Silyl nitronates intramolecular cycloadditions

Intramolecular Silyl Nitronate-Olefin Cycloaddition (ISOC)... 

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]. 

One-pot tandem sequences involving 1,4-addition and ISOC as the key steps have been developed for the construction of N and 0 heterocycles as well as of carbocycles [44]. In this sequence, the nitronate arising from 1,4-addition to an a, -unsaturated nitro alkene is trapped kinetically using trimethyl silyl chloride (TMSCl). The resulting silyl nitronate underwent a facile intramolecular 1,3-dipolar cycloaddition with the unsaturated tether (e.g.. Schemes 20-22). 

The Michael addition of allyl alcohols to nitroalkenes followed by intramolecular silyl nitronate olefin cycloaddition (Section 8.2) leads to functionalized tetrahydrofurans (Eq. 4.15).20... 

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. 

The use of silylketals derived from allylic alcohols and 1-substituted nitroethanols for the stereocontrolled synthesis of 3,4,5-trisubstituted 2-isoxazolines via intramolecular 1,3-dipolar cycloaddition has been demonstrated. Here again, the use of silyl nitronates (ISOC) increases the level of selectivity compared to INOC (Eq. 8.92).145... 

This process was carried out with the use of diastereomerically and enan-tiomerically pure five-membered cyclic nitronates (213). After selective silylation of the hydroxy group and intramolecular cycloaddition, these compounds give enantiomerically pure fused systems, which are similar precursors of enantiomer-ically pure hydroxyamino acids and other polyfunctional compounds possessing potential biological activity. 

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

Intramolecular cyclizations of silyl nitronates were also used in the preparation of aminosugars. In 2003 Kudoh et al. reported the stereoselective conversion of 2-nitroalkanols by silyl nitronate generation followed by an intramolecular nitronate-olefin [3 + 2] cycloaddition reaction (Scheme 51).88... 

TABLE 2.31. STEREOSELECTIVITY IN THE INTRAMOLECULAR CYCLOADDITION OF SILYL NITRONATES... 

The intramolecular cycloaddition of a silyl nitronate bearing a dipolarophilic appendage provides easy access to fused, bicyclic isoxazolidines (22). This process, in general, is very facile, and has allowed the use of unfunctionalized alkenes as dipolarophiles (Table 2.39) (106,124). Thus, a silyl nitronate bearing an allyl group will undergo the [3 + 2] cycloaddition at room temperature over 15 h to provide the corresponding isoxazoline upon acidic workup in moderate yield. 

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). 

Less well-established cycloaddition chemistry has also found application in the synthesis of heterocyclic compounds in recent years. An example is the intramolecular cycloaddition of silyl nitronates that has been employed by Ishikawa and Saito to afford 136 in their synthesis of amino polyols (Scheme 14) <2003OL3875>. 

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