A-Nitroketones, cyclic

One-pot syntheses of 1,4-diketones, y-oxoaldehydes, y-ketoesters, and co-oxoalkanoates have been reported by bond cleavage of cyclic a-nitroketones with KOH in methanol and subsequent Nef reaction (Section 6.1) with KMn04 (Eq. 5.16).31... 

Oxidative ring opening of cyclic a-nitroketones under mild conditions C... 

Ring expansion of cyclic a-nitroketones by three C-atoms M acrocyclic a-(aminomethylene)ketones... 

Unusual Nef reaction—N-Hydroxydicarboxylic acid imides from cyclic a-nitroketones s. 19, 399... 

Nitroacetic acid esters and anudes are potential precursors of amino acids. They are good substrates in Pd(0)-catalyzed allylation with carbonates (Scheme 18) the same as the structurally related open-chain and cyclic a-nitroketones. An intramolecular version is aimed at the preparation of precursors of alkaloid ergoline. 3,4-Dimethylenecyclopentane nitroacetate is prepared in one synthetic step from allyl carbonate (R = Br, R = H) including a C—C bond formation by Pd-catalyzed reductive coupling.f There are more examples of Pd(0)-catalyzed allylation of nitroderiva-tives including nitromethane.f ... 

Nitro-compounds are also prepared by the replacement of benzylic hydroxyl by 2-nitropropyl groups," the replacement of activated bromine with silver nitrate in the presence of triphenylphosphine," and the Michael addition of nitroethane to a,/3-ethylenesulphoximines under phase-transfer conditions." The preparation and reactions of cyclic a-nitroketones have been reviewed." The conversion of primary and secondary nitroalkanes into the corresponding carbonyl compounds, i.e. the Nef reaction, is a useful synthetic transformation. Three new methods" " to effect this important reaction offer a variety of oxidative conditions, and thus enable the minimization of side reactions (Scheme 36). 

A number of routes can be envisioned for the preparation of polysubstituted pyrrolidines, and the intramolecular addition of a silyl ketene acetal to an oxime ether has been employed in the synthesis of ABT-627 (4). However, the reductive cyclization of a nitroketone, which could be obtained via the conjugate addition of a ketoester to a nitrostyrene, was viewed as being the most direct, convergent approach to ABT-546. In this approach, the nitro functionality is reduced to generate the cyclic imine, which is then further reduced to the trisubstituted pyrrolidine (Figure 2). As the trans-trans isomer is thermodynamically favored, both it and the cis-cis isomer are usable intermediates. 

Redncdons of y-nitroketones yield cyclic nitrones, which undergo inter- and intramolecular cycloadthdon to various alkenes. The result of adthdon to acrylonitrile is shown in Eq. 8.43, in which a rruxnire of regio- and stereoisomers is formed. - ... 

Examples of such three-carbon synthons are 2-nitro-2-propen-l-yl acetates and piva-lates, which have been developed by Seebach and coworkers57,58 as reagents for [3 + 3] cyclizations with cyclic and acyclic ketone enamines. After workup these reactions give 4-nitrocyclohexanones. With enamines from prolinol methyl ether and cyclic ketones, enantiomerically pure compounds were obtained58. An example of such a [3 + 3] cyclization is the synthesis of bicyclic nitroketone 99 from nitroallylic ester 97 and enamine 98 (equation 18). 

In fact, as shown in Figure 3, this approach has been employed in the synthesis of ABT-627. The coupling of ketoester 1 with nitrostyrene 2 was accomplished with a catalytic quantity of KOtAm. Product nitroketone 3 was reduced over Raney nickel to prepare cyclic imine 4, which was further reduced on addition of TFA to produce Ae cis-cis pyrrolidine 5 with good selectivity. Following epimerization with DBU, trans-trans pyrrolidine 6 was resolved with good efficiency as the mandelate salt. 

Whereas the nitroketone intermediate in the synthesis of ABT-627 was reduced to the pyrrolidine by treatment first with Raney nickel, then by the addition of TEA to provide the cis-cis substituted pyrrolidine selectively, nitroketone 9 gave a mixture of products under those conditions. Modified conditions were identified under which the nitroketone was reduced to the cyclic imine over Raney nickel (Eigure 7). Eurther reduction was carried out with NaHB(OAc)3 to provide the trans-trans substituted pyrrolidine directly in 91% yield over two steps, with less than 2% of diastereomeric products. 

This approach also allows a very efficient synthesis of different y-nitroketones containing quaternary stereogenic centers starting from cyclic as weU as selected acyclic P,P-disubstituted enones and cinchonine-based primary amine catalyst (Figure 21.4). The reaction is also possible with more demanding 2-nitropropane and nitroethane. In most cases, under lOkbar pressure and in the presence of 1-5 mol% of the simple chiral primary amine catalyst, good yields and good to excellent enantioselectivities were obtained. 

---