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A comparative study of the effectiveness of selected coupling reagents in dipeptide synthesis was conducted. Included in the study were a new coupling reagent, pentafluorophenyl diphenylphosphinate (FDPP, 1), benzotriazol-1-yl-oxytris(dimethylamino) phosphonium hexafluorophosphate (BOP, 2), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 3), and isobutyl chloroformate (IBCF, 4). We found that BOP (2) afforded the highest yields and lowest limits of racemization.

The detoxin complex, metabolites produced by Streptomyces caespitosus var. detoxicus 7072 GC1, is a selective antagonist of the antibiotic blasticidin S. Two approaches toward the total synthesis of (+)-valyldetoxinine and (−)-detoxin D1 are described. These routes involve a 2,3-disubstituted pyrrolidine as a common intermediate and utilize glucose as the chiral precursor.

The first total synthesis of the 14-membered para ansa cyclopeptide alkaloid (-)-nummularine F is reported. The pivotal transformations of the synthetic strategy are (1) a stereocontrolled approach for introducing the absolute stereochemistry at the α- and β-carbons of the parent β-hydroxyproline utilizing D-serine as a source of chirality; (2) cyclization to a rigid 14-membered ring; and (3) introduction of the enamide double bond. The synthesis began with the conversion of D-serine to (2S,3S)-3-(4-cyanophenoxy)-1-[(1,1-dimethylethoxy)carbonyl]proline.After conversion of the cyano function to a formyl group, a Henry reaction between the 4-formylphenoxy group and the anion of nitromethane gave a mixture of epimeric benzyl alcohols containing a terminal nitro group.The nitro group was reduced to an amine and coupled to Z-protected L-isoleucine to afford the desired acyclic precursor.Cyclisation was achieved by the coupling of the proline pentafluorophenyl ester and the amino group of the L-isoleucine.The enamide bond was introduced after cyclisation,via thermal selenoxide elimination

The reactions of D-ribono-1,4-lactone, and 2-deoxy-D-ribono-1,4-lactone with benzaldehyde and acetone in acidic media were investigated. The products obtained were isolated and characterized. The 1H NMR spectra of the 1,5-lactone product resulting from the thermodynamically controlled reaction of D-ribono-1,4-lactone with benzaldehyde were examined between 300 °K and 200 °K in a polar solvent. No conformational changes in the 1,5-lactone ring were observed within this temperature range. Detailed NMR studies showed that the acetalization of D-ribono-1,4-lactone proceeded with the initial formation of the endo-2,3-acetal derivative, which in the presence of aqueous acids underwent ring expansion and isomerization to the 3,4-acetal of the 1,5-lactone. The endo preference of benzylidene acetals was explained by the transition state conformation of the reactants and the thermodynamic stability of the products, as calculated with molecular mechanics.

Two nonessential amino acids, (+)-(S)-2-aminobutanoic acid and the methyl ester of L-β-phenylalanine [(+)- (R)-3-amino-3-phenyl propanoic acid], were synthesized to provide a tripeptide which will be used in the total syntheses of astins A, B, and C.

N-Fluorenylmethoxycarbonyl groups may be removed by potassium fluoride/18-crown-6 in the presence of methyl, ethyl, tert-butyl, benzyl, and p-methoxybenzyl esters.

(1S,2S,3R)-3-Hydroxy-2-methoxy-1-cyclohexanecarboxylic acid was synthesized for the construction of an amino acid to be used in a constrained ring didemnin B analog ( 2 ). The amine functionality was introduced into the cyclohexane ring by reductive amination using sodium triacetoxyborohydride or by oxime formation followed by reduction.

The esterification of sterically hindered or non-nucleophilic alcohols may often be problematic. The reaction of alcohols with acid fluorides is reported to be superior to standard acid activation protocols frequently used for difficult esterifications. The acid fluoride methodology was used to produce a hindered linkage between a secondary alcohol (4) and a cyclohexyl amino acid 3, a key intermediate in the formation of a constrained ring didemnin analog.

The commercially available α-ketoxime of camphorquinone (1) was reduced to the corresponding exo,exo-amino alcohol (2) in a two-step, one-pot procedure using sodium borohydride and nickel(II) chloride hexahydrate.

A practical and convenient procedure is described for the preparation of gram quantities of (2S, 3S)-3-hydroxyleucine. The key step involves the triflatemediated cyclization of spirooxazolidine 4 to the spirobicyclic compound 5, which is easily converted to the title compound in high yield.

An X-ray crystal analysis of φ-lactone N-{1-(N-{4-{[3-hydroxy-5-methyl-1-oxo-4-(N-L-threonylamino)heptyl]oxy}-2,5-dimethyl-1,3-dioxohexyl}-L-leucyl}-L-prolyl}-N,O-dimethyl-L-tyrosine hydrobromide hydrate (1a), C 42 H 66 N 5 O 11 + .Br - .H 2 O, was obtained in order to determine the backbone folding of the macrocycle and to compare the results obtained with those reported previously for the natural product didemnin B (1b). Some differences were noted in the torsion angles of the two conformers of the hydrobromide salt, denoted (1a) and (1a'). The conformation of (1a') resembled the conformation of (1b) more closely than did that of (1a). Certain regions of both crystal backbones were more flexible than those in didemnin B ; however, the transannular hydrogen bonds in both (1a) and (1a') were somewhat stronger than in (1b).

N-Alkylation of amino acid esters by reductive amination using sodium cyanoborohydride may often be problematic. Sodium triacetoxyborohydride was found to be a convenient reagent for this transformation. This methodology was employed to alkylate various amino acid methyl esters.

Modest to high levels of asymmetric induction are observed with Grignard additions to Garner type aldehydes. The resultant secondary alcohols are important precursors of chiral building blocks for asymmetric synthesis and we have demonstrated that they can be readily converted into their respective γ-hydroxy-β-amino alcohols and β-hydroxyamino acids. Additionally, aryloxy ethers, important components of many natural products, can be obtained from these precursors.

Magnesium bromide etherate has been previously shown to cleave β-(trimethylsilyl)ethoxymethyl (SEM) esters of aliphatic acids. This methodology has now been extended to amino acid and peptide derivatives in the presence of protecting groups typically encountered in peptide chemistry, including the Boc, Cbz, Fmoc and Troc carbamates as well as benzyl-, tert-butyl- and tert-butyldimethylsilyl ethers. The stability of fluoride sensitive protecting groups to magnesium bromide allows for added selectivity in the removal of SEM esters in organic synthesis.

Efficient syntheses of the esters of cis-3,4-dihydroxyprolines and the first synthesis of the ester of the rare amino acid (−)-(3S,4R)-dichloroproline from trans-4-hydroxy-L-proline are presented. The synthetic route provides easy access to several substituted prolines and cis-hydroxylated proline esters. Various types of biological activities have been associated with these substituted prolines. The role of (−)-(3S,4R)-dichloroproline in astins A, B and C is under investigation.

Indanediones are more sensitive and less expensive than materials currently used by most police departments, and the procedure for using them is less damaging to evidence.

A strained 14-membered cyclopeptide was prepared from the Garner aldehyde derived from D-serine. The key steps in the synthesis were the construction of the alkyl-aryl ether linkage via an SNAr reaction involving 4-fluorobenzonitrile and the macrolactamization using a modification of the Schmidt protocol involving an activated pentafluorophenyl ester.

The naturally occurring cyclopeptide alkaloid sanjoinine G1 and its C-11 epimer were synthesized in 18 steps from D -serine. The key steps in the synthesis were the formation of the alkylaryl ether linkage via an SNAr reaction with 4-fluorobenzonitrile and the macrocyclization to form the 14-membered ring using a modification of the Schmidt protocol involving an activated pentafluorophenyl ester.

Sanjoinine A ( 1 ) was synthesized from a 14-membered cyclopeptide prepared from a Garner aldehyde derived from d -serine. The key steps in the synthesis were the catalytic asymmetric reduction of ketone 2(b) and the final removal of the Boc group.

The astin family of cyclopentapeptides contains several noncoded amino acids, including β-phenylalanine, α-aminobutyric acid and several substituted prolines. The difficult cyclization of the macrocycle and the subsequent first total synthesis of a member of this family, astin G, are discussed herein. This synthesis provides a model for the syntheses of the astins which contain the highly sensitive 3,4-dichloroproline.

An efficient asymmetric Strecker synthesis of the unnatural α-amino acid, d -alloisoleucine (3), from commercially available and inexpensive (S)-2-methyl-1-butanol (4) was accomplished in four steps.

[formula: see text] Tamandarin A (1), a newly isolated natural product similar in structure to didemnin B (2), was shown to be somewhat more active in vitro than 2 against pancreatic carcinoma with an ED50 value 1.5 to 2 ng/mL. We report here the first total synthesis of 1. The key steps include a practical stereoselective synthesis of the Hiv-isostatine unit, high-yielding linear precursor formation, a successful macrocyclization, and coupling of the macrocycle with the side chain to afford tamandarin A (1).

The total synthesis of ustiloxin D, a highly potent inhibitor of microtubule assembly, has been achieved. Notable features are the use of nucleophilic aromatic substitution (SNAr) for the construction of a chiral tertiary alkyl-aryl ether linkage, Sharpless asymmetric aminohydroxylation for the formation of the beta-hydroxytyrosine moiety, macrolactamization, and regioselective methylation.

The discovery of the didemnin family of marine depsipeptides launched an exciting and intriguing chapter in natural product chemistry. The unusual structure of the didemnin congeners has led to several total syntheses by research groups from around the world. The impressive in vitro and in vivo biological activities of the didemnins resulted in the first human clinical trials in the U.S. of a marine natural product against cancer, and additional clinical trials of a second-generation didemnin, dehydrodidemnin B (aplidine), are underway. As we mark the 20-year anniversary of the discovery of the didemnins, this class of natural products continues to stimulate active research in fields ranging from synthetic and medicinal chemistry to clinical oncology and cell biology. While some progress was made in dissecting the molecular mechanism of action and in establishing structure-activity relationships, there are still more questions than answers. This review covers the recent didemnin literature, highlighting the work directed towards understanding how this group of natural products interact with fundamental processes such as cell proliferation, protein biosynthesis, and apoptosis. The didemnin field illustrates how natural product chemistry may be used as a critical tool for the study of cell biology.

Isoroquefortine E and phenylahistin were synthesized using the Horner–Wadsworth–Emmons reaction as the key step to build the dehydroamino acid moiety. The syntheses provided the materials for the biological studies of the roquefortine–phenylahistin molecules.

The first total synthesis of the 14-membered para ansa cyclopeptide alkaloid (-)-nummularine F is reported. The pivotal transformations of the synthetic strategy are (1) a stereocontrolled approach for introducing the absolute stereochemistry at the α- and β-carbons of the parent β-hydroxyproline utilizing D-serine as a source of chirality; (2) cyclization to a rigid 14-membered ring; and (3) introduction of the enamide double bond. The synthesis began with the conversion of D-serine to (2S,3S)-3-(4-cyanophenoxy)-1-[(1,1-dimethylethoxy)carbonyl]proline.After conversion of the cyano function to a formyl group, a Henry reaction between the 4-formylphenoxy group and the anion of nitromethane gave a mixture of epimeric benzyl alcohols containing a terminal nitro group.The nitro group was reduced to an amine and coupled to Z-protected L-isoleucine to afford the desired acyclic precursor.Cyclisation was achieved by the coupling of the proline pentafluorophenyl ester and the amino group of the L-isoleucine.The enamide bond was introduced after cyclisation,via thermal selenoxide elimination

Quaternary AlxGa1-xAsySb1-y (x≈0.37 and 0.47) alloy has been grown on GaSb substrate by liquid phase epitaxy from melts containing Xl(Al)=0.02 and 0.03. Satisfactory layers could be obtained at TG=605°C using small supercooling (ΔT=1–4°C) and small As content in the melt (Xl(As)=10-4). The conditions of growing lattice-matched structures have been theoretically evaluated and experimentally determined. Growth kinetics obey the law: d=KΔTt 1 2 , which is characteristic of a diffusion-lim ited growth, with K=0.054 μm°C-1 s- 1 2 for (100) orientation and K=0.036 μm°C-1 s- 1 2 for the (111)B. Undop ed layers are p-type with a residual carrier concentration p≈1016 cm-3. Photoluminescence measurements at 2 K show excitonic and phonon assisted lines, characteristic of good quality indirect gap material. High doping levels were achieved by Ge doping (p=1019 cm-3) and Te doping (n=2x1018 cm-3).

We conducted structural and pharmacological studies of galanthamine, a cortical acetylcholinesterase (AChE) inhibitor, and 19 structural analogs. Systematic derivatization of galanthamine at the cyclohexene ring, tertiary amino, hydroxyl and methoxyl functions indicated that these structural features are essential for biological activity. Molecular modeling studies suggested that the low energy conformations of the analogs are similar to that of the parent. One derivative, galanthamine n-butyl carbamate, had an LD 50 of over 100 mg/kg (ip) in mice. In a passive avoidance paradigm, this analog improved performance in a dose-dependent fashion with a peak effect at 0.1 mg/kg in control and 0.5 mg/kg in basal forebrain lesioned mice. In the same paradigm, the peak effect of the parent compound is a 6-fold higher dose. With this surprisingly high therapeutic ratio, this compound may be of interest in treating cholinergic deficits of the central nervous system such as Alzheimer's disease.

An efficient stereocontrolled total synthesis of (−)-detoxin D 1 , the most active component of the detoxin complex, is described.

Mid-infrared laser diodes with compressively strained InAsSb/InAs type-II slightly coupled quantum wells are reported. These lasers, grown on InAs by molecular-beam epitaxy, have emission wavelength near 3.5 μm. They exhibit pulsed operation up to 220 K, with at 90 K threshold current density of 150 A/cm2. Ridge lasers continuous wave (cw) operated up to 130 K with cw output power of 40 mW/A/facet and a characteristic temperature T0=40 K.

A one-step copper-carbodimide elimination was used to provide the (E)-dehydroisoleucine moiety in the phomopsin side chain stereoselectively. An efficient approach to the phomopsin tripeptide side chain was developed to be used in the total syntheses of phomopsins A and B.