Chelation stereocontroL

Examples were given above of stereocontrol due to substrate bias of a steric nature. Substrate bias can also result from coordinative or chelate effects. Some instances of coordinative (or chelate) substrate bias are shown retrosynthetically in Chart 18. 

Ketone 13 possesses the requisite structural features for an a-chelation-controlled carbonyl addition reaction.9-11 Treatment of 13 with 3-methyl-3-butenylmagnesium bromide leads, through the intermediacy of a five-membered chelate, to the formation of intermediate 12 together with a small amount of the C-12 epimer. The degree of stereoselectivity (ca. 50 1 in favor of the desired compound 12) exhibited in this substrate-stereocontrolled addition reaction is exceptional. It is instructive to note that sequential treatment of lactone 14 with 3-methyl-3-butenylmagnesium bromide and tert-butyldimethylsilyl chloride, followed by exposure of the resultant ketone to methylmagnesium bromide, produces the C-12 epimer of intermediate 12 with the same 50 1 stereoselectivity. 

The completion of the synthesis of the polyol glycoside subunit 7 requires construction of the fully substituted stereocenter at C-10 and a stereocontrolled dihydroxylation of the C3-C4 geminally-disub-stituted olefin (see Scheme 10). The action of methyllithium on Af-methoxy-Af-methylamide 50) furnishes a methyl ketone which is subsequently converted into intermediate 10 through oxidative removal of the /j-methoxybenzyl protecting group with DDQ. Intermediate 10 is produced in an overall yield of 83 % from 50) , and is a suitable substrate for an a-chelation-controlled carbonyl addition reaction.18 When intermediate 10 is exposed to three equivalents of... 

Reaction of the bis-chelate complex 149 and various bis(arylalkyl)barium complexes generates heteroleptic barium complexes with one chelate and one reactive arylalkyl ligand 164. The homoleptic and heteroleptic barium complexes both induce living polymerization of styrene to atactic polystyrene in cyclohexane solution. The fact that no stereocontrol is observed during polymerization despite the presence of the chiral carbanionic ligands is... 

Until now, only two families of ligands have been realized where both P groups are attached to side chains, probably because the resulting metal complexes have relatively large chelate rings which usually are not suitable for enantioselective catalysis. A cursory inspection of the ligands depicted in Fig. 25.14 shows that, due to steric bulk of the ferrocene backbone, both diphosphines probably have sufficiently restricted flexibility so that good stereocontrol is still possible. 

Indolizidine alkaloids. The key step in a new stereocontrolled synthesis of these alkaloids, such as castanospermine (5), depends upon the diastereoselective reaction of an azagluco aldehyde with allylmetal reagents catalyzed by Lewis acids (12, 21-22). Thus reaction of allyltrimethylsilane with the aldehyde 1 and TiCL, (excess) in CH2C12 at - 85° results in the product 2, formed by selective chelation of the ot-amino aldehydo group with TiCl4. The product can be converted into 5... 

The presence of the two spirotetrahydrofuran rings in these reactive intermediates is obviously not condudve to the stereocontrolled synthesis of 14. This problem was resolved by making recourse to 22, a precursor to 15, the silyl-protected (3-hydroxypropyl) substituent which was viewed to be sufficiently bulky to guarantee its equatorial occupancy in the lowest energy conformation (Scheme 3-4). Furthermore, treatment of 22 with Grignard reagent should be met with rapid deprotonation of the hydroxyl and formation of chelate 23. At this point, customary equatorial... 

The intramolecular chelation between the ether oxygen and the zinc atom shown in equation 34 can be utilized to create stereocontrol as demonstrated in equation 3 545. 

The addition of acetate-derived, achiral lithium enolates to monoprotected a-amino aldehydes is controlled by chelation, and leads to a modest stereochemical preference in favor of the 3,4-syn configuration (Table 1, entry a). 18 The formation of the 3, A-syn-product is enhanced by the use of acetate-derived silyl ketene acetals and the addition of titanium(IV) chloride or tin(IV) chloride to the reaction mixture (Table 1, entries b and c). 22-23 The same enolates add stereoselectively to A2 A-dibenzyl a-amino aldehydes but with diastereomeric ratios in favor of the Felkin-Ahn 3,4-anti-product (Table 1, compare entries a and d, and b and f). 22-24 Reverse stereocontrol is observed in the presence of a Lewis acid such as tita-nium(IV) chloride, but the yield is low (Table 1, entry e). 24 ... 

Starling with the N-acyl derivative, sodium hexamethyldisilazide selectively forms the Z-enulate 38 (amides usually form Z-eno-lates). Chelate formation between sodium and the two oxygen atoms requires a conformation for 38 in which the isopropyl group shields the bottom of the molecule, so attack by the nucleophile oc curs from above. This method generally provides outstanding selectivity. The Fmns auxiliary has also been used successfully to achieve stereocontrol in aldol15 and Diels-Atder reactions.16... 

A systematic study of methyl ketone aldol additions with a-alkoxy and o ,/5-bisalkoxy aldehydes has been undertaken, under non-chelating conditions.130 With a single a-alkoxy stereocentre, diastereoselectivity generally follows Cornforth/polar Felkin-Anh models. With an additional /5-alkoxy stereocentre, 7r-facial selectivity is dramatically dependent on the relative configuration at a- and /3-centres if they are anti, high de results, but not if they are syn. A model for such acyclic stereocontrol is proposed in which the /5-alkoxy substituent determines the position in space of the a-alkoxy relative to the carbonyl, thus determining the n-facial selectivity. 

A highly Z-selective olefination of a-oxy and a-amino ketones via ynolate anions has been reported (Scheme 9).43 The stereocontrol mechanism has been explained by (g) orbital interactions between the s orbital of the breaking C-O bond or n orbital of the enolate and the s orbital of the C-O or C-N bonds of the substituent in the ring opening of the /I-lactone enolate intermediates, and/or the chelation to lithium. 

Asymmetric aldol reactions5 (11, 379-380). The lithium enolate of the N-propionyloxazolidinone (1) derived from L-valine reacts with aldehydes with low syn vs. anti-selectivity, but with fair diastereofacial selectivity attributable to chelation. Transmetallation of the lithium enolate with ClTi(0-i-Pr)3 (excess) provides a titanium enolate, which reacts with aldehydes to form mainly the syn-aldol resulting from chelation, the diastereomer of the aldol obtained from reactions of the boron enolate (11, 379-380). The reversal of stereocontrol is a result of chelation in the titanium reaction, which is not possible with boron enolates. This difference is of practical value, since it can result in products of different configuration from the same chiral auxiliary. 

Bu3SnLi reacts quite efficiently with (Z)-a,f3-unsaturated esters to provide compounds that arise from the attack on the Si face. On the other hand, stannylzincates add to (Z)-a,/3-unsaturated esters with complete stereocontrol in favor of the Re adducts.281 The differences can be explained by the ability to form chelates with the counter metal species (Equation (112)). 

The applications described below outline the effectiveness of cyclic chiral sulfoxides as stereocontrol elements, and highlight the ready removal of the sulfoxide group after its contribution to the synthetic scheme. In all cases, the sense of stereochemical induction can be rationalized and predicted on the basis of steric, stereoelectronic, and/or chelation control factors. 

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