Simon J. Meek

Catalytic Z-selective olefin cross-metathesis for natural product synthesis

Alkenes are found in many biologically active molecules, and there are a large number of chemical transformations in which alkenes act as the reactants or products (or both) of the reaction. Many alkenes exist as either the E or the higher-energy Z stereoisomer. Catalytic procedures for the stereoselective formation of alkenes are valuable, yet methods enabling the synthesis of 1,2-disubstituted Z alkenes are scarce. Here we report catalytic Z-selective cross-metathesis reactions of terminal enol ethers, which have not been reported previously, and of allylic amides, used until now only in E-selective processes. The corresponding disubstituted alkenes are formed in up to >98% Z selectivity and 97% yield. These transformations, promoted by catalysts that contain the highly abundant and inexpensive metal molybdenum, are amenable to gram-scale operations. Use of reduced pressure is introduced as a simple and effective strategy for achieving high stereoselectivity. The utility of this method is demonstrated by its use in syntheses of an anti-oxidant plasmalogen phospholipid, found in electrically active tissues and implicated in Alzheimer’s disease, and the potent immunostimulant KRN7000.

Highly efficient molybdenum-based catalysts for enantioselective alkene metathesis

Discovery of efficient catalysts is one of the most compelling objectives of modern chemistry. Chiral catalysts are in particularly high demand, as they facilitate synthesis of enantiomerically enriched small molecules that are critical to developments in medicine, biology and materials science. Especially noteworthy are catalysts that promote—with otherwise inaccessible efficiency and selectivity levels—reactions demonstrated to be of great utility in chemical synthesis. Here we report a class of chiral catalysts that initiate alkene metathesis with very high efficiency and enantioselectivity. Such attributes arise from structural fluxionality of the chiral catalysts and the central role that enhanced electronic factors have in the catalytic cycle. The new catalysts have a stereogenic metal centre and carry only monodentate ligands; the molybdenum-based complexes are prepared stereoselectively by a ligand exchange process involving an enantiomerically pure aryloxide, a class of ligands scarcely used in enantioselective catalysis. We demonstrate the application of the new catalysts in an enantioselective synthesis of the Aspidosperma alkaloid, quebrachamine, through an alkene metathesis reaction that cannot be promoted by any of the previously reported chiral catalysts.

Catalytic Enantioselective Olefin Metathesis in Natural Product Synthesis. Chiral Metal-Based Complexes that Deliver High Enantioselectivity and More

Chiral olefin metathesis catalysts enable chemists to access enantiomerically enriched small molecules with high efficiency; synthesis schemes involving such complexes can be substantially more concise than those that would involve enantiomerically pure substrates and achiral Mo alkylidenes or Ru-based carbenes. The scope of research towards design and development of chiral catalysts is not limited to discovery of complexes that are merely the chiral versions of the related achiral variants. A chiral olefin metathesis catalyst, in addition to furnishing products of high enantiomeric purity, can offer levels of efficiency, product selectivity and/or olefin stereoselectivity that are unavailable through the achiral variants. Such positive attributes of chiral catalysts (whether utilized in racemic or enantiomerically enriched form) should be considered as general, applicable to other classes of transformations.

Design and Stereoselective Preparation of a New Class of Chiral Olefin Metathesis Catalysts and Application to Enantioselective Synthesis of Quebrachamine: Catalyst Development Inspired by Natural Product Synthesis

A total synthesis of the Aspidosperma alkaloid quebrachamine in racemic form is first described. A key catalytic ring-closing metathesis of an achiral triene is used to establish the all-carbon quaternary stereogenic center and the tetracyclic structure of the natural product; the catalytic transformation proceeds with reasonable efficiency through the use of existing achiral Ru or Mo catalysts. Ru- or Mo-based chiral olefin metathesis catalysts have proven to be inefficient and entirely nonselective in cases where the desired product is observed. In the present study, the synthesis route thus serves as a platform for the discovery of new olefin metathesis catalysts that allow for efficient completion of an enantioselective synthesis of quebrachamine. Accordingly, on the basis of mechanistic principles, stereogenic-at-Mo complexes bearing only monodentate ligands have been designed. The new catalysts provide significantly higher levels of activity than observed with the previously reported Ru- or Mo-based complexes. Enantiomerically enriched chiral alkylidenes are generated through diastereoselective reactions involving achiral Mo-based bispyrrolides and enantiomerically pure silyl-protected binaphthols. Such chiral catalysts initiate the key enantioselective ring-closing metathesis step in the total synthesis of quebrachamine efficiently (1 mol % loading, 22 degrees C, 1 h, >98% conversion, 84% yield) and with high selectivity (98:2 er, 96% ee).

Intermolecular Hydroamination of 1,3-Dienes Catalyzed by Bis(phosphine)carbodicarbene–Rhodium Complexes

A carbodicarbene (CDC)-based pincer ligand scaffold is reported, along with its application to site-selective Rh(I)-catalyzed intermolecular hydroamination of 1,3-dienes with aryl and alkyl amines. To the best of our knowledge, this is the first example of the use of a well-defined CDC complex as an efficient catalyst. Transformations proceed in the presence of 1.0-5.0 mol % Rh complex at 35-120 °C; allylic amines are obtained in up to 97% yield and with >98:2 site selectivity.

Enantio- and Diastereoselective Synthesis of 1,2-Hydroxyboronates through Cu-Catalyzed Additions of Alkylboronates to Aldehydes

The first catalytic enantio- and diastereoselective synthesis of 1,2-hydroxyboronates is reported. Reactions are promoted by a readily available chiral monodentate phosphoramidite-copper complex in the presence of an alkyl 1,1-diboron reagent. Products contain two contiguous stereogenic centers and are obtained in up to 91% yield, >98:2 d.r., and 98:2 e.r. The reaction is tolerant of aryl and vinyl aldehydes, and the 1,2-hydroxyboronate products can be transformed into versatile derivatives. Mechanistic experiments indicate control of absolute stereochemistry of the α-boryl component.

The Significance of Degenerate Processes to Enantioselective Olefin Metathesis Reactions Promoted by Stereogenic-at-Mo Complexes

The present study provides spectroscopic and experimental evidence demonstrating that degenerate metathesis is critical to the effectiveness of this emerging class of chiral catalysts. Isolation and X-ray characterization of both diastereomeric complexes, as well as an examination of the reactivity and enantioselectivity patterns exhibited by such initiating neophylidenes in promoting ring-closing metathesis processes, are disclosed. Only when sufficient amounts of ethylene are generated and inversion at Mo through degenerate processes occurs at a sufficiently rapid rate is high enantioselectivity achieved, irrespective of the stereochemical identity of the initiating alkylidene (Curtin-Hammett kinetics). With diastereomeric metal complexes that undergo rapid interconversion, stereomutation at the metal center becomes inconsequential, and stereoselective synthesis of a chiral catalyst is not required.

Lewis Acid Activation of Carbodicarbene Catalysts for Rh-Catalyzed Hydroarylation of Dienes

The activation of carbodicarbene (CDC)-Rh(I) pincer complexes by secondary binding of metal salts is reported for the catalytic site-selective hydro-heteroarylation of dienes (up to 98% yield and >98:2 γ:α). Reactions are promoted by 5 mol % of a readily available tridentate (CDC)-Rh complex in the presence of an inexpensive lithium salt. The reaction is compatible with a variety of terminal and internal dienes and tolerant of ester, alkyl halide, and boronate ester functional groups. X-ray data and mechanistic experiments provide support for the role of the metal salts on catalyst activation and shed light on the reaction mechanism. The increased efficiency (120 to 22 °C) made available by catalytic amounts of metal salts to catalysts containing C(0) donors is a significant aspect of the disclosed studies.

Enantioselective synthesis of P-stereogenic phosphinates and phosphine oxides by molybdenum-catalyzed asymmetric ring-closing metathesis.

Chiral phosphines have found widespread use in chemical synthesis as ligands for transition metal catalysis.[1] Along with phosphine oxides and other derivatives, they have also become popular choices as catalysts in organic synthesis.[2] Organophosphorus-based catalysis will undoubtedly benefit from a more diverse range of P-stereogenic phosphines. In response to this demand, metal-catalyzed asymmetric syntheses of P-stereogenic phosphines and their derivatives have recently emerged, with key contributions including alkyne hydrophosphorylation,[3] the alkylation and arylation of secondary phosphines,[4] enantioselective deprotonation,[5] and rhodium-catalyzed [2+2+2] cycloaddition.[6] To date, these catalytic enantioselective routes remain largely outnumbered by well-established methods based on resolutions[7] or on the use of chiral auxiliaries.[8] In spite of recent advances in the area of olefin metathesis, the utility of asymmetric ring-closing metathesis (ARCM)[9] has not been applied to the preparation of P-stereogenic phosphine derivatives.[10] In light of literature precedents, which demonstrate that various P-containing dienes, trienes, and tetraenes are suitable substrates for olefin metathesis,[11] we reasoned that the ARCM of P-templates would be a strategically unique and valuable reaction for the preparation of P-stereogenic compounds. We opted for a catalytic enantioselective desymmetrization process of prochiral P-templates, as this approach offers the opportunity to explore ARCM with the chirality arising from the formation of a stereogenic center other than a carbon atom (Scheme 1). Moreover, the resulting products are structurally novel P-stereogenic scaffolds amenable to rich chemistry further downstream. Herein, we report the first examples of catalytic enantioselective olefin metathesis reactions of phosphinates and phosphine oxides, which lead to the formation of five-, six-, and seven-membered P-heterocycles in up to 98% ee. We also report an unprecedented case of complementary asymmetric induction in reactions promoted by a pair of chiral molybdenum-based complexes differing structurally in their achiral imido ligand.

Stereoselective Tandem Bis-Electrophile Couplings of Diborylmethane

A copper-catalyzed three-component linchpin coupling method for the stereoselective union of readily available epoxides and allyl electrophiles is disclosed. Transformations employ [B(pin)]2-methane as a conjunctive reagent, resulting in the formation of two C-C bonds at a single carbon center bearing a C(sp3) organoboron functional group. Products are obtained in 42-99% yield, and up to >20:1 dr. The utility of the approach is highlighted by stereospecific transformations entailing allylation, tandem cross coupling, and application to the synthesis 1,3-polyol motifs.