Nitroalkanes cyclization

Convenient preparative access to such chiral euninocyclitols as should facilitate chemical analog synthesis and biochemical muta-synthesis in the field of 2uninocyclitol antibiotics. A short and economical synthesis of and its hitherto unknown IL-(1,3,4,5/2), or D-epi, stereoisomer was therefore devised (7). It is based on the nitroalkane cyclization method (8), and is delineated in Figure 1. 

Knoevanagel reaction, 575 myo-inositol, 579 nitrile oxides, 582 nitroalcohols, 571 nitroalkane cyclizations, 571, 585, 586... 

The earliest reported Fxs were the result of the reaction of nitrous acid with naturally occurring alkenes being the identified intermediate a a-nitrooxime that suffers dehydration with cyclization. Apart from these conditions, the most recent Fxs synthesis descriptions have involved reactions between alkenes and dinitrogen trioxide (Fig. 3), nitroalkanes and aluminum trichlo-... 

Asymmetric synthesis of tricyclic nitro ergoline synthon (up to 70% ee) is accomplished by intramolecular cyclization of nitro compound Pd(0)-catalyzed complexes with classical C2 symmetry diphosphanes.94 Palladium complexes of 4,5-dihydrooxazoles are better chiral ligands to promote asymmetric allylic alkylation than classical catalysts. For example, allylic substitution with nitromethane gives enantioselectivity exceeding 99% ee (Eq. 5.62).95 Phosphi-noxazolines can induce very high enatioselectivity in other transition metal-catalyzed reactions.96 Diastereo- and enantioselective allylation of substituted nitroalkanes has also been reported.9513... 

All of these reactions proceed in a similar pathway which involves the Michael type additions of enamines to nitroalkenes or addition of nitroalkanes to imines and cyclization. This process has been achieved by solid-phase variation (Scheme 10.2).14... 

Alternatively, Ballini devised a new strategy to synthesize tri-alkylated pyrroles from 2,5-dialkylfurans and nitroalkanes <00SL391>. This method involves initial oxidation of 2,5-dimethylfuran with magnesium monoperoxyphthalate to cA-3-hexen-2,5-dione (6). Conjugate addition of the nitronate anion derived from the nitro compound 7 to 6 followed by chemoselective hydrogenation of the C-C double bond of the resulting enones 8 (obtained by elimination of nitrous acid from the Michael adduct) completes the conversion to the alkylated y-diketones 9. Final cyclization to pyrroles 10 featured improved Paal-Knorr reaction conditions involving reaction of the diketones with primary amines in a bed of basic alumina in the absence of solvent. 

Internal DCR of Nitroaldol Libraries (Scheme 6.10) [5,6] iDCR was demonstrated by using a conceptual nitroaldol library including five benzaldehyde derivatives (24,36, and 47-49) and one nitroalkane (50, DCL-F, Scheme 6.11). The benzaldehydes, all with a unique substitution pattern, were selected in order to make analysis clear and simple. However, one of the henzaldehydes contained a cyano functionality in the 2-position (49), deliberately making it a candidate for subsequent tandem cyclization following nitroalcohol formation. 5-exo-dig type cyclizations of hydrox-ynitriles to the corresponding iminolactones are expected [40,41], albeit unexplored [42 5], intramolecular transformations, which in this case could lead to possible kinetic resolution of the library. 

A stereocontrolled synthesis of racemic monomorine I (16a) has been accomplished by Stevens and Lee (438). An allyl alcohol obtained by reaction of acrolein with the Grignard reagent of the chloroacetal (367) was oxidized to yield the enone (368). The Michael addition of 1-nitropentane to 368 was catalyzed by tetramethylguanidine to yield the nitroalkane (369). Reductive cyclization of 369... 

Cycloaddition of Nitroalkanes/Nitroalkenes to Unsaturated Compounds. 9.2 Inter- and Intramolecular Cyclization of Oximes... 

Reaction at the C atom of nitronate salts is known with a variety of electrophiles, such as aldehydes (Henry reaction) and epoxides (191-193). Thus the incorporation of the nitro moiety and the cyclization event can be combined into a tandem sequence. Addition of the potassium salt of dinitromethane to an a-haloaldehyde affords a nitro aldol product that can then undergo intramolecular O-alkylation to provide the cyclic nitronate (208, Eq. 2.17) (59). This process also has been expanded to a-nitroacetates and unfunctionalized nitroalkanes. Other electrophiles include functionalized a-haloaldehydes (194,195), a-epoxyaldehydes (196), a-haloenones (60), and a-halosulfonium salts (197), (Chart 2.2). In the case of unsubstituted enones, it is reported that the intermediate nitronate salt can undergo formation of a hemiacetal, which can be acetylated in moderate yield (198). 

Cyclization of nitro-stabilized radicals provides another method for the generation of cyclic nitronates (221). Oxidation of the aci-foim of nitroalkanes with ceric ammonium nitrate generates the ot-carbon centered radical, which in the presence of an alkene, leads to the homologation of the a-radical. In the case of a tethered alkene of appropriate length, radical addition leads to a cyclic nitronate (Scheme 2.20). 

In 1992, Trost and his co-workers investigated desymmetrization of cyclic w j-o-diesters with lithium sulfonyl-methylenenitronate as a nucleophile in the presence of Trost s ligand 118, where the corresponding cyclic compounds are obtained with an excellent enantioselectivity via intramolecular cyclization (Scheme 15),103,103a Asymmetric cyclopropanation and lactone annulation are achieved according to this protocol (Scheme Nitroalkanes can also be employed as carbon-centered nucleophiles in lieu of malonates (Scheme 17). ... 

C-l, obviously owing to base-catalyzed epimerization at the aldehyde stage. As compared with nitromethane cyclizations (wherein such epi-merizations have not been observed), nitroalkanes react less readily, thus providing longer exposure of the dialdehyde to the alkaline conditions required for cyclization. 

The cyclizing bis(aminoalkyl)ation of nitromethane,305 which provides a ready entry into pyranoid and cyclohexane nitrodiamines, and, hence, triamino sugars,308 may also be extended to nitroalkanes. Accordingly, glutaraldehyde reacts with nitroethane in the presence of benzylamine to afford the C-methyl-branched nitrodiamine 171 (56%) which may be obtained from the nitrodiol 172 in even better yield (83%) by exposure to the same conditions.305,307 This procedure carries considerable potential for the preparation of C-branched triamino sugars. 

This is rather surprising because primary nitroalkanes (which would give more stable alkyl radicals) are not readily reduced by tin hydride. The third example in Scheme 43 illustrates a cyclization of an alkoxyl radical derived from a nitrate ester. 

Ishii has shown that diversely substituted pyrroles 152 can be prepared by a one-pot operation involving formation of intermediate a,/ -un saturated imines 153 via a SmCl3-catalyzed self-aldol-type condensation. The targeted heterocydes are formed upon addition of a nitroalkane and subsequent cyclization according to the mechanism depicted in Scheme 8.64 [140]. Interestingly, a,/i-unsaturated ketones also participate in this process. 

Pyrrole synthesis. A new route to pyrroles1,2 is based on a base-catalyzed Michael addition of an alkyl isocyanoacetate to a nitroalkene to give an intermediate that cyclizes to a pyrrole. The nitroalkene is generally obtained from a P-acetoxy nitroalkane (1), prepared by a nitro aldol reaction of an aldehyde with a nitroalkane. The synthesis of ethyl 3,4-diethylpyrrole-2-carboxylate (2) is typical. 

Further uses of nitroalkanes are in 1,4-additions (Michael reaction) to a,p-unsaturated carbonyl compounds and the like. Recent reports deal with transformations of 1,4-nitro ketones, 7, into 1,4-keto aldehydes, 8, and cyclization to cyclopentenones.16... 

Aldol-type cyclization of dialdehydes with nitroalkanes is a valuatde syndietic loute to amino sugars, amino cyclitols and nucleosides of amino sugars. Recently, die cyclization of die di- and tetra- de-hydes derived from sucrose (15) with nitroalkanes has appeared. It is notewordiy that the oxidadve cleavage of sucrose with LTA affords the dialdehyde selectively (Scheme 8). ... 

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