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Copper-catalyzed cross-coupling of amino acid-derived amides with (Z)-vinyl iodides: Unexpected solvent effect and preparation of plocabulin
A copper-catalyzed cross-coupling reaction of amino acid-derived amides and (Z)-vinyl iodide was studied to improve a key step in the synthesis of plocabulin, a novel microtubule destabilizer agent of marine origin. The study revealed a profound solvent effect with 1,2-dimethoxyethane (DME), which gave consistently high yields across a large variety of the amide and (Z)-vinyl iodide substrates. The protocol was successfully utilized in the preparation of plocabulin and provided a significantly improved yield.
Wang, Leiming,Lei, Xinsheng,Wang, Quanrui,Li, Yingxia
(2021/02/01)

Stereospecific Nickel-Catalyzed Reductive Cross-Coupling of Alkyl Tosylate and Allyl Alcohol Electrophiles
The stereospecific cross-coupling of easily accessed electrophiles holds significant promise in the construction of C-C bonds. Herein, we report a nickel-catalyzed reductive coupling of allyl alcohols with chiral, nonracemic alkyl tosylates. This cross-coupling delivers valuable allylation products with high levels of stereospecificity across a range of substrates. The catalytic system consists of a simple nickel salt in conjunction with a commercially available reductant and importantly represents a rare example of a cross-coupling involving the C-O bonds of two electrophiles.
Alexanian, Erik J.,Tercenio, Quentin D.
supporting information
p. 7215 - 7219
(2021/09/22)

Stereoselective synthesis of resorcylic acid lactone Cochliomycin B
The total synthesis of 14-membered resorcylic acid lactone, Cochliomycin B has prescribed, in a convergent manner, from readily available starting materials, D-galactose, L-aspartic acid and ethyl acetoacetate. The key reactions involved in the synthesis are Julia-Kocienski olefination, E-selective Horner-Wadsworth-Emmons olefination and intramolecular lactonization.
Nagalatha,Siva Ganesh,Venkat Narsaiah
(2021/09/22)

Stereoselective total synthesis of obolactones and 7′,8′-dihydroobolactones
A concise stereoselective total synthesis of two diastereomeric obolactones and 7′,8′-dihydroobolactones has been achieved using a metal-free catalytic δ-hydroxyalkynone rearrangement, which could provide the required dihydro-γ-pyrone moiety. The desired first stereogenic center was installed through the chiral pool material,l-aspartic acid. Next, the allylation reaction was strategically utilized to provide the requisite olefin bond for the intended ring-closing metathesis, allowing the installation of the remaining dihydro-α-pyrone moiety in the natural products. It also enabled the targeting of both dihydro-α-pyrone diastereomers. Thus, the first stereoselective total synthesis of (+)-7′,8′-dihydroobolactone was accomplished, establishing its structure and absolute configuration.
Fernandes, Rodney A.,Kumar, Praveen,Saini, Deepak
p. 18976 - 18982
(2021/10/29)

Nanoprecipitation of biocompatible poly(Malic acid) derivative, its ability to encapsulate a molecular photothermal agent and photothermal properties of the resulting nanoparticles
Biocompatible nanoparticles (NPs) of hydrophobic poly(benzyl malate) (PMLABe) were prepared by nanoprecipitation. The influence of nanoprecipitation parameters (initial PMLABe, addition rate, organic solvent/water ratio and stirring speed) were studied to optimize the resulting formulations in terms of hydrodynamic diameter (Dh) and dispersity (PDI). PMLABe NPs with a Dh of 160 nm and a PDI of 0.11 were isolated using the optimized nanoprecipitation conditions. A hydrophobic near infra-red (NIR) photothermally active nickel-bis(dithiolene) complex (Ni8C12) was then encapsulated into PMLABe NPs using the optimized nanoprecipitation conditions. The size and encapsulation efficiency of the NPs were measured, revealing that up to 50 weight percent (wt%) of Ni8C12 complex can efficiently be encapsulated with a slight increase in Dh of the corresponding Ni8C12-loaded NPs. Moreover, we have shown that NP encapsulating Ni8C12 were stable under storage conditions (4?C) for at least 10 days. Finally, the photothermal properties of Ni8C12-loaded NPs were evaluated and a high photothermal efficiency (62.7 ± 6.0%) waswas measured with NPs incorporating 10 wt% of the Ni8C12 complex.
Bellec, Nathalie,Camerel, Franck,Cammas-Marion, Sandrine,Pluta, Jean-Baptiste,Vargas Guerrero, Marian Gabriela
(2021/12/27)

Preparation method of antirust agent 2-(1, 3-benzothiazole-2-sulfenyl) succinic acid
The invention discloses a preparation method of an antirust agent 2-(1, 3-benzothiazole-2-sulfenyl) succinic acid. The method is characterized in that L-aspartic acid is taken as a raw material, bromosuccinic acid is synthesized through diazotization bromination reaction, bromo succinic acid and 2-mercaptobenzothiazole are subjected to nucleophilic substitution reaction, and a product is acidified, filtered and washed to obtain 2-(1, 3-benzothiazole-2-sulfenyl) succinic acid. Wherein a water phase for producing bromo succinic acid can be used for the acidification process of 2-(1, 3-benzothiazole-2-sulfenyl) sodium succinate in the next step, and a water phase after acidification can be reused for producing bromo succinic acid. A water phase of a whole reaction system can be recycled, thedischarge amount of wastewater is greatly reduced, the wastewater after multiple cycles can be used for extracting sodium salt or liquid bromine, the produced 2-(1, 3-benzothiazole-2-sulfenyl) succinic acid product has high purity, and the purity can reach 97% through high performance liquid chromatography detection. The whole reaction system is environment-friendly, pollution-free, high in atomutilization efficiency, simple in process operation, high in yield and particularly suitable for industrial production.
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Paragraph 0034-0037; 0045-0048

(2020/07/12)

Stereoselective total synthesis of C2-symmetric natural products pyrenophorol and its derivatives
A stereoselective total synthesis of 16-membered C2-symmetric macrodiolide Pyrenophorol, Tetrahydropyrenophorol and 4,4-diacetylpyrenophorol have been accomplished. The synthesis started from commercially available L-Aspartic acid and the key reactions involved are regioselective epoxide opening, CBS reduction, Pinnick oxidation and Mitsunobu dilactonization.
Narala, Siva Ganesh,Nagalatha,Venkat Narsaiah
supporting information
p. 2173 - 2178
(2019/03/11)

Synthesis and Evaluation of Novel TLR2 Agonists as Potential Adjuvants for Cancer Vaccines
Cancer immunotherapy has gained increasing attention due to its potential specificity and lack of adverse side effects when compared to more traditional modes of treatment. Toll-like receptor 2 (TLR2) agonists are lipopeptides possessing the S-[2,3-bis(palmitoyloxy)propyl]-l-cysteine (Pam2Cys) motif and exhibit potent immunostimulatory effects. These agonists offer a means of providing "danger signals" in order to activate the immune system toward tumor antigens. Thus, the development of TLR2 agonists is attractive in the search of potential immunostimulants for cancer. Existing SAR studies of Pam2Cys with TLR2 indicate that the structural requirements for activity are, for the most part, very intolerable. We have investigated the importance of stereochemistry, the effect of N-terminal acylation, and homologation between the two ester functionalities in Pam2Cys-conjugated lipopeptides on TLR2 activity. The R diastereomer is significantly more potent than the S diastereomer and N-terminal modification generally lowers TLR2 activity. Most notably, homologation gives rise to analogues which are comparatively active to the native Pam2Cys containing constructs.
Lu, Benjamin L.,Williams, Geoffrey M.,Verdon, Daniel J.,Dunbar, P. Rod,Brimble, Margaret A.
supporting information
p. 2282 - 2291
(2019/10/02)

PEPTIDE CONJUGATES, CONJUGATION PROCESS, AND USES THEREOF
The invention relates to peptide conjugates, methods for making peptide conjugates, conjugates produced by the methods, and pharmaceutical compositions comprising the conjugates. Methods of eliciting immune responses in a subject and methods of vaccinating a subject, uses of the conjugates for the same, and uses of the conjugates in the manufacture of medicaments for the same are also contemplated.
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Page/Page column 135

(2019/03/17)

Site-Selective Conversion of Azido Groups at Carbonyl α-Positions to Diazo Groups in Diazido and Triazido Compounds
This paper reports on the selective conversion of alkyl azido groups at the carbonyl α-position to diazo compounds. Through β-elimination of dinitrogen, followed by hydrazone formation/decomposition, α-azidocarbonyl moieties were transformed into α-diazo carbonyl groups in one step. As these reaction conditions do not involve aryl or general alkyl azides, site-selective conversions of di- and triazides were achieved. Through this method, the successive site-selective conjugation of the triazido molecule with three different components is demonstrated.
Yokoi, Taiki,Tanimoto, Hiroki,Ueda, Tomomi,Morimoto, Tsumoru,Kakiuchi, Kiyomi
p. 12103 - 12121
(2018/10/09)

AMINO ACID AND PEPTIDE CONJUGATES AND CONJUGATION PROCESS
The invention relates to amino acid and peptide conjugates, methods for making amino acid and peptide conjugates, conjugates produced by the methods, and pharmaceutical compositions comprising the conjugates. Methods of eliciting immune responses in a subject and methods of vaccinating a subject, uses of the conjugates for the same, and uses of the conjugates in the manufacture of medicaments for the same are also contemplated.
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Page/Page column 131; 132

(2017/09/09)

Identification and pharmacological characterization of succinate receptor agonists
Background and Purpose: The succinate receptor (formerly GPR91 or SUCNR1) is described as a metabolic sensor that may be involved in homeostasis. Notwithstanding its implication in important (patho)physiological processes, the function of succinate receptors has remained ill-defined because no pharmacological tools were available. We report on the discovery of the first family of potent synthetic agonists. Experimental Approach: We screened a library of succinate analogues and analysed their activity on succinate receptors. Also, we modelled a pharmacophore and a binding site for this receptor. New agonists were identified based on the information provided by these two approaches. Their activity was studied in various bioassays, including measurement of cAMP levels, [Ca2+]i mobilization, TGF-α shedding and recruitment of arrestin 3. The in vivo effects of activating succinate receptors with these new agonists was evaluated on rat BP. Key Results: We identified cis-epoxysuccinic acid and cis-1,2-cyclopropanedicarboxylic acid as agonists with an efficacy similar to that of succinic acid. Interestingly, cis-epoxysuccinic acid was 10- to 20-fold more potent than succinic acid on succinate receptors. For example, cis-epoxysuccinic acid reduced cAMP levels with a pEC50?=?5.57?±?0.02 (EC50?=?2.7?μM), compared with succinate pEC50?=?4.54?±?0.08 (EC50?=?29?μM). The rank order of potency of the three agonists was the same in all in vitro assays. Both cis-epoxysuccinic and cis-1,2-cyclopropanedicarboxylic acid were as potent as succinate in increasing rat BP. Conclusions and Implications: We describe new agonists at succinate receptors that should facilitate further research on this understudied receptor.
Geubelle, Pierre,Gilissen, Julie,Dilly, Sébastien,Poma, Laurence,Dupuis, Nadine,Laschet, Céline,Abboud, Dayana,Inoue, Asuka,Jouret, Fran?ois,Pirotte, Bernard,Hanson, Julien
supporting information
p. 796 - 808
(2017/04/14)

Diphosphoric acid compounds, and preparation method and application thereof
The invention discloses compounds disclosed as Formula II. In the Formula II, R is disclosed in the specification, wherein R1 is H, OH or halogen; R2 is disclosed in the specification, n1=0-10, n2=0-10, and n3=0-10; Ar is aryl, arylidene, R99-substituted aryl or R99-substituted arylidene; at least one of R3, R4, R5 and R6 is selenium or sulfur atom, and the rest is carbon or nitrogen atom; and R3, R4, R5 and R6 are connected through a single bond or double bond. As for old patients with osteoporosis, the compounds can keep the osteocyte bone formation and bone destroy at an ideal dynamic balance.
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Paragraph 0113; 0125

(2016/10/31)

Accessing Centnerszwer's quasiracemate-molecular shape controlled molecular recognition
M. Centnerszwer's seminal 1899 report investigated the stereochemical relationship between optical antipodes of different substances using melting-point behavior. One intriguing melting-point phase diagram produced from this early investigation combined (+)-2-chlorosuccinic acid [(+)-1] and (-)-2-bromosuccinic acid [(-)-2]. While Centnerszwer's data clearly indicates the formation of a quasiracemic phase-i.e., materials constructed from pairs of isosteric molecules of opposite handedness-at the 1:1 component ratio, this material is energetically less favorable than the chiral counterparts. The consequence of this crystal instability is significant as evident by the absence of literature sited crystal structures for the quasiracemic phase (+)-1/(-)-2 and racemates (±)-1 and (±)-2. This study circumvented this challenge by generating multi-molecular assemblies using additional crystallizing agents capable of complementing the hydrogen-bond abilities of succinic acids 1 and 2. Both imidazole (Im) and 4,4′-bipyridyl-N,N′-dioxide (BPDO) served as tailor-made additives that effectively modified the crystal packing landscape of quasiracemate of (+)-1/(-)-2. Combining imidazole with the quasiracemate, racemate, and enantiopure forms of 1 and 2 resulted in crystal structures characterized as molecular salts with layered motifs formed from highly directional N+-H?carboxylate and carboxyl?carboxylate interactions. In contrast to the enantiopure [(+)-1·Im and (-)-2·Im] and racemic [(±)-1·Im and (±)-2·Im] systems, neighboring molecular layers observed in quasiracemate (+)-1/(-)-2·Im are organized by approximate inversion symmetry. Assessment of the crystal packing efficiency for this series of molecular salts via crystal densities and packing coefficients (Ck) indicates imidazole greatly alters the crystal landscape of the system in favor of racemic and quasiracemic crystal packing. A similar desymmetrized crystal environment was also realized for the ternary cocrystalline system of (+)-1/(-)-2·BPDO where the components organize via N+-O-?carboxyl contacts. This study underscores the importance of molecular shape to molecular recognition processes and the stabilizing effect of tailor-made additives for creating new crystalline phases of previously inaccessible crystalline materials.
Spaniol, Jacqueline M.,Wheeler, Kraig A.
p. 64921 - 64929
(2016/07/21)

SYNTHESIS OF DELTA 12-PGJ3 AND RELATED COMPOUNDS
In one aspect, the present invention provides novel derivatives of Δ12-PGJ3 and modular synthetic pathways to obtaining Δ12-PGJ3 and derivatives thereof. In some aspects, the present derivatives of Δ12-PGJ3 are useful as chemotherapeutic agents. The present disclosure also describes compositions of these derivatives as well as methods of use of the derivatives thereof.
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Page/Page column 136

(2015/04/15)

Synthesis of the griseusin B framework via a one-pot annulation- methylation-double deprotection-spirocyclization sequence
A highly convergent synthesis of the griseusin B scaffold is described. The key step involves an efficient one-pot Hauser-Kraus annulation-methylation- double deprotection-spirocyclization sequence that directly affords the target parent tetracyclic ring system.
Naysmith, Briar J.,Brimble, Margaret A.
supporting information
p. 2006 - 2009
(2013/06/04)

Design, synthesis, biophysical and primer extension studies of novel acyclic butyl nucleic acid (BuNA)
A novel nucleic acid analogue called acyclic (S)-butyl nucleic acid (BuNA) composed of an acyclic backbone containing a phosphodiester linkage and bearing natural nucleobases was synthesized. Next, (S)-BuNA nucleotides were incorporated in DNA strands and their effect on duplex stability and changes in structural conformation were investigated. Circular dichroism (CD), UV-melting and non-denatured gel electrophoresis (native PAGE) studies revealed that (S)-BuNA is capable of making duplexes with its complementary strands and integration of (S)-BuNA nucleotides into DNA duplex does not alter the B-type-helical structure of the duplex. Furthermore, (S)-BuNA oligonucleotides and (S)-BuNA substituted DNA strands were studied as primer extensions by DNA polymerases. This study revealed that the acyclic scaffold is tolerated by enzymes and is therefore to some extent biocompatible.
Kumar, Vipin,Gore, Kiran R.,Pradeepkumar,Kesavan, Venkitasamy
p. 5853 - 5865
(2013/09/12)

Acyclic butyl nucleic acid (BuNA): A novel scaffold for A-switch
The construction of an A-switch, derived from the artificial nucleic acid called acyclic Butyl Nucleic Acid (BuNA) was accomplished. The phosphoramidite building blocks of (S)-BuNA were synthesized from (R)-aspartic acid. To demonstrate its use as an A-switch, a stretch of polyadenine nucleotides of (S)-BuNA was studied by circular dichroism (CD) and ultraviolet (UV) spectroscopy under neutral and acidic conditions. Acid-base titration revealed two state transitions at pH 4.8 and highly pH-dependent structural conformation reversibility. Thermal melting (Tm) studies suggest that at neutral pH, poly BuNA(A) is a weakly organized single strand, while at low pH it adopts a highly organized and rigid structure. Furthermore, MALDI-TOF-MS data revealed intermolecular interactions which led to the formation of an A-motif composed of a double helical structure. Since BuNA does not suffer from depurination under acidic conditions, this allowed us to determine the thermodynamic parameters of the A-motif. This is the first report of the construction of an A-switch using artificial nucleic acids.
Kumar, Vipin,Kesavan, Venkitasamy
p. 19330 - 19340
(2013/10/22)

Total synthesis of the myxobacterial macrolide ripostatin b?
This article describes the total synthesis of ripostatin B, which is a 14-membered macrolide of myxobacterial origin that inhibits E. coli RNA polymerase by a different mechanism of action than the first-line anti-tuberculosis drug rifampicin. Structurally, ripostatin B features a labile and synthetically challenging doubly skipped triene motif embedded in the macrolactone ring. Key steps in the synthesis were a Paterson aldol reaction, a low-temperature Yamaguchi esterification and an alkene metathesis reaction to close the macrolide ring. The natural product was synthesized in a longest linear sequence of 21 steps and 3.6% overall yield. Schweizerische Chemische Gesellschaft.
Glaus, Florian,Altmann, Karl-Heinz
p. 227 - 230
(2013/07/25)

Convergent and enantioselective total synthesis of (-)-amphidinolide O and (-)-amphidinolide P
A convergent and enantioselective total synthesis of (-)-amphidinolide O (1) and P (2), 15-membered macrolides with seven chiral centers along with many functional groups, is described. The key reactions include enantioselective Brown allylation, anti- and syn-selective aldol reactions, (E)-selective olefin metathesis, conformation-controlled stereoselective epoxidation, and selective introduction of the exomethylene group. Assignments of the absolute stereochemistries of the natural (+)-amphidinolide O (ent-1) and P (ent-2) are also discussed in detail.
Hwang, Min-Ho,Han, Seo-Jung,Lee, Duck-Hyung
p. 3318 - 3321
(2013/07/26)

The stereoselective total synthesis of (3R,5R)-sonnerlactone and (3R,5S)-sonnerlactone
The stereoselective synthesis of (3R,5R)-sonnerlactone (1) and (3R,5S)-sonnerlactone (2) has been accomplished starting from l-aspartic acid. Our strategy involves asymmetric allylation, Alder-Rickert reaction and Mitsunobu macrolactonization as the key steps.
Yadav, J. S.,Shiva Shankar, K.,Srinivas Reddy, A.,Subba Reddy, B. V.
p. 6380 - 6382,3
(2012/12/12)

Second-generation synthesis of (-)-viriditoxin
Viriditoxin is a secondary metabolite isolated from Aspergillus viridinutans that has been shown to inhibit FtsZ, the bacterial homologue of eukaryotic tubulin. A streamlined, scalable, and highly diastereoselective synthesis of this complex natural product is described. Key advances include a more efficient synthesis of the requisite unsaturated pyranone, scalable assembly of the naphthopyranone monomer, and improved diastereoselectivity in the biaryl-coupling reaction. In addition, we disclose a serendipitous ruthenium-catalyzed anion dimerization resulting from trace metal left by an RCM reaction. Georg Thieme Verlag Stuttgart New York.
Grove, Charles I.,Fettinger, James C.,Shaw, Jared T.
scheme or table
p. 362 - 371
(2012/03/27)

Total synthesis of (-)-zampanolide and structure-activity relationship studies on (-)-dactylolide derivatives
A new total synthesis of the marine macrolide (-)-zampanolide (1) and the structurally and stereochemically related non-natural levorotatory enantiomer of (+)-dactylolide (2), that is, ent-2, has been developed. The synthesis features a high-yielding, selective intramolecular Horner-Wadsworth-Emmons (HWE) reaction to close the 20-membered macrolactone ring of 1 and ent-2. The β-keto phosphonate/aldehyde precursor for the ring-closure reaction was obtained by esterification of a ω-diethylphosphono carboxylic acid fragment and a secondary alcohol fragment incorporating the THP ring that is embedded in the macrocyclic core structure of 1 and ent-2. THP ring formation was accomplished through a segment coupling Prins-type cyclization. Employing the same overall strategy, 13-desmethylene-ent-2 as well as the monocyclic desTHP derivatives of 1 and ent-2 were prepared. Synthetic 1 inhibited human cancer cell growth in vitro with nM IC50 values, while ent-2, which lacks the diene-containing hemiaminal-linked side chain of 1, is 25- to 260-fold less active. 13-Desmethylene-ent-2 as well as the reduced versions of ent-2 and 13-desmethylene-ent-2 all showed similar cellular activity as ent-2 itself. The same activity level was attained by the monocyclic desTHP derivative of 1. Oxidation of the aldehyde functionality of ent-2 gave a carboxylic acid that was converted into the corresponding N-hexyl amide. The latter showed only μM antiproliferative activity, thus being several hundred-fold less potent than 1. It's the side chain that matters: The marine macrolide (-)-zampanolide (1) has been synthesized via (-)-dactylolide (ent-2), the non-natural enantiomer of the marine natural product (+)-dactylolide (2), employing a high-yielding intramolecular Horner-Wadsworth-Emmons reaction to close the macrolactone ring. While the hemiaminal-linked side chain in 1 is crucial for nanomolar antiproliferative activity, the methylene group and the aldehyde functionality in ent-2 are dispensable. A monocyclic destetrahydropyran derivative of 1 shows equal activity as ent-2. Copyright
Zurwerra, Didier,Glaus, Florian,Betschart, Leo,Schuster, Julia,Gertsch, Jürg,Ganci, Walter,Altmann, Karl-Heinz
supporting information
p. 16868 - 16883
(2013/03/14)

Total synthesis of the bacterial RNA polymerase inhibitor ripostatin B
A modular and highly stereoselective synthesis of the title compound was developed. Key steps in the assembly of the carbon framework of ripostatin B (1; see scheme) were a stereoselective Paterson aldol reaction and a high-yielding ring-closing metathesis mediated by Grubbs first generation catalyst. The C15 hydroxy group was established through Tishchenko-Evans reduction in excellent yield and selectivity. Copyright
Glaus, Florian,Altmann, Karl-Heinz
supporting information; experimental part
p. 3405 - 3409
(2012/06/29)

Total synthesis of laulimalide: Synthesis of the northern and southern fragments
The first stage in the development of a synthetic route for the total synthesis of laulimalide (1) is described. Our retrosynthetic analysis envisioned a novel macrocyclization route to the natural product by using a Ru-catalyzed alkene-alkyne coupling. This would be preceded by an esterification of the C19 hydroxyl group, joining together two equally sized synthons, the northern fragment 7 and the southern fragment 8. Our first generation approach to the northern fragment entailed a key sequential Ru/Pd coupling sequence to assemble the dihydropyran. The key reactions proceeded smoothly, but the inability to achieve a key olefin migration led to the development of an alternative route based on an asymmetric dinuclear Zn-catalyzed aldol reaction of a hydroxyl acylpyrrole. This key reaction led to the desired diol adduct 66 with excellent syn/anti selectivity (10:1), and allowed for the successful completion of the northern fragment 7. The key step for the synthesis of the southern fragment was a chemoselective Rh-catalyzed cycloisomerization reaction to form the dihydropyran ring from a diyne precursor. This reaction proved to be selective for the formation of a six-membered ring, over a seven. The use of an electron-deficient bidentate phosphine allowed for the reaction to proceed with a reduced catalyst loading. Making the pieces: The synthesis of two equal-sized fragments of laulimalide is described (see scheme). A key Rh-catalyzed cycloisomerization reaction allowed for an efficient synthesis of the endocyclic dihydropyran and a stereoselective acylpyrrole Zn-aldol reaction allowed for the formation of the syn-diol. Copyright
Trost, Barry M.,Seganish, W. Michael,Chung, Cheol K.,Amans, Dominique
supporting information; experimental part
p. 2948 - 2960
(2012/04/23)

Tumor-targeting, pH-responsive, and stable unimolecular micelles as drug nanocarriers for targeted cancer therapy
A new type of multifunctional unimolecular micelle drug nanocarrier based on amphiphilic hyperbranched block copolymer for targeted cancer therapy was developed. The core of the unimolecular micelle was a hyperbranched aliphatic polyester, Boltorn H40. The inner hydrophobic layer was composed of random copolymer of poly(εcaprolactone) and poly(malic acid) (PMA-co-PCL) segments, while the outer hydrophilic shell was composed of poly(ethylene glycol) (PEG) segments. Active tumor-targeting ligands, i.e., folate (FA), were selectively conjugated to the distal ends of the PEG segments. An anticancer drug, i.e., doxorubicin. (DOX) molecules, was conjugated onto the PMA segments with pH-sensitive drug binding linkers for pH-triggered drug release. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis showed that the unimolecular micelles were uniform with a mean hydrodynamic diameter around 25 nm. The drug loading content was determined to be 14.2%. The drug release profile, cell uptake and distribution, and cytotoxicity of the unimolecular micelles were evaluated in vitro. The folate-conjugated micelles can be internalized by the cancer cells via folate-receptormediated endocytosis; thus, they exhibited enhanced cell uptake and cytotoxicity. At pH 7.4, the physiological condition of bloodstream, DOX conjugated onto the unimolecular micelles exhibited excellent stability; however, once the micelles were internalized by the cancer cells, the pH-sensitive hydrazone linkages were cleavable by the intracellular acidic environment, which initially caused a rapid release of DOX. These findings indicate that these unique unimolecular micelles may offer a very promising approach, for targeted cancer therapy.
Yang, Xiaoqiang,Grailer, Jamison J.,Pilla, Srikanth,Steeber, Douglas A.,Gong, Shaoqin
experimental part
p. 496 - 504
(2011/01/03)

Stereoselective synthesis of a monocyclic peloruside A analogue
Chemical Equation Presentation The stereoselective synthesis of the monocyclic peloruside A analogue 4 has been achieved, following a new efficient approach for the introduction of the side chain, involving a late-stage addition of vinyl lithium species 7a to aldehyde 8. Further key steps are a highly diastereoselective allyltitanation reaction and a RCM-based macrocyclization.
Wulischleger, Christoph W.,Gertsch, Juerg,Altmann, Karl-Heinz
supporting information; experimental part
p. 1120 - 1123
(2010/06/13)

Synthesis of (-)-dactylolide and 13-desmethylene-(-)-dactylolide and their effects on tubulin
An efficient new synthesis has been elaborated for non-natural (-)-dactylolide ((-)-2) and its 13-desmethylene analogue 4, employing a HWE-based macrocyclization approach with β-keto-phosphonate/aldehyde 19 and the respective 13-desmethylene derivative as the key intermediates. Both (-)-2 and 4 as well as the corresponding C20 alcohols inhibit human cancer cell proliferation with IC50 values in the sub-micromolar range and induce the polymerization of tubulin in vitro.
Zurwerra, Didier,Gertsch, Juerg,Altmann, Karl-Heinz
supporting information; experimental part
p. 2302 - 2305
(2010/08/05)

Stereoselective total synthesis of achaetolide and reconfirmation of its absolute configuration
The stereoselective total synthesis of achaetolide 1 has been achieved and its absolute stereochemistry has been reconfirmed to be 3S,6R,7S,9R configuration. Keck allylation, Sharpless asymmetric dihydroxylation, and ring closing metathesis are the key steps involved in the target synthesis.
Srihari,Kumaraswamy,Shankar,Ravishashidhar,Yadav
scheme or table
p. 6174 - 6176
(2011/01/04)

Synthesis of the anti-Helicobacter pylori agent (+)-spirolaxine methyl ether and the unnatural (2″S)-diastereomer
The first enantioselective synthesis of the anti-Heliocbacter pylori agent (+)-spirolaxine methyl ether 2b has been carried out in a convergent fashion establishing that the absolute stereochemistry of the natural product is in fact (3R, 2″R, 5″R, 7″R) after initial synthesis of the unnatural (2″S)-diastereomer 2a. The key step in the synthesis of (+)-spirolaxine methyl ether 2b involved a heterocycle-activated Julia-Kocienski olefination between benzothiazole-based spiroacetal sulfone 4b and phthalide aldehyde 3a. (2″R, 5″S, 7″S)-Spiroacetal sulfone 4b was prepared via cyclisation of protected dihydroxyketone 6b, which in turn was derived from the coupling of the acetylide derived from (R)-acetylene 24b with aldehyde 3a. Phthalide aldehyde 3a was prepared via intramolecular acylation of bromocarbamate 15, which was available via titanium tetrafluoride-(+)-BINOL- mediated allylation of 3,5-dimethoxybenzaldehyde 13. Union of the sulfone 4b and aldehyde 3a fragments successfully completed the enantioselective synthesis of (+)-spirolaxine methyl ether 2b. The synthesis of the unnatural (3R, 2″S, 5″R, 7″R)-diastereomer of spirolaxine methyl ether 2a was also undertaken in a similar manner by union of phthalide aldehyde 3a with (2″S, 5″S, 7″S)-spiroacetal sulfone 4a derived from (S)-acetylene 24a. The Royal Society of Chemistry.
Robinson, James E.,Brimble, Margaret A.
p. 2572 - 2582
(2008/03/12)

The first enantioselective total synthesis of the anti-Helicobacter pylori agent (+)-spirolaxine methyl ether
The first enantioselective synthesis of the anti-Helicobacter pylori agent (+)-spirolaxine methyl ether has been carried out in a convergent fashion by heterocycle-activated Julia olefination of a spiroacetal-containing sulfone fragment with a phthalide-containing aldehyde fragment. The total synthesis of (+)-spirolaxine methyl ether establishes the absolute stereochemistry of the natural product to be (3R,2″R,5″R,7″R). The Royal Society of Chemistry 2005.
Robinson, James E.,Brimble, Margaret A.
p. 1560 - 1562
(2007/10/03)

Biocompatible polymers, process for their preparation and compositions containing them
A biocompatible polymer constituted by a sequence of identical or different components of the general formula (I): AaXxYy, in which A represents a monomer, X represents a carboxyl group fixed on a monomer A, Y represents a sulfate or sulfonate group fixed on a monomer A; a represents the number of monomers A, x represents the substitution rate of the set of monomers A by the groups X, y represents the substitution rate of the set of monomers A by the groups Y. The invention also pertains to the pharmaceutical or diagnostic compositions containing at least one polymer of general formula (I).
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(2008/06/13)

Stereocontrolled Synthesis of (2R,3S)-2-Methylisocitrate, a Central Intermediate in the Methylcitrate Cycle
2-Methylisocitrate (=3-hydroxybutane-1,2,3-tricarboxylic acid) is an intermediate in the oxidation of propanoate to pyruvate (=2-oxopropanoate) via the methylcitrate cycle in both bacteria and fungi (Scheme 1). Stereocontrolled syntheses of (2R,3S)- and (2S,3R)-2-methylisocitrate (98% e.e.) were achieved starting from (R)- and (S)-lactic acid (=(2R)- and (2S)-2-hydroxypropanoic acid), respectively. The dispiroketal (6S,7S,15R)-15-methyl-1,8,13,16-tetraoxadispiro[5.0.5.4]hexadecan-14-one (2a) derived from (R)-lactic acid was deprotonated with lithium diisopropylamide to give a carbanion that was condensed with diethyl fumarate (Scheme 3). The configuration of the adduct diethyl (2S)-2-[(6S,7S,14R)-14-methyl-15-oxo-1,8,13,16-tetraoxadispiro[5.0.5.4] hexadec-14-yl]butanedioate (3a) was assigned by consideration of possible transition states for the fumarate condensation (cf. Scheme 2), and this was confirmed by a crystal-structure analysis. The adduct was subjected to acid hydrolysis to afford the lactone 4a of (2R,3S)-2-methylisocitrate and hence (2R,3S)-2-methylisocitrate. Similarly, (S)-lactic acid led to (2S,3R)-2-methylisocitrate. Comparison of 2-methylisocitrate produced enzymatically with the synthetic enantiomers established that the biologically active isomer is (2R,3S)-2-methylisocitrate.
Darley, Dan J.,Selmer, Thorsten,Clegg, William,Harrington, Ross W.,Buckel, Wolfgang,Golding, Bernard T.
p. 3991 - 3999
(2007/10/03)

Block and star block copolymers by mechanism transformation. 7. Synthesis of polytetrahydrofuran/poly(1,3-dioxepane)/polystyrene ABC miktoarm star copolymers by combination of CROP and ATRP
Polytetrahydrofuran (PTHF)/poly(1,3-dioxepane) (PDOP)/polystyrene (PSt) ABC miktoarm star copolymers were synthesized by combination of cationic ring-opening polymerization (CROP) and atom transfer radical polymerization. TWO different functional groups, carboxylic acid and CHBr, were capped at one end of PTHF through the reaction of PTHF-OH with 2-bromosuccinic anhydride (BSA). After PTHF-OOCCHBrCH2COOH reacted with thionyl chloride, block copolymer PTHF-b-PDOP was synthesized by CROP of DOP at -30 to -35 °C with PTHF-OOCCHBrCH2COCl and AgClO4 as catalyst. Finally, (PTHF) (PDOP)-Br was used to initiate the polymerization of St in the presence of CuBr and bipyridine at 110 °C, and ABC miktoarm star polymer, s-[(PTHF) (PDOP) (PSt)] was successfully prepared. The copolymers obtained were characterized by 1H NMR and gel permeation chromatography measurements.
Feng, Xiao-Shuang,Pan, Cai-Yuan
p. 2084 - 2089
(2007/10/03)

Antagonists of follicle stimulating hormone activity
The present invention provides a compound of the formula: and methods for using the same, wherein R1, R2, R3, R4and X are those defined herein.
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(2008/06/13)

A new highly enantioselective synthesis of both (R)- and (S)-2- mercaptosuccinic acids
(R)- and (S)-2-Mercaptosuccinic acids 4 were prepared in five steps in >96% ee and 49-52% overall yield via a new efficient synthesis starting from commercially available L- and D-aspartic acids.
Chen, Bang-Chi,Bednarz, Mark S.,Kocy, Octavian R.,Sundeen, Joseph E.
p. 1641 - 1644
(2007/10/03)

Thiomalate complexes of gold(I): Preparation, characterization and crystal structures of 1:2 gold to thiomalate complexes
The preparation and characterization of 1:2 gold to thiomalate complexes, as ammonium salts, has been described. The crystal structures of both racemic and optically pure samples are described and compared. In each case, the gold atom is linearly co-ordinated to two ligand sulfur atoms. Bond lengths and angles are normal.
LeBlanc, Daren J.,Smith, Richard W.,Wang, Zhixian,Howard-Lock, Helen E.,Lock, Colin J. L.
p. 3263 - 3267
(2007/10/03)

The Fungal Biosynthesos of 3-Nitropropionic Acid: Is the Decarboxylation of L-Nitrosuccinate an Enzymatic Reaction?
In vitro enzymatic hydrolysis of diethyl (RS)-nitrosuccinate 2c by pig liver esterase at pH 7.8 affords 3-nitropropionic acid 1 indicating that the decarboxylation of (RS)-nitrosuccinate 2b is spontaneous under physiological conditions.In the in vivo synthesis of 1 from L-aspartate by cells of Penicillium atrovenetum, which involves oxidation of L-aspartate to nitrosuccinic acid, the decarboxylation of the nitrosuccinate may not require a specific biological catalyst.
Baxter, Robert L.,Smith, Shona L.,Martin, Jennifer R.,Hanley, A. Bryan
p. 2297 - 2300
(2007/10/02)

An efficient synthesis of enantiomerically pure (R)-(2-benzyloxyethyl)oxirane from (S)-aspartic acid
A 3-step synthesis of the title compound from (S)-aspartic acid is described. The overall yield of this process is 65% and the enantiomeric purity (ep) of the product is greater than 99%.
Frick,Klassen,Bathe,Abramson,Rapoport
p. 621 - 623
(2007/10/02)

2-Thioalkyl Penems: An Efficient Synthesis of Sulopenem, a (5R,6S)-6-(1(R)-Hydroxyethyl)-2--2-penem Antibacterial
A practical synthesis of potent penem antibacterials, CP-70,429 (1) (sulopenam) and CP-81,054 (2), is described. (L)-Aspartic acid was utilized to generate both the (3S)- and (3R)-thiolanylthio side chains of (5R,6S)-6-(1-(R)-hydroxyethyl)-2--2-penem-3-carboxylic acids 1 and 2.This synthetic pathway provided in high yield enantiopure thioacetate intermediates 15 and 19.To accommodate the fragile side chain sulfoxide moiety of the targeted β-lactams, standard penem synthetic methodology was modified to facilitate the conversion of 15 and 19 to 1 and 2.The reactive chloroazetidinone 4b was utilized to generate key azetidinone trithiocarbonate intermediate 22 which contains the requisite penem side chain.A chemoselective oxalofluoride-based azetidinone N-acylation procedure, which avoids sulfoxide O-acylation, was required for the conversion of 22 to the penem framework.
Volkmann, Robert A.,Kelbaugh, Paul R.,Nason, Deane M.,Jasys, V. John
p. 4352 - 4361
(2007/10/02)

Diastereomeric 5R,6S-6-(1R-hydroxyethyl)-2-(cis-1-oxo-3-thiolanylthio)-2-penem-3-carboxylic acids
Diastereomeric 5R,6S-6-(1R-hydroxyethyl)-2-(1S-oxo-3R-thiolanylthio)-2-penem-3-carboxylic acid and 5R,6S-6-(1R-hydroxyethyl)-2-(1R-oxo-3S-thiolanylthio )-2-penem-3-carboxylic acid, and pharmaceutically-acceptable salts and in vivo hydrolyzable esters thereof, useful as systemic antibacterial agents; and intermediates and processes which are useful in the said synthesis of said diastereoisomers.
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(2008/06/13)

A novel synthesis of maleic anhydride-1 and 2- 13C and its subsequent conversion to labeled maleic hydrazide
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Patterson,Braun,Haidar,et al.
p. 439 - 443,441,442
(2007/10/05)