Bicyclic Oxazine Research Articles

Copper-Catalyzed Asymmetric Borylative Ring Opening of Diazabicycles

Highly enantioselective, copper-catalyzed ring opening of bicyclic hydrazines using a diboron reagent was accomplished with (R,R)-taniaphos as a chiral ligand. Desymmetrization of various bicyclic hydrazines by boryl substitution afforded 3-Bpin-4-hydrazino-cyclopentene derivatives with enantioselectivity up to >99% under mild conditions. The resulting allylic boron products were utilized in further organic transformations. Kinetic resolution of a racemic bicyclic oxazine gave useful information about the relative rates of C–O and C–N bond cleavage.

Reactions of Nitrosoalkenes with Dipyrromethanes and Pyrroles: Insight into the Mechanistic Pathway

The reactivity of nitrosoalkenes toward dipyrromethanes, pyrrole, and 2,5-dimethylpyrrole is described. 1-(p-Bromophenyl)nitrosoethylene shows a different chemical behavior with these heterocycles than the previously reported reactions of ethyl nitrosoacrylate, which proceeds via a Diels-Alder reaction. 1-(p-Bromophenyl)nitrosoethylene reacts with dipyrromethanes and pyrrole to afford two isomeric oximes via conjugate addition followed by rearomatization of the pyrrole unit. On the other hand, this nitrosoalkene reacts with 2,5-dimethylpyrrole through an initial conjugate addition followed by intramolecular O- and N-nucleophilic addition with the formation of the corresponding bicyclic oxazine and five-membered cyclic nitrone, respectively. Quantum chemical calculations, at the DFT level of theory, indicate that the barriers associated with the Diels-Alder reactions of ethyl nitrosoacrylate are over 30 kJ/mol lower than those that would be required for the cycloadditions of 1-(p-bromophenyl)nitrosoethylene. Thus, calculations predict that the Diels-Alder reaction is privileged in the case of ethyl nitrosoacrylate and point to a different reaction pathway for 1-(p-bromophenyl)nitrosoethylene, corroborating the experimental findings.

1,2-oxazine linker as a thermal trigger for self-immolative polymers

We have demonstrated the site-specific thermal activation of self-immolative polymers (SIPs) using a bicyclic oxazine as a temperature-sensitive triggering moiety. The oxazine-based trigger was installed at the junction of a SIP-poly(N,N-dimethylacrylamide) (PDMA) diblock copolymer via oxidation of hydroxyurea end groups on the SIP and in situ [4 + 2] cycloaddition with cyclopentadiene-functionalized PDMA. The trigger undergoes a thermally-driven cycloreversion which ultimately leads to initiation of the depolymerization process. The temperature dependence of activation and depolymerization were investigated, along with the mechanism of activation. The relative rates of depolymerization at different temperatures suggested to us that the thermal trigger design may be a good candidate for on-demand activation of SIPs with minimal background triggering.

Nitroso-Dienophile Additions to Dendralenes: A Short Synthesis of Branched Aminosugars

The first heteroatom-based dienophile cycloadditions to cross-conjugated alkenes ([n]dendralenes) are reported. Nitroso-dienophiles undergo smooth single and double Diels-Alder additions to the parent dendralenes with orientational regio- and stereoselectivity and, notably, with reactivity that depends upon the parity of the [n]dendralene. The first crystal structure of a cross-conjugated hexaene is reported. Vasella's nitroso-sugar reagent gives a highly enantiomerically enriched double cycloadduct with [3]dendralene. This bicyclic oxazine is successively dihydroxylated and then ring-opened to form a branched chain diamino tetrol.

Stereoselective Ring Opening of Bicyclic Nitroso Diels-Alder Cycloadducts with Carbon Nucleophiles

Bicyclic oxazines are attractive compounds and valuable synthetic intermediates as they can be easily obtained by hetero Diels-Alder reactions between cyclic dienes and nitroso dienophiles. In particular, the more strained case (i.e. the [2.2.1]-cycloadduct) represents an interesting powerful combination of stability and reactivity as it can be transformed into highly densely functionalized cyclopentene derivatives by a variety of ring-opening reactions. Aim of this article is to summarize the methods used by various chemists for opening of bicyclic oxazines by the formation of a new carbon-carbon bond, to give highly substituted ring systems containing multiple stereocenters. Particular emphasis will be given to regio- and stereoselective procedures, including the most recent developments on less strained [2.2.2]-cycloadduct. Keywords: Bicyclic oxazines, hetero Diels-Alder cycloadducts, acylnitroso cycloadducts, metal catalyzed ring opening, copper, rhodium, Grignard reagents, organoboronic derivatives, stereoselective synthesis, allylation, cross metathesis.

Regio- and Stereoselective Copper-Catalyzed Ring Opening of Dihetero­bicyclic Alkenes with Grignard Reagents

The ring opening of bicyclic hydrazines and bicyclic oxazines with organomagnesium reagents under the influence of copper catalysts allows functionalized cyclopentene and cyclohexene derivatives to be obtained. Whereas complete anti -stereoselective ring opening occurred in all cases, the regioselective outcome turned out to be highly dependent on the reaction conditions used.

ChemInform Abstract: Nonconcerted Cycloaddition of 2H‐Azirines to Acylketenes: A Route to N‐Bridgehead Heterocycles.

AbstractTreatment of acylketenes with 2‐unsubstituted and 2‐monosubstituted 3‐arylazirines leads to bicyclic oxazines of type (VIII) and/or unusual bridged 2:1 adducts like (IV) and (IX) depending on steric effects.

ChemInform Abstract: Syntheses and Antibacterial Activity Studies of New Oxazolidinones from Nitroso Diels—Alder Chemistry.

AbstractA series of novel oxazolidinone antibiotics, e.g. (III) and (V), having [2.2.1] and [2.2.2] bicyclic oxazine moieties at the C‐5 side chain of the A‐ring is synthesized via nitroso Diels—Alder reaction.

ChemInform Abstract: The Thermal Isomerization of Bicyclic Oxazines into Epoxyepimines. A Preliminary Theoretical Study.

The thermal isomerization of bicyclic oxazines 1 to epoxyepimines 2 depends on the N-substituent. BDE calculations on model systems agree with the mechanistic picture. The rate-determining step in N—O bond homolysis is facilitated by N-vinyl substituents. Keywords: oxazines, BDE, NO bond, substituent effect.

Syntheses and antibacterial activity studies of new oxazolidinones from nitroso Diels–Alder chemistry

A series of novel oxazolidinone antibiotics having [2.2.1] and [2.2.2] bicyclic oxazine moieties at the C-5 side chain of the A-ring was synthesized by nitroso Diels–Alder reactions, from three linezolid analogs containing morpholine, piperazine and thiomorpholine, respectively, as the C-ring components. Subsequent N–O bond cleavage generated oxazolidinones with 4-amino cyclo-2-en-1-ol substituents. The in vitro antibacterial activities of these oxazolidinone analogs were evaluated.

Structure−Activity Relationships of Antitubercular Nitroimidazoles. 1. Structural Features Associated with Aerobic and Anaerobic Activities of 4- and 5-Nitroimidazoles

The 4-nitroimidazole PA-824 is active against aerobic and anaerobic Mycobacterium tuberculosis (Mtb) while 5-nitroimidazoles like metronidazole are active against only anaerobic Mtb. We have synthesized analogues of both 4- and 5-nitroimidazoles and explored their antitubercular activities. The nitro group is required for both activities in all compounds. The key determinants of aerobic activity in the 4-nitroimidazoles include the bicyclic oxazine, the lipophilic tail, and the 2-position oxygen. For the 5-nitroimidazoles, neither the corresponding bicyclic analogue nor addition of a lipophilic tail conveyed aerobic activity. Incorporation of a 2-position oxygen atom into a rigid 5-nitroimidazooxazine provided the first 5-nitroimidazole with aerobic activity. Across both series, anaerobic and aerobic activities were not correlated and Mtb mutants lacking the deazaflavin-dependent nitroreductase (Ddn) retained anaerobic sensitivity to some compounds. Aerobic activity appears to be correlated with efficiency as a substrate for Ddn, suggesting a means of structure-based optimization of improved nitroimidazoles.

Investigation of steric and functionality limits in the enzymatic dihydroxylation of benzoate esters. Versatile intermediates for the synthesis of pseudo-sugars, amino cyclitols, and bicyclic ring systems

A series of benzoate esters (methyl, ethyl, n-Pr, i-Pr, n-Bu, t-Bu, allyl, and propargyl) were subjected to enzymatic dihydroxylation by E. coli JM 109(pDTG 601) strain in a whole-cell fermentation. The cis-cyclohexadienediols were obtained in yields of approximately 1g/L except for n-propyl- and i-propyl benzoate which were found to be poor substrates. n-Butyl and t-butyl benzoates were not oxidized at all. The absolute stereochemistry for all metabolites was determined by comparison with a standard prepared from (1S-cis)-3-bromo-3,5-cyclohexadiene-1,2-diol, whose absolute configuration is well established. The free diols were found to be quite stable compared to other cis-dihydrodiols of this type, however, their acetonides underwent a dimerization via a regio- and stereoselective Diels-Alder cycloaddition. The diol derived from ethyl benzoate was subjected to a stereo- and regioselective inverse electron demand Diels-Alder cycloadditions with several dienophiles. The new adducts were completely characterized. The hetero-Diels-Alder reaction of this diol with an acyl nitroso dienophile yielded regio- and stereoselectively a bicyclic oxazine, which upon reduction provided a useful derivative of amino shikimate that can be exploited in an approach to oseltamivir (Tamiflu) and other amino cyclitols. The diol was also converted to carba-alpha-L-galactopyranose to demonstrate its potential utility as a source of pseudo sugars. Experimental and spectral data are provided for all new compounds.

ChemInform Abstract: Stereoselective Synthesis of Acyltetrahydrofurans (V) via Bicyclic Oxazines (IV).

AbstractChemInform 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.

Asymmetric induction in the Diels–Alder reactions of α-hydroxy acyl nitroso compounds

The hydroxamic acids 7, derived from a series of α-hydroxy acids 5, have been oxidised with periodate to form transient, chiral acyl nitroso compounds 8, which were trapped in situ with cyclopentadiene and cyclohex-1,3-diene to give mixtures of diastereoisomeric, Diels–Alder cycloadducts 9 and 10, respectively. Cycloaddition at 0 °C occurred with moderate stereoselectivity, e.g. both the mandeloyl nitroso compound 8a with cyclopentadiene and the tert-butylglycoloyl nitroso compound 8d with cyclohexadiene gave ca. 5:1 mixtures of diastereoisomers. Much higher diastereoselectivities (cycloadduct ratios ca. 10:1 for 9a, 9d and 10d) were observed at –78 °C. The mandeloyl nitroso compound 8a, which can form an intramolecular hydrogen bond between the hydroxy and nitroso groups, showed higher stereoselectivities than its O-methyl ether 8b. The major cycloadduct 13a of the (S)-mandeloyl nitroso compound 12 and cyclohexadiene was degraded to the bicyclic oxazine 15 of known absolute configuration. Formation of the cycloadduct 13a as the major product is consistent with preferential endo addition of the hydrogen bonded nitroso compound 12 from the face anti to the phenyl group.

The thermal isomerization of bicyclic oxazines into epoxyepimines. A preliminary theoretical study

The thermal isomerization of bicyclic oxazines 1 to epoxyepimines 2 depends on the N-substituent. BDE calculations on model systems agree with the mechanistic picture. The rate-determining step in N—O bond homolysis is facilitated by N-vinyl substituents. Keywords: oxazines, BDE, NO bond, substituent effect.

Barriers to nitrogen inversion in 6-membered rings : Nitrogen inversion in tetrahydro-1,2-oxazines

A study of the nitrogen inversion process in the bicyclic oxazine, N-methyl-2-oxa-3-azabicyclo[2,2,2]octane, by 13C NMR spectrocopy reveals a free energy of activation of 14.9 kcal mole -1. Detailed examination of the kinetics of the process observed in the 1H spectra of N-methyl tetrahydro-1,2-oxazine shows ΔH ≠ 15.1±0.4 kcal mole -1 and ΔS ≠ 2.3 ±1.5 cal mol -1K -1. It is concluded from the similarity in the activation parameters that both processes arise from nitrogen inversion.