Substituted Pyrrolidines

Proline methyl esters with A-Boc-4-acetoxy or 4-0-TBDMS groups were converted by RuClj/aq. Na(IO )/EtOAc or CC1 -CH3CN to the corresponding pyrrolidin-5-ones 

5 Oxidations of Amines, Amides, Ethers, Sulfides, Phosphines, Arsines, Stibines 

---

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

Baker s yeast reduction of y-nitroketones offers the corresponding chiral nitro alcohols, which are useful building blocks for the synthesis of chiral natural compounds.120 For example, optically active 2-substituted pyrrolidine can be prepared using the chiral nitro alcohol (Eq. 10.75).121... 

The reaction can be extended to more elaborate systems as shown in the reactions of the substituted pyrrolidines (Equations (25) and (26)).85,86 Even though the 2-substituted pyrrolidine 8 has three electronically activated sites, two are sterically crowded. Furthermore, the Rh2(5-DOSP)4-catalyzed C-H insertion exhibited extreme stereodifferentiation, such that only one enantiomer of 8 was reactive under the reaction conditions. Consequently, a high level of kinetic resolution was observed, and the C-H insertion product was produced with 98% ee (Equation (25)).85 Similar reactivity was seen in the reaction of the 3-substituted pyrrolidine 9. In some regards, this reaction is even more impressive, because there was selective insertion into one of the two available methylene groups adjacent to nitrogen (Equation (26)).85... 

Table 6.15. STRUCTURES AND ANTIBACTERIAL ACTIVITY OF (45)-7-(4-AMINO-2-SUBSTITUTED-PYRROLIDIN-l-YL)QUINOLONES [85]...

A particular case for the generation of a y-substimted organolithium compound, derived from an imine, was used for the synthesis of 2-substituted pyrrolidines. DTBB-catalyzed (5%) lithiation of y-chloro imines 196 yielded, after hydrolysis, 2-substituted pyrrolidines 198, including nomicotine (R = H, R = 3-pyridyl). The corresponding y-nitrogenated organolithium intermediate 197 was probably involved (Scheme 68). ... 

The chiral base i-BuLi/(—)-sparteine enantioselectively deprotonates the benzylic position of Ai-Boc-3-chloropropyl carbamates, which then cyclize to yield 2-substituted pyrrolidines with enantiomeric ratios greater than 90 10 (Scheme 63). Beak and coworkers showed that enantioselectivity is achieved through an asymmetric deprotonation to give an enantioenriched organolithium intermediate, which undergoes cyclization faster than epimerization. 

Catalytic hydrogenation of 2-alkyl-2,5-dihydro-l//-pyrrole with 5% rhodium on carbon gave 2-substituted pyrrolidines in 95-96% ee (Pirkle analysis42) without attendant racemization. 

Pyrrolidine readily forms an IV-nitroso derivative. This can be lithiated in the 2-position, and subsequent reaction with electrophiles and deprotection yields 2-substituted pyrrolidines (780S(58)l 13), as illustrated in Scheme 54. The transformation of tetrahydrothiophene 1,1-dioxide (238) into its 2-bromo derivative (239) is similar in principle. This involves deprotonation with ethylmagnesium bromide followed by electrophilic attack by bromine. Sodium ethoxide treatment of (239) gives buta-1,3-diene in 74% yield (80LA1540). 

Trianthine. Central to Oppolzer s synthesis [70] of (+)-trianthine (278) [71] (Scheme 43) was the observation that appropriately substituted N-pentenylhydroxylamines undergo thermal suprafacial cyclisations to 2-substituted pyrrolidine derivatives, wherein the stereochemistry of the newly created asymmetric centres is found to be determined exclusively by the geometry of the starting olefins. Thus the E-olefin A, on thermolysis, yielded only B. None of its stereoisomer C was formed in the reaction (Figure 5). 

Amino cycttzation.1 In the presence of AgOTf or AgBF4 allenic amines cyclize to 2-substituted pyrrolidines. A stereogenic center adjacent to N can induce asymmetric induction, which is dependent on the concentration of Ag(I). 

Details are now available of the reactions of peracids and of hydrogen peroxide with the imines (10) and (11). The reactions of the product oxaziridines and nitrones with the same two oxidants were also discussed. The reactions of sodium borohydride, benzoyl chloride, and toluene-p-sulphonic acid with the hydroxy-nitrones (12) and (13) have been reported.12 The c.d. spectra of 2-substituted pyrrolidines have been compared with that of conanine (14).13... 

An interesting feature of this study is the enantiomeric purity analysis of the products. By converting the amine functionality of the pyrrolidine to a 3,5-dinitrobenzamide, the substrate can be analyzed by chiral HPLC. To date, the 3,5-dinitrobenzamide of 2-substituted pyrrolidines that the submitters have prepared have beer baseline-resolved by the Pirkle S-N1 N-Naphthylleucine column. This approach obviates the need for MPTA-derivativization which has been previously employed in enantiomeric purity determinations.3 5... 

Pyrrolidines. The Grignard reagent 2, obtained from 3-bromopropylamine protected as the stabase adduct with 1, reacts with the N-methoxy-N-methyl amides 3 (11, 201-202) to form an intermediate ketone that cyclizes to an imine on liberation of the free primary amino group. Reduction of the imine results in a 2-substituted pyrrolidine (4). 

Auxiliary-Induced Stereoselective Synthesis of 2-Substituted Pyrrolidines... 

A-Boc-pyrrolidines are similarly deprotonated and furnish enantioenriched 2-substituted pyrrolidines (eq 6). ... 

Cyclopropyl-containing carbocycles can be prepared from the initial [4 + 2] cycloadducts by an Af-acyliminium ion-enamide rearrangement. The unsaturated bicyclic lactam also undergoes 1,3-dipolar cycloadditions with azomethine ylides. Reduction of the bicyclic lactam with alane followed by hydrogenation affords enantiomerically pure 2-substituted pyrrolidines (eq 11). ... 

Reduction with Triethylsilane allows for the formation of enantiomerically pure 5-substituted pyrrolidinones and 2-substituted pyrrolidines in the same manner. ... 

Intramolecular nucleophilic ring-opening reactions of oxazolines are also known. Hydrozirconation of A -allylox-azolidine 141 gave a zirconocene intermediate 142, which reacted with TiCh to afford the corresponding 2-substituted pyrrolidine 143 in good yield and diastereoselectivity (Scheme 36) <2005OL4887>. 

According to the the work of P. Beak and coworkers on 2-substituted pyrrolidines [2], the following synthetic route, containing asymmetric deprotonation and transformation of the protecting group, was chosen for the preparation of the (aminomethyl)silanes 3 and 5. The (aminomethyl)(lithiomethyl)silane 4, a molecule of type E (Scheme 1), was achieved by subsequent metalation of 3 (Scheme 2). 

Addition of the titanium enolate of Af-acetyl-4-isopropyl-l,3-thiazohdme-2-thione 150 to the A-acyl iminium ions from 151 furnishes the corresponding Mannich-type adducts 152 and 153 with good diastereoselectivity <05JOC4214>. A similar diastereoselective addition of the titanium enolate derived from Af-4-chlorobutyryl-l,3-thiazolidine-2-thione 154 to A -Boc-2-methoxypyrrohdine 155 has been used to provide 2-substituted pyrrolidine 156, a key intermediate in the synthesis of (+)-isoretronecanol <05TL2691>. 

Ring expansion reactions of 2-substituted pyrrolidines, with the intermediacy of a bicyclic aziridinium ion, has provided new piperidines. Treatment of the chiral olefmic imine 264 with Br2, followed by reduction of the resultant ion 265 results in the formation of a separable mixture of spiromethylpyrrolidines and a single spiropiperidine 266 (23% yield), a precursor of (-)-nitramine 267 (Scheme 80) <05SL1726>. 

The above result suggested that kinetic resolutions would also be possible with appropriate substrates. When an excess of racemic 2-substituted pyrrolidines were treated with a rhodium catalyst and an aryldiazoacetate, only a single enantiomer of each starting material reacted efficiently with the carbenoid to afford the product... 

Asymmetric deprotonation of carbamates 4.2 under similar conditions, followed by trapping of the intermediate lithiated species by various electrophiles, also leads to 2-substituted pyrrolidines with very high enantiomeric excesses [564] (Figure 4.2). 

Figure 2. Synthesis of a pyridazinyl ether in the 2-substituted pyrrolidine series.

Figure3. Synthesis of pyridyl ethers in the 3- and 2-substituted pyrrolidine series...

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>. 

Substituted pyrrolidines Tinospora cordifolia Miers/ Menisperniaceae Whole plant Hypoglycemic and central nervous system (CNS) depressant activity pyrrolidines in rabbits was observed [17]. 

An asymmetric deprotonation of (ferf-buto-xycarbonyl)pyrrolidines 25 has been recently developed by Beak allowing a highly enantioselective synthesis of a variety of 2-substituted pyrrolidines (Eq. 14). [21] Also amino-substituted benzylic lithiums have been generated with 5 BuLi (-)-3 and quenched stereo-selectively with electrophiles. [22]... 

A cleavage of the lactams (175) <9iJOC2624> and (176) <87JOC4i8> with formation of 2-substituted pyrrolidines (177) and (178) has been reported (Equation (52)). 

---