Hexane Ring System Research Articles

Improved Synthesis of C4α- and C4β-Methyl Analogues of 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate

An efficient and divergent synthesis of C4α- and C4β-methyl-substituted analogues of 2-aminobicyclo[3.1.0]hexane 2,6-dicarboxylate, which are important tools in the study of metabotropic glutamate receptor function, has been achieved. By taking advantage of an unanticipated facial selectivity of the bicyclo[3.1.0]hexane ring system, either the C4α- or C4β-methyl substituent was introduced in a highly stereoselective and high-yielding manner.

ChemInform Abstract: Mode of Action and Biosynthesis of the Azabicycle‐Containing Natural Products Azinomycin and Ficellomycin

AbstractReview: 58 refs.

Mode of action and biosynthesis of the azabicycle-containing natural products azinomycin and ficellomycin

Only a handful of aziridine-containing natural products have been identified out of the more than 100,000 natural products characterized to date. Among this class of compounds, only the azinomycins (azinomycin A and B) and ficellomycin contain an unusual 1-azabicyclo[3.1.0]hexane ring system, which has been reported to be the reason for theDNAcrosslinking abilities and cytotoxicity of these metabolites. Both families of natural products are produced by Streptomyces species, Streptomyces sahachiroi and Streptomyces ficellus, respectively. Up until recently, much of the work on these molecules has focused on the synthesis of these natural products or their corresponding analogs for in vitro investigations evaluating their DNA selectivity. While one of the most intriguing aspects of these natural products is their biosynthesis, progress made in this area was largely impeded by difficulties with obtaining a reliable culture method and securing a consistent source of these natural products. In this review, we will cover the discovery and biological activity of the azinomycins, their mode of action, related synthetic analogs and biosynthesis, and finish with a discussion on the less studied metabolite, ficellomycin.

Potential Nicotinic Acetylcholine Receptor Ligands from 2,4-Methanoproline Derivatives

Potential nicotinic acetylcholine receptor (nAChR) ligands have been synthesized in which a methylisoxazole substituent is attached to the 1-position ( 26) of the 2-azabicyclo[2.1.1]hexane ring system or separated by "spacer" atoms ( 21 and 23). With ABT-594 as a model, a range of pyridine heterocycles have been attached to the 1-position via a -CH 2O- spacer ( 11, 14, and 6). The biological evaluation of target compounds showed there was no binding affinity at the alpha4beta2 and alpha3beta4 nAChR subtypes.

Selective A 3 adenosine receptor antagonists derived from nucleosides containing a bicyclo[3.1.0]hexane ring system

We have prepared 5′-modified derivatives of adenosine and a corresponding (N)-methanocarba nucleoside series containing a bicyclo[3.1.0]hexane ring system in place of the ribose moiety. The compounds were examined in binding assays at three subtypes of adenosine receptors (ARs) and in functional assays at the A 3 AR. The H-bonding ability of a group of 9-riboside derivatives containing a 5′-uronamide moiety was reduced by modification of the NH; however these derivatives did not display the desired activity as selective A 3 AR antagonists, as occurs with 5′- N, N-dimethyluronamides. However, truncated (N)-methanocarba analogues lacking a 4′-hydroxymethyl group were highly potent and selective antagonists of the human A 3 AR. The compounds were synthesized from d-ribose using a reductive free radical decarboxylation of a 5′-carboxy intermediate. A less efficient synthetic approach began with L-ribose, which was similar to the published synthesis of (N)-methanocarba A 3AR agonists. Compounds 33b– 39b ( N 6-3-halobenzyl and related arylalkyl derivatives) were potent A 3AR antagonists with binding K i values of 0.7–1.4 nM. In a functional assay of [ 35S]GTPγS binding, 33b (3-iodobenzyl) completely inhibited stimulation by NECA with a K B of 8.9 nM. Thus, a highly potent and selective series of A 3AR antagonists has been described.

Synthesis of Bicyclo[3.1.0]hexane Derivatives as Conformationally Restricted Analogues of β-Arabinofuranosyl and α-Galactofuranosyl Rings

A route for the synthesis of bicyclo[3.1.0]hexane-derived conformationally restricted analogues of beta-arabinofuranosyl and alpha-galactofuranosyl rings is described. Advantage is taken of the pseudo-enantiomeric relationship between the two ring systems to develop a route that provides both targets from a single precursor. Key steps include a base-promoted ring contraction of an epoxy ketone obtained from cyclohexane-1,4-dione to give the bicyclo[3.1.0]hexane ring system and a late stage resolution involving esterification with O-acetyl-(S)-mandelic acid.

Rearranging The Bicyclo[3.1.0]Hexane Template Of Carbocyclic Nucleosides To Improve Binding Recognition By Kinases

A novel bicyclo[3.1.0]hexane carbocyclic nucleoside (4) with a south-like conformation amenable to interact with the herpes thymidine kinase (HSV-tk) was synthesized with an endo-hydroxyl group positioned at the tip of the bicyclo[3.1.0]hexane ring system opposite to the tip of the fused cyclopropane ring. The introduction of the hydroxymethyl chain through a Baylis-Hillman type reaction and the regioselective opening of a cyclic sulfite intermediate to introduce the nitrogen functionality at the correct position are highlighted.

New Synthetic Approach to the Bicyclo[3.1.0]hexane Ring System from (+)‐(1R,4R)‐4‐(Benzyloxymethyl)‐4‐(hydroxymethyl)cyclopent‐2‐enol.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

New Synthetic Approach to the Bicyclo[3.1.0]hexane Ring System from (+)-(1R,4R)-4-(Benzyloxymethyl)-4-(hydroxymethyl)cyclopent-2-enol.

A methanocarba approach to conformationally constrain the sugar ring in nucleosides and nucleotides was introduced by Marquez and co-workers. Thus, a bicyclo[3.1.0]hexane system has been constrained in a North ((N), 2'-exo) or South ((S), 2'-endo) conformation, according to the pseudorotational cycle. In many studies of the ribose ring conformation of nucleosides and nucleotides binding to G proteincoupled receptors (GPCRs), novel (N)-ligands for adenosine receptors and P2Y receptors provided favorable receptor affinity and/or selectivity compared to their corresponding (S)-conformers. In addition, (N)-bicyclo[3.1.0]hexane nucleosides, -tides and oligonucleotides, including 2'-deoxy analogues, were good candidates for the development of a potent antiherpes agent, as an inhibitor of (cytosine C5)methyltransferase, for using in oligonucleotides and as a mechanistic probe of base flipping by Hhal DNA methyltransferase. Since the biological relevance of (N)-bicyclo[3.1.0]hexane derivatives is so high, additional effort is warranted to overcome the drawbacks of the previous synthetic pathways described in earlier publications. Those methods involved two or three operationally demanding steps and gave unexpectedly low yields when applied to a gram-scale synthesis (Figure 1). The preparation of (N)-bicyclo[3.1.0]hexanes in quantity is crucial to progress in the related research fields; thus, improving the yield of existing synthetic steps or developing novel synthetic pathways is desirable. In this letter we describe the conversion of (+)(1R,4R)-4-(benzyloxymethyl)-4-(hydroxymethyl)cyclopent2-enol into a key intermediate (+)-bicyclo[3.1.0]hexane alcohol 1. The starting material 2 contains a quaternary carbon, which eliminates the need for harsh conditions usually associated with the construction of a quaternary carbon center. Although there remain aspects for further refinement, this work provides a novel route to obtain the crucial intermediate (+)-bicyclo[3.1.0]hexane 1. The synthesis of (+)-(1R,4R)-4-(benzyloxymethyl)-4(hydroxymethyl)cyclopent-2-enol 2 was done according to the previously reported method. The versatility of diol 2 was demonstrated previously with the synthesis of the (N)locked bicyclo[2.2.1]heptane system. Preparation of silyl acetonide 3 from 2 followed a well-established method. The published report gave a synthetic method to a silyl triol, which was protected as the acetonide to afford silyl acetonide 3 (Scheme 1). Removal of the benzyl group with Pd/C in the presence of hydrogen in a variety of conditions was also accompanied by the unexpected deprotection of the silyl group. Treatment of silylated acetonide 3 with Pd black

Modification of 1-substituents in the 2-azabicyclo[2.1.1]hexane ring system; approaches to potential nicotinic acetylcholine receptor ligands from 2,4-methanoproline derivatives.

Successful nucleophilic substitution at a methylene attached to the bridgehead (1-) position of the 2-azabicyclo[2.1.1]hexane ring system opens the way to construction of novel derivatives having a wider range of functional groups attached to the 1-position via a methylene "spacer" (including the beta-amino acid homologue of 2,4-methanoproline) and provides access to epibatidine analogues containing heterocyclic substituents and also to further homologation at the 1-position. Displacements with loss of a nucleofuge (e.g., loss of mesylate anion from the 1-mesyloxymethyl derivative) require thermal activation but proceed without the rearrangement initially anticipated in such a strained bicyclic ring system. A novel tricyclic carbamate intermediate 17 has been isolated; nucleophilic attack on 17 leads directly to the isolation of N-deprotected substitution products (with concomitant decarboxylation).

2-Substitution of adenine nucleotide analogues containing a bicyclo[3.1.0]hexane ring system locked in a northern conformation: enhanced potency as P2Y1 receptor antagonists.

Preference for the northern (N) ring conformation of the ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of P2Y(1) receptors was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute (Nandanan et al. J. Med. Chem. 2000, 43, 829-842). We have now combined the ring-constrained (N)-methanocarba modification with other functionalities at the 2-position of the adenine moiety. A new synthetic route to this series of bisphosphate derivatives was introduced, consisting of phosphorylation of the pseudoribose moiety prior to coupling with the adenine base. The activity of the newly synthesized analogues was determined by measuring antagonism of 2-methylthio-ADP-stimulated phospholipase C (PLC) activity in 1321N1 human astrocytoma cells expressing the recombinant human P2Y(1) receptor and by using the radiolabeled antagonist [(3)H]2-chloro-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine 3',5'-bisphosphate 5 in a newly developed binding assay in Sf9 cell membranes. Within the series of 2-halo analogues, the most potent molecule at the hP2Y(1) receptor was an (N)-methanocarba N(6)-methyl-2-iodo analogue 12, which displayed a K(i) value in competition for binding of [(3)H]5 of 0.79 nM and a K(B) value of 1.74 nM for inhibition of PLC. Thus, 12 is the most potent antagonist selective for the P2Y(1) receptor yet reported. The 2-iodo group was substituted with trimethyltin, thus providing a parallel synthetic route for the introduction of an iodo group in this high-affinity antagonist. The (N)-methanocarba-2-methylthio, 2-methylseleno, 2-hexyl, 2-(1-hexenyl), and 2-(1-hexynyl) analogues bound less well, exhibiting micromolar affinity at P2Y(1) receptors. An enzymatic method of synthesis of the 3',5'-bisphosphate from the corresponding 3'-monophosphate, suitable for the preparation of a radiophosphorylated analogue, was explored.

2-Substitution of Adenine Nucleotide Analogues Containing a Bicyclo[3.1.0]hexane Ring System Locked in a Northern Conformation: Enhanced Potency as P2Y 1 Receptor Antagonists

2-Substitution of Adenine Nucleotide Analogues Containing a Bicyclo[3.1.0]hexane Ring System Locked in a Northern Conformation: Enhanced Potency as P2Y 1 Receptor Antagonists

A method for the parallel synthesis of multiply substituted oxazolidinones.

There are many examples of both naturally occurring and synthetic molecules containing a 2-oxazolidinone ring that have significant biological activity. The oxazolidinone ring potentially has three sites for attachment of diversity elements. A synthesis that can provide for inclusion of diversity elements at all three positions should be a powerful method for the preparation of oxazolidinone libraries. In this paper we present the preparation of a 3 x 3 x 3 array yielding 27 different products with minimal workup, high yields, and, most importantly, high purity. Using an intramolecular acylnitrene-mediated aziridination reaction, we have prepared (triphenylmethoxymethyl)-3-oxa-1-azabicyclo[3.1.0]hexan-2-one as a starting material for library generation. The first substitution involves opening the aziridine ring of the azabicyclo[3.1.0]hexane ring system using a Grignard reagent. The nitrogen of the oxazolidinone is now ready for substitution via alkylation or arylation. Removing the trityl protecting group via esterification under mildly acidic conditions accomplishes the final substitution.

A New Synthesis of 2-Azabicyclo[2.1.1]hexanes

An efficient synthesis of the 2-azabicyclo[2.1.1]hexane ring system has been accomplished starting from cis-cyclobut-3-ene-1,2-dicarboxylic anhydride 7, which was prepared using a photochemical method. The key step of this new strategy involved a stereoselective electrophilic addition of phenylselenyl bromide to the double bond of cyclobutene dicarbamate 16 derived from 7. The subsequent ring closure of 17a in the presence of sodium hydride afforded the 2-azabicyclohexane compound 18 with a satisfying overall yield. Reductive removal of the phenylselenyl group and subsequent deprotection led rapidly to the amino derivative 4a functionalized on the carbon ring. Syntheses of the hydroxy and carboxylic derivatives 4b,c were then achieved from the intermediary disulfonamide 23. Displacement of the activated amino group by potassium acetate yielded hydroxy derivative 4b after three additional steps. Finally, oxidation of the alcohol function of 4b under Jones conditions followed by hydrogenolysis afforded the carboxylic derivative 4c, which is the first reported beta-isomer of 2,4-methanoproline 1.

Conformationally locked nucleosides. Synthesis of 3( R, S)-(adenin-9-yl)-1- and 3( R, S)-(cytosin-1-yl)-1-hydroxymethylbicyclo[2,1,1]hexanes

3,3-Di(isopropoxycarbonyl)-1,1-dimethoxycyclobutane ( 1) was converted, in multi-steps, to 3-(1,3-dithiacyclohex-2-yl)-1,1-di( p-tosyloxymethyl)cyclobutane ( 7), which was subjected to a butyllithium-mediated cyclization to give the bicyclo[2,1,1]hexane ring system 8. Further transformations afforded 1-( t-butyldimethylsilyloxymethyl)-3( R, S)-hydroxybicyclo[2,1,1]hexanes ( 11), which were condensed with 6-chloropurine and 4-acetylcytosine via Mitsunobu reactions to give, after further treatment, 3( R, S)-(adenin-9-yl)- and 3( R, S)-(cytosin-1-yl)-1-hydroxymethylbicyclo[2,1,1]hexanes ( 14 and 17), respectively.

Synthesis of trovafloxacin using various (1α,5α,6α)-3-azabicyclo[3.1.0]hexane derivatives

Trovafloxacin, a novel broad spectrum antibacterial, contains the unusual (1α,5α,6α)-3-azabicyclo[3.1.0]hexane ring system. The prototype of the industrial synthesis of this ring system and possible mechanistic pathways to exclusive formation of the exo or 6α-nitro derivative 4 are described, which leads to the key 6α-nitro-3-azabicyclo[3.1.0]hexane intermediate 10. The synthesis of 6α-amino-3-azabicyclo[3.1.0]hexane 16 and useful protected exo 6-amino derivatives 15 and 17 follows from 10. These can be coupled with the 7-chloronaphthyridone 18 to yield protected trovafloxacin compounds 20–22 in good yield. The ethyl ester of trovafloxacin 21 can also be accessed from the product of coupling 19, derived from 18 and the exo 6-nitro-3-azabicyclo[3.1.0]hexane compound 12. Removal of protecting groups from 20–22 with methanesulfonic acid yields trovafloxacin mesylate from which trovafloxacin zwitterion 1 can be liberated with base treatment. Zwitterion 1 can also be prepared directly from 16 tosylate salt and naphthyridone-2-carboxylic acid 26.

Ring Expansion and Contraction of a Two-Carbon Bridged Spiropentane

The reactions of tricyclo[4.1.0.01,3]heptan-4-one (5) and two related systems with diazomethane and m-CPBA were examined in order to determine the relative reactivity and migratory aptitudes for the three compounds. The reactions of 5 with diazomethane and m-CPBA yielded new derivatives of the tricyclo[5.1.0.01,3]octane ring system that showed that migration of cyclopropylcarbinyl is favored over cyclopropyl migration in this system. Photolysis of 5-diazotricyclo[4.1.0.01,3]heptan-4-one (23) in methanol and dimethylamine did not lead to ring contraction to the tricyclo[3.1.0.01,3]hexane ring system, but an interesting product was derived from an unusual rearrangement process in the photolysis in dimethylamine. Matrix photolysis of 23 at 15 K gave a decrease in the diazo band at 2085 cm-1 and the appearance of a new band at 2117 cm-1, which is a normal position expected for a small-ring ketene such as cyclopropylketene. Thus, matrix photolysis appears to have yielded a derivative of the previously unknown tricyclo[3.1.0.01,3]hexane ring system. The lithium enolate of 5 was characterized by NMR spectroscopy at −80 °C and was found to rearrange to m-cresol at −65 °C. The geometries of the bridged spiropentanes of this work were optimized at the MP2(frozen core)/6-31G* level of theory, and group equivalent values were derived in order to calculate the heats of formation for these compounds using the calculated energies.

Synthesis of some carbocyclic nucleoside analogues based on a bicyclo[3.1.0]hexane ring system

The carbocyclic nucleoside analogues 11, 14 and 17 have been prepared from (endo-bicyclo[3.1.0]- hept-2-en-6-yl)methanol.

The tandem Michael-S N2 reaction for the construction of the 3-azabicyclo[3.1.0]hexane ring system

The 3-azabicyclo[3.1.0]-hexane ring system was constructed in a convergent one-pot procedure starting from readily available starting materials, using the intramolecular tandem Michael-S N2 reaction. The methodology was also extended to the synthesis of 3-azabicyclo[4.1.0]heptane ring system.

Synthesis of a novel prostacyclin analog containing the bicyclo[3.1.0] hexane ring system. Application of molecular mechanics calculations to organic synthesis

The synthesis of a novel prostacyclin analog I has been achieved, incorporating as a key strategic feature a regio-controlled epoxide ring opening (as predicted by MM2 calculations) of a readily available prostaglandin synthon.