Convergent Strategy For Synthesis Research Articles

The Biological Activities of Polyether Ionophore Antibiotic Routiennocin is Independent of Absolute Stereochemistry.

Carboxylic polyether ionophores (CPIs) are among the most prevalent agricultural antibiotics (notably in the US) and these compounds have been in use for decades. The potential to reposition CPIs beyond veterinary use, e. g. through chemical modifications to enhance their selectivity window, is an exciting challenge and opportunity, considering their general resilience towards resistance development. Given the very large societal impact of these somewhat controversial compounds, it is surprising that many aspects of their mechanisms and activities in cells remain unclear. Here, we report comparative biological activities of the CPI routiennocin and two stereoisomers, including its enantiomer. We used an efficient convergent synthesis strategy to access the compounds and conducted a broad survey of antibacterial activities against planktonic cells and biofilms as well as the compounds' effects on mammalian cells, the latter assessed both via standard cell viability assays and broad morphological profiling. Interestingly, similar bioactivity of the enantiomeric pair was observed across all assays, strongly suggesting that chiral interactions do not play a decisive role in the mode of action. Overall, our findings are consistent with a mechanistic model involving highly dynamic behaviour of CPIs in biological membranes.

Chemoselective reaction of bifunctional carboxysulfonic acid systems: Preparation of useful intermediates for chemiluminescent, fluorescent and UV absorbing bifunctional linkers

Heterobifunctional compounds are of considerable interest in convergent synthesis strategies as well as in the labeling/tagging of biological molecules. Herein is described a synthetic strategy to functionalize sulfonic acids in the presence of carboxylic acids without the need for protection/deprotection steps. Bifunctional carboxysulfonic acids are transformed under mild conditions to the corresponding carboxysulfonyl fluorides which are reacted with the amine of choice to provide sulfonamides. The carboxylic acid remains free and is available for subsequent activation and further chemical elaboration. The generality of this approach is demonstrated herein, and an example of utility is outlined in which carboxysulfonyl-containing chemiluminescent reagents are transformed into unique red-shifted chemiluminescent reagents.

Multigram Synthesis of Advanced 6,6-Difluorospiro[3.3]heptane-derived Building Blocks.

A convenient methodology for constructing 6,6-difluorospiro[3.3]heptane scaffold - a conformationally restricted isostere of gem-difluorocycloalkanes - is developed. Alarge array of novel 2-mono- and 2,2-bifunctionalized difluorospiro[3.3]heptane building blocks was obtained through the convergent synthesis strategy using a common synthetic precursor - 1,1-bis(bromomethyl)-3,3-difluorocyclobutane. The target compounds and intermediates were prepared by short reaction sequences (6-10 steps) on multigram scale (up to 0.47 kg).

Discovery of class I histone deacetylase inhibitors based on romidpesin with promising selectivity for cancer cells.

Aim: Class I histone deacetylases (HDACs) are considered to be promising anticancer targets, but selective inhibition of class I HDAC isoforms remains a challenge. Methods & results: Previously, we obtained a selective class I HDAC inhibitor 9 based on a macrocyclic HDAC inhibitor Romidpesin. As our continuous efforts, a library of novel cyclicdepsipeptides based on 9 was established using a convergent synthesis strategy. The most active compounds 10, 16 and 19 selectively inhibit class I HDACs and exhibit promising nanomolar antiproliferative activities against several cancer cell lines with excellent selectivity toward cancer cells over normal cells. Besides, compound 10 demonstrates excellent antitumor effects in human prostate carcinoma PC3 xenograft models with no observed toxicity. Conclusion: These cyclicdepsipeptides show great therapeutic potential as novel anticancer agents for clinical translation.

Synthesis of the isotopically labeled JAK1/3 inhibitor [D7]-R545 and its oxidative metabolite [D7]-R935: Protecting group-directed regioselective bromination to access 3,4,5-substituted anilines

An extensive medicinal chemistry campaign and subsequent SAR studies led to the discovery of the highly potent and selective JAK1/3 inhibitor R545. To support advanced pre-clinical DMPK studies of R545, the isotopically labeled versions of the drug and its metabolite R935 were required. Herein, we describe the development of synthetic routes to deuterium-labeled [D7]-R545 and its oxidative metabolite [D7]-R935. Deuterium atoms were introduced at several sites in the target molecules by employing a convergent synthesis strategy. The desired regiochemistry at the right-hand side of [D7]-R935 was established via a newly discovered protecting group-directed bromination. The described synthetic approach gave rise to the desired deuterium-labeled target compounds and sufficient quantities were synthesized to enable pre-clinical DMPK studies.

A thermostable d-polymerase for mirror-image PCR.

Biological evolution resulted in a homochiral world in which nucleic acids consist exclusively of d-nucleotides and proteins made by ribosomal translation of l-amino acids. From the perspective of synthetic biology, however, particularly anabolic enzymes that could build the mirror-image counterparts of biological macromolecules such as l-DNA or l-RNA are lacking. Based on a convergent synthesis strategy, we have chemically produced and characterized a thermostable mirror-image polymerase that efficiently replicates and amplifies mirror-image (l)-DNA. This artificial enzyme, dubbed d-Dpo4-3C, is a mutant of Sulfolobus solfataricus DNA polymerase IV consisting of 352 d-amino acids. d-Dpo4-3C was reliably deployed in classical polymerase chain reactions (PCR) and it was used to assemble a first mirror-image gene coding for the protein Sso7d. We believe that this d-polymerase provides a valuable tool to further investigate the mysteries of biological (homo)chirality and to pave the way for potential novel life forms running on a mirror-image genome.

Fragment Coupling with Tertiary Radicals Generated by Visible-Light Photocatalysis.

Convergent synthesis strategies in which a target molecule is prepared by a branched approach wherein two or more complex fragments are combined at a late stage are almost always preferred over a linear approach in which the overall yield of the target molecule is eroded by the efficiency of each successive step in the sequence. As a result, bimolecular reactions that are able to combine complex fragments in good yield and, where important, with high stereocontrol are essential for implementing convergent synthetic strategies. Although intramolecular reactions of carbon radicals have long been exploited to assemble polycyclic ring systems, bimolecular coupling reactions of structurally complex carbon radicals have rarely been employed to combine elaborate fragments in the synthesis of structurally intricate molecules. We highlight in this Account recent discoveries from our laboratories that demonstrate that bimolecular reactions of structurally elaborate tertiary carbon radicals and electron-deficient alkenes can unite complex fragments in high yield using nearly equimolar amounts of the two coupling partners. Our discussion begins by considering several aspects of the bimolecular addition of tertiary carbon radicals to electron-deficient alkenes that commend these transformations for the union of structurally complex, sterically bulky fragments. We then discuss how in the context of synthesizing rearranged spongian diterpenoids we became aware of the exceptional utility of coupling reactions of alkenes and tertiary carbon radicals to unite structurally complex synthetic intermediates. Our initial investigations exploit the early report of Okada that N-(acyloxy)phthalimides reductively fragment at room temperature in the presence of visible light and catalytic amounts of the photocatalyst Ru(bpy)3Cl2 to form carbon radicals that react with alkenes. We show that this reaction of a tertiary radical precursor and an enone can combine two elaborate enantioenriched fragments in good yield with the formation of new quaternary and secondary stereocenters. As a result of the ready availability of tertiary alcohols, we describe two methods that were developed, one in collaboration with the MacMillan group, to generate tertiary radicals from tertiary alcohols. In the method that will be preferred in most instances, the tertiary alcohol is esterified in high yield to give a tert-alkyl hemioxalate salt, which-without purification-reacts with electron-deficient alkenes in the presence of visible light and an Ir(III) photocatalyst to give coupled products having a newly formed quaternary carbon in high yield. Hemioxalate salts containing Li, Na, K, and Cs countercations can be employed in this reaction, whose only other product is CO2. These reactions are carried out using nearly equimolar amounts of the addends, making them ideal for coupling of complex fragments at the late stage in a synthetic sequence. The attractive attributes of the fragment-coupling chemistry that we discuss in this Account are illustrated by an enantioselective total synthesis of a tricyclic trans-clerodane diterpenoid in eight steps and 34% overall yield from commercially available precursors. We anticipate that bimolecular reactions of carbon radicals will be increasingly used for fragment coupling in the future.

Convergent Synthesis Strategy of Novel Fused Azines: 1H-15N HMBC NMR as a Tool for Assertion of the Site Selectivity of Aza-Michael Addition Reaction

A unified convergent strategy has been developed for the facile synthesis of a series of novel fused azines bearing a phenothiazine moiety based on the aza-Michael addition reaction of an enaminone derivative to a variety of different heterocyclic amines under microwave irradiation conditions. The results of this study revealed that new methods are required to allow for the simple and efficient analysis of the fused azine products of this reaction other than single-crystal X-ray crystallography. With this in mind, 1H–15N HMBC experiments were used in the current study to allow for the unambiguous structural characterization of the fused azine products. These results provided further support in favor of the proposed structures and allowed for the resolution of several discrepancies reported in the literature regarding the structural characterization of these compounds. Keywords: Microwave irradiations, pyrazolo[1, 5-a]pyrimidines, triazolo[1, 5-a]pyrimidine, pyrimido[1, 2-a]benzimidazole, 1H-15N HMBC.

Efficient Syntheses of Star-Branched, Multifunctional Mesogens.

Star-branched molecular architectures lend themselves to convergent synthesis strategies for creating materials that combine three or more functional modalities, but these approaches require a core moiety with several reactive groups that are orthogonal to one another. The direct synthesis of three-arm, star-branched mesogens has been investigated via the Passerini three-component reaction to demonstrate how multicomponent reactions circumvent the need to identify and synthesize specialized branched core molecules.

A Unified Strategy for the Synthesis of Mucin Cores 1–4 Saccharides and the Assembled Multivalent Glycopeptides

By displaying different O-glycans in a multivalent mode, mucin and mucin-like glycoproteins are involved in a plethora of protein binding events. The understanding of the roles of the glycans and the identification of potential glycan binding proteins are major challenges. To enable future binding studies of mucin glycan and glycopeptide probes, a method that gives flexible and efficient access to all common mucin core-glycosylated amino acids was developed. Based on a convergent synthesis strategy starting from a shared early stage intermediate by differentiation in the glycoside acceptor reactivity, a common disaccharide building block allows for the creation of extended glycosylated amino acids carrying the mucin type-2 cores 1-4 saccharides. Formation of a phenyl-sulfenyl-N-Troc (Troc=trichloroethoxycarbonyl) byproduct during N-iodosuccinimide-promoted thioglycoside couplings was further characterized and a new methodology for the removal of the Troc group is described. The obtained glycosylated 9-fluorenylmethoxycarbonyl (Fmoc)-protected amino acid building blocks are incorporated into peptides for multivalent glycan display.

Efficient synthesis and identification of novel propane-1,3-diamino bridged CCR5 antagonists with variation on the basic center carrier

By employing pharmacophore-based design and the privileged fragments reassembly, a series of piperidine-/tropane-/piperazine-bridged CCR5 antagonists were designed and synthesized via an efficient convergent synthesis strategy, with focus on the optimal choice of the basic center carrier structure. Significantly, the 4-amino-4-methylpiperidine bridged 1-acyl-1,3-propanediamine compounds were identified as a new class of nanomolar CCR5 antagonists, providing an efficient approach and novel scaffolds for further development of potent CCR5 inhibitors.

Studies toward the total synthesis of cyclodidemniserinol trisulfate. Part II: 3,5,7-Trisubstituted 6,8-dioxabicyclo [3.2.1] octane core structure construction via I 2-mediated deprotection and ring closure tandem reaction

The 3,5,7-trisubstituted 6,8-dioxabicyclo [3.2.1] octane core structure was synthesized by employing a chiral pool convergent synthesis strategy and the I 2-mediated simultaneous deprotection and ring closure reaction as the key step, providing a practical and efficient synthetic approach applicable to the further total synthesis of the natural product cyclodidemniserinol trisulfate.

Evolution of a Strategy for the Synthesis of Structurally Complex Batzelladine Alkaloids. Enantioselective Total Synthesis of the Proposed Structure of Batzelladine F and Structural Revision

Stereoselective synthesis of octahydro-5,6,6a-triazaacenaphthalenes 29 and 34 having the anti-relationship of the angular hydrogens flanking the pyrrolidine nitrogen confirmed suspicions that the relative configuration of the left-hand tricyclic guanidine fragment of batzelladine F should be revised to have the syn relationship of these hydrogens. Several strategies were examined for coupling tricyclic guanidine fragments to prepare potential structures for batzelladine F. Eventually, a convergent synthesis strategy was devised, whose central step was a fragment-coupling tethered-Biginelli reaction (Scheme 17). Using this approach we synthesized four potential structures of batzelladine F, 35-38. None of these compounds, nor their enantiomers, were identical to natural batzelladine F. Reinvestigation of mass spectra of natural batzelladine F, and fragments 88 and 89 obtained upon saponification of batzelladine F, demonstrated that the originally proposed connectivity of this alkaloid was also incorrect. The revised connectivity, 90, of natural batzelladine F depicted in Scheme 21 is proposed.

A Pentenyl Dianion Based Strategy for Convergent Synthesis of Ene‐1,5‐diols

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Pentenyl Dianion Based Strategy for Convergent Synthesis of Ene‐1,5‐diols.

ChemInformVolume 36, Issue 31 Preparative Organic Chemistry A Pentenyl Dianion Based Strategy for Convergent Synthesis of Ene-1,5-diols. Adilah B. Bahadoor, Adilah B. Bahadoor Dep. Chem., Yale Univ., New Haven, CT 06520, USASearch for more papers by this authorAlec Flyer, Alec Flyer Dep. Chem., Yale Univ., New Haven, CT 06520, USASearch for more papers by this authorGlenn C. Micalizio, Glenn C. Micalizio Dep. Chem., Yale Univ., New Haven, CT 06520, USASearch for more papers by this author Adilah B. Bahadoor, Adilah B. Bahadoor Dep. Chem., Yale Univ., New Haven, CT 06520, USASearch for more papers by this authorAlec Flyer, Alec Flyer Dep. Chem., Yale Univ., New Haven, CT 06520, USASearch for more papers by this authorGlenn C. Micalizio, Glenn C. Micalizio Dep. Chem., Yale Univ., New Haven, CT 06520, USASearch for more papers by this author First published: 19 July 2005 https://doi.org/10.1002/chin.200531069Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume36, Issue31August 2, 2005 RelatedInformation

A Pentenyl Dianion-Based Strategy for Convergent Synthesis of Ene-1,5-diols

A convergent two-step process is described for the synthesis of ene-1,5-diols that provides for union of two carbonyl electrophiles via a formal pentenyl dianion equivalent.

Efficient Strategy for Convergent Synthesis of trans‐Fused Polycyclic Ethers Based on an Intramolecular SmI2‐Promoted Cyclization of Iodo Ester.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Efficient strategy for convergent synthesis of trans-fused polycyclic ethers based on an intramolecular SmI 2-promoted cyclization of iodo ester

An efficient convergent strategy for the construction of a trans-fused 6-6-6-6-membered tetracyclic ether ring system was developed. The key steps involve coupling of two cyclic ethers by esterification, SmI 2-promoted intramolecular reductive cyclization of iodo ester to hemiacetal, dehydration to dihydropyran, hydroboration, oxidation, intramolecular acetalization, and Lewis-acid catalyzed silane reduction.

De novo synthesis of a new diethylenetriaminepentaacetic acid (DTPA) bifunctional chelating agent.

Diethylene triamine pentaacetic acid (DTPA) has been in extensive use as a metal chelator in the development of radiopharmaceuticals and contrast agents. The former application uses DTPA mostly as a bifunctional chelating agent (BCA) conjugated to tumor-targeting vehicles (TTVs) such as monoclonal antibodies (MAbs) and receptor-directed peptides. A new bifunctional DTPA derivative was synthesized by a fully organic scheme. This compound, N(4),N(alpha),N(alpha),N(epsilon),N(epsilon)-[pentakis(carboxymethyl)]-N(4)-(carboxymethyl)-2,6-diamino-4-azahexanoic hydrazide (20) was prepared by a convergent synthesis strategy using N(alpha)-benzyloxycarbonyl-2,3-diaminopropionic acid as the starting compound. This commercially available material was used to build a functionalized triamine which served as the molecular core template for assembling the target molecule. To evaluate the conjugation and radiolabeling capabilities of this new molecule, it was covalently attached to the anti-TAG-72 MAb, Delta CH2HuCC49, and the conjugate was radiolabeled in near-quantitative yields with yttrium-90 ((90)Y) and lutetium-177 ((177)Lu). Biodistribution of the (177)Lu-labeled DTPA-Delta CH2HuCC49 in tumor-bearing nude mice demonstrated preservation of the immunoreactivity of the MAb as indicated by high tumor uptake. In addition to the introduction of a new bifunctional DTPA, this work reports on a novel synthetic approach for preparation of this useful metal chelator and introduces a new conjugation protocol.

Total synthesis and determination of the absolute configuration of coscinosulfate. A new selective inhibitor of Cdc25 protein phosphatase.

The first total synthesis of coscinosulfate 1, a metabolite isolated from a sea sponge, starting from (+)-sclareolide 3 is described. The convergent synthesis strategy relies on the coupling of sulfone 21 with the bromide 26. The sulfone fragment 21 was obtained by successive asymmetric aldol reaction with aldehyde 2 to introduce the stereocenters at C-12 and C-13, followed by one-carbon homologation via Horner-Wadsworth-Emmons olefination. The selective sulfatation at C-12 was accomplished through the quinone intermediate 31 obtained by selective oxidation of hydroquinone 30; this, when followed by reduction, furnished the desired coscinosulfate 1. X-ray analysis of the intermediate aldehyde 18 confirmed the proposed structure.