3- Pyrrolidinone derivatives, synthesis

Lactams are cyclic amides and they are reduced by LiAlHq to the cyclic amine. The reduction of a typical lactam such as 2-pyrrolidinone derivative 36 presumably proceeds via initial formation of the a-amino alcohol (37), followed by elimination to an iminium salt (38), and then reduction by hydride to give the amine (39). This reaction is very useful in the synthesis of alkaloids, as seen in the reduction of 40 to 41 in 88% yield as part of Overman s synthesis of (-i-)-aloperine. O The lactam nitrogen is significantly less basic than the corresponding amine and cyclic amines are often protected as the lactam. The amine is then unmasked late in the synthetic sequence by hydride reduction. 

This methodology with some variations has been utilized in the synthesis of numerous heterocyclic systems, such as heterocycle-fused quinolinone derivatives [391], l,4-benzodiazepin-2-ones [392], benzo-, naphtho- and heterocycle-fused pyrrolo[2,l-c][l,4]diazepines [393], quinolinone or pyrrolidinone derivatives [394], dibenzo[fl,c]phenanthridines [395], thiazolo-fused quinolinones [396], isoindolinone and isoquinolin-2-one derivatives [397], indoline derivatives [398], 5-aroyl-pyrrolidinones [399,400], indazolone derivatives [401,402], substituted indolizidinones [403], 1-arylpyrrolopyrazinones [404], stmcturally diverse... 

The intramolecular C-H insertion of rhodium carbenoids, described earlier for the synthesis of 2-azetidinones, has also been reported to form pyrrolidinone derivatives [36]. The Rh-catalyzed reactions of a-diazo amides 67 by heating in water afford pyrrolidine derivatives 69 together with 2-azetidinones 68 (Scheme 22). 

Azomethine ylide 26 reacts with (—)-8-phenylmenthyl derivatives of Fischer alkenyl carbene complex 25 to afford 2-pyrrolidinone derivative 27 with high regioselectivity and diastereoselectivity (Scheme 5.7) [16]. A total synthesis of the anti-inflammatory and antidepressant drug (+)-roli-pram is achieved via the stereoselective [3+2] cycloaddition as a key reaction. 

Transition metal catalysis on solid supports can also be applied to indole formation, as shown by Dai and coworkers [41]. These authors reported a palladium- or copper-catalyzed procedure for the generation of a small indole library (Scheme 7.23), representing the first example of a solid-phase synthesis of 5-arylsulfamoyl-substituted indole derivatives. The most crucial step was the cydization of the key polymer-bound sulfonamide intermediates. Whereas the best results for the copper-mediated cydization were achieved using l-methyl-2-pyrrolidinone (NMP) as solvent, the palladium-catalyzed variant required the use of tetrahydrofuran in order to achieve comparable results. Both procedures afforded the desired indoles in good yields and excellent purities [41]. 

A method has been reported for the solid-phase synthesis of tetrazolo[5,1 -tf]phthalazine derivatives 501 based on the cyclization of resin-bound chlorophthalazines 500 with NaN3 in l-methyl-2-pyrrolidinone (NMP) at 120°C (Scheme 63) <2005TL3107>. 

Facile synthesis of simple 3-arylpyrroles from pyrroline by tandem Suzuki dehydrogenation reaction is depicted in Scheme 229. Thus, treatment of l-benzyl-2,5-dihydro-l//-pyrrol-3-yl trifluoromethanesulfonate 1195 (prepared in 55% yield from l-benzyl-3-pyrrolidinone 1194 by trapping the enolate with a triflating reagent), with boronic acid derivatives leads to the formation of 3-arylpyrroles 1196 in good yields (65-74%) <2000TL3423>. 

The synthesis started with the known hydrindenone derivative, 154 (Scheme 15) (177). Surprisingly, the group transformation of the secondary alcohol to the cyanide 155 via the tosylate occurred under retention of configuration in 64% yield. The authors were able to exclude a retroaldol-aldol reaction sequence as the reason for the unusual stereochemistry but did not further elaborate. To form the annelated pyrrolidinone, the enone was chemo- and stereoselectively reduced by... 

Tanaka, T., Watarumi, S., Fujieda, M., and Kouno, I. 2005. New black tea polyphenol having V-ethyl-2-pyrrolidinone moiety derived from tea amino acid theanine Isolation, characterization and partial synthesis. Food Chem. 93 81-87. 

The primary alcohol of diol ester 45a is susceptible to selective activation that allows reactions to take place at the C-4 carbon. Tosylation of 45a under standard conditions produces the crystalline 4-tosyloxy alcohol 59. Displacement of the tosyl group with pro-pargylamine followed by concomitant cyclization gives the propargylic pyrrolidinone 60 in 25% overall yield from L-malic acid (1) (the esterification and reduction steps are not shown). This pyrrolidinone is used as an intermediate in the synthesis of enantiomerically pure hydroxylated oxotremorine derivatives [40]. 

The use of alkoxides as nucleophiles is not common in the area of DKR. In 1997, Camps et al. reported, however, the asymmetric synthesis of a-hydroxyacids based on the DKR of a diastereomeric mixture of a-bromoesters derived from (R)- or (S)-3-hydroxy-4,4-dimethyl-l-phenyl-2-pyrrolidinone with p-methoxyphenoxide in the presence of tetra- -hexylammonium iodide (Scheme 1.6). ... 

Vol. 28, p. 226, ref. 44 for related work). Similar cycloadditions of dienyl pyrrolidinones [le. AT-(peiita-l,3-dienyl)- or -(buta-l,3-dienyl)-pyrolidin-2-one] with the in situ generated acyl nitroso compound derived from benzyl-JV-hydroxy-carbamate with periodate have led to the preparations of racemic pyroUidines 56 and 57 (R = H or Me). The latter compound is thought to exist as a dimer. An asymmetric synthesis of l,S,6-trideoxy-l,5-imino-D-altritol in which the piperidine ring is formed from a pyiidinium ring bearing Seebach s oxazolidinone chiral auxiliary has also been described. ... 

Synthesis of the morpholine-derivative renin inhibitor BW-175 (254) and the spiroammonium derivative 255 are described in chapter 18. The antibiotic ( —)-anisomycin 258 has been prepared from glycosylamine 256. Grignard addition, oxidation and cyclization affords pyrrolidinone 257 which was elaborated by known means to 258. ... 

Synthesis of (+)-lactacystin Lactacystin 7 is one of the most important biologically active pyrrolidinone-based natural products found in nature. It was isolated from the culture broth of a Streptomyces in 1991, and since that time, it has generated an enormous interest as a consequence of its highly selective and irreversible inhibition of the 20S pro-teasome. Its synthesis was first reported by Corey and Reichard, and an alternative more recent approach is based on the preparation of an oxazoline 8 that is produced via formation of a 2-ethynyl-allyl epoxide 10 via Sharpless asymmetric epoxidation of the allyl alcohol 9 (Scheme 34.3). The reaction was carried out in the presence of catalytic amounts of calcium hydride and silica gel (whose role is not described in the paper) at —40°C to — 18°C obtaining the desired product 10 in 89% yield and >95% ee determined by integration of the F resonances of the corresponding Mosher ester derivative. 

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