Chiral additives stoichiometric amounts

High enantioselectivities may be reached using the kinetic controlled Michael addition of achiral tin enolates, prepared in situ, to a,/i-unsaturated carbonyl compounds catalyzed by a chiral amine. The presence of trimethylsilyl trifluoromethanesulfonate as an activator is required in these reactions236. Some typical results, using stoichiometric amounts of chiral amine and various enolates are given below. In the case of the l-(melhylthio)-l-[(trimethylsilyl)thio]ethene it is proposed that metal exchange between the tin(II) trifluoromethanesulfonate and the ketene acetal occurs prior to the 1,4-addition237,395. 

On the other hand, chiral sulfur-containing but noncoordinating ligands such as sulfonamides have been widely used in the asymmetric Michael reaction. In 1997, Sewald et al. reported the use of a series of chiral sulfonamides depicted in Scheme 2.25 in the Cu-catalysed conjugate addition of ZnEt2 to 2-cyclohexenone. Even the use of a stoichiometric amount of catalyst did not allow the enantioselectivity to be higher than 31% ee. 

Mejorado investigated the asymmetric addition of various organometallic nucleophiles using method A, but the reaction could not be catalyzed. The intermediates proved to be far too reactive. However, he established that the addition of a stoichiometric amount of a preformed chiral complex [an admixture of Taddol (r/om-a, -(dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenyl methanol)) and EtMgBr] to 5 affords some enantiomeric excess in the resulting phenol product 6 (Fig. 4.12).13... 

FIGURE 4.12 Stoichiometric amounts of chiral additives afford low %ee. 

Based on these reports, we started investigation of the asymmetric addition of acetylide to pMB protected 5, mainly in the presence of chiral P-amino alcohols. Many types of chiral amines were also screened (e.g., diamines, diethers), and it was soon found that addition of P-amino alkoxides effectively induced enantiose-lectivity on the addition. Since the best result was obtained with a stoichiometric amount of chiral amino alcohols, we focused our screen on readily available chiral P-amino alcohols and the results are summarized in Table 1.2. 

Using a stoichiometric amount of (i ,i )-DIPT as the chiral auxiliary, optically active 2-isoxazolines can be obtained via asymmetric 1,3-dipolar addition of achiral allylic alcohols with nitrile oxides or nitrones bearing an electron-withdrawing group (Scheme 5-53).86a Furthermore, the catalytic 1,3-dipolar cycloaddition of nitrile oxide has been achieved by adding a small amount of 1,4-dioxane (Scheme 5-53, Eq. 3).86b The presence of ethereal compounds such as 1,4-dioxane is crucial for the reproducibly higher stereoselectivity. 

Maruoka and co-workers recently reported an example of a Zr-catalyzed cyanide addition to an aldehyde [64]. As is also illustrated in Scheme 6.20, the reaction does not proceed at all if 4 A molecular sieves are omitted from the reaction mixture. It has been proposed that the catalytic addition proceeds through a Meerwein—Ponndorf—Verley-type process (cf. the transition structure drawn) and that the crucial role of molecular sieves is related to facilitating the exchange of the product cyanohydrin oxygen with that of a reagent acetone cyanohydrin. The example shown is the only catalytic example reported to date the other reported transformations require stoichiometric amounts of the chiral ligand and Zr alkoxide. 

Copper has long played a dominant role in stoichiometric organometallic reactions in synthesis. Organocuprate mediated conjugate addition reactions are a cornerstone of carbon-carbon bond-forming reactions. Its preeminence has not been overlooked in the search for asymmetric versions of the reaction (134-136). However, the requirement for stoichiometric amounts of the metal has dampened efforts to introduce chirality into this process. 

The templates used in these reactions have a significant impact on the reaction outcome and in determining product enantioselectivity. Sibi et al. also showed that changing the oxazolidinone template as in 119 to a 3,5-dimethylpyrazole in 131 resulted in a reversal of stereochemistry using the same chiral Lewis acid (Scheme 34) [91]. Additions in the presence of stoichiometric amounts of zinc triflate and ligand 19 gave good yields and moderate selectivities of 132. These acylated pyrazoles 131 form 5-membered... 

The aldol product containing donor atoms may not readily dissociate from the chiral Lewis acid and thus compete for coordination with the substrate. This explanation is consistent with the need for stoichiometric amounts of the chiral Lewis acid to obtain high ee s. REACT IR studies provide additional support for our explanation. These results will be reported in a full account. 

The absolute stereochemistry for 150 (entries 2 and 3) was determined by hydrolysis and conversion to known compounds. Assuming a tetrahedral or cis octahedral geometry for the magnesium [110], the product stereochemistry is consistent with si face radical addition to an s-cis conformer of the substrate. This is the same sense of selectivity as that obtained with oxazo-lidinone crotonates or cinnamates suggesting that the rotamer geometry of the differentially substituted enoates is the same. The need for stoichiometric amount of the chiral Lewis acid to obtain high selectivity with 148 in contrast to successful catalytic reactions with crotonates is most likely a reflection of the additional donor atom present in the substrate. 

Sibi and Chen demonstrated for the first time that relative and absolute stereocenters of both a and fJ> carbons can be controlled in the intermolecular addition trapping experiments (Scheme 55) [149]. Magnesium and copper Lewis acids performed better than zinc. The use of 30 mol % of chiral Lewis acid gave higher selectivities than the stoichiometric amounts for both magnesium and copper. Interestingly, copper triflate gave better selectivities with... 

A number of conjugate additions delivering excellent enantioselectivities through the use of organocuprates in the presence of stoichiometric amounts of chiral (non-transferable) ligands are known today [7-9]. 

In addition, Iseki et al. reported a highly enantioselective allylation reaction with ahphatic and unconjugated aldehydes. They used chiral DMF derivatives and observed a dramatic increase in the yield and enantioselectivity of the reaction, when a stoichiometric amount of HMPA was employed [57, 58]. 

On the other hand, approaches to the use of catalytic amounts of chiral ligands have been developed. Thus, the use of a sub-stoichiometric amount (50 mol%) of DBNE (1) affords A,A-diphenylphosphinylamine with 85% in 69% yield121a. Similarly, 25 mol% of chiral aziridinyl alcohol 56 (R = - ) affords (V,(V-diphenylphosphinylamine with 65% in 60% yield123. In the enantioselective addition reaction of diethylzinc to a nitrone, 20 mol% of the metal alkoxide of diisopropyl tartrate 62 catalyzed the formation of a... 

An alternative approach is the modification of heterogeneous catalysts by the addition of naturally occuring chiral molecules. The first example (H2) by Lipkin [17] might not be a real modified Pt catalyst because a stoichiometric amount of hydrocinchonine as salt of P-methyl-cinnamic acid was used. Nakamura [18] and later Isoda [22] and Izumi [4] chose chiral acids to... 

A number of techniques are now available allowing the preparation of enantiomerically pure (or at least enriched) compounds via asymmetric nucleophilic addition to electron-deficient alkenes. Some of these transformations have already been successfully applied in total synthesis. In most cases, the methods are based on diastereoselective reactions, employing chirally modified substrates or nucleophiles. There are only very few useful enantioselective procedures accessible so far. The search for efficient en-antioselective methods, especially for those which are catalytic and do not require the use of stoichiometric amounts of chiral auxiliaries, remains a challenging task for the future. 

Compared with asymmetric ethylation, reports on asymmetric phenylation are limited. We disclosed the enantioselective phenylation using diphenylzinc prepared in situ from phenyl Grignard reagent and zinc chloride. This method needs a stoichiometric amount of chiral amino alcohol DBNE 18 but good ee of 82% was achieved [32], A catalytic phenylation was examined using planar chiral compound 1 based on ferrocene, and chiral diaryl carbinols of moderate ee were provided from diphenylzinc and 4-chlorobenzaldehyde (Scheme 10) [33]. A catalytic and highly enantioselective phenylation was realized by binaphthyl-based chiral catalyst 23. In this reaction, the addition of 2 equivalents of diethyl-zinc against catalyst increases the yield and ee [34]. Recently, chiral amino alcohol DPMPM 9 was also reported to be an efficient catalyst for asymmetric phenylation [35]. 

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