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Biomedical subjects

Johann Mulzer

Publications and source records attributed to Johann Mulzer.

At least 19 recordsLinked to original sources
PubMed2006

A tether controlled exo-selective trans-annular Diels-Alder (TADA) reaction.

[reaction: see text] A fully substrate controlled stereoselective route to construct cis-hexahydronaphthalene 4 is described starting from nonracemic butenolide 6. The key step is an exo-selective transannular Diels-Alder reaction (TADA) of tetraene 5, whose intrinsic constraint allows selective formation of one stereodefined product. Compound 4 is a key intermediate in the synthesis of the novel antibiotic branimycin (1).

Anti-Bacterial Agents↗
PubMed2006

Cross metathesis as a general strategy for the synthesis of prostacyclin and prostaglandin analogues.

[reaction: see text] A cross metathesis (CM) approach has been successfully applied to introduce fully functionalized omega-side chain appendages of various prostacyclin and prostaglandin analogues, resulting in high (E)-selectivities for the C13-C14 double bond and leading to the total syntheses of isocarbacyclin, 15R-TIC, carbacyclin, and PGF(2)(alpha) and the formal syntheses of 15-deoxy-TIC and PGJ(2).

Epoprostenol↗
PubMed2005

Access to isocarbacyclin derivatives via substrate-controlled enolate formation: total synthesis of 15-deoxy-16-(m-tolyl)- 17,18,19,20-tetranorisocarbacyclin.

[reaction: see text] We describe a convergent and flexible synthesis of 15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC), a simple isocarbacyclin derivative. The synthesis takes advantage of two key step reactions: a regioselective deprotonation of the described ketone under substrate control which is then trapped, as the enol triflate, to generate the C6-C9alpha endocyclic double bond, followed by an sp2-sp3 Pd-catalyzed cross-coupling reaction (C5-C6) with a suitable primary alkyl Grignard reagent. Introduction of the C13-C14 (E)-double bond in the omega-side chain is performed by the Julia-Kocieñski olefination.

Catalysis↗
PubMed2005

Synthesis of epothilones via a silicon-tethered RCM reaction.

[reaction: see text] A short synthesis of epothilone B and D is reported. The key step for generating the C12-13-trisubstituted Z-double bond uses a ring-closing metathesis reaction of a disiloxane to form a nine-membered silicon-tethered ring.

Catalysis↗
PubMed2005

Recent applications of olefin ring-closing metathesis (RCM) in the synthesis of biologically important alkaloids, terpenoids, polyketides and other secondary metabolites.

With the commercial availability of well-defined ruthenium metathesis catalysts which combine high stability and broad functional group compatibility with undiminished activity, ring-closing metathesis (RCM) is now routinely integrated in the planning of natural product syntheses. Thus, ring sizes of practically any kind from five onward may be formed. The presence of heteroatoms such as oxygen and nitrogen is of minor importance. Ring-strain and the presence of additional double bonds may be overcome by judicious selection of conditions. A major drawback of macrocyclic RCM still is the lack of E/Z stereocontrol. Nevertheless, the current overview will demonstrate the overwhelming power and scope of RCM in the total synthesis of structurally demanding natural products.

Alkaloids↗
PubMed2004

Synthesis of analogue structures of the p-quinone methide moiety of kendomycin.

[reaction: see text] The synthesis of two model p-quinone methide ring systems of the antibiotic and antiosteoporotic compound kendomycin is reported. Two approaches were examined in detail, and the two-step (i) demethylation and (ii) DMDO oxidation were found to be reliable and generally applicable. Additionally, it was found that oxidation of a benzofuran by NaIO(4) on silica produced a long-lived semiquinone radical.

Catalysis↗
PubMed2004

Toward the synthesis of the carbacylic ansa antibiotic kendomycin.

The convergent synthesis of a benzofuran analog of the carbacyclic ansa compound kendomycin has been achieved by assembling three major fragments by means of epoxide opening and directed ortho lithiation. The crucial tetrahydropyran ring was formed by a highly stereoselective cationic cyclization. Analysis of all synthesized tetrahydropyran-arene compounds reveals a hindered sp(2)-sp(3) rotation, which results in rotational isomers or atropisomers affecting macrocyclization reactions. The latter could only be achieved by means of Horner-Wadsworth-Emmons olefination.

Anti-Bacterial Agents↗
PubMed2004

Total synthesis of the boron-containing ion carrier antibiotic macrodiolide tartrolon B.

The first total synthesis of the boron-containing macrodiolide antibiotic tartrolon B is reported in full detail. Two convergent approaches to the target compound are described, the first of which eventually failed, due to sensitive functionality. In the second, successful route the key step was a stereoselective boron-mediated aldol addition of a bicyclic acetonide protected ketone to a diene-aldehyde. In this case the synthesis could be completed without major problems, using a Yamaguchi dimerization macrolactonization endgame.

Aldehydes↗
PubMed2004

Lessons learned from macrolide synthesis.

The highlights of three macrolide syntheses recently completed in our laboratory are described. In the epothilone B synthesis we developed the "early epoxide approach," which resulted in the first completely stereocontrolled synthesis of this natural product. In the laulimalide synthesis our contribution was the auxiliary controlled ene-macrocyclization and Sharpless' kinetic resolution for achieving a regioselective epoxidation of two pseudo-enantiomorphic allylic alcohol subunits. The tartrolon B synthesis was the first to be completed. In this case, a substrate controlled aldol addition was used to assemble the entire carbon skeleton of the compound.

Borates↗
PubMed2003

A novel approach toward the synthesis of kendomycin: selective synthesis of a C-aryl glycoside as a single atropisomer.

[reaction: see text] A convergent and concise route to an advanced precursor 2b of kendomycin (1) has been developed by applying a S(N)1 ring cyclization as a key step. The resulting C-aryl glycoside was initially isolated as a rotameric mixture, but after MOM protection of the o-hydroxyl of the phenol, the conformation was frozen to the desired kendomycin-like atropisomer.

Glycosides↗
PubMed2003

Total synthesis of Elisabethin A: intramolecular Diels-Alder reaction under biomimetic conditions.

We describe the first total synthesis of the marine diterpenoid elisabethin A. The synthesis uses (S)-hydroxy-2-methyl-propionate as the chiral starting material, which is elaborated into a dienyl-iodide and added to an aryl acetic acid ester via enolate alkylation. The hydroquinoid system is oxidized to the quinone which serves as the dienophile in a highly stereocontrolled intramolecular Diels-Alder addition. This IMDA reaction, which to our knowledge is the first one to employ a terminal (Z)-diene, proceeds under biomimetic conditions (water, ferrichloride as the oxidant, room temperature) with high yield and stereoselectivity. The Diels-Alder adduct is transformed into the natural product via a three-step sequence including selective hydrogenation, base-catalyzed epimerization of the cis- into the trans-decalin system and O-demethylation.

Animals↗
PubMed2003

Total synthesis of the microtubule stabilizing antitumor agent laulimalide and some nonnatural analogues: the power of Sharpless' asymmetric epoxidation.

Three different routes are described for the synthesis of deoxylaulimalide (3), which is the immediate precursor of the marine sponge metabolite laulimalide (1). These routes mainly differ with respect to their ring closing step. Thus, route 1 uses a Still-Gennari olefination, route 2 a Yamaguchi lactonization, and route 3 an intramolecular allylsilane-aldehyde addition for establishing the macrocyclic structure. The unprotected deoxy derivative 3 was subjected to Sharpless' asymmetric epoxidation (SAE). With (R,R)-tartrate the 16,17-epoxide laulimalide (1) is formed selectively, whereas (S,S)-tartrate generates the 21,22-epoxide 142. This demonstrates the high reagent control involved in the SAE process, which in this case is used to achieve high stereo- and regioselectivity. Laulimalide and some derivatives thereof have been tested with respect to antitumor activity and compared to standard compounds paclitaxel and epothilone B.

Animals↗
PubMed2002

Borane-ammonia complexes stabilized by hydrogen bonding.

Novel boron-ammonia complexes, wherein an NH(3) molecule is tightly bound through all four of its atoms, have been prepared and studied. The solid-state structure of ortho MOM-phenyllithium is reported. [reaction: see text]

Journal Article↗
PubMed1998

Synthesis of Enantiomerically Pure Morphine Alkaloids: The Hydrophenanthrene Route.

A concise, linear, total synthesis of (-)-dihydrocodeinone-a close synthetic precursor of (-)-codeine and (-)-morphine-has been achieved. The carbocyclic core of the alkaloid was provided in the form of a phenanthrenone, which was resolved by chromatography on cellulose triacetate. A cuprate conjugate addition was used to establish the crucial benzylic quaternary stereocenter and to introduce the C(2)-side chain. Dimeric byproducts provide evidence for a single electron transfer (SET) mechanism. Unusual S(N)2 and radical cyclizations were employed for the formation of the dihydrobenzofuran and the piperidine ring, respectively.

Journal Article↗