Two synthetic routes have been utilized to prepare a number of chiral bis-hydrazone ligands with 2,5-diarylpyrrolidine substituents. The first route (Table 17) is an improvement of literature procedure using a modified Corey-Itsuno protocol to access the critical 1,4-diaryl-1,4- butanediol stereoselectively. This procedure allows the preparation of ligands with electron- deficient aromatic substituents. A novel and complementary synthetic approach based on sequential α-arylations of N-Boc-pyrrolidine permitted the preparation of electron-rich and sterically hindered hydrazone ligands (Scheme 52). During the investigations of both synthetic routes, interesting observations as well as difficulties were encountered in the preparation of some intermediates which are discussed below.
3.5.1.1 Enantio- and Diastereoselective Reduction of 1,4-Diaryl-1,4-butanediones
The high enantioselectivities (generally 99:1 or greater) observed in Corey-Itsuno reduction of 1,4-diketones (Table 16, entries 1-3) indicates an essentially perfect reduction of the first carbonyl group. The lower diastereoselectivity (63:37 to 84:26) suggests that the borinate moiety generated from the first reduction may either influence the reduction of the second carbonyl group sterically or act as a reductant competitively (Scheme 118). The latter scenario seems less likely given the tendency of (OR)2BH to undergo rapid disproportionation to
steric differentiation by the catalyst between the two substituents on the carbonyl group. It is intriguing that the modified protocol employing stannous chloride and sodium borohydride with the same diphenylprolinol ligand afforded better diastereoselectivities (Table 17).135 The reason for the improved selectivity is unclear.
Scheme 118
3.5.1.2 Instability of Electron-Rich Dimesylate
During the investigation, it was realized that the electron-rich dimesylates 54a and 54b are highly unstable. This is readily understood by analyzing the stability of the benzylic cation; resonance stabilization is particularly effective in the presence of an electron-donating substituent (σp = −0.27) (Scheme 119).64 Therefore, the elimination of mesylate occurs readily.
3.5.1.3 Glyoxal Condensation with 1-Amino-2,5-diarylpyrrolidine
The double condensation of 1-amino-2,5-diarylpyrrolidine with glyoxal can be carried out in a single operation by using slightly less than half equivalent of the glyoxal with respect to 2,5-diarylaminopyrrolidine. However, low yields and inconsistent results were obtained in early attempts possibly due to the presence of polymeric aldehyde species in the ~40% aqueous solution of glyoxal. The reaction using water-free glyoxal has been reported to provide doubly condensed products in moderate yield.122 However, dry glyoxal can be explosive and should be avoided.
3.5.1.4 αααα-Arylation of N-Boc-2-arylpyrrolidine
The α-arylation of the N-Boc-2-arylpyrrolidine by a sequence of stereoselective deprotonation, transmetalation and sp3-sp2 cross-coupling generally proceeded with low conversion (Table 18). This observation may be attributed to three factors. First, the removal of the α-proton trans to the aromatic substituent may cause severe interactions with the Boc group (Scheme 120). Second, HC(2) is more acidic than HC(5) because of the aromatic substituent. It has been reported that a C(2) disubstituted pyrrolidine can be prepared by lithiation of N-Boc-2- arylpyrrolidine followed by reaction with an electrophile,203 although the presence of (-)- sparteine should direct the deprotonation to the C(5) position. Third, because of the restricted rotation of tert-butoxycarbonyl functional group, two conformers of 58 were observed by 1H NMR spectroscopy.204 The interconversion is slow at -78 °C and a half-life of 10 h has been estimated. This finding implies that only a portion of 58 can undergo deprotonation at C(5) position at this temperature.
In this α-arylation step, a small amount of unsaturated 2,5-diarylpyrroline 137 was produced as side product (Scheme 121). A possible rationale is that N-Boc-2,5-diarylpyrrolidine undergoes deprotonation by residual base. The resulting anionic species reacts with [t- Bu3PPdX]2, a known impurity generated from oxidative addition of (t-Bu3P)2Pd,75 to yield a
alkylpalladium intermediate. β-Hydride elimination from 136 produces the undesired N-Boc- pyrroline 137.203 Acid mediated Boc-deprotection of 137 and olefin isomerization of the resulting product produces 2,5-diaryl-2,5-dihydro-1H-pyrrole 138 which has been characterized through 2-naphthyl substituted analog.
Scheme 121
3.5.1.5 Preparation of 1-Amino-2,5-diarylaminopyrrolidines
Another challenging step encountered in the development of the new synthetic route toward chiral bis-hydrazone ligands was the DIBAL-H reduction of 1-nitroso-2,5- diarylpyrrolidines. Prolonged reaction times led to an increased amount of 1,2-diarylcyclobutane 69 and 2-ethenylarene 70 at the expense of desired 2,5-diarylaminopyrrolidine. The inability to prepare 2,5-diaryl-substituted 1-aminopyrrolidine due to nitrogen extrusion has been documented. 133 In contrast, the 2,5-dialkyl analogs do not suffer from the same problem. The divergent behavior is likely due to different abilities of the substrates in stabilizing positive charge developed during the extrusion process. As suggested by Overberger et. al., the decomposition of 1-amino-1,5-diarylpyrrolidine 69 might proceed through a nitrene intermediate (Scheme 122).133 Ring-contraction pathway leads to 1,2-diarylcyclobutane 69 and fragmentation pathway leads to 2-ethenylarene 70. 1,2-Di(2-naphthyl)cyclobutane exhibits optical activity suggesting that the two aromatic substituents have a trans relationship and ring contraction might occur through a concerted mechanism as the major pathway.
Scheme 122
3.5.1.6 Lithium Aluminium Hydride Reduction of 1-Nitroso-(2R,5R)-di(2-tolyl)pyrrolidine The relative configuration of 1-amino-2,5-di(2-tolyl)pyrrolidine obtained from LAH reduction of the corresponding nitrosamine 66i was established through 2,5-di(2- tolyl)pyrrolidine 65i and its benzyl derivative 139 (Scheme 123). Diazotization was followed by nitrogen extrusion to produce meso-67i, which exhibits similar 1H NMR splitting pattern to C2-
symmetric 67i prepared previously. However, the chemical shifts for methine protons from the two diastereomers were clearly different (4.52 vs 4.78 ppm).
Reductive amination of meso-65i with benzaldehyde provided tertiary amine 139. The stereochemical identity of this compound was deciphered from the splitting pattern of the benzylic proton. A singlet and an integration of two are expected for meso-139 because of the enantiotopic relationship between the two geminal protons, whereas two doublets with an integration of one for each signal is expected for C2-symmetric 139 due to their diastereotopic
Scheme 123
The formation of meso 1-amino-2,5-di(2-tolyl)pyrrolidine from the chiral nitroso starting material may be due to epimerization at the C(2) or C(5) position after the first hydride is delivered from LAH (Scheme 124). The N-oxide bound to the aluminate may have sufficient basicity to abstract the benzo proton intramolecularly causing epimerization of the stereogenic center. However, it is remarkable that the same reduction protocol for singly aryl-substituted N- Boc pyrrolidine proceeded smoothly (Scheme 49). These divergent behaviors may be attributed to the directionality of the N-oxide. For 2-aryl substituted analog, the N-oxide aluminate moiety could reside on the less hindered side of the molecule and deprotonation at C(5) position is inconsequential. In contrast, this opportunity does not exist for 2,5-diaryl substituted analog. It is also intriguing that the reduction of other 1-nitroso-2,5-diarylpyrrolidines by DIBAL-H (Scheme 51) did not produce any meso product, presumably because of the steric bulk of two isobutyl groups that prevents intramolecular deprotonation. The actual mechanism behind LAH promoted epimerization remains unclear at this point.
Scheme 124