Anh transition state model

Numerous examples of additions to carbonyl compounds incorporating a stereogenic center at Ca exist that yield products with impressive diastereo-selectivity, in accordance with the Felkin-Anh transition state model (Scheme 2.2) [51]. In a demonstration of the importance of the metal counterion, Reetz found that nucleophilic addition of organometallic species to (R)-2-phenylpropanal (19) occurs with Felkin-Anh selectivity. The diastereo-selectivity was much more pronounced when organotitanium reagents were... 

For carbonyl addition, three transition state models have been proposed the Felkin-Anh model36, the chelate Cram model37 and the dipolar Cornforth model37 . 

The Reason for Cram and Anti-Cram Selectivity and for Felkin-Anh and Cram Chelate Selectivity Transition State Models... 

In additions of hydride donors to a-chiral carbonyl compounds, whether Cram or anti-Cram selectivity, or Felkin-Anh or Cram chelate selectivity occurs is the result of kinetic control. The rate-determining step in either of these additions is the formation of a tetrahedral intermediate. It takes place irreversibly. The tetrahedral intermediate that is accessible via the most stable transition state is produced most rapidly. However, in contrast to what is found in many other considerations in this book, this intermediate does not represent a good transition state model for its formation reaction. The reason for this deviation is that it is produced in an... 

The absolute stereochemical selectivities achieved in these reactions can be explained in terms of the nnf/-exo-transition-state models 16, 17, and 18, which are analogous to those previously proposed for the reaction of dienes and olefinic dienophiles (Fig. 8) [12,27d]. These transition-state models are based on three assumptions (i) the substituent in the chiral ligand blocks the same enantiofacial side of the carbonyl in the Diels-Alder reactions of acetylenic and olefinic aldehydes (ii) exo-transition structures predominate and (hi) anh-coordination of the bulky chiral Lewis acid to carbonyl is preferred in the transition state. 

There is a dichotomy in the sense of syn-anti diastereofacial preference, dictated by the bulkiness of the migrating group [94]. The sterically demanding silyl group results in syn diastereofacial preference but the less demanding proton leads to anti preference (Sch. 35). The anti diastereoselectivity in carbonyl-ene reactions can be explained by the Felkin-Anh-like cyclic transition-state model (Ti) (Sch. 36). In the aldol reaction, by contrast, the now inside-crowded transition state (Ti ) is less favorable than Tg, because of steric repulsion between the trimethylsilyl group and the inside methyl group of aldehyde (Ti ). The syn-diastereofacial selectivity is, therefore, visualized in terms of the anti-Felkin-like cyclic transition-state model (T2 )-... 

A second example concerns the reaction of glyceraldehyde acetonide (151) and y-alkoxyallylcadmium reagent (181).This reaction apparently proceeds preferentially by way of a Felkin-Anh transition state (183) analagous to (160) in the reactions of ( )-crotylboronates, because of the smaller steric requirements of the 7-alkoxy group in (181). Here again, additional experimental data are required to verify this hypothesis. The reaction of (151) and allylzine reagent (127) appears also to be in disagreement with this stereochemical model (Scheme 29). 

Addition of -butylmagnesium bromide to 624 followed by Swem oxidation affords the ketone 642. Zinc borohydride addition occurs with almost exclusive anri-selectivity (>99 1), leading to 646 in accordance with an a-coordinated transition-state model in which the r -face of the carbonyl is exposed to the reagent. Presumably the MOM-ethers display a crown ether effect to facilitate a-chelation. In marked contrast, L-Selectride shows excellent 5y -selectivity to provide 645 (92 8), consistent with a j5-chelation and/or Felkin— Anh model. The a ri-adduct 646 is converted in five steps to ketone 647, which undergoes a similar highly selective hydride reduction with zinc borohydride to yield the anti,syn,syn-alcohol 648 (96 4). This product is converted in six steps to the r n5-(2i ,57 )-pyrroline 649, which undergoes a Wacker oxidation followed by catalytic reduction to (— )-indolizidine 195B (650) and its C-5 epimer (86 14) (Scheme 142). 

Although increases in the acidity of the aqueous solution were found not to impact on product stereoselectivity, salt effects can prove beneficial (5), presumably as a consequence of the increased internal pressure brought about in the system. The sense of asymmetric induction conforms to operation of the illustrated Cram-like transition state (Scheme 1). This working model is consistent with the nondirective effects brought on by the sterically bulky a-oxy (OBn, OTBS), a-thia (PhS, MeS), and a-amino (BnaN, isoindolyl) groups (9). Under the latter circumstances, chelation is not observed and ir-facial discrimination is achieved instead via Felkin-Anh transition states under the steric control of the substituents. The dimethylamino... 

A cyclic transition state model, that differs from the Zimmerman-Traxler and the related cyclic models inasmuch as it does not incorporate the metal in a chelate, has been proposed by Mulzer and coworkers [78] It has been developed as a rationale for the observation that, in the aldol addition of the dianion of phenylacetic acid 152, the high ti-selectivity is reached with naked enolate anions (e.g., with the additive 18-crown-6). Thus, it was postulated that the approach of the enolate to the aldehyde is dominated by an interaction of the enolate HOMO and the n orbital of the aldehyde that functions as the LUMO (Scheme 4.31), the phenyl substituents of the enolate (phenyl) and the residue R of the aldehyde being oriented in anti position at the forming carbon bond, so that the steric repulsion in the transition state 153 is minimized. Mulzer s frontier molecular orbital-inspired approach reminds of a 1,3-dipolar cycloaddition. However, the corresponding cycloadduct 154 does not form, because of the weakness of the oxygen-oxygen bond. Instead, the doubly metallated aldol adduct 155 results. Anh and coworkers also emphasized the frontier orbital interactions as being essential for the stereochemical outcome of the aldol reaction [79]. 

Scheme 4.68 Corey s syn- and anh -selectlve aldol protocols based on the Cj-symmetric diazaborolldines. Transition state models 308 and 309 for rationalizing the correlation between enolate and aldol configurations.

Figure 11.2 Felkin-Anh [49] and Cram [48] transition state models for addition to a-chiral imine derivatives.

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