N-Acylnitroso

The nitroso moiety of the N-acylnitroso function is a powerful dienophile and therefore N-acylnitroso compounds are trapped rapidly, especially in an intramolecular reaction, with a diene allowing the Diels Alder reaction to occur also in water, although N-acylnitroso compounds are short-lived in aqueous medium. 

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. 

Aoyagi, S., Tanaka, R., Naruse, M., Kibayashi, C. (1998) Total Synthesis of (—)-Epibatidine Using an Asymmetric Diels-Alder Reaction with a Chiral N-Acylnitroso DienophUe. Journal of Organic Chemistry, 63, 8397-8406. 

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. 

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... 

Pericycttc Reactions Although a wide variety of ring-expansion processes through pericyclic cyclizations have been described, only a few cycloaddition methods were depicted for the direct generation of medium-ring heterocycles. The most attractive approaches were the [4-1-3] cycloaddition, the 1,3-dipolar cycloaddition of nitrone, and the type-2 intramolecular N-acylnitroso Diels-Alder reaction. 

The adduct (137) was obtained diastereoselectively by reaction of cyclohexa-1,3-diene with the N-acylnitroso-compound derived from a chiral pyrrolidine, itself made from D-mannitol (Vol. 22, p. 181).108 An ene reaction between the 1-chloro-l-nitrososugar and cyclopentene gave the nitrone (138), which could be used as a precursor of the chiral hydroxylamine or amine.10 ... 

Kibayashi, C. Aoyagi, S. Nitrogenous Natural Products via N-Acylnitroso Diels-Alder Methodology Synlett 1995, 873-879. Corrie, J. E. T. Kirby, G. W. Sharma, R. P. Formation of Aryl Isocyanates by Deoxygenation of Nitroso-carbonylarenes J. Chem. Soc., Chem. Commun. 1975, 915-916. Kirby G. W. Sweeny, J. G. Nitrosocarbonyl Compounds as Intermediates in the Oxidative Cleavage of Hydroxamic Acids /. Chem. Soc., Chem. Commun. 1973, 704-705. 

A number of histrionicotoxins have been characterized. These differ largely in the position of unsaturation on the two side chains . Whereas the parent natural product eluded synthesis for many years, the saturated version of this compound, perhydrohistrionicotoxin (5), was first prepared by Kishi and Corey, and indeed, by many other groups thereafter. We will simply look at the Corey and Kishi approaches retrosynthetically and will then examine two syntheses of perhydrohistrionicotoxin in detail. The first synthesis will introduce the use of 2ST-acyliminium ions as electrophiles, and the second will revisit N-acylnitroso compounds as reactive species for use in alkaloid synthesis. 

The next perhydrohistrionicotoxin synthesis we will examine was reported by the Keck group (Utah). This synthesis featured chemistry of N-acylnitroso compounds, just as did the Keck synthesis of pyrrolizidines (Chapter 4). Rather than approaching this in a retrosynthetic manner , suffice it to say that this work intersects with the Kishi synthesis at the point of keto-lactam 46. Now we will jump right into the synthesis. 

Abe, H., Aoyagi, S., and Kibayashi, C. (2000) Total synthesis of the proposed structure of lepadiformine via intramolecular N-acylnitroso Diels-Alder reaction. Tetrahedron Lett., 41, 1205-1208. 

Acylnitroso compounds 197 (R = Me, Ph or Bn) react in situ with 1-methoxycarbonyl-1,2-dihydropyridine to yield solely the bridged adducts 198 quantitatively. On the other hand, 1 1 mixtures of the regioisomers 199 and 200 were formed from the nitroso-formates 187 (R = Me or Bn) (equation 110)103. The chiral acylnitroso compounds 201 and 202, which are of opposite helicity, add to cyclohexadiene to give optically active dihydrooxazines in greater than 98% diastereomeric excess (equations 111 and 112)104. Similarly, periodate oxidation of the optically active hydroxamic acid 203 in the presence of cyclopentadiene, cyclohexa-1,3-diene and cyclohepta-1,3-diene affords chiral products 204 (n = 1, 2 and 3, respectively) in 70-88% yields and 87-98% de (equation 113)105. 

A type 2 intramolecular /V-acylnitroso Diels-Alder reaction of hydroxamic acid 177 followed by catalytic hydrogenation of the double bond was employed for the synthesis of substituted bridged bicyclic derivative 178, as a single diastereomer (Scheme 75 <2002OL2637>). Cleavage of the N-O bond was performed by reduction with Na(Hg) amalgam and provided m-3,7-disubstituted azocane 9, as a single isomer in 80% yield. 

Vinylnitroso N-Acylimines x = o,s Acylnitroso 1,2-Keto imines o-Quinone... 

C- and N- nitroso compounds may exist as two Z and E (major) isomers due to the tautomeric effect which restricts the rotation about the C-N and N-N bonds. Thus CTI can occur via free rotation of the tautomeric form, doublet inversion etc. [29,14]. In this respect, C-nitroso compounds are the tautomeric form of the corresponding oximes (CH-N=0 —> C=N-OH). The energy barrier is usually between 12 and 27 kcal mol-1 [32], however, many factors may influence CTI, such as substituents, solvents, and pH [33]. For example, alkyl-substituted C- and N-nitroso compounds usually exist as a mixture of Z and E isomers [33], whereas acylnitroso [34] and nitrosocarbamate [35] species have an exclusive E relative stereochemistry due to oxygen-oxygen electronic repulsion. 

A final example of an allylic C-H animation process involves a mechanism that does not fall into the classification of either a Cu-bound nitrene or N-centered radical-type process. In this case, A-Boc-hydroxylamine serves as the nitrogen source and is converted to the acylnitroso species via a disproportionation mechanism facilitated by P(OEt)3 and CuBr [50]. Such compounds will react with olefin substrates through a thermal ene-like rearrangement to give A-Boc-A-hydroxy allylic amines. The Cu catalyst is not believed to play a specific role in the actual C-H oxidation event. 

Oxidation of diene-containing hydroxamic acids has been reported to give acylnitroso species which undergo spontaneous hetero-IMDA reactions to give heterobicyclic ketones. (E,E)-N-Hydroxy-5,7-dodecadienamide, upon treatment with tetrapropylammonium periodate, gave the pyrido[l,2-b][l,2]oxazine structure in high yield88. 

S. namaquense its structure is based on spectral study Several new syntheses of meserabrine have been reported. One uses a cinna-monitrile as a synthon, with introduction of a "formyl anion" at the S-position, followed by Robinson annelation and finally elaboration of the cyanomethyl side-chainA second employs an intramolecular ene cyclisation of an acylnitroso-olefin to a hydroxamic acid, reducible to a lactam. Then follows a series of simple steps (N-methylation, hydroxylation via bromohydrin formation, debromi-... 

C.iii. Nitroso-Type Compounds. Nitroso compounds (R—N=0) show reactivity as dienophiles in Diels-Alder reactions, giving heterocyclic rings. In Kibayashi s synthesis of fasicularin, " for example, hydroxamic acid 180 was treated with tetrapropylammonium periodate in the presence of 9,10-dimethyl-anthracene to give transient acylnitroso compound 181, and the resultant Diels Alder product 182 was formed in 84% yield. In this particular example, the Diels-Alder adduct essentially "protected" the acyl nitroso unit, which was used in a subsequent reaction. 

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-... 

Shea s group applied this type 2 A-acylnitroso intramolecular Diels-Alder cyclization to the synthesis of tricyclic BCD core of stenine. The C2-tethered cyclic diene 103 was converted to the corresponding hydroxamic acid by treatment with NH20H-HC1, which, upon oxidation with BU4NIO4, was converted to 104 as a 6 1 mixture of diastereomers. Reductive N-0 bond cleavage of 104 yielded the alcohol 105 and its diastereomer (not shown). Further elaboration of 105 provided the tricyclic core structure 106 of stenine (Scheme 4.22) [41],... 

The Keck group described an approach to the pyrrolizidine alkaloids that revolved around acylnitroso Diels-Alder chemistry. The plan, outlined within the context of an approach to heliotridine (38), was to once again use an intramolecular N-alkylation to construct the N4-C3 bond. N-Alkylation substrate 39 was to be prepared by reduction of the N-O bond of 40, which was to result from an intramolecular cycloaddition of 41. It was hoped that the C7 substituent might induce relative stereochemistry at 07 by occupying a site on the convex face of the incipient azaoxabicyclo[4.3.0]nonane ring system in the cycloaddition transition state. Note that the cycloaddition of 41 establishes the olefin geometry needed to support the intramolecular N-alkylation. 

A route to (- )-162 devised by Kibayashi and co-workers began with the chiral hydroxylamine 186, prepared in eleven steps from D-malic add (123). In situ oxidation of 186 with periodate produced the transient acylnitroso species 187, intramolecular Diels-Alder reaction of vidiich yielded stereoisomeric oxazine cycloadducts 188 and 189 (Scheme 26). The observed ratio was 1 1.3 when the oxidation was performed in chloroform, but the dramatic improvement to 1 4.1 in aqueous medium was ascribed to a hydroj obic packing effect . Reductive cleavage of the N-0 bond of 189 and silylation of the exposed alcohol group gave (2)-alkene 190. A moderately diastereoselective osmylation yielded the (75,8R)-cu-diol 191 and its chipmatographically separable (7R,8 isomer in a 4 1 ratio. The synthesis of ( - ) 162 from isomer 191 was completed as shown in five straightforward steps. 

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. ° ... 

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