Chiral auxiliaries prolinol

Prolinol-Type Chiral Auxiliaries. In this section, applications of chelation-enforced chirality transfers with nitrogen derivatives are discussed... 

Evans and Takacs23 demonstrated a diastereoselective alkylation based on metal ion chelation of a lithium enolate derived from a prolinol-type chiral auxiliary. This method can provide effective syntheses of a-substituted carbox-... 

In this reaction, prolinol serves as a chiral auxiliary, but it cannot be easily... 

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). 

There are several reports dealing with the use of tetrahydropyrrolo[l,4]oxazinones derived from natural proline or prolinol as chiral auxiliaries for the synthesis of enantiomerically pure compounds. The preparation of the heterocycle is described in Scheme 33 (Section 11.11.7.4). The presence of a rigid bicyclic skeleton allows stereoselective introduction of different substituents. The final ring opening of the system (generally by hydrolysis) provides enantiomerically pure compounds with the possibility of recycling the starting chiral auxiliary. 

The chiral auxiliary can be recycled, since methanolysis of the 1-alkylated 3-trimethylsilyl-2-propynamines regenerated prolinol ether, a precursor of (S)-l-[(dimethoxy)methyl]-2-(meth-Oxymethyl)pyrrolidine. 

Enantioselectire alkylation of amides. Two laboratories12 have used (S)-prolinol as the chiral auxiliary for a synthesis of chiral amides. Alkylation of the enolate of the amide 1 (prepared with LDA or f-butyllithium) proceeds with pronounced... 

Enantioselective Birch reduction-alkylation The chiral benzoic acid derivative 1, prepared by condensation of o-hydroxybenzoic acid with L-prolinol followed by cyclization (Mitsunobu reaction), undergoes Birch reduction (K, NH3, THF, t-butyl alcohol) followed by alkylation with C2H5I to give essentially only 2. Acid hydrolysis returns the chiral auxiliary and provides the 2-alkylated cyclo-hexenone 3. 

Kim et al have recently reported also the preparation and application of prolinol derivatives on mesoporous silicas43. In this case, higher enantioselectivities were obtained mainly due to the higher intrinsic efficiency of the chiral auxiliary and to the addition of butyl lithium as extra-metal reagent. 

Chiral Amines with C2 Symmetry, trans-2,5-Dimethylpyrrolidine (1) was the first chiral amine possessing C2 symmetry used as a chiral auxiliary in asymmetric synthesis. Since that time a number of related systems have been developed including the title compound (2) and (4). These amines were developed as C2-symmetric analogs to the commercially available prolinol derivative (5). While proline-derived chiral auxiliaries have been widely used in asymmetric synthesis, the C2-symmetric chiral auxiliaries often give enhanced stereoselectivity when compared directly to the prolinol derivatives. Unfortunately the preparation of the C2-symmetric compounds is more tedious and, at the time of writing, none are commercially available. For example, the standard route to chiral pyrrolidines (2) and (3) involves the resolution of tranf-N-benzylpyrrolidine-2,5-dicarboxylic acid, although other preparations have been... 

Formation of Chiral Quaternary Carbon. Birch reduction-alkylation of benzoic acids and esters establishes quaternary carbon centers. Neighboring stereocenters will influence the stereochemical outcome of the tandem reaction sequence. The following example illustrates how a chiral auxiliary (derived from prolinol) controls the stereoselection in the Birch reduction-alkylation step. ... 

More recently Katsuki and coworkers have reported that (Z)-enolates of a-alkyl and a-heterosub-stituted amides such as (134), derived from pyrrolidine derivatives having a C2 axis of symmetry, undergo very diastereoselective alkylations with secondary alkyl and other alkylating agents in good to excellent chemical yields (Scheme 62) As with prolinol ether amide enolates, it appears that the direction of approach of the alkylating agent to the enolate (134) is controlled mainly by steric factors within the chiral auxiliary, i.e. chelation effects seem to be of little importance. 

In order to overcome the problems associated with acid hydrolysis of amides of prolinol, the Evans research group has investigated the diastereoselectivity of the alkylation of imides derived from chiral 2-oxazolidones. Imide enolates are somewhat less nucleophilic than amide enolates, but they have the advantage that their diastereomeric alkylation products are easily separated and the imide linkage is cleaved with a variety of reagents under mild conditions. As shown in Scheme 64, alkylation of the chelated (Z)-enolate of the propionimide derived from (S)-valinol (135) with benzyl bromide occurred in high chemical yield and with high si-face diastereoselectivity. In addition to oxazolidones, imidazoli-diones have proved to be useful chiral auxiliaries for diastereoselective enolate alkylations. ... 

Prolinol methyl ether 31 is used in Enders s SAMP and RAMP chiral auxiliaries (chapter 27) and (S)-()-SAMP 32 can be made in 50-58% overall yield from (S)-L-(—) -proline on a 75 g scale.12... 

The use of hydrazines as chiral auxiliaries was initiated by Enders and coworkers [315]. They have developed the chemistry of hydrazones derived from epimeric 1 -amino-2-methoxymethylpyrrolidines 1.76, Samp and Ramp [161, 169, 253, 261, 315, 316], These compounds are commercially available, or they can easily be prepared from (S)-prolinol 1.64 (R = CH2OH) or (R)-glutamic add [261]. Hydrazones have some advantages over their related imine derivatives. First, they are formed in quantitative yield even from sterically hindered ketones. Second, their derived anions are often more reactive than the related aldehyde or ketone enolates. 

L-proline was reduced to prolinol, and conversion with benzyl chloride into N-benzyl substituted prolinol 17 followed. Subsequent complex formation was achieved by the usage of Cr(CO)6. Irradiabon of complex 18 in the presence of polystyrene-diphenylphosphine gave the polymer-supported chiral auxiliary 19 (Scheme 12.10). 

Asymmetric iodolactonization on solid support was carried out using a C2-sym-metric chiral auxiliary 35 [13, 22], The prolinol derived precursor was allylated, followed by treatment with iodine and H 20. The resulting lactone (36) was obtained with exclusive trans selectivity and 87% ee (Scheme 12.16). 

It is generally true that restrictions on conformational mobility minimize the number of competing transition states and simplify analysis of the factors that affect selectivity. Chelation of a metal by a heteroatom often provides such restriction and also often places the stereocenter of a chiral auxiliary in close proximity to the a-carbon of an enolate. This proximity often results in very high levels of asymmetric induction. A number of auxiliaries have been developed for the asymmetric alkylation of carboxylic acid derivatives using chelate-enforced intraannular asymmetric induction. The first practical method for asymmetric alkylation of carboxylic acid derivitives utilized oxazolines and was developed by the Meyers group in the 1970 s (Scheme 3.16a), whose efforts established the importance and potential for chelation-induced rigidity in asymmetric induction (reviews [77-79]). In 1980, Sonnet [80] and Evans [81,82] independently reported that the dianions of prolinol amides afford more highly selective asymmetric alkylations (Scheme 3.16b). 

In 1982, Evans reported that the alkylation of oxazolidinone imides appeared to be superior to either oxazolines or prolinol amides from a practical standpoint, since they are significantly easier to cleave [83]. As shown in Scheme 3.17, enolate formation is at least 99% stereoselective for the Z(0)-enolate, which is chelated to the oxazolidinone carbonyl oxygen as shown. From this intermediate, approach of the electrophile is favored from the Si face to give the monoalkylated acyl oxazolidinone as shown. Table 3.6 lists several examples of this process. As can be seen from the last entry in the table, alkylation with unactivated alkyl halides is less efficient, and this low nucleophilicity is the primary weakness of this method. Following alkylation, the chiral auxiliary may be removed by lithium hydroxide or hydroperoxide hydrolysis [84], lithium benzyloxide transesterification, or LAH reduction [85]. Evans has used this methology in several total syntheses. One of the earliest was the Prelog-Djerassi lactone [86] and one of the more recent is ionomycin [87] (Figure 3.8). 

Evans and Takacs prepared several chiral auxiliaries derived from amino alcohols such as valinol or prolinol. Prolinol amides such as 473 preferentially form the (Z)-enolate (474) over the ( )-enolate (475). Alkylation proceeds with chelation control and good diastereoselectivity (from the si face) to give the alkylated products 476 and 477, favoring 476 as shown in Table 9.14.23 L20 enolate (474) is preferred over... 

In the past Lewis acid-catalyzed [4+2] cycloaddition reactions of chiral alkyl acrylates have been systematically studied. Chiral auxiliaries derived from camphor, menthol and amino acids or from carbohydrates have been developed. Stereochemical and theoretical aspects of these chiral inductors have been intensively reviewed (see. Chapter 6). Asymmetric Diels-Alder reactions of chiral acrylamides derived from Ca-symmetrical secondary amines lead selectively to the cycloadducts in the presence of Lewis acids such as AICI3. In reactions of chiral auxiliaries derived from (iS)-proline and (iS)-prolinol excellent endo/exo selectivities and diastereoselectivities were obtained in the presence of catalytic amounts of Et2AlCl or TiCL. Cycloadducts of chiral crotonoyl derivatives derived from oxazolidinones 62, sultam 63 or for example (S)-lactate IS were obtained with high selectivities in the presence of Lewis acids such as Et2AICl. 

As another approach to AHR, an efficient AHR can be achieved based on the remarkable diastereoselectivity, which is caused by chiral auxiliaries. Coupling of the chiral prolinol vinyl ether 325, which contains a prochiral double bond, with o-iodoamsole using ligandless Pd(OAc)2 in aqueous DMF, afforded the product... 

The search for a single structural motif to serve as a chiral auxiliary for the diversity of examples of the aza-Claisen rearrangement continues to produce some advancement. The prolinol derivative 412, oxazoline derivative 416, and (i )-l-phenylethanamine derivative "" 419 have been utilized to provide moderate to good asymmetric induction in specific cases as exemplified below. 

In another example, the aiylation of ketone enolates was achieved indirectly via an intermolecular Heck reaction. In this case, the diastereoselectivity is induced by chelation of a metal-coordinating auxiliary. The inexpensive and commercially available amino alcohol (6()-l-methyl-2-pyrrolidine-methanol was selected as a suitable chiral auxiliary (Scheme 13.47). The prolinol vinyl ether 182 was... 

The investigations of Enders, Evans, and others have demonstrated the versatility of chiral auxiliaries based on the proline skeleton [80]. Katsuki designed and utilized a C2-symmetric, 2,5-disubstituted pyrrolidine auxiliary for asymmetric enolate alkylations (Equation 10) [81]. Enolates prepared from 112 generally undergo alkylations with superb diastereoselectivity dr >95 5). However, in contrast to the prolinol amide-derived systems described above, accessibility of the chiral auxiliary hinged upon a multi-step synthetic preparation involving resolution, and the hydrolytic removal of the auxiliary necessitated considerably harsher reaction conditions. 

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