The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: fragment couplings, completion of the synthesis, analogue generation and biological evaluation

Paterson, Ian; Chen, David Y.‐K.; Coster, Mark J.; Aceña, José Luis; Bach, Jordi; Wallace, Debra J.

doi:10.1039/b504151a

Cited by 45 publications

(27 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As reações aldólicas com dupla e tripla estereodiferenciação foram descritas por Paterson e colaboradores nos estudos visando a síntese do macrolídeo espongistatina 1 (altoirtina A) [36][37][38][39][40] . Na sín-tese da subunidade espiroacetal-AB, os autores exploraram combinações quirais diferentes entre β-alcóxi-aldeídos, β-alcóxi-metilcetonas e boranas aquirais e quirais (Esquema 10) 36,37 .…”

Section: Reações Aldólicas Com Estereoindução 15-antiunclassified

See 1 more Smart Citation

Indução assimétrica 1,5-Anti na adição de enolatos de boro de metilcetonas beta-oxigenadas a aldeídos

Dias¹,

Aguilar²

2007

Quím. Nova

View full text Add to dashboard Cite

# Esta revisão é dedicada à Prof a . Helena M. C. Ferraz em reconhecimento a sua grande contribuição acadêmica e científica para a área de Química Orgânica no Brasil. High levels of substrate-based 1,5-stereoinduction are obtained in the boron-mediated aldol reactions of β-oxygenated methyl ketones with achiral and chiral aldehydes. Remote induction from the boron enolates gives the 1,5-anti adducts, with the enolate π-facial selectivity critically dependent upon the nature of the β-alkoxy protecting group. This 1,5-anti aldol methodology has been strategically employed in the total synthesis of several natural products. At present, the origin of the high level of 1,5-anti induction obtained with the boron enolates is unclear, although a model based on a hydrogen bonding between the alkoxy oxygen and the formyl hydrogen has been recently proposed. INDUÇÃO ASSIMÉTRICA 1,5-ANTI NA ADIÇÃO DE ENOLATOS DE BORO DE METILCETONASKeywords: 1,5-anti induction; boron enolates; aldol reactions. INTRODUÇÃOA reação aldólica é seguramente um dos métodos mais poderosos para a formação de ligações carbono-carbono 1-7 . Esta reação representa uma ferramenta muito útil na construção de fragmentos com alta complexidade estrutural e com elevados níveis de seletividade, sendo bastante empregada na síntese assimétrica de produtos naturais com atividade farmacológica destacada 8,9 . A incorporação de convergência na construção de policetídeos requer que fragmentos complexos sejam acoplados em algum ponto da rota sintética e, neste sentido, a reação aldólica representa um mé-todo extremamente útil.Os fatores responsáveis pelo controle da estereosseletividade na reação aldólica envolvendo enolatos metálicos estão relacionados com a natureza do átomo do ácido de Lewis utilizado (B, Li, Zn, Ti, Mg etc); a geometria da dupla ligação do enolato preparado (Z ou E); a presença de centros estereogênicos no enolato, no aldeído, ou no ácido de Lewis; o volume e a natureza dos substituintes nos substratos e, as condições reacionais.Em termos gerais, a estereoquímica relativa esperada para os produtos de reações aldólicas envolvendo enolatos de boro E e Z pré-formados é bastante previsível. A reação aldólica com enolatos de boro Z fornece o aduto de aldol syn, e com enolatos de boro E, o aduto de aldol anti, como está delineado no Esquema 1. Estas reações passam por estados de transição cíclico-quelados, do tipo cadeira, como proposto por Zimmerman-Traxler (Esquema 1) 4,10,11 . Neste modelo observa-se que o controle da diastereosseletividade é dependente do volume do substituinte presente no aldeído, que preferencialmente ocupa uma posição pseudo-equatorial no estado de transição tipo cadeira, eliminando dessa maneira a interação 1,3-diaxial desfavorável entre o grupo R e o grupo X.Os parâmetros estéricos influenciam fortemente na formação de estados de transição diastereoisoméricos e, conseqüentemente, na estereoquímica dos produtos obtidos (a geometria do enolato se transfere para o produto em um processo altamente diastereosseletivo). Os dialquil...

show abstract

Section: Reações Aldólicas Com Estereoindução 15-antiunclassified

“…Vale destacar que a síntese total da espongistatina 1 foi concluí-da em 33 etapas por Paterson e colaboradores 40 . A reação aldólica mediada por boro foi utilizada na seqüência sintética descrita em 10 acoplamentos.…”

Section: Reações Aldólicas Com Estereoindução 15-antiunclassified

Indução assimétrica 1,5-Anti na adição de enolatos de boro de metilcetonas beta-oxigenadas a aldeídos

Dias¹,

Aguilar²

2007

Quím. Nova

View full text Add to dashboard Cite

show abstract

“…Where a product is particularly sensitive toward oxidants, the hydrolytic step can be achieved via a non-oxidative workup, such as exposure of the boron aldolate solution to silica gel. 13 As an example of the asymmetric aldol reaction using boron enolates, we report the procedure for a matched aldol reaction of chiral ketone 5, and chiral aldehyde 6, under (-)-Ipc 2 BCl mediation, via boron enolate 7 (Fig. 2).…”

mentioning

confidence: 99%

“…2). [14][15][16][17] This process is a key step in a stereocontrolled total synthesis of the potently cytotoxic marine natural product spongistatin 1/altohyrtin A, [13][14][15][16][17][18][19][20] and exploits triple asymmetric induction 4 to obtain the desired aldol adduct 8 in 78% yield, with exceptional diastereocontrol (>97:3 dr). It should be noted that boron-mediated aldol reactions with other substrates, using different boron Lewis acids, can be performed using analogous procedures, however, the reaction rates for each step may vary considerably.…”

mentioning

confidence: 99%

Asymmetric aldol reaction using boron enolates

Cergol

Coster

2007

Nat Protoc

View full text Add to dashboard Cite

The protocol for the preparation of boron enolates and their subsequent reaction with aldehydes is described, providing convenient access to β-hydroxy ketones in good yields and with high stereoselectivities. The reaction consists of three steps; firstly the ketone is rapidly converted to the corresponding boron enolate, by exposure to a chlorodialkylborane and tertiary amine base, which is then reacted in situ with the aldehyde. Finally, oxidative workup of the resultant boron aldolate provides aldol adduct. The reaction procedure requires approximately 28 h to complete over a two day period, consisting of 5 h to set up the reaction, whereupon the reaction mixture is left at -20 °C overnight (16 h), followed by 7 h for workup and purification. INTRODUCTIONThe directed aldol reaction of boron enolates and aldehydes has often been employed in stereoselective organic synthesis, including the syntheses of several complex natural products, owing in large part to the high levels of chemo-, regio-, diastereo and enantioselectivity that can be achieved. 1-3 One of the most universal stereochemical features of the boron-mediated aldol reaction is the transfer of enolate geometry to aldol product relative stereochemistry with high fidelity, where (Z)-boron enolates generally give syn aldol products and (E)-boron enolates afford anti aldol adducts. 2 High levels of absolute control in the creation of new stereogenic centres can be achieved by using certain chiral ketone and/or aldehyde substrates, or through the use of chiral ligands on boron. The use of two or more "matched" 4 chiral components in these aldol reactions can result in exceptionally high levels of diastereoselectivity. The generally predictable stereochemical outcomes observed in the aldol reaction between boron enolates and aldehydes result from kinetic control, and have been very effectively rationalised computationally with transition state models involving highly-ordered chair-or boat-like transition states. 5,6 An extension of this protocol to the reaction of boron enolates with certain ketones, particularly cyclohexanones, 7 pushes the boundaries of reactivity for this reaction manifold, and has recently been shown to be a reversible process, in sharp contrast to the situation with aldehyde reaction partners. 8 A typical procedure for carrying out a boron-mediated aldol reaction begins with treatment of the ketone starting material with a Lewis acidic boron reagent, L 2 BX (X = Cl, Br, OTf), and a tertiary amine base, thereby forming the boron enolate 1, in situ (Fig. 1). The most common achiral boron reagents for this purpose are B-chlorodicyclohexylborane 9 (Chx 2 BCl) or di-n-butylboron triflate 10 (n-Bu 2 BOTf), whereas both enantiomers of B-chlorodiisopinocampheylborane 11, 12 (Ipc 2 BCl) have frequently been used in aldol reactions where a chiral boron enolate is necessary for enantioselectivity or desirable in order to enhance or overturn inherent facial bias of the reaction substrates. All boron Lewis acids of this type react rapidly with wate...

show abstract

“…Even though the spongistatins are structurally complex, the total synthesis of spongistatin 1 has been just accomplished. 2 Recently, spongistatin 1 was shown to have an apoptosis-inducing effect in A549 cells by activating caspase-3 and by the cleavage of vimentin. 3 However, virtually no work has been carried out to elucidate the activity and underlying mechanisms of spongistatin 1 in leukemia.…”

Section: Introductionmentioning

confidence: 99%

Spongistatin 1: a new chemosensitizing marine compound that degrades XIAP

Schyschka

Rudy

Jeremias³

et al. 2008

Leukemia

View full text Add to dashboard Cite

Spongistatin 1 is a new experimental chemotherapeutic agent isolated from marine sponges. Here we show that spongistatin 1 potently induces cell death in patient primary acute leukemic cells with higher efficiency than 8/10 clinically used cytotoxic drugs and prevents long-term survival of leukemic cell lines. Spongistatin 1 triggers caspase-dependent apoptosis in Jurkat T cells by the release of cytochrome c, Smac/DIABLO and Omi/ HtrA2. As caspase-9 acts as an initiator caspase and Bcl-2 and Bcl-xL overexpression suppress spongistatin 1-induced apoptosis, cell death is mediated through the mitochondrial apoptosis pathway. Importantly, spongistatin 1 leads to the degradation of the antiapoptotic X-linked inhibitor of apoptosis protein. In apoptosis-resistant leukemic tumor cells overexpressing XIAP, spongistatin 1 effectively causes cell death and potentiates cell death induction by other apoptosis-promoting factors that might be caused by spongistatin 1-mediated degradation of XIAP. Our data show that spongistatin 1 represents a promising novel therapeutic agent for the treatment of leukemic tumor cells especially in the clinically highly relevant situation of chemoresistance due to overexpression of XIAP.

show abstract

The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: fragment couplings, completion of the synthesis, analogue generation and biological evaluation

Cited by 45 publications

References 44 publications

Indução assimétrica 1,5-Anti na adição de enolatos de boro de metilcetonas beta-oxigenadas a aldeídos

Indução assimétrica 1,5-Anti na adição de enolatos de boro de metilcetonas beta-oxigenadas a aldeídos

Asymmetric aldol reaction using boron enolates

Spongistatin 1: a new chemosensitizing marine compound that degrades XIAP

Contact Info

Product

Resources

About