Stellios Arseniyadis

Metathesis in natural product synthesis : strategies, substrates and catalysts

Preface SYNTHESIS OF NATURAL PRODUCTS CONTAINING MEDIUM-SIZE CARBOCYCLES BY RING-CLOSING ALKENE METATHESIS Introduction Formation of Five-Membered Carbocycles by RCM Formation of Six-Membered Carbocycles by RCM Formation of Seven-Membered Carbocycles by RCM Formation of Eight-Membered Carbocycles by RCM Formation of Nine-Membered Carbocycles by RCM Formation of 10-Membered Carbocycles by RCM Conclusion NATURAL PRODUCTS CONTAINING MEDIUM-SIZED NITROGEN HETEROCYCLES SYNTHESIZED BY RING-CLOSING ALKENE METATHESIS Introduction Five-Membered Nitrogen Heterocycles Six-Membered Nitrogen Heterocycles Seven-Membered Nitrogen Heterocycles Eight-Membered Nitrogen Heterocycles Conclusion SYNTHESIS OF NATURAL PRODUCTS CONTAINING MEDIUM-SIZE OXYGEN HETEROCYCLES BY RING-CLOSING ALKENE METATHESIS Introduction General RCM Approaches to Medium Rings Laurencin Eunicellins/Eleutherobin Helianane Octalactin A Microcarpalide and the Herbarums Marine Ladder Toxins Conclusion PHOSPHOROUS AND SULFUR HETEROCYCLES VIA RING-CLOSING METATHESIS: APPLICATION IN NATURAL PRODUCT SYNTHESIS Introduction Synthesis and Reactivity of Sulfones Derived from RCM Total Synthesis of the Originally Proposed Structure of (?)-Mycothiazole Synthesis and Reactivity of Phosphates from RCM Applications of Phosphate Tethers in the Synthesis of Dolabelide C Conclusion SYNTHESIS OF NATURAL PRODUCTS CONTAINING MACROCYCLES BY ALKENE RING-CLOSING METATHESIS Introduction Organization of the Chapter Macrocyclic Polyketides Terpenoids Macrocyclic Lipids Macrocyclic Glycolipids Conclusions and Outlook SYNTHESIS OF NATURAL PRODUCTS AND RELATED COMPOUNDS USING ENE-YNE METATHESIS Introduction Synthesis of Natural Products and Related Compounds Using Ene-Yne Metathesis Synthesis of Natural Products and Related Compounds Using Ene-Yne Cross-Metathesis (CM) Synthesis of Natural Products Using Skeletal Reorganization RING-CLOSING ALKYNE METATHESIS IN NATURAL PRODUCT SYNTHESIS Introduction Alkyne Metathesis Ring-Closing Alkyne Metathesis Applications of RCAM in Natural Product Synthesis Conclusions TEMPORARY SILICON-TETHERED RING-CLOSING METATHESIS REACTIONS IN NATURAL PRODUCT SYNTHESIS Introduction Temporary Silicon-Tethered Ring-Closing Metathesis Reactions Conclusions and Outlook METATHESIS INVOLVING A RELAY AND APPLICATIONS IN NATURAL PRODUCT SYNTHESIS Introduction Early Relay Metathesis Discoveries Examples of Relay Metathesis Directed at Targets Other tan Natural Products Examples of Relay Metathesis Motivated by Natural Product Synthesis Examples of Relay Metatheses Thwarted in Achieving the Desired Outcome Conclusion CROSS-METATHESIS IN NATURAL PRODUCT SYNTHESIS Introduction Functionalization of Olefins Appending a Side Chain Couplings Cascade Processes Involving CM Ene-Yne CM Alkyne CM Conclusion and Perspectives CASCADE METATHESIS IN NATURAL PRODUCT SYNTHESIS Introduction RCM-CM Sequences Ene-Yne-Ene RCM-RCM ROM-CM Sequences RCM-ROM Sequences - Ring-Rearrangement Metathesis (RRM) RCM-ROM Sequences Combined with Other Metathesis Reactions Conclusions and Outlook CATALYTIC ENANTIOSELECTIVE OLEFIN METATHESIS AND NATURAL PRODUCT SYNTHESIS Introduction Total Synthesis of Natural Products with Enantiomerically Pure Chiral Olefin Metathesis Catalysts Bearing a C2-Symmetric Diolate Ligand Enantioselective Synthesis of Quebrachamine through an Exceptionally Challenging RCM Reaction Synthesis of Baconipyrone C by Ru-Catalyzed Enantioselective ROCM Conclusions and Future Outlook METATHESIS REACTIONS IN SOLID-PHASE ORGANIC SYNTHESIS Introduction Metathesis-Based Cyclorelease Reaction Ring-Closing Metathesis (RCM) Intraresin Dimerization Restricting Peptide Conformation through Cyclization Cross-Metathesis on Solid Phase Ene-Yne Metathesis on Solid Phase Conclusion

Amine, Alcohol and Phosphine Catalysts for Acyl Transfer Reactions

An overview of the area of organocatalytic asymmetric acyl transfer processes is presented including O- and N-acylation. The material has been ordered according to the structural class of catalyst employed rather than reaction type with the intention to draw mechanistic parallels between the manner in which the various reactions are accelerated by the catalysts and the concepts employed to control transfer of chiral information from the catalyst to the substrates.

DNA vs. Mirror‐Image DNA: A Universal Approach to Tune the Absolute Configuration in DNA‐Based Asymmetric Catalysis

Mirror mirror on the wall: By taking advantage of the unique structural features of L-DNA, the first examples of left-helical enantioselective induction in the field of DNA-based asymmetric catalysis were realized. Most importantly, this approach is the only one that allows a reliable and predictable access to both enantiomers for any given reaction.

Molecular design and chemical synthesis of a highly potent epothilone.

Ever since the initial discovery of the epothilones in 1996 (for example, EpoA (1) and EpoB (2), Figure 1), synthetic chemists have been enamored with their structures from the perspectives of both synthesis and modification. This rather intense and persistent interest is neither surprising nor without merit, for these naturally occurring substances have proven themselves challenging targets for synthesis, powerful tools in biology, and worthy drug candidates currently in clinical trials as anticancer agents. Our structure–activity relationship (SAR) studies within the epothilone class 4] have defined a narrow range of structural motifs that, when present, endow the epothilone molecule with biological activity and have resulted in the development of several potent epothilones such as the methylthio-EpoB analogues 3 and 4. This model was more or less confirmed by a recent electron crystallographic and NMR-based conformational analysis of a tubulin–EpoA complex that appears to accommodate most of the published SAR data. Herein, we report a new study based on this model that has led to the identification of the most potent epothilone reported to date, natural or designed. From the several regions of the epothilone structure where modifications could be made with the potential to improve the activity of the molecule, we chose the heterocyclic ringcontaining side-chain domain. Having previously established the importance of the basic nitrogen atom in its specific location, we set that condition as a structural requirement for any new designs and kept the rest of the structure of EpoB intact. These limits had the advantage that any potential drug candidate I that could emerge from the investigation could, in principle, be produced either by total synthesis or through semisynthesis from a degradation-derived advanced intermediate II and a heterocyclic stannane III by a palladium-catalyzed cross-coupling reaction such as the Stille reaction, for example, as indicated retrosynthetically in Figure 2. Epothilones 5–21 (Figure 3) were designed within the structural constraints mentioned above and with certain further rationales. The beneficial effect of certain lipophilic substituents such as methyl and methylthio groups on tubulin binding and cytotoxicity did not escape our attention, and thus we introduced such moieties on several of these designs (compounds 5–20). We also wanted to probe the effect of additional rings on the heterocyclic side chain (compounds 7, 17–19, and 20) as well as the absence of a ring on the same side chain (compound 21). Finally, we wished to challenge the ability of the tubulin receptor pocket to accommodate bulky halogen substituents such as those in compounds 10 and 12.

Total Synthesis and Structural Revision of Vannusals A and B. Synthesis of the Originally Assigned Structure of Vannusal B

The total synthesis of the originally assigned structure of vannusal B (2) and its diastereomer (d-2) are described. Initial forays into these structures with model systems revealed the viability of a metathesis-based approach and a SmI(2)-mediated strategy for the key cyclization to forge the central region of the molecule, ring C. The former approach was abandoned in favor of the latter when more functionalized substrates failed to enter the cyclization process. The successful, devised convergent strategy based on the SmI(2)-mediated ring closure utilized vinyl iodide (-)-26 and aldehyde fragment (+/-)-86 as key building blocks, whose lithium-mediated coupling led to isomeric coupling products (+)-87 and (-)-88 (as shown in Scheme 17 in the article). Intermediate (-)-88 was converted, via (-)-89 and (-)-90/(+)-91, to vannusal B structure 2 (as shown in Scheme 18 in the article), whose spectroscopic data did not match those reported for the natural product. Similarly, intermediate (+)-25, obtained through coupling of vinyl iodide (-)-26 and aldehyde (+/-)-27 (as shown in Scheme 13 in the article) was transformed via intermediates (-)-97 and (+)-98 (as shown in Scheme 19 in the article) to diastereomeric vannusal B structure (+)-d-2 (as shown in Scheme 19 in the article) which was also proven spectroscopically to be non-identical to the naturally occurring substance. These investigations led to the discovery and development of a number of new synthetic technologies that set the stage for the solution of the vannusal structural conundrum.

Asymmetric Total Synthesis of the Immunosuppressant (! )-Pironetin**

Independently isolated by Yoshida et al. and Kobayashi and co-workers from Streptomyces sp. NK-10958 and the fermentation broths of Streptomyces prunicolor PA-48153, ( )-Pironetin (1) was found to display plant-growth-regulatory as well as immunosuppressive activities similar to those exhibited by cyclosporin A (CsA) and FK-506. More recently, ( )-pironetin has since been identified as a strong antitumor agent that influences the dynamics of the tubulin– microtubules system by inhibiting the polymerization of tubulin. Interestingly, whereas other antitumor agents such as colchicin, vinblastin, rhizoxin, and epothilone B, bind to btubulin, ( )-pironetin was shown to bind to the a subunit of tubulin.

Synthesis of vinyl-functionalized oxazoles by olefin cross-metathesis.

A ruthenium-based catalyzed olefin cross-methathesis reaction involving 2- and 4-vinyl-functionalized oxazoles was developed. A wide range of olefinic partners was coupled in good to excellent yields and high stereoselectivities under mild conditions. This methodology offers new opportunities for the synthesis of a plethora of biologically active natural products.

A straightforward preparation of amino–polystyrene resin from Merrifield resin

Abstract Azidomethyl–polystyrene, obtained by nucleophilic substitution of chloromethyl–polystyrene, undergoes a Schmidt rearrangement when treated with trifluoromethanesulfonic acid, affording amino–polystyrene. To assess its loading and reactivity the resin is used as a support for the preparation of triazene-linked amine.

Total synthesis of nominal lyngbouilloside aglycon.

The first enantioselective total synthesis of the originally assigned structure of lyngbouilloside aglycon has been achieved using a particularly flexible route featuring an acylketene macrolactonization of a tertiary methyl carbinol as the key step. Comparison of the C13 chemical shifts of our synthetic aglycon with the ones pertaining to natural lyngbouilloside and lyngbyaloside C resulted in a possible stereochemical reassignment of the C11 stereogenic center.

Enantioselective organocatalytic conjugate reduction of beta-azole-containing alpha,beta-unsaturated aldehydes.

Beta-azole-containing alpha,beta-unsaturated aldehydes were successfully reduced under highly enantioselective organocatalytic transfer hydrogenation conditions. The products were obtained in good yields and up to 94% optical purity. This simple process was successfully applied to the synthesis of the C7-C14 fragment of ulapualide A, a natural product which exhibits promising antitumor activity.