Prolinol condensation

Synthesis of 1,3,2 oxazaphospholidines 128a-c derived from (S)-prolinol 127 was based either on the thermal aminoalcoholysis of the latter with prochiral alkyl(aryl) phosphonousdiamides 51a-c or its condensation reaction with /-butylphosphonous dichloride carried out in the presence of triethylamine (Scheme 37) [68], The diastereomeric excesses of the prepared derivatives ranged from 80 to 95%. 

The condensation of 1-fluoro 4-nitrobenzene with prolinol gives NPP. Only POM is a commercial product. 

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). 

Attempts to use the lithium enolates of the prolinol amides in the aldol condensation were unrewarding, for these reactions proved stereorandom. On protecting the hydroxyl... 

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. 

Recently, two other groups have shown that exocyclic iminium salts can be useful mediators in asymmetric epoxidation. Komatsu has developed a system based on ketiminium salts [14], prepared through the condensation of aliphatic cyclic amines with ketones. A chiral variant was also produced, derived from prolinol and cyclohexanone, which gave 70% yield and 39% ee for cinnamyl alcohol (Scheme 5.7). 

The first total synthesis of cephalotaxine was reported by Auerbach and Weinreb (22,23) in 1972, as illustrated in Scheme 1. Condensation of prolinol... 

The structure proposed for septicine (20), the dehydroindolizidine constituent of Ficus septica, has recently been confirmed by two independent syntheses. The first synthesis proceeded from veratraldehyde, which was condensed with homoveratric acid to give the unsaturated acid (21) this was then converted into the primary chloride (22) by standard methods. Alkylation of L-prolinol with this chloride gave the amino-alcohol (23), which was converted into its O-methanesulphonate ester. Reaction of this ester with sodium hydride in anhydrous... 

Chiral boronales are generated m situ by reaction of binaphthols 3.7 (R = H, Ph) [231] with BH3 in the presence of acetic acid [778], with H BBr [781] or with B(OPh)3 [782, 783], Chiral borates are formed by reactions of substituted (S)-prolinol derivative 2.13 (R =- CPl OH) and BBr3 [784], These boronates and borates are valuable catalysts in asymmetric Diels-Alder reactions [73, 231, 601, 780], Tartaric acid derivatives, such as borate 3.8 and acyloxyboranes 3.9 recommended by Yamamoto and coworkers [73,601,778,780,785-791], are very efficient catalysts in asymmetric Diels-Alder reactions and in condensations of aldehydes with allylsilanes, enoxysilanes or ketene acetals. These catalysts are generated in situ from substituted monobenzoates of (RJl)- or (S -tartaric acid and BH3 (R = H) or an arylboric acid (R = Ar). The best asymmetric inductions are observed with catalysts 3.9, R = /-Pr. 1,3,2-OxazaboroMnes 3.10, prepared from a-aminoacids [44, 601, 780, 792, 793], are efficient catalysts in asymmetric Diels-Alder reactions. The catalyst generated from A -tosyltrytophan 3.11 is more efficient than borolidines 3.10 (R = Et, /-Pr). The catalysts 3.10 prepared from 3.11, 3.12 and 3.13 are also useful in asymmetric condensations of aldehydes with ketene acetals [794-797]. 

Ring expansion reactions of 2-substituted pyrrolidines to piperidines have been useful in certain cases, particularly in the iminosugar area. A careful analysis of the formation and fate of the condensed aziridinium ion intermediate 191 was made for the Mitsunobu reaction of 192 to maximize formation of 193 relative to simple alkylation <04SL1711> (Scheme 71). The known conversion of chiral prolinol 194 to 195 was used in the synthesis of thymine PNA monomer 196 <04BMCL2147>. 

Recently, Dominguez de Maria and co-workers [45] have studied experimentally the influence of the organocatalyst on the outcome of the aldol reaction reaction between acetone and isobutyraldehyde. Qrganocatalysts able to form bicyclic oxazolidine intermediates (proUne and prolinol) led predominantly to aldol adducts, while organocatalysts unable to form these oxazolidines (pyrrolidine, O-methyl prolinol and proline tcrt-butyl ester) afforded preferently (>2.5 1) the condensation product. In summary, most of the experimental evidence points toward a distinct catalytic role of oxazoUdinone intermediates in proline-catalyzed reactions. It should be pointed out, however, that DPT studies of the proline-catalyzed self-aldol reaction of propanal, in which the enamine carboxylic acid and the oxazoUdinone pathways were compared, concluded that the Seebach model was inadequate for rationalizing... 

To this aim the chiral secondary amine 0-methyl o-prolinol is prepared from o-proline and condensed with propiophenone to chiral enamine using tetraethyl silane at high temperature as condensing agent. On the parallel route, the immonium... 

High e/y/firo-selectivity has been obtained using optically active zirconium enolates (18) derived from prolinol in an enantioselective aldol condensation (Scheme 14). Much lower selectivity was obtained using the corresponding lithium enolate. 

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