Pauson-Khand Cyclization Research Articles

Asymmetric Total Synthesis of (2R)-Hydroxynorneomajucin, a Norsesquiterpene from Illicium jiadifengpi.

We report the first total synthesis of (2R)-hydroxynorneomajucin, a norsesquiterpene derived from the Illicium genus. This natural product displays neurotrophic properties. Small molecule neurotrophins have potential as therapeutics in neurodegenerative diseases. Key steps of our synthesis include a Tsuji-Trost reaction, a Pauson-Khand cyclization, and a Nagata hydrocyanation. A simple sequence of reductions and a Mukaiyama hydration introduce the A-ring substituents with the correct configurations. The overall synthesis was completed in 17 steps (longest linear sequence, LLS).

New insights into the biphasic “CO-free” Pauson–Khand cyclisation reaction through combined in situ spectroscopy and multiple linear regression modelling

Multiple linear regression modelling is used to analyse in situ Raman spectra recorded during a “CO-free” Pauson–Khand type cyclisation which enables a knowledge-driven optimisation protocol.

Highly functionalized five-membered bicyclic a-Hydroxy acids from synthetic equivalent of glycolic acids

Five-membered cyclic α-hydroxy acids (1-hydroxycycycloalkane-1-carboxylic acids) are important constituents in biologically active natural products and also important precursor molecules for the synthesis of pharmacologically active compounds. This paper presents stereo selective synthesis of polysubstituted five-membered bicyclic α-hydroxy acid derivatives from α, α, α-dialkylated 1,3-dixolan-4-one (9). The synthesis was initiated on the α-propagylation of 2-(tert-butyl)-5-(1-ethenylprop-2-enyl)-1, 3-dixololan-4-one (trans-8) via its enolate, followed by intramolecular Pauson-Khand cyclization. The reaction was stereo selective and afforded two isomers (10a and 10b) in 4:1 ratio out of four possible diastereoisomers of bicyclic α-hydroxy acid (bicyclic 1-hydroxycarboxylic acid) derivatives. This method opens a new avenue to prepare synthetically useful highly functionalized stereoselctive synthesis of five-membered bicyclic α-hydroxy acids using a convenient and very effective method.

Total synthesis 2-epi-α-cedren-3-one via a cobalt-catalysed Pauson-Khand reaction

Herein we target the total synthesis of 2-epi-α-cedren-3-one, a natural compound isolated from the essential oil of Juniperus thurifera. Overall, our synthetic sequence presents an optimised and robust series of chemical transformations, with prominent features including a low temperature and highly (Z)-selective Wittig olefination reaction, which is vital for the establishment of the relative stereochemistry within the final natural product, and a microwave-assisted, catalytic, intramolecular Pauson-Khand cyclisation reaction, which is used to construct the intriguing tricyclic core of the target molecule. Our optimum cyclisation protocol utilises only 20 mol% of transition metal, and delivers the complex tricyclic structure in just 10 min. Further manipulations of the annulation product culminate in the first total synthesis of the described natural target.

Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure-Activity Studies, Biological and X-ray Structural Analysis.

The design, synthesis, and biological evaluation of a new class of HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2' ligands are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand-backbone interactions in the protease active site. Inhibitors 5c and 5d containing this unprecedented fused 6-5-5 ring system as the P2 ligand, an aminobenzothiazole as the P2' ligand, and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson-Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.

Steric buttressing in the Pauson-Khand reactions of benzyl enynes

The application of the intramolecular Pauson-Khand reaction of 1,n-enynes provides a convenient method for the construction of polycyclic frameworks but this process has largely been limited to the formation of 5,5- and 5,6-fused ring systems. In this report, we describe the application of the Pauson-Khand cyclization to 1,8-enynes embedded in an aromatic ring system wherein it is determined that the presence of steric buttresses in the form of t-butyl groups facilitates the cycloaddition. These reactions proceed in good yields with either thermal or oxidative activation and in the former case, the diastereoselectivities are high. An investigation of the tolerance of this cycloaddition to substitution around the 1,8-enyne demonstrates that only 2,2-disubstitution does not result in productive cyclization. Cycloadditions with hydroxyl groups at the propargylic position while leading to fused rings are compromised by side reactions leading to reduction and in some cases tautomerization. However, these byproducts are easily minimized through conversion of the hydroxyl group to the corresponding silyl ether.

Efficient synthesis of N-nosyl-protected 3-azabicyclo[4.3.0]nonen-8-one by an aniline- and nitrobenzene-mediated Pauson–Khand cyclization

ABSTRACTThe intramolecular Pauson–Khand cyclization in the presence of both aniline and nitrobenzene was used to improve the construction of N-nitrobenzenesulfonyl-protected 3-azabicyclo[4.3.0]nonane skeletons. We found that aniline enhanced the cyclization and that nitrobenzene prevents the concurrent reduction in this process. This combination of mediators allows for the efficient synthesis of bioactive azabicyclic nonane-type alkaloids and the use of milder deprotection conditions in the synthetic route.

Alkynyldicobalt Derivatives of Dibenzosuberenol and Dibenzocyclooctatrien‐5‐ol: Ring Conformations, Ease of Carbonyl Elimination and Relevance to Pauson–Khand Cyclization

Under very mild conditions, (5‐alkynyl‐5H‐dibenzo[a,d]cycloheptatrien‐5‐ol)Co2(CO)6 clusters 1 lose a carbon monoxide ligand and form the corresponding η2‐alkene‐µ‐alkyne‐Co2(CO)5 complexes 2 (the first isolated examples of the initial phase of the Pauson–Khand reaction). This behaviour is not paralleled by the homologue in which an additional methylene group has been inserted within the seven‐membered ring, as in the [5‐alkynyl‐6H‐dibenzo[a,e]cyclooctatrienol]Co2(CO)6 system 8, for which several X‐ray crystal structures are reported. The apparent additional flexibility of this molecular framework does not translate into conformations appropriate for the formation of η2‐alkene‐µ‐alkyne‐Co2(CO)5 complexes. The relative inertness of the ethynyl complex 1a, compared with the ease of carbonyl loss in the trimethylsilylethynyl‐ and the tri(isopropyl)silylethynyl‐substituted hexacarbonyldicobalt clusters, 1b and 11, respectively, is discussed in terms of out‐of‐plane angle strain within the dibenzo[a,d]cycloheptatrienyl moiety. Comparison of the changing conformations of the seven‐membered ring in a series of free and complexed molecules reveals a marked flattening of the organic framework, as bulkier substituents are incorporated at C5. The possibility of η2‐alkene‐µ‐alkyne‐Co2(CO)5 clusters functioning as hemilabile systems was explored by monitoring the ease of carbonyl substitution by triphenylphosphine in 2b (alkynyl substituent C≡CSiMe3).

Total synthesis of 1α,25-dihydroxyvitamin D3 (calcitriol) through a Si-assisted allylic substitution.

Herein, we describe a versatile and efficient total synthesis of 1α,25-dihydroxyvitamin D3 (calcitriol). The synthetic strategy relies on an unprecedented Si-assisted SN2'-syn displacement of carbamates by cuprates to set the challenging pivotal quaternary methyl group at the fused-ring junction of the CD-trans-hydrindane core. Other key transformations involve the catalytic asymmetric reduction of an α,β,γ,δ-unsaturated ester with CuH to generate the natural steroidal configuration at C20 and a Pauson-Khand cyclization to form the CD-ring skeleton. This strategy enables the syntheses of novel analogs for structure-function studies and drug development.

Divergent Synthesis and Real-Time Biological Annotation of Optically Active Tetrahydrocyclopenta[c]pyranone Derivatives.

Sp3-rich compounds are underrepresented in libraries for probe- and drug-discovery, despite their promise of extending the range of accessible molecular shapes beyond planar geometries. With this in mind, a collection of single-enantiomer bicyclic, fused cyclopentenones underpinned by a complexity-generating Pauson–Khand cyclization was synthesized. A fingerprint of biological actions of these compounds was determined immediately after synthesis using real-time annotation−a process relying on multiplexed measurements of alterations in cell morphological features.

Synthesis of Tetracyclic Molecules Containing Medium-Sized Heterocycles: Scope Expansion of Cascade Nicholas and Pauson–Khand Methodology

Unique tetracyclic molecules containing heteroatom-embedded, medium-sized rings were synthesized by employing cascade Nicholas and Pauson–Khand cyclization reactions. We successfully established a divergent synthetic route for quick access to unprecedented multi-ring systems via an alkyne cobalt complex, and an expanded substrate scope for this methodology was realized.

ChemInform Abstract: Robust, Chiral, and Porous BINAP‐Based Metal—Organic Frameworks for Highly Enantioselective Cyclization Reactions.

AbstractBINAP‐based metal‐organic frameworks and their postsynthetic metalation with Rh‐complexes are designed and used as highly active and enantioselective single‐site solid catalysts for the enantioselective reductive cyclization and Alder‐ene cycloisomerization of 1,6‐enynes as well as for Pauson—Khand cyclization reactions between 1,6‐enynes and cinnamaldehyde as the CO source.

ChemInform Abstract: Domino Nicholas and Pauson—Khand Process Induced by Nitroarene Reduction.

AbstractThe enyne substrate (I) undergoes an unprecedented transformation into product (III) in which a nitroarene reduction step initiates an endocyclic Nicholas reaction followed by an intramolecular Pauson—Khand cyclization.

Robust, chiral, and porous BINAP-based metal-organic frameworks for highly enantioselective cyclization reactions.

We report here the design of BINAP-based metal-organic frameworks and their postsynthetic metalation with Rh complexes to afford highly active and enantioselective single-site solid catalysts for the asymmetric cyclization reactions of 1,6-enynes. Robust, chiral, and porous Zr-MOFs of UiO topology, BINAP-MOF (I) or BINAP-dMOF (II), were prepared using purely BINAP-derived dicarboxylate linkers or by mixing BINAP-derived linkers with unfunctionalized dicarboxylate linkers, respectively. Upon metalation with Rh(nbd)2BF4 and [Rh(nbd)Cl]2/AgSbF6, the MOF precatalysts I·Rh(BF4) and I·Rh(SbF6) efficiently catalyzed highly enantioselective (up to 99% ee) reductive cyclization and Alder-ene cycloisomerization of 1,6-enynes, respectively. I·Rh catalysts afforded cyclization products at comparable enantiomeric excesses (ee's) and 4-7 times higher catalytic activity than the homogeneous controls, likely a result of catalytic site isolation in the MOF which prevents bimolecular catalyst deactivation pathways. However, I·Rh is inactive in the more sterically encumbered Pauson-Khand reactions between 1,6-enynes and carbon monoxide. In contrast, with a more open structure, Rh-functionalized BINAP-dMOF, II·Rh, effectively catalyzed Pauson-Khand cyclization reactions between 1,6-enynes and carbon monoxide at 10 times higher activity than the homogeneous control. II·Rh was readily recovered and used three times in Pauson-Khand cyclization reactions without deterioration of yields or ee's. Our work has expanded the scope of MOF-catalyzed asymmetric reactions and showed that the mixed linker strategy can effectively enlarge the open space around the catalytic active site to accommodate highly sterically demanding polycyclic metallocycle transition states/intermediates in asymmetric intramolecular cyclization reactions.

Chiral diphosphine derivatives of alkylidyne tricobalt carbonyl clusters – A comparative study of different cobalt carbonyl (pre)catalysts for (asymmetric) intermolecular Pauson–Khand reactions

Reaction of the tricobalt carbyne cluster [Co3(μ3-CH)(CO)9] with chiral diphosphines of the Josiphos and Walphos families affords the new clusters [Co3(μ3-CH)(CO)7(P–P∗)] in good yield (P–P∗=J004 (1), J005 (2), J007 (3), W001 (4), W003 (5)). The new alkylidyne tricobalt clusters, and the previously known [Co3(μ3-CH)(CO)7(μ-J003)], have been tested as catalysts/catalyst precursors for intermolecular Pauson–Khand cyclization, using norbornene and phenylacetylene as substrate. The diphosphine-substituted tricobalt carbonyl clusters proved to be viable catalysts/catalyst precursors that gave products in moderate to good yields, but the enantiomeric excesses were low. When the chiral diphosphine ligands were used as promoters/auxiliary ligands for the same Pauson–Khand reaction, using either [Co2(CO)8] or [Co4(CO)12] as catalyst precursors, both the overall yields and the selectivities with respect to cyclopentenone formation were significantly improved. The best results were obtained for ligands J007 and W001, with [Co4(CO)12] as pre-catalyst, where yields of 96%, and virtually 100% selectivity were obtained. However, the enantioselectivity of product formation was low or non-existent. The crystal structure of [Co3(μ3-CH)(CO)7(μ-J004)] is described. [J003=[(R)-1-{(S)-2-(dicyclohexylphosphino)-ferrocenyl} ethyldicyclohexylphosphine], J004=[(R)-1-{(S)-2-(dicyclohexylphosphino)-ferrocenyl} ethyldiphenylphosphine], J005=[(R)-1-{(S)-2-(diphenylphosphino)ferrocenyl}ethyl-di-3,5-xylylphosphine], J007=[(R)-1-{(S)-2-di-(4-methoxy-3,5-dimethylphenyl)phosphino)ferrocenyl} ethyldicyclohexylphosphine], W001=[(R)-1-{(R)-2-(2′-diphenyl phosphinophenyl)ferrocenyl} ethyldi(bis-3,5-trifluoromethylphenyl)phosphine], W003 [(R)-1-{(R)-2-(2′-diphenylphosphino-phenyl)ferrocenyl}ethyldi(3,5-xylyl)phosphine].

A substrate-based approach to skeletal diversity from dicobalt hexacarbonyl (C1)-alkynyl glycals by exploiting its combined Ferrier-Nicholas reactivity.

Novel substrates that combine dicobalt hexacarbonyl propargyl (Nicholas) and pyranose-derived allylic (Ferrier) cations have been generated by treatment of hexacarbonyldicobalt (C-1)-alkynyl glycals with BF3 (.) Et2 O. The study of these cations has resulted in the discovery of novel reaction pathways that have shown to be associated to the nature of O-6 substituent in the starting alkynyl glycals. Accordingly, compounds resulting from ring expansion (oxepanes), ring contraction (tetrahydrofurans), or branched pyranoses, by incorporation of nucleophiles, can be obtained from 6-O-benzyl, 6-hydroxy, or 6-O-silyl derivatives, respectively. The use of a 6-O-allyl alkynyl glycal led to a suitable funtionalized oxepane able to experience an intramolecular Pauson-Khand cyclization leading to a single tricyclic derivative.

Isomerization of the (E)‐Alkene of a Conjugated Enyne During Intramolecular Pauson–Khand Cyclization

AbstractIn the presence of DMSO, the intramolecular Pauson–Khand reactions of two substrates with alkyne moieties substituted by carbon chains consisting of a conjugated (E)‐alkene and a terminal oxygen function provided cyclized products in which the conjugated alkene underwent E to Z isomerization. This isomerization was consistent with the acceleration of the cyclization process by the terminal oxygen function.

ChemInform Abstract: An Efficient Preparation of 3-Azabicyclo(3.3.0)oct-5-en-7-ones from Propargyl Alcohol. Cobalt Complexes via Nicholas Reaction with Amidic Nitrogen Nucleophiles Followed by Pauson-Khand Cyclization.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Stereocontrolled preparation of bicyclic alkaloid analogues: an approach towards the kinabalurine skeleton

An approach towards the construction of bicyclic analogues of monoterpene alkaloids belonging to the kinabalurine, incarvilline and skytanthine families of natural products is reported. These syntheses rely on a stereoselective intramolecular Pauson–Khand cyclisation of a chiral pool-derived enyne in order to prepare the bicyclic core. Stereoselective further elaboration generates diastereomeric analogues of the naturally occurring alkaloids.

Preparation of linearly fused 6-6-5 and 6-5-5 carbotricyclic ring systems related to the natural polyquinanes

A short pathway to the formation of the title framework is elaborated via (i) the tandem addition of arylsulfenium chloride and 1-siloxycycloalkenes across the double bond of dicobalthexacarbonyl complex of vinylacetylene, (ii) the diastereoselective Grignard reaction at the carbonyl group of the formed adducts; and (iii) the Pauson–Khand cyclization of 1,6- or 1,7-enyne precursors thus prepared.