Michael E. Jung

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Name: Jung, Michael E.

Organization: University of California , USA

Department: Department of Chemistry and Biochemistry

Title: (PhD)

TOPICS

Organic Chemistry

Phosphine Ligands Diels Alder Reaction

Chemicals
References

Structure-activity relationship study of small molecule inhibitors of the DEPTOR-mTOR interaction

Co-reporter:Jihye Lee, Yijiang Shi, Mario Vega, Yonghui Yang, Joseph Gera, Michael E. Jung, Alan Lichtenstein

Bioorganic & Medicinal Chemistry Letters 2017 Volume 27, Issue 20(Issue 20) pp:

Publication Date(Web):15 October 2017

DOI:10.1016/j.bmcl.2017.09.002

DEPTOR is a 48 kDa protein that binds to mTOR and inhibits this kinase within mTORC1 and mTORC2 complexes. Over-expression of DEPTOR specifically occurs in the multiple myeloma (MM) tumor model and DEPTOR knockdown is cytotoxic to MM cells, suggesting it is a potential therapeutic target. Since mTORC1 paralysis protects MM cells against DEPTOR knockdown, it indicates that the protein–protein interaction between DEPTOR and mTOR is key to MM viability vs death. In a previous study, we used a yeast two-hybrid screen of a small inhibitor library to identify a compound that inhibited DEPTOR/mTOR binding in yeast. This therapeutic (compound B) also prevented DEPTOR/mTOR binding in MM cells and was selectively cytotoxic to MM cells. We now present a structure–activity relationship (SAR) study around this compound as a follow-up report of this previous work. This study has led to the discovery of five new leads – namely compounds 3g, 3k, 4d, 4e and 4g – all of which have anti-myeloma cytotoxic properties superior to compound B. Due to their targeting of DEPTOR, these compounds activate mTORC1 and selectively induce MM cell apoptosis and cell cycle arrest.Download high-res image (59KB)Download full-size image

Thermodynamic Control of Isomerizations of Bicyclic Radicals: Interplay of Ring Strain and Radical Stabilization

Co-reporter:Michael E. Jung, Courtney A. Roberts, Felix Perez, Hung V. Pham, Lufeng Zou, and K. N. Houk

Organic Letters 2016 Volume 18(Issue 1) pp:32-35

Publication Date(Web):December 15, 2015

DOI:10.1021/acs.orglett.5b03112

The rearrangements of 4-substituted bicyclo[2.2.2]oct-5-en-2-yl radicals, generated from the corresponding Diels–Alder adducts with phenylseleno acrylates by radical-induced reductive deselenocarbonylations, give the 2-substituted bicyclo[3.2.1]oct-6-en-2-yl radicals with some substituents, e.g., alkoxy and phenyl, but not for silyloxymethyl or benzyl substituents. Theoretical calculations with DFT give the thermodynamics of these reactions and the origins of these processes.

Synthesis of 2-Ethenylcyclopropyl Aryl Ketones via Intramolecular SN2-like Displacement of an Ester

Co-reporter:Michael E. Jung, Daniel L. Sun, Timothy A. Dwight, Peiyuan Yu, Wei Li, and K. N. Houk

Organic Letters 2016 Volume 18(Issue 19) pp:5138-5141

Publication Date(Web):September 12, 2016

DOI:10.1021/acs.orglett.6b02588

The efficient synthesis of trans-2-ethenylcyclopropyl aryl ketones via an intramolecular SN2-like displacement of an allylic ester is reported. A novel 1,5-acyl shift process is also observed that contributes to the product mixture. Theoretical calculations provide a rationale for the observed product ratio.

Synthesis and Bioactivity of a Brasilicardin A Analogue Featuring a Simplified Core

Co-reporter:Michael E. Jung, Brian T. Chamberlain, Pierre Koch, and Kayvan R. Niazi

Organic Letters 2015 Volume 17(Issue 14) pp:3608-3611

Publication Date(Web):July 6, 2015

DOI:10.1021/acs.orglett.5b01712

An analogue 2 of Brasilicardin A, 1 (BraA), a potent immunosuppressive and cytotoxic agent, was synthesized in which the natural tricyclic skeleton was replaced with a synthetically more accessible substituted tetrahydronaphthalene core. BraA, this analogue (BraL), and cyclosporine A were tested for their ability to inhibit the proliferation of human T cells upon CD3/CD28 activation. Although BraL did not impact T cell activation over the dose range tested, this study shows the inhibitory activity of BraA on human T cells for the first time.

Development of 2-Deoxy-2-[18F]fluororibose for Positron Emission Tomography Imaging Liver Function in Vivo

Co-reporter:Nikolai M. Evdokimov; Peter M. Clark; Graciela Flores; Timothy Chai; Kym F. Faull; Michael E. Phelps; Owen N. Witte∞

Journal of Medicinal Chemistry 2015 Volume 58(Issue 14) pp:5538-5547

Publication Date(Web):June 23, 2015

DOI:10.1021/acs.jmedchem.5b00569

Life-threatening acute liver failure can be triggered by a variety of factors, including common drugs such as acetaminophen. Positron emission tomography (PET) is rarely used to monitor liver function, in part because of a lack of specific imaging agents for liver function. Here we report a new PET probe, 2-deoxy-2-[18F]fluororibose ([18F]-2-DFR), for use in imaging liver function. [18F]-2-DFR was synthesized and validated as a competitive substrate for the ribose salvage pathway. [18F]-2-DFR was prepared through an efficient late stage radiofluorination. The desired selectivity of fluorination was achieved using an unorthodox protecting group on the precursor, which could withstand harsh SN2 reaction conditions with no side reactions. [18F]-2-DFR accumulated preferentially in the liver and was metabolized by the same enzymes as ribose. [18F]-2-DFR could distinguish between healthy liver and liver damaged by acetaminophen. [18F]-2-DFR is expected to be a useful PET probe for imaging and quantifying liver functions in vivo, with likely significant clinical utility.

Trapping of Payne rearrangement intermediates with arylselenide anions

Co-reporter:Michael E. Jung, Daniel L. Sun

Tetrahedron Letters 2015 Volume 56(Issue 23) pp:3082-3085

Publication Date(Web):3 June 2015

DOI:10.1016/j.tetlet.2014.11.103

The intermediate epoxy alcohols prepared via a Payne rearrangement can be trapped with arylselenide anions, giving mixtures of ring-opened products. The 1-arylseleno-2,3-diols are generally favored over the 3-arylseleno-1,2-diols in this process although the reaction of trisubstituted epoxyalcohols, for example, 17, differs from those of disubstituted epoxyalcohols, for example, 21.

Palladium Hydride Promoted Stereoselective Isomerization of Unactivated Di(exo)methylenes to Endocyclic Dienes

Co-reporter:Michael E. Jung, Gloria S. Lee, Hung V. Pham, and K. N. Houk

Organic Letters 2014 Volume 16(Issue 9) pp:2382-2385

Publication Date(Web):April 11, 2014

DOI:10.1021/ol500710v

The exomethylenes of 2,6-disubstituted bicyclo[3.3.1]nonan-9-ones 2 are readily isomerized over a palladium catalyst under an atmosphere of hydrogen to predominantly form the isomer 3 with C2 symmetry with very little formation of the analogous product with Cs symmetry. A hydrogen source is essential to effect the rearrangement.

Synthesis of α-Diketones from Alkylaryl- and Diarylalkynes Using Mercuric Salts

Co-reporter:Michael E. Jung and Gang Deng

Organic Letters 2014 Volume 16(Issue 8) pp:2142-2145

Publication Date(Web):April 1, 2014

DOI:10.1021/ol500592m

Both alkylarylalkynes and diarylalkynes 1 are converted into the α-diketones 2 in good yield by the use of mercuric salts, e.g., mercuric nitrate hydrate or mercuric triflate, in the presence of water. Other mercuric salts, e.g., sulfate, chloride, acetate, or trifluoroacetate, do not provide the diketone product. A possible mechanism is proposed.

Structure–Activity Relationship of Semicarbazone EGA Furnishes Photoaffinity Inhibitors of Anthrax Toxin Cellular Entry

Co-reporter:Michael E. Jung, Brian T. Chamberlain, Chi-Lee C. Ho, Eugene J. Gillespie, and Kenneth A. Bradley

ACS Medicinal Chemistry Letters 2014 Volume 5(Issue 4) pp:363-367

Publication Date(Web):January 21, 2014

DOI:10.1021/ml400486k

EGA, 1, prevents the entry of multiple viruses and bacterial toxins into mammalian cells by inhibiting vesicular trafficking. The cellular target of 1 is unknown, and a structure–activity relationship study was conducted in order to develop a strategy for target identification. A compound with midnanomolar potency was identified (2), and three photoaffinity labels were synthesized (3–5). For this series, the expected photochemistry of the phenyl azide moiety is a more important factor than the IC50 of the photoprobe in obtaining a successful photolabeling event. While 3 was the most effective reversible inhibitor of the series, it provided no protection to cells against anthrax lethal toxin (LT) following UV irradiation. Conversely, 5, which possessed weak bioactivity in the standard assay, conferred robust irreversible protection vs LT to cells upon UV photolysis.Keywords: anthrax lethal toxin; aryl azide; endosomal trafficking; Photoaffinity labeling; semicarbazone;

Synthesis and Duplex-Stabilizing Properties of Fluorinated N-Methanocarbathymidine Analogues Locked in the C3-endo Conformation

Co-reporter:Michael E. Jung;Timothy A. Dwight;Frederic Vigant;Michael E. Østergaard;Eric E. Swayze;Punit P. Seth

Angewandte Chemie 2014 Volume 126( Issue 37) pp:10051-10055

Publication Date(Web):

DOI:10.1002/ange.201405283

Abstract

The efficient synthesis, antiviral activity, and duplex-stabilizing properties of both isomers of the 2′-fluoro analogue of Northern methanocarbathymidine (N-MCT), 2 and 3, are reported. We show that 2′-F incorporation on the N-MCT scaffold has a strong stabilizing effect on duplex thermal stability.

Synthesis of Highly Substituted Adamantanones from Bicyclo[3.3.1]nonanes

Co-reporter:Michael E. Jung and Gloria S. Lee

The Journal of Organic Chemistry 2014 Volume 79(Issue 21) pp:10547-10552

Publication Date(Web):October 2, 2014

DOI:10.1021/jo501368d

Trifluoromethanesulfonic acid and other electrophiles promote formation of the adamantanone core from the readily accessible 1,5-dimethyl-3,7-dimethylenebicyclo[3.3.1]nonan-9-one 2. Because adamantyl cation 3 can be trapped by a range of nucleophiles, including aromatic and heteroaromatic rings, alcohol, nitriles, and halides, access to a wide variety of functionality at the newly formed tertiary position is provided.

Synthesis and Duplex-Stabilizing Properties of Fluorinated N-Methanocarbathymidine Analogues Locked in the C3-endo Conformation

Co-reporter:Michael E. Jung;Timothy A. Dwight;Frederic Vigant;Michael E. Østergaard;Eric E. Swayze;Punit P. Seth

Angewandte Chemie International Edition 2014 Volume 53( Issue 37) pp:9893-9897

Publication Date(Web):

DOI:10.1002/anie.201405283

Abstract

An Epoxyisoprostane Is a Major Regulator of Endothelial Cell Function

Co-reporter:Wei Zhong ; James R. Springstead ; Ramea Al-Mubarak ; Sangderk Lee ; Rongsong Li ; Benjamin Emert ; Judith A. Berliner

Journal of Medicinal Chemistry 2013 Volume 56(Issue 21) pp:8521-8532

Publication Date(Web):October 13, 2013

DOI:10.1021/jm400959q

The goal of these studies was to determine the effect of 5,6-epoxyisoprostane, EI, on human aortic endothelial cells (HAEC). EI can form as a phospholipase product of 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphocholine, PEIPC, a proinflammatory molecule that accumulates in sites of inflammation where phospholipases are also increased. To determine the effect of EI on HAEC, we synthesized several stereoisomers of EI using a convergent approach from the individual optically pure building blocks, the epoxyaldehydes 5 and 6 and the bromoenones 14 and 16. The desired stereoisomer of EI can be prepared from these materials in only six operations, and thus, large amounts of the product can be obtained. The trans/trans isomers had the most potent activity, suggesting specificity in the interaction of EI with the cell surface. EI has potent anti-inflammatory effects in HAEC. EI strongly inhibits the production of MCP-1, a major monocyte chemotactic factor, and either decreases or minimally increases the levels of 10 proinflammatory molecules increased by PEIPC. EI also strongly down-regulates the inflammatory effects of IL-1β, a major inflammatory cytokine. Thus EI, a hydrolytic product of PEIPC, has potent anti-inflammatory function.

Studies Toward the Enantiospecific Total Synthesis of Rhodexin A

Co-reporter:Michael E. Jung and Mikhail Guzaev

The Journal of Organic Chemistry 2013 Volume 78(Issue 15) pp:7518-7526

Publication Date(Web):July 8, 2013

DOI:10.1021/jo400909t

Studies toward the enantiospecific total synthesis of rhodexin A via a very hindered inverse electron demand Diels–Alder reaction are described. The C8-diastereomer of the fully elaborated tetracyclic core of rhodexin A, 23, was prepared in good yield and excellent selectivity using as the key step the stepwise Diels–Alder reaction of the very hindered dienone 3 and the silyl enol ether 4 catalyzed by the very strong Lewis acid, dimethylaluminum triflimide.

Se-Phenyl Prop-2-eneselenoate: An Ethylene Equivalent for DielsAlder Reactions

Co-reporter: Michael E. Jung;Felix Perez;Dr. Collin F. Regan;Dr. Sung Wook Yi ;Dr. Quentin Perron

Angewandte Chemie International Edition 2013 Volume 52( Issue 7) pp:2060-2062

Publication Date(Web):

DOI:10.1002/anie.201208294

Se-Phenyl Prop-2-eneselenoate: An Ethylene Equivalent for DielsAlder Reactions

Co-reporter: Michael E. Jung;Felix Perez;Dr. Collin F. Regan;Dr. Sung Wook Yi ;Dr. Quentin Perron

Angewandte Chemie 2013 Volume 125( Issue 7) pp:2114-2116

Publication Date(Web):

DOI:10.1002/ange.201208294

Total Synthesis of the Proposed Structure of Mycosporulone: Structural Revision and an Unexpected Retro-Aldol/Aldol Reaction

Co-reporter:Michael E. Jung and Jonah J. Chang

Organic Letters 2012 Volume 14(Issue 18) pp:4898-4901

Publication Date(Web):September 6, 2012

DOI:10.1021/ol302234a

The proposed structure of the fungal metabolite, mycosporulone 1, was prepared starting from the cyclohexenone ester 11 and the d-(R)-glyceraldehyde acetonide 12. The spectroscopic data for both 1 and its C2 epimer 1a did not match those reported for the natural product. A revised structure 29 for mycosporulone is proposed.

Trimethylaluminum–Triflimide Complexes for the Catalysis of Highly Hindered Diels–Alder Reactions

Co-reporter:Michael E. Jung and Mikhail Guzaev

Organic Letters 2012 Volume 14(Issue 20) pp:5169-5171

Publication Date(Web):October 3, 2012

DOI:10.1021/ol302172y

Two catalysts, Me2AlNTf2 and MeAl(NTf2)2, derived from the mixing of trimethylaluminum with triflimide, proved to be highly effective catalysts in hindered Diels–Alder reactions, generating the desired Diels–Alder cycloadducts from both hindered 2-silyloxydienes and hindered dienophiles. Thus reaction of 1 with 2 afforded the hindered cycloadduct 4 in excellent yield in 0.5–1.5 h at −40 °C.

Synthesis of threo-β-aminoalcohols from aminoaldehydes via chelation-controlled additions. Total synthesis of l-threo sphingosine and safingol

Co-reporter:Michael E. Jung, Sung Wook Yi

Tetrahedron Letters 2012 Volume 53(Issue 32) pp:4216-4220

Publication Date(Web):8 August 2012

DOI:10.1016/j.tetlet.2012.05.153

Chelation-controlled addition of organocuprates to N-carbamoyl aminoaldehydes, prepared from functionalized amino acids, generated predominately the threo-β-amino alcohol derivatives through chelation with the carbamoyl moiety. The carbamate group is a stronger chelating group than other potentially good chelators, for example ethers, esters, thioethers, and gives good diastereoselectivity with cuprates. Thus addition of lithium divinylcuprate to the aldehyde generated from the serine derivative 25 in the presence of extra copper for chelation afforded the threo compound 26 in 83% yield. Cross-metathesis and cleavage of the protecting groups furnished l-threo sphingosine 21. In addition the lyso-sphingolipid protein kinase C inhibitor, safingol, 22, was prepared from commercially available O-benzyl N-BOC serine 28 in six steps and 56% overall yield by this method.

Synthesis of the 1-Monoester of 2-Ketoalkanedioic Acids, for Example, Octyl α-Ketoglutarate

Co-reporter:Michael E. Jung and Gang Deng

The Journal of Organic Chemistry 2012 Volume 77(Issue 23) pp:11002-11005

Publication Date(Web):November 19, 2012

DOI:10.1021/jo302308q

Oxidative cleavage of cycloalkene-1-carboxylates, made from the corresponding carboxylic acids, and subsequent oxidation of the resulting ketoaldehyde afforded the important 1-monoesters of 2-ketoalkanedioic acids. Thus ozonolysis of octyl cyclobutene-1-carboxylate followed by sodium chlorite oxidation afforded the 1-monooctyl 2-ketoglutarate. This is a cell-permeable prodrug form of α-ketoglutarate, an important intermediate in the tricarboxylic acid (TCA, Krebs) cycle and a promising therapeutic agent in its own right.

Computational Elucidation of the Origins of Reactivity and Selectivity in Non-Aldol Aldol Rearrangements of Cyclic Epoxides

Co-reporter:Hao Wang, K. N. Houk, Damian A. Allen, and Michael E. Jung

Organic Letters 2011 Volume 13(Issue 12) pp:3238-3241

Publication Date(Web):May 13, 2011

DOI:10.1021/ol2011488

The non-aldol aldol reaction of the isomeric epoxy silyl ethers is controlled by the conformation of the transition states leading to an internal hydride shift. One isomer rearranges to the β-silyloxy ketone whereas the other isomer gives a β-elimination product. Theoretical calculations show that the substrates with substituents that favor the formation of the chairlike transition state rearrange normally while those that do not undergo elimination instead.

Mild, selective deprotection of PMB ethers with triflic acid/1,3-dimethoxybenzene

Co-reporter:Michael E. Jung, Pierre Koch

Tetrahedron Letters 2011 Volume 52(Issue 46) pp:6051-6054

Publication Date(Web):16 November 2011

DOI:10.1016/j.tetlet.2011.08.102

An efficient method for the cleavage of the p-methoxybenzyl protecting group of several alcohols in the presence of 0.5 equiv of trifluoromethanesulfonic acid and 1,3-dimethoxybenzene in dichloromethane at room temperature is described.Triflic acid and 1,3-dimethoxybenzene in dichloromethane readily cleaves p-methoxybenzyl (PMB) ethers at room temperature, for example, 13 affords 14 in 98% yield.

Synthesis of BCD tricyclic analogues of the novel cardiac glycoside rhodexin A

Co-reporter:Michael E. Jung, Hiufung V. Chu

Tetrahedron Letters 2011 Volume 52(Issue 35) pp:4512-4514

Publication Date(Web):31 August 2011

DOI:10.1016/j.tetlet.2011.06.114

A concise synthesis of novel cardiac glycoside analogues of rhodexin A, 14 and 24, having the BCD tricyclic system is described. The key constructive step is an inverse-electron demand Diels–Alder reaction of the silyl enol ether 4 and the 2-acetyldiene, 7 and 15.A concise synthesis of the two BCD tricyclic analogues 14 and 24 of the cardiac glycoside rhodexin A is described.

Improved synthesis of 4-amino-7-nitrobenz-2,1,3-oxadiazoles using NBD fluoride (NBD-F)

Co-reporter:Michael E. Jung, Timothy A. Dong, Xiaolu Cai

Tetrahedron Letters 2011 Volume 52(Issue 20) pp:2533-2535

Publication Date(Web):18 May 2011

DOI:10.1016/j.tetlet.2011.02.111

The 7-nitrobenz-2,1,3-oxadiazole (NBD) unit is a highly useful fluorescent tag with wide application in biology. Installation of the NBD group typically proceeds via the SNAr reaction between an amine and an NBD halide. Herein, we demonstrate that NBD-F 1 results in significantly higher yields than NBD-Cl 2, and that triethylamine in dimethylformamide at 23 °C overnight is a broadly applicable set of conditions for this reaction. In particular, the highly useful fluorescent carbohydrate 2-NBD-glucosamine (2-NBDG, 3) can now be prepared in 75% yield with NBD-F as compared to 12% with NBD-Cl.NBD-F 1 gives much higher yields with amines than does NBD-Cl 2 giving the NBD amines, for example, 2-NBD-glucosamine, 3.

Synthesis and evaluation of compounds that induce readthrough of premature termination codons

Co-reporter:Michael E. Jung, Jin-Mo Ku, Liutao Du, Hailiang Hu, Richard A. Gatti

Bioorganic & Medicinal Chemistry Letters 2011 21(19) pp: 5842-5848

Publication Date(Web):

DOI:10.1016/j.bmcl.2011.07.107

Stereoselective synthesis of a fully protected C13–C23 fragment of tedanolide

Co-reporter:Michael E. Jung, Dongwon Yoo

Tetrahedron 2011 67(52) pp: 10281-10286

Publication Date(Web):

DOI:10.1016/j.tet.2011.10.024

Total Synthesis of Auripyrone B Using a Non-Aldol Aldol−Cuprate Opening Process

Co-reporter:Michael E. Jung, Manon Chaumontet and Ramin Salehi-Rad

Organic Letters 2010 Volume 12(Issue 12) pp:2872-2875

Publication Date(Web):May 25, 2010

DOI:10.1021/ol100985n

A non-aldol aldol−cuprate opening generates the polypropionate 11 from the epoxy ether 14 in eight steps as a single diastereomer. A highly stereoselective aldol reaction of 8 with 9 gives the aldol product 7 in high yield and excellent diastereoselectivity, due to double stereodifferentiation. This compound was used for an efficient synthesis of the natural product auripyrone B 2 in only 20 steps and 8% overall yield from 14 using a late-stage spiroketalization onto a stable hemiketal as the final key step.

Enantiospecific Formal Total Synthesis of (+)-Fawcettimine

Co-reporter:Michael E. Jung and Jonah J. Chang

Organic Letters 2010 Volume 12(Issue 13) pp:2962-2965

Publication Date(Web):June 1, 2010

DOI:10.1021/ol1009762

The diastereospecific attack of the silyl enol ether on the activated cyclopropyl diester 27 generated the hydrindanone 28 with complete stereocontrol. Thermal decarbomethoxylation of 28 gave the monoester 29, a key intermediate in Heathcock’s synthesis, thereby completing a formal total synthesis of (+)-fawcettimine 1. The analogous cyclization of 33, the diastereomer of 27, afforded the diastereomeric diester 34, thereby demonstrating that the cyclization process is diastereospecific.

Structure−Activity Relationship for Thiohydantoin Androgen Receptor Antagonists for Castration-Resistant Prostate Cancer (CRPC)

Co-reporter:Michael E. Jung ; Samedy Ouk ; Dongwon Yoo ; Charles L. Sawyers ; Charlie Chen ; Chris Tran ;John Wongvipat

Journal of Medicinal Chemistry 2010 Volume 53(Issue 7) pp:2779-2796

Publication Date(Web):March 10, 2010

DOI:10.1021/jm901488g

A structure−activity relationship study was carried out on a series of thiohydantoins and their analogues 14 which led to the discovery of 92 (MDV3100) as the clinical candidate for the treatment of hormone refractory prostate cancer.

Dipyrone approach toward the synthesis of the cytotoxic natural product auripyrone A

Co-reporter:Michael E. Jung, Ramin Salehi-Rad

Tetrahedron Letters 2010 Volume 51(Issue 38) pp:4931-4933

Publication Date(Web):22 September 2010

DOI:10.1016/j.tetlet.2010.07.034

An approach to the synthesis of the cytotoxic natural product auripyrone A 1 via the cyclization of an alcohol onto a γ-pyrone in 3 is described. The bis(pyrone) alcohol 3 was prepared efficiently from the advanced aldolate 4 via silyl ether cleavage, oxidation, pyrone formation, and PMB ether removal. Instead of providing auripyrone A 1, the attempted cyclization of 3 gave the product of 1,5-acyl migration 8. Model studies show this to be a general process; therefore, cyclization of an alcohol on such a hindered γ-pyrone under normal conditions is very difficult.Treatment of the bis(pyrone) alcohol 3 with an acid did not give the desired cytotoxic product, auripyrone A, 1, but rather an acyl transfer to give 8. Model studies show this to be a general process and therefore such a cyclization is very difficult.

Synthesis of a trans,syn,trans-Dodecahydrophenanthrene via a Bicyclic Transannular Diels−Alder Reaction: Intermediate for the Synthesis of Fusidic Acid

Co-reporter:Michael E. Jung, Ting-Hu Zhang, Rebecca M. Lui, Osvaldo Gutierrez, and K. N. Houk

The Journal of Organic Chemistry 2010 Volume 75(Issue 20) pp:6933-6940

Publication Date(Web):September 15, 2010

DOI:10.1021/jo101533h

While thermolysis of the macrobicyclic triene lactone 12 did not produce the expected bicyclic transannular Diels−Alder (BTADA) product 13, heating the corresponding ether 18 to 110 °C for 4 h afforded a quantitative yield of the desired cycloadduct 19, which could be easily reduced to the perhydrophenanthrene, an ABC ring analogue of fusidic acid 1. Theoretical calculations with hybrid density functional theory (B3LYP/6-31G(d)) help rationalize why the lactone does not cyclize whereas the ether does.

Synthesis of 2-Substituted 7-Hydroxybenzofuran-4-carboxylates via Addition of Silyl Enol Ethers to o-Benzoquinone Esters

Co-reporter:Michael E. Jung and Felix Perez

Organic Letters 2009 Volume 11(Issue 10) pp:2165-2167

Publication Date(Web):April 16, 2009

DOI:10.1021/ol900416x

Mukaiyama Michael addition of silyl enol ethers 13 to the 1,2-quinone-4-carboxylate 6 (formed in situ by oxidation of the catechol ester 8) afforded the 2-subsituted 7-hydroxybenzofuran-4-carboxylates 14 in fair to good yields. Alkyl and aryl systems work well, but highly electron-rich silyl enol ethers could not be used because of competing oxidation.

Total Synthesis of (±)-Kellermanoldione: Stepwise Cycloaddition of a Functionalized Diene and Allenoate

Co-reporter:Michael E. Jung, Jesus Cordova and Masayuki Murakami

Organic Letters 2009 Volume 11(Issue 17) pp:3882-3885

Publication Date(Web):August 5, 2009

DOI:10.1021/ol901455q

The total synthesis of the diterpene kellermanoldione 1 is reported. Stepwise [4 + 2] cycloaddition of the ketal diene 8 and the allenoate 3 afforded the exo adduct 10x as the major product. It was converted into 1 via six steps, among them a key nonconjugative hydrolysis of a γ-methylene silyl enol ether.

Total Synthesis of AuripyroneA Using a Tandem Non-Aldol Aldol/Paterson Aldol Process as a Key Step

Co-reporter:MichaelE. Jung ;Ramin Salehi-Rad

Angewandte Chemie 2009 Volume 121( Issue 46) pp:8922-8925

Publication Date(Web):

DOI:10.1002/ange.200904607

Total Synthesis of AuripyroneA Using a Tandem Non-Aldol Aldol/Paterson Aldol Process as a Key Step

Co-reporter:MichaelE. Jung ;Ramin Salehi-Rad

Angewandte Chemie International Edition 2009 Volume 48( Issue 46) pp:8766-8769

Publication Date(Web):

DOI:10.1002/anie.200904607

Discovery and structure–activity relationship analysis of Staphylococcus aureus sortase A inhibitors

Co-reporter:Nuttee Suree, Sung Wook Yi, William Thieu, Melanie Marohn, Robert Damoiseaux, Albert Chan, Michael E. Jung, Robert T. Clubb

Bioorganic & Medicinal Chemistry 2009 17(20) pp: 7174-7185

Publication Date(Web):

DOI:10.1016/j.bmc.2009.08.067

Co-reporter:Chris Tran;Samedy Ouk;Nicola J. Clegg;Yu Chen;Philip A. Watson;Vivek Arora;Andrew Kwon;John Wongvipat;Dongwon Yoo;Peter M. Smith-Jones;Teresa Wasielewska;Derek Welsbie;Charlie Degui Chen;Celestia S. Higano;Tomasz M. Beer;David T. Hung;Howard I. Scher;Charles L. Sawyers

Science 2009 Volume 324(Issue 5928) pp:

Publication Date(Web):

DOI:10.1126/science.1168175

A Second Act for Antiandrogens

Men with advanced prostate cancer are often treated with antiandrogens; drugs that inhibit the activity of male hormones, such as testosterone, that help drive tumor growth. Many of these drugs act by functionally disrupting the androgen receptor (AR), a transcriptional regulator of cell proliferation, but tumors eventually become resistant to the drugs by expressing higher levels of the AR. Tran et al. (p. 787, published online 9 April) have developed a “second-generation” antiandrogen, a thiohydantoin called MDV3100, which binds the AR with high affinity. MDV3100 retains its anticancer activity in cell culture and in mouse models even when AR levels are elevated. The drug appears to act both by inhibiting translocation of the AR into the nucleus and by reducing its transcriptional activity. MDV3100 is being tested in patients with advanced prostate cancer, the first group of which have shown a decline in blood levels of a marker of cancer growth, prostate-specific antigen.

Synthesis of (2R,3S) 3-amino-4-mercapto-2-butanol, a threonine analogue for covalent inhibition of sortases

Co-reporter:Michael E. Jung, Jeremy J. Clemens, Nuttee Suree, Chu Kong Liew, Rosemarie Pilpa, Dean O. Campbell, Robert T. Clubb

Bioorganic & Medicinal Chemistry Letters 2005 Volume 15(Issue 22) pp:5076-5079

Publication Date(Web):15 November 2005

DOI:10.1016/j.bmcl.2005.07.073

l-Threonine 2 was converted in seven steps into the protected aminomercaptoalcohol 8, a threonine mimic. This compound 8 was coupled to various oligopeptides to produce two different tetrapeptide analogues, for example, 11 and 17, which were shown to inhibit the Sortase enzymes (SrtA and SrtB) via covalent attachment of the thiol groups of 11 and 17 to the catalytically active cysteine residue of the Sortase enzymes.

Studies towards the total synthesis of an epoxy isoprostane phospholipid, a potent activator of endothelial cells

Co-reporter:Michael E. Jung, Annika Kers, Ganesamoorthy Subbanagounder and Judith A. Berliner

Chemical Communications 2003 (Issue 2) pp:196-197

Publication Date(Web):17 Dec 2002

DOI:10.1039/B209892J

We report studies toward the total synthesis of an epoxy isoprostane, namely the preparation of compound 9 which is an analogue of the elimination product 7 of the naturally occurring epoxy isoprostane 4 by a straightforward route using a three-component coupling, and have shown by several spectroscopic criteria that it closely resembles the natural material.

Efficient Synthesis of a Tricyclic BCD Analogue of Ouabain: Lewis Acid Catalyzed Diels–Alder Reactions of Sterically Hindered Systems

Co-reporter:Michael E. Jung ;Pablo Davidov Dr.

Angewandte Chemie 2002 Volume 114(Issue 21) pp:

Publication Date(Web):4 NOV 2002

DOI:10.1002/1521-3757(20021104)114:21<4299::AID-ANGE4299>3.0.CO;2-N

Auf die richtige Mischung kommt es an! AlBr₃ und AlMe₃ im Verhältnis 10:1 vermitteln die Diels-Alder-Reaktion sterisch gehinderter Dienophile. So ergab die Diels-Alder-Reaktion eines Acetyldiens mit einem tert-Butyldimethylsilyl(TBS)-Enolether vorwiegend das exo-Cycloaddukt in 77 % Ausbeute [Gl. (1); X=COMe, Y=OTBS]. Oxidation, Hydrolyse, Reduktion und Desilylierung dieses Cycloaddukts lieferten eine Verbindung, die der BCD-Ring-Substruktur von Ouabain entspricht.

Efficient Synthesis of a Tricyclic BCD Analogue of Ouabain: Lewis Acid Catalyzed Diels–Alder Reactions of Sterically Hindered Systems

Co-reporter:Michael E. Jung ;Pablo Davidov Dr.

Angewandte Chemie International Edition 2002 Volume 41(Issue 21) pp:

Publication Date(Web):31 OCT 2002

DOI:10.1002/1521-3773(20021104)41:21<4125::AID-ANIE4125>3.0.CO;2-E

The right mix! A 10:1 mixture of AlBr₃ and AlMe₃ promotes the Diels–Alder reaction of hindered dienophiles. For example, the Diels–Alder reaction of an acetyldiene with a tert-butyldimethylsilyl (TBS) enol ether gave mainly the exo cycloadduct in 77 % yield [Eq. (1); X=COMe, Y=OTBS]. Oxidation, hydrolysis, reduction, and desilylation of this cycloadduct afforded a BCD ring analogue of ouabain.