Stereocontrolled Total Synthesis of (+)‐Altohyrtin A/Spongistatin 1

Paterson, Ian; Chen, David Y.‐K.; Coster, Mark J.; Aceña, José Luis; Bach, Jordi; Gibson, Karl R.; Keown, Linda E.; Oballa, Renata M.; Trieselmann, Thomas; Wallace, Debra J.; Hodgson, Andrew P.; Norcross, Roger D.

doi:10.1002/1521-3757(20011105)113:21<4179::aid-ange4179>3.0.co;2-#

Cited by 57 publications

(53 citation statements)

References 75 publications

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“…Neste caso, a indução assimétrica remota promovida pelo estereocentro em γ-OTBS na metilcetona 72 deve ser contrária à indução 1,5-anti promovida pelo estereocentro em β-OMe. A influência remota de estereocentros distantes já foi observada em outros trabalhos do grupo 35,52 . Adicionalmente, o grupo protetor volumoso γ-OTBS deve afetar a conformação estereodirigente do estereocentro β-OMe, diminuindo a diastereosseletividade da reação.…”

Section: Esquema 12unclassified

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

Dias¹,

Aguilar²

2007

Quím. Nova

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# 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...

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Section: Esquema 12unclassified

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

Dias¹,

Aguilar²

2007

Quím. Nova

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“…In their work toward the total synthesis of altohyrtin A (spongistatin 1) (152), the Paterson group described a good degree of Felkin-Anh addition for the aldol coupling between the boron E-enolate E-150a and aldehyde 149 to produce the ABCD fragment 151 (dr = 90 : 10, 89% yield) on the multigram scale (Scheme 5.27) [68]. An identical aldol reaction using the lithium E-enolate produced the desired adduct …”

Section: Asymmetric Induction Using Chiral Aldehydesmentioning

confidence: 99%

“…A very interesting example of double diastereoselectivity was performed by Paterson and coworkers [101] during their synthesis of the C1-C13 fragment of altohyrtin A (spongistatin 1) (152) (Scheme 5.59).…”

Section: Asymmetric Induction In the Aldol Addition Of Chiral Enolatementioning

confidence: 99%

Asymmetric Induction in Aldol Additions

Dias¹,

Polo²,

Lucca³

et al. 2013

Modern Methods in Stereoselective Aldol Reactions

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The selectivity of aldol reactions involving kinetic enolates is related to various factors such as the nature of the Lewis acid (Li, Mg, B, Al, Ti, Sn, etc.), the presence of stereogenic centers in both the substrates and reagents, the nature of their substituents and the reaction conditions. Another factor of major importance is the nature of the enolate double bond (Z or E) [1].In general, it is well known that in aldol reactions involving metal enolates, which proceed through a six-membered cyclic transition state, the Z-enolate leads to the formation of 1,2-syn aldol adducts and the E-enolate affords aldol adducts with the 1,2-anti configuration. A rationalization for the observed selectivities of these aldol reactions was proposed by Zimmerman and Traxler (Scheme 5.1) [2]. According to this model, the nature of the double bond geometry plays a primary role in determining the energies of the competing transition states. For Z-enolates, the transition state TS2 is more destabilized than transition state TS1 because of the 1,3-diaxial interactions between the R 1 and R 3 substituents as well as between these substituents and one of the metal ligands (L). Therefore, the Z-enolate preferentially leads to the formation of the 1,2-syn aldol adduct.For the E-enolate, 1,3-diaxial interactions between the R 1 and R 3 substituents and between both R 1 and R 3 and one of the metal ligands are present in transition state TS4. Therefore, the 1,2-anti aldol adduct is obtained from the lower energy transition state TS3.Modern aldol reactions use preformed enolates to obtain good yields by preventing side reactions. This methodology has proven to be very effective for various Lewis acids derived from lithium, titanium, tin, and boron. By using preformed enolates with chiral substrates and reagents, it is possible to obtain aldol adducts with an excellent degree of asymmetric induction.The IUPAC defines asymmetric induction as the traditional term describing the preferential formation in a chemical reaction of one enantiomer (or diastereomer) over the other as a result of a chiral feature present in the substrate, reagent, catalyst, or the environment [3].

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“…The relationship between the hydroxyl-bearing stereocenters was determined by 13 C NMR analysis of the corresponding acetonide using the method reported by Rychnovsky and Skalitzky (36). After our disappointment in the Mukaiyama aldol coupling of the related aldehyde 14 (Scheme 6), synthesis of the dihydropyranone again relied on the Brown methallylboration-ring-closing metathesis protocol.…”

Section: Synthesis Of Fragment Library For Nmr Analysismentioning

confidence: 99%

Synthesis of antimicrofilament marine macrolides: Synthesis and configurational assignment of a C ₅ –C ₁₆ degradation fragment of reidispongiolide A

Paterson¹,

Britton²,

Ashton³

et al. 2004

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

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Reidispongiolide A is a representative member of the sphinxolide͞ reidispongiolide group of cytotoxic 26-membered macrolides of marine origin. By interacting with actin in the cell cytoskeleton, the reidispongiolides and sphinxolides are potent microfilament destabilizing agents that represent a promising mechanism of action for developing novel anticancer drugs. An aldol-based synthesis of a library of diastereomers of C 8 -C 16 and C 5 -C 16 fragments and detailed NMR comparison with a reported degradation fragment enabled a configurational assignment for a major part of the reidispongiolide macrocyclic core, thus setting a solid foundation for ongoing synthetic efforts.M arine macrolides provide a fascinating range of structural and functional diversity, which may find application inter alia as specific molecular probes for the investigation of the cytoskeleton and cell cycle events. Unique to eukaryotic cells, the actin cytoskeleton plays a critical role in the determination of cell shape, and in a variety of cellular processes, including cell motility, division, adhesion, and intracellular transportation (1). In comparison with microtubule-interacting agents (2), such as the taxanes and vinca alkaloids, the development of anticancer drugs based on selective binding to actin and disruption of microfilament assembly has attracted relatively little attention. However, recent insight into the role played by microfilaments in cell division and metastasis has highlighted the potential of certain structural classes of actin-binding natural products as useful leads for cancer chemotherapy (3).A growing family of actin-binding macrolides that disrupt microfilament organization includes the scytophycins (e.g., 1, Fig. 1), isolated from the blue-green algae Scytonema pseudohofmanni (4), aplyronines (e.g., 2), isolated from the sea hare Aplysia kurodai (5), and sphinxolides (e.g., 3, planar structure), first reported from an unidentified Pacific nudibranch (6) and later reisolated from the New Caledonian marine sponges Neosiphonia superstes and Reidispongia coreulea, along with the congeneric reidispongiolides (e.g., 4, planar structure) (7,8). A related family of trisoxazole-containing marine macrolides, typified by mycalolide A (5) and jaspisamide A (6), are also antimicrofilament agents (9). Recently, an x-ray crystal structure of the latter compound bound to actin (10) highlighted the importance of the characteristic N-vinyl formamide-containing side chain, common to all these macrolides, in determining their biological activity. Moreover, all these actin-binding macrolides inhibit the proliferation of human cancer cell lines; for example, the scytophycins and sphinxolides exhibit potent cytotoxicity against L1210 and KB cells, with IC 50 values ranging from ng͞ml to pg͞ml (9). In addition, aplyronine A shows potent antitumor activity in vivo and has potential as a clinical candidate (9). Notably, both the scytophycins and sphinxolides circumvent multidrug resistance mediated by the overexpression of P-glycoprotein...

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Stereocontrolled Total Synthesis of (+)‐Altohyrtin A/Spongistatin 1

Cited by 57 publications

References 75 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 Induction in Aldol Additions

Synthesis of antimicrofilament marine macrolides: Synthesis and configurational assignment of a C ₅ –C ₁₆ degradation fragment of reidispongiolide A

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Stereocontrolled Total Synthesis of (+)‐Altohyrtin A/Spongistatin 1

Cited by 57 publications

References 75 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 Induction in Aldol Additions

Synthesis of antimicrofilament marine macrolides: Synthesis and configurational assignment of a C 5 –C 16 degradation fragment of reidispongiolide A

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Synthesis of antimicrofilament marine macrolides: Synthesis and configurational assignment of a C ₅ –C ₁₆ degradation fragment of reidispongiolide A