Highly stereoselective Michael addition reactions of CamTHP*-desymmetrized glycinamide for the synthesis of functionally dense amino acid derivatives

The camphor-derived tetrahydropyran (camTHP*)-desymmetrized glycinamide 1 undergoes efficient and highly diastereoselective lithium enolate Michael additions to nitro olefins, alpha,beta-unsaturated ketones, esters, and lactones. Straightforward manipulation of these products affords 3-substituted pyroglutamides and beta-aryl-alpha,gamma-diamino acid derivatives, highlighting the ease of synthesis of enantiomerically enriched, functionally dense molecules using this novel building block. [reaction: see text]     

Applications of the sulfinimine-mediated asymmetric strecker synthesis to the synthesis of alpha-alkyl alpha-amino acids

Addition of Et(2)AlCN and i-PrOH to ketosulfinimines (N-sulfinyl imines) affords corresponding alpha-alkyl alpha-amino nitriles in moderate to good yields. The diastereoselectivity is largely dependent on the E/Z isomer ratio of the ketosulfinimine. Hydrolysis of the diastereomerically pure amino nitriles affords enantiopure alpha-alkyl alpha-amino acids in moderate to good yields.     

Solvent-controlled asymmetric Strecker reaction: stereoselective synthesis of alpha-trifluoromethylated alpha-amino acids

[reaction: see text] Stereoselective approaches to alpha-trifluoromethylated alpha-amino acids (alpha-Tfm AAs) have been developed. The stereoconfigurations of the resulting alpha-Tfm AA precursors were well controlled by using different solvents. The optically active (S)-2-amino-2-phenyl-1,1,1-trifluoropropanoic acid was synthesized by this method.     

Three-component condensation leading to beta-amino acid diamides: convergent assembly of beta-peptide analogues

A Passerini condensation of acyl cyanides, carboxylic acids, and isonitriles has been developed that affords efficient access to functionalized diamides as well as beta-peptides of alpha-hydroxy-beta-amino acids. Such compounds are protease-resistant and form stable helical and sheet structures when incorporated into larger peptides. N-Protected alpha-amino acids and isocyanoesters derived from alpha-amino acids participate in the condensation, leading to alpha/beta peptides embodying the heterogeneous alpha/beta/alpha backbone motif, recent examples of which display antibiotic activity.     

Asymmetric synthesis of alpha-amino 1,3-dithioketals from sulfinimines (N-sulfinyl imines). Synthesis of (2S,3R)-(-)-3-hydroxy-3-methylproline

[reaction: see text] N-Sulfinyl alpha-amino 1,3-dithioketals are prepared in high de and good yield by treating sulfinimines with lithio-1,3-dithianes. Selective removal of the N-sulfinyl or the thioketal groups affords stable alpha-amino 1,3-dithioketals and N-sulfinyl alpha-amino ketones, respectively. This new sulfinimine-derived chiral building block is employed in the asymmetric synthesis of polyoxypeptin amino acid (2S,3R)-(-)-3-hydroxy-3-methylproline.     

Introduction of gamma-glutamyl residue into chymotrypsin and agarose gel: application to cross-linking and immobilization of protein

In our previous work a new method for the cross-linking of protein was proposed. The method is based on the spontaneous chelate formation process between salicylaldehyde and alpha-amino acid residues. Thus, the facile procedure for the introduction of these residues into protein is required. In this paper, a modification reagent which affords gamma-glutamylation products, i.e., introducing an alpha-amino acid functional group to the protein was proposed. Versatility of the reagent for the preparation of a cross-linked enzyme was examined.     

Thiazolium-derived N-heterocyclic carbene-catalyzed cross-coupling of aldehydes with unactivated imines

Cross-coupling of aromatic aldehydes or benzoins with unactivated imines catalyzed by an N-heterocyclic carbene (NHC) affords alpha-amino ketones smoothly.     

Preparation of fluoroalkyl imines, amines, enamines, ketones, alpha-amino carbonyls, and alpha-amino acids from primary enamine phosphonates

A simple method for preparation of fluoroalkyl beta-enaminophosphonates 1 from alkylphosphonates 2 and perfluoroalkyl nitriles 3 is reported. Olefination reaction of functionalized phosphates 1 with aldehydes gives alpha,beta-unsaturated imines 5. Acid hydrolysis of these fluoroalkyl derivatives 5 affords alpha,beta-unsaturated ketones 6, while their selective reduction with hydrides leads to the formation of allylamines 7, enamines 8, and saturated ketones 9 or amines 10. Selective oxidative cleavage of the carbon-carbon double bond of allylamines 7 gives fluorinated alpha-amino aldehydes 12, alpha-amino ketones 13, or alpha-amino acid derivatives 14.     

Asymmetric synthesis of cyclic alpha-amino phosphonates using masked oxo sulfinimines (N-sulfinyl imines)

Five-, six-, and seven-membered cyclic alpha-amino phosphonates, amino acid surrogates, are prepared in enantiomerically pure form via the highly diastereomeric addition of metal phosphonates to masked oxo sulfinimines. Hydrolysis of the resulting masked oxo alpha-amino phosphonates followed by reduction of the intermediate cyclic imino phosphonates affords the title compounds in good yield.     

Sulfinimine-mediated asymmetric synthesis of beta-hydroxy alpha-amino phosphonates

The addition of potassium dialkyl phosphites to enantiopure O-protected alpha-hydroxy sulfinimine pseudoenantiomers affords beta-hydroxy alpha-amino phosphonates in good yield and de. The reaction exhibits a strong match-mismatch effect.     

Solvolytic hydroperoxide rearrangements V. A stereoselective synthesis of trans-fused butyrolactones.

Stereoselective rearrangement of cis-5-(4-methoxybenzyl)-spiro[5,2]-octan-4-ol cis-1 in acidified THF-90% H₂O₂ affords 9-oxabicyclo[6.2.1]nonyl hydroperoxides 7 and 8 which are converted to medium-ring, keto-butyrolactones 2 and 3.     

Umpolung of chiral 2-ethynylaziridines: Indium(I)-mediated stereoselective synthesis of nonracemic 1,3-amino alcohols bearing three chiral centers, catalyzed by palladium(0)

Treatment of 3-alkyl-2-ethynylaziridines with InI in the presence of Pd(PPh(3))(4) and H(2)O gave allenylindium reagents bearing a protected amino group in high yields. Stereoselective addition of the allenylindium to aldehydes affords 2-ethynyl-1,3-amino alcohols bearing three chiral centers in good yields.     

Upper rim appended hybrid calixarenes via click chemistry

We report the application of "click" chemistry for the synthesis of hybrid calixarenes appended on the upper rim with carbohydrate and N,C-protected alpha-amino acids. The chemoselective N- or C-deprotection of the alpha-amino acids and their subsequent transformation into dipeptides is described. The first example of a chemo-enzymatic synthesis on upper rim derived calix[4]arenes using trans-sialidase affords sialylated lactose calix[4]arenes. Our innovative chemo-enzymatic process paves the way for further applications.     

An expedient and practical method for the synthesis of a diverse series of cyclopropane alpha-amino acids and amines

A practical synthesis for the preparation of a diverse series of cyclopropane alpha-amino acids is described. Nitrocyclopropane carboxylates can be readily prepared through treatment of alpha-nitroesters and iodobenzene diacetate or alpha-nitro-alpha-diazoesters with a Rh(II) catalyst and an olefin. Reduction of the nitro group using zinc/HCl in i-PrOH affords substituted cyclopropane alpha-amino esters in modest to high yields (54-99%). A "one-pot" procedure involving sequential cyclopropanation and reduction is described. The method can also be applied to the preparation of arylcyclopropyl amines (three examples).     

Diastereoselective michael addition of nitrogen and sulfur-nucleophiles to α,β-unsaturated δ-thiolactams

5,6-Dihydropyridine-2-thiones 2 are synthesized from 5,6-dihydropyridin-2-ones 1 and Lawesson reagent. Stereoselective Michael-like addition of amines, methylhydrazine or functionalized thiols affords trans piperidine-2-thiones 5 with the corresponding heterosubstituent in position 4 as major products. The configuration of the adducts 5 was determined by nmr-techniques.     

An expedient route to the tetrazole analogues of alpha-amino acids

[reaction: see text] Convenient conditions are described for the transformation of alpha-aminonitriles to the tetrazole analogues of alpha-amino acids. Refluxing the starting material in water/2-propanol at 80 degrees C with sodium azide and catalytic zinc bromide affords the tetrazole product in yields generally exceeding 90%.     

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.     

Efficient synthesis of 1-azadienes derived from alpha-aminoesters. Regioselective preparation of alpha-dehydroamino acids, vinylglycines, and alpha-amino acids

An efficient synthesis of 1-azadienes derived from alpha-aminoesters is achieved through an aza-Wittig reaction of phosphazenes with beta,gamma-unsaturated alpha-ketoesters. Regioselective 1,2-reduction of these functionalized 1-azadienes affords vinylglycine derivatives, while conjugative 1,4-reduction gives alpha-dehydroamino acid compounds. Reduction of both the carbon-carbon and the imine-carbon-nitrogen double bonds leads to the formation of alpha-amino acid derivatives.     

S(N)1-like reactions of bicyclic alpha-amino ethers with sulfur,nitrogen, and carbon nucleophiles. Synthesis of 1-azabicyclo[3.2.2]nonanes functionalized at carbon C2 and C6 with complete stereocontrol

[reaction: see text] In the presence of nucleophiles, Lewis acid mediated cleavage of alpha-amino ethers derived from quincorine and quincoridine affords a variety of C2-substituted and C6-vinylated 1-azabicyclo[3.2.2]nonanes. These are enantiopure and are formed in S(N)1-like reactions with complete stereocontrol. There is no leakage into 2-Nu en route to product 1-Nu or vice versa. Me(3)SiCN provides new Strecker-type alpha-amino nitriles. In the presence of TTMPP-BF(3).OEt(2), the ketene acetal Me(2)C=C(OMe)OSiMe(3) delivers enantiopure bicyclic beta-amino acid esters.     

New entry for synthesis of N-acylhydrazones, pyridazinones, and 1,3,4-oxadiazin-6-ones from alpha-amino acid esters

Versatile electrophiles N-acylhydrazones are synthesized via diazotization, reduction, and acylation of alpha-amino acid esters. Reduction of diazo esters with L-selectride or tributylphosphine affords the corresponding hydrazones in good yields. Both reducing agents give anti-hydrazones as the major product although the reactivity of each reductant is slightly different. The resulting hydrazones are acylated to give N-acylhydrazones, which are subjected to further reactions to give 1,3,4-oxadiazin-6-ones that serve as useful synthetic intermediates for the Diels-Alder reaction.