Dipolarophiles facial selectivity

There have been two main approaches to the development of dipolarophile facial selectivity (1) the use of chiral substrates, templates, and auxiharies and (2) the use of chiral rhodium catalysts [35]. In one of the earhest examples of chiral substrate selectivity, Pirmng and Lee reported a selective hydroxy-directed cycloaddition with chiral hydroxy-substituted vinyl ethers [95]. This effort was followed by a number of chiral template approaches to diastereocontrol, including the use of (R)- or (S)-phenylglycinol to form a cycHc phenyloxazinone for the facially selective cycloaddition of isomtinchnones [96, 97]. Padwa and Prein demonstrated acycHc diastereofacial control in the cycloaddi-... 

In the reaction of fused aziridines with alkene dipolarophiles, the opportunity for stereoselectivity as well as facial selectivity arises since exo- or entfo-isomers can be formed (Scheme 10). In practice, maleic anhydride 6, A-methyl maleimide and JV-phenyl maleimide each reacted exo-stereoselectively with TV-benzyl aziridine 69 to form adducts of type 71 (Scheme 10b), the stereochemistries of which were confirmed by NOE measurement between Hb and He. Similar reaction of the Y-phenyl aziridine 67 with N-Ph maleimide gave a 1 1 mixture of endo-adduct 72 and exo-adduct 73 (Scheme 10c). Adducts 68, 71-73 all exhibited a low-field methano-bridge proton (Ha) in the range 5 3.06-3.60 confirming the syn-facial stereochemistry of the two bridges. 

Norbomene-type dipolarophiles offered yet another stereochemical consideration owing to the facial selectivity posed by the dipolarophile. While no examples of endo-face attack on... 

The reactions of some SENAs with chiral dipolarophiles (284a,b) were also described (411) (Scheme 3.177, Eq. 2). It should be noted that the yields of the target cycloadducts were not always high due to steric hindrance in vicinally substituted dipolarophiles. Also the facial selectivity is rather moderate. 

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... 

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. 

Koizumi and co-workers (38) reported the first asymmetric synthesis of (15)-(—)-a-tropanol (149) via a 1,3-dipolar cycloaddition protocol. Treatment of the chiral dipolarophile 150 with 151 in tetrahydrofuron (THF) delivered cycloadducts exo-152 and endo-153. Although the reaction proceeded with low facial selectivity,... 

In synthetic efforts toward the DNA reactive alkaloid naphthyridinomycin (164), Gamer and Ho (41) reported a series of studies into the constmction of the diazobicyclo[3.2.1]octane section. Constmction of the five-membered ring, by the photolytic conversion of an aziridine to an azomethine ylide and subsequent alkene 1,3-dipolar cycloaddition, was deemed the best synthetic tactic. Initial studies with menthol- and isonorborneol- tethered chiral dipolarophiles gave no facial selectivity in the adducts formed (42). However, utilizing Oppolzer s sultam as the chiral controlling unit led to a dramatic improvement. Treatment of ylide precursor 165 with the chiral dipolarophile 166 under photochemical conditions led to formation of the desired cycloadducts (Scheme 3.47). The reaction proceeded with an exo/endo ratio of only 2.4 1 however, the facial selectivity was good at >25 1 in favor of the desired re products. The products derived from si attack of the ylide... 

The only concern is die cis stereochemistry of die cycloadduct O. If die planar azomethine ylide adopts the least sterically hindered W geometry, then the cis isomer will be produced as a pair of enantiomers. The use of d.v-stilbenc as the dipolarophile to obtain die all-cis geometry in one step would require that only die endo transition state produces product. Although endo transitions are favored in 1,3 dipolar cycloadditions, mixtures of diastereomers from the exo and endo transition states are usually formed. Catalytic hydrogenation has a higher facial selectivity and is much more likely to give a single diastereomer. 

The stereochemical course of these reactions was also explained by assuming an exo approach of dipole to the vinyl sulfoxide in s-trans conformation, which in this case would be the less destabilized by electrostatic repulsions (Scheme 95). A similar stereochemical course would explain the results obtained in the reactions of nitrone 194 with (Z)-vinyl sulfoxides 13 (Scheme 96) [159a]. With these dipolarophiles, the exo selectivity is complete, and the 7r-facial selectivity is very high (de 82-98 %) and depends on the size of the R group, which must be responsible for the shifting the conformational equilibrium around the C-S bond toward the s-trans rotamer. The major adduct exo(t)-202 (R = Me) was transformed into the enantiomerically pure piperidine alkaloid (-l-)-sedridine. 

The 7r-facial selectivity of cycloadditions between (Z)-13 and the five-mem-bered cyclic nitrone 194 was slightly lower (de 64%). The pyrrolidine natural compound (-)-hygroline was obtained from the major adduct, exo(t)-202 [159b]. Both exo and rr-facial selectivities decreased in reactions with vinyl sulfoxides of (E)-configuration. The stereochemical results obtained from (Z)-13 were explained by assuming the exo approach of the dipole to the less hindered face of the dipolarophile 13 which adopts conformation A depicted in Scheme 96, with the lone electron pair at sulfur in an s-cis arrangement. This explana-... 

The stereochemical outcome of these reactions may be understood on the basis of the predominant exo sulfinyl approach of the ylid (endo with respect to the Ar group) toward the less hindered face of the sulfinimine, in s-cis conformation. The conformational preferences of the sulfinylimines, which would be responsible for the 7r-facial selectivity, can be easily rationalized considering the electrostatic repulsion between the lone electron pair at nitrogen and the sulfinyl oxygen, which suggests a great potential interest of these substrates as heterodienophiles and dipolarophiles. 

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