Spiro Centre Research Articles

Synthesis of α‐Heterocycle Anchored Spirocyclic Azetidin‐2‐ones in a Minute by p‐TSA Catalyzed Cyclocondensation of Azetidin‐2,3‐diones with Difunctionalized Substrates

AbstractMonocyclic azetidin‐2,3‐diones provide easy extensions to spiro‐fused azetidin‐2‐ones upon p‐toluenesulfonic acid (p‐TSA) catalyzed cyclocondensation reaction with difunctionalized substrates [mercaptoacids (mercaptoacetic acid, 2‐mercaptopropionic acid, 3‐mercaptopropionic acid), ethan‐1,2‐dithiol, ortho‐difunctionalized benzenes (ortho‐phenylenediamine, ortho‐aminothiophenol)]. 1,3‐Oxathiolan‐5‐one/6‐one, 1,3‐dithiolane, 2,3‐dihydrobenzo[d]imidazole and 2,3‐dihydrobenzo[d]thiazole tethered spirocyclic azetidin‐2‐ones were obtained in good overall isolated yields (69–89 %) in a very short‐time duration (max 1 min) using toluene Dean‐Stark reflux/dichloromethane rt stirring conditions. The stereochemical and spectral studies, stabilities and diastereoisomeric ratio for trans and cis spiro‐fused products are reported. The trans and cis configuration has been assigned to spiro‐β‐lactams wrt the stereochemical relationship between sulfur atom (at spiro centre) and the vicinal methine hydrogen atom at C3/C2. The absolute configuration of one trans 1,3‐oxathiolan‐5‐one fused spirocyclic azetidin‐2‐one was clearly identified by X‐ray single crystal structure analysis.

Synthetic Approaches to the Anticancer Agent Fredericamycin A

AbstractIn this minireview, we have highlighted various developments related to the total synthesis of an anticancer agent, fredericamycin A (NSC‐305263). The presence of a unique molecular architecture and significant biological properties associated with fredericamycin A have greatly enhanced the research activity, and we cover the total synthesis of this molecule since its isolation. Different methodologies adopted for the construction of the stereogenic spiro centre are radical spirocyclization, Diels−Alder (DA) reaction, [3+2] annulation, photochemical approach, ring‐closing metathesis (RCM), palladium‐catalyzed cross‐coupling reaction, rearrangement approach, benzannulation etc. This minireview provides an overview of the contribution of different research groups in the total synthesis of fredericamycin A. We also cover various model studies related to the synthesis of this molecule.

Synthesis of Spiro Compounds Based on 1H-Pyrrole-2,3-Diones

Polycyclic structures fused at a central carbon are of great interest due to their appealing conformational features and their structural implications in biological systems. Although progress in the development of synthetic methodologies towards such structures has been impressive, the stereoselective construction of such quaternary stereocentres remains a significant challenge in the total synthesis of natural products. This review summarises a series of studies on the reactions of 1H-pyrrole-2,3- diones with nucleophiles and highlights the progress in the formation of new polyheterocyclic compounds with concomitant formation of the quaternary spiro centre.

5′-Nitro-1,4-dihydrospiro[3,1-benzoxazine-2,3′-indolin]-2′-one

In the title compound, C15H11N3O4, the six-membered oxazine ring adopts a half-chair conformation and is oriented at an angle of 78.63 (9)° with respect to the pyrrolidine ring of the indoline ring system, which adopts an envelope conformation. The spiro centre C atom is tetrahedral and lies 0.147 (1) Å out of the plane of other four pyrrolidone ring atoms. The nitrobenzene and benzene rings exhibit near planar conformations with C—C—C—N and C—C—C—C torsion angles of 178.1 (2) and 178.8 (2)°, respectively. In the crystal, N—H...O and C—H...O hydrogen bonds connect the molecules, generating a sheet-like structure parallel to thebcplane. Within the sheets, pairs of intermolecular N—H...O hydrogen bonds form inversion dimers enclosingR22(8) ring motifs. In addition, the N—H...O and C—H...O hydrogen bonds generateR32(11) andR22(10) graph-set ring motifs extending the two-dimensional structure. A supramolecularR66(28) loop for each set of six molecules is formed by N—H...O hydrogen bonds within the extended sheet structure and stabilizes the packing. π–π stacking interactions between the nitrobenzene and benzene rings [intercentroid distance = 3.711 (1) Å] and N—O...π interactions further consolidate the crystal packing.

Synthesis of novel hybrid steroid dimers by BF3·Et2O-catalyzed aldol condensation of 2-formyl-estradiol diacetate and steroid sapogenins

BF3·Et2O-catalyzed aldol condensation of steroid sapogenins with 2-formyl-estradiol diacetate afforded two novel classes of steroid dimers in which an estrogenic core is attached to the spirostanic side chain of an steroid sapogenin through an exocyclic double bond in position C-23, or through a spiro centre in C-22.

Crystal structure of (5'S,8'S)-3-(2,5-di-methyl-phen-yl)-8-meth-oxy-3-nitro-1-aza-spiro-[4.5]decane-2,4-dione.

The title compound, C18H22N2O5, was synthesized by nitrification of its enol precursor. The pyrrolidine ring plane adopts a twisted conformation about the C—C bond linking the spiro centre and the C=O group remote from the N atom. It makes dihedral angles of 71.69 (9) and 88.92 (9)°, respectively, with the benzene ring plane and the plane defined by the four C atoms that form the seat of the of the cyclo­hexane chair. At the spiro centre, the NH group is axial and the C=O group is equatorial with respect to the cyclo­hexane ring. In the crystal, inversion dimers linked by pairs of N—H⋯O hydrogen bonds generate R 2 2(8) loops. The dimers are linked by C—H⋯O inter­actions, generating a three-dimensional network.

(+)-Geodin fromAspergillus terreus

The fungal metabolite (+)-geodin [systematic name: (2R)-methyl 5,7-dichloro-4-hydroxy-6'-methoxy-6-methyl-3,4'-dioxospiro[benzofuran-2,1'-cyclohexa-2',5'-diene]-2'-carboxylate], C(17)H(12)Cl(2)O(7), was isolated from Aspergillus terreus. The crystal structure contains two independent molecules in the asymmetric unit. Molecules denoted 1 interact through O-H...O hydrogen bonds creating chains of molecules parallel to the crystallographic 2(1) screw axis. Molecules denoted 2 interact through an O...Cl halogen bond, also creating chains of molecules parallel to the crystallographic 2(1) screw axis. Molecules 1 and 2 interact through another O...Cl halogen bond. The two molecules are similar but molecules 2 have a slightly more planar cyclohexadiene ring than molecules 1. The absolute structure of (+)-geodin has been unequivocally assigned with the spiro centre having the R configuration in both molecules. The structurally related (+)-griseofulvin has an S configuration at the spiro centre, a difference of potential biological and biosynthetic relevance.

Construction of spirolactones with concomitant formation of the fused quaternary centre – application to the synthesis of natural products

Polycyclic structures fused at a central carbon are of great interest due to their appealing conformational features and their structural implications in biological systems. Although progress in the development of synthetic methodologies towards such structures has been impressive, the stereoselective construction of such quaternary stereocentres remains a significant challenge in the total synthesis of natural products. This review highlights the progress in the formation of 1-oxaspiro[4.n]alkan-2-ones (2≤n≤7) with concomitant formation of the quaternary spiro centre.

2,3-Dimethylbutane-2,3-diyl 1,2-phenylene orthocarbonate

The title compound, C13H16O4, is a mixed orthocarbonic acid ester derived from the alcohol components benzene-1,2-diol and 2,3-dimethyl­butane-2,3-diol (pinacol). The spiro­cyclic mol­ecules exhibit noncrystallographic C2 symmetry. The C—O bonds between the spiro centre and the aliphatic di­oxy fragment are markedly shorter than the bonds to the aromatic residue. Neither steric strain, which equalizes the bond lengths in a glucoside analogue, nor the packing of the mol­ecules in the crystal structure are responsible for the large C—O bond-length range, which obviously is a mol­ecular property.

4,6-O-Benzylidene-1-O-methyl-2,3-deoxy-α-D-glucopyranose-2,3-diyl 1,2-phenylene orthocarbonate

The title compound, C21H20O8, is the mixed orthocarbonic acid ester of the alcohol components benzene-1,2-diol and 4,6-O-benzyl­idene-1-O-methyl-α-d-glucopyran­oside. The compound represents the first example of a structurally characterized carbohydrate ester of orthocarbonic acid. Both oxacyclic six-membered rings in the structure adopt a chair conformation. The puckered five-membered ring at the spiro centre is present in a twist conformation. No special inter­actions are observed in the mol­ecular packing.

Cyclopropanation of 3,4-dihydro-1 H-benzo[ e][1,4]diazepine-2,5-diones

A two step parallel synthesis protocol for the preparation of 1 N-substituted spirobenzodiazepineones is described. Treatment of 4-methyl-3,4-dihydro-1 H-benzo[ e][1,4]diazepine-2,5-dione with a series of alkyl halides using a microwave-assisted heating protocol provided N-derivatized compounds, which were transformed to the corresponding cyclopropylamines employing modified Kulinkovich-type reaction conditions. X-ray structural analysis gave conclusive evidence of the newly created spiro centre and revealed a significant flattening of the seven-membered ring system compared with the benzodiazepinedione system providing a characteristically different pattern of bond exit vectors. The physicochemical parameters log D, p K a, solubility and membrane permeability of both cyclopropanated and precursor compounds were assessed.

Synthesis of an Isomer of the Oxaspirobicyclic Tetronic Acid Unit of the CCK‐B Receptor Antagonist Tetronothiodin.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of an Isomer of theOxaspirobicyclic Tetronic Acid Unit of the CCK-B ReceptorAntagonist Tetronothiodin

An isomer of the oxaspirobicyclic tetronic acid unit of the CCK-B Receptor antagonist tetronothiodin, diastereoisomeric at the spiro centre, has been synthesized in five steps from dienol 4.

Formal Synthesis of Both Atropomers of Desertorin C and an Example of Chirality Transfer from a Biphenyl Axis to a Spiro Centre and its Reverse

In connection with the synthesis of 4,4′,7,7′-tetramethoxy-5,5′-dimethyl-6,8′-bicoumarin (desertorin C) (11) in enantiopure form, the diastereomeric ratios of the products of the reactions between 2-isopropyloxy-6-methoxy-4- methylphenylmagnesium bromide (24) and (4S)-4-isopropyl-2-(2,3,5-trimethoxyphenyl)-4,5-dihydrooxazole (23), between 2,4-dimethoxy-6-methylphenylmagnesium bromide (37) and (4S)-4-isopropyl-2-(2,3-dimethoxy-5-methylphenyl)-4,5-dihydrooxazole (36), and between 2,4-dimethoxy-6-(t-butyldimethylsilyloxy)methyl-phenylmagnesium bromide (46) and the oxazole (36) were explored. The major product of the last mentioned reaction was converted into (S,4S)-4-isopropyl-2-(2′-hydroxymethyl-4′,6,6′-trimethoxy-4-methyl-1,1′-biphenyl-6-yl)-4,5-dihydroxazole (49), the axial configuration of which was confirmed by single crystal X-ray structural determination. The similar product (S,4S)-2-(2′,4′,6-trimethoxy-4,6′-dimethyl-1,1′-biphenyl-6-yl)-4,5-dihydrooxazole (43) was converted into (S)-1-(2,4′,6′-trimethoxy-4,6′-biphenyl-2-yl)ethanone (57) which furnished (S)-1-(2′,4′,6-trimethoxy-4,6′-dimethyl-1,1′-biphenyl-2-yl)acetamide (58) (43%) and (S)-2,7′-dimethoxy-3′,5′,6-trimethylspiro[cyclohexa-2,5-diene-1,1′-(1H)isoindole]-4-one (61) (30%) on Schmidt rearrangement. The dienone (61) on reduction and methylation regenerated the ketone (57). The methodology of Lipschutz was adapted for the synthesis of both enantiomers of 1,1′-(2′,4-dihydroxy-6,6′-dimethoxy-2,4′-dimethylbiphenyl-3,3′-diyl)bisethanone (32) and (83) which constitutes a formal synthesis of both enantiomers of desertorin C.

Chirality transfer from a biphenyl axis to a spiro centre and its reverse: sequential self-immolation

Schmidt reaction of ( S)-1-(2′, 4′, 6-trimethoxy-4, 6′-dimethylbiphenyl-2-yl)ethanone 8 furnished the expected amide 9 (43%) accompanied by ( S)-2, 7′-dimethoxy-3′, 5′, 6-trimethylspiro[cyclohexa-2, 5-diene-1, 1′-(1 H)isoindole]-4-one 12 (30%) which on reduction with zinc and acetic acid and subsequent methylation regenerated ketone 8. Schmidt rearrangement of the ketone 1 provided besides the expected amide 2 the dienone 3 in which chirality has been transferred from the biphenyl axis to the spiro centre. Reductive cleavage and subsequent methylation of 3 regenerated 1. [Display omitted]

A Reinvestigation of the Oxidative Rearrangement of Yohimbane‐Type Alkaloids. Part A. Formation of pseudoindoxyl ( = 1,2‐dihydro‐3H‐indol‐3‐one) derivatives

AbstractContrary to earlier reports, the base‐induced rearrangement of the 7‐hydroxy‐7H‐indolenines derived from ajmalicine (1), yohimbine (5), corynanthine (6), methyl reserpate (16), and methyl isoreserpate (17) in each case furnished not just one, but two epimeric spiro‐pseudoindoxyl derivatives which have opposite configuration at the spiro centre C(2). In all cases, the major component was shown by NOE experiments to be the A‐type isomer (carbonyl group located below the plane defined by rings C and D). The thermodynamically less stable B‐type pseudoindoxyl epimers 4, 10, 12, and 22 were isolated and characterized for the first time.

Synthetic approach to novel crinipellin diterpenes. Construction of the functionalised C20-tetraquinane framework

A synthetic approach towards novel tetraquinane diterpenes of the crinipellin group compounds (4–8) is delineated. The main theme of this approach centres around the use of readily available and adequately functionalised triquinane 10 as the key synthon to which an appropriately substituted five-membered ring can be annulated with concurrent generation of the spiro centre. Consequently, compound 10 was elaborated to the enone 22, which was in turn subjected to cyclopentannulation employing three different intramolecular strategies, viz. photochemical cycloaddition (22→23→24), cationic enone–olefin cyclisation (22→24→27) and radical cyclisation (22→32→27). While five of the six stereogenic centres on the carbocyclic framework of tetraquinane 27 could be correctly set, the C(12)-isopropyl group was epimeric with respect to that in the natural products. Nevertheless, compound 27 was further elaborated to the C20-tetraquinane 40 through chemical modifications in ring D, constituting the first synthesis of the complete skeleton of the criniepellins.

Angular Distortions at Tetracoordinate Carbon Planoid Configurations in Substituted Spiro[4.4]nonanes

AbstractThe configuration of the spiro centre in polycyclic compounds containing a spiro[4.4]nonane substructure is analyzed in terms of symmetry coordinates. As revealed by X‐ray structures of such compounds, the local distortions around the quaternary C‐atom are dominated by a decrease of the ring‐bond angles at the spiro centre and a twist of one ring relative to the other. The planoid deformations given by the planarization index PC are comparatively small for spiro[4.4]nonanes, which contain either no additional bridges between the rings or only α,β′–or β,β′‐polymethylene bridges. This indicates that the local strain in the spiro C(C)4 fragments is rather small.

Intramolecular reactions of N-nitrenes with alkynes: conformational anchoring in spiro-fused 2H-azirines

Oxidation of N-aminoquinazolin-4(3H)-ones (7)–(11) with lead tetra-acetate in dichloromethane results in the intramolecular addition of the N-nitrene to the triple bond in each case and azirines (20), (22), (17), (23), and (30), respectively, are isolated with (31) identified as a by-product in the oxidation of compound (11). An X-ray crystal structure determination on compound (17) reveals a remarkable deformation of bond angles at the spiro centre and this feature appears to be common to all azirines. The five membered ring in the azirines (17), (20), (22), and (23) has the envelope conformation (26) and the six-membered ring in azirine (30) has the twist-boat conformation (32): a possible explanation for this conformational anchoring is offered.

Intramolecular Michael-type additions. IV. Synthesis of 2-azabicyclo[3.2.1]oct-3-enes from 4-chloroalkyl-1,4-dihydropyridines

2-Azabicyclo[3.2.1]oct-3-enes, including examples having a spiro centre at C(8), may be obtained by the reaction of anions derived from 1,3-diketones or cyclopentadiene with 4-chloroalkyl-1,4-dihydropyridines or with azepines. Intermediate 4,5-dihydro-1H-azepines have been isolated under milder conditions. The structures of the bicyclic compounds were established using infrared, ultraviolet, nuclear magnetic resonance, and mass spectrometry. Pharmacological examination of selected compounds revealed low antimicrobial and hypotensive activity.