Hydroxamic acids Diels-Alder reactions

The intramolecular /zetero-Diels-Alder reactions of 4-O-protected acyl-nitroso compounds 81, generated in situ from hydroxamic acids 80 by periodate oxidation, were investigated under various conditions in order to obtain the best endo/exo ratio of adducts 82 and 83 [65h] (Table 4.15). The endo adducts are key intermediates for the synthesis of optically active swainsonine [66a] and pumiliotoxin [66b]. The use of CDs in aqueous medium improves the reaction yield and selectivity with respect to organic solvents. 

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... 

An intramolecular hetero-Diels-Alder reaction of enantiomerically pure iV-acyl nitroso derivatives 78, prepared from hydroxamic acids 77 by oxidation on treatment with Pr4NI04 in an aqueous medium, afforded a mixture of diastereomeric pyrido[l,2-A][l,2]oxazin-8-ones 79 and 80 (Scheme 5) <1996J(P1)1113, 20000L2955,... 

In general, C-acyl nitroso compounds-9,10-dimethylanthracene cycloadducts derived from hydroxamic acids (-R = alkyl, aryl, ti/2 = 4.1 h for -R = -Ph at 60°C) decompose more slowly than those derived from N-hydroxycarbamates or N-hydroxyureas [11, 13, 14]. Further addition of alkyl groups to the N atom of N-hydroxyurea-derived cycloadducts produces a further increase in the rate of the retro-Diels-Alder reaction of these cycloadducts [36]. These general trends suggest the possibility of the development of acyl nitroso compound-9, 10-dimethylanthracene cycloadducts as a general class of HNO or NO donors with varied release profiles. 

The cyclohexene 121, which was readily accessible from the Diels-Alder reaction of methyl hexa-3,5-dienoate and 3,4-methylenedioxy-(3-nitrostyrene (108), served as the starting point for another formal total synthesis of ( )-lycorine (1) (Scheme 11) (113). In the event dissolving metal reduction of 121 with zinc followed by reduction of the intermediate cyclic hydroxamic acid with lithium diethoxyaluminum hydride provided the secondary amine 122. Transformation of 122 to the tetracyclic lactam 123 was achieved by sequential treatment with ethyl chloroformate and Bischler-Napieralski cyclization of the resulting carbamate with phosphorus oxychloride. Since attempts to effect cleanly the direct allylic oxidation of 123 to provide an intermediate suitable for subsequent elaboration to ( )-lycorine (1) were unsuccessful, a stepwise protocol was devised. Namely, addition of phenylselenyl bromide to 123 in acetic acid followed by hydrolysis of the intermediate acetates gave a mixture of two hydroxy se-lenides. Oxidative elimination of phenylselenous acid from the minor product afforded the allylic alcohol 124, whereas the major hydroxy selenide was resistant to oxidation and elimination. When 124 was treated with a small amount of acetic anhydride and sulfuric acid in acetic acid, the main product was the rearranged acetate 67, which had been previously converted to ( )-lycorine (108). 

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. 

Aliphatic nitroso compounds can be prepared from IV-alkylhydroxylamines by oxidation with bromine, chlorine or sodium hypochlorite in weakly acidic solution, by reaction with potassium dichromate in acetic or sulfuric acid, and by oxidation with yellow mercury(II) oxide in suspension in an organic solvent. Silver carbonate on (Telite has also been used to prepare aliphatic nitroso compounds, such as ni-trosocyclohexane, in high yield from the corresponding hydroxylamines. Aqueous sodium periodate and tetraalkylammonium periodates, which are soluble in organic solvents, are the reagents most commonly used for the oxidation of hydroxamic acids and / -acylhydroxylamines to acylnitroso compounds (40). These compounds are rarely isolated, but are useful as highly reactive dienophiles in the Diels-Alder reaction. ... 

The use of acyl nitroso compounds as dienophiles was first described by Kirby. The primary method for generating these highly reactive, unstable species is by periodate oxidation of hydroxamic acids. The acyl nitroso compounds can be trapped in a Diels-Alder reaction with 9,10-dimethylanthracene to give adduct (95) (equation 36) which can act as an alternative source of the dienophile, since retro [4 + 2] cycloaddition occurs under mild thermal conditions. 

Acylnitroso alkenes produced via rDA reactions are key intermediates in the synthesis of alkal-oids. The acylnitroso alkene intermediate (167) that is generated from anthracene adduct (166) can react by an intramolecular ene reaction, resulting in the formation of hydroxamic acid (168). If the acylnitroso alkene is produced in the presence of a diene, an intramolecular Diels-Alder reaction can occur to give a 1,2-oxazine derivative such as (170) as shown in equation (76). ... 

Diastereoselective acylnitroso Diels-Alder reactions were performed using enantiopure hydroxamic acids derived from camphor and a-amino acids as chiral auxiliaries (Equation 90) <1997JOC3806, 1998T10537, 2003TL4571>. 

Recently, Kibayashi s group (85JA5534) elegantly carried out the stereo-controlled total synthesis of gephyrotoxin (skin extracts of neopropical poison dart frog) based upon an intramolecular nitroso Diels-Alder reaction. The hydroxamic acid 365 was treated with tetrapropylammonium periodate... 

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. 

Kibayashi and coworkers reported that total synthesis of (+)-azimine (9) and (+)-carpaine (10) using intramolecular hetero-Diels—Alder reaction [38], The synthesis began with (5)-l,2,4-butanetriol (119) as a single source of chirality. Protection of 1,2-diol with PhCHO of triol 119 and subsequent oxidation of the primary alcohol and Wittig reaction followed by protection of the primary alcohol as a MOM ether and DIBALH reduction afforded 120. The resulting alcohol 120 was converted into tosylate and photoisomerized followed by conversion to hydroxamic acid via nucleophilic displacement of the tosylate by cyanide ion, alkaline hydrolysis, esterification with diazomethane, and... 

Aza-Diels-Alder reactions, where the nitrogen is part of the diene component, have also featured prominently this year. Fowler and co-workers, in a continuation of their studies of the formation and trapping of 1-aza-dienes generated by thermal elimination of acetic acid from hydroxamic acid derivatives, have now described an application of the reaction to the total synthesis of the quino-lizidine alkaloid (-)-deoxynupharidine (288) (Scheme 25). Reaction to give (286) and (28 ) probably proceeds via exo, chair transition states where the major product (286) is derived from the transition state which has the methyl group on the connecting chain in an equatorial position. Kametani and co-workers have reported a useful extension to their earlier work on the Intramolecular aza-Diels-Alder reaction. Cycloaddition can now be carried out under much milder conditions than those previously described by using a trialkylsilyl trifluoromethanesulphonate as catalyst. BenzoCa ]-quinolizidine (290), for example, is obtained in excellent yield from the enamide (289). ... 

Diels-Alder precursor hydroxamic acid 174 (prepared by a multistep reaction) was subjected to subsequent oxidation and cycloaddition to provide bicyclic intermediates 175, which underwent ring cleavage by reduction with Na(Hg) amalgam, affording the eight-membered heterocycle 176 (Scheme 74 <2004JOC3025>). 

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