Reagent-Controlled Enantioselection

Occasionally, enantioselective reactions are possible where a prochiral substrate is allowed to react with a chiral reagent such that the diastereomeric transition state provides facial bias for the pending transformation. As previously stated, this is most beneficial when the chiral reagent can be recycled back into a useful form after the reaction has taken place. 

Recently, a number of chiral tin reagents were surveyed and significant improvements in the levels of asymmetric induction and chemical yield were achieved. 

Utilizing the menthol-derived chiral tin reagents 77-80 in conjunction with bulky Lewis acids such as zirconocene dichloride or a manganese-salen complex, selective reductions of esters (81a-d) offered excellent levels of selectivity up to 96% ee in a 75% yield (for reduction of 81c) [36], Chiral stannane 80 offered the most consistent high levels of enantioselectivity for reduction of all substrates, ranging from 62% ee to above 90% ee in many cases with a bulky Lewis acid additive. 

Additional examples of reagent-based enantioselection involve the enantioselective hydrogen atom abstraction by chiral amine-boryl [37] or silanethiyl radicals 

Enantioselective hydrogen atom abstraction by chiral amine boryl radical 83 allows for kinetic resolution of racemic ester 84. In the specific example illustrated in Eq. (23), the enantioselectivity of the residual enantiomer of the substrate reached 74% (/ ,/ ). It is postulated that a transition state as shown in 86 could account for the asymmetric hydrogen atom abstraction. 

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Reagent-controlled enantioselective addition to achiral carbonyl compounds ... 

The yields of the allenes and the enantioselectivities are not very high, and the method could possibly be further developed by the use of more rigid, e.g., bidentate ligands. Since no satisfactory reagent-controlled enantioselective synthesis of chiral allenes is known to date, this is a challenge for the future. 

Finally, it should be noted that enantiomerically pure derivatives of the Schwartz reagent are very appealing candidates for reagent controlled enantioselective and diastereoselective radical reductions. This is because a plethora of enantiomerically pure zirconocenes are available from other applications in enantioselective catalysis. 

Scheme 3.48 Reagent-controlled enantioselective homo-aldol reaction with chiral 1-oxyallyllithium derivatives.

Scheme 2.5) was recently reported by Komatsu, Minakata, and coworkers [12]. The reaction with the (i ,i )-complex 12 provided the first reagent-controlled asymmetric aziridination of conjugated dienes, although enantioselectivities were only low to moderate (20-40% ee). 

The enantioselectivity of these reagents is explained by comparison of transition structures 72 and 73 shown in Scheme 7. The disfavored transition structure 73 leading to the minor enantiomer displays a steric interaction between the methylene of the allylic unit and the methyl group of one of the pinane units. Unlike the tartrate boronates described above, the directing effect of the bis(isopinocampheyl) allylic boranes is extremely powerful, giving rise to high reagent control in double diastereoselective additions (see section on Double Diastereoselection ). 

By enantiotopos-differentiating deprotonation the lithiated complex is formed in a reagent-controlled reaction with excellent selectivity. The lithiated center of the complex is assumed to have the S configuration, as follows from the carboxylation, to give an (7 )-lactic acid derivative based on the reasonable assumption of metalloretentive electrophilic attack. Trapping with chlorotrimethylstannane gave the corresponding chiral (.S -SjS-dimethyl-l-trimethylstannyl-alkyl-l-oxa-4-azaspiro[4.5]decane-4-carboxylates. Enantioselectivity of the overall transformation is excellent. 

BBN effects the hydration of the C=C double bond of 1-methylcyclohexene according to Figure 3.25 in such a way that after the oxidative workup, racemic 2-methyl-l-cyclohexanol is obtained. This brings up the question Is an enantioselective H20 addition to the same alkene possible The answer is yes, but only with the help of reagent control of stereoselectivity (cf. Section 3.4.2). 

This particular methodology has been used extensively for the DKR of a wide variety of structurally related /3-keto-esters to give /3-hydroxy-esters, such as rac-75 yielding (S,S)-76 (equation 10) " " and rac-77 yielding (R,R)-79 (equation 11) ", with excellent diastereo- and enantioselectivities. The diastereoselectivity can be influenced using reagent control. 

The first substrate which was asymmetrically hydroborated using IPC2BH was c/s -2-butene, and the enantiomeric purity of the product 2-butanol (87% ee) obtained in this preliminary experiment was spectacular (eq 2), since Ipc2BH was made from a-pinene of low optical purity. This reaction represents the first nonenzymatic asymmetric synthesis for achieving high enantioselectivity. Its discovery marked the beginning of a new era of practical asymmetric synthesis obtained via reagent control. ... 

Carbonyl Allylation and Propargylation. Boron complex (8), derived from the bis(tosylamide) compound (3), transmeta-lates allylstannanes to form allylboranes (eq 12). The allylboranes can be combined without isolation with aldehydes at —78°C to afford homoallylic alcohols with high enantioselectivity (eq 13). On the basis of a single reported example, reagent control might be expected to overcome substrate control in additions to aldehydes containing an adjacent asymmetric center. The sulfonamide can be recovered by precipitation with diethyl ether during aqueous workup. Ease of preparation and recovery of the chiral controller makes this method one of the more useful available for allylation reactions. 

Important limitations were observed with regard to reagent control in reactions with highly sterically hindered aldehydes involving a chiral hydroxy function at the p position (Eq. 58) [43g]. When (S)-3f was used for 32, diastereo- and enantioselectivity were less satisfactory. When (l )-3f was used, however, the reaction proceeded more smoothly to give the corresponding aldols with moderate syn selectivity in 87 % yield. Each of the isomers obtained was almost enantiomericaUy pure. The spatial orienta-... 

Reagent-control strategy (external control) Powerful enantiomerically pure catalysts or auxiliaries are used for constructing chiral molecules in a diastereo- and enantioselective manner. Using this strategy, it is often possible to enhance or reverse... 

The reaction of the (Z)-crotyldiisopinocampheylborane derived from (+-)-a-pinene with aldehydes at -78 °C, followed by oxidative workup, furnishes the corresponding j yn-P-methylhomoallyl alcohols with 99% diastereoselectivity and 95% enantioselectiv-ity. Use of (Z)-crotyldiisopinocampheylborane derived from (-)-a-pinene also produces 5yn-alcohols with 99% diastereoselectivity but with opposite enantioselectivity, an example of reagent control. 

Catalysis of D-A reactions by Lewis acids makes it possible to conduct the cycloadditions under mild conditions, which promotes higher levels of diastereoselection and enantioselection in comparison to the thermally induced reactions. Control over the formation of single diastereomers or enantiomers in D-A reactions may be achieved using chiral promoters functioning either as chiral auxilliaries substrate control) or chiral catalysts reagent control). 

The reactions of selected achiral aldehydes with the allyl- and 2-butenylboro-nates 195, ( )- and (Z)-196, and 197 illustrate the power of reagent control in synthesis (Table 10-16). The highest enantioselectivities were observed with the... 

An alternative approach to 1,4-addition affording / -amino acid derivatives, by use of Lewis acid-hydroxyamine hybrid reagents (LHHR), was also investigated [122]. LHHR were ten times more reactive than benzylhydroxyamine itself. This reagent-controlled asymmetric 1,4-addition using aluniinum-hydroxyamine complexes resulted in moderate enantioselectivity (43-71% ee) (Scheme 6.98). 

Kiyooka et al. have reported that stoichiometric use of chiral oxazaborolidines (e.g. (S)-47), derived from sulfonamides of a-amino acids and borane, is highly effective in enantioselective aldol reactions of ketene TMS acetals such as 48 and 49 (Scheme 10.39) [117]. The use of TMS enolate 49 achieves highly enantioselective synthesis of dithiolane aldols, which can be readily converted into acetate aldols without epimerization. The chiral borane 47-promoted aldol reaction proceeds with high levels of reagent-control (Scheme 10.40) [118] - the absolute configuration of a newly formed stereogenic center depends on that of the promoter used and not that of the substrate. 

Controlling enantioselectivity at the enol centre alone can be achieved with special reagents and a very complex catalyst. An allylic carbonate with a fluorinated esterifying group allylates a prochiral enolate derived from i-propyl cyanopropionate catalysed by Pd, Rh, and the chiral Fe TRAP ligand 257, gives excellent results. The explanations for these last two examples are complicated and you are referred to the papers if you want to know more.60... 

Scheme 8.9c shows how the aldehyde could be homologated to a new allylic alcohol and how simple choice of tartrate ligand afforded the diastereomeric epoxides shown, since the AE process effectively ignores the resident stereocenter in the new substrate. This is the essence of reagent-controlled synthesis the utilization of a tool for enantioselective elaboration to permit the selective synthesis of diastereomeric compounds. Once prepared, the utilization of the diisobutyl aluminum hydride variant of the iterative sequence followed by final deprotection steps led to the synthesis of L-allose. A useful exercise is to arbitrarily draw an isomer of allose and synthesize it using this technique (on paper, of course), or to imagine a modification that would lead to the corresponding pentoses [47]. 

Another example of reagent control can be found in the Sharpless epoxidation of 7. With achiral reagents in the absence of a tartrate ligand, there is weak stereoselection. The tartrate-based catalysts control the enantioselectivity, although there is a noticeable difference between the matched and mismatched pairs. 

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