Nitronates facial selectivity

It should be mentioned that the stereoselectivity of cycloaddition of chiral sugar-derived nitrone to an alkene is difficult to predict, and would appear to be dependent on minor structural changes in either component. Three structural features can influence the stereochemical outcome of nitrone/alkene cycloadditions /Z nitrone isomerization about the C = Nbond, alkene or/and nitrone facial selectivity, and endolexo preferences [6j. 

Nitronate Facial Selectivity in Intermolecular [3+2] Cycloadditions of Nitronates The majority of asymmetric dipolar cycloadditions of nitronates have been investigated in the context of the tandem [4 + 2]/[3 + 2] cycloadditions of nitroalkenes. With chiral, cyclic nitronates, the facial selectivity is primarily controlled by the steric environment that defines the diastereotopic faces of the nitronate. Nitronates obtained from [4 + 2] cycloadditions with vinyl ethers contain an acetal stereocenter that controls the approach of the dipolarophile. Nitronate 103 (Scheme 16.26) reacts with dimethyl maleate to produce predominantly nitroso acetal distal- QA through a distal approach of the dipolarophile [23]. The proximal approach provided the minor isomer with dr 7/l. Calculations suggest that the distal approach of the dipolarophile that leads directly to a chair-Uke conformation of the six-membered ring is slightly favored over the proximal approach [121]. 

Cycloaddition of a-aryl-A-phenylnitrones to the C16-C17 n-bond in 16-dehydropregnenolone-3P-acetate (545) involves only the minor rotamer (A-form) of the nitrones. It proceeds regio-, stereo- and Jt-facial-selectively to give steroido[16,17-d]isoxazolidines (546) in high yield (Scheme 2.257), (Table 2.24) (760). Similarly the cycloaddition of a,N -diphenylnitrones proceeds with five-membered heterocyclic enones (761). 

Cyclo-reversions proceed readily in reactions of enantiopure D7i and D7i ent with cyclic (551) and acyclic (585) nitrones. The sulfinyl group in lactones D7i and D7i ent controls the Jt-facial selectivity and is also controller of the endo/exo selectivity (Scheme 2.274) (788). 

This chapter is divided into four major sections. The first (Section 2.1) will deal with the structure of both alkoxy and silyl nitronates. Specifically, this section will include physical, structural, and spectroscopic properties of nitronates. The next section (Section 2.2) describes the mechanistic aspects of the dipolar cycloaddition including both experimental and theoretical investigations. Also discussed in this section are the regio- and stereochemical features of the process. Finally, the remaining sections will cover the preparation, reaction, and subsequent functionalization of silyl nitronates (Section 2.3) and alkyl nitronates (Section 2.4), respectively. This will include discussion of facial selectivity in the case of chiral nitronates and the application of this process to combinatorial and natural product synthesis. 

This section shall consider the effects of substitution on both the nitronate as well as the dipolarophile, as they relate to both the inter- and intramolecular versions of the dipolar cycloaddition. Also included will be a discussion of facial selectivity in the reaction of a chiral dipolarophile. 

Only a few attempts to control the facial selectivity of this [3+2] process are on record, all dealing with the use of chiral, non-racemic dipolarophiles (117). The reactions of a vinyl substituted cephem (121) with the silyl nitronates derived from nitromethane, nitroethane, and nitropropane proceed over 3 days at room temperature to provide a single stereoisomer in moderate yields, Eq. 2.8 (118,119). Approach of the simple nitronate to the dipolarophile is believed to be from the less hindered a-face, however, the configuration of the newly created stereocenter could not be unambiguously assigned. 

In a second report on the use of chiral dipolarophiles, the cycloadditions of silyl nitronates with 123 and 124 provide modest facial selectivity (Table 2.37) (35). Unfortunately, the yields of the cycloadducts are only moderate because of the steric bulk of the dipolarophile. 

A second strategy to control facial selectivity involves the use of chiral sultams and lactams as auxiliaries for the dipolarophile (120-123). Cycloaddition of 132 with a variety of substituted nitronates provides up to 9 1 selectivity of the major diastereomer (Table 2.38). However, substitution at the a-position of the dipolarophile leads to a reduction in stereoselectivity (entry 5). Assuming an s-cis conformation of the dipolarophile, it is proposed that the major isomer arises from an endo approach of the nitronate to the Re face of the dipolarophile (Fig. 2.13). This is supported by X-ray crystallographic analysis of one of the cycloadducts, which resides in a conformation similar to the proposed transition state. However, this analysis assumes that the silyl nitronate is only reacting through the... 

E) configuration. The dipolar cycloaddition of 141 with a silyl nitronate shows a slight increase of facial selectivity over 132 (Eq. 2.9). Because the cycloadducts are converted directly to the corresponding isoxazolines, only the facial selectivity can be determined. It is believed that the cycloaddition proceeds on the Re face of the dipolarophile due to shielding of the Si face by the auxihary. Both chiral auxiliaries can be liberated from the cycloadduct upon reduction with L-Selectride. 

The number of investigations on the enantioselective dipolar cycloaddition of nitronates is still rather limited. In the case of simple alkyl nitronates, the facial selectivity is controlled solely by the steric environment about the two faces of the chiral unit. For example, the reaction of steroid dipolarophile 270 proceeds with the nitronate approaching the Re face of the alkene (Eq. 2.23) (234). The facial selectivity is controlled by the C(19) methyl group, which blocks the Si face of the dipolarophile. Similarly, exposure of 279 to ethyl acrylate at 40 °C for 24 h, provides a single nitroso acetal (Scheme 2.21) (242). The facial selectivity is presumed to arise from steric shielding by the menthol group, however the full stereostructure has not been established. 

Similar facial selectivity has been observed in nitronates derived from chiral vinyl ethers (69), as well as from nitronates prepared with a chiral Lewis acid, which lack any bias from a chiral auxiliary (66). Even in the absence of a substituent at C(4), as in the nitronate 287, there remains a high facial selectivity upon the addition of a dipolarophile (Eq. 2.28) (84). Both RHE and B3LYP calculations for the approach of a dipolarophile to the nitronates 289 and 290 show at least a... 

Figure 2.14. Computaional examination of the facial selectivity of nitronates.

In both bridged cases, chiral vinyl ethers have been utilized to prepare diastereomerically enriched nitronates (86,253). Since only a single atom tether has been investigated for two bridged modes, the facial selectivity of the dipolar cycloaddition is completely controlled by the configuration of the nitronate at the point of attachment. 

Since the dipolarophile is not predisposed toward one face of the dipole at the point of attachment, the facial selectivity is governed by the configuration of the acetal center on the starting nitronate. As with the intermolecular case (Section 2.4.3.2), the preferred approach of the dipolarophile is distal to the acetal substituent. Lower facial selectivity is observed in the case of a four-atom tether, presumably due to the additional heating involved in driving the reaction to completion. 

The dipolar cycloaddition of nitronates has been applied to the synthesis of several natural products in the context of the tandem [4+2] / [3 + 2] nitroalkene cycloaddition process. All of these syntheses have focused on the construction of pyrrolidine, pyrrolizidine, and indolizidine alkaloids. For example, the synthesis of ( )-hastanecine (316), a necine alkaloid, involves the elaboration of a p-benzoy-loxynitroalkene 311 via [4 + 2] cycloaddition with a chiral vinyl ether (312) in the presence of a titanium based Lewis acid, to provide the nitronate 313 with high diastereo- and facial selectivity (Scheme 2.30) (69). The dipolar cycloaddition of... 

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