Synthesis of Heterocycles and Amino Acids

A new strategy for the synthesis of heterocyclic a-amino acids utilizing the Hantzsch dihydropyridine synthesis was developed in the laboratory of A. Dondoni." ° The enantiopure oxazolidinyl keto ester was condensed with benzaldehyde and fert-butyl amino crotonate in the presence of molecular sieves in 2-methyl-2-propanol to give a 85% yield of diastereomeric 1,4-dihydropyridines. The acetonide protecting group was removed and the resulting amino alcohol was oxidized to the target 2-pyridyl a-alanine derivative. 

Figure 3 Solid-ph e synthesis of heterocycles from amino acids and peptides through imine formation. Synthesis of (a) isoquinolines 2, (b) thiazolidinones 3 and methathiazanones 4, (c) j8-carbolines 5, (d) -lactams 6, (e) pyrrolidines 7, (f) thia-zolidines 8, and (g) quinolinones 9.

Design and synthesis of conformationally fixed amino acids of heterocyclic series as versatile building blocks 97T12789. 

Amino-2//-azirines as amino acid equivalents 86U3. 3-Amino-2//-azirines as synthons for a,a-disubstituted a-amino acids in the synthesis of heterocycles and peptides 91AG(E)238. 

Asymmetric alkylation of imines has been employed most frequently for the construction of chiral amino moieties involved in the syntheses of nitrogen heterocycles and amino acids [17]. This approach is also useful for fluorinated amino acid synthesis as shown in Scheme 9.7. Mannich reaction of enolate with imino ester 23 in the presence of L-proline gives a-amino esters 24 and 25 enantio-and diastereoselectively [18]. 

Recent advances in the synthesis of unnatural a-amino acids (heterocycles are of considerable importance both during the synthetic build-up and as targets) 07COC801. 

Synthesis of Unsaturated a-Amino-acids.—The lactim ether (284) is converted into the enantiomerically pure unsaturated amino-acids (285) (Scheme 140) ethyl (J5)-2-formylamino-4-methoxybut-3-enoate and its 2-alkyl derivatives have also been prepared, using heterocyclic intermediates. ... 

N-acylated esters of (cyclohexa-l,4-dienyl)-L-alanine are ozonized aiming at the synthesis of novel uimatural amino acids. The combined reduction and ozonolysis followed by condensation with a suitable nucleophile results in transformation of the aromatic ring of L-Phe to isooxasolyl, N-phenylpyrazolyl and to bicyclic pyrazolo[l,5-a]pyrimidine groups. The preparation of heterocyclic alanine derivatives is reported [89]. 

The transformation of the cyano group could also introduce a new chiral center under diastereoselective control (Figure 5.13). Grignard-transimination-reduction sequences have been employed in a synthesis of heterocyclic analogues of ephedrine [81]. The preferential formation of erythro-/3-amino alcohols may be explained by preferential hydride attack on the less-hindered face of the intermediate imine [82], and hydrocyanation of the imine would also appear to proceed via the same type of transition state. In the case of a,/3-unsaturated systems, reduction- transimination-reduction may be followed by protection of the /3-amino alcohol to an oxazolidinone, ozonolysis with oxidative workup, and alkali hydrolysis to give a-hydroxy-/3-amino acids [83]. This method has been successfully employed in the synthesis L-threo-sphingosine [84]. 

Recent research deals with stereoselective 1,3-dipolar cycloadditions of nitrones for the syntheses of alkaloids and aza heterocycles asymmetric synthesis of biologically active compounds such as glycosidase inhibitors, sugar mimetics, /3-lactams, and amino acids synthesis of peptido-mimetics and peptides chemistry of spirocyclopropane heterocycles synthesis of organic materials for molecular recognition and photochemical applications. 

At that time, as now, the enantiomers of many chiral amines were obtained as natural products or by synthesis from naturally occurring amines, a-amino acids and alkaloids, while others were only prepared by introduction of an amino group by appropriate reactions into substances from the chiral pool carbohydrates, hydroxy acids, terpenes and alkaloids. In this connection, a recent review10 outlines the preparation of chiral aziridines from enantiomerically pure starting materials from natural or synthetic sources and the use of these aziridines in stereoselective transformations. Another report11 gives the use of the enantiomers of the a-amino acid esters for the asymmetric synthesis of nitrogen heterocyclic compounds. 

The oxazolidine-2,5-dione heterocycle, perhaps better known as the N-carboxyanhydride of an amino acid, has been incorporated employing a modification of chloromethylated poly(styrene) (192) (76USP3985715). The reaction sequence involved utilization of a masked amino acid, ethyl acetamidocyanoacetate (205). The amino acid was liberated in a subsequent hydrolysis/decarboxylation step (Scheme 98). The cyclized, IV-carboxyanhydride-functional resins (206) were reported to be useful in solid phase peptide synthesis and as supports for enzyme immobilization. 

Various N-alkylated derivatives of amino acids are natural products [e.g., H-D-(Me)Tyr-OH (D-surinamine) and H-(Me)Trp-OH (abrin) were found in cabbage tree bark1691] and many of them are used as enzyme inhibitors, receptor agonists and antagonists, building blocks for heterocyclic scaffolds in combinatorial chemistry, etc. In this section the preparation of N-alkyl amino acids in solution for their use in peptide synthesis is described. This implies that the synthetic procedures described in this section will ultimately result in V-alkyl amino acids appropriately protected for peptide synthesis. 

Huisgen and coworkers have also described the cycloaddition behavior of the munchnones , unstable mesoionic A2-oxazolium 5-oxides with azomethine ylide character.166 Their reactions closely parallel those of the related sydnones. These mesoionic dipoles are readily prepared by cyclodehydration of N-acyl amino acids (216) with reagents such as acetic anhydride. The reaction of munchnones with alkynic dipolarophiles constitutes a pyrrole synthesis of broad scope.158-160 1,3-Dipolar cycloaddition of alkynes to the A2-oxazolium 5-oxide (217), followed by cycloreversion of carbon dioxide from the initially formed adduct (218), gives pyrrole derivative (219 Scheme 51) in good yield. Cycloaddition studies of munchnones with other dipolarophiles have resulted in practical, unique syntheses of numerous functionalized monocyclic and ring-annulated heterocycles.167-169... 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

Solid-Phase Synthesis of Heterocyclic Compounds from Resin-Bound Amino Acids, Short Peptides, and Polyamines... 

Our interest in expanding the acylative pyrrole annulation approach to additional heterocyclic systems has led to an efficient synthesis of pyrrolo[3,2-c]pyridin-2-ones and pyrido[3,4-6]pyrrolizidin-l-ones starting from 4-chloro-N-benzyl-2(l//)-pyridinone and amino acid salts.811 Over the years pyrrolo[3,2-c]pyridines (5-azaindoles)41 have been of interest for applications as elements in new drug design, nucleotide analogues,42 and biochemical tools. However, available synthetic routes to multifunctionalized members from this class of heterocyclic structures are limited.41 43... 

Due to the widespread use of structurally diverse amino acid derivatives in practically all areas of the physical and life sciences, the synthesis and applications of these compounds are of fundamental importance. Heterocyclic f)-substituted-a-alanincs are non-proteinogenic amino acids that are widely found in nature [138-147]. Naturally occurring (l-amino acids are also compounds with interesting pharmacological aspects. N,N-Bis(tert-butyloxycarbonyl)-dehydroalanine methyl ester (186) was reacted at room... 

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