Asymmetric reactions 1,3-dipoles

The carbo- and hetero-Diels-Alder reactions are excellent for the constmction of six-membered ring systems and are probably the most commonly applied cycloaddition. The 1,3-dipolar cycloaddition complements the Diels-Alder reaction in a number of ways. 1,3-Dipolar cycloadditions are more efficient for the introduction of heteroatoms and are the preferred method for the stereocontrolled constmction of five-membered heterocycles (1 ). The asymmetric reactions of 1,3-dipoles has been reviewed extensively by us in 1998 (5), and recently, Karlsson and Hogberg reviewed the progress in the area from 1997 and until now (6). Asymmetric metal-catalyzed 1,3-dipolar cycloadditions have also been separately reviewed by us (7-9). Other recent reviews on special topics in asymmetric 1,3-dipolar cycloadditions have appeared. These include reactions of nitrones (10), reactions of cyclic nitrones (11), the progress in 1996-1997 (12), 1,3-dipolar cycloadditions with chiral allyl alcohol derivatives (13) and others (14,15). 

Azomethine ylides are typical 1,3-dipoles, their participation in [3+2]cycloaddition is greatly influenced by Cu catalysts. Asymmetric reactions are realized by the addition of chiral ferrocene ligands such as 141 (called Fesulphos) and 142. ... 

Most a-thio carbanions are configmationally labile and racemize rapidly even at low temperature as shown in the preceding section. This may be the reason why the asymmetric reaction of a-lithiated thiocarbamates reported by Hoppe and coworkers does not show such high enantioselectivity [34] as attained in the reaction of similar dipole-stabilized a-oxy organolithium compounds [Eq. (4)] [2, 39]. Note that the stereochemistry of the products obtained from a-lithiated thiocarbamates is different from that obtained in the a-lithiated carbamate [Eq.(5)]. 

The 1,3-dipoles consist of elements from main groups IV, V, and VI. The parent 1,3-dipoles consist of elements from the second row and the central atom of the dipole is limited to N or O [10]. Thus, a limited number of structures can be formed by permutations of N, C, and O. If higher row elements are excluded twelve allyl anion type and six propargyl/allenyl anion type 1,3-dipoles can be obtained. However, metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions have only been explored for the five types of dipole shown in Scheme 6.2. 

No single examples have been reported so far for the catalyzed asymmetric diazoalkane cydoadditions. Based on the kinetic data on the relative reaction rates observed by Huisgen in the competitive diazomethane cydoadditions between 1-alkene and acrylic ester (Scheme 7.32), it is found that diazomethane is most nu-deophilic of all the 1,3-dipoles examined (kaciyiate/fci-aikene = 250000) [78]. Accordingly, the cydoadditions of diazoalkanes to electron-defident alkenes must be most efficient when catalyzed by a Lewis acid catalyst. The author s group has become aware of this possibility and started to study the catalyzed enantioselective diazoalkane cydoadditions of 3-(2-alkenoyl)-2-oxazolidinones. 

Since Huisgen s definition of the general concepts of 1,3-dipolar cycloaddition, this class of reaction has been used extensively in organic synthesis. Nitro compounds can participate in 1,3-dipolar cycloaddition as sources of 1,3-dipoles such as nitronates or nitroxides. Because the reaction of nitrones can be compared with that of nitronates, recent development of nitrones in organic synthesis is briefly summarized. 1,3-Dipolar cycloadditions to a double bond or a triple bond lead to five-membered heterocyclic compounds (Scheme 8.12). There are many excellent reviews on 1,3-dipolar cycloaddition, in particular, the monograph by Torssell covers this topic comprehensively. This chapter describes only recent progress in this field. Many papers have appeared after the comprehensive monograph by Torssell. Here, the natural product synthesis and asymmetric 1,3-dipolar cycloaddition are emphasized.630 Synthesis of pyrrolidine and -izidine alkaloids based on cycloaddition reactions are also discussed in this chapter. 

To control the stereochemistry of 1,3-dipolar cycloaddition reactions, chiral auxiliaries are introduced into either the dipole-part or dipolarophile. A recent monograph covers this topic extensively 70 therefore, only typical examples are presented here. Alkenes employed in asymmetric 1,3-cycloaddition can be divided into three main groups (1) chiral allylic alcohols, (2) chiral amines, and (3) chiral vinyl sulfoxides or vinylphosphine oxides.63c... 

As discussed in Section 6.2, nitro compounds are good precursors of nitrile oxides, which are important dipoles in cycloadditions. The 1,3-dipolar cycloaddition of nitrile oxides with alkenes or alkynes provides a straightforward access to 2-isoxazolines or isoxazoles, respectively. A number of ring-cleaving procedures are applicable, such that various types of compounds may be obtained from the primary adducts (Scheme 8.18). There are many reports on synthetic applications of this reaction. The methods for generation of nitrile oxides and their reactions are discussed in Section 6.2. Recent synthetic applications and asymmetric synthesis using 1,3-dipolar cycloaddition of nitrile oxides are summarized in this section. 

Pentanenitrile oxide, BuCNO, formed in situ from 1-nitropentane, PhNCO and Et3N in benzene, added stereo- and regioselectively to 8-.vv7/-(dimethoxymethyl)-3-oxo-2-oxabicyclo[3.2. l]oct-6-ene to give 75% of the tricyclic lactone 111 (276). Introduction of a methoxycarbonyl group into the plane asymmetrical double bond of 2,3-dioxa- and 2,3-oxazabicyclo[2.2.2]oct-5-enes, brought about a clear-cut increase in syn selectivity of their reactions with 1,3-dipoles (277). 

The [3+2] cycloaddition strategy provides an effective method to access valuable intermediates for the construction of biologically important alkaloids, amino acids, amino carbohydrates and P-lactams [58-62]. The reaction involves the concerted pericyclic addition of a dipole and a dipolarophile and considerable efforts have been made to render these reactions asymmetric nsing Lewis acid catalysis and chiral anxiliaries [63]. 

Chiacchio et al. (43,44) investigated the synthesis of isoxazolidinylthymines by the use of various C-functionalized chiral nitrones in order to enforce enantioselec-tion in their cycloaddition reactions with vinyl acetate (Scheme 1.3). They found, as in the work of Merino et al. (40), that asymmetric induction is at best partial with dipoles whose chiral auxiliary does not maintain a fixed geometry and so cannot completely direct the addition to the nitrone. After poor results with menthol ester-and methyl lactate-based nitrones, they were able to prepare and separate isoxazo-lidine 8a and its diastereomer 8b in near quantitative yield using the A-glycosyl... 

The use of chiral azomethine imines in asymmetric 1,3-dipolar cycloadditions with alkenes is limited. In the first example of this reaction, chiral azomethine imines were applied for the stereoselective synthesis of C-nucleosides (100-102). Recent work by Hus son and co-workers (103) showed the application of the chiral template 66 for the formation of a new enantiopure azomethine imine (Scheme 12.23). This template is very similar to the azomethine ylide precursor 52 described in Scheme 12.19. In the presence of benzaldehyde at elevated temperature, the azomethine imine 67 is formed. 1,3-Dipole 67 was subjected to reactions with a series of electron-deficient alkenes and alkynes and the reactions proceeded in several cases with very high selectivities. Most interestingly, it was also demonstrated that the azomethine imine underwent reaction with the electronically neutral 1-octene as shown in Scheme 12.23. Although a long reaction time was required, compound 68 was obtained as the only detectable regio- and diastereomer in 50% yield. This pioneering work demonstrates that there are several opportunities for the development of new highly selective reactions of azomethine imines (103). 

The 1,3-dipolar cycloadditions of 1,3-dipoles with chiral alkenes has been extensively reviewed and thus only selected examples will be highlighted here. We have chosen to divide this section on the basis of the different types of alkenes rather than on the basis of the type of 1,3-dipole. For 1,3-dipolar cycloadditions, as well as for other reactions, it is important that the chiral center intended to control the stereoselectivity of the reaction is located as close as possible to the functional group of the molecule at which the reaction takes place. Hence, alkenes bearing the chiral center vicinal to the double bond are most frequently apphed in asymmetric 1,3-dipolar cycloadditions. Examples of the application of alkenes with the chiral center localized two or more bonds apart from the alkene will also be mentioned. Application of chiral auxiliaries for alkenes is very common and will be described separately in Section 12.3. 

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