Ellman and coworkers have reported a Rh(I)-catalyzed arylation reaction of pyridines and quinolines. While the analogous alkylation they developed requires use of an electron-rich Rh-catalyst, the authors found it was necessary to switch to a catalyst system composed of an electron-deficient metal center           ([RhCl(CO)₂]₂) for optimal yields. The substrate scope was examined with respect to branching of the pyridine derivatives and aryl bromide coupling partners were examined in the quinoline couplings (including electron-rich and electron-poor aryl halides).  This C-H arylation method does not necessitate any prefunctionalization and provides the desired functionalized heterocycle in good yield.

Berman A. M.; Lewis, J. C.; Bergman, R. G. Ellman, J. A. J. Am. Chem. Soc. ASAP.

Rovis and coworkers have recently communicated a Ni-catalyzed reductive carboxylation of styrene derivatives. The use of CO₂ is appealing because it is cheap, renewable, and widely available. However, its use in metal-catalyzed reactions has not been exhausted and often involves molecules with extensive pi-systems. The Ni-catalyzed hydrocarboxylation has reasonable substrate scope and is effective with electron-deficient and neutral ortho, meta, and para-substituted styrene derivatives. Additionally, only 1 atm of CO₂ is necessary in the presence of Ni(acac)₂, Cs₂CO₃, and the reductant Et₂Zn. The authors favor a distinct mechanism (from related stoichiometric work) revolving around a nickel-hydride species, which is believed to be the active catalyst. Insertion of styrene, followed by transmetalation from Ni to Zn, allows for net hydrozincation and regenerates the precatalyst Et-NiLn. After beta-hydride elimination, the active catalyst is generated (H-NiLn). Transmetalation back to Ni, insertion of CO₂, and a final transmetalation with Et₂Zn generates the precursor to the product (before the quench) and regenerates the precatalyst.

Williams, C. M.; Johnson, J. B.; Rovis, T. J. Am. Chem. Soc. ASAP.

Written by: Dr. Sharbil J. Firsan

Professor Yamamoto and co-workers at the University of Chicago have recently reported a novel and highly enantioselective method of desymmetrizing meso secondary allylic and homoallylic alcohols to the corresponding optically active monoepoxides.  The method, which relies on the use of low loadings of a vanadium–bishydroxamic acid catalyst system, has the following beneficial features:

•  High stereoselectivities (dr = 87:13 to 99:1 and ee = 92–97%) and moderate-to-good yields (51–73%)
• More efficient than kinetic resolution, since the theoretical yield of the optically pure epoxy alcohol product could be as high as 100%
• Mild reaction conditions and easy workup procedure
• Tolerance of aqueous peroxide oxidizing agents

The method has been applied to the highly stereoselective synthesis of (2R,4R)-4-hydroxy-6-hepten-1,2-oxide, a highly valuable synthetic intermediate.

(1) Li, Z.; Zhang, W.; Yamamoto, H. Angew. Chem., Int. Ed. 2008, 47, 7520.  (2) For a review on Trost’s DYKAT method, see Trost, B. M.; Fandrick, D. R. Aldrichimica Acta 2007, 40, 59.

Written by: Dr. Sharbil J. Firsan

While highly reactive and environmentally friendly, the organozinc reagents generally employed in the Negishi cross-coupling suffer from being air- and moisture-sensitive.  Knochel and co-workers have recently reported a practical, one-pot reaction sequence in which the Negishi cross-coupling is carried out with in situ generated organozincs.  In the cross-coupling step, PEPPSI™-IPr worked best as the precatalyst (e.g., shorter reaction times and higher yields than those obtained with Pd(PPh₃)₄).  This process:

• Avoids the need to manipulate the air- and water-sensitive organozincs.
• Is generally applicable to functionalized aryl-, heteroaryl-, alkyl-, and benzylzinc reagents.
• Works well for a wide range of electrophiles: functionalized aryl, heteroaryl, and vinyl halides and triflates undergo the cross-coupling smoothly to give moderate-to-high yields of the cross-coupled products.

(1) Sase, S.; Jaric, M.; Metzger, A.; Malakhov, V.; Knochel, P. J. Org. Chem. 2008, 73, 7380.  (2) For a recent review of Pd–NHC Catalysts, including the various PEPPSI™ catalysts, see Kantchev, E. S. B.; O’Brien, C. J.; Organ, M. G. Aldrichimica Acta 2006, 39(4), 97.  PEPPSI is a trademark of Total Synthesis Ltd.

Burke and coworkers have recently disclosed the extensive versatility of the MIDA boronate technology by demonstrating the stability of the MIDAs in the presence of an array of common synthetic reagents. For example, MIDA boronates were stable towards various oxidizing conditions such as Swern reaction conditions (COCl₂, DMSO), PDC, TPAP/NMO, and Dess-Martin periodinane. The MIDA boronates were also compatible under Jones conditions (H₂SO₄/CrO₃). Common synthetic transformations in the presence of the MIDA boronates such as the Evans aldol, Horner-Wadsworth-Emmons olefination, reduction with NaBH₄, debenzylation with DDQ all provided the desired product with the MIDA intact. Various functional group transformations are shown in the scheme below. Additionally, an efficient synthesis of (+)-crocacin C utilizing an acrolein substituted MIDA boronate as the precursor provided the natural product in nine steps (longest linear sequence).

Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. ASAP.

Sigma-Aldrich has announced an exclusive licensing agreement with the University of Illinois at Urbana-Champaign offering research-scale quantities of MIDA boronate esters, which are trivalent protecting groups for boronic acids, a technology recently developed by Dr. Martin Burke and coworkers. The MIDA boronates behave as boronic acid surrogates and allow for historically more difficult couplings. For example, though the preparation of polyene natural products using the Suzuki reaction is complicated by the instability of polyenylboronic acids, iterative Suzuki cross-coupling for the preparation of polyenes is now feasible using the MIDA boronates. The corresponding polyenyl MIDA boronates are more stable then the corresponding polyenylboronic acids and attenuate transmetallation due to their sp³ hydbridization. These assets coupled with the mild and readily deprotectable nature of the MIDA boronates allows for their use in a variety of more challenging Suzuki reactions. This chemistry was demonstrated earlier this year in the synthesis of the left half of amphotericin B using trans-2-bromovinylboronic acid MIDA ester in the first step of the iterative cross-coupling sequence.

Lee, S. J.; Gray, K. C.; Paek, J. S.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 466-468.

Heck carbonylation is a commonly employed method for the preparation of carboxylic acid derivatives. Giri and Yu have recently described a C-H activation/C-O insertion sequence, which allows for he preparation of dicarboxylic acids. Substituted benzene carboxylic acid derivatives are treated in the presence of CO with Pd(OAc)₂, Ag₂CO₃, and NaOAc in dioxane to provide the 1,2-dicarboxylic acids. Electron-rich arenes are the preferred substrates, which is suggestive of an electrophilic palladation pathway. Additionally, the scope of the C-H activation/C-O insertion was expanded to phenylacetic acid derivatives as well as one example of a carboxylation of a beta-vinyl C-H bond in an alpha,beta-unsaturated carboxylic acid derivative. Finally, the mechanism of this intriguing reaction was probed, which led to the observation of a cyclopalladated intermediate, and ultimately upon treatment with PPh₃ allowed for characterization of the first C-H insertion intermediate obtained from carboxylic acids.

Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. ASAP.

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