Felkin-Anh-Modell

The issue of stereochemistry, on the other hand, is more ambiguous. A priori, an aldol condensation between compounds 3 and 4 could proceed with little or no selectivity for a particular aldol dia-stereoisomer. For the desired C-7 epimer (compound 2) to be produced preferentially, the crucial aldol condensation between compounds 3 and 4 would have to exhibit Cram-Felkin-Anh selectivity22 23 (see 3 + 4 - 2, Scheme 9). In light of observations made during the course of Kishi s lasalocid A synthesis,12 there was good reason to believe that the preferred stereochemical course for the projected aldol reaction between intermediates 3 and 4 would be consistent with a Cram-Felkin-Anh model. Thus, on the basis of the lasalocid A precedent, it was anticipated that compound 2 would emerge as the major product from an aldol coupling of intermediates 3 and 4. 

Cram s open-chain model 229 Cram s rule 229, 233 Cram chelate model 229 Cram cyclic model 229 Cram-Felkin-Anh model 191,207, 236 f 246 cubane 12,318 cyanoacetic acid 636 f. cyanohydrin, protected 145, 150 f. cyclic carbonate protection 541 f., 657, 659 f., 666, 670 cyclization -,6-endo 734 -, 5-exo 733 f. 

In accord with the Felkin-Anh model, a-chiral ketones react more diastereoselectively than the corresponding aldehydes. Increasing steric demand of the acyl substituent increases the Cram selectivity. Due to the size of the acyl substituent, the incoming nucleophile is pushed towards the stereogenic center and therefore the diastereoface selection becomes more effective (see also Section 1.3.1.1.). Thus, addition of methyllithium to 4-methyl-4-phenyl-3-hexanonc (15) proceeds with higher diastercoselectivity than the addition of ethyllithium to 3-methyl-3-phenyl-2-pen-tanone (14)32. 

As outlined in Section D.2.3.5., the stereochemical outcome of the addition of nucleophilic reagents to chiral aldehydes or ketones is rationalized most plausibly by the Cram-Felkin-Anh model. On the other hand, the corresponding reactions of oxygen- or nitrogen-heterosub-stituted aldehydes or ketones may be interpreted either by the same transition state hypothesis or, alternatively, by Cram s cyclic model. 

If a chiral aldehyde, e.g., methyl (27 ,4S)-4-formyl-2-methylpentanoate (syn-1) is attacked by an achiral enolate (see Section 1.3.4.3.1.), the induced stereoselectivity is directed by the aldehyde ( inherent aldehyde selectivity ). Predictions of the stereochemical outcome are possible (at least for 1,2- and 1,3-induction) based on the Cram—Felkin Anh model or Cram s cyclic model (see Sections 1.3.4.3.1. and 1.3.4.3.2.). If, however, the enantiomerically pure aldehyde 1 is allowed to react with both enantiomers of the boron enolate l-rerr-butyldimethylsilyloxy-2-dibutylboranyloxy-1-cyclohexyl-2-butene (2), it must be expected that the diastereofacial selec-tivitics of the aldehyde and enolate will be consonant in one of the combinations ( matched pair 29), but will be dissonant in the other combination ( mismatched pair 29). This would lead to different ratios of the adducts 3a/3b and 4a/4b. 

These results may be explained by a chelation-controlled mechanism A with M representing a complex of JVtg(ll), Ce( 111) or of both cations. The highly stereoselective addition of the organocop-per reagent can be rationalized either by the dipolar model B or the Felkin-Anh model C (see also ref 12). 

The stereochemical course of the reaction may be explained by analogy to the Felkin-Anh model 7. 

After recrystallization from hexane, the major diastereomer is obtained in a 71 % yield. Although interpretation of the steric course of the reaction is difficult25, the preferred formation of the (6S )-diastereomer may be rationalized in terms of an imine conformation which is favored according to the Felkin-Anh model (vicinal C-O orthogonal to C = N)26 and by chelation21. 

Scheme 21.11 Felkin-Anh model for the hydrogenation of keto phosphate.

Usually, the diastereoselectivity in Michael additions is the one predicted by the Felkin-Anh model.57 However, it was discovered that in the case of the addition of highly hindered nucleophiles, as potassium phthalimide and succinimide, the major product has the opposite configuration to the one predicted by this model, because of the presence of steric hindrance interactions.58... 

To account for the observed diastereoselectivity, a modified Felkin-Anh model has been proposed [18]. In analogy to the classical Felkin-Anh model, originally developed for the addition of organometallic reagents to aldehydes possessing a... 

With glyceraldehyde-derived enones and enoates, it has been found that addition of aryl or alkenyl copper reagents is almost independent of the enone geometry [24, 25]. In agreement with the modified Felkin-Anh model, Z enoates usually provide high levels of anti selectivity (Scheme 6.11). Hence, the Z derivative 64 reacted with complete stereochemical control, whereas the -enoate 64 gave a lower selectivity of 4 1 in favor of the anti-conjugate adduct [25]. 

This result clearly marks the difficulties and limitations inherent in the modified Felkin-Anh model, which so far is nothing more than a rule of thumb. To account for these results, a switch in mechanism towards a tt-complex model has been proposed [36b, 37]. 

Diastereofacial selection on addition of organocoppper reagents to chiral y-alkyl-substituted Michael acceptors has been investigated less extensively, due to the usually low selectivities generally observed for these systems [38, 39]. This is exemplified by the reaction of E and Z enoates 90 (Scheme 6.19). Thus, either syn-91 or anti-93 is formed upon conjugate addition with BF3-modified reagents, as a function of enoate geometry. The stereochemistry of the reaction is in accordance with the modified Felkin-Anh model [40]. 

A desymmetrizing reduction of a dicarbonyl has also been achieved as a route to flMfi-aldol adducts. Yamada and coworkers have shown that a chiral cobalt complex catalyzes the desymmetrization of diaryl-1,3-diketones in excellent yield and enantioselectivity, greatly favoring the anti isomer [Eq. (10.65)]. Anti selectivity is rationalized using a Felkin-Anh model ... 

The approach, which differs from other recent syntheses (3,4,5), is outlined in Scheme 1. Three points may be noted (i) in the Grignard addition to 2,3-0-isopropylidene-D-ribose (2) the D-allo configuration in (3 is in accordance with the Felkin-Anh model (0 and is to be expected from our earlier work (1 ) (ii) methane-sulfonylation of the oxime ( ) serves not only to dehydrate the oxime but to introduce a leaving group for ring closure at the next step (iii) the intramolecular displacement to form the pyrrolidine ring (( ) ] proceeds cleanly and with complete inversion of... 

In related experiments, it was reported that reduction with sodium borohydride of acyl intermediate 43 forms the a,/f-unsaturated product 42 in excellent stereoselectivity and in 58-84% yield [59]. The diastereoselectivity of the reduction was predicted by the Felkin-Anh model (Fig. 7) (Scheme 15). 

A and B differ in the angle which the trajectory of the nucleophile forms with the plane of the olefin. For obtuse angles, the Felkin-Anh model is preferred, as the steric crowding outside the olefin has to be minimized (attack from the side of S). In contrast, B (Houk model)41 is superior for acute angles (minimal steric crowding inside the olefin). 

Normally, additions depicted by model C lead to the highest asymmetric induction. The antiperiplanar effect of OR substituents can be very efficient in the Houk model B ( , , , , ) however it plays no role in model C. Furthermore, the Houk model B must be considered in all cycloaddition-like reactions. The Felkin-Anh model A is operative for nucleophilic additions other than cuprate additions ( ). The epoxidation reactions are unique as they demonstrate the activation of one diastereoface by a hydroxy group which forms a hydrogen bridge to the reagent ( Henbest phenomenon ). The stereochemical outcome may thus be interpreted in terms of the reactive conformations 1 and 2 where the hydroxy function is perpendicular to the olefinic plane and has an optimal activating effect. 

BunCu BF3, compound (42) was formed with similar selectivity. However, if the cis compound (43) was treated with a BFj-complexed diorganocuprate, then the syn isomer (44) was formed. The dia-stereoselectivities were explained in terms of a modified Felkin-Anh model, and electron transfer from the cuprate was used to account for the different stereochemical preferences of RCu and R2CuLi with (43).101... 

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. 

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