Acylnitroso Diels-Alder 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). 

The hetero-Diels-Alder reaction of steroidal dienes (156) with nitroso-aromatics are regioselective with two stereoisomers (157) and (158) produced in a 2 1 ratio (Scheme 60) The regio-, stereo-, and enantio-selectivity of 4 -I- 2-cycloadditions of nitrosoalkenes to alkenes have been extensively reviewed.The intramolecular acylnitroso Diels-Alder cycloaddition of (159) produced the bicyclic adducts (160) in high yields (Scheme 61). ... 

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... 

The 1-amino-l,3-diene 1, which is readily prepared using literature procedures, undergoes regio- and stereoselective hetero-Diels- Alder cycloaddition with acylnitroso derivatives to give the 3,6-dihydro-2/f-2,3-oxazines 2. The yields are generally good and diastereomeric ratios vary as a function of both the dienophile s substituent and the temperature. The simple asymmetric induction is moderate112. 

However, [4 + 2] cycloadditions are usually more rapid than the corresponding ene reaction. Table 3-III shows some representative examples of Diels-Alder cycloadditions of acylnitroso dienophiles.38... 

The hetero Diels-Alder reaction <01H1591, 01TL5693> and dipolar cycloadditions continue to constitute important approaches to piperidines. Kibayashi and co-workers used an intramolecular acylnitroso Diels-Alder reaction to synthesize (-)-lepadins A,B, and C from an acyclic precursor <01JOC3338>. An intramolecular nitrone cycloaddition was used by Machetti and co-workers to produce both enantiomers of 4-oxopipecolic acid <01T4995>. Their synthesis proceeds from a nitrone bearing an a-methylbenzylamine chiral auxiliary. Noteworthy in this report is the presence of large-scale experimental procedures the nitrone formation and cycloaddition reactions were performed on 285 mmol and 226 mmol scales, respectively. 

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... 

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. 

Cycloadditions The intramolecular A -acylnitroso Diels-Alder (D-A) reaction of a substrate, in which the dienophile is attached to the position 2 of the diene (type 2 D-A reaction), provided an interesting solution to the highly regioselective synthesis of bridged bicyclic oxazinolactams containing a bridgehead... 

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. 

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. ... 

Stereoselective Diels-Alder reactions have been performed variously, using chirally modified sulfines as dienophiles, chiral ynamines, SMP enamines, SMP acrylamides, and the in situ preparation of SMP A-acylnitroso dienophiles. The [2 + 2] cycloaddition reactions of chiral keteniminium salts obtained from SMP amides with alkenes have been studied. ... 

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. 

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). 

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