Asymmetric a-alkylation

In view of this background, we developed a new chiral auxiliary to allow for the first time the efficient asymmetric a-alkylation of sulfonamides [90]. After testing some amine auxiliaries mainly based on proline, which did not show high diastereoselectivities, we synthesized the 4-biphenyl-substituted 2,2-dimethyl-l,3-dioxan-5-amine 108 as a new auxiliary. The racemate obtained according to Erlenmeyer s phenylserine synthesis was resolved with tartaric acid to give both enantiomers. 

Early investigations have demonstrated that aldehydes and ketones can be enantioselectiveiy a-alkyl-ated via Michael reactions of the corresponding enamines, prepared from proline-derived secondary amines.149-156 However, optical purities of the products were generally low and never exceeded 59% ee.iS1 This kind of asymmetric a-alkylation could later be improved, allowing for example the preparation of compound (141) with high ee (Scheme 51).156-160... 

The asymmetric a-alkylation of carbonyl compounds is a fundamental reaction. Under PTC conditions, acidic substrates such as phenylketone derivatives can be used to create chiral stereogenic centers. Andrus demonstrated asymmetric glycolate alkylation with up to 90% ee using various electrophiles and its application to the synthesis of (-)-ragaglitazar in six steps (Scheme 3.16) [37-39]. 

It is worth mentioning that chiral N,N-dialkylhydrazones (SAMP, RAMP) had been introduced by Enders for asymmetric a-alkylation of carbonyl compounds [29], and addition of organometallic reagents to the C=N bond had also been demonstrated ([30] selected organometallic additions to other chiral hydrazones [31-34]). However, the SAMP and RAMP hydrazones require a multistep preparation, and lacked a carbonyl function for two-point binding, which we regarded as a key design element (see below). 

Nicewicz and MacMillan merged later photoredox catalysis and asymmetric organocatalysis to an efficient approach to the otherwise difficult asymmetric a-alkylation of aldehydes 118 by activated alkyl bromides 117 (Fig. 30) [183]. The concept of face differentiation at the a-position of aldehydes via chiral enamines 121 provides the basis for the method. This allows the formation of functionalized... 

The major diastereomer 95 could be obtained in optically pure form by silica gel chromatography. The absolute configuration of the amination product was dictated by the choice of the chiral diamine, and correlated with previous results in asymmetric a-alkylation. Furthermore, the major diastereomer 95 was converted to the corresponding (ft)-a-aminoethyl phosphonic acid 96 by sequential treatment with (i) TFA, CH2C12,0 °C (ii) 1 N HC1 and (iii) H2, Pt02,70 psi, followed by Dowex 50 (H+) resin chromatography in 73 % overall yield. Optical rotation of the a-amino phosphonic acid 96 allowed the confirmation of its optical purity (> 98 %) and of its absolute configuration. 

It is worthwhile to apply the memory of chirality principle to asymmetric alkylation of a-amino acids because nonproteinogenic a,a-disubstituted-a-amino acids are important class of compounds in the fields of medicinal and biological chemistry.21 Typical methods for their asymmetric synthesis involve chiral auxiliary-based enolate chemistry 22-24 However, the most straightforward synthesis would be direct asymmetric a-alkylation of the parent a-amino acids in the absence of external chiral sources. Asymmetric... 

Scheme 2. Asymmetric a-alkylation of a substituted phenylalanine (Boc = tert-butoxycarbonyl).

The report includes details for asymmetric a-alkylation of a symmetrical ketone (97% ee) via the SAMP hydrazone and references to other stereoselective reactions of SAMP (or RAMP) hydrazones. Under standard conditions (LDA, 0°), deprotonation takes place regioselectively at the less substituted a-position with uniform dia.stereoface differentiation. 

Asymmetric a-alkylatlon of ketones (7, 10-11 8, 16-17). Enders and Eichenauer have now obtained almost complete asymmetric a-alkylation of acyclic ketones by way of hydrazones formed with 1. An example is the synthesis of (+)-(S)-4-methyl-3-heptanone (4), an ant alarm pheromone, from diethyl ketone. The hydrazone 2 was metalated and alkylated with n-propyl iodide in ether to give 3. 

D. Asymmetric a-Alkylation with a Chiral Lewis Acid. 363... 

SCHEME 10.71 WAcylated sugar-derived chiral oxazolidinones are substrates for asymmetric a-alkylation reactions. 

Besides the asymmetric a-alkylation of a-amino add derivatives described above, a-substitution of other types of carbonyl compounds using cinchona PTCs have been adively developed as well. In 1990, Vandewalle and coworker used the asymmetric alkylation of isotetralone derivative 55 with 1,5-dibromopentane using... 

In 2004, Kim and coworker developed their own cinchona PTCs containing a specific bulky aryl moiety, 3,5-di-tert-butyl-4-methoxybenzyl group, such as 75, and applied them to the asymmetric a-alkylation of the cyclic [i-kctocstcrs, for example, 2-(ethoxycarbonyl)-l-indanone73 (n — 0) or 2-(cthoxycarbonyl)-1 -tctralonc 73 (n— 1) as shown in Scheme 6.22 [47]. The enantioselectivities showed a considerable variation (44—99% ee) depending on the nature of electrophile. 

The immobilized Evans chiral auxiliary 56 has also been employed in asymmetric a-alkylation of resin-bound propionic amide [13, 27]. Reductive cleavage afforded the a-benzylated propanol (2-methyl-3-phenylpropanol). 

Asymmetric a-alkylation of amines was achieved applying an immobilized chiral sulfonamide (Scheme 12.29) [13, 40]. To synthesize auxiliary 76, a tertiary alcohol (73) was converted into Grignard reagent 74. Addition of sulfur dioxide and subsequent chlorination furnished the sulfinyl chloride 75. Reaction with (S)-2-amino-l,l,2-triphenylethanol, followed by reduction, hydroboration and... 

Owens, T.D., Souers, A.J. and Ellman, J.A. (2003) The preparation and utility of bis(sulfinyl) imidoamidine ligands for the copper-catalysed Diels-Alder reaction. The Journal of Organic Chemistry, 68, 3-10 Kochi, T. and Ellman, J.A. (2004) Asymmetric a-alkylation of N -tert-butanesulfinyl amidines. Application to the total synthesis of (6R,75)-7-amino-7,8-dihydro-a-bisabolene. Journal of the American Chemical Society, 126, 15652-15653. 

Liebscher and co-workers reported a general method of preparing optically active 2-(a-aminoalkyl)oxazoles 1167 via an asymmetric a-alkylation of 2-(ami-nomethyl)-4,5-diphenyloxazole 1164 (Scheme 1.301). Their work complements the known methodology for asymmetric a-alkylation of other aminomethyl hetero-cycles. Thus Lewis acid-catalyzed condensation of 1164 with commercially available (IS, IS, 5S)-2-hydroxypinanone generated (IS, 2S, 5S)-3-(4,5-diphenyl-oxazol-2-ylmethylimino)-2,6,6-trimethylbicyclo[3.1.1]heptan-2-ol 1165 in 65% yield. 

TABLE 1.80 OPTICALLY ACTIVE 2-(a-AMINOMETHYL)OXAZOLES FROM ASYMMETRIC a-ALKYLATION OF 2-(AMINOMETHYL)-4,5-DIPHENYLOXAZOLE, 255... 

L-proline and derivatives function as effective catalysts in the a-fimctionahsation of aldehydes with a range of heteroatomic species (see Section 5.3) and Vignola and List have attempted to apply this methodology to the asymmetric a-alkylation. While the intermolecular reaction has proved unsuccessful, high ees in the cycli-sation of aldehydes such as (12.53) have been achieved using (S)-a-methylproline (12.52). 

In 2004 List and Vignola proposed the use of 7a to tackle the challenging asymmetric a-alkylation of aliphatic aldehydes. The transformation itself is complicated by the possibility of many side reactions, among which are self-aldolisation and N-alkylation of the amine catalyst, producing a cataly-tically inactive tertiary ammonium salt. Thus, when the proline-catalysed reaction between cyclohexanone or propanal and benzylbromide was tested, only the products of proline benzylation were identified. Luckily, the intramolecular a-allg lation worked successfully and after a screening of several proline derivatives and different amines, 7a was identified as the catalyst of choice (Scheme 11.6). Bromides and iodides may be used efficiently in these reactions, whereas tosylates gave particularly slow reactions. 

Scheme 11.35 Michael addition of propionaldehyde to ( )-p-nitrostyrene (A) and asymmetric a-alkylation of /2-octanal (B) using pyrrolidines (5)-35c and (5)-35d.

These are potent phase transfer organocatalysts for asymmetric a-alkylation of A/-arylideneglycine fert-butyl ester derivatives for the synthesis of chiral a-substituted a-amino acids at extremely low concentrations of catalyst [Ooi et al. Tetrahedron Asymm 17 603 2006],... 

Jang and co-workers explored the asymmetric a-alkylation of aldehydes with xanthene by merging electro-oxidation and organocatalysis to synthesize the corresponding xanthene-derived benzylic products 65a in up to 68% yield and 68% ee (Scheme 2.22). This study showed that anodic oxidation, in addition to stoichiometric amounts of chemical oxidation, was applicable to the benzylic C—H bond functionalization for coupling with enamine. 

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