Chelation-controlled reactions

The addition of vinylmagnesium bromide to methyl (S)-3-benzyloxy-4-oxobutanoate (5) in tetrahydrofuran proceeded with a slight preference for the nonchelation-controlled reaction product (40 60)5°. A reversal of the diastereoselectivity (80 20) could be observed when the Grignard reagent, as a solution in tetrahydrofuran, was added to a dichloromethane solution of the aldehyde which had been precomplexed with one equivalent of magnesium bromide. The almost exclusive formation of the chelation-controlled reaction product 6 was achieved when tetrahydrofuran was completely substituted by dichloromethane the presence of tetrahydrofuran interferes with the formation of the chelate complex, which is a prerequisite for high chelation-controlled diastereoselection. 

No difference in diastereoselectivity was observed when phenyllithium and phenylmagnesium bromide were added to tetrahydrofurfural (15, R = H) in both cases there was a moderate preference for the chelation-controlled reaction product. The same trend holds for tetrahydro-5,5-dimethylfurfural (15, R = CH3), however, with a lower level of stereoselectivity58. 

The nucleophilic addition of Grignard reagents to a-epoxy ketones 44 proceeds with remarkably high diastereoselectivity70. The chelation-controlled reaction products are obtained in ratios >99 1 when tetrahydrofuran or tetrahydrofuran/hexamethylphosphoric triamide is used as reaction solvent. The increased diastereoselectivity in the presence of hexamethylphos-phoric triamide is unusual as it is known from addition reactions to a-alkoxy aldehydes that co-solvents with chelating ability compete with the substrate for the nucleophile counterion, thus reducing the proportion of the chelation-controlled reaction product (vide infra). 

A-acetylmannosamine undergoes a chelation-controlled reaction and leads to 90% of the syn-f3-amino alcohol when reacted in a 0.5 M NH4G1 solution. While a dibenzylamino substitutent of a-aminopropionaldehyde is too bulky to enter complexation, a dimethylamino group is not and leads to high levels (99%) of the. sy/z-diastereomer (Table 4).159... 

Even though the model shown above is consistent with the stereochemical outcome, Flowers has shown that changing the reaction conditions or the substituents in the (3-hydroxy ketone substrates can have an impact on the stereochemical outcome of the chelation-controlled reaction.23,24 A more detailed discussion of the mechanism of this reduction can be found in Chapter 4, Section 4.3. 

In addition to the aforementioned X-ray analysis to disclose the structure of a few crystalline titanium chelates, and NMR studies have been performed to provide evidence for the chelation structure of a- and /1-oxycarbonyl compounds in solution [33-35]. Approximate solution structures for -alkoxyaldehydes are as shown in Fig. 7 [34]. The mechanism of chelation-controlled reactions of organotitanium reagents has been investigated experimentally [5] and theoretically [36], and the subject has been reviewed [10]. The formation of a chelate structure with titanium metal at the center plays a pivotal role in determining the reactivity and selectivity [37] in many synthetic reactions as shown in the following discussion. 

Similar selectivities (>99 1) are observed in the cyclic chelation controlled reaction of a-benzyloxy carbonyls such as (4a equation 4) with Grignard reagents. However when the a-hydroxy group is protected as a silyl ether (4b), the selectivities observed in the addition reaction diminish (60 40), or reverse (10 90 Table 3). The nonchelating nature of a silyl group, as well as its steric bulk, are responsible for this change in selectivity. In the case of (4b), nucleophilic addition via the Felkin-Anh model effectively competes with the cyclic-chelation control mode of addition. 

This discrepancy can at least be partially explained by taking into account that in chelation-controlled reactions the acyclic substrate is essentially locked into one rigid cyclic conformation. The reactants taking part in nonchelation-controlled additions have many more degrees of freedom, and exclusive reaction with one conformer is less likely. These reactions rely on reagents which are incapable of chelation and/or substrates containing sterically or electronically differentiated substituents. ... 

The addition of HCN to aldehydes has been a well-known reaction since the 19th century, especially in the context of the Kiliani-Fischer synthesis of sugars. Even older is the Strecker synthesis of amino acids by simultaneous reaction of aldehydes with ammonia and HCN followed by hydrolysis. The challenge in recent years has been to achieve face-selectivity in the addition to chiral aldehydes. These face-selective additions, known as nonchelation-controlled processes, refer to the original formulation of Cram s for the reaction of nucleophiles with acyclic chi carbonyl compounds. The chelation-controlled reactions refer also to a formulaticxi of Cram s, but whose stereochemical consequences sometimes differ. 2... 

High diastereoselectivities in p-chelation-controlled reactions have also been observed with aldehydes and ketones in the presence of a Lewis acid where the chiral center is 3 to the carbonyl group, resulting in 1,3-asymmetric induction - The high diastereoselectivity observed in the reaction shown below, using Lil as the Lewis acid arises from 3-chelation of both the ketone and the ether oxygen with Li. This locks the conformation of the P-alkoxy ketone chain, and the hydride attacks from the less hindered side. ... 

The effect of concentration in the chelation-controlled reactions of allylsilanes and a- and //-alkoxy aldehydes has been studied (Scheme 10-11) [31]. The a-al-koxy aldehyde 27 was allowed to react with varying amounts of TiCLj and allyl-trimethylsilane to produce the homoallylic alcohol 28. With less than 0.5 equivalents of TiCl4, the reaction affords a mixture of products. When 0.5 equivalents or more of TiCl4 are used, the reaction gives only the product of chelation control. Intervention of chelation control with the a-alkoxy aldehyde was independent of substrate concentration. The reaction of the y9-alkoxy aldehyde 29 is found to be highly sensitive to both the substrate concentration and the stoichiometry of TiCl4 employed. The reaction gave primarily the product of chelation control 30 when... 

The reaction of //-methyl-2-butenylsilanes 36 and stannanes with chiral a-al-koxyaldehydes has also been reported [33]. Surprisingly, the anti homoallylic alcohols were predominantly observed (94/6, ant i/syn) when a bivalent Lewis acid such as SnCl4 was used (Scheme 10-13). A synclinal transition structure is proposed to account for the observed selectivity. In the chelation-controlled reactions the synclinal transition structure is favored over the corresponding antiperiplanar transition structure because there exists an open space wherein the complexed Lewis acid can reside. The monovalent Lewis acid BF3-OEt2 provides the expected syn homoallylic alcohol, presumably through the antiperiplanar transition structure shown (66% of the product was the syn alcohol 37). 

Chelate-Controlled Reactions of Type 1 Allylmetal Reagents... 

Reactions of the a-methyl- -benzyloxy aldehyde 97 with allyltri-n-butylstannane 98 are summarized in Table 11-7 [83]. While little stereocontrol is observed in the BF3 OEt2-promoted allylation reaction, the chelate-controlled reaction catalyzed by either TiC or SnCl4 is much more selective, favoring formation of the Cram-chelate adduct 100 with up to 98 2 selectivity. The chelate transition state 101, where C-C bond formation occurs anti to the aldehyde a-methyl group, rationalizes the observed stereoselective formation of 100. Although the BF3-OEt2-cata-... 

Keck further demonstrated that the anti,syn- ddact 114 can be formed with high selectivity from the chelate-controlled reaction of aldehyde 97a with the (y-silyloxyallyl)tri-n-butylstannane 113, presumably through transition state 115 (Eq.(11.3)) [90]. 

In the complementary chelate-controlled reaction of the a-benzyloxy aldehyde 127 with the (y-silyloxyallyl)stannane 113, the. s yn,.sy -adduct 128 arises as the major adduct, presumably through transition state 129 (Eq. (11.6)) [90]. 

Panek and Cirillo demonstrated that the -methyl chiral crotylsilane (5)-217b favors formation of the 5,6-anti diastereomer in the chelate-controlled reaction with the achiral a-benzyloxy aldehyde 353 (Eq. (11.26)) [57, 58]. Here, the synclinal transition state 355 best explains the stereochemistry of the major adduct. 

Scheme 5.2.14 Chelation-controlled reaction ofy-alkoxy-Z-stannane with a-benzyloxyaldehyde 56...

Scheme 5.2.15 A study of Lewis acids for a-chelation controlled reactions...

Cyclic ethers also serve as excellent ligands for chelation-controlled reactions, and this technique is especially useful for the synthesis of carbohydrate derivatives and polyether antibiotics. Studies toward ciguatoxin (Scheme 5.2.18) illustrate the oxidative cleavage of alkene 73 to provide the a-alkoxy aldehyde 74 for subsequent chelation-controlled allylation to yield 75.29... 

The hydroxyalkylation of phenols with chiral glyoxylates, followed by hydrolysis, gives regioselectively 2-hydroxymandelic acids with high enantioselectivity (eqnation 28). The crystal-structure determination of the titanium phenoxide complex shows evidence for chelation-controlled reaction giving the observed high enantioselectivities . ... 

A major improvement was realized with the use of indium, a metal with a very low first ionization potential (5.8 eV) which works without ultrasonic radiation even at room temperature [87]. As the zero-valent indium species is regenerated by either zinc, aluminum, or tin, a catalytic amount of indium trichloride together with zinc, aluminum [88], or tin [89] could be utilized in the allylation of carbonyl compounds in aqueous medium. The regeneration of indium after its use in an allylation process could be readily carried out by electrodeposition of the metal on an aluminum cathode [90], Compared with tin-mediated allylation in ethanol-water mixtures, the indium procedure is superior in terms of reactivity and selectivity. Indium-mediated allylation of pentoses and hexoses, which were however facilitated in dilute hydrochloric acid, produced fewer by-products and were more dia-stereoselective. The reactivity and the diastereoselectivity are compatible with a chelation-controlled reaction [84, 91]. Indeed, the methodology was used to prepare 3-deoxy-D-galacto-nonulosonic acid (KDN) [92, 93], N-acetylneuraminic acid [93, 94], and analogs [95],... 

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