Substitution prolines

Spirapril (37) is a clinically active antihypertensive agent closely related structurally and mechanistically to enalapril. Various syntheses are reported with the synthesis of the substituted proline portion being the key to the methods. This is prepared fkim l-carbobenzyloxy-4-oxopro-line methyl ester (33) by reaction with ethanedithiol and catalytic tosic acid. The product (34) is deprotected with 20% HBr to methyl l,4-dithia-7-azospiro[4.4 nonane-8-carboxylate (35), Condensation of this with N-carbobenzyloxy-L-alanyl-N-hydroxysuccinate leads to the dipeptide ester which is deblocked to 36 by hydrolysis with NaOH and then treatment with 20% HBr. The conclusion of the synthesis of spirapril (37) follows with the standard reductive alkylation [11]. 

Fluorous Synthesis of Biaryl-Substituted Proline Analogs... 

Scheme 35 Combinatorial approach towards substituted prolines...

A library of 800 substituted prolines of type 112 was described using a similar synthetic approach. The [3 + 2] cycloaddition occurred via a multicomponent reaction of a-amino esters, aldehydes, and maleimides (Scheme 38). 

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

In 2001, Sarko and coworkers disclosed the synthesis of an 800-membered solution-phase library of substituted prolines based on multicomponent chemistry (Scheme 6.187) [349]. The process involved microwave irradiation of an a-amino ester with 1.1 equivalents of an aldehyde in 1,2-dichloroethane or N,N-dimethyl-formamide at 180 °C for 2 min. After cooling, 0.8 equivalents of a maleimide dipo-larophile was added to the solution of the imine, and the mixture was subjected to microwave irradiation at 180 °C for a further 5 min. This produced the desired products in good yields and purities, as determined by HPLC, after scavenging excess aldehyde with polymer-supported sulfonylhydrazide resin. Analysis of each compound by LC-MS verified its purity and identity, thus indicating that a high quality library had been produced. 

Recently, a novel method for the synthesis of a library of substituted prolines with microwave technology [95] has been described. In the first step, 1 equivalent of an amine is added to 1.1 equivalents of an aldehyde in 1,2-dichloroethane (DCE), with subsequent irradiation at 180 °C for 2 min. In the second step, 0.85 equivalents of the maleimide are added and the resulting solution is heated at 180 °C for an additional 5 min. This methodology allowed the production of a solution-phase library of 800 compounds with a crude purity between 65 and 82% (Scheme 9.45). The compounds were purified by solid-supported reagent scavenging to afford the final products with a purity between 90 and 98% and in 79-85 % yield [96]. 

Mykhailiuk PK, Afonin S, Palamarchuk GV, Shishkin OV, Ulrich AS, Komarov IV (2008) Synthesis of trifluoromethyl-substituted proline analogues as F-19 NMR labels for peptides in the polyproline II conformation. Angew Chem Int Edit 47 5765-5767... 

Several syntheses of l,3-dioxoperhydropyrrolo[l,2-c]imidazoles have been developed using different strategies. a-Substituted bicyclic proline hydantoins were prepared by alkylation of aldimines 135 of resin-bound amino acids with a,tu-dihaloalkanes and intramolecular displacement of the halide to generate cr-substituted prolines 136 and homologs (Scheme 18). After formation of resin-bound ureas 137 by reaction of these sterically hindered secondary amines with isocyanates, base-catalyzed cyclization/cleavage yielded the desired hydantoin products <2005TL3131>. 

The numerous synthetic approaches relied principally on the formation of a 5-substituted proline ester by reductive amination followed by cyclization of the lactam ring. 

The 3,5-diphenylmorpholine-2-one 161 was used to prepare bicyclic lactams 162 by reaction with the cesium fluoride/tetramethoxysilane system and different Michael acceptors. The adducts were rapidly obtained as a mixture of diastereoisomers that could be separated by column chromatography just after TFA-mediated cyclization to the 8-substituted-4,8a-diphenyltetrahydro-l//-pyrrolo[2,l-r1[l,4]oxazine-l,6(7//)-diones 62 and 163 <1997SL935>. These compounds were then reduced to give substituted prolines as described in Section 11.11.6.1. 

Anodic oxidation reactions have also been used to functionalize substituted proline derivatives. For example, an anodic amide... 

Scheme 49 Parallel synthesis for N-a-substituted proline derivatives.

This reversal of elution order is due to the changed CIP priorities, but not a result of an altered binding and chiral recognition mechanism. Moreover, in yet another study, BOC and DNP-protected a-substituted proline derivatives have been resolved into enantiomers and elution orders were determined [48], The method allowed the sensitive and accurate analysis of samples with regards to their enantiomeric purities. 

TBDMS=fert-butyl-dimethylsilyl) X=OAc, OTBDMS Fig. 5.9) other A-(Boc-aminoethyl)-4-(/ /S) substituted proline esters were similarly oxidised (X=H, OCOMe, OSO Me) [61],... 

The zinc-enolate carbocyclization reaction was applied to the synthesis of diverse 3-substituted proline chimeras. To this end, the stable cyclic organozinc intermediate... 

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. 

Substituted prolines - typically with additional chiral centre(s) in the substituent - have been found to be much more enantioselective than proline itself in aldol reactions.113... 

MA Ondetti, A Miguel, J Krapcho. Mercaptoacyl derivatives of substituted prolines. U.S. Patent 4316906, 1982. 

Alsina, J., Scott, W. L., and O Donell, M. J., (2005) Solid-phase synthesis of a-substituted proline hydantoins and analogs. Tetrahedron Lett. 46, 3131-3135. 

Angiotensin-Converting Enzyme Inhibition by 4-Substituted Proline Phosphinic Acidsa... 

Baldwin et al. employed 20 mol% 255 to synthesize isopropenyl-substituted prolinates 265 and kainic acid 268 in good yields from /V-prenylated haloamino acids 264 (Y=NC02R) (Fig. 65, entry 7) [318]. As observed before for many radical cyclizations employing trisubstituted alkenes as acceptors, the diastereo-selectivity remains, however, poor. 

Scheme 12.1 Synthesis of 5-substituted proline derivatives from = r< /t-butoxy carbonyl).

Click chemistry also found applications in peptides and peptidomimetics. Alkyne-azide cycloaddition between two peptide strands provided an efficient convergent synthesis of triazole ring-based P-tum mimics <07CC3069>. The synthesis of a-substituted prolines has been accomplished by microwave-assisted Huisgen 1,3-dipolar cycloaddition between azides and orthogonally protected a-propynyl proline in the presence of Cu(I) sulfate <07SL2882>. The synthesis of new trifluoromethyl peptidomimetics with a triazole moiety has been reported <07TL8360>. 

FIGURE 1.5 Synthesis of diaryl-substituted proline derivatives 6. 

Zhang, W. and Chen, C.H.-T. 2005. Fluorous synthesis of biaryl-substituted prolines by 1,3-dipolar cycloaddition and Suzuki coupling reactions. Tetrahedron Letters, 46 1807-10. 

A series of N-protected substituted prolines have been prepared from /3-aminoaldehydes, as illustrated by the stereoselective conversion of 245 into the heterocycle 246 using benzyl diazoacetate as a source of the final required carbon atom (Equation 79) <2004JOC4361>. 

Dipolar Cycloadditions. Highly substituted proline derivatives can be prepared by removal of the r-Boc protecting group from the oxazinone followed by condensation of the heterocycle with an aldehyde in the presence of p-Toluenesulfonic Acid in benzene. Under these conditions, Schiff base formation and ylide generation occur. Subsequent [3 + 2] cycloaddition with a dipolarophile affords the bicyclic heterocycle, which is then de-protected to yield the desired proline derivative (eqs 10 and 11). ... 

---