The Nitro Group in Organic Synthesis

Scheme 8.22.

Evans and coworkers have reported the synthesis and absolute stereochemical assignment of (+)-miyakolide.111 Miyakolide was isolated from a sponge of the genus Polyfibrospongia by Higa et al.112 The elegant synthesis is illustrated in Scheme 8.23, in which the carbon skeleton is assembled in a convergent fashion from three fragments via esterification, [3+2] cycloaddition, and aldol reaction. Here, intermolecular and intramolecular [3+2] cycloadditions of nitrile oxides are used to assemble small components to complex large sized molecules.

1,3-Dipolar cycloaddition of nitrile oxides using chiral alkenes or chiral nitrile oxides has been extensively studied. It has been established that allylic substituents have a strong

influence in determining the π-facial selectivity and that notable high levels of diastereoselectivity (de 56–93%) are observed for cycloaddition to chiral allyl ethers.63c,113 For example,

benzonitrile oxide adds to (S)-isopropylidenebut-3-ene-1,2-diol to afford an 85:15 mixture of the isoxazolines (Eq. 8.72).114 The preferred formation of the adduct (erythro) has been rationalized by Houk et al. in terms of an inside alkoxide effect that involves allylic oxygen (Scheme 8.24).115 The diastereomeric preferences observed in cycloaddition result from the alkoxy group preference for the inside conformation and the alkyl group preference for anti. Examples of the corresponding reactions with chiral allylamine derivatives have also been reported, but, in general, the degree of selectivity is lower and less predictable.116

Scheme 8.23.

265

72% (ds = 6.9:1)

Eguchi and Ohno have used silyl nitronate induced 1,3-dipolar cycloaddition for function-

alization of fullerene C60 (Eq. 8.76).127a Nitrile oxides also undergo 1,3-dipolar cycloaddition

to C60.127b

Et3N

42% (8.76)

Nitroethane undergoes base-catalyzed addition to C60 to give 2-hydroxy-1,2-dihydrofulleryl ketoxime by way of a unique intramolecular redox process, which is not observed in normal electron deficient alkenes (Eq. 8.77).128 (See Section 4.3 Michael addition of nitroalkanes).

Denmark and coworkers have developed an elegant method for generating cyclic nitronates using nitroalkenes as heterodienes in the Diels-Alder reaction (Eq. 8.78). The synthetic utility of this reaction is discussed in Section 8.3.

Lewis acid

Recently, Kanemasa and coworkers found a new method for preparing cyclic nitronates. ω-Halo-α-nitropropane and -butane are cyclized with base to form cyclic nitronates which are labile 1,3-dipoles. They can be trapped by a variety of monosubstituted ethenes to give the corresponding adducts (Eq. 8.79).129a The N–O bonds in adducts are cleaved on treatment with acid to give functionalized isoxazeles. Cyclic nitronates are also prepared by intramolecular O-alkylation of ω-nitro alcohols via Mitsunobu condensation using triphenylphosphine and diethyl azodicarboxylate.128b

Another approach to cyclic nitronates has been developed by Rosini et al. in which nitro-aldol and subsequent cyclization is used as a key step. For example, 2,3-epoxy aldehydes react with ethyl nitroacetate on alumina surface in the absence of solvent to give 4-hydroxyisoxazoline 2-oxides in good yields (Eq. 8.80).130

Treatment of 2-bromo aldehydes and ethyl nitroacetate with alumina gives 4-hydroxy-2- isoxazoline-2-oxides with high stereoselectivity (Eq. 8.81).131

The products shown in Eqs. 8.80 and 8.81 are good precursors for biologically important compounds such as polyhydroxylated amino acids, aminopolyols, and amino sugars. Furthermore, 4-hydroxy-2-isoxazoline 2-oxides can be converted into tricyclic compounds via silicontethered 1,3-dipolar cycloaddition reactions, as shown in Eq. 8.82.132 The temporary silicon connection methodology gives rise to the regioand stereoselective formation of new bonds by temporarily linking together the two reactants by means of an eventually removable silicon atom.133 This strategy is very useful for the control of stereochemistry in cycloaddition reactions (also see Section 8.3).

(8.82)

One-pot multi-bond-forming reactions are one of the ways to address the ever growing demand for efficiency in organic synthesis. Rosini and coworkers have developed (tandem) processes for the synthesis of a highly functionalized tricyclic system. The reaction is simply performed by bringing together, at room temperature, α-bromo aldehydes, ethyl

nitroacetate, and chlorodimethylvinylsilane in the presence of imidazole as the base (Eq. 8.83).134

61% (cis/trans = 1/1) (8.83)

The cleavage of the tricyclic structure such as the product presented in Eq. 8.83 leads to a linear aminopolyhydroxylated structure (Scheme 8.25).135 Two-step unfolding (silyl ether hydroxydesilylation/nitroso acetal hydrogenolysis) can be useful in the preparation of hydroxylated amino acids (Eq. 8.84).

The present tandem nitro aldol-cyclization process is used for the preparation of the enantiomerically pure 4-hydroxy-2-isoxazoline-2-ones. They are prepared starting from chiral α-mesyloxy aldehydes and ethyl nitroacetate under mild reaction conditions (Eq. 8.85).136

93% (trans/cis = 43/57)

(8.85)

Hassner and coworkers have developed a one-pot tandem consecutive 1,4-addition intramolecular cycloaddition strategy for the construction of fiveand six-membered heterocycles and carbocycles. Because nitroalkenes are good Michael acceptors for carbon, sulfur, oxygen, and nitrogen nucleophiles (see Section 4.1 on the Michael reaction), subsequent intramolecular silyl nitronate cycloaddition (ISOC) or intramolecular nitrile oxide cycloaddition (INOC) provides one-pot synthesis of fused isoxazolines (Scheme 8.26). The ISOC route is generally better than INOC route regarding stereoselectivity and generality.

Michael additions of secondary allylamines to nitroalkenes followed by treatment with Me3SiCl and Et3N afford highly functionalized pyrrolidines via the stereoselective ISOC reaction (Eq. 8.86).137