Robert M. Williams

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Organization: Colorado State University

Department: Department of Chemistry

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Chemicals
References

Bioconversion of 6-epi-Notoamide T produces metabolites of unprecedented structures in a marine-derived Aspergillus sp.

Co-reporter:Hikaru Kato, Takashi Nakahara, Michitaka Yamaguchi, Ippei Kagiyama, Jennifer M. Finefield, James D. Sunderhaus, David H. Sherman, Robert M. Williams, Sachiko Tsukamoto

Tetrahedron Letters 2015 Volume 56(Issue 1) pp:247-251

Publication Date(Web):1 January 2015

DOI:10.1016/j.tetlet.2014.11.083

We previously described the bioconversion of Notoamide T into (+)-Stephacidin A and (−)-Notoamide B, which suggested that Versicolamide B (8) is biosynthesized from 6-epi-Notoamide T (10) via 6-epi-Stephacidin A. Here we report that [13C]2-10 was incorporated into isotopically enriched 8 and seven new metabolites, which were not produced under normal culture conditions. The results suggest that the addition of excess precursor activated the expression of dormant tailoring genes giving rise to these structurally unprecedented metabolites.

Comparative pharmacokinetic properties and antitumor activity of the marine HDACi Largazole and Largazole peptide isostere

Co-reporter:John L. Pilon;Dane J. Clausen;Ryan J. Hansen;Paul J. Lunghofer;Brad Charles;Barbara J. Rose;Douglas H. Thamm;Daniel L. Gustafson;James E. Bradner;Robert M. Williams

Cancer Chemotherapy and Pharmacology 2015 Volume 75( Issue 4) pp:671-682

Publication Date(Web):2015/04/01

DOI:10.1007/s00280-015-2675-1

Largazole is a potent class I-selective HDACi natural product isolated from the marine cyanobacteria Symploca sp. The purpose of this study was to test synthetic analogs of Largazole to identify potential scaffold structural modifications that would improve the drug-like properties of this clinically relevant natural product.The impact of Largazole scaffold replacements on in vitro growth inhibition, cell cycle arrest, induction of apoptosis, pharmacokinetic properties, and in vivo activity using a xenograft model was investigated.In vitro studies in colon, lung, and pancreatic cancer cell lines showed that pyridyl-substituted Largazole analogs had low-nanomolar/high-picomolar antiproliferative activity, and induced apoptosis and cell cycle arrest at concentrations equivalent to or lower than the parent compound Largazole. Using IV bolus delivery at 5 mg/kg, two compartmental pharmacokinetic modeling on the peptide isostere analog of Largazole indicated improved pharmacokinetic parameters. In an A549 non-small cell lung carcinoma xenograft model using a dosage of 5 mg/kg administered intraperitoneally every other day, Largazole, Largazole thiol, and Largazole peptide isostere demonstrated tumor growth inhibition (TGI %) of 32, 44, and 66 %, respectively. Largazole peptide isostere treatment was statistically superior to control (p = 0.002) and to Largazole (p = 0.006). Surprisingly, tumor growth inhibition was not observed with the potent pyridyl-based analogs.These results establish that replacing the depsipeptide linkage in Largazole with an amide may impart pharmacokinetic and therapeutic advantage and that alternative prodrug forms of Largazole are feasible.

Epidithiodioxopiperazines. occurrence, synthesis and biogenesis

Co-reporter:Timothy R. Welch and Robert M. Williams

Natural Product Reports 2014 vol. 31(Issue 10) pp:1376-1404

Publication Date(Web):09 May 2014

DOI:10.1039/C3NP70097F

Covering: 1936 to 2013 Epidithiodioxopiperazine alkaloids possess an astonishing array of molecular architecture and generally exhibit potent biological activity. Nearly twenty distinct families have been isolated and characterized since the seminal discovery of gliotoxin in 1936. Numerous biosynthetic investigations offer a glimpse at the relative ease with which Nature is able to assemble this class of molecules, while providing synthetic chemists inspiration for the development of more efficient syntheses. Herein, we discuss the isolation and characterization, proposed fungal biogeneses, and total syntheses of epidithiodioxopiperazines.

Synthetic studies towards zetekitoxin AB: preparation of 4,5-epi-11-hydroxy-saxitoxinol

Co-reporter:Aaron D. Pearson, Robert M. Williams

Tetrahedron 2014 70(43) pp: 7942-7949

Publication Date(Web):

DOI:10.1016/j.tet.2014.08.058

Efficient synthesis of the cyclopentanone fragrances (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone and Magnolione®

Co-reporter:Guojun Pan, Robert M. Williams

Tetrahedron 2014 70(2) pp: 276-279

Publication Date(Web):

DOI:10.1016/j.tet.2013.11.066

Mitomycinoid Alkaloids: Mechanism of Action, Biosynthesis, Total Syntheses, and Synthetic Approaches

Co-reporter:Phillip D. Bass, Daniel A. Gubler, Ted C. Judd, and Robert M. Williams

Chemical Reviews 2013 Volume 113(Issue 8) pp:6816

Publication Date(Web):May 8, 2013

DOI:10.1021/cr3001059

Synthesis and Bioconversions of Notoamide T: A Biosynthetic Precursor to Stephacidin A and Notoamide B

Co-reporter:James D. Sunderhaus, Timothy J. McAfoos, Jennifer M. Finefield, Hikaru Kato, Shengying Li, Sachiko Tsukamoto, David H. Sherman, and Robert M. Williams

Organic Letters 2013 Volume 15(Issue 1) pp:22-25

Publication Date(Web):December 18, 2012

DOI:10.1021/ol302901p

In an effort to further elucidate the biogenesis of the stephacidin and notoamide families of natural products, notoamide T has been identified as the likely precursor to stephacidin A. The total synthesis of notoamide T is described along with it is C-6-epimer, 6-epi-notoamide T. The chemical conversion of stephacidin A to notoamide T by reductive ring opening is described as well as the oxidative conversion of notoamide T to stephacidin A. Furthermore, [13C]2-notoamide T was synthesized and provided to Aspergillus versicolor and Aspergillus sp. MF297-2, in which significant incorporation was observed in the advanced metabolite, notoamide B.

Studies on the biosynthesis of chetomin: enantiospecific synthesis of a putative, late-stage biosynthetic intermediate

Co-reporter:Timothy R. Welch, Robert M. Williams

Tetrahedron 2013 69(2) pp: 770-773

Publication Date(Web):

DOI:10.1016/j.tet.2012.10.075

Synthetic studies on lemonomycin: construction of the tetracyclic core

Co-reporter:Alberto Jiménez-Somarribas, Robert M. Williams

Tetrahedron 2013 69(35) pp: 7505-7512

Publication Date(Web):

DOI:10.1016/j.tet.2013.05.009

The early stages of taxol biosynthesis: An interim report on the synthesis and identification of early pathway metabolites

Co-reporter:Jennifer Guerra-Bubb, Rodney Croteau and Robert M. Williams

Natural Product Reports 2012 vol. 29(Issue 6) pp:683-696

Publication Date(Web):01 May 2012

DOI:10.1039/C2NP20021J

Covering: 1966 to 2012 The biosynthesis of the anti-cancer drug taxol (paclitaxel) has required the collaborative efforts of several research groups to tackle the synthesis and labeling of putative biosynthetic intermediates, in concert with the identification, cloning and functional expression of the biosynthetic genes responsible for the construction of this complex natural product. Based on a combination of precursor labeling and incorporation experiments, and metabolite isolation from Taxus spp., a picture of the complex matrix of pathway oxygenation reactions following formation of the first committed intermediate, taxa-4(5),11(12)-diene, is beginning to emerge. An overview of the current state of knowledge on the early-stages of taxol biosynthesis is presented.

Fungal Origins of the Bicyclo[2.2.2]diazaoctane Ring System of Prenylated Indole Alkaloids

Co-reporter:Jennifer M. Finefield, Jens C. Frisvad, David H. Sherman, and Robert M. Williams

Journal of Natural Products 2012 Volume 75(Issue 4) pp:812-833

Publication Date(Web):April 15, 2012

DOI:10.1021/np200954v

Over eight different families of natural products consisting of nearly 70 secondary metabolites that contain the bicyclo[2.2.2]diazaoctane ring system have been isolated from various Aspergillus, Penicillium, and Malbranchea species. Since 1968, these secondary metabolites have been the focus of numerous biogenetic, synthetic, taxonomic, and biological studies and, as such, have made a lasting impact across multiple scientific disciplines. This review covers the isolation, biosynthesis, and biological activity of these unique secondary metabolites containing the bridging bicyclo[2.2.2]diazaoctane ring system. Furthermore, the diverse fungal origin of these natural products is closely examined and, in many cases, updated to reflect the currently accepted fungal taxonomy.

Synthetic studies toward MPC1001: preparation of a β-hydroxyl-tyrosine derivative

Co-reporter:Paul T. Schuber Jr., Robert M. Williams

Tetrahedron Letters 2012 Volume 53(Issue 4) pp:380-382

Publication Date(Web):25 January 2012

DOI:10.1016/j.tetlet.2011.11.069

A procedure for the asymmetric synthesis of a novel β-hydroxy-α-amino acid derivative to be used in the preparation of the natural product MPC1001 and analogs has been developed. The amino acid was efficiently prepared in six steps via a Mukaiyama aldol reaction via a diphenyloxazinone and 3-bromo-4-methoxybenzaldehyde.We have developed a method for the asymmetric synthesis of a novel β-hydroxy-α-amino acid derivative to be used in the preparation of analogs of the natural product MPC1001. The amino acid was efficiently prepared in six steps via a Mukaiyama aldol reaction by a chiral oxazinone and 3-bromo-4-methoxybenzaldehyde.

Total Synthesis of Hapalindoles J and U

Co-reporter:Ryan J. Rafferty and Robert M. Williams

The Journal of Organic Chemistry 2012 Volume 77(Issue 1) pp:519-524

Publication Date(Web):November 29, 2011

DOI:10.1021/jo202139k

The total synthesis of d,l-hapalindoles J and U has been accomplished. Hapalindole J was prepared in 11% overall yield over 11 synthetic steps and hapalindole U was prepared in 25% overall yield over 13 synthetic steps from commercially available materials. The route employs a novel silyl ether-based strategy for accessing the 6:5:6:6 ring system of the hapalindoles rapidly and in good yields.

Unified Total Syntheses of Fawcettimine Class Alkaloids: Fawcettimine, Fawcettidine, Lycoflexine, and Lycoposerramine B

Co-reporter:Guojun Pan and Robert M. Williams

The Journal of Organic Chemistry 2012 Volume 77(Issue 10) pp:4801-4811

Publication Date(Web):April 21, 2012

DOI:10.1021/jo3006045

The total syntheses of the lycopodium alkaloids fawcettimine, fawcettidine, lycoflexine, and lycoposerramine B have been accomplished through an efficient, unified, and stereocontrolled strategy that relies on a Diels–Alder reaction to construct the cis-fused 6,5-carbocycles with one all-carbon quaternary center. Access to the enantioselective syntheses of both antipodes of those alkaloids can be achieved by kinetic resolution of the earliest intermediate via a Sharpless asymmetric dihydroxylation (Sharpless AD). Compared to existing approaches to these alkaloids, our synthetic route possesses superior stereocontrol over the C-4 and C-15 stereogenic centers as well as allowing for more functional variation on the 6-membered ring.

Enantiomeric Natural Products: Occurrence and Biogenesis

Co-reporter:Jennifer M. Finefield;Dr. David H. Sherman;Dr. Martin Kreitman;Dr. Robert M. Williams

Angewandte Chemie International Edition 2012 Volume 51( Issue 20) pp:4802-4836

Publication Date(Web):

DOI:10.1002/anie.201107204

Abstract

In nature, chiral natural products are usually produced in optically pure form—however, occasionally both enantiomers are formed. These enantiomeric natural products can arise from a single species or from different genera and/or species. Extensive research has been carried out over the years in an attempt to understand the biogenesis of naturally occurring enantiomers; however, many fascinating puzzles and stereochemical anomalies still remain.

Enantiomere Naturstoffe: Vorkommen und Biogenese

Co-reporter:Jennifer M. Finefield;Dr. David H. Sherman;Dr. Martin Kreitman;Dr. Robert M. Williams

Angewandte Chemie 2012 Volume 124( Issue 20) pp:4886-4920

Publication Date(Web):

DOI:10.1002/ange.201107204

Abstract

In der Natur werden chirale Substanzen meist in enantiomerenreiner Form synthetisiert – manchmal entstehen aber auch beide Enantiomere. Solche enantiomeren Naturstoffe können von einer Art oder von verschiedenen Gattungen und/oder Arten gebildet werden. Intensive Forschungen wurden über viele Jahre durchgeführt, um die Biogenese natürlich vorkommender Enantiomere zu verstehen, doch viele faszinierende Rätsel und stereochemische Anomalien sind nach wie vor ungelöst.

Biochemical Characterization of NotB as an FAD-Dependent Oxidase in the Biosynthesis of Notoamide Indole Alkaloids

Co-reporter:Shengying Li, Jennifer M. Finefield, James D. Sunderhaus, Timothy J. McAfoos, Robert M. Williams, and David H. Sherman

Journal of the American Chemical Society 2011 Volume 134(Issue 2) pp:788-791

Publication Date(Web):December 20, 2011

DOI:10.1021/ja2093212

Notoamides produced by Aspergillus spp. bearing the bicyclo[2.2.2]diazaoctane core structure with unusual structural diversity represent a compelling system to understand the biosynthesis of fungal prenylated indole alkaloids. Herein, we report the in vitro characterization of NotB, which catalyzes the indole 2,3-oxidation of notoamide E (13), leading to notoamides C (11) and D (12) through an apparent pinacol-like rearrangement. This unique enzymatic reaction with high substrate specificity, together with the information derived from precursor incorporation experiments using [13C]2–[15N]2 quadruply labeled notoamide S (10), demonstrates 10 as a pivotal branching point in notoamide biosynthesis.

Biosynthetic Studies of the Notoamides: Isotopic Synthesis of Stephacidin A and Incorporation into Notoamide B and Sclerotiamide

Co-reporter:Jennifer M. Finefield, Hikaru Kato, Thomas J. Greshock, David H. Sherman, Sachiko Tsukamoto, and Robert M. Williams

Organic Letters 2011 Volume 13(Issue 15) pp:3802-3805

Publication Date(Web):June 30, 2011

DOI:10.1021/ol201284y

The advanced natural product stephacidin A is proposed as a biosynthetic precursor to notoamide B in various Aspergillus species. Doubly 13C-labeled racemic stephacidin A was synthesized and fed to cultures of the terrestrial-derived fungus, Aspergillus versicolor NRRL 35600, and the marine-derived fungus, Aspergillus sp. MF297-2. Analysis of the metabolites revealed enantiospecific incorporation of intact (−)-stephacidin A into (+)-notoamide B in Aspergillus versicolor and (+)-stephacidin A into (−)-notoamide B in Aspergillus sp. MF297-2. 13C-Labeled sclerotiamide was also isolated from both fungal cultures.

Meta-omic Characterization of the Marine Invertebrate Microbial Consortium That Produces the Chemotherapeutic Natural Product ET-743

Co-reporter:Christopher M. Rath, Benjamin Janto, Josh Earl, Azad Ahmed, Fen Z. Hu, Luisa Hiller, Meg Dahlgren, Rachael Kreft, Fengan Yu, Jeremy J. Wolff, Hye Kyong Kweon, Michael A. Christiansen, Kristina Håkansson, Robert M. Williams, Garth D. Ehrlich, and David H. Sherman

ACS Chemical Biology 2011 Volume 6(Issue 11) pp:1244

Publication Date(Web):August 29, 2011

DOI:10.1021/cb200244t

In many macroorganisms, the ultimate source of potent biologically active natural products has remained elusive due to an inability to identify and culture the producing symbiotic microorganisms. As a model system for developing a meta-omic approach to identify and characterize natural product pathways from invertebrate-derived microbial consortia, we chose to investigate the ET-743 (Yondelis) biosynthetic pathway. This molecule is an approved anticancer agent obtained in low abundance (10–4–10–5 % w/w) from the tunicate Ecteinascidia turbinata and is generated in suitable quantities for clinical use by a lengthy semisynthetic process. On the basis of structural similarities to three bacterial secondary metabolites, we hypothesized that ET-743 is the product of a marine bacterial symbiont. Using metagenomic sequencing of total DNA from the tunicate/microbial consortium, we targeted and assembled a 35 kb contig containing 25 genes that comprise the core of the NRPS biosynthetic pathway for this valuable anticancer agent. Rigorous sequence analysis based on codon usage of two large unlinked contigs suggests that Candidatus Endoecteinascidia frumentensis produces the ET-743 metabolite. Subsequent metaproteomic analysis confirmed expression of three key biosynthetic proteins. Moreover, the predicted activity of an enzyme for assembly of the tetrahydroisoquinoline core of ET-743 was verified in vitro. This work provides a foundation for direct production of the drug and new analogues through metabolic engineering. We expect that the interdisciplinary approach described is applicable to diverse host–symbiont systems that generate valuable natural products for drug discovery and development.

Studies on the Biosynthesis of the Stephacidin and Notoamide Natural Products: A Stereochemical and Genetic Conundrum

Co-reporter:James D. Sunderhaus;David H. Sherman

Israel Journal of Chemistry 2011 Volume 51( Issue 3-4) pp:442-452

Publication Date(Web):

DOI:10.1002/ijch.201100016

Abstract

The stephacidin and notoamide natural products belong to a group of prenylated indole alkaloids containing a bicyclo[2.2.2]diazaoctane core. Biosynthetically, this bicyclic core is believed to be the product of an intermolecular Diels–Alder (IMDA) cycloaddition of an achiral azadiene. Since all of the natural products in this family have been isolated in enantiomerically pure form to date, it is believed that an elusive Diels–Alderase enzyme mediates the IMDA reaction. Adding further intrigue to this biosynthetic puzzle is the fact that several related Aspergillus fungi produce a number of metabolites with the opposite absolute configuration, implying that these fungi have evolved enantiomerically distinct Diels–Alderases. We have undertaken a program to identify every step in the biogenesis of the stephacidins and notoamides, and by combining the techniques of chemical synthesis and biochemical analysis we have been able to identify the two prenyltransferases involved in the early stages of the stephacidin and notoamide biosyntheses. This has allowed us to propose a modified biosynthesis for stephacidin A, and has brought us closer to our goal of finding evidence for, or against, the presence of a Diels–Alderase in this biosynthetic pathway.

Study on the biosynthesis of the notoamides: pinacol-type rearrangement of the isoprenyl unit in deoxybrevianamide E and 6-hydroxydeoxybrevianamide E

Co-reporter:Hikaru Kato, Yuichi Nakamura, Jennifer M. Finefield, Hideharu Umaoka, Takashi Nakahara, Robert M. Williams, Sachiko Tsukamoto

Tetrahedron Letters 2011 Volume 52(Issue 51) pp:6923-6926

Publication Date(Web):21 December 2011

DOI:10.1016/j.tetlet.2011.10.065

Notoamide E: biosynthetic incorporation into notoamides C and D in cultures of Aspergillus versicolor NRRL 35600

Co-reporter:Jennifer M. Finefield, Thomas J. Greshock, David H. Sherman, Sachiko Tsukamoto, Robert M. Williams

Tetrahedron Letters 2011 Volume 52(Issue 16) pp:1987-1989

Publication Date(Web):20 April 2011

DOI:10.1016/j.tetlet.2011.02.078

Notoamide E, a short-lived secondary metabolite, has been proposed as a biosynthetic intermediate to several advanced metabolites isolated from Aspergillus versicolor. In order to verify the role of this indole alkaloid along the biosynthetic pathway, synthetic doubly 13C-labeled notoamide E was fed to Aspergillus versicolor. Analysis of the metabolites showed significant incorporation of notoamide E into the natural products notoamides C and D.

Synthetic studies on the ambiguine family of alkaloids: construction of the ABCD ring system

Co-reporter:Ryan J. Rafferty, Robert M. Williams

Tetrahedron Letters 2011 Volume 52(Issue 17) pp:2037-2040

Publication Date(Web):27 April 2011

DOI:10.1016/j.tetlet.2010.09.086

A racemic synthesis of the ABCD ring core of the ambiguines that preserves the tertiary alcohol has been accomplished in a convergent synthesis in 10 synthetic steps, in an overall yield of 46% from commercially available 4-bromoindole and m-methylanisole.

R. B. Woodward’s unfinished symphony: designing organic superconductors (1975–79)

Co-reporter:Michael P. Cava, M.V. Lakshmikantham, Roald Hoffmann, Robert M. Williams

Tetrahedron 2011 67(36) pp: 6771-6797

Publication Date(Web):

DOI:10.1016/j.tet.2011.05.004

Studies on the Biosynthesis of the Notoamides: Synthesis of an Isotopomer of 6-Hydroxydeoxybrevianamide E and Biosynthetic Incorporation into Notoamide J

Co-reporter:Jennifer M. Finefield, David H. Sherman, Sachiko Tsukamoto, and Robert M. Williams

The Journal of Organic Chemistry 2011 Volume 76(Issue 15) pp:5954-5958

Publication Date(Web):April 19, 2011

DOI:10.1021/jo200218a

6-Hydroxydeoxybrevianamide E is proposed as a biosynthetic precursor to several advanced metabolites isolated from both marine-derived Aspergillus sp. and a terrestrial-derived Aspergillus versicolor. To verify the role of this reverse-prenylated indole alkaloid as an intermediate along the biosynthetic pathway, [13C]2-[15N]-6-hydroxydeoxybrevianamide E was synthesized and fed to Aspergillus versicolor. Analysis of the metabolites showed incorporation of the intermediate only into the natural product notoamide J.

Natural Products Synthesis: Enabling Tools To Penetrate Nature’s Secrets of Biogenesis and Biomechanism

Co-reporter:Robert M. Williams

The Journal of Organic Chemistry 2011 Volume 76(Issue 11) pp:4221-4259

Publication Date(Web):March 25, 2011

DOI:10.1021/jo2003693

Selected examples from our laboratory of how synthetic technology platforms developed for the total synthesis of several disparate families of natural products was harnessed to penetrate biomechanistic and/or biosynthetic queries is discussed. Unexpected discoveries of biomechanistic reactivity and/or penetrating the biogenesis of naturally occurring substances were made possible through access to substances available only through chemical synthesis. Hypothesis-driven total synthesis programs are emerging as very useful conceptual templates for penetrating and exploiting the inherent reactivity of biologically active natural substances. In many instances, new enabling synthetic technologies were required to be developed. The examples demonstrate the often untapped richness of complex molecule synthesis to provide powerful tools to understand, manipulate and exploit Nature’s vast and creative palette of secondary metabolites.

Genome-Based Characterization of Two Prenylation Steps in the Assembly of the Stephacidin and Notoamide Anticancer Agents in a Marine-Derived Aspergillus sp.

Co-reporter:Yousong Ding ; Jeffrey R. de Wet ; James Cavalcoli ; Shengying Li ; Thomas J. Greshock ; Kenneth A. Miller ; Jennifer M. Finefield ; James D. Sunderhaus ; Timothy J. McAfoos ; Sachiko Tsukamoto ; Robert M. Williams ;David H. Sherman

Journal of the American Chemical Society 2010 Volume 132(Issue 36) pp:12733-12740

Publication Date(Web):August 19, 2010

DOI:10.1021/ja1049302

Stephacidin and notoamide natural products belong to a group of prenylated indole alkaloids containing a core bicyclo[2.2.2]diazaoctane ring system. These bioactive fungal secondary metabolites have a range of unusual structural and stereochemical features but their biosynthesis has remained uncharacterized. Herein, we report the first biosynthetic gene cluster for this class of fungal alkaloids based on whole genome sequencing of a marine-derived Aspergillus sp. Two central pathway enzymes catalyzing both normal and reverse prenyltransfer reactions were characterized in detail. Our results establish the early steps for creation of the prenylated indole alkaloid structure and suggest a scheme for the biosynthesis of stephacidin and notoamide metabolites. The work provides the first genetic and biochemical insights for understanding the structural diversity of this important family of fungal alkaloids.

Synthetic studies on palau’amine. Construction of the cyclopentane core via an asymmetric 1,3-dipolar cycloaddition

Co-reporter:Kosuke Namba, Makoto Inai, Uta Sundermeier, Thomas J. Greshock, Robert M. Williams

Tetrahedron Letters 2010 Volume 51(Issue 50) pp:6557-6559

Publication Date(Web):15 December 2010

DOI:10.1016/j.tetlet.2010.10.037

Studies on paraherquamide biosynthesis: synthesis of deuterium-labeled 7-hydroxy-pre-paraherquamide, a putative precursor of paraherquamides A, E, and F

Co-reporter:Konrad Sommer, Robert M. Williams

Tetrahedron 2009 65(16) pp: 3246-3260

Publication Date(Web):

DOI:10.1016/j.tet.2008.08.102

Asymmetric synthesis of the core of AMPTD, the key amino acid of microsclerodermins F-I

Co-reporter:Cameron M. Burnett, Robert M. Williams

Tetrahedron Letters 2009 50(39) pp: 5449-5451

Publication Date(Web):

DOI:10.1016/j.tetlet.2009.06.144

Synthetic studies toward the mitomycins: construction of the tetracyclic core via a reductive aminocyclization reaction

Co-reporter:Daniel A. Gubler, Robert M. Williams

Tetrahedron Letters 2009 50(29) pp: 4265-4267

Publication Date(Web):

DOI:10.1016/j.tetlet.2009.05.004

Synthesis of (±)-oleocanthal via a tandem intramolecular Michael cyclization–HWE olefination

Co-reporter:Brandon J. English, Robert M. Williams

Tetrahedron Letters 2009 50(23) pp: 2713-2715

Publication Date(Web):

DOI:10.1016/j.tetlet.2009.03.145

Detection of VM55599 and Preparaherquamide from Aspergillus japonicus and Penicillium fellutanum: Biosynthetic Implications

Co-reporter:Yousong Ding, Sabine Gruschow, Thomas J. Greshock, Jennifer M. Finefield, David H. Sherman and Robert M. Williams

Journal of Natural Products 2008 Volume 71(Issue 9) pp:1574-1578

Publication Date(Web):August 28, 2008

DOI:10.1021/np800292n

The secondary metabolites VM55599 (4) and preparaherquamide (5) have been identified by LC-MSn analysis as natural metabolites in cultures of Penicillium fellutanum, whereas preparaherquamide has been identified only in cultures of Aspergillus japonicus. In accord with a previous proposal, the identification of both metabolites, which have a diastereomeric relationship, provides indirect support for a unified biosynthetic scheme.

Calmodulin inhibitory activity of the malbrancheamides and various analogs

Co-reporter:Kenneth A. Miller, Mario Figueroa, Meriah W.N. Valente, Thomas J. Greshock, Rachel Mata, Robert M. Williams

Bioorganic & Medicinal Chemistry Letters 2008 Volume 18(Issue 24) pp:6479-6481

Publication Date(Web):15 December 2008

DOI:10.1016/j.bmcl.2008.10.057

The preparation and biological activity of various structural analogs of the malbrancheamides are disclosed. The impact of indole chlorination, C-12a relative stereochemistry, and bicyclo[2.2.2]diazaoctane core oxidation state on the ability of these analogs to inhibit calmodulin dependent phosphodiesterase (PDE1) was studied, and a number of potent compounds were identified.

Studies on Taxol biosynthesis. Preparation and tritium labeling of biosynthetic intermediates by deoxygenation of a taxadiene tetra-acetate obtained from Japanese yew

Co-reporter:Tohru Horiguchi;Christopher D. Rithner;Rodney Croteau

Journal of Labelled Compounds and Radiopharmaceuticals 2008 Volume 51( Issue 9) pp:325-328

Publication Date(Web):

DOI:10.1002/jlcr.1529

Abstract

Taxa-4(20),11(12)-diene-5α-acetate 5 and taxa-4(20),11(12)-diene-5α-acetate, 10β-ol 6, have been identified as early stage intermediates involved in the biosynthesis of Taxol^® (paclitaxel). Tritium-labeled 5 and 6 were successfully prepared by Barton deoxygenation using tri-n-butyltintritiide of the C-14-hydroxyl group of a taxoid obtained from Japanese yew. Copyright © 2008 John Wiley & Sons, Ltd.

A diastereoselective intramolecular Pauson–Khand approach to the construction of the BC-ring system in tuberostemoninol

Co-reporter:Xiangna Jia, Robert M Williams

Tetrahedron: Asymmetry 2008 Volume 19(Issue 24) pp:2901-2906

Publication Date(Web):12 December 2008

DOI:10.1016/j.tetasy.2008.11.022

Herein, we describe an asymmetric approach to the synthesis of a BC-ring synthon in tuberostemoninol via an intramolecular Pauson–Khand reaction stereocontrolled by a commercially available chiral glycinate.C28H29NO6Absolute stereochemistry, [α]D25=-24.9 (c 1, CH2Cl2)C24H23NO3Absolute stereochemistry, [α]D25=+135.3 (c 1, CH2Cl2)

Rabe Rest in Peace: Confirmation of the RabeKindler Conversion of d-Quinotoxine Into Quinine: Experimental Affirmation of the WoodwardDoering Formal Total Synthesis of Quinine

Co-reporter:AaronC. Smith Dr.;RobertM. Williams

Angewandte Chemie 2008 Volume 120( Issue 9) pp:1760-1764

Publication Date(Web):

DOI:10.1002/ange.200705421

Isolation, Structure Elucidation, and Biomimetic Total Synthesis of VersicolamideB, and the Isolation of Antipodal ()-StephacidinA and (+)-NotoamideB from Aspergillus versicolor NRRL35600

Co-reporter:ThomasJ. Greshock Dr.;AlanW. Grubbs;Ping Jiao;DonaldT. Wicklow;JamesB. Gloer ;RobertM. Williams

Angewandte Chemie 2008 Volume 120( Issue 19) pp:3629-3633

Publication Date(Web):

DOI:10.1002/ange.200800106

Rabe Rest in Peace: Confirmation of the RabeKindler Conversion of d-Quinotoxine Into Quinine: Experimental Affirmation of the WoodwardDoering Formal Total Synthesis of Quinine

Co-reporter:AaronC. Smith Dr.;RobertM. Williams

Angewandte Chemie International Edition 2008 Volume 47( Issue 9) pp:1736-1740

Publication Date(Web):

DOI:10.1002/anie.200705421

Isolation, Structure Elucidation, and Biomimetic Total Synthesis of VersicolamideB, and the Isolation of Antipodal ()-StephacidinA and (+)-NotoamideB from Aspergillus versicolor NRRL35600

Co-reporter:ThomasJ. Greshock Dr.;AlanW. Grubbs;Ping Jiao;DonaldT. Wicklow;JamesB. Gloer ;RobertM. Williams

Angewandte Chemie International Edition 2008 Volume 47( Issue 19) pp:3573-3577

Publication Date(Web):

DOI:10.1002/anie.200800106

Effects of Photochemically Activated Alkylating Agents of the FR900482 Family on Chromatin

Co-reporter:Vidya Subramanian, Pascal Ducept, Robert M. Williams, Karolin Luger

Chemistry & Biology 2007 Volume 14(Issue 5) pp:553-563

Publication Date(Web):29 May 2007

DOI:10.1016/j.chembiol.2007.04.004

Bioreductive alkylating agents are an important class of clinical antitumor antibiotics that crosslink and monoalkylate DNA. Here, we use a synthetic, photochemically activated derivative of FR400482 to investigate the molecular mechanism of this class of drugs in a biologically relevant context. We find that the organization of DNA into nucleosomes effectively protects it against drug-mediated crosslinking, while permitting monoalkylation. This modification has the potential to lead to the formation of covalent crosslinks between chromatin and nuclear proteins. Using in vitro approaches, we found that interstrand crosslinking of free DNA results in a significant decrease in basal and activated transcription. Finally, crosslinked plasmid DNA is inefficiently assembled into chromatin. Our studies suggest pathways for the clinical effectiveness of this class of reagents.

Asymmetric Total Synthesis of (−)-Cribrostatin 4 (Renieramycin H)

Co-reporter:Guillaume Vincent Dr.;Robert M. Williams

Angewandte Chemie International Edition 2007 Volume 46(Issue 9) pp:

Publication Date(Web):19 JAN 2007

DOI:10.1002/anie.200604126

Out of the blue: The convergent asymmetric total synthesis of the antitumor antibiotic (−)-cribrostatin 4 from the blue sponge Cribrochalina features asymmetric Staudinger and Pictet–Spengler reactions to form the tetrahydroisoquinoline moiety. These reactions were followed by a reductive opening/elimination of a tricyclic β-lactam and a Pictet–Spengler cyclization to access the unsaturated pentacyclic core.

Asymmetric Total Synthesis of (−)-Cribrostatin 4 (Renieramycin H)

Co-reporter:Guillaume Vincent Dr.;Robert M. Williams

Angewandte Chemie 2007 Volume 119(Issue 9) pp:

Publication Date(Web):19 JAN 2007

DOI:10.1002/ange.200604126

Blaues Wunder: Die konvergente asymmetrische Totalsynthese des Krebsantibiotikums (−)-Cribrostatin 4 aus dem blauen Schwamm Cribrochalina nutzt asymmetrische Staudinger- und Pictet-Spengler-Reaktionen zur Bildung der Tetrahydroisochinolineinheit, eine reduktive Öffnung/Eliminierung eines tricyclischen β-Lactams und eine Pictet-Spengler-Cyclisierung, um zum ungesättigten pentacyclischen Gerüst zu gelangen.