Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 1: Protecting Groups 1

"This first-of-its-kind four-volume book series, Amino Acids: Insights and Roles in Heterocyclic Chemistry, provides readers with up-to-date information on alpha-amino acids, the potential challenges in working with alpha-amino acids, the protecting groups for the carboxyl, amino and side chain groups of the amino acids, and the most popular heterocyclic compounds that are originating from alpha-amino acids. These heterocyclic compounds include hydantoins, thiohydantoins (including 2-thiohydantoins, 4-thiohydantoins, 2,4-dithiohydantoins), 2,5-diketopiperazines, N-carboxyanhydrides, N-thiocarboxyanhydrides, sydnones, sydnonimines, azlactones, pseudoazlactones, and oxazolidin-5-ones. This is the first resource to comprehensively collect all the heterocycles that can be directly prepared from alpha-amino acids. In addition, almost all kinds of synthetic methods for a particular type of heterocycles from alpha-amino acids are include, along with the detailed mechanistic discussions and experimental procedures. Volume 1: Protecting Groups, the first volume of this set, has collected the 260 protecting groups relating to amino acids, which have been organized by carboxyl group, amino group, and side chain group. The conditions to introduce these protecting groups as well as their deprotecting procedures have also been incorporated, along with the physical properties, solvent effect and temperature effect on the solubility of amino acids. It presents the solubility of glycine and phenylalanine in a variety of solvent systems to show the impact of solvent on the solubility of amino acid, where glycine generally represents the polar amino acid whereas phenylalanine represents the amino acid of non-polar side chain."-- Provided by publisher Cover Half Title Amino Acids: Insights and Roles in Heterocyclic Chemistry Series Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 1: Protecting Groups Copyright About the Author Contents Abbreviations Acknowledgments Preface 1. Introduction to Amino Acids 1.1 Introduction to Carboxylic Acids 1.2 Introduction to Aliphatic Amines 1.3 Introduction to General Amino Acids 1.4 The Common α-Amino Acids that Construct Proteins 1.4.1 The Common α-Amino Acids 1.4.2 Stereochemistry of α-Amino Acids 1.4.3 Amphiprotic Properties of α-Amino Acids 1.4.4 Essential Amino Acids and Nonessential Amino Acids 1.4.5 Unnatural Amino Acids 1.4.6 D-α-Amino Acids Keywords References 2. The Dilemma of Working with α-Amino Acids 2.1 Impact of Solvent on the Solubility of α-Amino Acids 2.2 Temperature Effect on the Solubility of α-Amino Acids 2.3 Salting Effect and pH Effect on the Solubility of α-Amino Acids 2.4 Measures to Deal With Amino Acid Solubility Keywords References 3. The Carboxyl Protecting Groups 3.1 Introduction to Carboxyl Protecting Groups 3.2 Alkyl Protecting Groups 3.2.1 Methyl Protecting Group 3.2.1.1 Exemplary Experimental Procedures for the Preparation of Amino Acid Methyl Esters 3.2.1.1.1 Preparation of L-Phenylalanine Methyl Ester in the Presence of HCl [1] 3.2.1.1.2 Preparation of D-Phenylglycine Methyl Ester in the Presence of H2SO4 [2] 3.2.1.1.3 Preparation of L-Phenylalanine Methyl Ester in the Presence of Phosphoric Acid [4] 3.2.1.1.4 General Procedure to Prepare Amino Acid Methyl Ester Hydrochlorides in the Presence of Trimethylsilyl (TMS) Chloride [7] 3.2.1.1.5 General Procedure to Prepare Amino Acid Methyl Ester with 2,2-Dimethoxypropane [10] 3.2.1.2 Exemplary Experimental Procedures for the Removal of Methyl Esters 3.2.1.2.1 Removal of Methyl Ester with AlCl3/N,N-dimethylaniline [17, 20] 3.2.1.2.2 Removal of Methyl Ester with LiOH [11] 3.2.1.2.3 General Method for Enzymatic Hydrolysis [13] 3.2.2 Ethyl Protecting Group 3.2.2.1 Exemplary Experimental Procedures for the Preparation of Amino Acid Ethyl Esters 3.2.2.1.1 Preparation of Amino Acid Ethyl Ester Hydrochloride with Thionyl Chloride [21] 3.2.2.1.2 General Procedure for the Synthesis of Amino Acid Ethyl Ester in the Presence of HCl [22] 3.2.2.1.3 Formation of N-Norborn-2-ene-5-Carboxy-LPhenylalanine Ethyl Ester in the Presence of p-Toluenesulfonic Acid [23] 3.2.2.1.4 Preparation of Amino Acid with Orthoester Under Microwave Irradiation [24] 3.2.2.1.5 Preparation of Amino Acid Ethyl Ester in the Presence of α-Chymotrypsin (CT) [25] 3.2.2.2 Exemplary Experimental Procedures for the Removal of Ethyl Esters 3.2.2.2.1 Removal of Ethyl Group by Protease Trypsin [21] 3.2.2.2.2 Removal of Ethyl Group with LiOH [26] 3.2.3 Isopropyl Protecting Group 3.2.3.1 Exemplary Experimental Procedures for the Preparation of Amino Acid Isopropyl Esters 3.2.3.1.1 Preparation of Isopropyl Phenylglycinate Hydrochloride 3.2.4 n-Heptyl Protecting Group 3.2.5 tert-Butyl Protecting Group 3.2.5.1 Exemplary Experimental Procedures for the Preparation of Amino Acid t-Butyl Esters 3.2.5.1.1 Preparation of t-Butyl Carbobenzoxyglycinate with Isobutylene [29] 3.2.5.1.2 Preparation of t-Butyl Phenylglycinate Hydrochloride [27] 3.2.5.1.3 General Procedure for the Preparation of Amino Acid t-Butyl Ester with DCC [31] 3.2.5.1.4 General Procedure to Prepare Amino Acid t-Butyl Ester under Basic Condition [31] 3.2.5.2 Exemplary Experimental Procedures for the Removal of t-Butyl Group 3.2.5.2.1 Removal of t-Butyl Protecting Group by HNO3 [31] 3.2.5.2.2 Removal of t-Butyl Group by Trifluoroacetic Acid and Triethylsilane [26] 3.2.5.2.3 General Procedure for the Selective Removal of tert-Butyl Esters with ZnBr2 [35] 3.2.6 Adamantyl Protecting Group 3.2.6.1 General Procedure to form Amino Acid Adamantyl Ester [36] 3.2.6.2 Representative Procedure to Remove Adamantyl Protecting Group [36] 3.2.7 α-Phenylethyl Protecting Group 3.2.7.1 Synthesis of N-Phthaloyl-DL-Phenylalanine α-Phenylethyl Ester [36] 3.2.7.2 Removal of the α-Phenylethyl Protecting Group [36] 3.2.8 The 2-(4-acetyl-2-nitrophenyl)ethyl (Anpe) Protecting Group 3.2.8.1 Preparation of Nα-Boc-L-Aspartic Acid β-Anpe Esters, Boc-Asp(X)-OH [37] 3.2.8.1.1 Route A 3.2.8.1.2 Route B 3.2.9 Fluorenylmethyl (FM) Protecting Group 3.2.9.1 Exemplary Experimental Procedures for the Preparation of Amino Acid Fluorenylmethyl Ester 3.2.9.1.1 General Procedure for the Synthesis of Boc-Amino Acid Fluorenylmethyl Esters [45] 3.2.9.1.2 Preparation of Nα-Boc-Glycine α-Fluorenylmethyl Ester [40] 3.2.9.1.3 Preparation of N-Boc-Leucine 9-Fluorenylmethyl Ester via Transesterification [42] 3.2.9.2 Removal of the 9-Fluorenylmethyl Ester Protecting Group [42] 3.2.10 2-Pyridylethyl (PET) Protecting Group 3.2.10.1 General Procedure for the Preparation of Amino Acid 2-Pyridylethyl Ester [47] 3.2.10.2 Removal of the 2-Pyridylethyl Group [47] 3.3 α-Heteroatom Substituted Methyl Protecting Groups 3.3.1 Methylthiomethyl (MTM) Protecting Group 3.3.1.1 General Procedure for Esterification of N-Boc Protected L-Amino Acids with Chloromethyl Methyl Sulfide [48] 3.3.1.2 General Procedure for the Methylthiomethylation of N-Protected Amino Acids [50] 3.3.2 Acetyloxymethyl Protecting Group 3.3.3 THE β-(TRIMETHYLSILYL)ETHOXYMETHYL (SEM) PROTECTING GROUP 3.3.4 PHTHALIMIDOMETHYL PROTECTING GROUP 3.3.4.2.1 Removal of the Phthalimidomethyl Group under Acidic Condition [57] 3.3.4.2.2 Removal of the Phthalimidomethyl Group Under Basic Condition [57] 3.3.5 BENZYLOXYMETHYL (BOM) PROTECTING GROUP 3.4 β-HETEROATOM SUBSTITUTED ETHYL PROTECTING GROUP 3.4.1 2-HALOETHYL PROTECTING GROUP 3.4.1.1 EXEMPLARY EXPERIMENTAL PROCEDURES FOR THE PREPARATION OF AMINO ACID 2-HALOETHYL ESTERS 3.4.1.1.1 Preparation of Z-L-Alanine 2-Bromoethyl Ester in the Presence of DCC [60] 3.4.1.1.2 General Procedure for the Preparation of Amino Acid 2-Chloro- or Bromoethyl Ester [60] 3.4.1.1.3 Conversion of Amino Acid 2-Bromoethyl Ester to Corresponding 2-Iodoethyl Ester (Preparation of N-Benzyloxycarbonyl-L-Phenylalanyl-L-Leucine 2-Iodoethyl Ester) [60] 3.4.1.2 EXEMPLARY EXPERIMENTAL PROCEDURES FOR THE REMOVAL OF 2-HALOETHYL GROUP 3.4.1.2.1 Removal of 2-Haloethyl Protecting Group (Preparation of N-Benzyloxycarbonyl-L-Phenylalanyl-L-Leucine) [60] 3.4.1.2.2 One-Pot Procedure to Remove 2-Haloethyl Protecting Group [60] 3.4.1.2.3 Removal of 2-Chloroethyl Ester Group with Na2S [61]] 3.4.2 POLYETHYLENE GLYCOL (PEG) AND ETHYLENE GLYCOL RELATED PROTECTING GROUPS 3.4.2.1 EXEMPLARY EXPERIMENTAL PROCEDURES FOR THE PREPARATION OF AMINO ACID PEG ESTERS 3.4.2.1.1 Preparation of Dioleoylserinyldodecaethylene Glycol [67] 3.4.2.1.2 Preparation of Poly(Ethylene Glycol)-2000 Di(tert-Butyloxycarbonylglycinate) [68] 3.4.2.1.3 Synthesis of Bis(Tyrosyl Hydrochloride) Poly(Ethylene Glycol)-6000 Diester (Bis-Tyr·HCl-PEG-6000) [66] 3.4.2.2 EXEMPLARY EXPERIMENTAL PROCEDURES FOR THE REMOVAL OF ETHYLENE GLYCOL TYPE GROUP 3.4.2.2.1 Removal of 2-[(2-Methoxy)Ethoxy]Ethyl (MEE) Protecting Group [65] 3.4.3 2-TRIMETHYLSILYLETHYL (TMSE) AND 2-PHENYL-2-TRIMETHYLSILYLETHYL (PTMSE) PROTECTING GROUPS 3.4.4 2-MORPHOLINO-ETHYL PROTECTING GROUP 3.4.1 2-HALOETHYL PROTECTING GROUP 3.4.1.1 EXEMPLARY EXPERIMENTAL PROCEDURES FOR THE PREPARATION OF AMINO ACID 2-HALOETHYL ESTERS 3.4.1.1.1 Preparation of Z-L-Alanine 2-Bromoethyl Ester in the Presence of DCC [60] 3.4.1.1.2 General Procedure for the Preparation of Amino Acid 2-Chloro- or Bromoethyl Ester [60] 3.4.1.1.3 Conversion of Amino Acid 2-Bromoethyl Ester to Corresponding 2-Iodoethyl Ester (Preparation of N-Benzyloxycarbonyl-L-Phenylalanyl-L-Leucine 2-Iodoethyl Ester) [60] 3.4.1.2 EXEMPLARY EXPERIMENTAL PROCEDURES FOR THE REMOVAL OF 2-HALOETHYL GROUP 3.4.1.2.1 Removal of 2-Haloethyl Protecting Group (Preparation of N-Benzyloxy 3.4.1.2.2 One-Pot Procedure to Remove 2-Haloethyl Protecting Group [60] 3.4.1.2.3 Removal of 2-Chloroethyl Ester Group with Na2S [61] 3.4.5 2-(DIPHENYLPHOSPHINO)ETHYL PROTECTING GROUP 3.4.6 β-METHYLTHIOETHYL PROTECTING GROUP 3.4.6.1 EXEMPLARY EXPERIMENTAL PROCEDURES FOR PREPARATION OF AMINO ACID β-METHYLTHIOETHYL ESTERS 3.4.6.1.1 Preparation of β-Methylthioethyl Esters of N-Protected Amino Acids without Solvent [75] 3.4.6.1.2 Preparation of β-Methylthioethyl Esters of N-Protected Amino Acids in EtOAc [75] 3.4.6.2 EXEMPLARY EXPERIMENTAL PROCEDURES FOR REMOVAL OF β-METHYLTHIOETHYL GROUP 3.4.6.2.1 Removal of the β-Methylthioethyl Ester Group [75] 3.4.6.2.2 Removal of β-Methylthioethyl Group without Isolation of Methiodide 3.4.7 CYANOMETHYL PROTECTING GROUP 3.4.8 2-(4-NITROPHENYLSULFONYL)ETHYL PROTECTING GROUP 3.5 β-KETO ALCOHOL PROTECTING GROUPS 3.5.1 ACETOL PROTECTING GROUP 3.5.1.1 GENERAL PROCEDURE FOR PREPARATION OF AMINO ACID ACETOL ESTER [78] 3.5.1.2 GENERAL PROCEDURE FOR DEPROTECTION OF ACETOL [78] 3.5.2 PHENACYL PROTECTING GROUP 3.5.2.1 EXEMPLARY EXPERIMENTAL PROCEDURES FOR PREPARATION OF AMINO ACID PHENACYL ESTERS 3.5.2.1.1 Synthesis of H-L-Hyp(Bzl)-OPac·HCl [85] 3.5.2.1.2 Preparation of Benzyloxycarbonylamino Acid p-Bromophenacyl Esters 3.5.2.1.3 Preparation of N-(9-Fluorenylmethyloxycarbonyl)-L Serine Phenacyl Es 3.5.2.1.4 General Synthetic Procedure for the Preparation of N-Nosyl-α-Amino 3.5.2.2 EXEMPLARY EXPERIMENTAL PROCEDURES FOR REMOVAL OF PHENACYL GROUP 3.5.2.2.1 Cleavage of p-Bromophenacyl by PhSNa [80] 3.5.2.2.2 General Procedure for Deprotection of N-Methyl-N-Nosyl α-Amino Acid 3.5.2.2.3 General Procedure for the Deprotection of Phenacyl Esters in N-Prot 3.5.2.2.4 Deprotection of Phenacyl Group with Magnesium and Acetic Acid [86] 3.6 UNSATURATED PROTECTING GROUPS 3.6.1 ALLYL AND SUBSTITUTED ALLYL PROTECTING GROUPS 3.6.1.1 EXEMPLARY EXPERIMENTAL PROCEDURES FOR PREPARATION OF AMINO ACID ALLYL ESTERS 3.6.1.1.1 Preparation of (S)-1-Allyl 5-Ethyl 2-Benzyloxycarbonylamino-Pentanedioate [92] 3.6.1.1.2 Preparation of Glycine Allyl Ester, Trifluoroacetate Salt (H-Gly-OA 3.6.1.2 EXEMPLARY EXPERIMENTAL PROCEDURES FOR REMOVAL OF ALLYL GROUP 3.6.1.2.1 Removal of the Allyl Group from Peptide Resin [95] 3.6.1.2.2 Catalytic Removal of Allyl Group to Form Boc-D-Leu-L Leu-L-threo-O-[ 3.6.2 PROPARGYL PROTECTING GROUP 3.6.2.1.1 General Procedure for the Synthesis of Propargyl Esters Under Basic 3.6.2.1.2 General Procedure for the Synthesis of Propargyl Esters Under Acidi 3.6.3 BENZYL AND SUBSTITUTED BENZYL PROTECTING GROUPS 3.6.3.1 BENZYL PROTECTING GROUPS 3.6.3.2 α-SUBSTITUTED BENZYL GROUPS 3.6.3.3 EXEMPLARY EXPERIMENTAL PROCEDURES FOR PREPARATION OF AMINO ACID BENZYL ESTER 3.6.3.3.1 General Preparation of Amino Acid Benzyl Ester Under Microwave Irra 3.6.3.3.2 Preparation of L-Serine Benzyl Ester Benzenesulfonate (L-Ser-OBn·Ph 3.6.3.3.3 Preparation of N-Boc-L-Serine Benzyl Ester with Dudley’s Reagent [1 3.6.3.3.4 Preparation of L-Proline 2,4,6-Trimethylbenzyl Ester Hydrochloride 3.6.3.3.5 Preparation of N-Benzyloxycarbonyl-L-Alanine 4-Methoxybenzyl Ester 3.6.3.3.6 Preparation of N-Benzyloxycarbonyl Phenylalanine p-Methylsulfinylbe 3.6.3.3.7 Preparation of N-Tritylglycine Diphenylmethyl Ester [136] 3.6.3.4 EXEMPLARY EXPERIMENTAL PROCEDURES FOR REMOVAL OF BENZYL PROTECTING GROUPS 3.6.3.4.1 Removal of 4-Methylsulfinylbenzyl Group [115] 3.6.3.4.2 Synthesis of N-Linked Glycopeptide-Ac-Asn(β-GlcNAc)-Gly- Ala-Tyr-Ser 3.6.3.4.3 Deprotection of Diphenylmethyl Group by Trifluoroacetic Acid [136] 3.6.3.4.4 Deprotection of Diphenylmethyl Group by Hydrogen Bromide in Nitrome 3.6.3.4.5 Removal of Diphenylmethyl Group via Hydrogenolysis [136] 3.7 THE ARYL PROTECTING GROUPS 3.7.1 EXEMPLARY EXPERIMENTAL PROCEDURES FOR THE PREPARATION OF AMINO ACID ARY 3.8 ORTHOESTER PROTECTING GROUPS 3.8.1 EXEMPLARY EXPERIMENTAL PROCEDURES FOR THE PREPARATION OF AMINO ACID ORT 3.8.2 EXEMPLARY EXPERIMENTAL PROCEDURES FOR REMOVAL OF THE ORTHOESTER GROUP 3.9 p-AZOBENZENECARBOXAMIDOMETHYL (OABC) PROTECTING GROUP 3.9.1 GENERAL PROCEDURE FOR THE PREPARATION OF AMINO ACID OABC ESTER 3.9.2 REMOVAL OF THE OABC PROTECTING GROUP 3.10 HYDRAZINE PROTECTING GROUP 3.10.1 EXEMPLARY EXPERIMENTAL PROCEDURES FOR THE PREPARATION OF AMINO ACID HY 3.10.2 EXEMPLARY EXPERIMENTAL PROCEDURES FOR REMOVAL OF HYDRAZINE PROTECTING 3.11 5,6-DIHYDROPHENANTHRIDINE PROTECTING GROUP 3.11.1 PREPARATION OF 4-PHENYLBUTYRIC ACID 5,6-DIHYDROPHENANTHRIDINE AMIDE [1 3.11.2 DEPROTECTION OF 5,6-DIHYDROPHENANTHRIDINE AMIDE [196] 3.12 OXAZOLINE, OXAZOLIDINE, 5,6-DIHYDRO-1,3-OXAZINE AND BOROXAZOLIDONE PROTECTING GROUPS 3.12.1 EXEMPLARY EXPERIMENTAL PROCEDURES FOR THE INTRODUCTION OF PROTECTING G 3.12.2 EXEMPLARY EXPERIMENTAL PROCEDURES FOR REMOVAL OF PROTECTING GROUP 3.13 TRANSIENT OR TEMPORARY PROTECTION OF CARBOXYL GROUP 3.13.1 EXEMPLARY EXPERIMENTAL PROCEDURES FOR INTRODUCTION OF TRANSIENT CARBOX Keywords References 4. Amino Protecting Groups 4.1 INTRODUCTION ON AMINO PROTECTING GROUPS 4.2 ACID-LABILE AMINO PROTECTING GROUPS 4.2.1 tert-BUTOXYLCARBONYL (t-BOC) GROUP 4.2.1.1 EXEMPLARY EXPERIMENTAL PROCEDURES FOR THE INTRODUCTION OF N-BOC GROUP 4.2.1.1.1 Preparation of Nα-Boc-γ-(p-Bromobenzyl)Glutamic Acid 4.2.1.1.2 Preparation of N-Boc Thiozolidine from tert- Butoxycarbonyl Chlorofo 4.2.1.1.3 Preparation of N-(tert-Butoxycarbonyl)-L-Alanine from Mixed Carbona 4.2.1.2 EXEMPLARY EXPERIMENTAL PROCEDURES FOR THE REMOVAL OF THE BOC GROUP 4.2.1.2.1 General Procedure for the Deprotection of the Boc Group 4.2.1.2.2 Deprotection of N-Boc-Leu-O-TAGc [17] 4.2.2 1-(1-ADAMANTYL)-1-METHYLETHOXYCARBONYL (ADPOC) GROUP 4.2.2.1 EXEMPLARY EXPERIMENTAL PROCEDURES FOR THE PROTECTION OF AMINO ACIDS WITH THE ADPOC GROUP 4.2.2.1.1 Preparation of 2-((3R,5R,7R)-Adamantan-1-yl)Propan-2- yl Carbonofluo 4.2.2.1.3 Preparation of 2-((3R,5R,7R)-Adamantan-1-yl)Propan-2- yl Phenyl Carb 4.2.2.1.2 Preparation of Adpoc-Amino Acid (Glycine as an Example) 4.2.2.1.4 Preparation of Adpoc-Amino Acid (Glycine as an Example) [23] 4.2.3 1-ADAMANTYLOXYCARBONYL (ADOC) GROUP 4.2.3.1.1 Preparation of 1-Adamantyl Chloroformate [24] 4.2.3.1.2 Preparation of 1-Adamantyloxycarbonyl Amino Acids (General Procedur 4.2.3.1.3 Preparation of Adamantyloxycarbonyl-D-Tryptophan [25] 4.2.3.1.4 General Procedure for the Preparation of Nα-Adoc-Amino Acid Benzyl 4.2.3.2.1 Partial Deprotection of Adoc2-Tyr(Adoc)-OBzl [24] 4.2.4 tert-AMYLOXYCARBONYL (t-AMOC) GROUP 4.2.4.1.1 General Procedure for the Preparation of N-tert- Amyloxycarbonyl Ami 4.2.4.1.2 Preparation of N-tert-Amyloxycarbonyl Leucine [27] 4.2.4.1.3 Preparation of N-tert-Amyloxycarbonyl Glycine [36] 4.2.4.1.4 Preparation of N-tert-Amyloxycarbonyl Glycine [31] 4.2.5 [1-(3,5-DI-TERT-BUTYLPHENYL)-1-METHYLETHOXY] CARBONYL (T-BUMEOC) GROUP 4.2.5.1.1 Preparation of 3,5-Di-tert-Butylbenzoic Acid [40] 4.2.5.1.2 Preparation of 2-(3,5-di-tert-Butylphenyl)-2-propanol [40] 4.2.5.1.3 Preparation of [1-(3,5-di-tert-Butylphenyl)-1- Methylethyl] Fluorofo 4.2.5.1.4 Preparation of [1-(3,5-di-tert-Butylphenyl)-1- Methylethyl] Phenyl C 4.2.5.1.5 General Procedure for the Preparation of t-Bumeoc- Amino Acid [40] 4.2.6 2-ADAMANTYLOXYCARBONYL (2-ADOC) GROUP 4.2.6.1.1 Preparation of N-(2-Adamantyloxycarbonyl)-2-[9- (Methylsulfonyl)-β-C 4.2.6.1.2 Preparation of α-Methyl-N-[(Tricyclo[3.3.1.13,7]dec-2- yloxy)Carbony 4.2.6.1.3 Preparation of H-Tyr(2-Adoc)-OH [47] 4.2.6.1.4 Preparation of Z-His(2-Adoc)-OH [48] 4.2.6.1.5 Preparation of 2-(Adamantyloxycarbonyl)Amino-3-indol- 1-yl-2-Methyl 4.2.7 ISOBORNYLOXYCARBONYL (IBOC) GROUP 4.2.7.1.1 Preparation of N-Isobornyloxycarbonyl-D-p- Chlorophenylalanine Isopr 4.2.7.1.2 Preparation of DL-Isobornyl Chloroformate [53] 4.2.7.1.3 General Procedure for the Preparation of Isobornyloxycarbonylamino 4.2.7.1.4 NaHCO3 Procedure to Prepare D-Isobornyloxycarbonyl-L Aspargine [53] 4.2.7.2.1 Acidolysis of N-Isobornyloxycarbonyl Glycine with 20% HBr in Acetic 4.2.7.2.2 Acidolysis of N-Isobornyloxycarbonyl Glycine with TFA [53] 4.2.8 TRIPHENYLMETHYL (TRT) GROUP AND ITS ANALOGOUS GROUPS 4.2.8.1.1 Preparation of N-Trityl-Glycine Methyl Ester [61] 4.2.8.1.2 Preparation of N-Trityl-Threonine [57] 4.2.8.1.3 Preparation of N-Trityl-Amino Acid Through Metallic Pertritylation 4.2.8.1.4 General Procedure to Prepare N-Trityl α-Amino Acids with Triphenylm 4.2.8.1.5 Preparation of L-Nα-(4-Monomethoxytrityl)-β -[Thymin- 1-yl]Alanine [ 4.2.8.2.1 Detritylation of N-Trityl-Glycine Ethyl Ester [61] 4.2.8.2.2 N-Detritylation of Tr-Gly-OH in Aprotic Solvent Catalyzed by Metall 4.2.9 MISCELLANEOUS ACID LABILE AMINO PROTECTING GROUPS 4.2.9.1.1 Preparation of 1,1-Dimethyl-2-Methacrylmethanamido- 2-Ethyl-(4-Nitro 4.2.9.1.2 Preparation of N-(1,1-Dimethyl-2-Methacrylmethanamido-Ethoxycarbonyl)-L Phenylalanine Methyl Ester 4.2.9.2.1 Preparation of Cyclohexyldithiocarbonyl Chloride 4.2.9.2.2 Preparation of Alkyldithiocarbonyl Amino Acids (Method A) 4.2.9.2.3 Preparation of Alkyldithiocarbonyl Amino Acids (Method B) 4.3 ALKALI-LABILE AMINO PROTECTING GROUPS 4.3.1 FLUORENYLMETHOXYCARBONYL (FMOC) GROUP 4.3.1.1.1 Preparation of 9-Fluorenylmethyl Chloroformate [75] 4.3.1.1.2 Preparation of 9-Fluorenylmethyl Azidoformate [75] 4.3.1.1.3 Preparation of N-Fmoc-1H-Benzotriazole [85] 4.3.1.2.1 Preparation of 9-Fluorenylmethoxycarbonylglycine from Fmoc-Cl [75] 4.3.1.2.2 Synthesis of N-Fmoc-L-Cysteine [85] 4.3.1.2.3 Preparation of (2S,3S)-2-N-(9H-Fluorenylmethoxy) Carbonylamino-4-(Be 4.3.1.2.4 Synthesis of 3,4;5,6-di-O-Isopropylidene-2-Deoxy-2- (Fmoc-Amino)-D-M 4.3.1.3.1 Liquid Ammonia Cleavage of 4.3.1.3.2 Cleavage of Fmoc by DABCO to Prepare (3-Clicylamino-2- Methyleneprop 4.3.1.3.4 Deprotection of Fmoc-Gly-Pz(H)-OEt by 20% Piperidine in DMF [93] 4.3.1.3.3 Deprotection of Fmoc with DBU for the Preparation of Peptide H-Gly- 4.3.2 METHYLSULFONYLETHYLOXYCARBONYL (MSC) GROUP 4.3.2.1.1 Preparation of Methylsulfonylethyloxycarbonyl Chloride (Msc-Cl) [95 4.3.2.1.2 Preparation of Methylsulfonylethyl p-Nitrophenyl Carbonate (Msc-ONp 4.3.2.1.3 Preparation of Methylsulfonylethyl Succinimido Carbonate (Msc-OSu) 4.3.2.1.4 Preparation of Methylsulfonylethyloxycarbonyl Azide (Msc-N3) [95] 4.3.2.2.1 General Procedure for the Preparation of Methylsulfonylethyloxy-Car 4.3.2.2.2 Preparation of Nε-Methylsulfonylethyloxycarbonyl-L Lysine [95] 4.3.2.3.1 Deprotection of Msc-Protected Amines, Solvent Composition [95] 4.3.2.2.3 Preparation of Methylsulfonylethyloxycarbonyl (Msc)- Octadeuterophen 4.3.2.3.2 Deprotection of Methylsulfonylethyloxycarbonyl-L Phenylalanyl-L-Argi 4.3.3 2-CHLORO-3-INDENYLMETHYLOXYCARBONYL (CLIMOC) AND BENZ[F]INDEN-3-YLMETHY 4.3.3.1.1 Preparation of (2-Chloroinden-3-yl)Methyl Chloroformate [103] 4.3.3.1.2 Preparation of (2-Chloroinden-3-y1)Methyl Succinimido Carbonate [10 4.3.3.1.3 Preparation of Benz[f]Inden-3-Ylmethyl Chloroformate [103] 4.3.3.1.4 Preparation of Benz[f]Inden-3-Ylmethyl Azidoformate [103] 4.3.3.2.1 Preparation of N-(2-Chloroinden-3- 4.3.3.2.2 Preparation of N-(Benz[f]Inden-3-Ylmethyloxycarbonyl) Phenylalanine 4.3.4 BENZOTHIOPHENESULFONE-2-METHYLOXYCARBONYL (BSMOC), 2-TERT-BUTYLSULFONYL 4.3.4.1.1 Preparation of Benzo[b]Thiophen-2-Methanol [104] 4.3.4.1.2 Preparation of Benzothiophenesulfone-2-Methanol [104] 4.3.4.1.4 Preparation of N-(Benzothiophenesulfone-2-Methyl)-N Succinimidyl Car 4.3.4.1.3 Preparation of Benzothiophenesulfone-2-Methyl Chloroformate (Bsmoc- 4.3.4.1.5 Preparation of (E)-3-(Methylsulfonyl)-3-Phenyl-2- Propenyl Alcohol [ 4.3.4.1.6 Preparation of (E)-2-(Methylsulfonyl)-3-Phenyl-2- Propenyl Chlorofor 4.3.4.1.7 Preparation of N-[(E)-2-(Methylsulfonyl)-3-Phenyl-2- Propenyloxy-Car 4.3.4.2.1 General Procedures for the Preparation of Benzothiophenesulfone-2-M 4.3.4.2.2 Preparation of Bsmoc-Protected Amino Acids via Bsmoc-Osu in Acetoni 4.3.4.2.3 Preparation of Bsmoc-Protected Amino Acids via Bsmoc- OSu in Acetone 4.3.4.2.4 Preparation of Mspoc-Phenylalanine from Mspoc-OSu [105] 4.3.4.2.5 Preparation of tert-Butyl N-(2-(tert-Butylsulfonyl)-2- Propenyl)Phen 4.3.5 (9H-FLUOREN-9-YL)METHANESULFONYL GROUP 4.3.6 2-(4-NITROPHENYL)SULFONYLETHOXYCARBONYL (NSC) AND 2-(4-NITROPHENYLTHIO) 4.3.7 MISCELLANEOUS BASE-LABILE AMINO PROTECTING GROUPS 4.4 PROTECTING GROUPS REMOVABLE BY HYDROGENOLYSIS 4.4.1 BENZYLOXYCARBONYL (CBZ, BZ OR Z) GROUP 4.4.1.1.1 Preparation of Dibenzyl Dicarbonate [133] 4.4.1.1.2 Preparation of Dibenzyl Dicarbonate [137] 4.4.1.1.3 Preparation of 1-Benzyloxycarbonyl Benzotriazole [133] 4.4.1.2.1 Preparation of N-Benzyloxycarbonyl-L-Threonine [141] 4.4.1.2.2 Preparation of N-Benzyloxycarbonyl Tryptophan with Dibenzyl Dicarbo 4.4.1.2.3 Preparation of N-Benzyloxycarbonyl-L-Alanine with 1-Benzyloxycarbon 4.4.1.2.4 Catalytic Preparation of N-Benzyloxycarbonyl- Tryptophan [138] 4.4.1.3.1 Synthesis of Poly(ε-Caprolactone) (PCL)-(CH2)6-NH2 [139] 4.4.1.3.2 Deprotection of Cbz Group via Hydrogenation [142] 4.4.1.3.3 Deprotection of Cbz Group via Hydrogenation Over Pd(OH)2 [143] 4.4.1.3.4 Deprotection of Cbz-Protected Methionine [140] 4.4.2 p-NITROBENZYLOXYCARBONYL (PNZ) GROUP 4.4.3 4,5-DIARYL-4-OXAZOIN-2-ONE DERIVATIVE OF AMINO ACIDS 4.4.4 ISONICOTINYLOXYCARBONYL (INOC) PROTECTING GROUP 4.4.4.1.1 Method 1 4.4.4.1.2 Method 2 4.4.4.1.3 Preparation of ε-iNoc-Lys [128] 4.4.4.1.4 Removal of iNoc by Hydrogenation [128] 4.4.5 p-TRIMETHYLAMMONIUM CHLORIDOBENZYLOXYCARBONYL PROTECTING GROUP 4.5 THIOLYSIS CLEAVABLE AMINO PROTECTING GROUP 4.5.1 N-DITHIASUCCINOYL (DTS) AND (ALKYLDITHIO)CARBONYL GROUPS 4.5.1.1.1 Preparation of N-[2-(N-Ethoxythiocarbonyl)Aminoethyl]-N- [[6-N-(Benz 4.5.1.1.2 Formation of N-[2-(N-Dithiasuccinoyl)Aminoethyl]-N-[[6- N-(Benzyloxy 4.5.1.1.3 Preparation of 1,3,4,6-Tetra-O-Acetyl-2-Deoxy- 2-Dithiasuccinimido-α 4.5.1.1.4 Preparation of (Butyldithio)Carbonyl-Alanine [69] 4.5.1.2.1 Thiolysis of Dts-Glycine to β-Hydroxyethyldithiocarbonyl glycine [14 4.5.2 O-NITROPHENYLSULFENYL GROUP 4.6 HYDRAZINE LABILE AMINO PROTECTING GROUP 4.6.1 PREPARATION OF C(DAP-TCP-GLN) [158] Keywords References 5. Side Chain Protecting Groups 5.1 INTRODUCTION 5.2 HYDROXYL PROTECTING GROUPS FOR SERINE, THREONINE, TYROSINE, AND HYDROXYPROLINE 5.2.1 PROTECTION OF HYDROXY GROUP BY ETHERS 5.2.1.1.1 Preparation of tert-Butyl N-Benzyloxycarbonyl-O-(tert- Butyl)Serinat 5.2.1.2.1 Preparation of N-tert-Butyloxycarbonyl-O-Benzyl-L Serine Cyclohexyla 5.2.1.3.1 Preparation of N-(p-Methoxybenzyloxycarbonyl)-O-(2.2.2-Trifluoro-1-Benzyloxycarbonylaminoethyl)-L Serine [17] 5.2.1.4.1 Preparation of O-(Cyclohexyl)-L-Tyrosine [14] 5.2.1.4.2 Preparation of Boc-Ser(cHex)-OH⋅CHA [16] 5.2.2 PROTECTION OF HYDROXY GROUP BY SILYL ETHERS 5.2.3 PROTECTION OF HYDROXY GROUP BY ACETALS 5.2.4 PROTECTION OF HYDROXY GROUP BY ESTERS 5.2.5 PROTECTION OF HYDROXY GROUP BY CARBONATES 5.3 AMINO PROTECTING GROUPS FOR LYSINE 5.3.1 EXAMPLES OF PROTECTING LYSINE SIDE CHAIN 5.3.1.2.1 Preparation of (1R,4’S,5S)-4’-(4-Aminobutyl)- 9λ4-Boraspiro[Bicyclo[ 5.3.1.2.2 Preparation of Nε-Benzyloxycarbonyl-L-Lysine 5.3.1.3.1 Formation of 9-BBN-L-Lysine Complex 5.3.1.3.3 Decomposition of the 9-BBN-L-Lysine Complex (Method B) 5.3.1.3.2 Decomposition of the 9-BBN-L-Lysine Complex (Method A) 5.3.1.4.1 Preparation of Nε-Fmoc-L-Lysine Cu(II) Complex 5.3.1.4.2 Preparation of Nε-Fmoc-L-Lysine 5.4 PROTECTING GROUPS FOR ARGININE 5.4.1 PROTECTION OF ARGININE WITH NITRO GROUP AND ITS DEPROTECTION [127] 5.4.1.2.1 Reduction of N-Nitro-L-Arginine in Boiling Water 5.4.1.2.2 Reduction of N-Nitro-L-Arginine in Warm Water 5.4.2 PREPARATION OF Nω-2,4,6-TRIMETHOXYBENZENESULFONYL L-ARGININE (H-ARG(MTB) 5.4.3 PREPARATION OF H-ARG(MIS)-OH [108] 5.5 PROTECTING GROUPS FOR HISTIDINE 5.5.1 EXEMPLARY PROCEDURES TO PROTECT HISTIDINE SIDE CHAIN 5.6 PROTECTING GROUPS FOR ASPARAGINE AND GLUTAMINE 5.6.1 EXEMPLARY PROCEDURES TO PROTECT ASPARAGINE AND GLUTAMINE SIDE CHAINS 5.6.1.3.1 Preparation of Benzyl N2-(Benzyloxycarbonyl)-N4- ((2,2,4,6,7-Pentame 5.6.1.3.2 Preparation of Nω-(2,2,4,6,7-Pentamethyl-2,3- Dihydrobenzofuran-5-yl 5.6.1.3.3 Preparation of Nα-(9-Fluorenylmethoxycarbonyl)-Nω- (2,2,4,6,7-Pentam 5.7 PROTECTING GROUPS FOR ASPARTIC ACID AND GLUTAMIC ACID 5.7.1 EXEMPLARY PROCEDURES TO PROTECT ASPARTIC ACID AND GLUTAMIC ACID SIDE CH 5.7.1.2.1 Preparation of N-Benzyloxycarbonyl-L-Glutamic Acid [264] 5.7.1.2.2 Preparation of Benzyl N-Benzyloxycarbonyl-L-Glutamate [264] 5.7.1.2.3 Preparation of Benzyl N-Benzyloxycarbonyl-ω- Cycloheptyl-Glutamate [ 5.7.1.2.4 Preparation of ω-Cycloheptyl-L-Glutamate [240] 5.8 PROTECTING GROUPS FOR CYSTEINE AND SELENOCYSTEINE 5.8.1 EXEMPLARY PROCEDURES TO PROTECT CYSTEINE AND SELENOCYSTEINE SIDE CHAINS 5.8.1.2.1 Preparation of (2R,2’R)-3,3’-Diselanediylbis(2- Aminopropanoic Acid) 5.8.1.2.2 Preparation of Se-p-Methoxybenzyl-L-Selenocysteine [362] 5.9 PROTECTING GROUPS FOR TRYPTOPHAN 5.9.1 EXEMPLARY PROCEDURES TO PROTECT TRYPTOPHAN SIDE CHAIN 5.9.1.2.1 Preparation of Benzyl 1-Tosyl-Nα-Trityl-Tryptophanate 5.9.1.2.2 Preparation of 1-Tosyl-L-Tryptophan 5.9.1.3.1 Preparation of N-(4-Methoxybenzyloxycarbonyl)-Nin- Mesitylenesulfony 5.9.1.3.2 Preparation of Nin-Mesitylenesulfonyl-L-Tryptophan (H-Trp(Mts)-OH) 5.10 PROTECTING GROUPS FOR METHIONINE 5.10.1 EXEMPLARY PROCEDURES TO PROTECT METHIONINE SIDE CHAIN Keywords References Index This is the first volume of a first-of-its-kind four-volume book set that provides readers with up-to-date information on α-amino acids, the potential challenges in working with α-amino acids, the protecting groups for the carboxyl, amino and side chain groups of the amino acids, and the most popular heterocyclic compounds that are originating from α-amino acids. These heterocyclic compounds include hydantoins, thiohydantoins (including 2-thiohydantoins, 4-thiohydantoins, 2,4-dithiohydantoins), 2,5-diketopiperazines, N-carboxyanhydrides, N-thiocarboxyanhydrides, sydnones, sydnonimines, azlactones, pseudoazlactones, and oxazolidin-5-ones. This is the first resource to comprehensively collect all the heterocycles that can be directly prepared from α-amino acids. In addition, almost all kinds of synthetic methods for a particular type of heterocycles from α-amino acids are included, along with the detailed mechanistic discussions and experimental procedures. Volume 1: Protecting Groups collects and discusses the 260 protecting groups relating to amino acids, which have been organized by carboxyl group, amino group, and side chain group. The conditions to introduce these protecting groups as well as their deprotecting procedures have also been incorporated, along with the physical properties, solvent effects, and temperature effects on the solubility of amino acids. It presents the solubility of glycine and phenylalanine in a variety of solvent systems to show the impact on amino acid, where glycine generally represents the polar amino acid whereas phenylalanine represents the amino acid of non-polar side chain. The other volumes include: Volume 2: Hydantoins, Thiohydantoins, and 2,5-Diketopiperazines Volume 3: N-Carboxyanhydrides, N-Thiocarboxyanhydrides, and Sydnones Volume 4: Azlactones and Oxazolidin-5-ones All together, this unique 4-volume set thoroughly covers the two types of heterocyclic compounds that are originated from alpha-amino acids, providing carefully compiled updated information with detailed examples. The author has shared many thoughtful insights based on his strong background in physical organic chemistry. The volumes will be highly valuable for graduate students and senior students, as well as for professors and researchers working in the field of medicinal and pharmaceutical chemistry, organic chemistry, organic synthesis, heterocycles, and proteins and peptides.