Design and synthesis of chiral alpha,alpha-disubstituted amino acids and conformational study of their oligopeptides

alpha,alpha-Disubstituted amino acids are alpha-amino acids in which the hydrogen atom at the alpha-position of the L-alpha-amino acid is replaced with an alkyl substituent. The introduction of an alpha-alkyl substituent changes the properties of amino acids, with the conformational freedom of the side chain in the amino acids and the secondary structure of their peptides being especially restricted. The author developed a synthetic route of optically active alpha-ethylated alpha,alpha-disubstituted amino acids using chiral cyclic 1,2-diol as a chiral auxiliary. It was found that the preferred secondary structure of peptides composed of chiral alpha-ethylated alpha,alpha-disubstituted amino acids is a fully extended C5-conformation, whereas that of peptides composed of chiral alpha-methylated alpha,alpha-disubstituted amino acids is a 3(10)-helical structure. Also, a new chiral cyclic amino acid; (3S,4S)-1-amino-3,4-di(methoxy)cyclopentanecarboxylic acid {(S,S)-Ac5c(dOM)}, and a bicyclic amino acid; (1R,6R)-8-aminobicyclo[4.3.0]non-3-ene-8-carboxylic acid {(R,R)-Ab5,6= c}, in which the alpha-carbon atom is not the chiral center but chiral centers exist at the side-chain cycloalkane skeleton, were designed and synthesized. The (S,S)-Ac5c(dOM) hexa- and octapeptides preferentially formed left-handed (M) helices, in which the helical-screw direction is exclusively controlled by the side-chain chiral centers. Contrary to the left-handed helices of (S,S)-Ac(5)c(dOM) peptides, the (R,R)-Ab5,6= c hexapeptide formed both diastereomeric right-handed (P) and left-handed (M) helices, and the twelve chiral centers at the side chain showed no preference for helical-screw direction. Thus, the chiral environment at the side chain is important for the control of helical-screw direction. Furthermore, the author designed a new class of chiral cyclic alpha,alpha-disubstituted amino acids that have pendant chiral centers at the substituent of the delta-nitrogen atom. The synthetic route would provide various optically-active cyclic alpha,alpha-disubstituted amino acids bearing a pendant chiral moiety.     

Practical synthesis of optically active alpha,alpha-disubstituted malonamic acids through asymmetric hydrolysis of malonamide derivatives with Rhodococcus sp. CGMCC 0497

A variety of alpha,alpha-disubstituted malonamides undergo enantioselective hydrolysis with Rhodococcus sp. CGMCC 0497 to give challenging enantiopure alpha,alpha-disubstituted malonamic acids with up to >99% enantiomeric excesses and 98% chemical yields. The enantioselectivity originated from the effects of a highly enantioselective amidase. The products could be converted to valuable (R)- or (S)-alpha,alpha-dialkylated amino acids after routine conversions.     

S(N)2 reaction of sulfur nucleophiles with hindered sulfamidates: enantioselective synthesis of alpha-methylisocysteine

The work described here demonstrates that the five-membered cyclic alpha-methylisoserine-derived sulfamidate, (R)-1, behaves as an excellent chiral building block for the ring-opening reaction by S(N)2 attack with sulfur nucleophiles at the quaternary carbon. As a synthetic application of this methodology, and to show that this sulfamidate is a valuable starting material, the synthesis of two new alpha-methylisocysteine derivatives has been carried out to cover the lack of alpha- and beta-methylated amino acids that incorporate the cysteine or isocysteine skeleton. These compounds are two new alpha,alpha-disubstituted beta-amino acids (beta(2,2)-amino acids), and the synthetic routes involve nucleophilic ring opening followed by acid hydrolysis.     

Three component coupling of alpha-iminoesters via umpolung addition of organometals: synthesis of alpha,alpha-disubstituted alpha-amino acids

The synthesis of alpha,alpha-disubstituted alpha-amino acids by means of a three component coupling is reported. The coupling occurs through umpolung addition of organometallic reagents to the nitrogen of alpha-iminoesters. The resulting enolate intermediates subsequently react with electrophiles (aldehydes, imines, alpha,beta-unsaturated nitro, alkyl halides, acyl cyanides) to form a quaternary center. Tethering of the electrophile and nucleophile components provides cyclic alpha,alpha-disubstituted alpha-amino acid derivatives.     

An extended planar C5 conformation and a 310-helical structure of peptide foldamer composed of diverse alpha-ethylated alpha,alpha-disubstituted alpha-amino acids

Optically active peptide foldamers Tfa-[(S)-(alphaEt)Leu]-[(S)-(alphaEt)Nva]-Deg-[(S)-(alphaEt)Nle]-OEt (10) and Tfa-[(S)-(alphaEt)Val]-[(S)-(alphaEt)Leu]-[(S)-(alphaEt)Nva]-Deg-[(S)-(alphaEt)Nle]-OEt (11) composed of diverse alpha-ethylated alpha,alpha-disubstituted alpha-amino acids were synthesized. The dominant conformation of these peptides in solution was an unusual, fully extended planar conformation, and that in the crystal state was both right-handed (P) and left-handed (M) 3(10)-helical structures in 10 and a P 3(10)-helical structure in 11, respectively. The preferred planar C(5) conformation of the peptides prepared from chiral alpha-ethylated alpha,alpha-disubstituted alpha-amino acids was drastically different from the 3(10)-helical structure of the peptides prepared from chiral alpha-methylated alpha,alpha-disubstituted alpha-amino acids.     

Phenylglycine methyl ester, a useful tool for absolute configuration determination of various chiral carboxylic acids

A new chiral anisotropic reagent, phenylglycine methyl ester (PGME), developed for the elucidation of the absolute configuration of chiral alpha,alpha-disubstituted acetic acids, has turned out to be applicable to other substituted carboxylic acids, such as chiral alpha-hydroxy-, alpha-alkoxy-, and alpha-acyloxy-alpha, alpha-disubstituted acetic acids, as well as to chiral beta, beta-disubstituted propionic acids. Because a carboxylic moiety is convertible from other functional groups, e.g., ozonolysis of an olefin and oxidative cleavage of a glycol, the present findings can expand the utility of the PGME method to the absolute configuration determination of various types of organic compounds, even those which initially lack oxygen functions. Several examples of the combination of chemical reactions and the PGME method are described.     

Stereocontrolled alkylative construction of quaternary carbon centers

Protocols for the stereodefined formation of alpha,alpha-disubstituted enolates of pseudoephedrine amides are presented followed by the implementation of these in diastereoselective alkylation reactions. Direct alkylation of alpha,alpha-disubstituted pseudoephedrine amide substrates is demonstrated to be both efficient and diastereoselective across a range of substrates, as exemplified by alkylation of the diastereomeric pseudoephedrine alpha-methylbutyramides, where both substrates are found to undergo stereospecific replacement of the alpha-C-H bond with alpha-C-alkyl, with retention of stereochemistry. This is shown to arise by sequential stereospecific enolization and alkylation reactions, with the alkyl halide attacking a common pi-face of the E- and Z-enolates, proposed to be opposite the pseudoephedrine alkoxide side chain. Pseudoephedrine alpha-phenylbutyramides are found to undergo highly stereoselective but not stereospecific alpha-alkylation reactions, which evidence suggests is due to facile enolate isomerization. Also, we show that alpha,alpha-disubstituted pseudoephedrine amide enolates can be generated in a highly stereocontrolled fashion by conjugate addition of an alkyllithium reagent to the s-cis-conformer of an alpha-alkyl-alpha,beta-unsaturated pseudoephedrine amide, providing alpha,alpha-disubstituted enolate substrates that undergo alkylation in the same sense as those formed by direct deprotonation. Methods are presented to transform the alpha-quaternary pseudoephedrine amide products into optically active carboxylic acids, ketones, primary alcohols, and aldehydes.     

Sulfamidation of 2-arylaldehydes and ketones with chloramine-T

[reaction: see text] A series of aliphatic and aromatic carbonyl compounds has been transformed into the corresponding sulfamidated products by means of amine-catalyzed nitrene transfer of chloramine-T. Depending on the residues R, either alpha-sulfamidation in the case of aromatic aldehydes and acetone derivatives or direct sulfamidation at the carbonyl functionality of aliphatic aldehydes has been observed. Applying microwave conditions, good to excellent yields under significantly reduced reaction times could be obtained, thus providing a facile access to alpha,alpha-disubstituted amino acids.     

Asymmetric synthesis of alpha,alpha-disubstituted alpha-amino acids by diastereoselective alkylation of camphor-based tricyclic iminolactone

A novel and convenient route for the preparation of chiral tricyclic iminolactones 9 and 10 from camphorquinone has been developed. Alkylation of iminolactones 9 and 10 provided iminolactones 16 and 17 in high yields which were, in turn, alkylated again to afford the alpha,alpha-disubstituted products in good yields (70-90%) and excellent diastereoselectivities (>98%). Hydrolysis of the alkylated iminolactones furnished the desired alpha,alpha-disubstituted alpha-amino acids in good yields and high enantiomeric excesses with good recovery yields of the chiral auxiliary 12 and 13. The extremely high endo-face selectivity for alkylation is discussed using semiempirical (MOPAC 93) calculations.     

SN2 vs. E2 on quaternary centres: an application to the synthesis of enantiopure beta2,2-amino acids

S(N)2 and E2 competing reactions in cyclic sulfamidates can be modulated by the change of an amide group to an ester group attached to the quaternary carbon activated for the nucleophilic attack, allowing an easy approach to enantiopure alpha,alpha-disubstituted beta-amino acids.     

Residue requirements for helical folding in short alpha/beta-peptides: crystallographic characterization of the 11-helix in an optimized sequence

Design of functional foldamers requires knowledge of the conformational propensities of constituent residues. Here, we explore the effects of variations in both alpha-amino acid and beta-amino acid substitution on alpha/beta-peptide helicity. We also report the first X-ray crystal structure of a helical alpha/beta-peptide. We conclude that a certain amount of conformational preorganization in alpha/beta-peptides (via the inclusion of constrained beta-amino acids or alpha,alpha-disubstituted alpha-amino acids) is needed to promote helical folding; acyclic beta-amino acids and beta-branched alpha-amino acids are tolerated to only a limited extent.     

Asymmetric synthesis of quaternary alpha- and beta-amino acids and beta-lactams via proline-catalyzed mannich reactions with branched aldehyde donors

[reaction: see text] L-Proline-catalyzed direct asymmetric Mannich reactions of N-PMP protected alpha-imino ethyl glyoxylate with various alpha,alpha-disubstituted aldehydes affords quaternary beta-formyl alpha-amino acid derivatives with excellent yields and enantioselectivities. The Mannich products are further converted to the corresponding quaternary alpha- and beta-amino acids and beta-lactams.     

A solid-phase synthetic route to unnatural amino acids with diverse side-chain substitutions

Reacting imine derivatives of resin-bound amino acids with alpha,omega-dihaloalkanes provides highly versatile intermediates to racemic alpha,alpha-disubstituted amino acids with a wide variety of side-chain functionality. Two strategies were developed to convert the intermediate omega-chloro or omega-bromo derivatives to the desired products. Together, they allow the creation of amino acids with diverse functionalities (omega-chlorides, nitriles, azides, acetates, thioacetates, thioethers, secondary and tertiary aliphatic amines, and anilines) placed at varying chain lengths (2-5) from the alpha-center of the amino acid.     

Asymmetric synthesis of alpha-amino acids: preparation and alkylation of monocyclic iminolactones derived from alpha-methyl trans-cinnamaldehyde

Two novel chiral monocyclic iminolactones 14a and 14b have been prepared. The chiral auxiliary 12 was obtained from alpha-methyl-trans-cinnamaldehyde through reduction, methylation, Sharpless asymmetric dihydroxylation, and oxidation in 87% overall yield. Esterification of compound 12 with the respective protected amino acids followed by deprotection and cyclization provided the corresponding iminolactones, each in 82% overall yield. Alkylation of the iminolactone 14a afforded the alpha-methyl-alpha,alpha-disubstituted products 15 and 16 in good yields (78-99%) and excellent diastereoselectivity (de >98%). Alkylations of the iminolactone 14b furnished the alpha-benzyl-alpha,alpha-disubstituted products 15a, 16b, 17, and 18 in good yields (51-86%) but moderate diastereoselectivities (43-56%). When HMPA or DMPU was used as a cosolvent, the rate of alkylation of the iminolactone 14b was accelerated with improved yields (56-99%) and diastereoselectivities (50-83%). Hydrolysis of the dialkylated iminolactones yielded the alpha,alpha-disubstituted alpha-amino acids in good yields (80-98%) and high enantiomeric excesses (98-99%) with good recovery of compound 12 (83-92%).     

Exploiting an inherent neighboring group effect of alpha-amino acids to synthesize extremely hindered dipeptides

The creation of highly hindered peptides that contain combinations of non-natural N-alkyl amino acids and N-alkyl-alpha,alpha-disubstituted amino acids presents a formidable challenge. Hindered, non-natural amino acids are of interest because they import resistance to proteolysis and unusual conformational properties to peptides that contain them. Toward a solution to this problem, we describe a new approach to creating extremely hindered dipeptides that is operationally simple and uses mild conditions and commercially available amino acids. The approach reduces the need for protecting groups and yields urethane-protected dipeptide acids that can be used as building blocks in the synthesis of larger peptides. We propose that the reaction proceeds through a previously unexploited intramolecular O,N-acyl transfer pathway.     

Synthesis of spirohydantoins and spiro-2,5-diketopiperazines via resin-bound cyclic alpha,alpha-disubstituted alpha-amino esters

A seven-step solid-phase synthesis of spirohydantoins and an eight-step solid-phase synthesis of spiro-2,5-diketopiperazines is reported. Key intermediate in the synthesis of both compound libraries is the resin-bound cyclic alpha,alpha-disubstituted alpha-amino ester, which can be obtained after selective homogeneous reduction of the aliphatic nitro ester using tin(II) chloride dihydrate. Nitro ester, in turn, is synthesized by a high-pressure-assisted [4 + 2] cycloaddition of resin-bound nitro alkene and butadiene, whereas nitro alkene is obtained by a Knoevenagel condensation of resin-bound nitro acetate with an imine. Novel spirohydantoins are obtained by isocyanate coupling with the resin-bound amino ester 5, followed by cyclization cleavage using a base. Novel spiro-2,5-diketopiperazines are obtained by PyBOP coupling of a Fmoc-protected amino acid with resin-bound amino ester, followed by Fmoc deprotection and an acid-assisted cyclization cleavage. After preparation of seven different resin-bound alpha,alpha-disubstituted alpha-amino esters, a 7 x 8 compound library of spirohydantoins was synthesized using eight different isocyanates, and a 7 x 8 compound library of spiro-2,5-diketopiperazines was synthesized using eight different Fmoc amino acids.     

Highly enantioselective amination of alpha-substituted alpha-cyanoacetates with chiral catalysts accessible from both quinine and quinidine

[Reaction: see text] The catalytic construction of nitrogen-substituted quaternary stereocenters is an important and challenging task in asymmetric synthesis. In this paper, we describe the use of 6'-OH-modified cinchona alkaloids that are accessible from either quinine or quinidine for the development of a highly enantioselective amination of alpha,alpha-disubstituted carbonyl compounds that is suitable for the creation of nitrogen-substituted quaternary stereocenters in either the R or S configuration.     

Lewis acid-mediated rearrangement of activated cyclic amines: a facile synthetic protocol for the preparation of amino carbonyl compounds

Ring opening of activated cyclic amines to produce amino carbonyl compounds has been studied in the presence of Lewis acids. Whereas five- and six-membered rings cleave and rearrange via a 1,2-hydride shift, reaction in three- and four-membered rings takes place via a C-C bond migration. In the case of a three-membered ring, a wide variety of Lewis acids proved to be effective for the reaction. Base-induced ring opening of activated alpha,alpha-disubstituted azetidinemethanol and its mechanistic aspects have been studied.     

Synthesis of novel alpha-substituted and alpha,alpha-disubstituted amino acids by rearrangement of ammonium ylides generated from metal carbenoids

[reaction: see text] A new and general four-step synthesis of protected alpha-substituted and alpha,alpha-disubstituted amino acids has been developed. The key step involves intramolecular ammonium ylide generation from a copper carbenoid with concomitant [2,3] rearrangement. The aromatic template serves as a tether, protecting group, and activating group for peptide coupling. The ylide rearrangement products can be converted into protected cyclic amino acids by ring-closing metathesis.     

Asymmetric synthesis of alpha,alpha-disubstituted alpha-amino acids using (S,S)-cyclohexane-1,2-diol as a chiral auxiliary

Diastereoselective alkylation of ethyl 2-methyl- and/or 2-ethylacetoacetates using the (S,S)-cyclohexane-1,2-diol as an acetal chiral auxiliary afforded enol ethers (2a-f and 5a-f) of 92->95% de in 31-70% yields. Removal of the cyclohexane-1,2-diol with BF(3)-OEt(2) afforded beta-keto esters (3 and 6) bearing a chiral quaternary carbon. The beta-keto esters could be easily converted into optically active alpha-methylated and/or alpha-ethylated alpha,alpha-disubstituted amino acids (12 and 13) in 21-99% yields using Schmidt rearrangement.