Enantiomerically enriched 4-substituted

Firooznia has reported the synthesis of 4-substituted phenylalanine derivatives via cross-coupling of protected (4-pinacolylboron)phenylalanine derivatives such as 61 with aryl and alkenyl iodides, bromides and triflates [44]. They have further shown that BOC derivatives of (4-pinacolylboron)phenylalanine ethyl ester 61 or the corresponding boronic acids undergo Suzuki-Miyaura reactions with a number of aryl chlorides in the presence of PdCl2(PCy)3 or NiCl2(dppf), respectively providing diverse sets of 4-substituted phenylalanine derivatives of type 62 [45]. This strategy has also been used for the synthesis of enantiomerically enriched 4-substituted phenylalanine derivatives (Scheme 3.28) [46]. 

The tartaric acid scaffold also led to the design of one of the most effective and general methods to generate enantiomerically enriched substituted cyclopropyhnethanol derivatives. Indeed, the chiral dioxaborolane ligand 19, prepared from tetramethyltartramide and butylboronic acid, is a superb chiral additive in allylic alcohol-directed cyclopropanation reactions (equation 83) . The best procedure requires the use of the soluble bis(iodomethyl)zinc DME complex . The reaction affords high yields and enantiomeric... 

Starting from a single and stereochemically well-defined diene, it is possible to generate enantiomerically pure acyclic ( 7 -pentadienyl)iron complexes that provide a route to enantiomerically enriched substituted dienes. The optically active leukotriene 49 has been synthesized from the acyclic [l-methoxycarbonyl-( 7 -pentadienyl)]iron cation 50 in a key step that involves nucleophilic addition of an organocuprate to the G5 position (Scheme... 

The a-substitution of enantiomerically enriched (-)-sparteine complexes of lithioalkenyl carbamates with methyl chloroformate76 or carbon dioxide77, in a manner contrary to a former assumption 76, proceeds with inversion of the configuration 131 131, leading to optically active 3-alkenoic acid esters. 

The synthesis of enantiomerically enriched vinyl carbamates is described in Section 1.3.3.3.8.2.2. by applying this procedure, these were also obtained efficiently in the racemic form. Some further examples of substituted carbamates are collected below ... 

The protocol of the allylic alkylation, which proceeds most likely via a c-allyl-Fe-intermediate, could be further improved by replacing the phosphine ligand with an M-heterocyclic carbene (NHC) (Scheme 21) [66]. The addition of a ferf-butyl-substituted NHC ligand 86 allowed for full conversion in the exact stoichiometric reaction between allyl carbonate and pronucleophile. Various C-nucleophiles were allylated in good to excellent regioselectivities conserving the 71 bond geometry of enantiomerically enriched ( )- and (Z)-carbonates 87. Even chirality and prochirality transfer was observed (Scheme 21) [67]. 

This homoenolate methodology has been extended to the use of nitrones 170 as electrophiles [72]. Scheldt and co-workers have shown that enantiomerically enriched y-amino esters 172 can be prepared with excellent levels of stereocontrol from an enal 27 and a nitrone 170 using the NHC derived from triazolium salt 164 (Scheme 12.37). The oxazinone product 171, formally a result of a [3-1-3] cycloaddition, is cleaved to afford the y-amino ester product 172. The reaction shows broad substrate scope, as a range of substituted aryl nitrones containing electron donating and withdrawing substituents are tolerated, while the enal component is tolerant of both alkyl and aryl substituents. 

The catalytic enantioselective desymmetrization of meso compounds is a powerful tool for the construction of enantiomerically enriched functionalized products." Meso cyclic allylic diol derivatives are challenging substrates for the asymmetric allylic substitution reaction owing to the potential competition of several reaction pathways. In particular, S 2 and 5n2 substitutions can occur, and both with either retention or inversion of the stereochemistry. In the... 

The pivotal role of natural a-amino acids among a myriad of biologically active molecules is widely appreciated, and is of particular importance in the pharmaceutical industry. Unnatural a-amino acids also have a prominent position in the development of new pharmaceutical products. It has been shown that substitution of natural a-amino acids for unnatural amino acids can often impart significant improvements in physical, chemical and biological properties such as resistance to proteolytic breakdown, stability, bioavailability, and efficacy. One of the many synthetic methods available for the production of enantiomerically enriched a-amino acids is the metal-catalyzed enantioselective reduction of a-de-hydroamino acid derivatives [90]. 

Due to the distance between the stereogenic center and the place of the nucleophilic attack, the enantioselective 1,5-substitution of chiral enyne acetates constitutes one of the rare cases of remote stereocontrol in organocopper chemistry. Moreover, the method is not limited to substrate 51, but can also be applied to the synthesis of enantiomerically enriched or pure vinylallenes 53-57 with variable substituent patterns (Scheme 2.20) [28]. 

Scheme 2.20 Enantiomerically enriched or pure vinylallenes formed by 1,5-substitution of chiral enyne acetates in the presence of tri-n-butylphosphine (53-56) or triethyl phosphite (57).

A propargyl substrate having a substituent at the propargyl position is centrally chiral and an allenic product from the SN2 substitution reaction will be axially chiral. Chirality transfer in the SN2 reaction, accordingly, may be achieved starting from an enantiomerically enriched propargyl electrophile [29]. The reactions in Scheme 3.11 are some recent examples of the center to axis chirality transfer by Pd-catalyzed SN2 reactions [41, 42]. 

Aryl- and alkylsulfonyl radicals have been generated from the corresponding iodides and added to, e.g., propadiene (la), enantiomerically enriched (P)-(+)-propa-2,3-diene [(P)-(lc)] and (P)-(-)-cyclonona-l,2-diene [(P)-(lk)] [47]. Diaddition of sulfo-nyl radicals may compete considerably with the monoaddition [48,49]. Also, products of diiodination have been purified from likewise obtained reaction mixtures, which points to a more complex reactivity pattern of these substrates towards cumulated Jt-bonds. An analysis of regioselectivities of arylsulfonyl radical addition to allenes is in agreement with the familiar trend that a-addition occurs in propadiene (la), whereas alkyl-substitution at the cumulated Jt-bond is associated with a marked increase in formation of /3-addition products (Scheme 11.7). 

Irradiation of the enantiomerically enriched allenenone 42 afforded alkylididecy-clobutane 43 with high levels of chirality transfer. The silyl moiety of optically active allenylsilanes 44 and 47 functioned as a removable auxiliary to control the stereochemistry. Thus, the silyl-substituted photoadducts 45 and 48 underwent protode-silylation on treatment with TBAF to give the unsubstituted exo-mcth ylenccyclo-butanes 46 and 49, respectively [46]. 

In Scheme 17.2 palladium is coordinated from below, but it is also possible that it coordinates from above and forms the other enantiomer of the chiral syn,syn Jt-allyl complex. If palladium has another chiral ligand then these Jt-allyl complexes become diastereomers. Thus, from an unsymmetrically substituted allene (R R ), eight diastereomeric Jt-allyl complexes can be formed. If one of the diastereomers is preferred then further reaction of the Jt-allyl moiety leads to an enantiomerically enriched product. 

The preparation of cyclopropanes by intermolecular cyclopropanation with acceptor-substituted carbene complexes is one of the most important C-C-bond-forming reactions. Several reviews [995,1072-1074,1076,1077,1081] and monographs have appeared. In recent decades chemists have focused on stereoselective intermolecular cyclopropanations, and several useful catalyst have been developed for this purpose. Complexes which catalyze intermolecular cyclopropanations with high enantiose-lectivity include copper complexes [1025,1026,1028,1029,1031,1373,1398-1400], cobalt complexes [1033-1035], ruthenium porphyrin complexes [1041,1042,1230], C2-symmetric ruthenium complexes [948,1044,1045], and different types of rhodium complexes [955,998,999,1002-1004,1010,1062,1353,1401-1405], Particularly efficient catalysts for intermolecular cyclopropanation are C2-symmetric cop-per(I) complexes, as those shown in Figure 4.20. These complexes enable the formation of enantiomerically enriched cyclopropanes with enantiomeric excesses greater than 99%. Illustrative examples of intermolecular cyclopropanations are listed in Table 4.24. 

Better results were obtained for the carbamate of 163 (entry 3) [75, 80). Thus, deprotonation of the carbamate 163 with a lithium base, followed by complexation with copper iodide and treatment with one equivalent of an alkyllithium, provided exclusive y-alkylation. Double bond configuration was only partially maintained, however, giving 164 and 165 in a ratio of 89 11. The formation of both alkene isomers is explained in terms of two competing transition states 167 and 168 (Scheme 6.35). Minimization of allylic strain should to some extent favor transition state 167. Employing the enantiomerically enriched carbamate (R)-163 (82% ee) as the starting material, the proposed syn-attack of the organocopper nucleophile could then be as shown. Thus, after substitution and subsequent hydrogenation, R)-2-phenylpentane (169) was obtained in 64% ee [75]. 

The use of chiral catalysts as an approach to enantiomerically enriched products by means of copper-mediated substitution reactions is covered in this chapter. Reactions in vhich a chiral auxiliary resides in the leaving group of the substrate vill also be dealt vith, since these reactions provide direct and efficient routes to single enantiomers of the desired products. Most studies so far have been concerned vith allylic substrates, vith a new chiral center being produced in the course of a selective Sn2 reaction. 

A wide range of carbon, nitrogen, and oxygen nucleophiles react with allylic esters in the presence of iridium catalysts to form branched allylic substitution products. The bulk of the recent literature on iridium-catalyzed allylic substitution has focused on catalysts derived from [Ir(COD)Cl]2 and phosphoramidite ligands. These complexes catalyze the formation of enantiomerically enriched allylic amines, allylic ethers, and (3-branched y-8 unsaturated carbonyl compounds. The latest generation and most commonly used of these catalysts (Scheme 1) consists of a cyclometalated iridium-phosphoramidite core chelated by 1,5-cyclooctadiene. A fifth coordination site is occupied in catalyst precursors by an additional -phosphoramidite or ethylene. The phosphoramidite that is used to generate the metalacyclic core typically contains one BlNOLate and one bis-arylethylamino group on phosphorus. 

In another report of Singh and Han [61], Ir-catalyzed decarboxylative amidations of benzyl allyl imidodicarboxylates derived from enantiomerically enriched branched allylic alcohols are described. This reaction proceeded with complete stereospecificity-that is, with complete conservation of enantiomeric purity and retention of configuration. This result underlines once again (cf. Section 9.2.2) that the isomerization of intermediary (allyl) Ir complexes is a slow process in comparison with nucleophilic substitution. 

Ahlbrecht and coworkers showed that the stereoselective alkylation of Af-cinnamyl (5 )-2-methoxymethylpyrrolidine (STdR), followed by hydrolysis, affords enantiomerically enriched 3-substituted phenylpropionaldehydes, as shown in Scheme 45. This method is analogous to the asymmetric alkylation of S AMP/RAMP hydrazones, as the anions are isoelectronic. The mechanisms of asymmetric induction for the two systems are probably similar. For the lithio cinnamyl amine, methylation can be optimized up to 97.5% ds. Most of the procedures in this paper include potassium tert-butoxide, so the cation in these examples may be potassium. Under these conditions, methyl, primary and secondary alkyl iodides typically afford the products with selectivities in the 90-93% ds range. 

Recently, an asymmetric version of this reaction has been reported by Gong and co-workers, allowing an efficient access to highly enantiomerically enriched 4-aryl-substituted 1,4-DHPs [152]. Thus, the use of chiral phosphoric acids as catalysts allowed the preparation of the desired products with enantiomeric excesses up to 97% (Scheme 53). To illustrate the importance of this asymmetric cyclization reaction, the authors developed the synthesis of some optically active heterocycles... 

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