Tetrahydrofurans pyrrolidine synthesis

The monomer synthesis and cyclopolymerization were carried out following the procedure of Butler et al. (21). The resulting polyimide was shown to possess primarily pyrrolidine rings as indicated by infrared spectroscopy (21). Initially, the reduction was carried out with LiAlH in tetrahydrofuran. 

The preparation of five-membered rings in solid-phase organic chemistry has been reported in several publications. Versatile syntheses of these heterocycles with different numbers and kinds of heteroatoms have been described. The synthesis of five-membered rings containing one nitrogen atom (Fig. 3.6) as pyrrolidines (231) [311-316] pyrroles (232) [317-320] pyrrolidinones (233) [321-323] pyr-rolinones (234) [324—326] 2,5-pyrrolidinediones (235) [327-329] 2,4-pyrrolidine-diones (236) [330-332] 2,5-pyrrolinediones (237) [333] or heterocycles with one oxygen or one sulfur atom like tetrahydrofurans (238) [334—336] 2,5-dihydrofurans (239) [337], furans (240) [338, 339], yS-lactones (241) [340-343], 2,5-dihydrofura-nones (242) [344] (Scheme 3.35) and thiophenes (243) [345, 346] can be accomplished on solid supports. 

Lewis acid-promoted [3+2] cycloadditions of aziridines and epoxides proceeding via carbon-carbon bond cleavage of three-membered ring heterocycles are demonstrated for the first time. This proposal details plans for extending these initial results into a general synthetic method for the enantioselective synthesis of structurally diverse pyrrolidine- and tetrahydrofuran-containing organic compounds. Expected outcomes of the proposed work will include... 

Shibata and co-workers have reported an effective protocol for the cyclization/hydrosilylation of functionalized eneallenes catalyzed by mononuclear rhodium carbonyl complexes.For example, reaction of tosylamide 13 (X = NTs, R = Me) with triethoxysilane catalyzed by Rh(acac)(GO)2 in toluene at 60 °G gave protected pyrrolidine 14 in 82% yield with >20 1 diastereoselectivity and with exclusive delivery of the silane to the G=G bond of the eneallene (Equation (10)). Whereas trimethoxysilane gave results comparable to those obtained with triethoxysilane, employment of dimethylphenylsilane or a trialkylsilane led to significantly diminished yields of 14. Although effective rhodium-catalyzed cyclization/hydrosilylation was restricted to eneallenes that possessed terminal disubstitution of the allene moiety, the protocol tolerated both alkyl and aryl substitution on the terminal alkyne carbon atom and was applicable to the synthesis of cyclopentanes, pyrrolidines, and tetrahydrofurans (Equation (10)). 

A number of complex heterocycles have been assembled using dipolar cycloadditions (Fig. 6). The Affymax group [32] published an approach to the synthesis of tetrasubsti-tuted pyrrolidines by the reaction of azomethine ylids with electron-deficient olefins. A similar approach was described by researchers at Monsanto however, the aldehyde component was bound to the resin instead of the amino acid [33]. Kurth and co-workers [34] described a route to 2,5-disubstituted tetrahydrofurans using a nitrile oxide cycloaddition as the key reaction. Mjalli et al. [35] synthesized highly substituted pyrroles using the dipolar cycloaddition of intermediate 5 with mono- or disubstituted acetylenes. 

A chemoselective addition of allylic alcohols (82) to 3-halogenovinyl sulfones (81) has been accomplished using KF-basic alumina as the basic medium.55 The resulting adducts (83) can be stereoselectively cyclized by a radical process, affording 2,4-disubstituted tetrahydrofurans (84) (Scheme 22, Eq. 1). The same group has recently reported an analogous protocol using allylic amines (85) for the synthesis of 2,4-disubstituted pyrrolidines (87) (Scheme 22, Eq. 2)56... 

The ease of these cyclization reactions may be due to the fact that, in the transition state, anionic character can be partially displaced onto oxygen. Independently of the mechanism of these processes which also could be considered as intramolecular Sw cyclization reactions, this useful trick has been used sometimes for the synthesis of vinylcyclopentanes, vinyl tetrahydrofurans and pyrrolidines, as described above. 

The anionic form usually obtained in using enamines as synthesis reagents is usually the allyl form. Thus, Blomquist and Moriconi46" showed that, by reacting a solution of the pyrrolidine enamine of indan-2-one in tetrahydrofuran with w-butyl lithium in -hexane at —65 °C (equation 22), the proton removal is complete in about 10 min. 

Musso et al. (87,97) have developed an elegant synthesis of muscaflavin dimethyl ester (61) (Scheme 8). It is conceptionally similar to the synthesis of decarboxybetalains described before. The synthesis starts with conversion of pyridylalanine derivative 86 to the dimethyl ester 87 by esterification and consecutive N-protection with the base-labile p-toluenesulfonylethoxycarbonyl group. For cleavage of the pyridine ring, 87 was transformed into the A -methoxy-pyridinium salt (88) which was then reacted with pyrrolidine in tetrahydrofuran... 

The previously described zinca-ene-allene reaction was successfully applied to the diastereoselective synthesis of tetrahydrofurans [68] and pyrrolidines [69] as described in Scheme 7-62. 

Illustrative of the chemistry of the aminyl radical is a synthesis of the A -methyl derivative of the antibiotic (—)-anisomycin (73) [20]. It was obtained by treating (E )-5-alkenylamine 71 with -butyllithium at —78°C, followed by anodic oxidation at a constant current (17.5mA/cm") in a 100 1 mixture of tetrahydrofuran (THE) and hexamethyl-phosphor-ous-triamide (HMPA) containing 0.25 M lithium perchlorate at — 10°C. A 5-exo,trig cycli-zation of the metalated aminyl radical afforded pyrrolidine 72 as a single isomer in a 53% yield. A routine series of transformations converted 72 to the target structure 73. 

In a somewhat similar synthesis (16) the lactam 46 which was prepared by two distinct routes was shown to undergo reductive cycliza-tion to give elaeocarpidine and dihydroelaeocarpidine. When this reduction step was carried out with lithium aluminum hydride in tetrahydrofuran a 1 2 mixtime of elaeocarpidine and dihydroelaeocarpidine was obtained but reduction with lithium aluminum hydride in pyrrolidine-tetrahydrofuran (1 1) at 0° gave a 52% yield of elaeocarpidine along with unchanged lactam (46). 

Cyclization of dienes and trienesReaction of a diene or tricne with at least one terminal double bond with (CHj)jSnCI, A1BN, and NaBH CN in f-BuOH results in addition of the (CH Sn radical to the terminal double bond followed by cyclization to the other double bond. The C-Sn bond of the carbocycle is oxidatively cleaved by CAN in methanol to the dimethyl acetal of an aldehyde. This two-step synthesis provides a useful route to tetrahydrofurans and pyrrolidines as well as 1,6-dioxatriquinancs from allyl ethers. 

Scheme 8.21 Schematic representation of the synthesis of polyfcyclic poly(tetrahydrofnran)), bottom right, utilizing a bifunctional alkyne-modifled initiator for the living CROP followed by end-capping with -phenyl-pyrrolidine to moderate the end-group reactivity. Subsequent end-group modification with a bifunctional acid modified with an azide moiety yields the cyclic poly(tetrahydrofuran) comprising both aUcyne and azide functionalities, which is subsequently polymerized by cycloaddition in the presence of copper(I).

Palladium-catalyzed carboetherification and carboamination reactions of y-hydroxy- and y-aminoalkenes for the synthesis of tetrahydrofurans and pyrrolidines 07EJO571. 

Recently, Kim et al. have disclosed an expeditious route for the synthesis of tetrahydrofurans 429 and pyrrolidines 430, starting from the suitably modified MBH adducts, that involves RCM followed by hydrogenation or radical cyclization and subsequent hydrogenation protocols (Scheme 3.191). " ... 

Best results were obtained when n-BuLi as base (10%) and Pd(OAc)2(PPh3) as catalyst were used. This reaction has provided an efficient route to highly functionalized 3-methylene tetrahydrofurans since electron-rich and electron-poor arylidene acceptors as well as enolizable alkylidene malonates reacted. This methodology was later applied to the synthesis of methylene pyrrolidines (Table 7). "... 

TABLE 7. Two-Component Synthesis of 3-(4)-Methylene Tetrahydrofurans and Pyrrolidines. 

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