Chelated transition states

With a-alkyl-substituted chiral carbonyl compounds bearing an alkoxy group in the -position, the diastereoselectivity of nucleophilic addition reactions is influenced not only by steric factors, which can be described by the models of Cram and Felkin (see Section 1.3.1.1.), but also by a possible coordination of the nucleophile counterion with the /J-oxygen atom. Thus, coordination of the metal cation with the carbonyl oxygen and the /J-alkoxy substituent leads to a chelated transition state 1 which implies attack of the nucleophile from the least hindered side, opposite to the pseudoequatorial substituent R1. Therefore, the anb-diastereomer 2 should be formed in excess. With respect to the stereogenic center in the a-position, the predominant formation of the anft-diastereomer means that anti-Cram selectivity has occurred. 

This different stereochemical outcome can be qualitatively understood by assuming two different conformations of the seven-membered-chelated transition state. Thus, compound 1 should react via a transition state similar to 5, whereas with compound 3, a transition state similar to 6 seems reasonable. 

Similar results are found with the threose derivatives 11 and 13. Both aldehydes can be readily synthesized in either enantiomeric form from l- and D-tartaric acid. The open-chain aldehyde 11 with Grignard reagents affords predominantly the all-.v> n(xj/o)-diastereomer 12. The steric demand of the nucleophile apparently does not affect the diastereoselectivity, and the extremely high selectivity observed with [(l,3-dioxolan-2-yl)methyl]magnesium bromide is attributed to the presence of the dioxolane moiety, which is thought to stabilize the a-chelated transition state. 

Although modern transition state hypotheses may be adequate in special cases, the majority of aldol additions leading to enantiomerically pure products are still rationalized by the classical six-membered chelate transition state models40. 

When chiral enolates or chiral Michael acceptors are used, for instance, when stereogenic centers are present in the substrate or when X or Y are chiral auxiliaries, both simple and induced diastereoselectivity is observed. This results, in principle, in the formation of four diastereomers 1 -4. The diastereoselectivity in the Michael addition of lithium enolates to enones can be rationalized by consideration of chelated transition states A-D372. 

A diastereomeric ratio (synjanti) of 90 10 is found, whereas within the syn-adduct the ratio between the ( ,5)/(S, )-isomers is 95 5. With methyl (Z)-2-butenoate the diastereomeric ratio (synjanti) is 25 75, and in the anti-adduct the (R,S) (S,S) ratio is 88 12186. These results are consistent with a chelated transition state as shown in Section 1.5.2.4.1. This enantioselcctivc Michael addition was used in the synthesis of 7,20-diisocyanoadocianc18 7. 

The chiral auxiliary can be recovered without any racemization. A chelated transition state has been suggested in which the Grignard reagent is delivered to the 7t-face more distal from the sterically demanding toy-butyl group1 2. 

In some cases the yields were poor due to competing deprotonation of the substrate by the organolithium reagent. Deprotonation was the predominant reaction with methyllithium or when (Z)-2-(l-alkenyl)-4,5-dihydrooxazoles were employed. The stereochemical outcome has been rationalized as occurring from a chelated transition state. The starting chiral amino alcohol auxiliary can also be recovered without racemization for reuse. 

The reaction shows a dependence on the E- or Z-stereochemistry of the enolate. Z-Enolates favor anti adducts and /i-enolates favor syn adducts. These tendencies can be understood in terms of a chelated transition state.94... 

Other structural features may influence the stereoselectivity of aldol condensations. One such factor is chelation by a donor substituent.68 69 Several /i-alkoxyaldchydcs show a preference for vyw-aldol products on reaction with Z-enolates. A chelated transition state can account for the observed stereochemistry.70 The chelated aldehyde is most easily... 

Reduction of jl-hydroxyketones through chelated transitions states fovors syn-1,3-diols. Boron chelates have been exploited to achieve this stereoselectivity.86 One procedure involves in situ generation of diethylmethoxyboron, which then forms a chelate with the /1-hydroxy ketone. Reduction with NaBH4 leads to the syn diol.87... 

For ketones and aldehydes in which adjacent substituents permit chelation with the metal ion in the transition state, the stereochemistry can often be interpreted in terms of the steric requirements of the chelated transition state. In the case of a-alkoxyketones, for example, an assumption that both the alkoxy and carbonyl oxygens will be coordinated with the metal ion and that addition will occur from the less hindered side of this structure correctly predicts the stereochemistry of addition. The predicted product dominates by as much as 100 1 for several Grignard reagents." Further supporting the importance of chelation is the correlation between rate and stereoselectivity. Groups which facilitate chelation cause an increase in both rate and stereoselectivity.99 100... 

Aldehydes with 7-hydroxy and similar donor substituents react through chelated transition states, which convey good stereoselectivity to the addition. 

The authors proposed a chelating transition state model to explain these results (Fig. 8.14). The thermodynamically more stable intermediate resulting from initial lithium amide addition should have the amino group on the face opposite to the bulky tert-butyl group. Due to the same steric effect, the HMPA ligand should also occupy a position on the p face. The electrophile approaches the enolate from the ot face and gives the trans product. For bulky amines, either the aza enolate does not form due to severe steric hindrance or the aza enolate is inactive for the same reason. 

Figure 8.14. Chelating transition state model for addition of lithium amides to oxazolinylnaphthalenes.

If thioamide enolates are prepared by conjugate addition of Grignard reagents to a,/3-unsaturated thioamides of secondary amines, the reaction of these enolates with aldehydes affords anti aldols. These results are rationalized by the formation of a boat-like, chelate transition state" Representative examples are provided in equation 112 and Table 16. 

Rate enhancement should be a requirement for chelation control because if chelation is the source of stereoselectivity it necessarily follows that the chelation transition state should be of a lower energy pathway.13... 

The third section will contain direct reactions of stable chelates. This is a large and diffuse topic and many examples of reactions of this type are included in Chapter 7.4. In the current chapter, a more detailed discussion of the most important areas, namely complexes of fl-diketones and q-amino acids and their derivatives, will be offered. Also some important organic reactions of carbonyl compounds will be considered with regard to the nature of their chelated transition states and the effects these have on product formation. 

Grignard reagents also add diastereoselectively to oc-chiral, oc-oxygenated aldehydes and ketones. The chelation-controlled product constitutes the major product (Figure 10.41). It is the diastereomer that is produced via the Cram chelate transition state of Figure 10.16... 

The coupling addition of crotyl bromide to a triad of conformationally unrestricted a-oxy aldehydes in water, aqueous THF, and anhydrous THF has been examined. The proportion of. sy/z-isomers reaches a maximum (syn anti = 5.6 1) when the neighboring hydroxyl group is unprotected and water is the reaction medium (Scheme 33). Crotyl bromide adds to the hydroxy aldehyde with a preference for the adoption of the cyclic chelated transition states 31 and 32 (Scheme 34). 

A /3-carboxyl group on the aldehyde also influences the diastereoselection. The high diastereoselectivity observed with the y-hydroxy lactone can be rationalized by a chelated transition state with the carboxylic acid group (Scheme 41).174 2-Oxocarboxylic acids also undergo diastereoselective allylation with cinnamyl bromide to provide the corresponding a-hydroxy acids as a single diastereomer (Equation (19)).1... 

For the anti substrate 10, although the chelated transition state relies solely on the 2-methyl substituent to exert any steric hindrance toward the approach of the Grignard reagent (Fig. 3), good stereoselectivities are achieved at low temperature (entry h). 

Figure 2. Chelated transition-state model for syn substrate.

The major product diastereoisomer 12 from addition of methylmagnesium iodide to syn substrate 8 was isolated by recrystallization, and the structure solved by X-ray analysis. The structure was found to be in accordance with the expected chelated transition state (Fig. 2) and approach of the nucleophile from the least hindered face of the carbonyl group. 

Transition states for reduction according to our usual model of chelation-controlled 2-acyl 1,3-dithiane 1-oxide reactivity, together with steric approach control were proposed to rationalize the high levels of observed stereoselectivity. Previous work by Solladie suggests that ketone reduction by the DIBAL/ZnCl2 system does indeed involve such chelated transition states.15... 

---