Prochiral nucleophiles enantioselective allylation

This reinforced the expectation that simple chiral ligands would not be able to produce useful levels of enantioselectivity at the nucleophilic center. Since then a number of workers have devised chiral ligands specifically designed for inducing enantioselectvivity at the nucleophilic center of prochiral nucleophiles in allylic alkylations [35]. In 1982 Kumada and coworkers constructed a series of lig-... 

A final approach to enantioselective allylic substitution is the reaction of prochiral nucleophiles with allylic esters. In this case, the stereocenter is not generated on the allyl unit it is generated at the nucleophilic carbon. This chemistry has been conducted with cyanoesters and related unsymmetrical stabilized carbon nucleophiles, including azlactones, which are a protected form of ammo acids. This generation of a stereocenter in the nucleophile is thought to be particularly challenging because the position at which the stereocenter is formed is further from the metal than it is in reactions that form a stereocenter at the allyl group. 

Trost and his co-workers succeeded in the allylic alkylation of prochiral carbon-centered nucleophiles in the presence of Trost s ligand 118 and obtained the corresponding allylated compounds with an excellent enantioselec-tivity. A variety of prochiral carbon-centered nucleophiles such as / -keto esters, a-substituted ketones, and 3-aryl oxindoles are available for this asymmetric reaction (Scheme jg) Il3,ll3a-ll3g Q jjg recently, highly enantioselective allylation of acyclic ketones such as acetophenone derivatives has been reported by Hou and his co-workers, Trost and and Stoltz and Behenna - (Scheme 18-1). On the other hand, Ito and Kuwano... 

When a prochiral nucleophile is reacted with 1,3-disubstituted allylic systems, the issue of diastereo- as well as enantioselectivity arises. In the alkylation of a tetralone, both the acyclic... 

Kagan was the first to study reactions in which enantioselectivity at a prochiral nucleophile was examined. In the reaction of 2-acetyltetralone with allylic ethers in the presence of a chiral DIOP-Pd catalyst, Eq. (10), the allylated products were obtained with ee s of only 10% [34]. 

The cascade process was initially explored with prochiral trienyl iodide 44 (Scheme 16.11) [36, 37]. Mizoroki-Heck cyclization of this precursor produced -ally(palladium species 45, which was trapped by acetate at the least-hindered terminus of the ry -aWyl system to provide CM-bicyclo[3.3.0]octadiene 46 in 60% yield, albeit with very low enantioselectivity (20% ee). Attempts to use silver salts as halide scavengers in this reaction led to the decomposition of 44, presumably resulting from the sensitivity of the cyclopentadienyl moiety. Mizoroki-Heck cyclization of prochiral vinyl triflate 47 with Pd(OAc)2, (S)-BINAP and tetrabutylammonium acetate was more productive, giving diquinane product 48 in excellent yield and 80% ee (Scheme 16.12). The corresponding allylic amine 49 was obtained in analogous fashion using benzylamine as the nucleophile [38]. Allylic acetate 48 was elaborated in seven steps to triquinane /3-ketoester 50, an intermediate in Shibasaki and coworkers [39] earlier total syntheses of ( )-A -capnellene-3/3,8/3,10a-triol (51) and )-A. -c3i me ene-5p, P,l0a,lA-i xdiO (52). 

When prochiral nucleophiles are employed with more complex allyl electrophiles, there is the possibility of forming two sterocenters in the product (Scheme 32). For example, imino phosphonate 147 has been used as the nucleophile in the reaction with allyl acetate 4. The control of enantioselectivity at the benzylic position is very high, but there is lower relative stereocontrol at the newly formed stereocenter a to the phosphonate group.f ... 

Moving away from ketones to other prochiral nucleophiles has also been an important goal in our group. We choose to explore lactam-derived substrates in part because we envisioned that the products formed would be useful intermediates in the synthesis of various alkaloids and because we would be able to modulate the electronics and sterics of the lactam enolate by attaching different groups at nitrogen with the aim of optimizing the enantioselectivity of the allylic alkylation. In the event, we chose to initially test tosyl-protected lactam allyl ester 29 and Boc-protected lactam aUyl ester 30 with two Pd PHOX catalysts in several solvents (Scheme 18). 

Whereas preparation of a-amino acid derivatives by asymmetric allylation of an acyclic iminoglycinate gave a modest enantioselectivity (62% ee) in an early investigation [189], the use of conformationally constrained nucleophiles in an analogous alkylation resulted in high selectivities (Scheme 8E.43) [190], With 2-cyclohexenyl acetate, the alkylation of azlactones occurred with good diastereomeric ratios as well as excellent enantioselectivities. This method provides very facile access to a variety of a-alkylamino acids, which are difficult to synthesize by other methods. When a series of azlactones were alkylated with a prochiral gem-diacetate, excellent enantioselectivities were uniformly obtained for both the major and minor diastereom-ers (Eq. 8E.20 and Table 8E.12). 

An interesting use of the nickel-catalyzed allylic alkylation has prochiral allylic ketals as substrate (Scheme 8E.47) [206]. In contrast to the previous kinetic-resolution process, the enantioselectivity achieved in the ionization step is directly reflected in the stereochemical outcome of the reaction. Thus, the commonly observed variation of the enantioselectivity with respect to the structure of the nucleophile is avoided in this type of reaction. Depending on the method of isolation, the regio- and enantioselective substitution gives an asymmetric Michael adduct or an enol ether in quite good enantioselectivity to provide further synthetic flexibility. 

Alcohols can be obtained from many other classes of compounds such as alkyl halides, amines, al-kenes, epoxides and carbonyl compounds. The addition of nucleophiles to carbonyl compounds is a versatile and convenient methc for the the preparation of alcohols. Regioselective oxirane ring opening of epoxides by nucleophiles is another important route for the synthesis of alcohols. However, stereospe-cific oxirane ring formation is prerequisite to the use of epoxides in organic synthesis. The chemistry of epoxides has been extensively studied in this decade and the development of the diastereoselective oxidations of alkenic alcohols makes epoxy alcohols with definite configurations readily available. Recently developed asymmetric epoxidation of prochiral allylic alcohols allows the enantioselective synthesis of 2,3-epoxy alcohols. 

Having demonstrated the potential of artificial metalloenzymes for the reduction of V-protected dehydroaminoacids, we turned our attention towards organometallic-catalyzed reactions where the enantiodiscrimination step occurs without coordination of one of the reactants to the metal centre. We anticipated that incorporation of the metal complex within a protein enviromnent may steer the enantioselection without requiring transient coordination to the metal. In this context, we selected the palladium-catalyzed asymmetric allylic alkylation, the ruthenium-catalyzed transfer hydrogenation as well as the vanadyl-catalyzed sulfoxidation reaction. Indeed, these reactions are believed to proceed without prior coordination of the soft nucleophile, the prochiral ketone or the prochiral sulfide respectively. Figure 13.5. 

The mechanisms of the reactions of the cluster Ru3(CO)i2 with halide ions, alkoxide ions and amines, all of which involve initial rapid nucleophilic addition at a carbonyl hgand, have been reviewed.In a related study, addition of 5-proline methylester or 5-methoxymethyl pyrrolidine to a carbonyl ligand of Ru3(CO)j2 has yielded chiral carbamoyl clusters of the type (84) R = C02Me or CH20Me, Eq. (16). Such chiral clusters may have potential as new enantioselective catalysts, as shown by the observation that cluster (84), R = CH20Me) catalyzes the isomerization of the prochiral allylic alcohol nerol to give the chiral aldehyde citronellal with an enantiomeric excess of 12%. 

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