C2-symmetric reagents

With C2-symmetric reagents (5,5)-2,5-dimethyl-l-trifluoromethylsulfonylborolane34 and (R,R)-l-chloro-2,5-diphenylborolane , (S)-(3-ethylpent-3-yl) thiopropanoate is added, via the corresponding enolates, to aldehydes with remarkable auxiliary-induced stereoselectivity. Thus, /1-hydroxy thioestcrs arc obtained with 87-94% ee when the borolanyl triflate auxiliary reagent is used. These ee values do not exactly reflect the enantiofacial selectivity since the borolane is not available in enantiomerically pure form (see Section 1.3.4.2.2.2.). Use of the chiral chloroborolane auxiliary gives the thioestcrs with 95-96% cc70,11. o... 

Use of the valine derived (4S )-3-acetyl-4-isopropyl-1,3-oxazolidine (8)92, the C2-symmetric reagents (2.5,55)-l-acetyl-2,5-bissubstituted pyrrolidine 994, or the doubly deprotonated acetyl urea /V-acetyl- V..V -bis[(.S)-l-phcnylethyl]urea (10), also does not lead to sufficient induced stereoselectivity combined with acceptable chemical yield. When the acetyl urea enolate is reacted with aliphatic and aromatic aldehydes, the diastereomeric adducts (ratios ranging from 1 1 to 3 1) may be separated by column chromatography to give ultimately both enantiomers of the 3-hydroxy acids in 99% ee110. 

To overcome this problem, Whitesell and Felman [19] introduced the use of a C2-symmet-ric chiral auxiliary, (S,S)-trans 2,5-dimethylpyrrolidine, to generate the enamine (reaction E). Rotation around the N-C bond simply results in a topomerization [5] and, therefore, in the reduction of the number of the non-stereocontrolled attacks by the electrophile. Since the appearance of this seminal paper, C2-symmetric reagents have become a standard tool in the hands of the organic chemists interested in stereoselective synthesis [20]. 

Reactions of enantiotopic faces "e" are either afacioselective (ql) or nonfacioselective with achiral reagents (ql0,qll,ql2,ql5,ql6,ql7,ql8), but stereofacioselective (enantiofacioselective) with chiral reagents (q23,q24,q27,q37,q38,q41). With only enantio-facioselectivity at work, and no role for vectoselectivity - e.g. with C2-symmetric reagents - one would expect two chiral diastereomers (q23). With non-C2-symmetric reagents, vectoselectivity would come into play, and more complex mixtures may result (vide infra). Here, enantiofacioselectivity refers to the face type in the reactant substrate. 

Several highly enantioselective Diels-Alder reactions are known for which the di-enophile does not fit any of the above classes. Corey and coworkers applied the chiral aluminum reagent 36 with a C2-symmetric stilbenediamine moiety (videsu-pra) to the Diels-Alder reaction of maleimides as dienophiles [54] (Scheme 1.68). In most asymmetric Diels-Alder reactions the reactants are usually relatively simple dienes such as cyclopentadiene or monosubstituted butadienes, and unsym-... 

The C2-symmetric epoxide 23 (Scheme 7) reacts smoothly with carbon nucleophiles. For example, treatment of 23 with lithium dimethylcuprate proceeds with inversion of configuration, resulting in the formation of alcohol 28. An important consequence of the C2 symmetry of 23 is that the attack of the organometallic reagent upon either one of the two epoxide carbons produces the same product. After simultaneous hydrogenolysis of the two benzyl ethers in 28, protection of the 1,2-diol as an acetonide ring can be easily achieved by the use of 2,2-dimethoxypropane and camphor-sulfonic acid (CSA). It is necessary to briefly expose the crude product from the latter reaction to methanol and CSA so that the mixed acyclic ketal can be cleaved (see 29—>30). Oxidation of alcohol 30 with pyridinium chlorochromate (PCC) provides alde-... 

The highest ee s reported to date for the addition of achiral organometallic reagents in the presence of aprotic chiral additives were observed with the C2-symmetric diamines 10, 11 and 12 (Table 25)13 — 15. Enantioselectivities as high as 89% ee were observed with chiral auxiliary 1012. Addition of phenyllithium to pentanal proceeds with lower enantioselection that the analogous addition of butyllithium to benzaldehydeu. Generally, the enantioselcctivity in-... 

The latter is estimated to be at least 50 1. Unfortunately, the C2-symmetric borolane reagent is not readily available34. 

Chiral amide and imide enolates are amongst the most effective reagents providing. yv -3-hy-droxycarboxylic acids in both high simple diastereoselectivity and induced stereoselectivity, e.g., the amides 1 and 2, and especially, the imides 3 and 4 (derived from (S(-valine and (l/ ,2S)-norephedrine, respectively)93 and the C2-symmetric amide 594 are highly effective systems ... 

The reaction of butyllithium with 1-naphthaldehyde cyclohexylimine in the presence of (/C )-l,2-diphenylethane-1,2-diol dimethyl ether in toluene at —78 °C, followed by treatment with acetate buffer, gave 2-butyl-1,2-dihydronaphthalene-l-carbaldehyde, which was then reduced with sodium borohydride in methanol to afford (1 R,2.S)-2-butyl-1 -hydroxymcthyl-1,2-dihydronaphthalene in 80% overall yield with 91 % ee83. Similarly, the enantioselective conjugate addition of organolithium reagents to several a,/J-unsaturated aldimines took place in the presence of C2-symmetric chiral diethers, such as (/, / )-1,2-butanediol dimethyl ether and (/, / )- ,2-diphenylethane-1,2-diol dimethyl ether. 

Simple 1,2,4-triazole derivatives played a key role in both the synthesis of functionalized triazoles and in asymmetric synthesis. l-(a-Aminomethyl)-1,2,4-triazoles 4 could be converted into 5 by treatment with enol ethers <96SC357>. The novel C2-symmetric triazole-containing chiral auxiliary (S,S)-4-amino-3,5-bis(l-hydroxyethyl)-l,2,4-triazole, SAT, (6) was prepared firmn (S)-lactic acid and hydrazine hydrate <96TA1621>. This chiral auxiliary was employed to mediate the diastereoselective 1,2-addition of Grignard reagents to the C=N bond of hydrazones. The diastereoselective-alkylation of enolates derived from ethyl ester 7 was mediated by a related auxiliary <96TA1631>. 

Scheme 21 Diastereoselective synthesis of Ci- and C2-symmetric 1,2-diamines by addition of organometallic reagents to enantiopure a-aminoimines...

The preparation and the use of several C2-symmetric disulfonamides derived from 1,2-amino alcohols in the Ti-catalysed enantioselective addition of di-alkylzinc reagents to aldehydes was described by Yus et al., in 2002. The best... 

In 2005, a novel C2-symmetric bis(sulfonamides) ligand was easily prepared in three steps by Wang et al. and further applied to the enantioselective addition of alkynylzine reagents to aldehydes performed in the presence of Ti(Oi-Pr)4. When a catalyst loading of 4 mol% was used, a high enantioselectivity of up to 97% ee was achieved, as shown in Scheme 3.65. When the amount of the... 

In addition, the enantioselective addition of akynylzinc reagents to aromatic ketones has been developed by Wang et al. using novel C2-symmetric... 

There can be two kinds of chiral tin reagents tin chiral and C-chiral. Early reports of chiral tin hydride involved transfer of chirality via a chiral tin center [45-47]. These tin hydrides were prone to racemization. Thus, chiral carbon-based ligands attached to the tin center were synthesized to minimize racemization. The first chiral tin hydride containing a C2-symmetric binaphthyl substituent was reported by Nanni and Curran (Scheme 16) [48]. a-Bromoketone 58 was reduced by chiral tin hydride 59 (R3 = Me), where the reactivity and selectivity was dependent on the reaction conditions (entry 4). 

The use of tartrate esters was an obvious place to start, especially since both enantiomers are readily available commercially and had already found widespread application in asymmetric synthesis (Figure 11) (e.g.. Sharpless asymmetric epoxidation).23.24 Reagents 36-38 are easily prepared and are reasonably enantioselective in reactions with achiral, unhindered aliphatic aldehydes (82-86% ee) typical results are given in Figure 12.3c,h Aromatic and a,p-unsaturated aldehydes, unfortunately, give lower levels of enantioselection (55-70% e.e.). It is also interesting to note that all other C2 symmetric diols that we have examined (2,3-butanediol, 2,4-pentanediol, 1,2-diisopropylethanediol, hydrobenzoin, and mannitol diacetonide, among others) are relatively ineffective in comparison to the tartrate esters (see Table ll).25... 

An important consequence of the use of a C2 symmetric auxiiiary is that the number of competing transition states is reduced from four (as in the case of Hoffmann s bornandiol reagents) to two, thereby increasing the probabiiity that a single, selective pathway will be found. 

The alkenes 149 and 150 are easily cleaved by ozonolysis either directly or after protection of the hydroxy gronp. Depending on the workup conditions of the ozonolysis, either diols 151 or 0-protected aldehydes 152 can be obtained. The C2 symmetric ketone 153 dr 75 25) is available from another addition of the dilithium reagent 148 (R = Ph)... 

The C2 symmetric chiral diether 28" and the naturally occurring chiral diamine, (—)-sparteine (29), have been the most successful external chiral ligands for asymmetric conjugate addition of organolithium reagents. The rest of this review highlights organolithium addition, which is mediated or sometimes catalyzed by 28 or 29. 

To carry out tethered [3-i-2]-cycloadditions Nakamura et al. developed the new annulating reagents 123 [109, 110]. The reagents carry, in one molecule, two cyclopropenone acetals that are connected with an n-carbon methylene tether. Upon thermolysis in the presence of Cjq, the reagent undergoes [3-i-2]-cycloaddition reaction twice in a regio- and stereoselective manner to give Q- and C2-symmetrical bisadducts with cis-l - and cis-3-addition patterns, respectively. The selectivity varies... 

Trons-l,2-diaminocyclohexane, the most popular representative of the primary diamines and its derivatives, has been widely utilized in the field of stereoselective organometallic catalysis as chiral reagents, scaffolds, and ligands [137]. This C2 symmetrical chiral diamine first reported in 1926 by Wieland and co-workers [193] is commercially available, since it is a component in a byproduct amine stream generated during the purification of 1,6-hexanediamine that is used in the industrial Nylon 66 production. The racemic mixture of this diamine can be easily... 

Few methods are available to determine enantiomeric purity of aldehydes by NMR spectroscopy of diastereomeric derivatives. The formation of imines. oxazolidines and more recently the advantageously C2-symmetrical imidazolidines with optically pure reagents can be utilized. 

The above-mentioned study was followed by a report of the groups of Ji, Loh and coworkers, who reported the application of a catalyst based on cuprous iodide and Tol-BINAP for the same purpose . Noteworthy is that the effective use of a C2-symmetric ligand in this reaction marks the end of the aforementioned metal-differentiating coordination concept. It was shown that a variety of Grignard reagents could be used for the... 

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