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

Abstract

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....

Total Synthesis of (−)-Luminacin D

“…In this context, we achieved a highly diastereoselective synthesis of (−)-luminacin D in 19 steps. 10 As shown in Scheme 1, our synthetic approach relied on the stereoselective introduction of the epoxide moiety at an early stage of the synthesis starting from the enantiopure sulfoxide 5, and subsequently to utilize the chirality of the epoxide group in 4 for the diastereoselective completion of the aliphatic fragment. This was achieved via a chelation-controlled allylation procedure of the enantiopure αepoxy aldehyde 4a, which proceeded in excellent yield and diastereoselectivity.…”

Diastereodivergent and Enantioselective Access to Spiroepoxides via Organocatalytic Epoxidation of Unsaturated Pyrazolones

“…Five- and six-membered spirocyclic compounds, bearing different heteroatoms and stereocenters, are now obtainable with a high level of diastereo- and enantioselectivity, exploiting domino reactions . Concerning spiroepoxides, only a few examples for their asymmetric synthesis have been developed so far, although representative natural spiroepoxides are important compounds; examples include fumagillin, lumacinin D, and FR901464, which show potent antibiotic, antiangiogenic, and anticancer activities, respectively. The few protocols reported are based on chiral substrates or auxiliary tools .…”

Asymmetric Allylation of Glycidols Mediated by Allyl Acetate via Iridium-Catalyzed Hydrogen Transfer

“…Epoxides are important building blocks in chemical synthesis, including the construction of polyketide natural products where they also appear as native structural motifs . Accordingly, several methods have been reported for the asymmetric allylation of glycidic aldehydes using reagents based on boron, , tin, , silicon, , indium, and magnesium . These methods have proven effective in certain contexts; − however, due to pronounced match–mismatch effects, only one diastereomer of the secondary homoallylic glycidol is generally accessible in highly diastereomerically enriched form .…”

“…Accordingly, several methods have been reported for the asymmetric allylation of glycidic aldehydes using reagents based on boron, , tin, , silicon, , indium, and magnesium . These methods have proven effective in certain contexts; − however, due to pronounced match–mismatch effects, only one diastereomer of the secondary homoallylic glycidol is generally accessible in highly diastereomerically enriched form . Additionally, indirect formation of secondary homoallylic glycidols via enantioselective allylation of α,β-unsaturated aldehydes followed by Sharpless asymmetric epoxidation is problematic, as modest diastereoselectivities are evident in reactions of secondary ( Z )-allylic alcohols …”

“…The identification of favorable conditions for the asymmetric C–H allylation of glycidol 1a prompted a more detailed investigation into the scope of this process (Table ). cis -Glycidols 1b – e were specifically selected for study as the corresponding secondary homoallylic glycidols 2b – e and epi - 2b – epi - 2e are inaccessible using conventional allylation methods − due to the modest diastereoselectivities reported in Sharpless asymmetric epoxidations of secondary ( Z )-allylic alcohols along with the stereochemically labile nature of (Z)-α,β-unsaturated aldehydes. In the event, cis -glycidols 1b – e were converted to the secondary homoallylic glycidols 2b – e and epi - 2b – epi - 2e , respectively, in good yields and good levels of catalyst-directed diastereoselectivity.…”