Acylnitroso compounds, cycloaddition

N-Acylnitroso compounds 4 are generated in situ by periodate oxidation of hydroxamic acids 3 and react with 1,3-dienes (e.g. butadiene) to give 1,2-oxazines 5 (Scheme 6.3). The periodate oxidation of 4-O-protected homo-chiral hydroxamic acid 6 occurs in water in heterogeneous phase at 0°C, and the N-acylnitroso compound 7 that is generated immediately cyclizes to cis and tranx-l,2-oxazinolactams (Scheme 6.4) [17a, b]. When the cycloaddition is carried out in CHCI3 solution, the reaction is poorly diastereo-selective. In water, a considerable enhancement in favor of the trans adduct is observed. 

The hetero-Diels-Alder reaction has also utilized dienophiles in which both reactive centers are heteroatoms. Kibayashi reported that the intramolecular hetero-Diels-Alder cycloaddition of chiral acylnitroso compounds, generated in situ from periodate oxidation of the precursor hydroxamic acid, showed a marked enhancement of the trans-selectivity in an aqueous medium compared with the selectivity in nonaqueous conditions (Eq. 12.55).125 The reaction was readily applied to the total synthesis of (—)-pumiliotoxin C (Figure 12.5).126... 

Pseudomonas putida mediated cis-dihydroxylation of bromo or chlorobenzene supplied the requisite chiral starting material 44 for a second synthesis of (+)-7-deoxynarciclasine reported by Hudlicky [18,19]. Subsequent to protection of the diol as the acetonide45 (Scheme 8), its cycloaddition reaction with the N-acylnitroso compound derived from benzyl-N-hydroxycarbamate 46 by in situ oxidation, occurred with complete regio and stereospecificity togive the bromo adduct 47. In a similar fashion, the chloro compound 48 was obtained. 

Enantioselective total syntheses of (-)-6-epitrehazolin and (+)-trehazolin were achieved by the synthesis of 275, which began with an asymmetric heterocycloaddition between [(benzyloxy)methyl]cyclopentadiene (263),108 prepared from thallous cyclopentadienide, and the acylnitroso compound arising from in situ oxidation of (,S )-mandelohydroxamic acid (264) with tetrabutylammonium periodate. Cycloaddition led to a mixture of 265 and its diastereomer (Scheme 35).109 The inseparable mixture was reduced to afford cyclopentenes 266 and 268 in 40% and 11 % overall yields, respectively, from thallous cyclopentadienide. Catalytic osmylation of 266 favored syn addition, while the osmylation of diacetate 267 was more selective and nearly quantitative, affording, after acetylation, compounds 270 and 269 in >5 1 ratio. 

A number of acylnitroso compounds derived from (/ )-mandelic acid or its analogs react in the cycloaddition with cyclic dienes with moderate to high asymmetric induction. The reaction is performed in methanol by oxidizing the A-acylhydrcixylamines 1 in the presence of the diene the diastereoselectivity increases by lowering the temperature (Table 3)99,10°. 

Table 3. Cycloaddition of Acylnitroso Compounds Derived from Chiral a-Hy-droxy Acids with 1,3-Dienes...

The pioneering studies of Kirby et al. have established that acylnitroso compounds are useful heterodienophiles in [4 -I- 2] cycloadditions. These species, which can best be generated by periodate oxidation of a hydroxamic acid, are unstable and may undergo rapid solvolysis or dimerization. However, in the presence of a diene such as 9,10-dimethylan-thracene an isolable adduct such as 14 is produced [Eq. (18)]. 

A few examples have recently appeared involving intramolecular cycloadditions of acylnitroso dienophiles in alkaloid total synthesis. Keck has utilized such an intramolecular reaction as the key step in total syntheses of the necine bases heliotridine (21) and retronecine (22) (Scheme 3-XIII). In this work, the dimethylanthracene adduct 19 was used as a precursor for the acylnitroso compound. The Diels-Alder cyclization afforded a 1.3 1 mixture of epimeric adducts 20, which was converted to the individual alkaloids. 

Boger and co-workers have recently determined the regioselectivity of acylnitroso compound additions to some 2-substituted 1,3-cyclohex-adienes.5 In the cases of both electron-rich and electron-deficient substituted dienes the same regioisomer predominated by about 3 1 (Scheme 3-IX). It was suggested that the first case is consistent with a normal (HOMOdiene controlled) Diels-Alder process, whereas the second reaction is consistent with either a HOMOdiene or inverse electron demand (LUMOdiene controlled) cycloaddition. 

During the past few years, acylnitroso Diels-Alder cycloadditions have been used as the key step in several natural product total syntheses. Retey et al.40 have used the adduct from cyclopentadiene and the acylnitroso compound derived from 3,5-dinitrobenzoic acid35 to synthesize the antitumor compound neplanocin A (16) (Scheme 3-XI). 

Kirby et al. have examined the [4 + 2] cycloaddition chemistry of nitrosyl cyanide.lc>44 This unstable species, which can be generated from nitrosyl chloride and silver cyanide, can be trapped in situ by conjugated dienes. However, as with acylnitroso compounds it is often cleaner and more convenient to use the 9,10-dimethylanthracene adduct 26 as a latent source of nitrosyl cyanide [Eq. (20)]. 

Synthesis by Cycloaddition. Earlier reports have shown that acylnitroso-com-pounds add efficiently to dienes. Now a full paper describes the oxidation of hydroxamic acids to give acylnitroso-compounds which can act both as dienophiles or as hetero-dienes with respect to cyclopentadiene. Heating the bridged oxazine adducts causes partial rearrangement to dioxazines (Scheme 1). 

Cycloadditions of chiral A -acylnitroso compounds have been widely studied. These heterodienophiles are accessible e.g. by oxidation of hydroxamic acid derivatives with periodate. C2-symmetric pyrrolidines lead to high selectivities. 1,2-Oxazines are useful precursors of amino alcohols and aza sugars. 

As our first model we chose N-benzoylnortropane (12) to investigate construction of the tropane ring system based on [4 + 2] nitroso cycloaddition with a 1 3-cycloheptadiene. A search of the literature indicated that only one example of a Diels-Alder cycloaddition of a nitroso compound with a seven-membered ring diene has been reported (ref. 8). In view of this the present study of tropane synthesis was initiated by the examination of the nitroso Diels-Alder reaction of 1 3-cycloheptadiene (7) (Fig. 1). Thus reaction of 7 with the acylnitroso compound 8 generated in situ from benzohydroxamic acid by oxidation with tetrapropyl-ammonium metaperiodate (ref. 9) was carried out at room temperature, affording the [4 +2] cycloadduct 9 in 85% yield. Reduc-... 

The nitroso functionality is a powerful dienophile and N-alkyl- and N-acylnitroso compounds give inter- and intrahetero Diels-Alder reactions easily. The cycloadditions also occur in aqueous medium although some nitroso compounds (i.e. N-acylnitroso derivative) are short-lived in the presence of water. The NO functionality is generated in situ by periodate oxidation of the hydroxylamine group and the cycloaddition with butadienes gives a 1,2-oxazine ring. Scheme 5.16 illustrates the utility of the nitroso Diels-Alder cycloaddition for the synthesis of (—l-swainsonine/ (—)-pumiliotoxin and BCX-1812... 

Heating of 96 gave the desired nitrone cycloaddition product (98) in excellent yield. This reaction involved a rfJtro-1,3-dipolar cycloaddition, followed by the key intramolecular cycloaddition, another nice example of the use of a rfJtro-cycloaddition to generate a reactive intermediate for use in a pericyclic reaction (recall the generation of acylnitroso compounds via a retro-Diels-Alder reaction). 

The normal demand hetero Diels-Alder cycloaddition between nitroso reagents 171 and dienes 172 leads to the formation of 3,6-dihydro-1,2-oxazines 173 via the concomitant stereoselective formations of a C—N and a C O bonds (Scheme 41.36). Several nitroso dienophiles like the a-chloronitroso, arylnitroso, or acylnitroso compounds are known to react efficiently in cycloadditions. Chiral nonracemic chloronitroso and acylnitroso compounds have been developed to achieve diastereoselective nitroso Diels-Alder reactions, and recently Yamamoto and co-workers reported on the first enantioselective-catalyzed cycloaddition with a pyridylnitroso dienophile. ° ... 

An extensive review of the hetero-Diels-Alder reactions of 1-oxabuta-1,3-dienes has been published. Ab initio calculations of the Diels-Alder reactions of prop-2-enethial with a number of dienophiles show that the transition states of all the reactions are similar and synchronous.Thio- and seleno-carbonyl compounds behave as superdienophiles in Diels-Alder reactions with cyclic and aryl-, methyl-, or methoxy-substituted open-chain buta-1,3-dienes.The intramolecular hetero-Diels-Alder reactions of 4-benzylidine-3-oxo[l,3]oxathiolan-5-ones (100) produce cycloadducts (101) and (102) in high yield and excellent endo/exo-selectivity (Scheme 39). A density functional theoretical study of the hetero-Diels-Alder reaction between butadiene and acrolein indicates that the endo s-cis is the most stable transition structure in both catalysed and uncatalysed reactions.The formation and use of amino acid-derived chiral acylnitroso hetero-Diels-Alder reactions in organic synthesis has been reviewed. The 4 + 2-cycloadditions of A-acylthioformamides as dienophiles have been reviewed. ... 

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