Catalytic Enantioselective Addition of Alkylzirconium Reagents to Aliphatic Aldehydes

A catalytic methodology for the enantioselective addition of alkylzirconium reagents to aliphatic aldehydes is reported here. The versatile and readily accessible chiral Ph-BINMOL ligand, in the presence of Ti(OiPr)4 and a zinc salt, facilitates the reaction, which proceeds under mild conditions and is compatible with functionalized nucleophiles. The alkylzirconium reagents are conveniently generated in situ by hydrozirconation of alkenes with the Schwartz reagent. This work is a continuation of our previous work on aromatic aldehydes.

Alkylzirconocenes in Organic Synthesis: An Overview

Organozirconium chemistry has found extensive applications in organic synthesis since its discovery in the last century. Alkyl­zirconocenes, which are easily generated by the hydrozirconation of alkenes with the Schwartz reagent, are widely utilized for carbon–carbon­ and carbon–heteroatom bond formation. This short review summarizes the progress to date on the applications alkylzirconocenes in organic synthesis.1 Introduction2 General Methods for Generating Alkylzirconocenes3 Transformations of Alkylzirconocenes by Heteroatoms4 Insertion of Unsaturated Groups into Alkylzirconocenes5 Transmetalations6 Cross-Coupling Reactions of Alkylzirconocenes7 Photochemistry of Alkylzirconocenes8 Bimetallic Reagents of Zirconium9 Asymmetric Transformations10 Applications of Alkylzirconocenes Generated from the Negishi Reagent11 Conclusions and Outlook

Reactions of Five-Membered Zirconacycloalkynes And Zirconacycloallenes with Cp2Zr(H)Cl; Formal Hydrogenation by Metal Hydrides

Reactions of five-membered zirconacycloalkynes and zirconacyloallenes (1-zirconacyclopent-3-ynes and 1-zirconacyclopenta-2,3-dienes) with an excess of Cp2Zr(H)Cl, known as the Schwartz reagent, was studied. Both reactions gave five-membered zirconacycloalkenes, 1-zirconacyclopent-3-enes without subsequent work-up...

Illuminating Anti-Hydrozirconation: Controlled Geometric Isomerization of an Organometallic Species

A general strategy to enable the formal anti-hydrozirconation of arylacetylenes is reported that merges cis-hydrometallation using the Schwartz Reagent (Cp2ZrHCl) with a subsequent light-mediated geometric isomerization at λ = 400...

Are Organozirconium Reagents Applicable in Current Organic Synthesis?

The search for mild, user-friendly, easily accessible, and robust organometallic reagents is an important feature of organometallic chemistry. Ideally, new methodologies employing organometallics should be developed with respect to practical applications in syntheses of target compounds. In this short review, we investigate if organozirconium reagents can fulfill these criteria. Organozirconium compounds are typically generated via in situ hydrozirconation of alkenes or alkynes with the Schwartz reagent. Alkyl and alkenylzirconium reagents have proven to be convenient in conjugate additions, allylic substitutions, cross-coupling reactions, and additions to carbonyls or imines. Furthermore, the Schwartz reagent itself is a useful reducing agent for polar functional groups.1 Introduction2 Synthesis and Generation of the Schwartz Reagent3 Structure and Properties of Cp2Zr(H)Cl4 Reactivity of Organozirconium Reagents4.1 Asymmetric Conjugate Addition4.2 Asymmetric Allylic Alkylations4.3 Desymmetrization Reactions4.4 Cross-Coupling Reactions4.5 1,2-Additions5 Conclusions

Chemoselective reduction of isothiocyanates to thioformamides mediated by the Schwartz reagent

Thioformamides are easily prepared – under full chemocontrol – through the partial reduction of isothiocyanates with the in situ generated Schwartz reagent.

C–N Ring Construction: The Hattori Synthesis of (+)-Spectaline

Magnus Rueping of RWTH Aachen University found (Chem. Commun. 2015, 51, 2111) that under Fe catalysis, a Grignard reagent would couple with the iodoazetidine 1 to give the substituted azetidine 2. Timothy F. Jamison of MIT established (Chem. Eur. J. 2015, 21, 7379) a protocol for converting 3, readily available from commercial homoserine lactone, to the alkylated azetidine 4. Long-Wu Ye of Xiamen University used (Chem. Commun. 2015, 51, 2126) a gold catalyst to cyclize 5, readily prepared in high ee, to the versatile ene sulfonamide 6. Chang- Hua Ding and Xue-Long Hou of the Shanghai Institute of Organic Chemistry added (Angew. Chem. Int. Ed. 2015, 54, 1604) the racemic aziridine 7 to the enone 8 to give the pyrrolidine 9 in high ee. Arumugam Sudalai of the National Chemical Laboratory employed (J. Org. Chem. 2015, 80, 2024) proline as an organocatalyst to mediate the addition of 11 to 10, leading to the pyrrolidine 12. Aaron D. Sadow of Iowa State University developed (J. Am. Chem. Soc. 2015, 137, 425) a Zr catalyst for the enantioselective cyclization of the prochiral 13 to 14. Masahiro Murakami of Kyoto University devised (Angew. Chem. Int. Ed. 2015, 54, 7418) a Rh catalyst for the enantioselective ring expansion of the photocycliza­tion product of 15 to the enamine 16. Sebastian Stecko and Bartlomiej Furman of the Polish Academy of Sciences reduced (J. Org. Chem. 2015, 80, 3621) the carbohydrate-derived lactam 17 with the Schwartz reagent to give an intermediate that could be coupled with an isonitrile, leading to the amide 18. Lei Liu of Shandong University oxidized (Angew. Chem. Int. Ed. 2015, 54, 6012) the alkene 19 in the presence of 20 to give 21. Tomislav Rovis of Colorado State University optimized (J. Am. Chem. Soc. 2015, 137, 4445) a Zn catalyst for the addition of 22 to the nitro alkene 23, leading, after reduction, to the piperidine 24. Carlos del Pozo and Santos Fustero of the Universidad de Valencia used (Org. Lett. 2015, 17, 960) a chiral auxiliary to direct the cyclization of 25 to the bicyclic amine 26. In another illustration of the use of microwave irradiation to activate amide bond rotation, G. Maayan of Technion showed (Org. Lett. 2015, 17, 2110) that 27 could be cyclized efficiently to the medium ring lactam 28.

Metal-Mediated C–C Ring Construction: The Sun/Lin Synthesis of Huperzine A

Zachary T. Ball of Rice University found (Chem. Sci. 2014, 5, 1401) that the on-bead performance of a designed Rh- peptide complex was markedly superior to the corre­sponding solution catalysis for the addition of 2 to 1 to give 3. Jin-Quan Yu of Scripps/La Jolla achieved (J. Am. Chem. Soc. 2014, 136, 8138) remarkable ee in the conversion of 4 to 5. Adriaan J. Minnaard of the University of Groningen developed (Adv. Synth. Catal. 2014, 356, 2061) practical conditions for enantioselective conjugate addi­tion– enolate trapping, converting 6 to 8. Alexandre Alexakis of the University of Geneva had reported (Org. Lett. 2014, 16, 118) related results. Jérôme Waser of the Ecole Polytechnique Fédérale de Lausanne assembled (J. Am. Chem. Soc. 2014, 136, 6239) the amino cyclopentane 11 by adding 9 to 10. Jean-Luc Vasse of the Université de Reims used (Org. Lett. 2014, 16, 1506) the Schwartz reagent to cyclize 12 to 13. Eric V. Johnston and Armando Córdova of the University of Stockholm combined (Angew. Chem. Int. Ed. 2014, 53, 3447) Pd and organocatalysis in a cascade of first oxi­dation of 14, then conjugate addition by 15, then cyclization to 16. Professor Alexakis found (Org. Lett. 2014, 16, 2006) that the enolate from con­jugate addition to 17 could be trapped with a nitroalkene 18 to give, after in situ Nef reaction, the 1,4-diketone 19. Fangzhi Peng and Zhihui Shao of Yunnan University added (Chem. Eur. J. 2014, 20, 6112) malonate to the nitro alkene 20 to give an inter­mediate that could be carried to the cyclohexanone 21. Masahisa Nakada of Waseda University devised (Tetrahedron Lett. 2014, 55, 1100) a cascade conjugate reduc­tion—intramolecular conjugate addition to cyclize 22 to 23. Hye-Young Jang of Ajou University dimerized (Synthesis 2014, 46, 1329) cinnamaldehyde 24 with nitrometh­ane to give the fully-substituted cyclohexanol 25. In a remarkable cascade transformation, Joëlle Prunet of the University of Glasgow used (Org. Lett. 2014, 16, 3300) the Zhang Ru catalyst to cyclize 26 to the taxol skeleton 27. In an even more remarkable transformation, Professor Nakada showed (Tetrahedron Lett. 2014, 55, 1597) that cascade conjugate addition– conjugate addition converted 28 to 29, having the rare chair- boat- chair skeleton of the biologically potent fusidic acid and brasilicardin A.