Studies toward the Synthesis of Azadirachtin, Part 1: Total Synthesis of a Fully Functionalized ABC Ring Framework and Coupling with a Norbornene Domain

Abstract

We recently embarked on a program directed towards the total synthesis of azadirachtin (1, Scheme 1), the remarkable antifeedant agent isolated from the Neem tree [1] and currently in use as an insecticide.[2] Our radical-based approach towards this unusually challenging target molecule (see Scheme 1) was validated by a number of model studies, [3][4][5] which, however, left much to be desired in terms of functionalities on the crowded decalin system of the natural product. Herein we report the total synthesis of a fully functionalized ABC decalin intermediate 3 and its coupling with a suitable norbornene system 4 to afford a C7-C13 linked product, which was elaborated into the advanced intermediate 2 and whose structural disposition might allow its eventual conversion into azadirachtin (1). In the following Communication in this issue, [6] we describe both the total synthesis and semisynthesis of a different decalin intermediate and its elaboration into a close precursor of the target molecule, as well as some interesting reactions made possible by the special proximity effects that uniquely characterize the azadirachtin structural motif. [7] According to our previously disclosed strategy, [3][4][5] azadirachtin (1) was to be approached through a path marked by key intermediates such as 2, 3, and 4 as retrosynthetically outlined in Scheme 1. Crucial to the success of such a plan is the availability of fully functionalized advanced decalin systems such as 3, which have the potential to yield azadirachtin upon coupling with norbornene derivatives such as 4 followed by appropriate elaboration. The fundamental strategy for the synthesis of the norbornene precursor 4 has already been reported in a previous Communication.[5] The construction of the fully functionalized decalin system 3 in its enantiomerically pure form is depicted in Scheme 2. Thus, starting from enantiopure compound 5,[5] ketone 6 was produced by dibenzylation (for abbreviations and conditions, see legends in schemes) followed by desilylation and Swern oxidation of the resulting secondary alcohol. Ketone 6 was then converted into enone 7 in 81 % overall yield for the three-step sequence with a regioselectivity of approximately 10:1. Subsequent functionalization of 7 by Mander carboxylation [8] followed by aldol reaction of the resulting b-ketoester with paraformaldehyde in the presence of Yb(OTf) 3 led to the corresponding hydroxyester, whose hydroxy group was protected as a TBS ether (69 % yield for three steps). Subsequent epoxidation of the enone moiety of the so-obtained intermediate by TBHP in the presence of triton B furnished, stereoselectively, epoxide 8 in 87 % yield. The required 1,3-diaxial diol system within the growing substrate was established first by regioselective opening of the epoxide moiety of 8 (91 % yield) with PhSeNa (generated in situ from PhSeSePh and NaBH 4 ) [9] and then stereoselective reduction (NaBH 4 ) of the intermediate hydroxyketone to afford the desired compound 9 in 63 % yield. Selective removal of the TBS group, p...

Toosendanin: Synthesis of the AB-ring and investigations of its anti-botulinum properties (Part II)

“…Subsequent regioselective carboxymethylation with Mander's reagent16 in the presence of LHMDS at −78 °C afforded a β-ketomethylester; this was followed by methylation, thus methyl iodide in the presence of NaH granted the corresponding α-methyl-β-ketomethylester 17. Epoxidation of the enone moiety by TBHP in the presence of benzyltrimethylammonium hydroxide (triton B)18 furnished stereoselectively epoxide ( 14 ), in 65% yield for three steps from 13 19. The regioselective opening of the epoxide moiety20 found within 14 was established by PhSeNa (generated in situ from diphenyl diselenide and NaBH 4 ) in 86% yield followed by silylation of 15 with SEMCl, which led to disilyl ether ( 16 ) in 85% yield from 14 (Scheme 1).…”

Total Syntheses of the Tetracyclic Cyclopiane Diterpenes Conidiogenone, Conidiogenol, and Conidiogenone B

“…The epoxidation of enone (+)‐ 3 with Triton B and t BuO 2 H gave the epoxide 25 in 77 % yield (d.r.>10:1). Reduction with with NaSePh then afforded (+)‐ 1 as a single isomer. Further reduction of (+)‐ 1 with L‐selectride furnished (+)‐ 2 in 77 % yield (d.r.>20:1).…”

Total Synthesis of (−)‐Indoxamycins A and B

“…Although reactions between 1, 3‐dicarbonyl compounds and formaldehyde to construct quaternary carbon centers are well documented in the literature, we unfortunately found that a variety of conditions, such as [KHCO 3 /HCHO (aq. )], [Yb(OTf) 3 , (CH 2 O) n ], and (LiHMDS/benzotriazolylmethanol), either gave complex mixtures or caused the decomposition of the starting material. Eventually, we were able to conquer this challenge using a Mukaiyama aldol reaction approach (Scheme ).…”