The Nitro Group in Organic Synthesis

Scheme 7.10.

Biologically active natural products frequently contain medium or large rings, and many methods have been used in preparing of such compounds.81 Hesse and coworkers have exploited an elegant ring expansion reaction of α-nitroketones using the ability of the nitro group to stabilize a carbanion (retro-acylation of nitro compounds). Various macro cyclic compounds are now prepared by this route (see Section 5.3).82 The carbon-carbon bondforming reactions of α-nitroketones followed by an intramolecular addition of the alkoxide to the carbonyl group give the ring-expanded products. The nitro groups are finally removed on treatment with Bu3SnH. For example, tetradecano-14-lactone is prepared via palladiumcatalyzed allylation (Section 5.5) of 2-nitrocyclodecanone followed by ozonolysis, reduction, ring expansion, and denitration, as shown in Scheme 7.12.83 In a similar way,

(–)-15-hexadodecanolide (Scheme 7.13)84, (+)-13-tetradodecanolide (Scheme 7.14),85 and muscone (Scheme 7.15)86 are prepared.

Scheme 7.11.

Enantioselective nitro-aldol reaction (see Section 3.3) or Michael reaction (see Section 4.4) followed by radical denitration is useful as an alternative indirect method of enantioselective 1,2- or 1,4-addition of alkyl anions (see Eq. 7.7087 and Eq. 7.7188).

cat.: La-K-(S)-6,6-bis(triethylsilyl)ethynyl BINOL (see Section 3.3)

Bu3SnH, AIBN

toluene, reflux

47%

Scheme 7.13.

The reduction of nitro ketones with baker’s yeast is a good method for the preparation of chiral nitro alcohols.89 The reduction of 5-nitro-2-pentanone with baker’s yeast gives the corresponding (S)-alcohol, which is an important chiral building block. Various chiral natural products are prepared from it. In Scheme 7.16, the synthesis of the pheromone of Andrena haemorrhoa is described, where the acylation of the chiral nitro alcohol followed by radical denitration is involved as key steps.89a

The Michael addition of heteroatom nucleophiles to nitroalkenes (Section 4.1.1) followed by denitration provides a useful method for the preparation of various natural products.

Scheme 7.15.

Kitagawa and coworkers have used this strategy for the preparation of pseudo-nucleosides exhibiting various biological activities. The synthesis of (–)-aristeromycin from D-glucose is demonstrated in Scheme 7.17.90

Naturally occurring and synthetic polyhydroxylated pyrrolidine and piperidines have recently received considerable attention due to their biological activities. Barco has used tandem Michael-Henry reactions to synthesize 2-hydroxymethyl-3-hydroxy-4-nitro-pyrrolidines, from which the nitro group is removed to give the natural product, trans 2-hydroxymethyl-3-hy- droxypyrrolidine (Eq. 7.72).91

(-)-aristeromycin

Scheme 7.17.

7.2 R–H FROM R–NO2 207

terpenoid is prepared by the double Michael addition and subsequent denitration with NaTeH, as shown in Eq. 7.77.97

(7.77)

Denitration of nitro compounds with Bu3SnD provides an elegant method for the synthesis of deuterated compounds.98 Recently, the synthesis of deuterium labeled plant sterols has been reported (see Eq. 7.78).99

(7.78)

Other applications of radical denitration in organic synthesis are summarized in Table 7.3. Application of radical reactions to organic synthesis has recently received much attention, and various important reactions have been discovered in this field. Alkyl halides, sulfides, selenides, and thiocarbonyl compounds have been used as precursors to alkyl radicals. Some

examples are illustrated in Scheme 7.18.125

Bu3Sn

CO2Et

R

CO2Et

Radical cyclization

Scheme 7.18.