A Relay Route for the Synthesis of Azadirachtin

Abstract

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...

The Azadirachtin Story

“…The next major challenge was the epoxidation of the tetra‐substituted olefin present in 287 and, as is often the case in complex natural product synthesis, material was scarce. Nevertheless, we were fortunate to have access to both 23α and 23β epimers of the product epoxide 288 93 and we were therefore able to perform initial epoxidation reactions on a very small scale, using NMR to determine whether any of the desired product was present. Since alkene 287 contains many potentially reactive functional groups, we were concerned that other undesired oxidative reaction pathways might complicate identification of the reaction product.…”

“… Final steps in the synthesis of azadirachtin 93. 119, 121 Reagents and conditions: a) TBAF, THF, RT, 95 %; b) H 2 , Pd/C, EtOH, RT, 3 h, 95 %; c) Ac 2 O, Et 3 N, DMAP, CH 2 Cl 2 , RT, 76 %; d) CH 3 CHC(CH 3 )(CO)O(CO)C 6 H 2 Cl 3 , Cs 2 CO 3 , toluene, reflux, 6 d, 50 % (95 % brsm); e) Et 3 N, MeOH, H 2 O, RT, 93 %; f) NaBH 4 , CeCl 3 ⋅7 H 2 O, MeOH, RT, 91 %; g) Ac 2 O, Et 3 N, DMAP, CH 2 C l2 , RT, 87 %; h) Pd/C, H 2 , THF, RT, 14 h, 89 %; i) PhSeH, PPTS, ClCH 2 CH 2 Cl, reflux; j) H 2 O 2 , pyridine, 0 °C, 85 % over 2 steps.…”

Medizinische Chemie: Ley, Seeberger und Kubinyi ausgezeichnet

“…Besonderes Aufsehen erregte Leys Totalsynthese von Azadirachtin zwanzig Jahre nach der Isolierung dieses Naturstoffs 1a. b Zuletzt berichtete seine Arbeitsgruppe in Chemistry—A European Journal über die enantioselektive Addition von Malonaten an α,β‐ungesättigte Enone 1c …”

Total Synthesis of Azadirachtin—Finally Completed After 22 Years

“…If this is successful, the last steps in the synthesis have been reliably worked out and further work can focus on the synthesis of the intermediates obtained in the degradation studies. [13] In 1999 strategy (b) was chosen independently by the research groups of both Murai [14] and Ley [15] (Scheme 3). [7a] Shortly after the correct structure of azadirachtin had been established, Ley and co-workers began their total synthesis of this highly interesting molecule.…”

“…Strategy (a) was favored by Watanabe et al, and was intensively investigated at the time (Scheme 2). [13] In 1999 strategy (b) was chosen independently by the research groups of both Murai [14] and Ley [15] (Scheme 3). The synthetic plan of Nicolaou et al [16] also corresponds to that strategy (Scheme 4).…”