As part of a program directed at the development of palladium-and nickel-catalyzed couplings of alkyl electrophiles, 1 we have been exploring the possibility of achieving a variant of the Heck reaction wherein an alkyl, rather than an aryl, electrophile is coupled with an olefin. In an initial study, we were pleased to discover that such a transformation can indeed be accomplished, albeit in very poor yield (1.2%; eq 1). Interestingly, however, control reactions established that carbon-carbon bond formation proceeds more efficiently in the absence of palladium (24%; eq 1)! Our mechanistic hypothesis for this unanticipated carbene-catalyzed cyclization is outlined in Figure 1. 2,3 Thus, the catalyst (Nu:) adds to the electrophilic β carbon of the α, β-unsaturated ester, generating an enolate (A). Tautomerization then affords B ,4 in which the β carbon is now nucleophilic (umpolung5 ,6 ). An intramolecular S N 2 reaction provides C, which undergoes elimination to furnish the observed product and to regenerate the catalyst (Nu:).For most of the previously described nucleophile-catalyzed reactions of Michael acceptors, the initial adduct (e.g., A) reacts with electrophiles in the α position (e.g., the Morita-BaylisHillman reaction 7 ). Indeed, we have only been able to identify one previous report of a process wherein conjugate addition of a catalyst leads to the β carbon serving as a nucleophile. 8 Furthermore, an interesting contrast is provided by the recent work of Krafft, who has established that enones/enals that bear pendant halides undergo cyclization in the α position when treated with stoichiometric PMe 3 or PBu 3 and then KOH (e.g., eq 2). 9

Increased white matter mean diffusivity and decreased fractional anisotropy (FA) has been observed in subjects diagnosed with mild cognitive impairment (MCI) and Alzheimer's disease (AD). We sought to determine whether similar alterations of white matter occur in normal individuals at risk of AD. Diffusion tensor images were acquired in 42 cognitively normal right-handed women with both a family history of dementia and at least one apolipoprotein E4 allele. These were compared with images from 23 normal women without either AD risk factor. Group analyses were performed using tract-based spatial statistics. Reduced FA was observed in the fronto-occipital and inferior temporal fasciculi (particularly posteriorly), the splenium of the corpus callosum, subcallosal white matter and the cingulum bundle. These findings demonstrate that specific white matter pathways are altered in normal women at increased risk of AD years before the expected onset of cognitive symptoms.

The potential use of SCD inhibitors for the chronic treatment of diabetes and dyslipidemia has been limited by preclinical adverse events associated with inhibition of SCD in skin and eye tissues. To establish a therapeutic window, we embarked on designing liver-targeted SCD inhibitors by utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs). In doing so, we set out to target the SCD inhibitor to the organ believed to be responsible for the therapeutic efficacy (liver) while minimizing its exposure in the tissues associated with mechanism-based SCD depletion of essential lubricating lipids (skin and eye). These efforts led to the discovery of MK-8245 (7), a potent, liver-targeted SCD inhibitor with preclinical antidiabetic and antidyslipidemic efficacy with a significantly improved therapeutic window.

A metal-catalyzed cross-coupling of organosilicon compounds with alkyl halides has been developed. Noteworthy attributes of the method are its scope (secondary electrophiles), its high functional-group compatibility, and the air stability of the catalyst components.

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