Crotylation versus Propargylation:  Two Routes for the Synthesis of the C13−C18 Fragment of the Antibiotic Branimycin

Felzmann, Wolfgang; Castagnolo, Daniele; Rosenbeiger, Daniela; Mulzer, Johann

doi:10.1021/jo062502m

Cited by 41 publications

(23 citation statements)

References 21 publications

(18 reference statements)

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“…We also investigated the behaviour of glyceraldehyde 21 b (entries 4–6), for which we found, to our surprise, only a single precedent as substrate under comparable conditions 26. 27 MgBr 2 ⋅ OEt 2 mediated allylstannation was again very selective, to give syn ‐diastereomer 22 b .…”

Section: Methodsmentioning

confidence: 94%

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: 94%

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

Bartlett

Gross

Péron

et al. 2014

Chemistry A European J

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“…These processes were identified early on in the development of the silicon reagents, often as unwanted side reactions. [45] As in the mechanism above, this process mandates a [1,2]-silicon shift, which must occur preferentially to desilylation. This stipulation is known to occur when the silicon atom bears bulky substituents because nucleophilic addition to silicon (and hence desilylation) is retarded (Figure 7).…”

Section: Allenylsilanesmentioning

confidence: 91%

Vinyl‐, Propargyl‐, and Allenylsilicon Reagents in Asymmetric Synthesis: A Relatively Untapped Resource of Environmentally Benign Reagents

Long¹,

Aye

2009

Chemistry A European J

104

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An up-to-date in-depth review of the current virtues and limitations in the realm of carbonyl addition reactions with allenyl-, propargyl-, and vinylsilicon reagents, encompassing numerous practical as well as pedagogical principles is presented. Comparisons of chemo-, regio-, and stereoselectivity and reactivity are drawn. Synthetic applications and challenges associated with each class of organosilane are discussed threading together the prospects of these green carbanion surrogates.

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“…Although the observed anti-Felkin selectivity with the α-[(p-methoxybenzyl)oxy] aldehyde 41 could, in retrospect, be explained by the intervention of chelation control in the nucleophilic addition, [21] this explanation could not be so readily applied to the corresponding α-silyloxy compound 11, which gave the same selectivity. To allow us to test the selectivities more rapidly as well as to allow the stereochemistry of the newly formed stereocenter to be checked in a more straightforward manner, a set of model studies with simpler α,β-dioxygenated aldehydes bearing a tertiary protected C-O system was carried out ( Table 4).…”

Section: Synthesis Of the Epi-c10 Abcde Ring System Of Ptx2mentioning

confidence: 97%

“…Chelation with the β-oxy substituent would be expected to afford the Felkin product. Although chelation to the α-substituent would indeed afford the anti-Felkin product, [21] α-silyloxy aldehydes that are generally poor substrates for chelation control also displayed anti-Felkin selectivity when the β-carbon was heavily substituted (two carbon chains and an alkoxy substituent). Although several models could be conceivably presented that account for these observations, at present we simply wish to issue a cautionary note that the usual Felkin/Cornforth selectivities appear to break down with these heavily substituted substrates.…”

Section: Synthesis Of the Epi-c10 Abcde Ring System Of Ptx2mentioning

confidence: 99%

Synthetic Studies towards Pectenotoxin‐2: Synthesis of the Nonanomeric 10‐epi‐ABCDE Ring Segment by Kinetic Spiroketalization

et al. 2011

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The synthesis of the nonanomeric 10‐epi‐ABCDE ring system of pectenotoxin‐2 has been achieved by using a kinetic spiroketalization reaction. The synthesis of the spiroketalization precursor was achieved through a cross‐metathesis/hydrogenation sequence. The formation of the epi‐C10 isomer resulted from an unexpected anti‐Felkin selective addition of organometallic nucleophiles to the advanced CDE ring precursor. This addition reaction was investigated with differently protected α,β‐dioxygenated model aldehydes, which displayed similar anti‐Felkin selectivities with organometallic nucleophiles.

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Crotylation versus Propargylation: Two Routes for the Synthesis of the C13−C18 Fragment of the Antibiotic Branimycin

Cited by 41 publications

References 21 publications

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

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

Vinyl‐, Propargyl‐, and Allenylsilicon Reagents in Asymmetric Synthesis: A Relatively Untapped Resource of Environmentally Benign Reagents

Synthetic Studies towards Pectenotoxin‐2: Synthesis of the Nonanomeric 10‐epi‐ABCDE Ring Segment by Kinetic Spiroketalization

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