α‐Amino Acid‐Isosteric α‐Amino Tetrazoles

The synthesis of all 20 common natural proteinogenic and 4 otherα‐amino acid‐isosteric α‐amino tetrazoles has been accomplished, whereby the carboxyl group is replaced by the isosteric 5‐tetrazolyl group. The short process involves the use of the key Ugi tetrazole reaction followed by deprotection chemistries. The tetrazole group is bioisosteric to the carboxylic acid and is widely used in medicinal chemistry and drug design. Surprisingly, several of the common α‐amino acid‐isosteric α‐amino tetrazoles are unknown up to now. Therefore a rapid synthetic access to this compound class and non‐natural derivatives is of high interest to advance the field.     

β‐Amino Alcohol Properfumes

Amino‐alcohol derivatives of fragrant, volatile aldehydes and ketones were synthesized in a one‐pot procedure by sequential cyanohydrin formation with trimethylsilyl cyanide and reduction with lithium aluminium hydride, or by ammonolysis of epoxide precursors. The amino alcohols are nonvolatile, stable properfumes releasing fragrant carbonyls by oxidation with sodium periodate or sodium bismuthate. Examples include amino alcohol properfumes of citronellal, Lilial^®, lauryl aldehyde, menthone, benzaldehyde, and anisaldehyde.     

Dye‐Labeled Cα‐Tetrasubstituted α‐Amino Acids

We report the synthesis of pyrene‐ and carboxyfluorescein labeled C^α‐tetrasubstituted amino acids (TAAs). The fluorescent dye can be coupled to the TAA before or after its incorporation into a peptide sequence using a Suzuki‐type C? C bond formation.     

Asymmetric and Geometry‐Selective α‐Alkenylation of α‐Amino Acids

Both E‐ and Z‐N′‐alkenyl urea derivatives of imidazolidinones may be formed selectively from enantiopure α‐amino acids. Generation of their enolate derivatives in the presence of K⁺ and [18]crown‐6 induces intramolecular migration of the alkenyl group from N′ to Cα with retention of double bond geometry. DFT calculations indicate a partially concerted substitution mechanism. Hydrolysis of the enantiopure products under acid conditions reveals quaternary α‐alkenyl amino acids with stereodivergent control of both absolute configuration and double bond geometry.     

Pseudoephedrine‐Directed Asymmetric α‐Arylation of α‐Amino Acid Derivatives

Available α‐amino acids undergo arylation at their α position in an enantioselective manner on treatment with base of N′‐aryl urea derivatives ligated to pseudoephedrine as a chiral auxiliary. In situ silylation and enolization induces diastereoselective migration of the N′‐aryl group to the α position of the amino acid, followed by ring closure to a hydantoin with concomitant explulsion of the recyclable auxiliary. The hydrolysis of the hydantoin products provides derivatives of quaternary amino acids. The arylation avoids the use of heavy‐metal additives, and is successful with a range of amino acids and with aryl rings of varying electronic character.     

Palladium‐Catalyzed Insertion of α‐Diazoesters into Vinyl Halides To Generate α,β‐Unsaturated γ‐Amino Esters

As easy as 1, 2, 3 : A palladium‐catalyzed three‐component coupling generates α,β‐unsaturated γ‐amino acids in a single step (see scheme). The reaction is believed to involve migration of a vinyl substituent to a highly electrophilic palladium carbene. Unlike previous synthetic approaches, this synthesis provides access to γ‐amino acids with non‐natural side chains.

     

Enantioselective Synthesis of α‐Hydroxy Amides and β‐Amino Alcohols from α‐Keto Amides

Synthesis of enantiomerically enriched α‐hydroxy amides and β‐amino alcohols has been accomplished by enantioselective reduction of α‐keto amides with hydrosilanes. A series of α‐keto amides were reduced in the presence of chiral Cu^II/(S)‐DTBM‐SEGPHOS catalyst to give the corresponding optically active α‐hydroxy amides with excellent enantioselectivities by using (EtO)₃SiH as a reducing agent. Furthermore, a one‐pot complete reduction of both ketone and amide groups of α‐keto amides has been achieved using the same chiral copper catalyst followed by tetra‐n‐butylammonium fluoride (TBAF) catalyst in presence of (EtO)₃SiH to afford the corresponding chiral β‐amino alcohol derivatives.     

β‐Hairpins Generated from Hybrid Peptide Sequences Containing both α‐ and β‐Amino Acids

The incorporation of the β‐amino acid residues into specific positions in the strands and β‐turn segments of peptide hairpins is being systematically explored. The presence of an additional torsion variable about the C(α) C(β) bond (θ) enhances the conformational repertoire in β‐residues. The conformational analysis of three designed peptide hairpins composed of α/β‐hybrid segments is described: Boc‐Leu‐Val‐Val‐^DPro‐β Phe ‐Leu‐Val‐Val‐OMe ( 1 ), Boc‐Leu‐Val‐β Val ‐^DPro‐Gly‐β Leu ‐Val‐Val‐OMe ( 2 ), and Boc‐Leu‐Val‐β Phe ‐Val‐^DPro‐Gly‐Leu‐β Phe ‐Val‐Val‐OMe ( 3 ). 500‐MHz ¹H‐NMR Analysis supports a preponderance of β‐hairpin conformation in solution for all three peptides, with critical cross‐strand NOEs providing evidence for the proposed structures. The crystal structure of peptide 2 reveals a β‐hairpin conformation with two β‐residues occupying facing, non‐H‐bonded positions in antiparallel β‐strands. Notably, βVal(3) adopts a gauche conformation about the C(α) C(β) bond (θ=+65°) without disturbing cross‐strand H‐bonding. The crystal structure of 2 , together with previously published crystal structures of peptides 3 and Boc‐β Phe ‐β Phe ‐^DPro‐Gly‐β Phe ‐β Phe ‐OMe, provide an opportunity to visualize the packing of peptide sheets with local ‘polar segments' formed as a consequence of reversal peptide‐bond orientation. The available structural evidence for hairpins suggests that β‐residues can be accommodated into nucleating turn segments and into both the H‐bonding and non‐H‐bonding positions on the strands.     

Organocatalytic Enantioselective Synthesis of Tetrasubstituted α‐Amino Allenoates by Dearomative γ‐Addition of 2,3‐Disubstituted Indoles to β,γ‐Alkynyl‐α‐imino Esters

The first asymmetric synthesis of tetrasubstituted α‐amino allenoates by a chiral phosphoric acid catalyzed dearomative γ‐addition reaction of 2,3‐disubstituted indoles to β,γ‐alkynyl‐α‐imino esters is reported. This method provides access to a series of highly functionalized tetrasubstituted allenes featuring quaternary stereocenters in high yields, and with excellent regio‐, diastereo‐, and enantioselectivities under mild conditions without by‐product formation. Representative large‐scale reactions and diverse transformations of the products into various scaffolds with potential biological activities render are also disclosed. The mechanism of the reaction was elucidated by control reactions and DFT calculations.     

Arrangement of Proteinogenic α‐Amino Acids on a Cyclic Peptide Comprising Alternate Biphenyl‐Cored ζ‐Amino Acids

Aiming at precisely arranging several proteinogenic α‐amino acids on a folded scaffold, we have developed a cyclic hexapeptide comprising an alternate sequence of biphenyl‐cored ζ‐amino acids and proteinogenic α‐amino acids such as l ‐leucine. The amino acids were connected by typical peptide synthesis, and the resultant linear hexapeptide was intramolecularly cyclized to form a target cyclic peptide. Theoretical analyses and NMR spectroscopy suggested that the cyclic peptide was folded into an unsymmetrical conformation, and the structure was likely to be flexible in CHCl₃. The optical properties including UV/Vis absorption, fluorescence, and circular dichroism (CD) were also evaluated. Furthermore, the cyclic peptide became soluble in water by introducing three carboxylate groups at the periphery of the cyclic skeleton. This α/ζ‐alternating cyclic peptide is therefore expected to serve as a unique scaffold for arranging several functionalities.     

A Study on the Diastereoselective Synthesis of α‐Fluorinated β3‐Amino Acids by α‐Fluorination

The treatment of a β³‐amino acid methyl ester with 2.2 equiv. of lithium diisopropylamide (LDA), followed by reaction with 5 equiv. of N‐fluorobenzenesulfonimide (NFSI) at ?78° for 2.5 h and then 2 h at 0°, gives syn‐fluorination with high diastereoisomeric excess (de). The de and yield in these reactions are somewhat influenced by both the size of the amino acid side chain and the nature of the amine protecting group. In particular, fluorination of N‐Boc‐protected β³‐homophenylalanine, β³‐homoleucine, β³‐homovaline, and β³‐homoalanine methyl esters, 5 and 9 – 11 , respectively, all proceeded with high de (>86% of the syn‐isomer). However, fluorination of N‐Boc‐protected β³‐homophenylglycine methyl ester ( 16 ) occurred with a significantly reduced de. The use of a Cbz or Bz amine‐protecting group (see 3 and 15 ) did not improve the de of fluorination. However, an N‐Ac protecting group (see 17 ) gave a reduced de of 26%. Thus, a large N‐protecting group should be employed in order to maximize selectivity for the syn‐isomer in these fluorination reactions.     

Enantioselective Rhodium‐Catalyzed Allylic Alkylation of β,γ‐Unsaturated α‐Amino Nitriles: Synthetic Homoenolate Equivalents

An enantioselective rhodium‐catalyzed allylic alkylation of β,γ‐unsaturated α‐amino nitriles is described. This protocol provides a novel approach for the construction of β‐stereogenic carbonyl derivatives via the catalytic asymmetric alkylation of a homoenolate equivalent. The particularly challenging nature of this transformation is highlighted by the fact that three modes of selectivity must be manipulated, namely regio‐ and enantioselectivity, in addition to geometrical control. The γ‐stereogenic cyanoenamine products can be readily hydrolyzed in situ to afford the β‐substituted carboxylic acids, which in turn provide expedient access to a number of related carbonyl derivatives. Additionally, control experiments indicate that the chiral rhodium‐allyl intermediate facilitates the selective formation of the E‐cyanoenamine products, which is critical since the Z‐isomer affords significantly lower enantiocontrol.