Stereoarrays with an All‐Carbon Quaternary Center: Diastereoselective Desymmetrization of Prochiral Malonaldehydes

Linclau, Bruno; Cini, Elena; Oakes, Catherine S.; Josse, Solen; Light, Mark E.; Ironmonger, Victoria

doi:10.1002/anie.201107370

Cited by 22 publications

(13 citation statements)

References 40 publications

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“…To construct the 11 R chiral center, we examined stereoselective allylation under various conditions. Eventually, when 31 was treated with allyltributylstannane and magnesium bromide ethyl etherate (MgBr 2 ·Et 2 O) in CH 2 Cl 2 at 0 °C according to Linclau’s method, the allylation was found to take place with perfect chemo- and diastereoselectivities to afford 33 in excellent yield. The selective allylation can be rationalized via chelated intermediate 32 where the re face attack of the allyl nucleophile is favored by steric reasons.…”

supporting

confidence: 70%

Formal Synthesis of (−)-Haliclonin A: Stereoselective Construction of an Azabicyclo[3.3.1]nonane Ring System by a Tandem Radical Reaction

et al. 2020

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confidence: 70%

Formal Synthesis of (−)-Haliclonin A: Stereoselective Construction of an Azabicyclo[3.3.1]nonane Ring System by a Tandem Radical Reaction

et al. 2020

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“…Similar considerations can be made for the reaction of 3 c , with chelation between the two carbonyl groups giving two interconverting “open book” structures9, 10a,e III and IV . Apart from the different steric environments between a half‐chair and open book conformation, the stereoselectivity compared to 3 a is thought to be enhanced due to the absence of 1,2 A strain in III , compared to IV 19.…”

Section: Methodsmentioning

confidence: 80%

“…The key allylation reactions are shown in Scheme . Although treatment of 3 with 3 equiv of MgBr 2 ⋅ OEt 2 at −40 °C9 led to epoxide opening to form a bromohydrin (data not shown), reducing the number of equivalents to 1.6, and the temperature to −78 °C, fully suppressed this side reaction. Thus, allylation of 3 a led to a mixture of diastereomers 10 and 11 in a good yield and ratio, but the better results were obtained with 3 c , giving isomer 12 virtually exclusively in excellent yield.…”

Section: Methodsmentioning

confidence: 93%

“…Its construction was envisaged by spontaneous hemiacetal ring closure, syn ‐aldol reaction, and by the key step, diastereoselective allylation controlled by 1,2‐induction of the quaternary epoxide centre of the enantiopure intermediate 3 . This chelation‐controlled allylation step was inspired by previous work from our group showing excellent levels of diastereocontrol exerted by all‐C quaternary stereocentres for allylstannation of 2,2‐disubstituted malonaldehydes 9. However, a 1,3‐dialdehyde group (c.f.…”

Section: Methodsmentioning

confidence: 99%

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Stereocontrol by Quaternary Centres: A Stereoselective Synthesis of (−)‐Luminacin D

Bartlett

Gross

Péron

et al. 2014

Chemistry A European J

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Natural products continue to be a robust source of novel therapeutics, with ~50% of currently approved anticancer drugs being natural products or their derivatives. 1 The luminacin family of natural products, discovered from the fermentation broth of the soil bacterium Streptomyces sp., 2 contains several members that have shown promising anticancer activity in multiple assays and cell lines. Two members of this family, luminacin D (1a), and luminacin C2 (1b, also known as UCS15A), have been shown to be potent inhibitors of angiogenesis in several in vitro assays. 3 Luminacin D was also shown to inhibit the proliferation of several cancer cell lines. 3 Additional studies with Luminacin C2 have shown it to be a protein-protein interaction inhibitor that targets Src signal transduction by inhibiting the SH3 domain-mediated interactions of Src kinase with its targets, thus preventing the src-specific tyrosine phosphorylation of numerous proteins. 4 Src kinases play a key role in the signaling and regulation of multiple processes associated with cancer, such as cell migration, cell adhesion, extracellular matrix sensing, cell cycle timing, as well as several poorly understood events necessary for angiogenesis.Luminacin C2 was further demonstrated to inhibit the invasion and metastasis of model breast cancer cell lines in vitro, by inhibition of the protein-protein interaction of the src-homology domain of cortactin with AMAP1. 5 The recent report that two structurally related compounds, named migracin A and B (1c), inhibit the migration of a breast cancer cell line, 6 provides further evidence for the anticancer potential of this molecule, or its derivatives.There is comparatively little information about the mode of action or biological function of luminacin D. Given that it is the most potent member of this family in several of the originally reported assays, 3 there is significant potential and need for an approach that enables the synthesis of sufficient quantities of this molecule to enable further research into its cellular mode of action.There are a few syntheses of the luminacins reported, 7 however each with shortcomings in terms of length and/or unselective reaction steps. A particular concern is the epoxide introduction, with three total syntheses featuring a late stage epoxidation step with very low, or undesired selectivity. 7b-d,8 Because of this, we sought to develop a synthetic approach in which an enantiopure epoxide intermediate is assembled first, to then utilise its stereochemistry for diastereoselective completion of the aliphatic portion, from which the luminacins and the migracins can be synthesised.Herein we report a successful total synthesis of (-)-luminacin D using this strategy, and report on the excellent diastereocontrol possible by allylation of aldehydes having α-oxygenated centres, including quaternary centres, under 1,3-chelation conditions. We also unambiguously show that this type of aldehyde addition is consistent with the Cornforth-Evans (CE) model of stereoinduction. Scheme 1....

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“…To a solution of compound 18 [4] (400 mg, 1.10 mmol) and the tosylate linker [5] (944 mg, 3.30 mmol) in anhydrous DMF (5.0 mL) was added 60% sodium hydride (198 mg, 4.95 mmol) at 0 °C. After stirring overnight at room temperature, MeOH (200 µL) was added at 0 °C to quench the reaction.…”

Section: Synthesis Of Scaffold (22)mentioning

confidence: 99%

General and Robust Chemoenzymatic Method for Glycan-Mediated Site-Specific Labeling and Conjugation of Antibodies: Facile Synthesis of Homogeneous AntibodyDrug Conjugates

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Stereoarrays with an All‐Carbon Quaternary Center: Diastereoselective Desymmetrization of Prochiral Malonaldehydes

Cited by 22 publications

References 40 publications

Formal Synthesis of (−)-Haliclonin A: Stereoselective Construction of an Azabicyclo[3.3.1]nonane Ring System by a Tandem Radical Reaction

Formal Synthesis of (−)-Haliclonin A: Stereoselective Construction of an Azabicyclo[3.3.1]nonane Ring System by a Tandem Radical Reaction

Stereocontrol by Quaternary Centres: A Stereoselective Synthesis of (−)‐Luminacin D

General and Robust Chemoenzymatic Method for Glycan-Mediated Site-Specific Labeling and Conjugation of Antibodies: Facile Synthesis of Homogeneous AntibodyDrug Conjugates

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