Chiral proline-derived

The chiral, proline-derived a-aminoalcohol ligand (606) was applied to the enantioselective, nucleophilic addition of trimethylsilylacetylene (605) to aromatic, heteroaromatic and aliphatic A-(diphenylphosphinoyl)imines (603) to give optically active propargylic phosphinoamides (605) in good yields (up to 92%) and enantioselectivities (up to 95%) (Scheme 150). ° ... 

Frechet and coworkers explored the synthesis of polyester dendrons on solid support. These dendrons, based on 2,2-bis(hydroxymethyl)propanoic acid monomers, were assembled up to the fourth generation on poly(2-hydroxyethyl methacrylate-co-ethylene dimethacrylate) resin and decorated with chiral proline derivatives (Scheme 15.15). T vo methods for preparation of these materials were reported. The solid-phase divergent approach yielded polymer with higher loading but a less precise architecture than the second approach. The second approach, the divergent synthesis of the dendrons in solution, followed by the focal point deprotection and then attachment to the solid support, led to well-defined structures on the polymer, but relatively low loading. 

Chiral proline derivatives have proven to be extremely valuable in a variety of asymmetric syntheses. A further example of this is in condensations between the enolate of ethyl acetate and derivatives (148) leading, after hydrolysis, to the hydroxy-esters (149) in chemical yields of 50—85% with enantiomeric enrichments of >80%. ... 

Complementary hydrogen-bonding interactions have also been used by the group of Clarke [18, 19] for the construction of catalyst hbraries based on the self-assembly of chiral proline-derived pre-catalyst 8 [designated (S)-ProNap] with a series of achiral substrates (Figure 9.3). These studies were aimed at modulating the stereoselectivity of the asymmetric nitro-Michael reaction of ketones and nitrostyrenes simply by modifying the achiral co-catalyst. Since catalyst formation relies on self-assembly, this provides easy access to a catalyst Hbrary with different... 

The first organocatalytic enanhoselective nucleophilic addition to a, ]3-unsaturated ketones was reported by Kawara and Taguchi in 1994 [9]. In this report they stated that chiral proline-derived ammonium hydroxides catalyzed the reaction between malonates and a,(3-unsaturated ketones in good yields and moderate enantioselectivities (up to 71%). 

In addition, the Cheng group also synthesized chiral proline derivative-functionalized SBA-15 and applied it to the asymmetric addition of diethylzinc to benzaldehyde. This heterogeneous catalyst showed high activity in enantioselective addition of diethylzinc to benzaldehyde to form (S)-l-phenyl-propanol (about 66% ee). These results indicate that the chiral proline species in the mesopores is in a more favorable position for achieving higher enantioselectivity. Also, the reaction rate increased with the hydrophobicity around the active sites [91]. 

One of the most intensively studied protic chiral ligands, which moreover allows enantioselectivities of up to 95% ee, is the proline-derived (25 )-l- [(25,)-l-methyl-2-pyrrolidinyl]methyl -2-pyrrolidine methanol (6)19-21. 

The proline derived diamines 2 and 4 (vide supra) are also suitable chiral additives in enantiose-lective additions of a-unsubstituted enolates. Best results are obtained with the naphthyl derivative, as demonstrated in the tin(II) triflate mediated addition of the O-silylketene thio-acetal l-toT-butylthio-l-trimethylsilyloxyethane to aldehydes which delivers 3-hydroxythio esters in optical purities of up to 95% ee and chemical yields between 50 and 90 %24... 

A proline derived chiral nickel complex 1 may be used instead of oe,/J-unsaturated esters of lactones modified with a chiral alcohol as the Michael acceptor. The a,(9-unsaturated acid moiety in 1 reacts with various enolates to afford complexes 2 with diastereomcric ratios of 85 15 to 95 5. Hydrolysis of the imine moiety yields the optically active /(-substituted r-alanines. A typical example is shown296. 

Thus the product in such cases can exist as two pairs of enantiomers. In a di-astereoselective process, one of the two pairs is formed exclusively or predominantly as a racemic mixture. Many such examples have been reported. In many of these cases, both the enolate and substrate can exist as (Z) or (E) isomers. With enolates derived from ketones or carboxylic esters, (E) enolates gave the syn pair of enantiomers (p. 146), while (Z) enolates gave the anti pair. Addition of chiral additives to the reaction, such as proline derivatives, or (—)-sparteine lead to product formation with good-to-excellent asynunetric induction. Ultrasound has also been used to promote asymmetric Michael reactions. Intramolecular versions of Michael addition are well known. ... 

Palladium-catalysed asymmetrie allylations of various carbonyl compounds have been studied by Hiroi et al. using various types of chiral sulfonamides derived from a-amino acids. In particular, the chiral bidentate phosphinyl sulfonamide derived from (5)-proline and depicted in Scheme 1.63 was employed in the presence of palladium to eatalyse the allylation of methyl aminoacetate diphenyl ketimine with allyl aeetate, leading to the eorresponding (7 )-product with a moderate enantioseleetivity of 62% ee. This ligand was also applied to the allylation of a series of other nueleophiles, as shown in Seheme 1.63, providing the eorresponding allylated produets in moderate enantioseleetivities. 

The synthesis in Scheme 13.30 was also done in such a way as to give enantiomer-ically pure longifolene. A starting material, whose chirality is derived from the amino acid L-proline, was enantioselectively converted to the product of Step A in Scheme 13.30. 

These authors were also able to perform this domino process in an enantioselec-tive fashion using the Rh-proline derivative 6/2-57 (Rh2(S-DOSP)4) as chiral catalyst for the cyclopropanation [202]. Reaction of 2-diazobutenoate 6/2-56 and alkenes 6/2-55 in the presence of the catalyst 6/2-57 led primarily to the cyclopropane derivative... 

Gais and co-workers recently reported the preparation and use of chiral sulfoximine-substituted allyltitanium(iv) complexes of type 78 for the asymmetric synthesis of 3-substituted unsaturated proline derivatives 79 (Scheme 31).108... 

The optically active //-amino alcohol (1 / . 3 R. 5 / )-3-(di phenyl hydroxymethyl )-2-azabicyclo[3.3.0]octane [(li ,3i ,5i )-121], can be derived from a bicyclic proline analog. It catalyzes the enantioselective addition of diethylzinc to various aldehydes. Under mild conditions, the resulting chiral secondary alcohols are obtained in optical yields up to 100%. The bicyclic catalyst gives much better results than the corresponding (S )-proline derivative (S )-122 (Scheme 2-47).114... 

The hexahydro-l//-pyrrolo[2,l-f][l,4]oxazin-l-one 82 (obtained by radical cyclization see Section 11.11.7.3) was transformed into the proline derivative 83 by hydrogenation in the presence of the Pearlman s catalyst and a stoichiometric amount of trifluoroacetic acid (TFA) (Scheme 10). This reaction led with high yield to the disub-stituted proline 83 in an enantiomerically pure form <2003SL1058>. In an analogous approach, the chiral (4/ ,7/ ,8aA)-methyl 6,6-dimethyl-l-oxo-4-phenylhexahydro-l//-pyrrolo[2,l-r-][l,4]oxazine-7-carboxylate 84 was hydrogenated on Pd(OH)2 in the presence of TFA to give enantiomerically pure 5,5-dimethylproline derivatives 85 <2001SL1836> (Scheme 10). 

The chiral auxiliaries anchored to the substrate, which is subjected to diastereoselective catalysis, is another factor that can control these reactions. These chiral auxiliaries should be easily removed after reduction without damaging the hydrogenated substrate. A representative example in this sense is given by Gallezot and coworkers [268], They used (-)mentoxyacetic acid and various (S)-proline derivates as chiral auxiliaries for the reduction of o-cresol and o-toluic acid on Rh/C. A successful use of proline derivates in asymmetric catalysis has also been reported by Harada and coworkers [269,270], The nature of the solvent only has a slight influence on the d.e. [271],... 

A more recent report by Sibi and co-workers displayed the utility of chiral lanthanide Lewis acids for addition-trapping reactions [150]. An exhaustive screening of lanthanide Lewis acids and several chiral ligands revealed that Y(OTf)3 and proline derived ligand 138 was optimal (data not shown). Upon further optimization it was discovered that achiral additives 139 and 212 increased ee s (Scheme 56, entries 2 and 3). Bulkier radicals were found to decrease the enantioselectivity (entries 4 and 5). Also, larger aryl substituents on the ligand gave similar ee s as observed for 138 (compare entries 1, 6, and 7). 

This reversal of elution order is due to the changed CIP priorities, but not a result of an altered binding and chiral recognition mechanism. Moreover, in yet another study, BOC and DNP-protected a-substituted proline derivatives have been resolved into enantiomers and elution orders were determined [48], The method allowed the sensitive and accurate analysis of samples with regards to their enantiomeric purities. 

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