Macrocyclisations using allylic radical intermediates. A new synthetic approach to natural 14-membered cembranoids

Cox, N. J. G.; Mills, S. D.; Pattenden, Gerald

doi:10.1039/p19920001313

Cited by 24 publications

(3 citation statements)

References 46 publications

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“…Síntese de ciclopeptídeos por reação de carbociclização radicalar preferenciais em relação às exo", [66][67][68] o que pode ser confirmado pelos trabalhos subseqüentes. [69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87] Em outro estudo, 88 a o-iodobenzamida 62 (Esquema 34), desprovida de unidade sacarídica, conduziu à macrolactama 63 (14%), proveniente da ciclização 11-endo, mas com rendimento inferior aos das lactamas contendo unidade de açúcar. Este resultado demonstra a importância da restrição conformacional conferida pela presença do açúcar na macrociclização.…”

Section: Esquema 31 Síntese De Triciclos Derivados De Carboidratosunclassified

Macrolactamas bioativas e síntese de macrociclos por reação de carbociclização radicalar mediada por hidreto de tri-n-butilestanho

Faraco¹,

Pires²,

Rocha³

et al. 2008

Quím. Nova

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Recebido em 27/2/07; aceito em 27/9/07; publicado na web em 13/8/08 BIOACTIVE MACROLACTAMS AND SYNTHESIS OF MACROCYCLES BY TRI-N-BUTYLTIN HYDRIDE-MEDIATED RADICAL CARBOCYCLIZATION REACTION. This review presents natural, semi-synthetic and synthetic bioactive macrolactams and their structure-activity relationships when available. For macrolactams in clinical use the advantages and disadvantages in relation to other drugs are presented, and for synthetic macrolactams the method used in the cyclization is showed. Regarding macrocyclic synthesis by the tri-n-butyltin hydride-mediated radicalar carbocyclization reaction the precursor, the reaction conditions, products and yields, mechanism and cyclization mode are discussed.Keywords: bioactive macrolactams; radical carbocyclization; macrocyclization. introduçãoOs macrociclos apresentam importantes atividades biológicas e muitos deles, ou seus derivados, são usados como fármacos (eritromicina, ciclosporina, vancomicina e anfotericina B).1-3 As atividades biológicas dos macrociclos, substâncias com enorme variedade estrutural, são atribuídas, em parte, a uma característica comum: a restrição conformacional em relação a compostos de cadeia aberta. 2,4Entre os macrociclos que são agentes bioativos encontram-se as macrolactamas, cujas atividades biológicas se devem, em parte, ao fato de serem macrociclos e também amidas. Em um trabalho publicado recentemente, no qual são apresentados dados relativos a 128 candidatos a fármacos em desenvolvimento em três grandes indústrias farmacêuticas, é relatado que 12% das reações realizadas na síntese das 128 substâncias são de acilação, especialmente N-acilações. Os autores não se surpreendem com esse dado, uma vez que as amidas estão presentes em um grande número de fármacos. Além disso, de 53 fármacos que, em 2003, foram responsáveis pela arrecadação acima de 1 bilhão de dólares, 9 apresentam o grupo amida e 3, o grupo sulfonamida. 5Tendo em vista sua importância, as macrolactamas vêm sendo amplamente estudadas sob vários aspectos: isolamento e elucidação estrutural de produtos naturais, síntese, modificações moleculares, estudos de relação estrutura química/atividade biológica, mecanismo de ação e triagem clínica. MacrolactaMas naturais e seMi-sintéticas coM atividade biológicaDiversos depsipeptídeos macrocíclicos apresentam atividade biológica: criptoficina A (atividade antitumoral 6 ), hapalosina (atividade citotóxica leve 7 ) e estevastelina B (inibe ativação de células T e B 8 ) (Esquema 1). Outros depsipeptídeos cíclicos, isolados de cianobactéria marinha (Lyngbya majuscula) e denominados lingbiabelinas A e B (Esquema 1), apresentam atividade contra células tumorais. 9,10A indolactama-V e benzolactama-V8 (Esquema 2), de 9 e 8 membros respectivamente, ligam-se à proteína quinase C ativando-a para a promoção de tumores. Esta atividade parece estar diretamente

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Section: Esquema 31 Síntese De Triciclos Derivados De Carboidratosunclassified

Macrolactamas bioativas e síntese de macrociclos por reação de carbociclização radicalar mediada por hidreto de tri-n-butilestanho

Faraco¹,

Pires²,

Rocha³

et al. 2008

Quím. Nova

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“…The acetates 13a ± c were then transformed into the cyclisation precursors 5a ± c via an identical synthetic route. Thus, selective epoxidation of the terminal CC bonds in 13a ± c with N-bromosuccinimide (NBS) in THF/H 2 O, followed by saponification [11], first produced the (all-E)-epoxy alcohols 14a ± c. Treatment of 14a ± c with aqueous HIO 4 resulted in hydrolysis, and simultaneous 1,2-diol cleavage [12] to produce the corresponding aldehydes, which were then converted to the primary alcohols 15a ± c in two steps. Mesylations of 15a ± c, followed by displacement reactions with NaCN next led to the nitriles 16a ± c, which were converted into the corresponding carboxylic acids 18a ± c via a reduction/ oxidation sequence.…”

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confidence: 99%

Novel Regio- and Stereoselective Cascade 6-endo-trig Cyclisations from Polyene Acyl Radical Intermediates Leading to Steroid-Like Pentacycles and Heptacycles

Handa

Nair

Pattenden

2000

HCA

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Dedicated to Professor Albert Eschenmoser on the occasion of his 75th birthday In a quite remarkable regio-and stereoselective manner, each of the (all-E)-polyene selenoates 5a ± c is shown to undergo cascade radical-mediated polycyclisations via consecutive 6-endo-trig reactions, leading to the corresponding all-trans, anti, tri-, penta-and heptacycles, i.e., 20, 23, and 25, in good yields. The configurations of these steroid-like polycycles followed from detailed examination and correlation of chemical shift data in their 13 C-NMR spectra.1. Introduction. ± Much of our present knowledge of the stereoelectronic factors governing consecutive electrophilic cyclisations of polyenes to polycyclic compounds, including steroids, stems from speculations following the so-called Stork-Eschenmoser hypothesis of 1955 [1], and the extensive biomimetic studies of Johnsons and many other research groups that ensued [2]. Indeed, the delicate tuning of the reactivity of the double bonds, in combination with careful choice of functionality for both the initiation and the termination of cyclisations, has now made electrophilic polyene cyclisations a concise synthetic route to all types of linear, angular, and other ring-fused polycycle constructions.In more recent years, complementary cascade radical-mediated cyclisations of polyene precursors have also become a powerful synthetic tool for the elaboration of steroid and polycyclic terpene ring systems [3]. Thus, among other cascade processes [4], our own laboratory has described serial 6-endo-trig cyclisations [5], together with 6-endo-trig cyclisations, followed by a macrocyclisation sequence [6], from the polyene acyl radical precursors 1 and 3 leading to steroid ring constructions, i.e., 2 and 4, respectively. The stereochemical outcomes of these cascade radical processes, similar to the aforementioned electrophilic polyene cyclisations, show an interesting dependence on the nature of the substituents on the alkene bonds participating in the polycyclisations, e.g., the (all-E)-polyene 1 gives the all-trans-anti polycycle 2 on treatment with Bu 3 SnH/AIBN, whereas bis(methoxycarbonyl)-substituted triene-selenoate 3 instead leads to the cis-anti-cis-anti-cis tetracycle 4 under similar reaction conditions (Scheme 1). Alongside other studies, we have attributed these outcomes to a degree of pre-organisation in the polyene compounds, and in the reaction intermediates, favouring the different pathways followed in the cascade radical reactions. To determine the limitations of radical-mediated processes based on cascade 6-endo-trig cyclisations leading to polycycle constructs containing more than four rings, we have

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“…It is well established that electron-deficient alkenes (and alkynes), e.g., 8, act as efficient radical acceptor groups, or electrophores, in macrocyclizations involving nucleophilic car-bon-centered radicals (41)(42)(43)(44)(45). There are also many illustrations of the applications of radical-mediated transannulations in the current literature (46)(47)(48).…”

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A total synthesis of estrone based on a novel cascade of radical cyclizations

Pattenden

González

McCulloch

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Two conceptually different and novel radical-mediated cascade reactions leading to a total synthesis of the steroid (؎)-estrone 1 and to a synthesis of 14-epiestrone 40 are described. Treatment of the iododienynone 23 with Bu3SnH͞2,2-azobis(isobutyronitrile) (AIBN) triggers a 13-endo-dig radical macrocyclization followed by two sequential radical transannulation reactions leading to the crystalline estrane 24 in 50% yield. The x-ray crystal structure of 24 established its trans, syn, stereochemistry. Transposition of the enone functionality in 24 next led to 38, which was then converted into 39 by reductive methylation. Deprotection of the methyl ether 39 finally gave 14-epiestone 40. When the substituted iodovinylcyclopropane 55 was treated similarly with Bu3SnH͞AIBN, the resulting radical center underwent a different sequence of cascade macrocyclization-transannulation reactions producing the trans, anti, trans estrane 56 in 12% overall yield. Oxidation of 56, using CrO 3-H2SO4 next led to the cyclopentanone 57, which, on deprotection using BBr3 gave (؎)-estrone 1. A number of alternative substituted iodopolyenynones and iodovinylcyclopropanes, i.e., 8a, 8b, 33, 49a, and 49b, underwent similar radical-mediated cascade cyclizations leading to other estranes, i.e., 21a, 21b, 35, and 50, and, in one case, to the 6,6,5,6-tetracycle 51, in variable overall yields. The structures and stereochemistries of several estranes were established by using x-ray crystal structure measurements in combination with analysis of their NMR spectroscopic data and correlation with literature precedent. Since the synthesis of the female sex hormone estrone 1 by Anner and Miescher in 1948 (1), and the syntheses of nonaromatic steroids, such as cortisone 2 and aldosterone 3 during the 1950s, a plethora of ingenious designs have been explored to synthesize members of the steroid family of natural products. Prominent among the methods that have been developed are those based on Diels-Alder reactions (2-12), transition metal-catalyzed cyclizations of enynes and triynes (13-16), and biogenetic-type electrophilic cyclizations of polyene precursors (17-21).Over the past 10 years, we (22-26) and others (27-38) have examined the scope of a variety of cascade radical-mediated processes to elaborate steroids and other polycyclic ring systems. Thus, we have already described an approach to steroids based on consecutive 6-endo-trig (ref. 39 and references therein) and sequential transannular (40) radical cyclizations from appropriate polyene selenyl ester precursors, illustrated in the conversions 4 3 5 and 6 3 7, respectively.We have now extended our studies and examined a different approach to estrone 1 and estranes, whereby the nonaromatic tricyclic B,C,D ring system is produced in a single step by radical-mediated macrocyclizations in tandem with consecutive transannulations from an appropriate ortho-disubstituted arylpolyene precursor.These approaches to estranes are captured in a retrosynthetic manner in Scheme 1. Thus, in one approach, we ha...

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Macrocyclisations using allylic radical intermediates. A new synthetic approach to natural 14-membered cembranoids

Cited by 24 publications

References 46 publications

Macrolactamas bioativas e síntese de macrociclos por reação de carbociclização radicalar mediada por hidreto de tri-n-butilestanho

Macrolactamas bioativas e síntese de macrociclos por reação de carbociclização radicalar mediada por hidreto de tri-n-butilestanho

Novel Regio- and Stereoselective Cascade 6-endo-trig Cyclisations from Polyene Acyl Radical Intermediates Leading to Steroid-Like Pentacycles and Heptacycles

A total synthesis of estrone based on a novel cascade of radical cyclizations

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