Stereoselective Synthesis of [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐D‐valine]]‐ and [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐L‐valine]cyclosporin A

Addition of various amines to the 3,3‐bis(trifluoromethyl)acrylamides 10a and 10b gave the tripeptides 11a – 11f , mostly as mixtures of epimers (Scheme 3). The crystalline tripeptide 11f ₂ was found to be the N‐terminal (2‐hydroxyethoxy)‐substituted (R,S,S)‐ester HOCH₂CH₂O‐D ‐Val(F₆)‐MeLeu‐Ala‐O^tBu by X‐ray crystallography. The C‐terminal‐protected tripeptide 11f ₂ was condensed with the N‐terminus octapeptide 2b to the depsipeptide 12a which was thermally rearranged to the undecapeptide 13a (Scheme 4). The condensation of the epimeric tripeptide 11f ₁ with the octapeptide 2b gave the undecapeptide 13b directly. The undecapeptides 13a and 13b were fully deprotected and cyclized to the [5‐[4,4,4,4′,4′,4′‐hexafluoro‐N‐(2‐hydroxyethoxy)‐D ‐valine]]‐ and [5‐[4,4,4,4′,4′,4′‐hexafluoro‐N‐(2‐hydroxyethoxy)‐L ‐valine]]cyclosporins 14a and 14b , respectively (Scheme 5). Rate differences observed for the thermal rearrangements of 12a to 13a and of 12b to 13b are discussed.     

β‐Selective Glycosylation by Using O‐Aryl‐Protected Glycosyl Donors

New glycosyl donors have been developed that contained several para‐substituted O‐aryl protecting groups and their stereoselectivity for the glycosylation reaction was evaluated. A highly β‐selective glycosylation reaction was achieved by using thioglycosides that were protected by 4‐nitrophenyl (NP) groups, which were introduced by using the corresponding diaryliodonium triflate. Analysis of the stereoselectivities of several glycosyl donors indicated that the β‐glycosides were obtained through an S_N2‐type displacement from the corresponding α‐glycosyl triflate. The NP group could be removed by reduction of the nitro group and acylation, followed by oxidation with ceric ammonium nitrate (CAN).     

A Simple Synthesis of Polyfunctionalized 4‐Aminopyrazolidin‐3‐ones as ‘Aza‐deoxa’ Analogs of D‐Cycloserine

A simple five‐step synthesis of fully substituted (4RS,5RS)‐4‐aminopyrazolidin‐3‐ones as analogs of D ‐cycloserine was developed. It comprises a two‐step preparation of 5‐substituted (4RS,5RS)‐4‐(benzyloxycarbonylamino)pyrazolidin‐3‐ones, reductive alkylation at N(1), alkylation of the amidic N(2) with alkyl halides, and simultaneous hydrogenolytic deprotection/reductive alkylation of the primary NH₂ group. The synthesis enables an easy stepwise functionalization of the pyrazolidin‐3‐one core with only two types of common reagents, aldehydes (or ketones) and alkyl halides. The structures of products were elucidated by NMR spectroscopy and X‐ray diffraction.     

Synthesis of 5′‐O‐(2‐Azido‐2‐deoxy‐α‐D‐glycosyl)nucleosides and Their Antitumor Activities

The 1,3,4,6‐tetra‐O‐acetyl‐2‐azido‐2‐deoxy‐β‐D ‐mannopyranose ( 4 ) or the mixture of 1,3,6‐tri‐O‐acetyl‐2‐azido‐2‐deoxy‐4‐O‐(2,3,4,6‐tetra‐O‐acetyl‐β‐D ‐galactopyranosyl)‐β‐D ‐mannopyranose ( 10 ) and the corresponding α‐D ‐glucopyranose‐type glycosyl donor 9 / 10 reacted at room temperature with protected nucleosides 12 – 15 in CH₂Cl₂ solution in the presence of BF₃?OEt₂ as promoter to give 5′‐O‐(2‐azido‐2‐deoxy‐α‐D ‐glycosyl)nucleosides in reasonable yields (Schemes 2 and 3). Only the 5′‐O‐(α‐D ‐mannopyranosyl)nucleosides were obtained. Compounds 21, 28, 30 , and 31 showed growth inhibition of HeLa cells and hepatoma Bel‐7402 cells at a concentration of 10 μM in vitro.     

A New Route for Preparation of 5‐Deoxy‐5‐(hydroxyphosphinyl)‐ D‐mannopyranose and ‐L‐gulopyranose Derivatives

Starting from methyl 2,3‐O‐isopropylidene‐α‐D ‐mannofuranoside ( 5 ), methyl 6‐O‐benzyl‐2,3‐O‐isopropylidene‐α‐D ‐lyxo‐hexofuranosid‐5‐ulose ( 12 ) was prepared in three steps. The addition reaction of dimethyl phosphonate to 12 , followed by deoxygenation of 5‐OH group, provided the 5‐deoxy‐5‐dimethoxyphosphinyl‐α‐D ‐mannofuranoside derivative 15a and the β‐L ‐gulofuranoside isomer 15b . Reduction of 15a and 15b with sodium dihydrobis(2‐methoxyethoxy)aluminate, followed by the action of HCl and then H₂O₂, afforded the D ‐mannopyranose ( 17 ) and L ‐gulopyranose analog 21 , each having a phosphinyl group in the hemiacetal ring. These were converted to the corresponding 1,2,3,4,6‐penta‐O‐acetyl‐5‐methoxyphosphinyl derivatives 19 and 23 , respectively, structures and conformations (⁴C₁ or ¹C₄, resp.) of which were established by ¹H‐NMR spectroscopy.     

Identification of (6R)‐5,6,7,8‐Tetrahydro‐D‐monapterin (=(6R)‐2‐Amino‐5,6,7,8‐tetrahydro‐6‐[(1R,2R)‐1,2,3 ‐trihydroxypropyl]pteridin‐4(3H)‐one) as the Native Pteridine in Tetrahymena pyriformis

The structure of the native pteridine in Tetrahymena pyriformis was determined as (6R)‐5,6,7,8‐tetrahydro‐D ‐monapterin (=(6R)‐2‐amino‐5,6,7,8‐tetrahydro‐6‐[(1R,2R)‐1,2,3‐trihydroxypropyl]pteridin‐4(3H)‐one; 4 ). First, the configuration of the 1,2,3‐trihydroxypropyl side chain was confirmed as D ‐threo by the fluorescence‐detected circular dichroism (FDCD) spectrum of its aromatic pterin derivative 2 obtained by I₂ oxidation (Fig. 1). The configuration at the 6‐position of 4 was determined as (R) by comparison of its hexaacetyl derivative 6 with authentic (6R)‐ and (6S)‐hexaacetyl‐5,6,7,8‐tetrahydro‐D ‐monapterins 6 and 7 , respectively, in the HPLC, LC/MS, and LC‐MS/MS (Figs. 3 – 6). (6R)‐5,6,7,8‐Tetrahydro‐D ‐monapterin ( 4 ) is a newly discovered natural tetrahydropterin.     

1‐(β‐d‐Erythrofuranos­yl)cytidine (β‐erythrocytidine)

1‐(β‐d ‐Erythrofuranosyl)cytidine, C₈H₁₁N₃O₄, (I), a derivative of β‐cytidine, (II), lacks an exocyclic hydroxy­methyl (–CH₂OH) substituent at C4′ and crystallizes in a global conformation different from that observed for (II). In (I), the β‐d ‐erythrofuranosyl ring assumes an E₃ conformation (C3′‐exo; S, i.e. south), and the N‐glycoside bond conformation is syn. In contrast, (II) contains a β‐d ‐ribofuranosyl ring in a ³T₂ conformation (N, i.e. north) and an anti‐N‐glycoside linkage. These crystallographic properties mimic those found in aqueous solution by NMR with respect to furan­ose conformation. Removal of the –CH₂OH group thus affects the global conformation of the aldofuranosyl ring. These results provide further support for S/syn–anti and N/anti correlations in pyrimidine nucleosides. The crystal structure of (I) was determined at 200 K.     

Three‐Residue Turn in β‐Peptides Nucleated by a 12/10 Helix

A new three‐residue turn in β peptides nucleated by a 12/10‐mixed helix is presented. In this design, β peptides were derived from the 1:1 alternation of C‐linked carbo‐β‐amino acid ester [BocNH‐(R)‐β‐Caa_(r)‐OMe] (Boc=tert‐butyloxycarbonyl), which consisted of a D ‐ribo furanoside side chain, and β‐hGly residues. The hexapeptide with (R)‐β‐Caa_(r) at the N terminus showed the ‘turn’ stabilized by a 14‐membered NH(4) ??? CO(6) hydrogen bond at the C terminus nucleated by a robust 12/10‐mixed helix, thus providing a ‘helix‐turn’ (HT) motif. The turn and the helix were additionally stabilized by intraresidue electrostatic interaction between the furan oxygen in the carbohydrate side chain and NH in the backbone. However, the hexapeptide with a β‐hGly residue at the N terminus demonstrated the presence of a 10/12 helix through its entire length, which again showed the intraresidue interaction between NH and furan oxygen. The intraresidue NH ??? O? Me electrostatic interactions observed in the monomer, however, were absent in the peptides.     

An Expeditious Access to Enantiomerically Pure cis‐Dialkyl‐Substituted γ‐ and δ‐Lactones

A facile general route to enantiomerically pure 3,4‐cis‐dialkyl‐substituted γ‐lactones and 4,5‐cis‐dialkyl‐substituted δ‐lactones by TiCl₄‐mediated Evans asymmetric aldolization as the key step is exemplified by synthesis of cis‐(3R,4R)‐3‐methyldecan‐4‐olide and (4R,5R)‐aerangis lactone.     

Synthesis of 4‐(trihalomethyl)dipyrimidin‐2‐ylamines from β‐alkoxy‐α,β‐unsaturated trihalomethyl ketones

The synthesis of a novel series of twelve 4‐(trihalomethyl)dipyrimidin‐2‐ylamines, from the cyclo‐condensation reaction of 4‐(trichloromethyl)‐2‐guanidinopyrimidine, with β‐alkoxyvinyl trihalomethyl ketones, of general formula: X₃C‐C(O)‐C(R²)=C(R¹)‐OR, where: X = F, Cl; R = Me, Et, ‐(CH₂)₂‐, ‐(CH₂)₃‐; R¹ = H, Me; R² = H, Me, ‐(CH₂)₂‐, ‐(CH₂)₃‐, is reported. The reactions were carried out in acetonitrile under reflux for 16 hours, leading to the dipyrimidin‐2‐ylamines in 65‐90% yield. Depending on the substituents of the vinyl ketone, tetrahydropyrimidines or aromatic pyrimidine rings were obtained from the cyclization reaction. When X = Cl, elimination of the trichloromethyl group was observed during the cyclization step. The structure of 4‐(trihalomethyl)dipyrimidin‐2‐ylamines was studied in detail by ¹H‐, ¹³C‐ and 2D‐nmr spectroscopy.     

Syntheses of β‐C(1→3)‐Glucopyranosides of 2‐ and 4‐Deoxy‐D‐hexoses

The Oshima? Nozaki (Et₂AlI) condensation of isolevoglucosenone ( 4 ) with 2,6‐anhydro‐3,4,5,7‐tetra‐O‐benzyl‐D ‐glycero‐D ‐gulo‐heptose ( 5 ) gave an enone 6 that was converted with high stereoselectivity to 3‐C‐[(1R)‐2,6‐anhydro‐D ‐glycero‐D ‐gulo‐heptitol‐1‐C‐yl]‐2,3‐dideoxy‐D ‐arabino‐hexose ( 1 ; 1 : 1 mixture of α‐ and β‐D ‐pyranose), and to 3‐C‐[(1R)‐2,6‐anhydro‐D ‐glycero‐D ‐gulo‐heptitol‐1‐C‐yl]‐2,3‐dideoxy‐D ‐lyxo‐hexose ( 2 ; 2.7 : 1.4 : 1.0 : 1.4 mixture of α‐D ‐furanose, β‐D ‐furanose, α‐D ‐pyranose, and β‐D ‐pyranose). The Oshima? Nozaki (Et₂AlI) condensation of levoglucosenone ( 17 ) with aldehyde 5 gave an enone 18 that was converted with high stereoselectivity to 3‐C‐[(1R)‐2,6‐anhydro‐D ‐glycero‐D ‐gulo‐heptitol‐1‐C‐yl]‐3,4‐dideoxy‐α‐D ‐arabino‐hexopyranose ( 3 ; single anomer).     

Synthesis of polypeptides from activated urethane derivatives of α‐amino acids

A series of activated urethane‐type derivatives of α‐amino acids were synthesized and applied to polypeptide synthesis. The urethane used herein, N‐(4‐nitrophenoxycarbonyl)‐α‐amino acids 1 , were synthesized by N‐carbamoylation of γ‐benzyl‐L ‐glutamate, β‐benzyl‐L ‐aspartate, L ‐leucine, L ‐phenylalanine, and L ‐proline, with 4‐nitrophenyl chloroformate. When 1 was dissolved in N,N‐dimethylacetamide (DMAc) and heated at 60 °C, it was smoothly converted into the corresponding polypeptides with releasing 4‐nitrophenol and carbon dioxide. Spectroscopic analyses of the obtained polypeptides revealed that they were comparable with the authentic polypeptides synthesized by the ring‐opening polymerizations of amino acid N‐carboxyanhydrides (NCAs). Besides the successful polycondensations of a series of 1 , their polycondensations of 1a and other 1 were also successfully carried out to obtain the corresponding statistic copolypeptides. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 2525–2535, 2008     

Disorder and conformational analysis of methyl β‐d‐galactopyranosyl‐(1→4)‐β‐d‐xylopyranoside

Methyl β‐d ‐galactopyranosyl‐(1→4)‐β‐d ‐xylopyranoside, C₁₂H₂₂O₁₀, (II), crystallizes as colorless needles from water with positional disorder in the xylopyranosyl (Xyl) ring and no water molecules in the unit cell. The internal glycosidic linkage conformation in (II) is characterized by a ϕ′ torsion angle (C2′_Gal—C1′_Gal—O1′_Gal—C4_Xyl) of 156.4 (5)° and a ψ′ torsion angle (C1′_Gal—O1′_Gal—C4_Xyl—C3_Xyl) of 94.0 (11)°, where the ring atom numbering conforms to the convention in which C1 denotes the anomeric C atom, and C5 and C6 denote the hydroxymethyl (–CH₂OH) C atoms in the β‐Xyl and β‐Gal residues, respectively. By comparison, the internal linkage conformation in the crystal structure of the structurally related disaccharide, methyl β‐lactoside [methyl β‐d ‐galactopyranosyl‐(1→4)‐β‐d ‐glucopyranoside], (III) [Stenutz, Shang & Serianni (1999). Acta Cryst. C 55 , 1719–1721], is characterized by ϕ′ = 153.8 (2)° and ψ′ = 78.4 (2)°. A comparison of β‐(1→4)‐linked disaccharides shows considerable variability in both ϕ′ and ψ′, with the range in the latter (∼38°) greater than that in the former (∼28°). Inter‐residue hydrogen bonding is observed between atoms O3_Xyl and O5′_Gal in the crystal structure of (II), analogous to the inter‐residue hydrogen bond detected between atoms O3_Glc and O5′_Gal in (III). The exocyclic hydroxymethyl conformations in the Gal residues of (II) and (III) are identical (gauche–trans conformer).     

Methyl 4‐O‐β‐d‐galactopyranosyl α‐d‐mannopyranoside methanol 0.375‐solvate

Methyl β‐d ‐galactopyranosyl‐(1→4)‐α‐d ‐mannopyranoside methanol 0.375‐solvate, C₁₃H₂₄O₁₁·0.375CH₃OH, (I), was crystallized from a methanol–ethanol solvent system in a glycosidic linkage conformation, with ϕ′ (O5_Gal—C1_Gal—O1_Gal—C4_Man) = −68.2 (3)° and ψ′ (C1_Gal—O1_Gal—C4_Man—C5_Man) = −123.9 (2)°, where the ring is defined by atoms O5/C1–C5 (monosaccharide numbering); C1 denotes the anomeric C atom and C6 the exocyclic hydroxymethyl C atom in the βGalp and αManp residues, respectively. The linkage conformation in (I) differs from that in crystalline methyl α‐lactoside [methyl β‐d ‐galactopyranosyl‐(1→4)‐α‐d ‐glucopyranoside], (II) [Pan, Noll & Serianni (2005). Acta Cryst. C 61 , o674–o677], where ϕ′ is −93.6° and ψ′ is −144.8°. An intermolecular hydrogen bond exists between O3_Man and O5_Gal in (I), similar to that between O3_Glc and O5_Gal in (II). The structures of (I) and (II) are also compared with those of their constituent residues, viz. methyl α‐d ‐mannopyranoside, methyl α‐d ‐glucopyranoside and methyl β‐d ‐galactopyranoside, revealing significant differences in the Cremer–Pople puckering parameters, exocyclic hydroxymethyl group conformations and intermolecular hydrogen‐bonding patterns.     

Crystal and NMR Structures of a Peptidomimetic β‐Turn That Provides Facile Synthesis of 13‐Membered Cyclic Tetrapeptides

Herein we report the unique conformations adopted by linear and cyclic tetrapeptides (CTPs) containing 2‐aminobenzoic acid (2‐Abz) in solution and as single crystals. The crystal structure of the linear tetrapeptide H₂N‐d ‐Leu‐d ‐Phe‐2‐Abz‐d ‐Ala‐COOH ( 1 ) reveals a novel planar peptidomimetic β‐turn stabilized by three hydrogen bonds and is in agreement with its NMR structure in solution. While CTPs are often synthetically inaccessible or cyclize in poor yield, both 1 and its N ‐Me‐d ‐Phe analogue ( 2 ) adopt pseudo‐cyclic frameworks enabling near quantitative conversion to the corresponding CTPs 3 and 4 . The crystal structure of the N ‐methylated peptide ( 4 ) is the first reported for a CTP containing 2‐Abz and reveals a distinctly planar 13‐membered ring, which is also evident in solution. The N ‐methylation of d ‐Phe results in a peptide bond inversion compared to the conformation of 3 in solution.     

Synthesis of β‐Substituted γ‐Aminobutyric Acid Derivatives through Enantioselective Photoredox Catalysis

β‐Substituted chiral γ‐aminobutyric acids feature important biological activities and are valuable intermediates for the synthesis of pharmaceuticals. Herein, an efficient catalytic enantioselective approach for the synthesis of β‐substituted γ‐aminobutyric acid derivatives through visible‐light‐induced photocatalyst‐free asymmetric radical conjugate additions is reported. Various β‐substituted γ‐aminobutyric acid analogues, including previously inaccessible derivatives containing fluorinated quaternary stereocenters, were obtained in good yields (42–89 %) and with excellent enantioselectivity (90–97 % ee). Synthetically valuable applications were demonstrated by providing straightforward synthetic access to the pharmaceuticals or related bioactive compounds (S)‐pregabalin, (R)‐baclofen, (R)‐rolipram, and (S)‐nebracetam.     

Stereocontrolled Synthesis of syn‐β‐Hydroxy‐α‐Amino Acids by Direct Aldolization of Pseudoephenamine Glycinamide

β‐Hydroxy‐α‐amino acids figure prominently as chiral building blocks in chemical synthesis and serve as precursors to numerous important medicines. Reported herein is a method for the synthesis of β‐hydroxy‐α‐amino acid derivatives by aldolization of pseudoephenamine glycinamide, which can be prepared from pseudoephenamine in a one‐flask protocol. Enolization of (R,R)‐ or (S,S)‐pseudoephenamine glycinamide with lithium hexamethyldisilazide in the presence of LiCl followed by addition of an aldehyde or ketone substrate affords aldol addition products that are stereochemically homologous with L ‐ or D ‐threonine, respectively. These products, which are typically solids, can be obtained in stereoisomerically pure form in yields of 55–98 %, and are readily transformed into β‐hydroxy‐α‐amino acids by mild hydrolysis or into 2‐amino‐1,3‐diols by reduction with sodium borohydride. This new chemistry greatly facilitates the construction of novel antibiotics of several different classes.     

Chiral discrimination of β‐3‐homo‐amino acids using the kinetic method

Chiral discrimination of seven enantiomeric pairs of β‐3‐homo‐amino acids was studied by using the kinetic method and trimeric metal‐bound complexes, with natural and unnatural α‐amino acids as chiral reference compounds and divalent metal ions (Cu²⁺ and Ni²⁺) as the center ions. The β‐3‐homo‐amino acids were selected for this study because, first of all, chiral discrimination of β‐amino acids has not been extensively studied by mass spectrometry. Moreover, these β‐3‐homo‐amino acids studied have different aromatic side chains. Thus, the emphasis was to study the effect of the side chain (electron density of the phenyl ring, as well as the difference between phenyl and benzyl side chains) for the chiral discrimination. The results showed that by the proper choice of a metal ion and a chiral reference compound, all seven enantiomeric pairs of β‐3‐homo‐amino acids could be differentiated. Moreover, it was noted that the β‐3‐homo‐amino acids with benzyl side chains provided higher enantioselectivity than the corresponding phenyl ones. However, increasing or decreasing the electron density of the aromatic ring by different substituents in both the phenyl and benzyl side chains had practically no role for chiral discrimination of β‐3‐homo‐amino acids studied. When copper was used as the central metal, the phenyl side chain containing reference molecules (S)‐2‐amino‐2‐phenylacetic acid (L ‐Phg) and (S)‐2‐amino‐2‐(4‐hydroxyphenyl)‐acetic acid (L ‐4′‐OHPhg) gave rise to an additional copper‐reduced dimeric fragment ion, [Cu^I(ref)(A)]⁺. The inclusion of this ion improved noticeably the enantioselectivity values obtained. Copyright © 2010 John Wiley & Sons, Ltd.     

An intermediate in a new synthesis approach to β‐substituted β‐hydroxy­aspartame

The crystal and molecular structure of 1‐tert‐butyl 4‐ethyl (2′R,3′R,5′R,2S,3S)‐3‐bromo­methyl‐3‐hydroxy‐2‐[(2′‐hydroxy‐2′,6′,6′‐tri­methyl­bi­cyclo­[3.1.1]­hept‐3′‐yl­idene)­amino]­succinate, C₂₁H₃₄BrNO₆, is presented. This compound is an intermediate in the new synthetic route to β‐substituted β‐hydroxy­aspartates, which are blockers of glutamate transport.     

Synthesis of new hydrolyzable polyurethanes from L‐gulonic acid‐derived diols and diisocyanates

New polyurethanes with lactone groups in the pendants and main chains were synthesized by the polyaddition of two kinds of L ‐gulonolactone‐derived diols (2,3‐O‐isopropylidene‐L ‐gulono‐1,4‐lactone and 5,6‐O‐isopropylidene‐L ‐gulono‐1,4‐lactone) with hexamethylene diisocyanate and methyl (S)‐2,6‐diisocyanatohexanoate and by the subsequent deprotection of isopropylidene groups. They were hydrolyzed more quickly than the polyurethane derived from methyl β‐D ‐glucofuranosidurono‐6,3‐lactone in a phosphate buffer solution, the pH value of which was 8.0, at 27 °C. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 4158–4166, 2002