Stereochemistry diastereomers, formation reaction

I-Oialkoxy carbonyl compounds are a special class of chiral alkoxy carbonyl compounds because they combine the structural features, and, therefore, also the stereochemical behavior, of 7-alkoxy and /i-alkoxy carbonyl compounds. Prediction of the stereochemical outcome of nucleophilic additions to these substrates is very difficult and often impossible. As exemplified with isopropylidene glyceraldehyde (Table 15), one of the most widely investigated a,/J-di-alkoxy carbonyl compoundsI0S, the predominant formation of the syn-diastereomer 2 may be attributed to the formation of the a-chelate 1 A. The opposite stereochemistry can be rationalized by assuming the Felkin-Anh-type transition state IB. Formation of the /(-chelate 1C, which stabilizes the Felkin-Anh transition state, also leads to the predominant formation of the atm -diastereomeric reaction product. 

In all of the cases described above, characterization of the product macrocycles was complicated by the presence of up to two diastereomers per U4CR. Induction of stereochemistry is typically low in Ugi reactions, and the formation of four new stereocenters in 114, for example, probably... 

Although one diastereomer 10 was largely favored, the product was obtained as a mixture of diastereomers, and the previously unreported minor diastereomer 11 was also characterized. The stereochemistry of the products was established by nuclear Overhauser effect (NOE) studies. A plausible mechanism assumes the intermediacy of an acetal, and its reaction with 2-methoxypropene generated from 2,2-dimethoxypropane [20]. In order to test this mechanism, the dimethyl acetal of salicylaldehyde was synthesized and reacted independently with both 2,2-dimethoxypropane and 2-methoxypropene. Indeed, both reactions gave the same products as those from the reaction of salicylaldehyde with 2,2-dimethoxypropane (Scheme 4). The condensation of salicylaldehyde and 2,2-dimethoxypropane was also carried out in CD3CN and reaction progress was followed by H NMR spectroscopy. This experiment also confirmed the formation of the acetal from salicylaldehyde (8 5.52, singlet, C//(OMe)2). 

Mori has reported the nickel-catalyzed cyclization/hydrosilylation of dienals to form protected alkenylcycloalk-anols." For example, reaction of 4-benzyloxymethyl-5,7-octadienal 48a and triethylsilane catalyzed by a 1 2 mixture of Ni(GOD)2 and PPhs in toluene at room temperature gave the silyloxycyclopentane 49a in 70% yield with exclusive formation of the m,//7 //i -diastereomer (Scheme 14). In a similar manner, the 6,8-nonadienal 48b underwent nickel-catalyzed reaction to form silyloxycyclohexane 49b in 71% yield with exclusive formation of the // /i ,// /i -diastereomer, and the 7,9-decadienal 48c underwent reaction to form silyloxycycloheptane 49c in 66% yield with undetermined stereochemistry (Scheme 14). On the basis of related stoichiometric experiments, Mori proposed a mechanism for the nickel-catalyzed cyclization/hydrosilylation of dienals involving initial insertion of the diene moiety into the Ni-H bond of a silylnickel hydride complex to form the (7r-allyl)nickel silyl complex li (Scheme 15). Intramolecular carbometallation followed by O-Si reductive elimination and H-Si oxidative addition would release the silyloxycycloalkane with regeneration of the active silylnickel hydride catalyst. 

The reaction with N-Boc-pyrrolidine may be taken a step further by inducing a double C-H insertion sequence [27]. This results in the formation of the elaborate C2-symmetric amine 35 as a single diastereomer with control of stereochemistry at four stereogenic centers. The enantiomeric purity of 35 is higher than that obtained for the single C-H insertion products, presumably because kinetic resolution is occurring in the second C-H insertion step. 

Typically, the product of an aldol reaction and its stereochemistry are predictable by using the formalism of the chair-like Zimmerman-Traxler transition state.However, if the formalism is used in this case, the stereochemistry of the product is predicted incorrectly. Using chelating metal ions (in this case zinc), favored transition states such as 31 should be formed. The heteroaryl substituent of aldehyde 8 is equatorially oriented and the substituents of the oxazolidinone auxiliary point outward. However, the favored transition state predicts the formation of the minor diastereomer epi-10. In transition state 32, the substituents of the Evans auxiliary point to the aldehyde, which destabilize this transition state and make it unfavored. The product predicted by this transition state is the major diastereomer 10, which is an astonishing result. 

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. 

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