[reaction: see text] Alkyl azides react with saturated ketones upon treatment with Lewis acids to afford ring-expansion products through the azido-Schmidt reaction, but this reaction does not proceed when alpha,beta-unsaturated ketones are used. In this study, alkyl azides were reacted with enones in the presence of Lewis acids to give enaminones (vinylogous amides), which formally involve a ring contraction reaction. The mechanism and scope of this reaction is discussed.

A series of tetrahydropyranyl (THP) derivatives has been developed as potent inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT) for use as anticancer agents. Structural modification of the submicromolar hit compound 3 led to the potent 3-methoxy substituted analogue 27. Further SAR development around the THP ring resulted in an additional 10-fold increase in potency, exemplified by analogue 75 with an IC(50) of 1.3 nM. Active and potent compounds demonstrated a dose-dependent increase in Ras cytosolic protein. Potent ICMT inhibitors also reduced cell viability in several cancer cell lines with growth inhibition (GI(50)) values ranging from 0.3 to >100 μM. However, none of the cellular effects observed using ICMT inhibitors were as pronounced as those resulting from a farnesyltransferase inhibitor.

During investigations of cyclization reactions between chiral allylsilanes and N-acyliminium ions, it was discovered that a suitably positioned benzyloxy group on the allylsilane component caused a reversal in the diastereoselectivity of these reactions relative to that normally observed with alkylsubstituted allylsilanes. This effect was subsequently observed in two other reaction types. Investigations into this effect led to the proposal of product formation through thermodynamic control facilitated by neighboring group interactions with a transient cationic species. This hypothesis was experimentally supported by the isolation of an intermediate in the proposed mechanistic pathway.The reactions of allylsilanes with electrophilic species, in particular iminium ions, have become standard means for the formation of carbon-carbon bonds. 1-4 This strategy has been enriched by the introduction of chiral allylsilane derivatives, which can afford products with a high degree of stereochemical control. 5-18 Still this strategy has considerable untapped promise, especially when combined with non-standard methods of generating the electrophilic component.Previous work in this laboratory has shown that reactive iminium ions can be prepared through the intramolecular reactions of an aryl imine bearing an NHBoc substituent in the ortho position and that this reaction affords a route to interesting ring systems. 19,20 As an extension of this methodology, we wished to examine chiral silanes in this reaction, with the overall goal being the synthesis of enantiomerically pure products. In this work, a most unexpected outcome was observed: the diastereoselectivity of the reactions can be reversed by the placement of a benzyloxy group γ to the silicon moiety. We have ascertained that this observation holds in at least two other reactions of allylsilanes. These observations will be discussed in the context of kinetic v. thermodynamic control of the stereochemistry of a cationic intermediate in the reaction through neighboring group interactions. Results Preparation of Chiral AllylsilanesInitially, chiral alkenyl silanes 1 and 2, each containing a terminal azido group were prepared in enantiomerically pure form. Thus, enantiomerically pure (S)-1,2,4-butanetriol derived from malic acid was converted into allylic alcohol 3 by a standard series of functional group transformations and protecting group manipulation steps (Scheme 1; see Supporting Information for details). Conversion of this allylic alcohol to alkenyl silane 5a was accomplished by the 1,3-transpositive bis-silylation protocol developed by Ito. 21-23 This process has been shown to proceed with syn relative stereocontrol and with high retention of enantiomeric purity. Conversion of the product 5a to azide 1 was accomplished through straightforward transformations.We synthesized chiral allylsilanes containing more highly functionalized side chains as shown in Scheme 2. The oxygenated allylsilane 2, was originally envisioned as an intermediate en route to martinellin...

We have shown previously that the target of the potent cytotoxic agent 4-[(7-bromo-2-methyl-4-oxo-3H-quinazolin-6-yl)methyl-prop-2-ynylamino]-N-(3-pyridylmethyl)benzamide (CB38065, 1) is nicotinamide phosphoribosyltransferase (Nampt). With its cellular target known we sought to optimize the biochemical and cellular Nampt activity of 1 as well as its cytotoxicity. It was found that a 3-pyridylmethylamide substituent in the A region was critical to cellular Nampt activity and cytotoxicity, although other aromatic substitution did yield compounds with submicromolar enzymatic inhibition. Small unsaturated groups worked best in the D-region of the molecule, with 3,3-dimethylallyl providing optimal potency. The E region required a quinazolin-4-one or 1,2,3-benzotriazin-4-one group for activity, and many substituents were tolerated at C² of the quinazolin-4-one. The best compounds showed subnanomolar inhibition of Nampt and low nanomolar cytotoxicity in cellular assays.

A concise and asymmetric total synthesis of the title compound is described. The key ring system was constructed using an intramolecular Schmidt reaction on a norbornenone derivative, which was subsequently subjected to ring-opening metathesis followed by reduction. An unusual isomerization of the C-6 ethyl group afforded the desired stereochemistry of the natural product. The synthesis is readily adaptable to analogue production.