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.
Azadirachtin has been the subject of intensive research within the scientific community ever since its isolation from the neem tree in 1968. There are now over 1000 publications relating to this natural product which cover all aspects of structural, biological and synthetic studies. Herein, we describe the worldwide synthesis efforts towards this fascinating molecule.
Bindungswilliger Katalysator: Die hoch enantioselektive Iodlactonisierung von 5‐Hexensäuren gelingt mit einem tertiären Aminoharnstoffkatalysator (siehe Schema). Der Einsatz von katalytischem Iod in diesem Prozess ist entscheidend, um die Reaktivität und Enantioselektivität der stöchiometrischen I+‐Quelle zu erhöhen. Der vorgeschlagene Mechanismus umfasst die Bindung einer Iodoniumimidat‐Zwischenstufe durch den als Wasserstoffbrückendonor wirkenden Katalysator.
Binding the anion: A highly enantioselective iodolactonization of 5-hexenoic acids has been achieved using a tertiary aminourea-catalyst. The use of catalytic iodine in this process is critical to enhancing both the reactivity and enantioselectivity of the stoichiometric I+source.The mechanism is proposed to involve binding of an iodonium imidate intermediate by the H-bond donor catalyst. Keywords asymmetric catalysis; iodolactonization; halogenation; organocatalysis; anion bindingThe intramolecular reaction of carboxylic acids with pendant olefins in the presence of a source of I + -the iodolactonization reaction -is a powerful method for the generation of five-and six-membered lactones (eq 1). Diastereoselective variants of this reaction provide efficient access to stereochemically defined lactones, and consequently this reaction has found widespread use in natural products synthesis. [1] In contrast, the development of catalytic enantioselective variants has proved challenging, [2],[3] a problem likely associated with the inherent difficulty of controlling the reactivity of iodonium ion intermediates through intermolecular interactions. [4] (1)The recent discovery of anion-binding mechanisms in H-bonding catalysis [5] that analogous pathways might be available to iodonium ions, thereby providing the control over halonium ion reactivity that is necessary for enantioselective iodolactonization and related reactions. Herein, we report the successful application of such a strategy in the development of a tertiary aminourea-catalyzed asymmetric iodolactonizationreaction.The iodolactonization of hexenoic acid derivtive 2a was selected as a model reaction for catalyst and reagent screening studies. A broad survey of potential H-bond donor catalysts revealed that bifunctional tertiary aminourea derivatives were required to induce useful levels of catalysis. A sharp dependence on the amino group substituents was observed, with di-n-pentyl derivative 1 affording highest enantioselectivities.[11] Whereas N-iodoimides or I 2 alone proved poorly reactive (Table 1, entries 1-4), the combination of stoichiometric levels of an N-iodoimide derivative and catalytic I 2 was found to produce a high-yielding and highly enantioselective system for iodolactonization (entries 5-6). It has been shown recently that N-iodoimides undergo conversion to the corresponding triiodide cations upon treatment with I 2 and a protic acid, [12] and this provides a likely explanation for the synergistic effect of these reagents in the present system. However, increasing the I 2 loading above that of the chiral catalyst (1) led to measurable decreases in enantioselectivity (entry 7). Variation of the identity of the N-iodoimide resulted in small but measurable changes in the enantioselectivity of the reaction, with N-iodo-4-fluorophthalimide derivative 5 proving optimal.[13] The sensitivity of the product ee to the structure of the imidate suggests a direct involvement of this counterion in the enantiodetermining step.Low-temperature 1 H ...
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.
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