Prolines, fused

The synthesis of proline-fused heterocyclic systems by 1,3-dipolar cycloaddition has been well-established in solution-phase synthesis (Scheme 14) [42]. It is usually performed as a one-pot, three-component reaction of a dipo-larophile with an in situ prepared azomethine ylide. Perfluoroalkanesulfonyl protected hydroxybenzaldehydes [43] or fluorous alcohol protected amino esters [44] have been developed as two different fluorous components for the synthesis of proline derivatives 11 and 12. 

The utility of lOOC reactions in the synthesis of fused rings containing a bridgehead N atom such as pyrrolizidines, indolizidines, and quinolizidines which occur widely in a number of alkaloids has been demonstrated [64]. Substrates 242 a-d, that possess properly positioned aldoxime and alkene functions, were prepared from proline or pipecolinic acid 240 (Eq. 27). Esterification of 240 and introduction of unsaturation on N by AT-alkylation produced 241 which was followed by conversion of the carbethoxy function to an aldoxime 242. lOOC reaction of 242 led to stereoselective formation of various tricyclic systems 243. This versatile method thus allows attachment of various unsaturated side chains that can serve for generation of functionalized five- or six-membered (possibly even larger) rings. 

The fused iV-(pynmidin-4-yl)proline derivative 291 undergoes cyclization to the zwitterionic pyrroloimidazopyr-imidine 292 upon treatment with acetic anhydride <1985JHC187> (Equation 49). 

What is described as a domino Knoevenagel-hetero-Diels-Alder reaction , involving the reaction of the glucose-derived aldehyde 93 with a 1,3-dicarbonyl compound in presence of either proline or ethylenediammonium acetate, leads to the doubly annulated 5 6 6-fused compound 94 (Scheme 30) <2004S1150>. If the dicarbonyl compound is Meldmm s acid, however, the sequence is completed by spontaneous elimination of acetone and carbon dioxide from the Diels-Alder adduct, to give compound 95 <2005ASC1353>. 

Scheme 6.187 Fused prolines from azomethine ylide-maleimide [3+2] cycloadditions.

Based on this concept, a large variety of HCLA bases incorporating a vicinal heteroatom (tertiary amine, ether) has been tested for this transformation. These are of two types the proline type, which can be considered as a conformationaUy restricted c/5-fused 5-membered ring bicyclic structure (type A), and the norephedrine- or phenylglycine-type, leading to a more flexible, substituted 5-membered ring structure (type B) (Figure 3). 

Attachment of the basic side chain to the phenothiazine nucleus by means of a carbonyl function apparently abolishes the usual CNS or antihistamine effects shown by most compounds in this class. The product azaclorzine instead is described as an anti anginal agent. Reduction of proline derivative 106 with lithium aluminum hydride gives the corresponding fused piperazine 107. Use of that base to alkylate the chloroamide 109, obtained from acylation of phenothiazine with 3-chloropropionyl chloride, leads to azaclorzine (110). ... 

A novel one-pot synthesis of various fused lactones has been achieved via a domino sequence of Knoevenagel/ hetero-Diels-Alder/elimination reactions of N- and 0-prenyl aryl aldehyde derivatives with Meldrum s acid in the presence of D- or L-proline with high diastereoselectivity (Scheme 68) <2005MI1353>. 

ACE inhibiting activity is retained when the pyrrohdine ring of the proline moiety is imbedded in fused bicyclic system this modihcation leads to several quite potent antihypertensive dmgs. 

The fusion of an additonal heterocyclic ring onto the above benzodiazepine restores at least partial agonistic activity. The benzodiazepine nucleus is built exactly as above using L-proline (20-2) instead of sarcosine to afford (20-3). The fused imidazole ring is again added by condensation with an isocyanoacetate, in this case the tert-butyl ester. This then affords bretazenil (20-4) [24], a compound that displays some antianxiety activity. 

J The imino acid proline. Because the side chain is fused to the oc-amino group, the entire structure, not just the side chain, is shown. 

In a simple microwave-assisted and solvent-free approach, substituted isatoic anhydrides were reacted with 4-substituted prolines to afford fused 1,4-benzodiazepine derivatives67. The reactions proceeded in less than 3 min and the fused 1,4-benzo-diazepine products were obtained in very good yields (Scheme 3.42). This condensation reaction represents a practical alternative approach to the typical traditional methods. 

Fused l,2,5-triazepine-3,6-diones 88-90 were synthesized from (2 S )-proline methyl ester 205 by treating the latter with bromoacetic acid 206 in the presence of tiro-butyl chloroformate 207 (Scheme 46). The resultant bromoacetamide 208 on further treatment with hydrazine hydrate in EtOH gave 88-90 via cyclization through displacement of bromine <1996CC85>. 

In the synthesis of l,2,5-triazepine-l,5-diones, which are expected to mimic the structural features of or-peptidyl prolin-amides, the preparation of N2,N3-disubstituted derivatives 213a from the reaction of (Z)-alanine with the N2-substituted triazepines 213 resulted in lower yields. It has been reported that these fused triazepinediones could be elaborated to give constrained rir-peptidyl proline peptide mimetics of defined stereochemistry and sequence <1997J(P1)2297>. 

The three-component reaction of indole (2) with sugar hydroxyaldehyde 281 and Meldrum s acid 282, with a catalytic amount of D,L-proline, afforded the 3-substitution product 283 as a single isomer [203]. The substituent possesses the czs-fused furo [ 3,2- b ] pyranonc skeleton. The proline catalyzes the Knoevenagel condensation of the sugar aldehyde 281 and Meldrum s acid 282 to provide the alkylidene derivative 284 of Meldrum s acid. Then a diastereo-selective Michael addition of indole and an intramolecular cyclization of this adduct 285 with evolution of carbon dioxide and elimination of acetone furnish the furopyranone in one-pot (Scheme 62). 

The scope of the reaction was subsequently expanded to the 1,3-dipolar cycloaddition of nitrones to cyclic a,/ -unsaturated aldehydes, allowing for the formation of fused bicyclic isoxazolidines (Scheme 3.7). Here, the use of catalyst 1 resulted in almost no reaction, whereas a proline-based diamine (9) afforded high levels of enantio-and diastereoselectivity [59, 60]. 

Table 1 Selected adamantanyl derivatives and their corresponding mass spectral data. HPLC data supplied by the author. Cyclopropyl-fused dehydro pyrrolidines were prepared using (C2H5)2Zn, C1CH2I, and A-Boc-4,5-L-proline ester derivatives in CH2C12 according to the method of co-author Robl (1)...

In one pot and under aqueous conditions, a proline-catalysed Knoevenagel -cyclocondensation sequence involving an aromatic aldehyde, an activated methylene compound and dimedone results in the rapid formation of fused 477-pyrans (Scheme 2) <06SL263>. 

L-proline NCA is comparatively reactive. In part this may arise from strain in the molecule. However, the fused rings confer a saucer-like shape on the molecule and attack at C5 from the convex side should be relatively free from obstruction by substituents on the ring nitrogen and C4. This is probably the explanation of the comparatively fast reaction of L-proline NCA with Al-isopropylglycine dimethylamide (R4 = iPr), of which the rate coefficient is approximately 6000 times that of the corresponding reaction with N-methyl-DL-alanine NCA (R, = R3 = Me, R2 = H). 

The analogous [c]-fused system has been obtained through an intramolecular Michael addition of a substituted oct-2-en-1,8-dial promoted by L-proline in DMSO <05JA3696>. 

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