Nitrone-based synthesis

A new nitrone-based synthesis of jS-lactams which makes provision for the 1-hydroxymethyl function in thienamycin has been described. More importantly, the relative stereochemical features of the natural product are defined in the initial step of the sequence (Scheme 129). 

As part of an extensive study of the 1,3-dipolar cycloadditions of cyclic nitrones, Ali et al. (392-397) found that the reaction of the 1,4-oxazine 349 with various dipolarophiles afforded the expected isoxazolidinyloxazine adducts (Scheme 1.78) (398). In line with earlier results (399,400), oxidation of styrene-derived adduct 350 with m-CPBA facilitated N—O cleavage and further oxidation as above to afford a mixture of three compounds, an inseparable mixture of ketonitrone 351 and bicyclic hydroxylamine 352, along with aldonitrone 353 with a solvent-dependent ratio (401). These workers have prepared the analogous nitrones based on the 1,3-oxazine ring by oxidative cleavage of isoxazolidines to afford the hydroxylamine followed by a second oxidation with benzoquinone or Hg(ll) oxide (402-404). These dipoles, along with a more recently reported pyrazine nitrone (405), were aU used in successful cycloaddition reactions with alkenes. Elsewhere, the synthesis and cycloaddition reactions of related pyrazine-3-one nitrone 354 (406,407) or a benzoxazine-3-one dipolarophile 355 (408) have been reported. These workers have also reported the use of isoxazoles with an exocychc alkene in the preparation of spiro[isoxazolidine-5,4 -isoxazolines] (409). 

A method for the stereoselective synthesis of a-aminophosphonates and their N-hydroxy derivatives by aminophosphonylation of carbohydrate and amino acid derivatives using nitrone- based chemistry has been reported (an example of reactions of N-monoprotected a-amino nitrones, whose progenitors were alanine, phenylalanine and leucine respectively, affording the corresponding N-hydroxy a-aminophosphonates, is given in Scheme 67). ... 

An interesting example of a nitrone featuring both carbon and nitrogen substituents, each with a stereocenter, was reported in a cycloaddition-based synthesis of aspartame70. Unfortunately, the matching combination of configurations that promotes a totally stereoselecLive cycloaddition leads to the epimer with the undesired configuration. 

A nitrone-based approach to the enantioselective total synthesis of (-)-anisomycin (1) has been developed from (3S,4S)-l-benzylpyrrolidine-3,4-diol (89), which was obtained from L-tartaric acid (Scheme 10) [29]. l-Tartaric acid was converted to pyrrolidine 89 [79] by condensation with benzylamine and then reduction with NaBH4/BF3 Et20. 

Total synthesis of loline (3) and norloline (4) was accomplished using a nitrone-based strategy (47). Methyl 2-hydroxy-7,7-dimethoxy-8-pyrrolizidine-1-carboxylate (20) was prepared from nitrone (21) and methyl 4-hydroxycrotonate (22). Epimerization at C(l) was accomplished with sodium methoxide in methanol to yield 23. Reduction of 23 with LiAlH4 produced... 

The required nitro compounds are easy to prepare, and are useful building blocks for synthesis. Treatment with an appropriate base—e.g. aqueous alkali—leads to formation of nitronates 2. Various substituted nitro compounds, such as nitro-ketones, -alcohols, -esters and -nitriles are suitable starting materials. 

Several approaches based on nitro-aldol for the synthesis of amino sugars have been reported Alumina-catalyzed reaction of methyl 3- nitropropanoate with O-benzyl-o-lactaldehyde gives the o-ribo-nitro-aldol fanti, and isomeri in 63% yield, which is converted into L-dannosamine fsee Secdon 3 3 Jager and coworkers have reported a short synthesis of L-acosamine based on the stereoselective nitro-aldol reaction of 2-O-benzyl-L-lactaldehyde with 3-nitropropanal dimethyl acetal as shovm in Scheme 3 10 The stereoselecdve nitro-aldol reacdon is carried ont by the silyl nitronate approach as discussed in Secdon 3 3... 

The elegant, enantiospecific synthesis of biotin (1) by Hoffmann-La Roche1 is based on a strategy that takes advantage of the powerful intramolecular nitrone-olefin cycloaddition reaction. Our analysis begins with model studies in which the straightforward conversion of L-cysteine (2) into aldehyde 3 (see Scheme 1) constitutes... 

A one pot synthesis of isoxazolines 78a-f involves base mediated 1,4-addition of malonate or alcohol 76 possessing an allylic substituent, conversion of the resulting nitronate to the a-chloroaldoxime (hydroxymoyl chloride 77) and its subsequent dehydrohalogenation to the nitrile oxide intermediate which cyclizes to isoxazoline 78 (Eq. 7, Table 6) [32]. 

The condensation of nitro compounds and imines, the so-called aza-Henry or nitro-Mannich reaction, has recently emerged as a powerful tool for the enantioselective synthesis of 1,2-diamines through the intermediate /3-amino nitro compounds. The method is based on the addition of a nitronate ion (a-nitro carbanion), generated from nitroalkanes, to an imine. The addition of a nitronate ion to an imine is thermodynamically disfavored, so that the presence of a protic species or a Lewis acid is required, to activate the imine and/or to quench the adduct. The acidic medium is compatible with the existence of the nitronate anion, as acetic acid and nitromethane have comparable acidities. Moreover, the products are often unstable, either for the reversibility of the addition or for the possible /3-elimination of the nitro group, and the crude products are generally reduced, avoiding purification to give the desired 1,2-diamines. Hence, the nitronate ion is an equivalent of an a-amino carbanion. 

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, 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.630 Synthesis of pyrrolidine and -izidine alkaloids based on cycloaddition reactions are also discussed in this chapter. 

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... 

The strategy based on tandem cycloaddition leads to a short and efficient asymmetric synthesis of the pyrrolizidine necine base (-)-hastanecine, as shown in Scheme 8.32.163 Pyrrolizidine alkaloids have a long history for attracting the interest of synthetic chemists because of their physiological properties. The method of Denmark shown in this scheme is very simple and applied to synthesis of various alkaloids. The Lewis acid-promoted [4+2] cycloaddition between 2-acyloxy nitroalkene and chiral vinyl ether gives a nitronate that... 

Imidazole nitrones 127 reacted with dimethyl acetylenedicarboxylate to yield imidazo[l,5-fc]isoxazoles 128, which in the presence of base afforded imidazoles 129 <00TL5407>. Chiral imidazoline nitrone 130 participated in a [3+2] cycloaddition reaction with various dienophiles to furnish imidazoisoxazoles 131 <00SL967>. A convenient synthesis of AyvyV -trisubstituted ethylenediamine derivatives from 2-methyl-2-imidazoline has been reported <00SC3307>. Dehydrogenation of 1,3-di- and 1,2,3-trisubstituted imidazolidines afforded l//-4,5-dihydroimidazolium salts <00SC3369>... 

Recently, based on such an oxidative system, the synthesis of nitrone (12) an inhibitor of 5a-reductase has been carried out (Scheme 2.7) (50). Oxidation of amines with H2O2 can be catalyzed with peroxotungstophosphate (PCWP) (51), Se02 (52-54), and titanium silicalite molecular sieves TS-1 and TS-2 (55, 56). 

Stereoselective synthesis of pseudo C2-symmetrical 1,3-dibenzyldiamino alcohol (S,S) (323) a core unit of HIV protease inhibitors, and the two meso-stereoisomers (323a) and (323b) was achieved by stereocontrolled addition of benzylmagnesium chloride to nitrones (63a) and (63b) (Scheme 2.137). The yield of (S,S)-(323), based on N-Boc-L-phenylalaninal, accounts for 23% (Scheme 2.137) (211). 

Transformation of chiral nitrones into enantiomer enriched a-chiral N -hydroxylamines and their derivatives, has been successfully employed in the enantioselective synthesis of (+ )-(R)- and (—)-(S)-zileuton (216). An expeditious synthesis of thymine polyoxin C (347), based on the stereocontrolled addition of 2-lithiofuran (a masked carboxylate group) to the A-benzyl nitrone derived from methyl 2,3-O-isopropylidene-dialdo-D-ribofuranoside, is described (Scheme 2.151) (194). 

Addition of Lithiated Sulfoxides and Sulfones Nucleophilic addition of lithiated methylaryl sulfoxides (384) to nitrones of various structures proceeds easily and in good yields (622). The reactions are applied to the synthesis of optically active a-substituted and a,a-disubstituted hydroxylamines, to secondary amines (623), and to enantioselective syntheses of alkaloids (624). The preferred approach to (+ )-euphococcinine is based on the use of homochiral 3-sullinyl nitrones (385) (Scheme 2.167). 

Nucleophilic addition of lithiated sulfones to nitrones made it possible to develop new stereoselective approaches to the synthesis of pyrrolidine-N -oxides based on a reverse-Cope-type elimination. One method is based on the reaction of lithiated sulfones with nitrones (386) (Scheme 2.168) (625). 

One of the processes most generally used for the synthesis of nitrones is based on reduction of AN to hydroxylamines followed by oxidation of the resulting intermediates. In this process, the nitrogen atom of the nitro group remains in the target nitrones. Another possible approach to the synthesis of nitrones from AN, which involves the replacement of the nitrogen atom that is present in AN, will be described later in this chapter. 

Nowadays the main method for the synthesis of alkyl nitronates is based on alkylation of the corresponding AN. 

Another approach to the synthesis of cyclic nitronates is based on cycloaddition reactions (Scheme 3.11, Eq. 2), where two bonds (C-C and C-O) are simultaneously formed. This strategy allows one to perform stereoselective processes with the use of very simple precursors. However, this approach to the synthesis of five-membered cyclic nitronates implies that reactive and very unstable nitrocarbenes are involved in the process. 

Yet another approach to the synthesis of five-membered cyclic nitronates (5) is based on the Henry condensation of a-halo-substituted aldehydes (9) with primary AN followed by cyclization of nitroaldols (Scheme 3.14, Eq. 4) to give five-membered nitronates containing the hydroxy group at the C-4 atom. 

Synthesis of Acyl Nitronates The most general approach to the synthesis of acyl nitronates is based on the reactions of anions of the corresponding AN with acyl halides or carboxylic acid anhydrides in the presence of bases. Here, we will not consider a series of studies, where the formation of intermediate O-acyl nitronates was postulated without conclusive proof or by detection of their decomposition products. 

As a result, diastereo- and enantiomerically pure functionalized nitro derivative (205) was synthesized in satisfactory yield. This compound was used in the ISOC procedure, which gave diastereo- and enantiomerically pure isoxazolidine (206) in good yield. The latter compound can be considered as a possible reagent for asymmetric synthesis. It should be noted that silylation in this procedure, like that described above (Scheme 3.145), was performed with the use of BSA as the silylating agent in the presence of a small amount of Hunig s base, the latter being evidently added for acceleration of silylation and stabilization of intermediate silyl nitronate. 

A recently developed general procedure for the synthesis of cyclic nitroso acetals is based on the reaction of cyclic nitronates with C-nucleophiles under conditions of electrophilic catalysis (Scheme 3.153 for more details, see Section 3.5.2.3). 

For silylation of six-membered cyclic nitronates (342), the influence of the nature of base on the regioselectivity of the synthesis of nitrosals (343) was studied in sufficient detail. Intermediate cations A can be deprotonated at the a-C atom of the substituent at C-3 as well as the C-4 atom (see Scheme 3.202 and Table 3.20) (264, 474). 

The general method, that has been widely used for the synthesis of perhydropyrrolo[1,2-6]isoxazoles, is based on a cycloaddition reaction of cyclic nitrones with dipolarophiles. The nitrone is easily available by oxidation of the corresponding hydroxylamine with mercuric chloride. The cycloaddition of nitrone to dipolarophiles is highly regioselective and stereoselective and have been often applied in the total synthesis of natural products <20010L1367, 2004BML3967, 2005JOC3157>. As one representative example of dipolar cycloaddition, reaction... 

The key step of the synthesis, which involved a classical Mannich condensation in the synthesis by Evans and Scott (as well as in the biogenesis of alkaloids in general [10]), is substituted by a 1,3-dipolar cycloaddition of a nitrone to a carbon-carbon double bond [11] which provides an alternative route for the formation of a new C(l)-C(2) bond with the concomitant creation of a 1,3-consonant relationship between an oxygen atom and a dialkylamino group. In order to arrive at a typical Mannich base two more steps are, however, necessary. The similarity between the two processes is shown is Scheme 13.2.7 ... 

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