Enantiomerically-Pure Heterocycles

Amino acids continue to be useful starting materials for the preparation of enantiomerically-pure heterocycles. Henk Hiemstra of the University of Amsterdam and Floris Ruljes of the University of Nijmegen report (J. Am. Chem. Soc. 2004,126,4100) that cyclization of the ally silane 9 followed by ring-closing metathesis leads to the highly-functionalized quinolizidine 11. 

Figure 13.43 illustrates alkylations of two propionic acid amides, where in each case the N atom is part of an enantiomerically pure heterocycle, proceeding via the respective Z-con-figured amide enolates. 

Karlsson, S. Hogberg, H.-E. Asymmetric 1,3-Dipolar Cycloadditions for the Construction of Enantiomerically Pure Heterocycles, Org. Prep. Proced. Intern. 2001, 33, 103-172. 

So lithium enolates react with the halide 73 by conjugate substitution. The lithium enolate of the enantiomerically pure heterocycle 74 prepared from natural alanine gives one diastereoisomer of E-75 in reasonable yield. After further manipulation the heterocycle was hydrolysed to give cyclopropanes that are glutamate antagonists.12... 

Asymmetric 1,3-dipolar cycloadditions for the construction of enantiomerically pure heterocycle 01OPP103. 

In order to search for conformationally restricted 5-HT2A/2C receptor agonists, a useful method for the synthesis of an enantiomerically pure heterocyclic tetrahydrobenzo[l,2-ft 4,5-fc Jdifuran based alkylamines was developed. The route to the core structure is illustrated below. Thus, when the ehlorobromo compound was treated with Mg in the presence of EtMgBr, the tetrahydrobenzodifuran was obtained. This was further functionalized by reaction with a chiral acyl chloride and AlCl, followed by reduction of the ketone carbonyl group with triethylsilane in trifluoroacetic acid <01JMC1003>. 

Sulfonylnitromethane (92) is an interesting nucleophile, which undergoes double substitution. Double C-, and 0-allylation of 92 with me5 0-3,6-dibenzoyloxy-cyclohexene (91) provided the enantiomerically pure heterocycle 93 in 87 % yield, and asymmetric synthesis of valienamine was achieved [37]. 

From the chemical viewpoint, biotin is a quite appealing enantiomerically pure heterocyclic compound with a basic thienoimidazole structure and three adjacent stereogenic centres, which are relative to the thiophane ring all-cis-configured. 

In an earlier study the authors proposed a [3.2.0] bicyclic sulfonium salt 8 as the reactive intermediate in the trimethylsilyl iodide mediated ring contraction of 4-methoxythiephane <1996T5989>. Enantiomerically pure thio-lane derivatives were synthesized via a ring contraction of a seven-membered sulfur heterocycle by nucleophilic transannular substitution <2000TA1389>. The thiepane derivative 15, derived from d-sorbitol, was converted into the dimesyl derivative 16 following deprotection under acidic conditions. Treatment of 16 with sodium azide in DMSO at 120°C yielded the corresponding thiolane as a mixture of two diastereoisomers, 17a and 17b, in a 5 1 ratio (see Scheme 1). 

There are several reports dealing with the use of tetrahydropyrrolo[l,4]oxazinones derived from natural proline or prolinol as chiral auxiliaries for the synthesis of enantiomerically pure compounds. The preparation of the heterocycle is described in Scheme 33 (Section 11.11.7.4). The presence of a rigid bicyclic skeleton allows stereoselective introduction of different substituents. The final ring opening of the system (generally by hydrolysis) provides enantiomerically pure compounds with the possibility of recycling the starting chiral auxiliary. 

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. 

A much improved synthesis of a dioxino[23-e]indolemethanol was described. This procedure now allows the preparation of multigram quantities of the enantiomerically pure compound. Application of this methodology to different 5-hydroxy heterocycles enables access to furo[33- [l,4]benzodioxin, thieno[33-/l[l,4]benzodioxin and l,4-dioxino[23-e]indazole ring systems <99S1181>. 

The synthetic plan was to assemble both the dihydropyran 3 and the cyclopentane 4 in enantiomerically-pure form, then to effect Lewis acid-mediated coupling of the ally silane of 4 with the anomeric ether of 3 to form a new stereogenic center on the heterocyclic ring. A critical question was not just the efficiency of this step, but whether or not the desired stereocontrol could be achieved at C-3. 

The construction of the heterocycle 3 started with enantiomerically-pure ethyl lactate. Protection, reduction and oxidation led to the known aldehyde 6. Chelation-controlled allylation gave the monoprotected-diol 7. Formation of the mixed acetal with methacrolein followed by intramolecular Grubbs condensation then gave 3. The dihydropyran 3 so prepared was a 1 1 mixture at the anomeric center. 

As new drug entities must be usually be prepared as single enantiomers, and as many contain one or more heterocyclic or carbocyclic rings, there is an increased emphasis on the development of practical methods for the construction of enantiomerically pure cyclic systems. In this three-part scries, we will cover the most important recent advances. 

With the same protocol, a heterocyclic dibenzoate 86 derived from furan in one step has been efficiently desymmetrized to provide facile entry to either D or L nucleosides (see Scheme 8E.10). As depicted in Scheme 8E.10, the catalyst derived from ligand 71 gave rise to high enantioselectivities in the alkylation with both a purine 83 and a pyrimidine 87 [62], Subsequent allylic alkylations with an achiral ligand introduced the tartronate and aminomalonate moieties to furnish enantiomerically pure Ci s-2,5-disubstituted-2,5-dihydrofurans 89 and 91, respectively. Only six steps from furan were required to synthesize the alio and talo isomers of the nucleoside skeleton of the polyoxin-nikkomycin complexes. It should be noted that the corresponding enzymatic desymmetrization of substrate 86 is impossible because the product is labile. 

The dione 214 upon treatment with hydrazine afforded 215, which was converted into 2,2 -bis(bromomethyl)-3,3 -biquinazoline-4,4 -dione 217 (Scheme 47) via 216. The racemic 1,2,5-triazepine ( )-53 was obtained from 217 by reaction with aqueous ammonia in THF. The enantiomerically pure (—)-53 was formed by refluxing ( )-53 with (+)-CSA (camphorsulfonic acid) <1999CC1991>. It is interesting that this work is the first nonracemic example of a C2-symmetric bis-heterocycle, which is atropisomeric by virtue of retarded rotation around an N-N bond. 

The reaction of 2- and 3-vinylindoles with dienophile 214 constitutes the first example of an asymmetric Diels-Alder reaction of vinyl heterocycles. From 3-vinylindoles, enantiomerically pure carbazoles 215a-c were obtained, whereas from the vinylindole 197 together with 215d, diastereomer 216 was obtained as a minor product. Conversely, 2-vinylindoles provided inseparable mixtures of diasteromeric carbazoles. On the other hand, the cycloaddition reactions of 3-vinylindoles with 217 furnish the tetrahy-drocarbazoles 218 with endo-diastereoselectivity (93T2863). 

An alternative way leading to optically active homoallylic alcohols involves the use of l,3-dioxan-4-ones 32. These heterocycles can be easily prepared, in good yield, from an aldehyde or ketone 6 and enantiomerically pure 3-hydroxybutanoic acid 94 (Scheme 13.13) [17]. 

For the synthesis of optically pure building blocks we mainly focused on the synthesis of protected noncoded (R)- and (S)-amino acids, as they can be synthesized reliably in enantiomerically pure form with a large variety of side chains using asymmetric hydrogenation of a-amino-a, 3-didehydroamino acids using cationic diphosphine rhodium catalysts.216,217 As a typical example of a reactophore we present a-alkynyl ketones, which is a representative bis-acceptor molecule. In Scheme 5 are depicted some of the many synthetic applications of acetylenic ketones in heterocyclic synthesis, which have great potential for combinatorial and parallel organic synthesis. 

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