Model Studies Towards Azadirachtin: Part 2. Construction of the Crowded C8bC14 Bond by Transition Metal Chemistry We thank Drs. D. H. Huang and G. Siuzdak for NMR spectroscopic and mass spectrometric assistance, respectively. This work was financially supported by the National Institutes of Health (USA), the Skaggs Institute for Chemical Biology, a predoctoral fellowship from the Division of Organic Chemistry of the American Chemical Society sponsored by Novartis (to A.J.R.), postdoctoral fellowships from

Nicolaou, K. C.; Roecker, A. J.; Follmann, Markus; Baati, Rachid

doi:10.1002/1521-3757(20020617)114:12<2211::aid-ange2211>3.0.co;2-w

Cited by 22 publications

(4 citation statements)

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“…It also provides useful insights into cascade reactions and other processes involving radical cyclizations that may prove useful in other situations where fusions of sterically congested carbon–carbon bonds may be required. In the following communication we report an alternative approach for constructing azadirachtin's most challenging bond, the C8C14 bridge 16…”

Section: Methodsmentioning

confidence: 99%

Model Studies Towards Azadirachtin: Part 1. Construction of the Crowded C8bC14 Bond by Radical Chemistry We thank Drs. D. H. Huang and G. Siuzdak for NMR spectroscopic and mass spectrometric assistance, respectively. This work was financially supported by the National Institutes of Health (USA), the Skaggs Institute for Chemical Biology, postdoctoral fellowships from Bayer AG (to M.F.) and the G. E. Hewitt Foundation (to K.W.H.), a predoctoral fellowship from the Division of Organic Chemistry of the Americ

et al. 2002

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Zwei Wege, ein Ziel: Zwei unterschiedliche Synthesestrategien wurden ausgearbeitet, mit denen die Knüpfung der sterisch überfrachteten C8‐C14‐Bindung des präparativ herausfordernden Syntheseziels Azadirachtin 1 gelingen könnte: Beim ersten Ansatz wurde eine Radikalreaktion genutzt, die zur Modellverbindung 2 führte, der zweite beruht auf einer Nickel‐vermittelten Kupplung und lieferte die Modellverbindung 3.

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Section: Methodsmentioning

confidence: 99%

Model Studies Towards Azadirachtin: Part 1. Construction of the Crowded C8bC14 Bond by Radical Chemistry We thank Drs. D. H. Huang and G. Siuzdak for NMR spectroscopic and mass spectrometric assistance, respectively. This work was financially supported by the National Institutes of Health (USA), the Skaggs Institute for Chemical Biology, postdoctoral fellowships from Bayer AG (to M.F.) and the G. E. Hewitt Foundation (to K.W.H.), a predoctoral fellowship from the Division of Organic Chemistry of the Americ

et al. 2002

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“…1:1 ratio, 80 % combined yield), whose NMR spectroscopic analysis revealed structures 12 and 13 (Scheme ). The ratio of the two isomers was found to be dependent on reaction time, temperature, and, apparently, on the steric environment around the attacking allylic alcohol moiety, since previous4, 5 and subsequent6 experiments with other decalin allylic alcohol substrates led to different results. Scheme provides a possible explanation for these results by invoking an oxonium ion intermediate 4 b derived from the rupture of the initially formed bromonium ion 4 a as the temperature is raised to 0 °C.…”

Section: Methodsmentioning

confidence: 93%

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

et al. 2005

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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...

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“…In a similar approach to Murai, initial efforts were focussed on an intramolecular C8C14 bond forming process using an ester linker at C30 to tether the two molecules 104. The key difference in this approach lies in the carboncarbon bond forming event in which a radical cyclisation was deemed to be the method of choice 105. Accordingly, an appropriate decalin precursor, 245 , was prepared and coupled with a simple surrogate for the dihydrofuranacetal unit in 5 (Scheme ).…”

Section: Attempts At Azadirachtin Fragment Unionmentioning

confidence: 99%