Catalytic Enantioselective Olefin Metathesis and Natural Product Synthesis

Hoveyda, Amir H.; Malcolmson, Steven J.; Meek, Simon J.; Zhugralin, Adil R.

doi:10.1002/9783527629626.ch12

Cited by 37 publications

(45 citation statements)

References 18 publications

(7 reference statements)

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“…[82] Olefin functionalization [83] and transition-metal-mediated technologies (e.g., see the above section: "Palladium-catalyzed convergent installation…") have also, over the last 20 years, seen momentous advancements that could be fruitfully applied to the development of more expedient and flexible semisynthetic [84] preparations of cardiotonic steroids. Given the pharmacologically privileged nature of the steroid scaffold and the vast possibilities for structural diversity when one considers varying stereochemical configurations, hydroxylation patterns and oxidative skeletal rearrangements, it is very likely that future work in this recently neglected field will produce biologically interesting medicinal lead compounds that might be further developed into clinically relevant new chemical entitities (NCEs).…”

Section: Discussionmentioning

confidence: 99%

Chemical Synthesis of the Cardiotonic Steroid Glycosides and Related Natural Products

Heasley

2012

Chemistry A European J

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The active components from the extracts of Digitalis, cardiotonic steroid glycosides, have been ingested by humans for more than 200 years as a medicinal therapy for heart failure and abnormal heart rhythms. The positive inotropic activity of the cardiotonic steroids that mediates clinically useful physiological effects in patients has been attributed largely to a high affinity inhibitory interaction with the extracellular surface of the membrane-bound sodium pump (Na(+)/K(+)-ATPase). However, previously unrecognized intracellular signaling pathways continue to be uncovered. This Review examines both partial and de novo synthetic approaches to the medicinally important and structurally captivating cardenolide and bufadienolide steroid families, with an emphasis on the stereocontrolled construction of the pharmacophoric aglycone (genin) framework.

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Section: Discussionmentioning

confidence: 99%

Chemical Synthesis of the Cardiotonic Steroid Glycosides and Related Natural Products

Heasley

2012

Chemistry A European J

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“…[3,4] The modularity of the established synthesis route allowed the operative motif of 1 to be systematically edited and hence gave rise to several generations of descendant catalysts with tailored properties. Most notable among them are Schrock alkylidenes with chiral alkoxide or diolate ligands and/or alkylidenes that are chiral at metal for all sorts of asymmetric metathesis reactions, [3,5] as well as catalysts that impose high Z-selectivity on certain metathesis reactions. [6] As complex 1 and relatives, however, are very sensitive to air and moisture, their handling is clearly more demanding than that of the competing ruthenium carbenes introduced by Grubbs.…”

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confidence: 99%

Rendering Schrock‐type Molybdenum Alkylidene Complexes Air Stable: User‐Friendly Precatalysts for Alkene Metathesis

Heppekausen

Fürstner

2011

Angew Chem Int Ed

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A matter of convenience: Schrock molybdenum alkylidenes are amongst the most powerful olefin metathesis catalysts known to date, but their sensitivity to air and moisture mandates their handling in a glove-box or by Schlenk techniques. This inconvenience is circumvented by using the corresponding phenanthroline- or bipyridine adducts, which are bench-stable and hence very user-friendly. The active species can be liberated from these precatalysts in uncompromised form on treatment with ZnCl₂ in toluene

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“…[1] For these kind of transformations, a range of molybdenum-catalysts containing one stereogen metal center have been very successful.…”

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A Novel Ligand for the Enantioselective Ruthenium‐Catalyzed Olefin Metathesis

et al. 2011

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Recently the interest for chiral olefin metathesis catalysts with respect to the synthesis of enantioenriched molecules, as well as enhanced product selectivities, has increased significantly.[1] For these kind of transformations, a range of molybdenum-catalysts containing one stereogen metal center have been very successful.[2] However, in comparison to these catalysts, ruthenium metathesis catalysts offer improved handling and stability. [3] A challenge with such catalysts is an efficient transfer of chirality from the N-heterocyclic carbene (NHC) to the metal center without substitution of the chlorine ligands, which are important for the reactivity.[4] Recently, we introduced chiral ruthenium metathesis catalysts of type 1, [5] which, compared to the catalysts of Grubbs et al. (e.g. 2), have a different orientation of the stabilizing N-aryl groups (Scheme 1) which arises from the monosubstitution in the NHC-backbone. [6] The C3 substituent in the NHC twists the framework and hinders rotation of the N-aryl substituent, while at the same time the absence of the C4 substitution allows a planar orientation for the mesitylene moiety. The resulting highly active catalyst was used for asymmetric ring-opening crossmetathesis providing excellent results.[5]Herein, we report a new type of chiral NHC-ligand in which rotation around the chirality transferring N-aryl bond is no longer possible, and the corresponding ruthenium metathesis catalysts. We decided to use a 2-substituted tetrahydroquinoline as the source of chirality, which is easy accessible via quinaldic acid 4. After esterification of 4 and hydration to rac-5, a kinetic enzymatic resolution leads to the desired key structure ent-5 in an overall yield of 41 % (! 99 % ee) (Scheme 2). [7] Protection of amine ent-5 (route A), ester saponification and subsequent amide coupling and deprotection, afforded amide 6. A further reduction with BH 3 ·SMe 2 led to the formation of diamine 7 in good yields. During this reaction a partial racemization and fluctuating ee-values were detected Scheme 1. Chiral ruthenium metathesis (pre)catalysts.

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Catalytic Enantioselective Olefin Metathesis and Natural Product Synthesis

Cited by 37 publications

References 18 publications

Chemical Synthesis of the Cardiotonic Steroid Glycosides and Related Natural Products

Chemical Synthesis of the Cardiotonic Steroid Glycosides and Related Natural Products

Rendering Schrock‐type Molybdenum Alkylidene Complexes Air Stable: User‐Friendly Precatalysts for Alkene Metathesis

A Novel Ligand for the Enantioselective Ruthenium‐Catalyzed Olefin Metathesis

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