Nitrone cycloaddition intramolecular

Intramolecular nitrone cycloadditions often require higher temperatures as nitrones react more sluggishly with alkenes than do nitrile oxides and the products contain a substituent on nitrogen which may not be desirable. Conspicuously absent among various nitrones employed earlier have been NH nitrones, which are tautomers of the more stable oximes. However, Grigg et al. [58 a] and Padwa and Norman [58b] have demonstrated that under certain conditions oximes can undergo addition to electron deficient olefins as Michael acceptors, followed by cycloadditions to multiple bonds. We found that intramolecular oxime-olefin cycloaddition (lOOC) can occur thermally via an H-nitrone and lead to stereospecific introduction of two or more stereocenters. This is an excellent procedure for the stereoselective introduction of amino alcohol functionality via N-0 bond cleavage. 

The structure-reactivity relationship between a 19-Me- and 19-nor-5,10-seco-steroid has been investigated using lOOC and intramolecular nitrone cycloaddition taking into account various stereochemical aspects (Schemes 27 and 28) [67]. The E-19-nor-5,10-seco-ketone 255 a, on treatment with hydroxylamine hydrochloride (R = H), undergoes lOOC via 256a to a single isoxazolidine 257... 

Entry 7 is another intramolecular nitrone cycloaddition, but in this case the hydroxyl-amine function is present in the alkene. 

Goti, Brandi and coworkers developed an effective synthesis of (-)-rosmarinecine (4-357) via a domino cycloreversion-intramolecular nitrone cycloaddition of 4-355, which led to 4-356 (Scheme 4.79) [125]. 

Hassner and coworkers have developed a one-pot tandem consecutive 1,4-addition intramolecular cycloaddition strategy for the construction of five- and six-membered heterocycles and carbocycles. Because nitroalkenes are good Michael acceptors for carbon, sulfur, oxygen, and nitrogen nucleophiles (see Section 4.1 on the Michael reaction), subsequent intramolecular silyl nitronate cycloaddition (ISOC) or intramolecular nitrile oxide cycloaddition (INOC) provides one-pot synthesis of fused isoxazolines (Scheme 8.26). The ISOC route is generally better than INOC route regarding stereoselectivity and generality. 

Fused (5 5 5) heterocycle 28, along with 342, has been synthesized in 34% yield via an intramolecular nitrone cycloaddition, using l-allyl-2-pyrrole carboxaldehyde 340 as a starting material (Scheme 72) <1998JOC9279>. 

The formation of enantiopure tricyclic compounds takes place by intramolecular 1,3-dipolar cycloadditions of acyclic nitrones to cyclic olefinic fragments (Scheme 2.214a,b) (706, 707a), or of cyclic nitrones to acyclic olefins (Scheme 2.214c) (116). Recently (707),b intramolecular nitrone cycloaddition reactions (according to Scheme 2.211a) have been applied in the synthesis of... 

Bicyclic cis- and frans-isoxazolidinyldiynes have been prepared by intramolecular nitrone cycloaddition of the two side chains of an acyclic enediyne-nitrone precursor (Scheme 2.233) (731). 

Cycloaddition to endocyclic unsaturation has been used by many researchers for the preparation of isoxazoUdinyl adducts with y-lactams derived from pyrogluta-minol and is discussed later in this chapter as a synthesis of unusual amino acids (Scheme 1.20, Section 1.6) (79,80). A related a,p-unsaturated lactam has been prepared by a nitrone cycloaddition route in the total synthesis of the fungal metabolite leptosphaerin (81). A report of lactam synthesis from acyclic starting materials is given in the work of Chiacchio et al. (82) who prepared isoxazolidine (47) via an intramolecular nitrone cycloaddition reaction (Scheme 1.11). 

The rare reports of quinolizidine formation by a nitrone cycloaddition strategy include the racemic total synthesis of lasubine II (58), one of a series of related alkaloid isolated from the leaves of Lagerstoemia subcostata Koehne (Scheme 1.14) (104). While these alkaloids were previously accessed by infennolecular nitrone cycloaddition reactions, this more recent report uses an intramolecular approach to form the desired piperidine ring. Thus, cycloaddition of nitrone 59 affords predominantly the desired bridged adduct 60 along with two related... 

In a related strategy, the dihydropiperidine skeleton of the macrocyclic alkaloid cannabisativine (208) (Fig. 1.6), isolated from the leaves and roots of the common cannabis plant, was prepared with regio- and stereoselectivity using an intramolecular allylsilane-nitrone cycloaddition reaction as a key step (260). 

Cyclopentyl isoxazolidine cycloadduct 324 was prepared by intramolecular nitrone cycloaddition by Baldwin et al. (280,281,352,353) as part of studies toward a total synthesis of pretazettine (Scheme 1.69). Related adducts have been prepared elsewhere (354—356) including fluorine-substituted carbocycles (357) and the adducts prepared by lOAC by Shipman and co-workers (333,334) who demonstrated their potential as a route to aminocyclopentitols (Scheme 1.66, Section 1.11.2). Such bicyclic structures have been prepared in rather unique intermolecular fashion by Chandrasekhar and co-workers (357a) from the cycloaddition of C,N-diphenyl nitrone to fulvene (325). 

The spectral data for nitroso acetals arising from intramolecular nitronate cycloadditions mirror those of the previously presented nitroso acetals. Selected examples are collected in Tables 2.27 and 2.28, as well as in Figure 2.9 (85-87). 

The use of alkynes has been investigated in the context of intramolecular nitronate cycloadditions (130). In this case, the starting material is consumed in 24 h at room temperature, however, the corresponding isoxazoline is not isolated (Table 2.41). Instead, the intermediate cycloadduct undergoes a fragmentation which, following the loss of the nitroso moiety, leads to an a,p-unsaturated aldehyde. 

TABLE 2.41. INTRAMOLECULAR SILYL NITRONATE CYCLOADDITIONS WITH ALKYNES... 

The convergence of the nitronate and nitrile oxide cycloadditions has allowed for the direct comparisons of yields and stereoselectivities of the two processes. For intramolecular reactions, the nitronate dipole typically required longer reaction times and/or elevated temperatures (22,98,135), however, the nitronate cycloaddition shows considerably higher diastereoselectivity (Table 2.42). Interestingly, the diastereoselectivity is dependent on the placement of a substituent on the tether. In the case of the silyl nitronate derived from 172, the diastereoselectivity is controlled by the substituent at C(l), while cyclization of the analogous nitrile oxide is governed by the substituent at C(l ) (Scheme 2.10) (124). 

The intramolecular dipolar cycloaddition of nitronates has remained relatively underexplored in comparison to the intermolecular variant. In the case of acyclic nitronates, there are only a few reports of an intramolecular nitronate cycloaddition (36,176,177). However, the intermediate nitroso acetal decomposes to the isoxazo-line due to the presence of HCl in the reaction mixture (Scheme 2.19). 

The use of mediators to improve reactivity or selectivity in nitrone cycloaddition chemistry begins with the nitrone generation step. As is well known, the N-alkyla-tion of oximes provides one of the most direct and convenient synthetic routes to N-alkylated nitrones from readily available aldehydes and ketones. Electrophilic mediators have been employed to activate alkenes for N-alkylation, both in intramolecular and intermolecular reactions. They include activation of the internal alkene function by the action of (a) strong nonmetallic electrophiles such as phenyl-selenenyl sulfate (159), and (b) metallic catalysts such as Ag(I) (160) and Pd(II) ions... 

The above dramatic dependence of regio- and stereoselectivity on the nature of the metal can be explained by the reaction mechanism shown in Scheme 11.49 (167). The nitrone cycloadditions of allylic alcohols are again magnesium-specific just like the nitrile oxide reactions described in Section 11.2.2. Magnesium ions accelerate the reaction through a metal ion-bound intramolecular cycloaddition path. On the other hand, zinc ions afford no such rate acceleration, but these ions catalyze the acetalization at the benzoyl carbonyl moiety of the nitrone to provide a hemiacetal intermediate. The subsequent intramolecular regio- and stereoselective cycloaddition reaction gives the observed products. 

A classical method for controlling the stereoselectivity of intramolecular nitrone cycloadditions is to have a chiral center located on the chain between the nitrone and the alkene moiety (175-222). In a few other cases, the chirality is located outside the formed ring system (223-229). Marcus et al. (230) recently described an intramolecular 1,3-dipolar cycloadditions of the 5-aIkenyl- and 6-aIkenylnitrones 124 and 127 (Schemes 12.42 and 12.43). The chiral starting material 123 was obtained in 97% ee from an enzymatic cyanohydrin formation. Subsequent... 

NITRONES FOR INTRAMOLECULAR 1,3-DIPOLAR CYCLOADDITIONS HEXAHYDRO-l,3,3,6-TETRAMETHYL-2,1-BENZISOXAZOLINE... 

Nitrogen heterocycles continue to be valuable reagents and provide new synthetic approaches such as NITRONES FOR INTRAMOLECULAR -1,3 - DIPOLAR CYCLOADDITIONS HEXAHYDRO-1,3,3,6-TETRAMETHYL-2,l-BENZISOX AZOLINE. Substituting on a pyrrolidine can be accomplished by using NUCLEOPHILIC a - sec - AM IN O ALKYL ATION 2-(DI-PHENYLHYDROXYMETHYL)PYRROLIDINE. Arene oxides have considerable importance for cancer studies, and the example ARENE OXIDE SYNTHESIS PHENANTHRENE 9,10-OXIDE has been included. An aromatic reaction illustrates RADICAL ANION ARYLATION DIETHYL PHENYLPHOSPHONATE. 

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