The Nitro group in organic sysnthesis - Feuer

8.2 1,3-DIPOLAR CYCLOADDITION 249

8.2 1,3-DIPOLAR CYCLOADDITION

Since Huisgen’s definition of the general concepts of 1,3-dipolar cycloaddition, this class of reaction has been used extensively in organic synthesis. Nitro compounds can participate in 1,3-dipolar cycloaddition as sources of 1,3-dipoles such as nitronates or nitroxides. Because the reaction of nitrones can be compared with that of nitronates, recent development of nitrones in organic synthesis is briefly summarized. 1,3-Dipolar cycloadditions to a double bond or a triple bond lead to five-membered heterocyclic compounds (Scheme 8.12). There are many excellent reviews on 1,3-dipolar cycloaddition;63 in particular, the monograph by Torssell covers this topic comprehensively. This chapter describes only recent progress in this field. Many papers have appeared after the comprehensive monograph by Torssell. Here, the natural product synthesis and asymmetric 1,3-dipolar cycloaddition are emphasized.63c Synthesis of pyrrolidine and -izidine alkaloids based on cycloaddition reactions are also discussed in this chapter.

Scheme 8.12.

8.2.1 Nitrones

Nitrones have been generally prepared by the condensation of N-hydroxylamines with carbonyl compounds (Eq. 8.40).63 There are a number of published procedures, including dehydrogenation of N,N-disubstituted hydroxylamines, N-alkylation of imines, and oxidation of secondary amines. Among them, the simplest method is the oxidation of secondary amines with H2O2 in the presence of catalytic amounts of Na2WO4; this method is very useful for the preparation of cyclic nitrones (Eq. 8.41).64

Reductions of γ-nitroketones yield cyclic nitrones, which undergo interand intramolecular cycloaddition to various alkenes. The result of addition to acrylonitrile is shown in Eq. 8.42, in which a mixture of regioand stereoisomers is formed.65

8.2 1,3-DIPOLAR CYCLOADDITION 253

Diastereoselective intramolecular cycloaddition of nitrones is useful for constructing nitrogen- containing cyclic structures. The reaction serves as a key step in a number of natural product syntheses.63 Tufarriello and coworkers have used this strategy for preparing cocaine and other alkaloids.74 As a classical example, enantioselective total synthesis of (+)-luciduline is presented in Scheme 8.13, in which a useful feature of the 1,3-dipolar addition of nitrones is nicely illustrated.75

(+) lucidine

Scheme 8.13.

Tandem transesterification and diastereoselective intramolecular 1,3-dipolar cycloaddition of α-methoxycarbonylnitrones with chiral allyl alcohols give polycyclic compounds in one step with high stereoselectivity (Scheme 8.14).76 Transition state A in Scheme 8.14 is more favorable than B because B has severe steric interaction (allylic 1,3-strain).77

Scheme 8.14.

254 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

Scheme 8.15.

Various kinds of chiral acyclic nitrones have been devised, and they have been used extensively in 1,3-dipolar cycloaddition reactions, which are documented in recent reviews.63 Typical chiral acyclic nitrones that have been used in asymmetric cycloadditions are illustrated in Scheme 8.15. Several recent applications of these chiral nitrones to organic synthesis are presented here. For example, the addition of the sodium enolate of methyl acetate to N-benzyl nitrone derived from D-glyceraldehyde affords the 3-substituted isoxazolin-5-one with a high syn selectivity. Further elaboration leads to the preparation of the isoxazolidine nucleoside analog in enantiomerically pure form (Eq. 8.52).78

Enantioselective total synthesis of antifungal agent Sch-38516 is reported. Stereocontrolled carbohydrate synthesis is based on the 1,3-dipolar cycloaddition of chiral nitrone to vinylene carbonate, as shown in Eq. 8.53.79

(8.53)

8.2 1,3-DIPOLAR CYCLOADDITION 255

Scheme 8.16.

Intramolecular cycloadditions of chiral nitrones provide a useful tool for the preparation of bioactive heterocyclic compounds.63 Shing et al. demonstrated that 1,3-dipolar cycloaddition of nitrones derived from 3-O-allyl-hexoses is dependent only on the relative configuration at C-2,3, as shown in Scheme 8.16. Thus 3-O-allyl-D-glucose and -D-altrose (both with threo-con- figuration at C-2,3) produce oxepanes selectively, whereas 3-O-allyl-D-allose and -D-man- nose (both with erythro-configuration at C-2,3) give tetrahydropyranes selectively.80

An optically active cyclic nitrone in 1,3-dipolar cycloaddition was first reported by Vasella in 1985.81 A variety of optically active cyclic nitrones have been devised since then. Some typical chiral nitrones described in Ref. 63c are shown in Scheme 8.17. Applications of these nitrones are also presented in this review.

O

Scheme 8.17.

8.2 1,3-DIPOLAR CYCLOADDITION 257

ds and 92.5% ee, which are comparable with those of Eq. 8.54.88 Introduction of tosylato ligands in the catalyst Ti(OTos)3-TADDOLate provides an excellent endo selectivity of the reaction of Eq. 8.54, in which 91–93% ee is obtained.87

The typical 1,3-dipolar cycloaddition reaction of nitrones with alkenes involves a dominant interaction of HOMO (nitrone) and LUMO (alkenes). The inverse-electron demand of the 1,3-dipolar cycloaddition reaction of nitrones with alkenes requires a dominant interaction of LUMO (nitrone) and HOMO (alkenes). Such a reaction requires an activation of the nitrone with a Lewis acid. In 1999, Jorgensen and coworkers reported that chiral 2,2′-dihydroxy-1,1′- binaphtol (BINOL)-AlMe complexes catalyzes a highly regio-, diastereo-, and enantioselective 1,3-dipolar cycloaddition reaction of aromatic nitrones with vinyl ether, giving the exo-dias- tereoisomer with 90% ds and 97% ee (Eq. 8.56).89

Copper(II)-bisoxazoline also catalyzes asymmetric 1,3-dipolar cycloaddition reactions of nitrones with electron-rich alkenes (Eq. 8.57).90

(5 mol%)

(exo/endo = 84:16)

Catalytic enantioselective 1,3-dipolar cycloaddition between nitrones with alkenes using a novel heterochiral ytterbium(III) catalyst is reported (Eq. 8.58).91 The desired isoxazolidine derivatives are obtained in excellent yields with excellent diastereoand enantioselectivities.

258 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

(8.58)

The products are converted into β-lactams with high enantiomeric purity (ee 96%), as shown in Eq. 8.59.

Reports on total synthesis of natural products using nitrones are numerous; some recent papers are as follows: marine alkaloid lepadiformine (Ref. 92) and β-lactam antibiotics (Ref. 93).

8.2.2 Nitrile Oxides

As discussed in Section 6.2, nitro compounds are good precursors of nitrile oxides, which are important dipoles in cycloadditions. The 1,3-dipolar cycloaddition of nitrile oxides with alkenes or alkynes provides a straightforward access to 2-isoxazolines or isoxazoles, respectively. A number of ring-cleaving procedures are applicable, such that various types of compounds may be obtained from the primary adducts (Scheme 8.18). There are many reports on synthetic applications of this reaction. The methods for generation of nitrile oxides and their reactions are discussed in Section 6.2. Recent synthetic applications and asymmetric synthesis using 1,3-dipolar cycloaddition of nitrile oxides are summarized in this section.

The review by Kozikowski94 and the monograph by Torssell63a demonstrate the synthetic utility of the isoxazolines. Reduction of isoxazolines with LiAlH4 or catalytic hydrogenation gives γ-amino alcohols, which have been used extensively in organic synthesis (Eq. 8.60).95 With alkyl or other noncoordinating substituents at C-4 or C-5 of the isoxazoline ring, addition of hydride taking place anti to the substituents to give erythro amino alcohols. Hydroxy or