a chemical reaction that involves the condensation of an aldehyde or ketone with an amine, followed by the reduction of the resulting imine or enamine intermediate to form a secondary or tertiary amine. This reaction is particularly useful in the synthesis of amines, including amino acids.
Proline: Proline is a unique amino acid that has a distinctive cyclic structure, setting it apart from the other 19 standard amino acids. Its distinct properties and role in protein structure make it an important consideration in the study of amino acids, their synthesis, and peptide sequencing.
S-NOBIN: S-NOBIN, or (S)-2-(1-naphthyl)alanine, is a chiral amino acid derivative that has been utilized in the synthesis of various amino acids. It serves as a valuable tool in the field of organic chemistry, particularly in the context of 26.3 Synthesis of Amino Acids.
S Enantiomer: An S enantiomer is one of the two possible stereoisomeric forms of a chiral molecule. Chirality refers to the property of a molecule that is non-superimposable on its mirror image, and the S enantiomer is the stereoisomer with the specific configuration where the priority groups are arranged in a counter-clockwise fashion when the molecule is viewed from the front.
Sodium Cyanoborohydride: Sodium cyanoborohydride is a reducing agent commonly used in organic synthesis, particularly in the context of amino acid synthesis. It is a milder and more selective reducing agent compared to other common reducing agents like sodium borohydride.
Diethyl Acetamidomalonate: Diethyl acetamidomalonate is an organic compound that is commonly used in the synthesis of amino acids. It is a derivative of malonic acid, with an acetamido group and two ethyl ester groups attached to the central carbon atom.
Strecker Synthesis: The Strecker synthesis is a method for the preparation of α-amino acids from aldehydes or ketones, ammonia, and hydrogen cyanide. It involves the formation of an imine intermediate, which then undergoes nucleophilic addition of cyanide to produce an α-aminonitrile that can be hydrolyzed to the final α-amino acid product.
(S)-2-amino-2′-hydroxy-1,1′-binaphthyl: (S)-2-amino-2′-hydroxy-1,1′-binaphthyl is a chiral organic compound with a binaphthyl backbone and an amino group at the 2-position and a hydroxyl group at the 2'-position. This compound is an important intermediate in the synthesis of various amino acids and other biologically active molecules.
Enantioselective Synthesis: Enantioselective synthesis is a type of organic reaction that selectively produces one enantiomer of a chiral molecule over the other. This is an important concept in the synthesis of amino acids, as the stereochemistry of the final product is crucial for biological activity and function.
α-amino acid: An α-amino acid is a type of organic compound that contains an amino group (NH2) and a carboxyl group (COOH) attached to the same carbon atom, known as the α-carbon. These amino acids are the building blocks of proteins and play a crucial role in various metabolic processes within the body.
Diethyl 2-acetamido-2-alkylmalonate: Diethyl 2-acetamido-2-alkylmalonate is an organic compound that is a key intermediate in the synthesis of amino acids. It consists of a malonate diester with an acetamido group and an alkyl substituent at the 2-position.
Pyruvic Acid: Pyruvic acid is a key intermediate in cellular metabolism, particularly in the process of glycolysis. It serves as a crucial link between carbohydrate breakdown and energy production within the cell.
Amidomalonate Synthesis Method: The amidomalonate synthesis method is a strategy for the synthesis of amino acids, involving the reaction of an amide with a malonate ester to form a new amino acid derivative. This approach is particularly useful in the context of 26.3 Synthesis of Amino Acids, as it provides a versatile route to access a variety of amino acid structures.
α-Keto Acids: α-Keto acids, also known as α-oxo acids, are a class of organic compounds characterized by the presence of a ketone group (C=O) at the α-carbon position relative to the carboxyl group (COOH). These compounds are intermediates in various metabolic pathways, including the synthesis of amino acids.