Toward High-Throughput Synthesis of Complex Natural Product-Like Compounds in the Genomics and Proteomics Age (original) (raw)
Related papers
Stereoselective Synthesis of Drugs and Natural Products
2013
Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com.
CHEMICAL & PHARMACEUTICAL BULLETIN, 2012
2,6-Dimethyl-9-Aryl-9-phosphabicyclo[3.3.1]nonanes (9-PBN and 9-NapBN) and the chiral diaminophosphine oxides (DIAPHOXs) derived from aspartic acid have been introduced as useful ligands and preligands, respectively, for transition metal-catalyzed asymmetric synthesis. anti-Selective asymmetric hydrogenation of α-amino-β-ketoesters using Ru-, Rh-, Ir-, and Ni-catalysts through dynamic kinetic resolution have been developed for the first time, producing efficiently important anti β-hydroxy-α-amino acids. The total synthesis of several biologically active natural products was achieved by use of the transition metal-catalyzed reaction using DIAPHOX, anti-selective asymmetric hydrogenation, and reactions developed by us. Synthesis of tangutorine, an antitumor indole alkaloid, has been enantioselectively achieved for the first time. Enantioselective synthesis of a martinelline chiral core was accomplished using the asymmetric tandem Michael-Aldol reaction as a key step developed by us. This synthesis represents the formal total synthesis of martinelline and martinellic acid. Papuamide B was synthesized through the elucidation of unknown stereostructures by using the anti-selective asymmetric hydrogenation and reactions developed by us.
Highlights in the solid-phase organic synthesis of natural products and analogues
Journal of The Brazilian Chemical Society, 2010
Neste trabalho nós apresentamos uma revisão sobre a síntese em fase sólida de metabólitos secundários, tais como alcalóides, poliaminas, esteróides, terpenos e flavonóides, descritos na literatura a partir de 2000. Um número considerável de rotas sintéticas elegantes e desafiadoras, usando suportes sólidos, será discutido.
Empowering Synthesis of Complex Natural Products
Chemistry: A European Journal, 2019
Despite their previously reported synthesis, 17 Baran and coworkers wanted to enhance the efficiency and scalability of their process to allow for further biological investigations (Scheme 1). Learning from previous experience, they identified the stereoselective formation of the imidazoline ring as a critical step for improvement, which they envisioned through a "chloro-guanidylation" via stereoselective chloronium ion formation with subsequent stereospecific displacement by the guanidine to form the desired scaffold. Towards this goal, the synthesis commenced with in situ TMS protection of bis-allylic alcohol 3 employing bis(trimethylsilyl)-acetamide, followed by an optimized stoichiometric Pauson−Khand reaction with complex 4 to yield cyclopentenone 5 in 45% yield on 6.17 g scale. Interestingly, it was found that polyols and NMO displayed a synergistic effect to enhance the yield; however, despite efforts to prepare a reagent containing both of these features, the yield did not exceed 49%. Subjecting 5 to a two-step sequence of Luche reduction and Appel reaction furnished tri-chloride 6, setting the stage for a Zn/In-mediated Barbier-type allylation to yield alcohol 7 on a 5.60 g scale. Double nucleophilic azidation with subsequent Boc deprotection and guanidylation produced the desired chloro-guanidylation precursor 9. Through optimization, it was shown that subjecting crude mixtures of allylic guanidine 9 to chloro-guanidylation gave a marked increase in yield. After careful analysis of the reaction mixture, it was found that byproducts of the guanidylation reaction were producing a potent chlorination reagent in situ, leading to the development of commercially available Palau'chlor (not shown). With the ability to synthesize imidazoline 10 on a 4.60 g scale, Baran and coworkers began the endgame of the synthesis with TFA deprotection and cyanamide-mediated cyclization leading to cyclic guanidine 11. Closure of the final ring of the natural product scaffold was achieved via DMDO epoxidation with concomitant epoxide opening. The remaining alcohol was introduced through silver(II)-picolinate oxidation to afford tetracycle 12 on a 1.60 g scale. Reduction of the azide functionalities with Adams' catalyst and one-pot amidation provided a mixture axinellamines A (1) and B (2) on gram scale. This practical synthesis allowed for the identification of more bacterial pathogens that could be treated with these natural products, adding to the arsenal of broad-spectrum antibiotic scaffolds. 2.1.2 Leiodermatolide (Fürstner, 2014). While the scales of syntheses are often restricted by availability of materials and reagents, step-count, or overall efficiency, there are a few examples of the where the final amount produced was limited due to safety concerns regarding the high toxicity of the target natural product. This is exemplified by Fürstner's highly convergent synthesis of leiodermatolide 13 (Scheme 2), a potent cytotoxic spongederived marine natural product with GI50 values ≤3 nM across multiple cell lines, including those that are efflux active. 18 Through their early studies, Fürstner and coworkers observed that the tubulin disruption caused by 13 did not proceed through direct tubulin binding, and they instead hypothesized that the mode of action was centrosome declustering. This unorthodox antineoplastic activity required additional study and the authors decided their previously reported synthesis from 2012 could not furnish the necessary quantities needed for biological assays. 19
A Comparative Study of Chemical versus Biological Functionalizations of Synthetic Intermediates
A combination of microbial hydroxylationand lipase mediated hydrolysis insured access to chiral synthetic intermediates whose relative inaccessibility by usual methods is evident. A few examples are given for allylic hydroxylations with Rhizopus arrhizus and ester hydrolysis with lipases. Rhizopus arrhizus ATCC 11145, was found to hydroxylate the allylic positions of bicyclic ketone derivatives, mainly derived from the well-known Hajos-Parrish and Wieland Miescher ketone. The process is " green " as only water is used, regio-/stereo-/chemoselective, rapid, as less than 24 hours are required, and, furthermore, compatible with a number of functional groups, which remain intact. Direct one step hydroxylations on substrates containing free hydroxy or keto groups can be realized in high yield in the absence of toxic chemicals and organic solvents and without the use of the costly protection-deprotection steps. Rhizopus arrhizus displayed practically no sensitivity to the absolute configuration in both hydrindene and octaline series, observed ee's on the biohydroxylated compounds being at the best around 10% when racemic substrates were incubated. A representative comparison of the chemical and biological 7-hydroxylation is given in the Scheme below; the biological way gives a higher chemical yield and b-selectivity, whereas the chemical transformation gives poor yields for the oxidation step and the opposite selectivity when L-Selectride is used to reduce the intermediate C7-ketone.