Chiral auxiliaries asymmetric alkylations

Boeckman, R.K., Jr, Pero, J.E. and Boehmler, D.J. (2006) Toward development of a general chiral auxiliary. Enantioselective alkylation of a new catalytic asymmetric addition of silylox-yfumas application to a total synthesis of (—)-rasfonin. Journal of the American Chemical Society, 128, 11032-11033. 

Asymmetric carbon-carbon bond formation reaction under solvent-free conditions was carried out by Bolm et al. in ball mill [58]. Here, nickel(II) complex 206 was used as a chiral auxiliary in alkylation with various bromides (Schane 2.67). Optimized reaction conditions were set to increase the stereoselectivity however, the desired monoalkylated product 207 was often accompanied by small amount of doubly alkylated side product 208. Two different bases were used (NaOMe/MgS04 or CS2CO3) and grinding of nickel complex 206 with bromides for 30-75 min afforded alkylation products in moderate to high yields and with complete stereoselectivity (selected examples. Table 2.54). 

Chiral imidazolidin-4-ones-chiral secondary amines-had already been successfully used in asymmetric synthesis before they started their own career as organo-catalysts [1]. They were deployed as chiral auxiliaries for alkylation processes [2], Michael additions [3], and aldol reactions [4], For syntheses of this class of catalyst see Reference [5]. The ability to activate both carbonyl compounds by enamine formation as well a, 3-unsaturated carbonyl compounds by intermediate formation of iminium ions makes imidazolidin-4-ones a valuable class of organocatalysts in both series. Thus, they can roughly be divided by their mode of activation into enamine [6] or iminium [7] catalysis (Scheme 4.1). These catalysts were successfully deployed in a wide range of several important enantioselective C-C bond formation and functionalization processes. Figure 4.1 shows the chiral imidazo-lidinones covered in this chapter. 

Oppolzer W, Rodriguez I, Starkemann C, Walther E. Chiral toluene-2,alpha-sultam auxiliaries—asymmetric alkylations, acylations and aldolizations of N-acyl derivatives. Tetrahedron Lett. 1990 31 5019-5022. 

Chiral oxazolines developed by Albert I. Meyers and coworkers have been employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. For example, metalation of chiral oxazoline 1 followed by alkylation and hydrolysis affords enantioenriched carboxylic acid 2. Enantioenriched dihydronaphthalenes are produced via addition of alkyllithium reagents to 1-naphthyloxazoline 3 followed by alkylation of the resulting anion with an alkyl halide to give 4, which is subjected to reductive cleavage of the oxazoline moiety to yield aldehyde 5. Chiral oxazolines have also found numerous applications as ligands in asymmetric catalysis these applications have been recently reviewed, and are not discussed in this chapter. ... 

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>. 

If the chiral auxiliary in Eq. 4.96 is modified by changing MeO into more bulky groups such as trityl (Tr) or t-butyldimethylsilyl (TBS) group, an improved asymmetric nitro-olefination of a-alkyl-y- and 8-lactones is possible (Eq. 4.97).120... 

Imide Systems. Imide compounds 22 and 23, or Evans reagents, derived from the corresponding oxazolidines are chiral auxiliaries for effective asymmetric alkylation or aldol condensation and have been widely used in the synthesis of a variety of substances. 

Table 2-5 summarizes the results of the asymmetric alkylation (Scheme 2-17) of the lithium enolates derived from 22 or 23.28 When chiral auxiliary 22 or 23 is involved in the alkylation reactions, the substituent at C-4 of the oxazolidine ring determines the stereoselectivity and therefore controls the stereogenic outcome of the alkylation reaction. 

Acylsultam Systems. Oppolzer et al.53 developed a general route to enantiomerically pure crystalline a,a-disubstituted carboxylic acid derivatives by asymmetric alkylation of A -acylsul tarns. Acylsultam 50 can be readily prepared from the inexpensive chiral auxiliary sultam 53.5 4... 

Sultam 53 has proved to be an excellent chiral auxiliary in various asymmetric C-C bond formation reactions. One more example of using sultam 53 is the asymmetric induction of copper(I) chloride-catalyzed 1,4-addition of alkyl magnesium chlorides to a,/ -disubstituted (/ )-enesultams 60. Subsequent protonation of the reaction product gives compound 61c as the major product (Scheme 2-30 and Table 2-11).56... 

As with the above pyrrolidine, proline-type chiral auxiliaries also show different behaviors toward zirconium or lithium enolate mediated aldol reactions. Evans found that lithium enolates derived from prolinol amides exhibit excellent diastereofacial selectivities in alkylation reactions (see Section 2.2.32), while the lithium enolates of proline amides are unsuccessful in aldol condensations. Effective chiral reagents were zirconium enolates, which can be obtained from the corresponding lithium enolates via metal exchange with Cp2ZrCl2. For example, excellent levels of asymmetric induction in the aldol process with synj anti selectivity of 96-98% and diastereofacial selectivity of 50-200 116a can be achieved in the Zr-enolate-mediated aldol reaction (see Scheme 3-10). 

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted much interest for their various applications in different synthetic transformations.2 Such simple structures, directly related to far better known chiral oxazolidinones,11,12,57 have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations, but mainly in condensation of their /V-acyl derivatives with aldehydes. Chiral OZTs have shown interesting characteristics in anti-selective aldol reactions58 or combined asymmetric addition. 

In the asymmetric reduction of ketones, stereodifferentiation has been explained in terms of the steric recognition of two substituents on the prochiral carbon by chirally modified reducing agents40. Enantiomeric excesses for the reduction of dialkyl ketones, therefore, are low because of the little differences in the bulkiness of the two alkyl groups40. In the reduction of ketoxime ethers, however, the prochiral carbon atom does not play a central role for the stereoselectivity, and dialkyl ketoxime ethers are reduced in the same enantiomeric excess as are aryl alkyl ketoxime ethers. Reduction of the oxime benzyl ethers of (E)- and (Z)-2-octanone with borane in THF and the chiral auxiliary (1 R,2S) 26 gave (S)- and (R)-2-aminooctane in 80 and 79% ee, respectively39. 

The optical yield was found to be very sensitive to structural modifications of the achiral agent. For example, use of the more bulky FV or Bu substituents in the 3,5-positions of phenol resulted in lower optical yields. In some cases a reversal of the sense of asymmetric induction was observed. Systematic variation of reaction conditions using the best achiral component, 3,5-xylenol, established that optimum results were obtained in ether solvent at about - 15°C. There was also a minor but definite influence of the rate of addition of ketone as well as an effect of concentration on optical yield, with a slower rate being advantageous. The results of reduction of aryl alkyl ketones are shown in Table 9, along with comparative results of reduction with similar chiral auxiliary reagents. 

Figure 2. Asymmetric alkylations with chiral auxiliaries.

The diastereomerically related keto esters 53 and 55, activated for removal of the chiral auxiliary, were obtained from 5 and 9. The requisite nitrogen atom was introduced by an azide displacement of chloride and at an opportune stage of the synthesis an intramolecular aminolysis of the carboxylic ester provided the enantiomerically related keto lactams 54 and 56. Although shorter routes to these popular synthetic targets have been reported in recent years, the conversion of 9 to (—)-iso-nitramine (ten steps, 50% overall yield) clearly illustrates the efficiency of the asymmetric Birch reduction-alkylation strategy for construction of the azaspiroundecane ring system. 

Chiral benzamides I and the pyrrolobenzodiazepine-5,11-dio-nes n have proven to be effective substrates for asymmetric organic synthesis. Although the scale of reaction in our studies has rarely exceeded the 50 to 60 g range, there is no reason to believe that considerably larger-scale synthesis will be impractical. Applications of the method to more complex aromatic substrates and to the potentially important domain of polymer supported synthesis are currently under study. We also are developing complementary processes that do not depend on a removable chiral auxiliary but rather utilize stereogenic centers from the chiral pool as integral stereodirectors within the substrate for Birch reduction-alkylation. 

Gawley and coworkers showed that oxazolines can be used in place of formamidines for asymmetric alkylations of tetrahydroisoquinolines. A number of substituted oxazolines were evaluated as chiral auxiliaries, and one derived from valinol was found to be optimal. Interestingly, the same enantiomer of valinol affords the opposite enantiomers of the substituted tetrahydroisoquinoline when incorporated into formamidine or oxazoline auxiliaries. An example is shown in Scheme 58, as applied to a synthesis of laudanosine and the morphinan 9-7 -0-methylflavinantine. ° ... 

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

Conversion of 2 to the highly crystalline oxazolidinone 3 with phosgene has been described by Thornton who has employed this substance as a chiral auxiliary in asymmetric aldol reactions of its N-propionyl derivative. Kelly has also used an oxazoline derived from 3 as a chiral auxiliary in asymmetric alkylation of a glycolate enolate. Oxazolidinone 3 has also been prepared from 2 with diethyl carbonate in the presence of potassium carbonate. The conversion of 2 to the oxazolidinone 3 is accomplished using triphosgene in this procedure because of the high toxicity of phosgene. 

The A -acyl derivatives of 4-substituted-3,4,5,6-tetrahydro-27/-l,3-oxazin-2-ones proved to behave as effective chiral auxiliaries in asymmetric enolate alkylations and aldol reactions, the stereoselectivities of which were found to be higher for 4-isopropyl than for 4-phenyl derivatives <2006OBC2753>. The transformations of 4-isopropyl-6,6-dimethyl-3-propa-noyl-3,4,5,6-tetrahydro-2/7-l,3-oxazin-2-one 251 to 252 or 253 proceeded with excellent diastereoselectivities (Scheme 47). 6,6-Dimethyl substitution within the oxazine ring facilitated exclusive exocyclic cleavage upon hydrolysis of the C-alkylated and the aldol products 252 and 253, to furnish a-substituted carboxylic acids 254 or a-methyl-/ -hydroxycarboxylic acids 256. 

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