Chiral pyrrolidine substituents

Chiral pyrrolidine substituents serve as efficient auxiliaries in diastereoselective zwit-terionic ketene aza-Claisen rearrangements (Scheme 18). ... 

Pyrrolo[l,2- ][l,2]oxazines are a class of compounds with very few references regarding synthesis and reactivity. An interesting preparation has been described by intramolecular cyclization of IV-hydroxy pyrrolidines carrying a methoxyallene substituent at C-2 (242, Scheme 32). These compounds were obtained by addition of a lithiated allene to chiral cyclic nitrones 241. Cyclization occurred spontaneously after some days at relatively high dilution (0.05 M). Compounds 243 (obtained with excellent diastereoselectivity) can be submitted to further elaboration of the double bond or to hydrogenolysis of the N-O bond to form chiral pyrrolidine derivatives (Section 11.11.6.1) <2003EJ01153>. 

Aminomethylferrocene 338, this time without further methoxy substituents, also lithi-ates diastereoselectively (Scheme 150) , and similar results may be obtained with simple chiral pyrrolidines. Treatment of 322 with the binaphthylamine 337 yields 338. Lithiation generates a 9 1 mixture of diastereoisomeric organoUthiums, which give the phosphine 339 (Scheme 150) Attempts to obtain reversed planar diastereoselectivity by using silylation to block the more reactive lithiation site failed. 

For this 1,2-addition Thompson et al. first tested lithiated quinine and quini-dine additives, which were applied successfully in additions to imines [91, 92, 93],but for ketone 24 [Eq. (3)] they obtained only 50-60% ee [90]. Higher enan-tioselectivities were achieved with lithiated ephedrine derivatives with different N-substituents (e.g., NMej, NEtj), among which the pyrrolidine substituent in 26 gave the highest enantioselectivity (82% ee) for the efavirenz precursor 27 [Eq. (3)]. An optimized protocol was developed, whereby the cyclopropylacety-lene (two equivalents) and the chiral amino alcohol (two equivalents) were lithiated with n-BuLi at -15 °C. This mixture of 25 and 26 was then aged for 30min at 0°C. Addition of the ketoaniline 24 (one equivalent) to this mixture at -55°C in THF affords 27 in up to 98% ee ... 

The marked temperature dependence of the enantioselective addition of diethylz-inc to aryl aldehydes catalysed by (S)-2-(3-methyl-2-pyridyl)-3,5-di-r-butylphenol displays an inversion temperature which is affected by the para-substituent of the aldehyde. Enantioselectivities of up to 78% ee for addition of diethylzinc to ben-zaldehyde have been achieved using (15, 45)-2,5-diazabicyclo[2.2.1]heptane derivatives as catalysts however, a study of chiral compounds related to the Betti base (51a) has identified r-aminonaphthol (51b) as a much more effective catalyst (99% ee) for this reaction. The catalytic efficiency of chiral pyrrolidine derivatives and (25)-3-eJt -(dimethylamino)isobomeol have also been explored. 

The chiral pyrrolidin-2-one (104) featuring a bulky 5-substituent has been found to give the a-tetralone (106) enantiometrically enriched up to 72% ee (R = Me) on reaction with the corresponding 2-substituted lithium enolate (105) pyrrolidin-2-ones... 

Chiral 2-amino-1,3-dienes with (5)-2-methoxymethyl pyrrolidine substituents react with vinyl carbene complexes, [(OC)5W=C(OMe)C(R3)=C(R )(R5)] to give the cyclohexyl tungsten carbene complexes S6. 27 Cyclic carbenes 57 (R = H, Br, OMe) and 58 are rather unreactive towards 1,3-dipoles and 1,3-dienes and their reactions with diazomethane are regio- but not chemoselective. s The tungsten atom of 59 has distorted octahedral coordination defined by one carbene and five carbonyl ligands. ... 

The enantioselective Michael addition of nitroalkanes to enones provides an attractive synthetic route towards chiral pyrrolidines, y-lactams, and y-amino acids. Du and coworkers have developed a squaramide-catalyzed Michael addition reaction of nitroalkanes to chalcones (Scheme 10.20) [98]. The authors noted that electron-withdrawing substituents on the aryl portion of squaramide enhanced the activity of the catalyst owing to the increased acidity of the squaramide N-H. Interestingly, the yield and enantioselectivity both increased when the reaction was performed at an elevated temperature. The reactions between nitromethane and various chalcones afforded the Michael adducts in high yields and high enantioselectivities at 80 °C. Varying the substituents on chalcones showed some effect on... 

Cyclopentanone derivatives 50 and 53 are stereoselec-tively obtained by the reaction of Fischer alkenyl carbene complexes 47 with chiral pyrrolidine enamines 48 (Scheme 5.12) [21]. The R -substituent on the pyrrolidine... 

Thermal cyclization of 2-vinyl-N,N-dialkylanilines 138 afforded 139 with creation of a new chiral center in 98% purity (89JOC199). In case of pyrrolidine with methyl or methoxymethyl substituent, cyclization with ZnCl2 occurs via an irreversible 1,5-hydrogen shift in boiling acetonitrile (87JA3136) or BuOH (91RTC115) to afford the diastereoisomers 140 (33%), 141 (35%) and 142 (6%) (87JA3136) (Scheme 27). 

Racemic 2,5-disubstituted 1-pyrrolines were kinetically resolved effectively by hydrogenation with a chiral titanocene catalyst 26 at 50% conversion, which indicates a large difference in the reaction rate of the enantiomers (Table 21.19, entries 4 and 5), while 2,3- or 2,4-disubstituted 1-pyrrolines showed moderate selectivity in the kinetic resolution (entries 6 and 7) [118]. The enantioselectivity of the major product with cis-configuration was very high for all disubstituted pyrrolidines. The high selectivity obtained with 2,5-disubstituted pyrrolines can be explained by the interaction of the substituent at C5 with the tetrahydroinde-nyl moieties of the catalyst [Eq. (17)]. 

Hydrogen-bonding between the 3-oxo group of 1,4,4-trisubstituted pyrrolidine-2,3,5-triones and catalytic amounts of cinchonidine controls the stereospecific hydrogenation of the system over Pt/Al203 to yield chiral 3-hydroxy compounds (-100% yield with ee >60) [21] the nature of the (V-substituent appears to be the controlling factor for the stereoselectivity with PhCH2> Et > n-Bu > cyclo-C6H . 

Another synthesis of pyrrolidines, in this case with high enantioselectivity, has seen several enones with a chiral alkoxy or amino substituent in the y-position react with azome-thine yields (derived from glycine imine derivatives) upon treatment with DBU/AgOAc (equation 171)612-614. This reaction may also be done using other alkene-containing substrates615,616. 

The stereochemical information on the chiral center formed by the mechanism outlined in Scheme 2.25 is determined by the R -substituent in the chiral amine. Here, two types of interaction are operating, namely electronic and steric. The electronic interaction [2] outlined to the left in Figure 2.5 seems to take place when the R -substituent has an acidic hydrogen atom/proton such as a carboxylic acid or tetrazole in the 2-position of a pyrrolidine ring. The acidic hydrogen atom in these R -substituents interacts with a lone pair in the heteroatom Y of the incoming electrophile. The electrophilic addition of the heteroatom takes thus place... 

The face-selectivity originating from a steric shielding is outlined to the right in Figure 2.5. The chiral substituent in e.g. the 2-position of the pyrrolidine ring shields the Re-face of the enamine carbon atom forcing an approach of the electrophile from the opposite site (Si-face approach) of the chiral substituent. 

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