Anti-Felkin products

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. 

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). 

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 stereoselectivity of the addition of pinacolone enolsilane 1 to P-alkoxy aldehydes bearing two stereocenters depends on the ability of the metal to form intermediate chelates. Those metals that monocoordinate the carbonyl group form Fel-kin products and the stereochemistry of these aldols is predicted by the Felkin-Anh s model. For metals chelating both the carbonyl and alkoxy groups, anti-Felkin products are obtained. In these cases the cyclic-Cram s model has to be used to predict the stereochemical outcome of the reaction. Therefore, non-chelated (Felkin-Ahn) and chelated models (cyclic-Cram) have been successively applied to understand the stereochemistry of the final reaction products. 

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. 

A very short and efficient synthesis based on the desymmetrization principle is shown in Scheme 13.39. mc.vo-2,4-Dimethylglularaldchyde reacted selectively with the diethylboron enolate derived from a bornanesultam chiral auxiliary. This reaction established the stereochemistry at the C(2) and C(3) centers. The dominant aldol product results from an anti-Felkin stereoselectivity with respect to the C(4) center. 

The stereochemistry of the diastereomeric products isolated in this reaction were confirmed to be those arising from incomplete relative face selectivity of the aldol reaction (Felkin Anti-Felkin). Thus the stereochemistry was proven by comparing the H NMR spectrum of the major diastereomer with a compound of known stereochemistry that had been independently synthesized. 

For a cuprate addition reaction to a diester derivative such as 88, it might be expected that the anti addition product would be favored, since a pronounced allylic strain in these substrates along modified Felkin-Anh lines should favor transition state 52 (see Fig. 6.1). However, experiments produced the opposite result, with the syn product 89 being obtained as the major diastereomer (Scheme 6.18) [36, 37]. 

On the other hand, with heterosubstituted chiral aldehydes, the product distribution for the reaction with methyl ketone enolates is strongly influenced by the nature of the metal, the nature of the heteroatom and its position within the molecule. A chair-like transition state explained the formation of the Felkin adduct, while a boat-like transition state was invoked for the formation of the anti-Felkin adduct. However, this assumption was recently challenged by Roush and coworkers using deuterated pinacolone lithium enolate565. Performing a set of aldolizations with chiral and non chiral aldehydes led these authors to show that the isomeric purity of the enolate correlates almost perfectly with the ratio and pattern of deuterium labeling in the 2,3-an/t-aldol formed consistent with a highly favoured chair-like transition state (Scheme 115). 

Less acidic than Ti and Zi chloroderivatives, MeTi(OPr )3 perfoims chelation-controlled addition to chiral alkoxy ketones as well as or better than organomagnesium compounds, but fails to chelate to aldehydes or hindered ketones. Should the formation of a cyclic chelation intermediate be forbidden, the reaction is subject to nonchelation control, according to Ae Felkin-Anh (or Comforth) model. Under these circumstances, the ratio of the diastereomeric products is inverted in favor of the anti-Cram product(s). In the case of benzil (83 Scheme 7) this can be accounted for by the unlikely formation of a cyclic intermediate such as (85), and thus the preferential intermediacy of the open chain intermediate (86) that leads to the threo compound (88). This view is substantiated by the fact that replacement of titanium with zirconium, which is characterized by longer M—O bonds, restores the possibility of having a cyclic intermediate and, as a consequence, leads to the erythro meso) compound (87) thus paralleling the action of Mg and Li complexes. 

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 diastereoselectivity of these reactions is consistent with product formation occurring through transition state 137, where the reactive conformation of the aldehyde in the transition state (corresponding to the normal Felkin-Anh model) minimizes steric interactions with the allylstannane as well as the 1,3-dipole interactions of the aldehyde and the /(-alkoxy group. The allylation reaction of the 2,3-syn aldehyde 138, however, with allyltri-n-butylstannanes 98, generates the anti-Felkin adducts 139 preferentially (Eq. (11.9)) [93], The stereochemistry of these reactions is consistent with product formation occurring preferentially through transition state 140, in which 1,3-dipole interactions of the aldehyde and the P-... 

In reactions of a-methyl chiral aldehydes with achiral (Z)-crotylboronates, the anti-Felkin adduct (cf. 107b) is favored (for further discussion see Section 11.2) [3, 65]. In the double asymmetric reaction of 97b and (S,S)-213, the anti,syn-di-propionate 107b is obtained with high selectivity (selectivity=95 5). The stereochemistry of 107b is consistent with product formation via the matched anti-Felkin transition state 247. Finally, the, vyn,5y -dipropionate 106c is obtained as the major product from the mismatched reaction of the TBDPS-protected aldehyde 97c with (f ,R)-(Z)-213 this reaction, however, is not sufficiently stereoselective to be synthetically useful (selectivity = 64 36). The mismatched transition state... 

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