Facile synthesis of polyamide dendrimers from unprotected AB2 building blocks

[structure: see text]. A fast, inexpensive, and highly efficient synthesis of aromatic polyamide dendrimers without the need for protection and deprotection steps has been developed. Dendrons and third-generation polyamide dendrimers were easily prepared by a convergent approach involving activation of a focal point with thionyl chloride, followed by condensation with unprotected AB2 building blocks.     

Formal Total Synthesis of Palmerolide A

A formal total synthesis of the 20‐membered marine macrolide, palmerolide A from chiral pool tartaric acid is described. Elaboration of a γ‐hydroxy amide, which is derived from the desymmetrization of tartaric acid amide, and Boord olefination are the pivotal reactions employed for the synthesis of the chiral building blocks, and Stille coupling and ring‐closing metathesis (RCM) are used to assemble the macrolactone.     

Metal-induced chiral folding of depsipeptide dendrimers

The synthesis and metal complexation of chiral depsipeptide dendrimers 3 and 7 containing an ethylenediaminetetraacetic acid (EDTA) ester-derived core is reported. The EDTA ester cavity of these dendrimers selectively complexes Zn(2+) and Cu(2+) ions leading to diastereoselective folding. To elucidate the coordination motif in the resulting "foldamers" of 3-ZnCl(2), 7-ZnCl(2), 3-CuCl(2), and 7-CuCl(2), the coordination behavior of the tetramethyl ester of EDTA (8) has been investigated as a model case. The corresponding complexes 8-ZnCl(2) and 8-CuCl(2) have been structurally characterized by (1)H NMR spectroscopy and X-ray analysis. The complexes involve the inherently chiral octahedral cis-alpha coordination motif, in which 8 serves as a tetradentate ligand. In the case of the Zn(II) complex 8-ZnCl(2), both Deltacis-alpha(S,S,lambda) and Lambdacis-alpha(R,R,lambda) stereoisomers were found in the unit cell. For the Cu(II) complex 8-CuCl(2), only one stereoisomer, namely Deltacis-alpha(S,S,lambda) was found in the crystal under investigation. (1)H NMR spectroscopy has shown that the same coordination motif is diastereoselectively formed in the chiral Zn(2+) dendrimers 3-ZnCl(2) and 7-ZnCl(2). Likewise, the calculated CD spectrum of the Deltacis-alpha(S,S,lambda) stereoisomer of the model complex 8-CuCl(2) shows good agreement with the experimental spectrum of the Cu(II) dendrimers 3-CuCl(2) and 7-CuCl(2), allowing assignment of the absolute configurations of the preferred foldamers as Lambdacis-alpha(R,R,lambda) for 3-CuCl(2) and Deltacis-alpha(S,S,lambda) for 7-CuCl(2). This work represents the first example of metal-complexation-mediated diastereoselective folding of chiral dendrimers with known absolute configuration.     

A Simple Procedure for the Preparation of Chiral ‘Tris(hydroxymethyl)methane’ Derivatives

The aldol adducts 1a – 13a of R,R-2(tertbutyl)-6-methyl-1,3-dioxan-4-one (from 3-hydroxybutanoic acid) to aldehydes, single diastereoisomers obtained as described previously, are acetylated or benzoylated to the corresponding esters 1b – 5b and 6c – 13c , respectively, which in turn are reduced with LiAlH₄ to the title compounds 14 – 24 . The enantiomerically pure triols thus available may be useful as chiral building blocks, as auxiliaries for enantioselective reactions, and as center pieces for chiral dendrimers.     

Convenient Syntheses of Some C4 Chiral Building Blocks Starting From (S)-Malic Acid

In the field of chiral technology, the synthesis of chiral intermediates and chiral building blocks occupies an important position. Chiral building blocks bearing double and / or multiple functionalities is particularly useful for the synthesis of chiral pharmaceuticals and chiral agrochemicals. In the recent years, we have been engaged in the development of synthetic methodology based on (S)-malic acid1-s. In these studies, malimide 2, easily accessible from (S)-malic acid, was shown to be a useful multifunctional building block in the asymmetric synthesis of natural products and chiral drugs (Scheme 1).     

Peptide dendrimers based on polyproline helices

We present a new family of peptide dendrimers based on polyproline helices and cis-4-amino-L-proline as a branching unit. Dendrimers were synthesized by a convergent solid-phase peptide synthesis approach. The conformational transition between polyproline type I helix and polyproline type II helix was observed by circular dichroism in branched polyproline building blocks with more than 14 proline residues and in the resulting dendrimers. Both linear and dendritic polyprolines were found to be actively internalized by rat kidney cells. Preliminary results show that the antibiotic ciprofloxacin form complexes with branched polyproline chains in 99.5% propanol.     

Synthesis of heteroaryl substituted α‐mercapto acids from thiomalic acid using hexafluoroacetone as protecting and activating reagent

The synthesis of heterocyclic α‐mercapto acids starting from (RS)‐thiomalic acid using hexafluoroacetone as protecting and activating agent is described. The new compounds are useful building blocks for peptide and depsipeptide modification as well as for drug design.     

Peptide-functionalized polyphenylene dendrimers

This contribution describes the synthesis of polyphenylene dendrimers that are functionalized with up to 16 lysine residues or substituted with short peptide sequences composed of 5 lysine or glutamic acid repeats and a C- or N-terminal cysteine residue. Polyphenylene dendrimers were prepared via a sequence of Diels-Alder cycloaddition and deprotection reactions from cyclopentadienone building blocks. Single amino acids could be introduced on the periphery of the dendrimers by using amino acid substituted cyclopentadienones in the last Diels-Alder addition reaction. Alternatively, peptide sequences were attached via a chemoselective reaction, which involved the addition of the sulfhydryl group of a cysteine residue of an oligopeptide to a maleimide moiety present on the surface of the dendrimer. These amino acid and peptide functionalized dendrimers may be of interest as model compounds to study DNA complexation and condensation or as building blocks for the preparation of novel supramolecular architectures via layer-by-layer self-assembly.     

从D-甘露糖醇制备(R)和(S)-3,3-二甲基-2,3-O-异亚丙基甘油酸甲酯

本文提出了一种由D-甘露糖醇出发合成一对高光学纯度的异亚丙基保护的3,3-二甲基甘油酸甲酯2a和2b的有效方法     

Homochiral 4-azalysine building blocks: syntheses and applications in solid-phase chemistry

Anomalous amino acids not only play central roles as mimics of natural amino acids but also offer opportunities as unique building blocks for combinatorial chemistry. This paper describes the chiral syntheses and solid-phase applications of a versatile atypical amino acid, 4-azalysine (2,6-diamino-4-azahexanoic acid) 1. The syntheses of differentially protected 4-azalysine derivatives 28a-e have been developed by two efficient and inexpensive routes that start either from Garner's aldehyde 16 or the chiron (S)-N(alpha)-Cbz-2,3-diaminopropionic acid 23. Both approaches employ the convergent modular concept and exploit reductive amination of aldehydes with amines as the key step for the fusion of the two segments. In the first route, the overall process inverts the chirality of the starting material, L-serine, and thus provides an excellent route to the unnatural D-isomers. The alternative route starting from L-asparagine provides a shorter and high-yielding route to orthogonally protected 4-azalysine derivatives. The corresponding N(2)-Fmoc-4-azalysines 31a-e, readily derived from the key intermediate 27, are compatible with the Fmoc-based solid-phase peptide synthesis (SPPS) and solid-phase organic chemistry (SPOC) protocols. Furthermore, the utility and versatility of another key structure, tris-Boc-4-azalysine 2 in the engineering of novel high-loading dendrimeric polystyrene resins 33 and 36, have been demonstrated. Following derivatization with the Rink amide linker 34, the stability and robustness of these resin-bound dendrimers 35 and 37 in the synthesis of small molecules using a range of reaction conditions (e.g., Mitsunobu and Suzuki reactions) have been effectively illustrated.     

Enantiospecific synthesis of the (9S,18R)-diastereomer of the leukocyte adhesion inhibitor cyclamenol A

Cyclamenol A is one of the very few non-carbohydrate and non-peptide natural products that inhibit leukocyte adhesion to endothelial cells. We report on the first enantioselective total synthesis of the (9S, 18R)-diastereomer of this macrocyclic polyene lactam. Key elements of the synthesis are i) the synthesis of the required chiral building blocks by employing readily accessible building blocks from the chiral pool, that is, (S)-malic acid and (R)-hydroxyisobutyric acid, ii) assembly of a linear polyene precursor by means of Wittig and Horner olefination reactions as key C-C bond-forming transformations, iii) ring closure by means of a vanadium-mediated pinacolisation reaction and iv) conversion of the generated cis-diol into a (Z)-olefin to complete the entire polyene system of the natural product. Attempts to close the macrocyclic ring by a macrolactamisation, a double Stille coupling or direct olefination in a McMurry reaction failed. Crucial to the successful completion of the synthesis was the correct orchestration of the final steps. It was necessary to first deprotect the intermediate formed after macrocycle formation and to generate the sensitive heptaene system in the last step by means of a Corey-Hopkins sequence.     

Assignment of absolute stereochemistry and total synthesis of (-)-spongidepsin

[structure: see text] An enantioselective total synthesis of (-)-spongidepsin (2) and elucidation of the absolute stereochemistry of its four stereocenters are described. Spongidepsin (2), a 13-membered depsipeptide isolated from the Vanuatu marine sponge Spongia sp., has shown potent antitumor properties against a variety of NCI tumor cell lines. Our synthesis is convergent, and the absolute stereochemistry of four of the five chiral centers was assigned through synthesis.     

The convergent synthesis of poly(glycerol-succinic acid) dendritic macromolecules

The high-yield convergent synthesis of dendrons, dendrimers, and dendritic-linear hybrid macromolecules composed of succinic acid, glycerol, and poly(ethylene glycol) (PEG) is described. This convergent synthesis relies on two orthogonal protecting groups; namely, the benzylidene acetal (bzld) for the protection of the 1,3-hydroxyls of glycerol and the tert-butyldiphenylsilyl (TBDPS) ester for protection of the carboxylic acid of succinic acid. These novel polyester dendritic macromolecules are composed entirely of building blocks known to be biocompatible or degradable in vivo to give natural metabolites. Derivatization of the dendritic periphery with a methacrylate affords a polymer that can be subsequently photo-cross-linked. The three-dimensional cross-linked gels formed by ultraviolet irradiation are optically transparent, with mechanical properties dependent on the initial cross-linkable dendritic macromolecule.     

A Preparatively Simple Access to Homochiral Heterocyclic α-Hydroxy Acids and their Derivatives

 The synthesis of homochiral heterocyclic α-hydroxy acids starting from (S)- and (R)-malic acid using hexafluoroacetone as protecting and activating agent is described. The new compounds are useful building blocks for peptide and depsipeptide modification.     

Synthesis and photoluminescent properties of 1,1'-binaphthyl-based chiral phenylenevinylene dendrimers

New chiral, soluble binaphthyl derivatives that incorporate stilbenoid dendrons at the 6,6'-positions have been prepared. The synthesis of the new enantiopure dendrimers was performed in a convergent manner by Horner-Wadsworth-Emmons (HWE) reaction of the appropriately functionalized 1,1'-binaphthyl derivative (R)-1 and the appropriate dendrons (R)(2n)G(n)-CHO. Different electroactive units were incorporated in the peripheral positions of the dendrons in order to tune both the optical and electrochemical behavior of these systems. Fluorescence measurements on the chiral dendrimers reveal a strong emission with maxima between 409 and 508 nm depending upon the substitution pattern. Finally, the redox properties of the dendrimers were determined by cyclic voltammetry, showing the influence of the functional groups at the peripheral positions of the dendrimer on the redox behavior of these systems.     

Self-assembly of chiral depsipeptide dendrimers

The self-assembly of chiral depsipeptide dendrons 4, which contain a cyanuric acid building block at their focal point, with the homotritopic Hamilton receptor 1 is reported. The 1:3 compositions of the resulting chiral supramolecular dendrimers, the association constants K(n), and the cooperativity of binding expressed by Scatchard plots and the Hill coefficients n(H) was determined by NMR titration experiments. The most pronounced positive cooperativity was found for the complexes 1 L(3) with L being the second-generation dendrons 4 c-e. The least stable complexes are formed with the bulky third-generation dendrons 4 f-h. Similar results are obtained by the corresponding complexation of the achiral Frechét-type first- to third-generation dendrons 3 with 1. Chiroptical investigations of 1:3 complexes of 1 and 4 reveal chirality transfer from the dendron to the Hamilton receptor as demonstrated by the appearance of new CD absorption bands at 310 nm.     

A Preparatively Simple Access to Homochiral Heterocyclic α-Hydroxy Acids and their Derivatives

Summary.  The synthesis of homochiral heterocyclic α-hydroxy acids starting from (S)- and (R)-malic acid using hexafluoroacetone as protecting and activating agent is described. The new compounds are useful building blocks for peptide and depsipeptide modification. Received May 21, 2001. Accepted (revised) July 6, 2001     

An efficient synthetic route to glycoamino acid building blocks for glycopeptide synthesis

[reaction: see text] Chemical glycopeptide synthesis requires access to gram quantities of glycosylated amino acid building blocks. Hence, the efficiency of synthesis of such building blocks is of great importance. Here, we report a fast and highly efficient synthetic route to Fmoc-protected asparaginyl glycosides from unprotected sugars in three steps with high yields. The glycosylated amino acids were successfully incorporated into target glycopeptides 7 and 8 by standard Fmoc solid-phase peptide synthesis.     

Total Synthesis of Cryptophycins via a Chemoenzymatic Approach

A highly convergent synthesis of cryptophycins in their enantiomerically-pure forms was achieved. Our strategy consists of the synthesis of the two units 3 and 4 and linking them together to form the macrocyclic ring. The upper unit 3 was prepared from 10 in four steps, and the lower unit 4 was prepared from 20 in three steps. Enantioselective biocatalytic methodology was used to prepare the requisite chiral building blocks, (R)-11 and (R)-19. The stereochemical versatility of this synthetic approach is demonstrated by the synthesis of cryptophycin A and the four diastereomers of cryptophycin C.     

Design and synthesis of a conformationally restricted trans peptide isostere based on the bioactive conformations of saquinavir and nelfinavir

The design and synthesis of a new peptide isostere which contains a trans alkene core is described. The key step involves a Wadsworth-Emmons reaction between chiral aldehyde (2S)-9a and chiral phosphonate 7 under base-sensitive conditions to give a chiral enone (2R)-24a which was reduced to afford the desired trans alkene isosteres (2R,5R)-6a and (2R,5S)-6b (Scheme 6). A potential application of this isostere in the synthesis of HIV protease inhibitors is also discussed.