Amino Acids as Synthons for Heterocyclic Compounds*

Miha Tišler; Patrik Kolar    Faculty of Chemistry and Chemical Technology, University of Ljubljana, 61000 Ljubljana, Slovenia

For proteinogenic amino acids common three-letter abbreviations are used: Ala—alanine, Gly—glycine, Gly-OMe—glycine methyl ester, and so forth.

I Introduction

Although amino acids (AAs) are usually regarded as important building blocks for peptides and proteins, in the last decade they have become important synthons in the construction of various heterocyclic systems. For various purposes of asymmetric synthesis, 375 chiral carbon fragments are available, among which are AAs as inexpensive stereochemically pure synthons (84MI1). There are many examples of biosynthesis in Nature that use AAs as starting compounds, i.e., alkaloids, pyrimidines, and purines. Last, but not least, the biochemical path involves the incorporation of l-Cys in penicillins and biotin.

α-Amino acids can act as multifunctional synthons. Quite often a combination of the amino and other functional groups occurs in the formation of a heterocycle (87MI1).

For the asymmetric synthesis of AAs, several heterocyclic systems have been used as chiral auxiliaries. Because these transformations are not included in this review article, we cite here some of the most important articles or reviews concerning this topic. For asymmetric derivatization of Gly, bis-lactim ethers of 2,5-piperazinediones (83PAC1799; 85CS105), or oxazinones (88JA1547) were used. Seebach introduced a method based on the principle of self-reproduction of stereogenic centers involving various heterocyclic systems (1,3-dioxolanes, 1,3-oxazolinones, imidazolidinones, and related systems) (86MI1). A general review is given also in a book (89MI1).

This review does not include many of the well known transformations of AAs that have already been reviewed. These include hydantoins (imidazoline-2,4-diones) or thiohydantoins, obtained from AAs and isocyanates or isothiocyanates [77H1227; 85AHC(38)177], as well as the synthesis and use of chiral thiazolidine-2-thiones (from Cys) [89AHC(45)1], piperazine-2,5-diones resulting from dimerization of AAs and related lactim ethers (93AHC187), azlactones (oxazolin-5-ones) (46OR198; 78AG493), sydnones (64CRV129), oxazoles via the Dakin-West reaction (88CSR91), oxazolidine-2,5-diones (NCA, N-carboxy-α-amino acid anhydrides—from α-AAs and phosgene) important in peptide synthesis (87MI2), β-lactam antibiotics, and cyclic peptides and macrocycles containing AAs. The chemistry of pyroglutamic acid has also been reviewed (91MI1).

In this review reactions are described which start from AAs, some β-AAs, and unsaturated AAs. Aromatic AAs having the amino and carboxylic group attached directly to the aromatic or heteroaromatic ring are not included.

II Three-Membered Rings

There are only few reports concerning AA as a starting material for the preparation of heterocyclic three-membered rings. Most of them describe the preparation of aziridines. For example, the diphenylimine derivative of Gly-OEt, when treated with sodium hydride and arylacetyl chlorides, is transformed into aziridines 1 (89TL4717). There are several reports concerning N- and O-protected Ser and Thr, which are cyclized in the presence of a base to give substituted aziridines (68BCJ1353; 93JOC7848). However, a report on a similar transformation yielding aziridines (72BCJ1162) has been corrected since careful analysis showed that the reaction products are oxazolines (77BCJ917). The tendency of Thr derivatives to form aziridines is much stronger than in the case of Ser and less dependent on several factors. This was also demonstrated when a p-toluidide derivative of N-Cbz-L-Thr was treated with triphenylphosphine and diethyl azodicarboxylate (DEAD) to give an aziridine, whereas a similar L-Ser derivative was transformed into an azetidine derivative (81JOC1229). After being reductively alkylated with benzaldehyde, D-Thr ester is easily transformed into 2 with TPP in good yield (85JOC4515).

Diazotization of AAs proceeds via the corresponding α-hydroxy acids to oxiranes. From chiral starting material chiral oxiranes are obtained with retention of configuration. This synthetic principle is generally applicable (79T1601; 89TL5505).

  (1)

  (2)

In a similar manner, nitrosation of L-Cys alkyl esters resulted in the formation of optically pure (S)-thiirane carboxylates 3. From the L-isomer the corresponding (R)-thiirane carboxylates were obtained. The reaction is interpreted as an SN2 displacement of the diazonium group by the sulfur atom [76CC234; 79JCS(P1)1852].

  (3)

III Four-Membered Rings

Derivatives of azetidine were prepared from α-, β-, or γ-AA. L-Threonine was transformed in eight steps into 4

  (4)

a key intermediate of the carbapenem and penem antibiotics (83TL1037). A related derivative was also prepared from a similar γ-hydroxy-α-AA (85JOC3457). Several examples of cyclodehydration of β-AAs are described. For these purposes cyclization was performed with mesyl chloride (91TL2299), with triphenylphosphine (TPP) and pyridyl disulfide (Mukaiyama reagent) (81JA2406), with diphenylphosphinic chloride (88CC1242), or with bis(5'-nitro-2'-pyridyl)-2,2,2,-trichloroethylphosphate (NPTP) (87TL2735). (2R,3R)-t-Butyl 3-(N-benzoylamino)-2-methylbutanoate was converted into an azetidinone derivative after treatment with a solution of BF3 ∙ THF, trifluoroacetic acid (TFA), and 2-chloro-1-methylpyridinium iodide (94JOC649). Azetidine 2-carboxylic acid, a natural nonproteinogenic AA, was synthesized either from Glu or from 4-aminobutanoic acid via the corresponding halogenated acids (Scheme 1) [55N(L)(176)347; 56BJ323].

α-Amino acids were transformed into the corresponding imines; and after the complexes with TiCl4 were formed, these underwent cycloaddition with dimethylketene methyl trimethylsilyl acetal to give the corresponding β-lactams (Scheme 2) (80TL2081).

N-Protected derivatives of Ser or Thr were cyclized into the corresponding β-lactones in low or moderate yields. For these purposes, either dicyclohexylcarbodiimide (DCC) (70CB788) or its isopropyl analog (59JA6086) p-bromobenzenesulfonyl chloride in pyridine (89JOC2311) or Mitsunobu conditions (TPP and DEAD) were used [85JA7105; 88JA2237; 90H(31)79], A substituted β-lactone was also prepared from esterified and N-protected L-Asp in three steps (89T6319).

There are two reports describing the preparation of derivatives of 1,2-thiazetidine-1,1-dioxide. The sulfur atom in L-cystine diethyl ester was oxidized and the corresponding sulfonyl chloride was cyclized with ammonia (Scheme 3) (60CB784). A similar transformation used protected β-homocysteine as starting material (94LA251).

A derivative of a fused three-and four-membered ring 5 (aza-1-bicyclo-[2.1.0]pentane) was obtained from Ala after alkylation with methyl α-bromoacrylate (85T2707).

  (5)

IV Five-Membered Rings

A PYRROLES

1 Incorporation of Only the Amino Group of Amino Acids into the Pyrrole Ring

Cyclic acetals such as 2,5-diethoxytetrahydrofuran react with the amino group of an AA ester to give the corresponding pyrrole derivative. The same transformation could also be performed by free AA or dipeptides (68CCC1307; 88OPP414; 91JA3513).

In a similar manner, N-Cbz-α-Lys-OMe reacted with an electrophilic cyclopropane derivative, and a mixture of diastereomeric γ-lactams was isolated. The reaction is postulated to proceed by an attack of the amino group on the methylene group with subsequent cyclization (Scheme 4) (85JOC3631).

2 Cyclizations Involving Two Functional Groups

It was found that AAs having an additional remote amino or carboxylic group are easily transformed into the corresponding cyclic pyrrole derivatives or into other six-or seven-membered cyclic systems, depending on the position of the additional functional group. From Cbz-L-Asp-O-tBu in alkaline solution a 3-aminopyrrole-2,5-dione was obtained (63JOC1251). Even in a polypeptide chain with an asparagine unit at...