Simple diastereoselectivity groups

With prostereogenic carbonyl components, the problem of simple diastereoselectivity arises, which is unsatisfactorily solved at present21. Both the intermediate alkoxides rearrange by migration of the carbonyl group at a different rate21 22, which might be used for the enrichment of one diastereomer. 

On the basis of this analysis, it may be anticipated that the extent of aldehyde diastereofa-cial selectivity will depend on the difference in size of the R3 aldehyde substituent relative to that of the methyl group. The examples summarized in Table 2 are generally supportive of this thesis, particularly the reactions of (F)-2-butenylboronntc. The data cited for reactions of 3-methoxymethoxy-2-methylbutanal with (Z)-2-butenylboronate and 2-propenylboronate, however, also show that diastereoselectivity depends on the stereochemistry at C-3 of the chiral aldehydes. These data imply that simple diastereoselectivity depends not simply on reduced mass considerations, but rather on the stereochemistry and conformation of the R3 substituent in the family of potentially competing transition states21,60. The dependence of aldehyde diastcrcofacial selectivity on the stereochemistry of remote positions of chiral aldehydes has also been documented for reactions involving the ( )-2-butenylchromium reagent62. 

Surprisingly, sense and degree of simple diastereoselectivity are not influenced by methyl groups in the and y-position of these chromium reagents13. 

The exchange of tert-butyl for a smaller group, e.g., alkyl or 4-methylpheny], causes a decrease in the induced diastereoselectivity70. If a prostereogenic aldehyde is used, in addition. the problem of simple diastereoselectivity arises and four diastereomeric products are... 

If the substituents are nonpolar, such as an alkyl or aryl group, the control is exerted mainly by steric effects. In particular, for a-substituted aldehydes, the Felkin TS model can be taken as the starting point for analysis, in combination with the cyclic TS. (See Section 2.4.1.3, Part A to review the Felkin model.) The analysis and prediction of the direction of the preferred reaction depends on the same principles as for simple diastereoselectivity and are done by consideration of the attractive and repulsive interactions in the presumed TS. In the Felkin model for nucleophilic addition to carbonyl centers the larger a-substituent is aligned anti to the approaching enolate and yields the 3,4-syn product. If reaction occurs by an alternative approach, the stereochemistry is reversed, and this is called an anti-Felkin approach. 

The distinction between simple and induced diastereoselectivity is not affected, and the concepts are useful. However, characterization of simple diastereoselectivity by stating ratios of groups of diastereomers can be troublesome. 

The general problem of simple diastereoselection (see Section A. 1.), as outlined below refers to the combination of two enantiofaces, which is possible in 4 different orientations (1, 3, 5 and 7). 1/7 and 3/5 are enantiomorphous and lead to enantiomeric pairs (2/8 and 4/6, respectively). In reactions with closed transition states , this means that the two olefins are in a syn orientation. Generally, this orientation is enforced by the transfer of a metal cation or a proton from D to A [ene-type reaction]8. D is a donor and A an acceptor group. 

Simple diastereoselectivity may also occur in Diels-Alder reactions between electron-poor dienophiles and cyclopentadiene (Figure 15.30). Acrylic acid esters or fraus-crotonic acid esters react with cyclopentadiene in the presence or absence of A1C13 with substantial selectivity to afford the so-called emfo-adducts. When the bicyclic skeleton of the main product is viewed as a roof the prefix endo indicates that the ester group is below this roof, rather than outside (exo). However, methacrylic acid esters add to cyclopentadiene without any exo.endo-selectivity regardless whether the reaction is carried out with or without added A1C13 (Figure 15.30, bottom). 

The high simple diastereoselectivities seen in Figures 15.29 and 15.30 are due to the same preferred orientation of the ester group in the transition states. The stereostructure of the cycloadduct shows unequivocally that the ester group points underneath the diene plane in each of the transition states of both cycloadditions and not away from that plane. Figure 15.31 exemplifies this situation for two transition states of simple Diels-Alder reactions of 1,3-butadiene A shows a perspective drawing of the transition state of the acrylic acid ester addition, and B provides a side view of the addition of ethene, which will serve as an aid in the following discussion. Both structures were determined by computational chemistry. 

The formation of trans-products is observed to a lesser extent in the reaction of 3-alkoxycarbonyl-substituted cyclohexenones, in the reaction with electron-deficient alkenes and in the reaction with olefinic reaction partners, such as alkynes and allenes, in which the four-membered ring is highly strained (Scheme 6.11). The ester 26 reacted with cyclopentene upon irradiation in toluene to only two diastereomeric products 27 [36]. The exo-product 27a (cis-anti-cis) prevailed over the endo-product 27b (cis-syn-cis) the formation of trans-products was not observed. The well-known [2 + 2]-photocycloaddition of cyclohexenone (24) to acrylonitrile was recently reinvestigated in connection with a comprehensive study [37]. The product distribution, with the two major products 28a and 28b being isolated in 90% purity, nicely illustrates the preferential formation of HH (head-to-head) cyclobutanes with electron-acceptor substituted olefins. The low simple diastereoselectivity can be interpreted by the fact that the cyano group is relatively small and does not exhibit a significant preference for being positioned in an exo-fashion. 

Simple diastereoselectivities are observed in the reaction of cyclo-alkenones with cyclic alkenes, e.g., cyclopentene, wherein the transoid tricycle is formed preferentially. Whereas cyclopent-2-enone (7) affords 36 selectively, the more flexible cyclohex-2-enone (8) gives a 3 1 mixture of diastereoisomers 37 and 38 [7,61]. A stereogenic center in the cycloalkenone also has a strong impact on the product ratio as shown for the reactions of 4-alkylcyclohex-2-enones 39 and 40 with acyclic alkenes wherein the major diastereoisomer formed is the one in which the enone-alkyl group is trans to the new ring forming C-C bonds, i.e., 41t and 42t, respectively (Sch. 12) [62,63]. Cycloadducts 42 have been further converted to the pheromone periplanone-B. 

Allylic azides, e.g., 1, were produced by treatment of the triisopropylsilyl enol ethers of cyclic ketones with azidotrimethylsilane and iodosobenzene78, but by lowering the temperature and in the presence of the stable radical 2,2,6,6-tetramethylpiperidine-/V-oxyl (TEMPO), 1-triso-propylsilyloxy-l,2-diazides, e.g., 2, became the predominant product79. The radical mechanism of the reaction was demonstrated. A number of 1,2-diazides (Table 4) were produced in the determined optimum conditions (Method B 16h). The simple diastereoselectivity (trans addition) was complete only with the enol ethers of unsubstituted cycloalkanones or 4-tert-butylcy-clohexanone. This 1,2-bis-azidonation procedure has not been exploited to prepare a-azide ketones, which should be available by simple hydrolysis of the adducts. Instead, the cis-l-triiso-propylsilyloxy-1,2-diazides were applied to the preparation of cw-2-azido tertiary cyclohexanols by selective substitution of the C-l azide group by nucleophiles in the presence of Lewis acids. 

A remarkable feature of the Evans process is its ability to mediate enantio-, chemo-, and diastereo-selective additions to 1,2-diketones (Eq. (8.18)). The Cu(II) and Sn(Il) bisoxazoline complexes display superb group selectivity, differentiating between ethyl and methyl groups in the addition of thiopropionate-derived Z-silyl ketene acetal to 84. As discussed above, the Cu(II) and Sn(ll) catalysts elicit complementary simple diastereoselectivity with the Cu(II) catalyst leading to the for-... 

The catalyzed cycloaddition of alkoxy or amino aldehydes has been the subject of extensive studies. The influence of different Lewis acids and protective groups on the diastereoselectivity has been investigated for various types of aldehydes and dienes. Induced and simple diastereoselectivities (endoiexo) in the [4 + 2] cycloaddition of aldehydes 1 are highly dependent on the Lewis acid applied as catalyst. Several reactions ofa-alkoxyaldehydes 1 to dienes 2 under Lewis acid catalysis have been performed to give adducts 3 and 435. Among the catalysts tested (see table below) the best results were achieved for the magnesium bromide catalyzed cycloaddition of 1 to several dienes. Adduct 3 was obtained as a single compound. 

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