Felkin product

The reactions with (25,35,45,55)-5-(tm-butyldimethylsilyloxy)-3-(4-methoxyphenylmethoxy)-2,4-dimethylheptanal (15) are particularly informative reagent (5)-3 is incapable of overriding the intrinsic diastereofacial preference of 15, and the normal Felkin product 17 is obtained with >95% selectivity. In contrast, reagent-controlled mismatched double diastereoselectivity is evident in the reaction with (5)-4 that provides 16 as the major component of a 73 22 5 mixture. The minor product 18 apparently derives from a reaction with the contaminating (/ )-4, since (5)-4 that was used is not enantiomerically pure. 

With conditions that allow for the diastereoselective addition of y-substi-tuted vinylogous ketene acetals various aldehydes were tested. Compounds 66 and 68 exhibited very good syn (4/5) and Felkin (5/6) selectivity even though the chiral center at C3 would disfavor the Felkin product (Scheme 28). 

Hydrogen bonding and steric effects have been investigated in a theoretical study of the origin of the diastereoselectivity in the remote 1,5-stereoinduction of boron aldol (g) reactions of /3-alkoxy methyl ketones 125 high levels of 1,5-anti-stereocontrol have been achieved in such reactions of tf-methyl-a-alkoxy methyl ketones, giving both Felkin and anti-Felkin products.126 (g)... 

The second total synthesis of swinholide A was completed by the Nicolaou group [51] and featured a titanium-mediated syn aldol reaction, followed by Tishchenko reduction, to control the C21-C24 stereocenters (Scheme 9-30). The small bias for anri-Felkin addition of the (Z)-titanium enolate derived from ketone 89 to aldehyde 90 presumably arises from the preference for (Z)-enolates to afford anti-Felkin products upon addition to a-chiral aldehydes [52], i.e. substrate control from the aldehyde component. 

An anti aldol reaction with Felkin control was now needed to couple the two spiroacetal fragments and generate the correct stereochemistry at C15 and C f, of the spongistatins. A study of the individual fragments indicated that while the enolate showed little facial selectivity, the aldehyde component had a considerable bias for the desired Felkin product. Best results were obtained with the lithium-mediated aldol coupling, which gave adduct 104 in good yield and acceptable selectivity [56 c]. 

Felkin product (69% ds, 2-anti). A (Z)-titanium enolate usually favours the anti-Felkin adduct, and the subsequent Oppolzer synthesis of denticulatins A (see Scheme 9-69) highlights this behaviour (see also Scheme 9-30) however, exceptions can be found (Scheme 9-45). Oxidation of the C3 and Cn hydroxyls of 258, and cyclization, under carefully controlled conditions to preserve the configuration of the Cio stereocenter, then allowed the selective synthesis of denticulatin B. 

The 4,5-anti diastereomer (formally the Felkin product) predominates when the aldehyde a-heteroatom substituent is larger than the aldehyde R group with both the ( )- and (Z)-crotylmetal reagents (see aldehydes 55b and 55c, Tables 11 -3 and 11-4). However, when the R substituent is larger than the heteroatom, X, as is the case with aldehyde 55e, the ( )-crotylboronate reagent strongly favors formation of the 4,5-syn adduct 57e, formally the anti-Felkin product (Table 11-3). 

The stereoselectivity of the antibody-catalyzed addition of acetone to aldehyde 67 revealed that the ketone was added to the re-face of 67 regardless of the stereochemistry at C2 of this substrate. The aldol process follows a classical Cram-Felkin mode of attack on (S)-67 to generate the (4S,5S)-68 diastereomer and the anti-Cram-Felkin mode of attack on the (R)-67 to yield the (4S,5R)-69 diastereomer. The products are formed at a similar rate and yield, therefore there is no concomitant kinetic resolution of the racemic aldehyde. The two antibodies differ in their diastereofacial selectivity, reflecting the ability of the antibodies to orient the 67 on opposite sides of the prochiral faces of the nucleophilic antibody-enamine complex of acetone. Heath cock and Flippin [79] have shown that the chemical reaction of the lithium enolate of acetone with (S)-67 yields the (4S,5S)-68 diastereomer a 5% de for this Cram-Felkin product. The generation of the (4S,5R)-69 and (4R,5R)-70 products in a ratio of 11 1 by the... 

In order to reverse the diastereoselectivity in the aldol reaction, the Lewis acid-catalyzed silyl enol ether addition (73) (Mukaiyama aldol reaction) was examined. Since the Mukaiyama aldol reaction is assumed to be proceeded via an acyclic transition state, a chelation controled aldol reaction of the a-alkoxy aldehyde should be possible (74). In the presence of TiCU, the silyl enol ether derived from 14 was reacted with aldehyde 13, followed by desilylation to afford the desired anti-Felkin product 122a as a single adduct (Scheme 21). Based on precedents for chelation-controlled Mukaiyama aldol reaction (74), the exceptional high selectivity in this reaction would be accounted for by chelation of TiCl4 with the C23-methoxy group of the aldehyde 13 (eq. 13). On the other hand, when the lithium enolate derived from 14 was treated with the aldehyde 13, followed by desilylation, it gave a 1 4 ratio of the two epimers in favour of the undesired (22S)-aldol product... 

The major isomer was the Cram/Felkin product 32 with the 6(R),7(S),8(R)-configuration which clearly indicated that in the (S),(R)-combination of chirality both effects work in the same direction and produce a matching case with very high selectivity. The same holds for the use of the (R)-enolate system as shown in Scheme 7.11 [26]. 

In contrast, a-chiral aldehydes of type 7 show the opposite behavior, favoring the anti-Cram/Felkin product as the major isomer. In these cases, the matched case is the ( S),( S)- or (R),(R)-combination of chirality benefiting of both chiral elements. 

All types of nucleophiles protected at C3 show a predominant effect in driving the aldol reaction in the direction of favoring the anti-Cram/Felkin product. This characteristic seems to be independent of the nature of the aldehyde. The best selectivities were obtained with nucleophile 50 and even superior to that, nucleophile 15 protected as an acetonide. The final part of this chapter will focus on a special type of aldehyde where a long range effect improves the stereochemical outcome of the aldol reaction. 

Earlier, Professor Roush had optimized the crotylation of the protected alaninal 7. In this case, the Brown reagent 8 delivered the desired Felkin product 9. Protection followed by ozonolysis gave the aldehyde 10. Crotylation with the Roush-developed tartrate 11 then gave the alkene 12, setting the stage for conversion to the iodide 13. Coupling of 13 with 6 completed the preparation of 14. 

Application of this model to aldehyde 2 results in conformation 10 fliat would lead to aldols 3 (Fig. 19.2). Compounds 3 are called Felkin products. This is the situation for the tin-promoted reaction. Therefore it is not necessary to proceed for the reaction with SnCU, as the simplest model perfectly explains the observed dia-stereoselectivity. 

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