Polyomavirus middle tumor antigen (MT) transform a large number of cell types by binding to and modulating the activities of cellular proteins. Previous genetic ansis defined in MT an independent motif, NPTY (Asn-Pro- Because expression of pp60v-ff induces tyrosine phosphorylation of SHC and subsequent activation of Ras, activated pp60c-src in complex with MT might do the same. A potential candidate for SHC had been reported in MT immunoprecipitates, a 51-kDa protein of unknown identity (34). Because phosphorylation at Tyr-250 was implicated in transformation, it was tempting to hypothesize that SHC might bind via its SH2 to this site. Our data confirm that SHC does bind to MT in an NPTY-dependent manner. MATERIALS AND METHODS 6344The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

22 Years in the making: Azadirachtin (1) was synthesized for the first time by a highly convergent approach, utilizing a Claisen rearrangement and a radical cyclization as key steps. End‐game strategies relied on intermediate 2, which could be obtained by synthetic methods as well as by degradation of 1. Bn=benzyl, TBS=tert‐butyldimethylsilyl.

We describe in full the first synthesis of the potent insect antifeedant azadirachtin through a highly convergent approach. An O-alkylation reaction is used to unite decalin ketone and propargylic mesylate fragments, after which a Claisen rearrangement constructs the central C8-C14 bond in a stereoselective fashion. The allene which results from this sequence then enables a second critical carbon-carbon bond forming event whereby the [3.2.1] bicyclic system, present in the natural product, is generated via a 5-exo-radical cyclisation process. Finally, using knowledge gained through our early studies into the reactivity of the natural product, a series of carefully designed steps completes the synthesis of this challenging molecule.

22 Years in the making: Azadirachtin (1) was synthesized for the first time by a highly convergent approach, utilizing a Claisen rearrangement and a radical cyclization as key steps. End‐game strategies relied on intermediate 2, which could be obtained by synthetic methods as well as by degradation of 1. Bn=benzyl, TBS=tert‐butyldimethylsilyl.

The study of a plants natural defence mechanisms against predatory insect attack often leads to the discovery of novel molecules that have important biological effects. Such is the case with azadirachtin (1), a fascinating natural product first isolated from the Indian neem tree Azadiracta indica (A. Juss), in 1968.[1] Azadirachtin exhibits potent antifeedant and growth-disruptant properties against a broad spectrum of insect species yet displays very low mammalian toxicity (LD 50 (rat) > 5 gkg À1 ) and appears to cause little disruption to beneficial species such as pollinating bees and ladybirds.[2]The structure of this complex natural product was finally elucidated following many years of intense research [1,[3][4][5][6][7][8][9][10][11] culminating in the publication of three back-to-back full papers in 1987. [7][8][9] Likewise, understanding of the precise mode of action of azadirachtin continues to evolve. Detailed studies have revealed an elaborate set of interactive pathways, the full discussion of which is beyond the scope of this short communication. [12] In preparation for the total synthesis and to define the structure-activity relationships of azadirachtin, [13][14][15][16][17] we have been engaged in an extensive investigation of its reactivity pattern, [18] in particular its propensity for rearrangement under acidic [19] basic [13] and photolytic [20] conditions. Based on our cumulated experience in this regard, [21,22] we have devised a new relay route that has proved instrumental for the synthesis of azadirachtin. [23,24] Azadirachtin (1) represents an exceptionally challenging synthetic target by virtue of its sixteen contiguous stereogenic centers and complex pattern of oxygen-containing functionalities. The conformation and reactivity of azadirachtin are strongly influenced by the presence of intramolecular hydrogen-bonding interactions, evident from X-ray crystallographic studies. [6,25] In addition, both the hemiacetal at C11 and the C22 À C23 enol ether are sensitive functionalities and are therefore important considerations in the design of any total synthesis.Potential strategies for the masking of the C22ÀC23 enol ether had been investigated previously, [21,22] where it was found that a C23 methyl acetal was particularly stable in subsequent transformations. Although this derivative was accessed as an epimeric mixture, further studies [21] employed only the b-C23 epimer. We anticipated that this might present a severe disadvantage in our forward synthesis, as it could be difficult to control this stereogenic center. Work reported herein addresses this problem by providing a new relay route that can utilize both epimeric forms (Scheme 1).Accordingly, preparation of relay target 4 commenced with a methoxybromination/reduction protocol, thus converting the reactive enol ether present in 1 to a 1:1 mixture of its C23 a and b methyl acetals. Silver oxide mediated alkylation then permitted selective protection of the C11 and C20 hydroxy groups providing dibenzyl ether 2.[26] Oxidation of the r...