Intramolecular reaction nitrone cycloaddition

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. 

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). 

Ishikawa T, Shimizu Y, Kudoh T, Saito S (2003) Conversion of D-glucose to cychtol with hydroxymethyl substituent via intramolecular silyl nitronate cycloaddition reaction application to total synthesis of (+)-cyclophelhtol. Org Lett 5 3879-3882... 

Ishikawa, T., Shimizu, Y., Kudoh, T., Saito, S. Conversion of D-Glucose to Cyclitol with Hydroxymethyl Substituent via Intramolecular Siiyi Nitronate Cycloaddition Reaction Application to Total Synthesis of (+)-Cyclophellitol. Org. Lett. 2003, 5, 3879-3882. 

Although nitrile oxide cycloadditions have been extensively investigated, cycloadditions of silyl nitronates, synthetic equivalent of nitrile oxides in their reactions with olefins, have not received similar attention. Since we found that the initial cycloadducts, hl-silyloxyisoxazolidines, are formed with high degree of stereoselectivity and can be easily transformed into isoxazolines upon treatment with acid or TBAF, intramolecular silylnitronate-olefin cycloadditions (ISOC) have emerged as a superior alternative to their corresponding INOC reactions [43]. Furthermore, adaptability of ISOC reactions to one-pot tandem sequences involving 1,4-addition and ISOC as the key steps has recently been demonstrated [44]. 

Intramolecular [4+2] cycloaddition of E,E- or L.Z-nitrodienes gives tranr-nitronates or ci.v-nitronates, respectively, with high stereoselectivity (Eq. 8.96).153 These products have been converted into y-lactones by the Nef reaction. 

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... 

Intramolecular [3+2]-Cycloaddition ofNitronates These reactions are more efficient than analogous intermolecular transformations of nitronates as [1,3]-dipoles, and, consequently, activation of the dipolarophilic fragment is not required. However, another problem arises, that is, the construction of the starting substrate combining the nitronate fragment and the C,C double bond in the required positions. 

In intramolecular [3+ 2]-cycloaddition reactions of five-membered cyclic nitronates, only a Si-containing tether was used (393) (Scheme 3.150, see also Scheme 3.120 and references therein). 

Intramolecular [3+ 2]-cycloaddition of six-membered cyclic nitronates was extensively studied by Prof. Denmark and coworkers for the tandem [4 + 2] [3 + 2] -cycloaddition reactions of nitroalkenes. Detailed considerations of this problem were summarized in two reviews (394a, b). Most data were comprehensively discussed in Reference 394b. It is unnecessary to repeat this information however, it is worthwhile to briefly review the available data. 

At the outset, it should be noted that, as in the above-considered intramolecular [3 + 2]-cycloaddition reactions, the regioselectivity of the process is retained, that is, the terminal (or more removed) atom of the C,C double bond is always bonded to the oxygen atom of the nitronate. 

Therefore, in spite of extensive investigations, it is difficult to a priori predict the stereochemical outcome of the intramolecular [3 + 2]-cycloaddition reaction involving six-membered cyclic nitronates as well as to find optimal reaction conditions. 

In intramolecular [3+ 2]-cycloaddition reactions, silyl nitronates also lead to substantially higher stereoselectivity than intermolecular reactions (see, e.g., Scheme 3.178) (193). 

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 acyclic precursor is an oc, 3-unsaturated amido aldehyde that was condensed with iV-methylhydroxylamine to generate the nitrone ( )-48, which then underwent a spontaneous cycloaddition with the alkene to afford the 5,5-ring system of the isoxazolidinyl lactam 47. The observed product arises via the ( )-nitrone transition state A [or the (Z)-nitrone equivalent] in which the position of the benzyl group ot to the nitrone effectively controls the two adjacent stereocenters while a third stereocenter is predicted from the alkene geometry. Both transition states maintain the benzyl auxiliary in an equatorial position and thus avoid the unfavorable 1,3-diaxial interaction with the nitrone methyl or oxygen found in transition state B. Semiempirical PM3 calculations confirm the extra stability, predicting exclusive formation of the observed product 47. Related cycloadducts from the intramolecular reaction of nitrones containing ester- rather than amide-tethered alkene functionality are also known (83-85). 

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... 

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. 

Alkenyl nitrones, having the alkene connected to the nitrone nitrogen atom, have been used in another approach to intramolecular reactions (231-235). Holmes and co-workers have this method for the synthesis of the alkaloid (—)-indolizidine 209B 137 (210,231). The alkenyl nitrone 134, was obtained from the chiral hydroxylamine 133 and an aldehyde. In the intramolecular 1,3-dipolar cycloaddition, 135 was formed as the only isomer (Scheme 12.45). The diastereofacial selectivity was controlled by the favored conformation of the cyclohexane-like transition state in which the pentyl group was in a pseudoequatorial position, as indicated by 134. Further transformation of 135 led to the desired product 137. 

For intramolecular 1,3-dipolar cycloadditions, the application of nitrones and nitrile oxides is by far most common. However, in increasing frequency, cases intramolecular reactions of azomethine ylides (76,77,242-246) and azides (247-259) are being reported. The previously described intermolecular approach developed by Harwood and co-workers (76,77) has been extended to also include intramolecular reactions. The reaction of the chiral template 147 with the alkenyl aldehyde 148 led to the formation of the azomethine ylide 149, which underwent an intramolecular 1,3-dipolar cycloaddition to furnish 150 (Scheme 12.49). The reaction was found to proceed with high diastereoselectivity, as only one diaster-eomer of 150 was formed. By a reduction of 150, the proline derivative 151 was obtained. 

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