Stereoselectivity, of cycloadditions

The regio- and stereoselectivities of cycloadditions of trifluoroacetonitrile oxide, which is generated m situ by treatment of the tnfluoroacetohydroxamyl bromide etherate with tnethylamine in toluene (equation 31), have been determined in a senes of studies by Tanaka [55, 36, 37, 5 ]. The highly reactive nitnle oxide reacts regioselectively with a variety of activated terminal alkenes and alkynes (equations 32 and 33)... 

Intermolecular Cycloaddition at the C=C Double Bond Addition at the C=C double bond is the main type of 1,3-cycloaddition reactions of nitrile oxides. The topic was treated in detail in Reference 157. Several reviews appeared, which are devoted to problems of regio- and stereoselectivity of cycloaddition reactions of nitrile oxides with alkenes. Two of them deal with both inter- and intramolecular reactions (158, 159). Important information on regio-and stereochemistry of intermolecular 1,3-dipolar cycloaddition of nitrile oxides to alkenes was summarized in Reference 160. 

At the same time, cycloaddition does not occur when the tether length is increased by one more atom (110). The stereoselectivity of cycloaddition depends on both the tether length (n = 1 or 2) and the configuration of the reacting C,C double bond, which was established in several reactions (110). 

The influence of the size and configuration of various cyclic vinyl carriers (Scheme 6.26) on the stereoselectivity of cycloaddition was studied, and included epoxides, (3-lactams, dioxaborolanes, and dioxans (22). Although the anti preference was maintained in all cases, the conformation of the carrier ring must also be taken into account in order to rationalize the stereoselections observed. The highest diastereomeric ratio was observed with the vinyl-tetrahydrofuran derived from glucose, where the conformational mobility of the carrier ring is substantially locked by an acetonide clamp and one face of the C=C bond is effectively shielded (22,165,215). 

The many successful applications of nitrile oxide cycloadditions in synthesis are intimately linked with theory, both the simple FMO variety as well as the more sophisticated ab initio treatment, where the work of Sustmann and subsequently of Houk and his group has been seminal. We, the practitioners, have thus been supplied with a consistent view on the nature of 1,3-dipoles, their reactivity toward dipolarophiles, and the origin and interpretation of stereoselectivity of cycloaddition chemistry. It is of course desirable that our understanding of the relative reactivities of alkenes as well as of many 1,3-dipoles would be also improved, thereby leading to simple, extended recipes for the chemist practicing synthetics. We hope that this account will stimulate further advances in this field of cycloaddition chemistry and promote further uses of nitrile oxides in organic synthesis. 

Ground-state conformations for cycloadditions involving 5 and 6 were analyzed by energy minimization of reactant conformations using MM2 force field to explain the effect on unsaturation in the stereoselectivity of cycloaddition <1998T7045>. 

An Investigation of the Trypsin Reaction Mechanism and the Prediction of Stereoselectivity of Cycloadditions with QUEST, a Tandem QM-MM Method. ... 

Interestingly, 2-phenylmethylenecyclopropane behaves differently. In the presence of phosphane-modified Ni(0) catalysts both types of cycloaddition products (A and B) are formed 27) (Eq. 88). Moreover the regioselectivity of Pathway b changes, as considerable amounts of frans-3-phenyl-4-methoxycarbonyl-methylenecyclopentanes are formed. On the other hand, the stereoselectivity of cycloaddition Products B is much better than in the same reactions with 2-methylmethylenecyclopropane. 

Peri-, regio-, and stereoselectivity of cycloaddition reactions of substituted mesomeric betaines (106) have been studied with different alkynic and alkenic dipolarophiles. High periselectivity has been observed in cycloaddition with both series of dipolarophiles, with the dipolarophile adding exclusively across the 1,3-azomethine ylide dipole (106a). The formation of 2,2 -bipyrroles (108) could be explained by a rearrangement of initial bicyclic cycloadduct (107) <90JOC910>. All these reactions are shown in Scheme 18. 

Tanaka, K. Nagatani, S. Ohsuga, M. Mitsuhashi, K. Regio- and stereoselectivity of cycloadditions of trifluoromethylated azomethine ylide. Bull. Chem. Soc. Jpn. 1994, 67, 589. 

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. 

In many cases the stereoselectivity of cycloadditions was dependent on the steric hindrance of the nitrone. The selectivity increases as the size of C- chirar group and N-alkyl group attached to the nitrone increases. 

The effect of the addition of Lewis acid upon the stereoselectivity of cycloaddition of chiral nitrones 3a and 34 to electron-rich alkene, with ethyl vinyl ether and the further transformation of so-prepared isoxazoli-dine 36b to new fi-amino acid ester 40, has been also investigated by the same team (Fig. 10). The 1,3-dipolar cycloaddition of nitrone 3a with ethyl vinyl ether imder AlMes and Et2AlCl catalysis proceeded diastereoselectively and finished at - 8 °C over 20 h, providing only two diastereoisomers 35a and 36a in a ratio of 90 10 with erythro-cis 35a predominant, although four diastereoisomers are possible. Indeed, cycloaddition in the absence of any Lewis acids proceeded very slowly with excess of ethyl vinyl ether at room temperature over 14 days to give a mixture of all four diastereoisomers 35-38 with a considerable decrease of the stereoselectivity in a ratio of 59 12 14 15, although erythro-cis 35a was still the major adduct. The 1,3-... 

The high stereoselectivity of cycloaddition of N-(alkoxyalkyl) nitrones obtained by the use of formaldehyde and acetone prompted Vasella to identify the factors that were responsible for this high stereoselectivity. 

The main reason for the stereoselectivity of cycloaddition of nitrone of type 3 is not due to destabilization of alternative transition states due to steric interactions but due to the selective stabilization of one transition state due to the favorable stereoelectronic interactions. Hence, the conformations of N-(alkoxyalkyl) nitrone will be limited to transition states 132 and 133 (Fig. 8.38), which can be named O-endo 132) and O-exo 133), whereby the stereoselectivity of cycloaddition increases with the increase of the number of substituents on the nitrone, indicating also that the reaction proceeds preferably via O-endo conformation 132). 

Concerted Ring-Forming Reactions. The mild Lewis acid character of ZnBr sometime imparts a catalytic effect on thermally allowed pericyclic reactions. The rate and stereoselectivity of cycloaddition reactions (eq 8), including dipolar cycloadditions (eq 9), are significantly improved by the presence of this zinc salt. 

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