Diastereoselective Synthesis of Vicinal Tertiary Diols

Loertscher, Brad M.; Young, Phil R.; Evans, Patrick; Castle, Steven L.

doi:10.1021/ol4005799

Cited by 18 publications

(10 citation statements)

References 41 publications

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“…Castle et al. recently demonstrated that analogous ketones (instead of aldehydes) react similarly with excellent diastereoselectivity 24. The 1,2 A strain involving the keto group will further benefit diastereoselectivity.…”

Section: Methodsmentioning

confidence: 99%

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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Section: Methodsmentioning

confidence: 99%

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

Bartlett

Gross

Péron

et al. 2014

Chemistry A European J

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“…Hence, by invoking 14 , hydride attack of the least congested Si -face would directly lead to the key intermediate 3 (Scheme ). We were encouraged in this approach by the work of Castle et al regarding the selective addition of various nucleophiles to a 1,3-alkoxy ketone containing an α-OTBS substituent, which was found to operate via a 1,3-chelation controlled transition state combined with CE-type stabilization . Furthermore, a number of methodologies for the metal-mediated diastereoselective reduction of β-keto esters, β-hydroxy ketones, and α-epoxy ketones have been described, leading in general to excellent facial selectivity. − …”

Section: Results and Discussionmentioning

confidence: 99%

Total Synthesis of (−)-Luminacin D

et al. 2016

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A second-generation synthesis of (-)-luminacin D based on an early stage introduction of the trisubstituted epoxide group is reported, allowing access to the natural product in an improved yield and a reduced number of steps (5.4%, 17 steps vs 2.6%, 19 steps). A full account of the optimization work is provided, with the reversal of stereoselection in the formation of the C4 alcohol in equally excellent diastereoselectivity as the key improvement.

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“…121,122 The three contiguous quaternary stereogenic carbons of jogyamycin, as well as the dense functionalization around the ring that includes sensitive urea and aniline moieties, have inspired a number of strategies to achieve a total synthesis of this molecule. [131][132][133][134][135][136][137][138][139][140][141][142] However, these efforts have either been unsuccessful or do not allow for deep-seated changes to the core of the molecule, rendering any future explorations of structureactivity relationships challenging.…”

Section: Synthesis Of the Core Of Jogyamycinmentioning

confidence: 99%

Oxidative allene amination for the synthesis of nitrogen-containing heterocycles

Eshon¹,

Gerstner²,

Schomaker³

2018

Arkivoc

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The prevalence of stereochemically complex amines in natural products, pharmaceuticals and other bioactive compounds, coupled with the challenges inherent in their preparation, has inspired work to develop new and versatile methodologies for the synthesis of amine-containing stereotriads ('triads'). The key step is a highly chemo-, regio-, and stereo-selective transition-metal catalyzed nitrene transfer reaction that transforms one of the cumulated double bonds of an allene precursor into a bicyclic methyleneaziridine intermediate. This account summarizes our strategies for elaboration of such intermediates into stereochemically rich, densely functionalized amine triads, nitrogen heterocycles, aminated carbocycles and other useful synthetic building blocks.

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Diastereoselective Synthesis of Vicinal Tertiary Diols

Cited by 18 publications

References 41 publications

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

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

Total Synthesis of (−)-Luminacin D

Oxidative allene amination for the synthesis of nitrogen-containing heterocycles

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