Stereochemistry reagent control

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

The third step is an Evans aldol reaction and employs the enolate of 26 that is the enantiomer of 50 that was used in the previous aldol reaction. The stereochemistry of the reaction is entirely reagent-controlled. Can you draw the favored transition state and predict the stereochemical outcome of the reaction ... 

The L-talo and L-gulo adducts 447 and 449 were obtained with very high stereoselectivity (no other diastereomers reported) from the reaction of aldehyde 444 with the [y-(alkoxy)allyl]indium reagents generated from (5)-230a and (R)-230a, respectively. In these double asymmetric reactions, reagent control is clearly dominant. The stereochemistry of adduct 447 is rationalized by the Felkin transition state 448 while the stereochemistry of adduct 449 is rationalized by the anti-Felkin transition state 450 [275]. 

In the asymmetric alkylation of a-chiral aldehydes using dialkylzinc reagents, the stereochemistry is controlled by the configuration of the chiral catalyst, not by the stereochemistry in the a-position. It is different from the diastereoselec-tive alkylation using other organometallic reagents where the stereochemistry follows from Cram s rule or the Felkin-Ahn model. Each diastereomer with high ee was obtained by the choice of the appropriate enantiomer of chiral catalyst [(IS, 2R)- or (li ,2S)-DBNE 1] (Scheme 6) [18]. 

We now wish to consider how these elements of stereochemistry come into play in synthesis. It is important to know how reaction stereochemistry is controlled by structural features of the reactant molecules. This topic can be broadly covered by the term asymmetric synthesis, which has been defined as a reaction in which an achiral unit in an ensemble of substrate molecules is converted by a reactant into a chiral unit in such a manner that the stereoisomeric products are produced in unequal amounts. Thus, we will be dealing with methods for controlling the configuration of newly formed chiral centers. As will be seen, these methods often depend on the fact that reagents attack molecules along the less hindered path. 

Under either the catalytic (eq 1) or the stoichiometric conditions (eq 2), the reagent undergoes addition to chiral aldehydes with complete reagent control , i.e. the stereochemistry of the aldol reaction is totally controlled by the chiral catalyst regardless of the inherent diastereofacial preference of the chiral aldehydes (eq 4). Titanium(IV) chloride and tm(TV) chloride mediate the addition of the title reagent to chiral a-alkoxy aldehydes and -alkoxy aldehydes with complete chelation control (eq 5), whereas the corresponding silyl ketene acetal is unselective. 4... 

Allylborane 235 exhibits excellent reagent control and provides high ee s for a wide range of carbonyl compounds regardless of the substrate stereochemistry. For example, in the reaction of a-chiral aldehydes S-237 and / -237 with allylboranes (-f-)-235 (-)-235, the prodnct stereochemistry entirely depends on the antipode of the reagent used and not on the substrate stereochemistry (Scheme 25.37). 

Determination of the absolute stereochemistry of the newly generated C(15) stereocenter of 2.353 was achieved by Mosher ester analysis of the major dia-stereomer following the procedure reported by Kakisawa and co-workers (Scheme 2.76) [225]. The Mosher esters of the organozinc addition reaction product were prepared as shown in Scheme 2.76. Analysis of the (S)- and (R)-MTPA esters prepared from 2.353 obviously indicated that the C(15) alcohol was of the desired configuration (/ ), which was consistent with the results via reagent controlled asymmetric organozinc addition reaction. 

Enantioselective processes involving chiral catalysts or reagents can provide sufficient spatial bias and transition state organization to obviate the need for control by substrate stereochemistry. Since such reactions do not require substrate spatial control, the corresponding transforms are easier to apply antithetically. The stereochemical information in the retron is used to determine which of the enantiomeric catalysts or reagents are appropriate and the transform is finally evaluated for chemical feasibility. Of course, such transforms are powerful because of their predictability and effectiveness in removing stereocenters from a target. 

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