Cyclopentane Ring Research Articles

Exploitation of in situ generated sugar-based olefin keto-nitrones: synthesis of carbocycles, heterocycles, and nucleoside derivatives.

Application of intramolecular 1,3-dipolar nitrone cycloaddition reaction on carbohydrate-derived precursors containing an olefin functionality at C-1 or C-3 or C-5 and a nitrone moiety at C-2 or C-3 as appropriate has resulted in the formation of structurally new cycloaddition products containing furanose-fused oxepane, thiepane, azepane, cyclopentane, cycloheptane, tetrahydrofuran, and pyranose-fused tetrahydrofuran rings. The structure and stereochemistry of these products have been characterized by spectral as well as single-crystal X-ray analyses. Two of the compounds have been transformed to the bicyclic nucleoside derivatives applying Vorbrüggen reaction conditions.

Algiolide A, secoiridoid glucoside from Mongolian medicinal plant Gentiana algida

A new secoiridoid glucoside, algiolide A (1), was isolated from the aerial parts of a Mongolian traditional herbal medicine Gentiana algida (Gentianaceae). The structure of 1 was elucidated on the basis of spectroscopic analysis and chemical conversion as well as calculations of NMR and ECD spectra. Algiolide A (1) has a novel skeleton consisting of fused α,β-unsaturated-δ-lactone and cyclopentene rings.

Synthesis of Akt Inhibitor Ipatasertib. Part 1. Route Scouting and Early Process Development of a Challenging Cyclopentylpyrimidine Intermediate

Herein, the route scouting and early process development of a key cyclopentylpyrimidine ketone intermediate toward the synthesis of Akt inhibitor Ipatasertib are described. Initial supplies of the intermediate were prepared through a method that commenced with the natural product (R)-(+)-pulegone and relied on the early construction of a methyl-substituted cyclopentyl ring system. The first process chemistry route, detailed herein, enabled the synthesis of the ketone on a hundred-gram scale, but it was not feasible for the requisite production of multikilogram quantities of this compound and necessitated the exploration of alternative strategies. Several new synthetic approaches were investigated towards the preparation of the cyclopentylpyrimidine ketone, in either racemic or chiral form, which resulted in the discovery of a more practical route that hinged on the initial preparation of a highly substituted dihydroxypyrimidine compound. The cyclopentane ring in the target was then constructed through a key carbonylative esterification and subsequent tandem Dieckmann cyclization–decarboxylation sequence that was demonstrated in a racemic synthesis. This proof-of-concept was later developed into an asymmetric synthesis of the cyclopentylpyrimidine ketone, which will be described in a subsequent paper, along with the synthesis of Ipatasertib.

Conformational landscape of indan-5-ol: A free-jet millimetre wave study

The rotational spectra of the normal and O-D species of two conformers of indan-5-ol, having about the same energy, have been assigned and measured by free jet millimetre wave absorption spectroscopy. The two conformers differ on the orientation of the hydroxyl group, towards or outwards with respect to the a-axis of the molecule, and have been identified on the basis of the different substitution coordinates of the hydroxyl hydrogen. No splittings of the rotational lines due to the ring puckering of the cyclopentane ring have been observed.

2-Pyridyl-phosphine and -diphosphine complexes of nickel(II), and their aqueous solution chemistry

The cis, square planar NiII complexes NiX2[d(py)pe], where d(py)pe is the 2-pyridyl-diphosphine ligand py2P(CH2)2Ppy2, and X=Cl (1a), Br (1b), I (1c), NCS, and NO3, and the corresponding d(py)pcp complexes, where d(py)pcp is ▪ with a cyclopentane ring bridge, are synthesized via use of the NiX2(PPh3)2 precursors, and fully characterized, including five X-ray structures. An X-ray structure of d(py)pcp is also reported.Complexes 1a–c dissolve in water to form cis-{Ni(H2O)2[d(py)pe]}2+, which is isolated as the PF6 salt; the d(py)pcp analogues behave similarly. All the diaquo complexes decompose slowly in H2O to generate Ni(H2O)62+ and the dioxides of the pyridyl-diphosphines, likely due to the presence of trace O2. Known, tetrahedral complexes of the type NiX2(PPh3−npyn)2 (X=Cl, Br; py=2-pyridyl, and n=1–3) also dissolve in H2O, again with generation of 2:1 electrolyte species. An attempted synthesis of Ni(CO)2(Ppy3)2 from Ni(CO)2(PPh3)2 and Ppy3 in CH2Cl2 accidentally gives the known NiCl2(P,N-Ppy3)·H2O via a laboratory light-induced reaction; this species partially converts into [Ni(Ppy3)2]Cl2, and a crystal structure confirms the octahedral, tripodal N,N′,N″-coordination of the cation. The water-soluble systems, studied because of their potential for catalysis in aqueous media, are not effective for catalyzed olefin hydration, or transfer-hydrogenation of cyclohexanone.

Crystal structure of hydro-cortisone 17-butyrate.

In the title compound, C25H36O6, the two central cyclo­hexane rings exhibit a chair conformation. The terminal cyclo­hexene and cyclo­pentane rings are in half-chair and envelope conformations (with the C atom bearing the methyl substit­uent as the flap), respectively. The methyl group of the butyrate chain is disordered over two orientations, with a refined occupancy ratio of 0.742 (6):0.258 (6). Intra­molecular O—H⋯O and C—H⋯O hydrogen bonds are observed. In the crystal, mol­ecules are linked by O—H⋯O hydrogen bonds into chains running parallel to the a axis.

Donors contribute more than acceptors to increase the two-photon activity--a case study with cyclopenta[b]naphthalene based molecules.

In the present work, we address the question -"which among the electron donors and the electron acceptors contribute more to the two-photon (TP) activity of a donor-π-acceptor type of molecule?" For this purpose we have performed ab initio calculations to calculate the TP transition probability (δTP) of a recently synthesized (Benedetti et al., J. Am. Chem. Soc., 2012, 134(30), 12418-12421) cyclopenta[b]naphthalene based chemo-sensor and its derivatives containing different electron donor and acceptor groups. Our study revealed that both under vacuum and in solvent phases, an increase in electron donor strength (-OMe, -NH2, -NMe2) increases the δTP value up to five times, whereas, an increase in the acceptor group strength (-COCH3, -NO2, -CN) increases it by a factor of two only. The highest δTP value is obtained for the molecule having the strongest donor-acceptor pair (-CN, -NMe2) considered in this work. We have also noted that, the removal of the cyclopentane ring from the original system increases the δTP value by ∼20% and the replacement of the naphthyl group by the benzene ring decreases it by ∼70%. All these results are explained by inspecting different TP tensor elements and different transition moment vectors involved in a two-state model approach. A close scrutiny of different parameters in 2SM clearly reveals that upon increasing the strength of either the donor or the acceptor group the parameters change in favour of increasing the overall δTP values but in the case of donors this effect is much larger.

Discovery of pyrrolo[1,2-b]pyridazine-3-carboxamides as Janus kinase (JAK) inhibitors

A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g–4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3–JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3–JAK1 pathway versus JAK2, and active in a human whole blood assay.

ChemInform Abstract: Synthesis of C‐Spiro‐glycoconjugates from Sugar Lactones via Zinc Mediated Barbier Reaction.

Anomeric gem-diallylation, mono-β-crotylation and mono-β-propargylation of sugar 1,5 and 1,4 lactones have been achieved under Barbier reaction conditions using Zn powder and a catalytic amount of TMSCl as an activator. Ring closing olefin metathesis of the synthesized gem-diallyl derivatives furnished C-spiro cyclopentene glycosides. Finally, the cyclopentene rings were converted into carbohydrate based tricyclic morpholine fused triazole glycoconjugates as potential SGLT2 inhibitors.

Biphenyl‐Derived Phosphepines as Chiral Nucleophilic Catalysts: Enantioselective [4+1] Annulations To Form Functionalized Cyclopentenes

AbstractBecause of the frequent occurrence of cyclopentane subunits in bioactive compounds, the development of efficient catalytic asymmetric methods for their synthesis is an important objective. Introduced herein is a new family of chiral nucleophilic catalysts, biphenyl‐derived phosphepines, and we apply them to an enantioselective variant of a useful [4+1] annulation. A range of one‐carbon coupling partners can be employed, thereby generating cyclopentenes which bear a fully substituted stereocenter [either all‐carbon or heteroatom‐substituted (sulfur and phosphorus)]. Stereocenters at the other four positions of the cyclopentane ring can also be introduced with good stereoselectivity. An initial mechanistic study indicates that phosphine addition to the electrophilic four‐carbon coupling partner is not the turnover‐limiting step of the catalytic cycle.

Biphenyl-derived phosphepines as chiral nucleophilic catalysts: enantioselective [4+1] annulations to form functionalized cyclopentenes.

Because of the frequent occurrence of cyclopentane subunits in bioactive compounds, the development of efficient catalytic asymmetric methods for their synthesis is an important objective. Introduced herein is a new family of chiral nucleophilic catalysts, biphenyl-derived phosphepines, and we apply them to an enantioselective variant of a useful [4+1] annulation. A range of one-carbon coupling partners can be employed, thereby generating cyclopentenes which bear a fully substituted stereocenter [either all-carbon or heteroatom-substituted (sulfur and phosphorus)]. Stereocenters at the other four positions of the cyclopentane ring can also be introduced with good stereoselectivity. An initial mechanistic study indicates that phosphine addition to the electrophilic four-carbon coupling partner is not the turnover-limiting step of the catalytic cycle.

Synthesis and Crystal Structure Studies on 6-Amino-5,5,7-Tricyano-3,3a,4,5-Tetrahydro-2H-Indene-4-Spirocyclopentane

A malononitrile derivative, 6-Amino-5,5,7-tricyano-3,3a,4,5-tetrahydro-2H-indene-4- Spirocyclopentane was synthesized in ethanol with malononitrile and cyclopentanone as raw materials. It was characterized by X-ray single crystal diffraction analysis.The crystal of the title complex belongs to Triclinic, P21/c space group with a=6.4687(13)Å, b=8.9901(18)Å, c=12.004(2)Å, α=93.55(3) deg, β=91.86(3) deg, γ=92.25(3) deg. V=695.8(2)Å3, Z=2, F(000)=278 and final R1=0.0524,WR2=0.1497. X-ray analysis reveals that The cyclohexene ring has a distorted half-chair conformation and the cyclopentene and cyclopentane rings adopt envelope conformations. The dihedral angles between planar fragments of the cyclohexene and cyclopentene rings and of the cyclohexene and cyclopentane rings are 10.67 (7) and 87.33 (3)°, respectively. In the crystal, intermolecular N-HN hydrogen bonds link the molecules into infinite chains running in the [10] direction.

The Nazarov Cyclization: A Valuable Method to Synthesize Fully Substituted Carbon Stereocenters

AbstractThe synthesis of fully substituted carbon stereocenters remains a challenging task in organic chemistry. Recent developments in the design of substrates that undergo the Nazarov cyclization have enabled this reaction to become a valuable way to form elaborately substituted cyclopentane rings containing fully substituted carbon stereocenters. Three major strategies have been utilized in this endeavor. Here we provide an overview of these three areas that should give insight into the usage of the Nazarov reaction for the challenging task of forming fully substituted carbon stereocenters.

In situ production of branched glycerol dialkyl glycerol tetraethers in anoxic marine water columns

Glycerol dialkyl glycerol tetraether (GDGT) compositions of suspended particulate matter in the water columns of two anoxic marine settings, the Black Sea and Cariaco Basin, were analyzed to better define the sources of GDGTs in marine environments. In deep anoxic waters the enhanced abundance of the conventional branched GDGTs (B-GDGTs) and recently introduced overly- and sparsely branched GDGTs (OB- and SB-GDGTs, respectively) indicated their in situ production by presently unidentified planktonic microorganisms favoring anoxic environment. The elevated concentrations of these branched GDGTs in anoxic waters were accompanied by an increase in their degree of methylation. Such a change in lipid composition may reflect either a microbial community shift or a physiological response of the source organism(s) to redox conditions, but nonetheless, confirms the in situ production of branched GDGTs in anoxic marine settings. In contrast to the B-GDGTs, which have originally been assumed to be of terrestrial origin, OB- and SB-GDGTs in marine sediments are more likely of anoxic marine origin. This notion is supported by a shelf-to-basin transect of surface sediments in the Black Sea, in which OB- and SB-GDGTs were restricted to distal sediments in the central anoxic basin. Even though the OB-, B- and SB-GDGTs are presumed to have related molecular structures, B-GDGTs were the only group that contained cyclopentane rings. The distribution of cycloalkylated vs. non-cycloalkylated B-GDGTs in the water columns of both the Black Sea and Cariaco Basin and surface sediments of the Black Sea suggests a primarily terrestrial origin for the cycloalkylated B-GDGTs but a mixed contribution from both terrestrial and marine sources for non-cycloalkylated B-GDGTs.

Polymorphic forms of lupane triterpenoid betulonic aldehyde (betulonal).

The lupane triterpenoid betulonic aldehyde [also known as betulonal; systematic name: lup-20(29)-en-28-al-3-one, C30H46O2] is a product of betulin oxidation. Crystals were obtained from hexane [form (I)] and dimethyl sulfoxide [form (II)] solutions. Forms (I) and (II) are both orthorhombic. The molecular geometric parameters in the two forms are similar, but the structures are different with respect to the crystal packing. Polymorph (I) contains two independent molecules in the asymmetric unit, while polymorph (II) contains only one molecule, which has a disordered aldehyde group [the disorder ratio is 0.769 (4):0.231 (4)]. In each molecule, the six-membered rings have chair conformations, whereas the cyclopentane ring in each molecule adopts an envelope conformation. All the rings in the lupane nucleus are trans-fused. The extended structures of both polymorphs are stabilized by weak intermolecular C-H...O and van der Waals interactions. Weak intramolecular C-H...O interactions are also observed.

A short access to the skeleton of Elisabethin A and formal syntheses of Elisapterosin B and Colombiasin A.

A short stereoselective synthesis of the Elisabethin A skeleton 4 is described, which opens a formal access to the diterpenes Elisapterosin B and Colombiasin A as well. Key reactions were an intermolecular endo-selective Diels-Alder reaction to generate the decalin part of the molecule, a chemo- and diastereoselective allylation of an aldehyde with allylzinc, a palladium ene annulation of the cyclopentane ring, and a novel sulfonium ylide induced fragmentation of a polycyclic ketone. Additional insights have been gained for the crucial epimerization at C-2.

Asymmetric synthesis of the 2,2,3-trisubstituted cyclopentanone, D-ring fragment of 9,11-secosterols

As a part of our studies on the total synthesis of 9,11-secosterols, the possibility of creating a substituted and functionalized D-ring fragment with three consecutive stereocentres, one of which was quaternary, was studied. The simple starting compound 2-methyl-cyclopent-2-ene-1-one was subjected to asymmetric 1,4-addition with (S,S)-crotyl phosphonamide and alkylation with methyl bromoacetate, resulting in a 2,2,3-substituted cyclopentanone in high diastereoselectivity. The covalently bonded chiral auxiliary was removed using oxidative methods. As a result, a stable D-ring fragment was obtained. The relative configuration of the substituents on the cyclopentane ring was assigned by comparison of the experimental with the quantum chemically calculated 1H–1H and 1H–13C J-coupling constants.

Betulin 3,28-di-O-tosyl-ate.

The title compound, C44H62O6S2 {systematic name: (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-penta­methyl-1-(prop-1-en-2-yl)-3a-[(tos­yloxy)meth­yl]icosa­hydro-1H-cyclo­penta­[a]chrysen-9-yl 4-methyl­benzene­sulfonate}, was obtained by tosyl­ation of naturally occurring betulin. All the cyclo­hexane rings adopt chair conformations and the cyclo­pentane ring adopts a twisted envelope conformation, with the C atom bearing the tosyl­methyl substituent forming the flap. In the crystal, mol­ecules form a three-dimensional network through multiple weak C—H⋯O hydrogen bonds.

Total synthesis of (-)-crinipellin A.

The first total synthesis of (-)-crinipellin A is described. The tetraquinane core skeleton of crinipellin A was assembled through the tandem [2 + 3] cycloaddition reaction of an allenyl diazo substrate containing a cyclopentane ring in a single operation. The absolute stereochemistry was confirmed through the total synthesis.

Differential temperature and pH controls on the abundance and composition of H-GDGTs in terrestrial hot springs

H-shaped glycerol dialkyl glycerol tetraethers (H-GDGTs), also called glycerol monoalkyl glycerol tetraethers (GMGTs), are a unique group of membrane lipids found in several lineages of Euryarchaeota and Crenarchaeota. Their function in these taxa is, however, not well understood. Here we show their presence in both core lipid and polar lipid fractions from microbial biomass sampled from hot springs in Tibet, China (21.9–80.0°C; pH 7.0–9.1), Tengchong, China (55.1–93.6°C; pH 2.5–9.4) and Yellowstone National Park (YNP), USA (16.3–86.7°C; pH 2.1–9.6) using high performance liquid chromatography–mass spectrometry. The number of cyclopentyl rings ranged from zero (H-GDGT-0) to six (H-GDGT-6) in lipid fractions in Tengchong and YNP and from zero to four (H-GDGT-4) in those from Tibet. While H-GDGT-0 was the most abundant H-GDGT in Tibetan springs, H-GDGT-4 predominated in Tengchong and H-GDGT-6 predominant in YNP, resulting in higher ring indices in the latter springs. While pH appeared to be the most important factor affecting the variation in the relative abundance and average number of cyclopentane rings in H-GDGTs from YNP communities, both temperature and pH appeared to be important controls on the abundance of H-GDGT lipids in Tengchong communities, whereas neither pH nor temperature appeared to influence the abundance or average number of cyclopentane rings in H-GDGTs from Tibetan spring communities. Furthermore, the relative abundance of H-GDGTs to total iGDGTs was greater in hot springs with acidic pH, particularly those from YNP. This finding, coupled with taxonomic profiling of archaeal 16S rRNA genes recovered from the same YNP springs, indicates that H-GDGTs in acidic springs may be synthesized by members of the archaeal order Thermoplasmatales, which are adapted to acidic pH.