The first examples of 1,3,2-diazaphospholene-catalyzed imine reduction and conjugate reduction reactions are reported. This approach employs readily synthesized alkoxydiazaphospholene precatalysts that can be handled in open air. Reduction of substrates containing Lewis basic functionality, isolated unsaturation, and protic functional groups was accomplished. The synthetic utility of this approach is demonstrated by the synthesis of the important antiparkinson medicine rasagiline and the natural product zingerone.

Macrocyclic compounds are central to discovery of new drugs but their preparation is often challenging because of the energy barrier required for bringing together and fusing the two ends of an acyclic precursor1. Ring-closing metathesis (RCM) 2,3,4 is a catalytic process that has allowed access to countless biologically active macrocyclic organic molecules even on large scale (up to 200 kilograms)5. The potency of a macrocyclic compound can depend on the stereochemistry of its alkene, or one isomer might be needed for subsequent stereoselective modification (e.g., dihydroxylation6). Still, while kinetically controlled Z-selective RCM reactions have been reported7,8,9,10, the only available olefin metathesis approach for accessing macrocyclic E olefins entails selective removal of the Z component of a stereoisomeric mixture by ethenolysis10, sacrificing substantial quantities of material if E/Z ratios are near unity. Use of ethylene can also cause adventitious olefin isomerization, a particularly serious problem when the E alkene is energetically less favored. Here, we show that dienes containing an E-alkenyl–B(pinacolato) group, widely used in catalytic cross-coupling11, possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E macrocyclic alkenes. Reactions are promoted by a molybdenum monoaryloxide pyrrolide complex and afford products in up to 73 percent yield and >98:2 E:Z ratio. Utility is highlighted by application to preparation of the twelve-membered ring antibiotic recifeiolide12,13 and the eighteen-membered ring Janus kinase 2/Fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor pacritinib14,15 the Z isomer of which has lower potency than the E16. The eighteen-membered ring moiety of pacritinib, a potent in vivo anti-cancer agent in advanced clinical trials for treatment of lymphoma and myelofibrosis, was prepared by an RCM carried out at 20 times higher concentration than when a ruthenium carbene was employed (0.02 vs. 0.001 M; 73% yield, 92% E).

A convergent synthesis of the marine natural product (+)-peloruside has been reported. This target has been assembled through the successive application of two methyl ketone boron aldol addition reactions to the latent C 7 -C 11 dialdehyde synthon. This approach afforded a 22-step synthesis of this natural product. The influence of resident stereocenters on aldol reaction diastereoselection has been examined in detail.Peloruside A (1) is a secondary metabolite of a marine sponge (Mycale genus) collected from Pelorus Sound, New Zealand. In addition to its structure elucidation, the initial disclosure by Northcote 1 also demonstrated peloruside A to be cytotoxic to P388 murine leukemia cells at nanomolar concentrations. Subsequent investigations 2 revealed peloruside's anti-proliferation potency is similar to that exhibited by paclitaxel. The first synthesis of 1, reported by De Brabander, established the absolute stereochemistry of this natural product. 3 In the interim, two additional syntheses have been published. 4,5 The purpose of this communication is to report a convergent approach to this natural product suitable for analogue synthesis.The deconstruction of 1 relies on the two highlighted aldol disconnections illustrated in Scheme 1. Based on prior art, 6 we anticipated that the C 3 and C 15 stereocenters would favorably influence the stereochemical outcome of these two bond constructions. In the following discussion, the syntheses of subunits 3 and 4 will be described along with their elaboration to (+)-peloruside A (1). The synthesis of 5 is included in the Supplementary Information.The synthesis of C 1 -C 6 synthon 3 requires six steps from commercially available (S)-4-benzyl-2-oxazolidinone 7a and is summarized in Scheme 2. Notably, the illustrated imideevans@chemistry.harvard.edu. Supporting Information Available: Experimental details and analytical data including copies of 1 H and 13 C NMR spectra for all new compounds (xx pages) (PDF). The synthesis of methyl ketone 5 is also included. This material is available free of charge via the Internet at http://pubs.acs.org. The synthesis of synthon 4, based on the use of (S)-pantolactone, is summarized in Scheme 3. The chelate-controlled borohydride reduction was quite diastereoselective (95:5); however, competing conjugate reduction was noted as a minor side reaction. NIH Public AccessSelection of the illustrated C 9 hydroxyl configuration in subunit 4 bears comment. On the basis of previous model studies probing the influence of β-oxygen stereocenters on aldehyde face selectivity, 8 we concluded that the (R)-C 3 , (S)-C 8 and (R)-C 9 stereocenters in fragments 3 and 4 would be mutually reinforcing in this double stereodifferentiating aldol addition. A recent study by Paterson documents the diminished selectivities if the other C 9 epimer is employed in a similar aldol addition.9The aldol union of methyl ketone 3 and aldehyde 4 is summarized in Scheme 4. In developing this reaction, we noted a surprising diastereoselectivity dependence on the par...

The first use of phosphenium cations in asymmetric catalysis is reported. A diazaphosphenium triflate, prepared in two or three steps on a multigram scale from commercially available materials, catalyzes the hydroboration or hydrosilylation of cyclic imines with enantiomeric ratios of up to 97:3. Catalyst loadings are as low as 0.2 mol %. Twenty-two aryl/heteroaryl pyrrolidines and piperidines were prepared using this method. Imines containing functional groups such as thiophenes or pyridyl rings that can challenge transition-metal catalysts were reduced employing these systems.

A convergent diastereo- and enantioselective total synthesis of anticancer and antifungal macrocyclic natural product disorazole C1 is reported. The central feature of the successful route is the application of catalytic Z-selective cross-metathesis (CM). Specifically, we illustrate that catalyst-controlled stereoselective CM can be performed to afford structurally complex Z-alkenyl–B(pin) as well as Z-alkenyl iodide compounds reliably, efficiently, and with high selectivity (pin = pinacolato). The resulting intermediates are then joined in a single-step operation through catalytic inter- and intramolecular cross-coupling to furnish the desired 30-membered ring macrocycle containing the critical (Z,Z,E)-triene moieties.

We demonstrate pyridine hydroboration catalyzed by a diazaphospholene hydride precatalyst. Pyridines bearing electron-withdrawing groups in the 3-position are hydroborated efficiently. This system features low catalyst loadings, fast reaction times at ambient temperature, and tolerance of other reducible functionality. Off-cycle products of pyridine hydrophosphination were also obtained in one case from a stoichiometric reaction and structurally characterized.

Polydicyclopentadiene (PDCPD) is a durable, highly cross-linked material that is used industrially for the production of automotive body panels among other applications. We recently described a novel C-linked, ester-functionalized polydicyclopentadiene (fPDCPD) that introduces a tunable surface energy and increased T g, without sacrificing the desirable thermal stability of the parent polymer. In this report, we describe an extensive spectroscopic study aimed at the rigorous characterization of the structure of the cross-link in our thermally cured material. The results from this study rule out the involvement of metathesis-derived interchain couplings and show that the majority of cross-links derive from thermally initiated radical polymerization of the embedded methyl methacrylate motif. We also show that the degree of cross-linking can be tuned by the applied thermal conditions; rapid high-temperature heating freezes the system at a relatively low cross-link density, while longer heating at a lower temperature allows cross-linking to proceed nearly to completion.

Get me a­ Z (olefin): Efficient catalytic cross‐metathesis reactions that afford Z‐disubstituted allylic silyl or benzyl ethers are reported (see scheme, MAP=monoalkoxide pyrrolide). The approach, in combination with catalytic cross‐coupling, provides a general entry to otherwise difficult‐to‐access alkyne‐containing Z olefins.