Pyrrolidine ring synthesis

A. Pyrrolidine Ring Synthesis from an Acyclic Precursor. .. 168... 

Pyrrolidine ring synthesis from an acyclic precursor... 

Recently, Kraus and Maeda have reported an elegant synthesis of the important C-4 o-anisyl derivative 26 in racemic form.85 This route involves pyrrolidine ring synthesis with key steps being Michael addition of the enolate of dimethyl a-ketoglutarate 174 to nitrostyrene derivative 175 followed by cyclization of the adduct 176 under reductive conditions to hemiaminal 177 (Scheme 63). 

The monomer synthesis and cyclopolymerization were carried out following the procedure of Butler et al. (21). The resulting polyimide was shown to possess primarily pyrrolidine rings as indicated by infrared spectroscopy (21). Initially, the reduction was carried out with LiAlH in tetrahydrofuran. 

Intramolecular cycloadditions are among the most efficient methods for the synthesis of fused bicyclic ring systems [30]. From this perspective, the hetisine skeleton encompasses two key retro-cycloaddition key elements. (1) a bridging pyrrolidine ring accessible via a [3+2] azomethine dipolar cycloaddition and (2) a [2.2.2] bicyclo-octane accessible via a [4+2] Diels-Alder carbocyclic cycloaddition (Chart 1.4). While intramolecular [4+2] Diels—Alder cycloadditions to form [2.2.2] bicycle-octane systems have extensive precedence [3+2], azomethine dipolar cycloadditions to form highly fused aza systems are rare [31-33]. The staging of these two operations in sequence is critical to a unified synthetic plan. As the proposed [3+2] dipolar cycloaddition is expected to be the more challenging of the two transformations, it should be conducted in an early phase in the forward synthetic direction. As a result, a retrosynthetic analysis would entail initial consideration of the [4+2] cycloaddition to arrive at the optimal retrosynthetic C-C bond disconnections for this transformation. 

To form the stereocenter at C-3 a direct reduction-alkynylation sequence was applied, that provided the diastereomeric homopropargylic alcohols 83 in a ratio of syn anti=76l2A, The major isomer syn-S3 was isolated in 55% yield. The key step of the synthesis was an intramolecular imidotitanium-al-kyne [2+2] cycloaddition/acyl cyanide condensation. With this sequence the pyrrolidine ring was formed and all the carbon atoms of the alkyl side chain were established in acrylonitrile 84. The reduction of the imine double bond proceeded stereoselectively and the nitrile group was removed reductively en route to the target compound. 

Two syntheses and one formal synthesis of (+)-preussin have been reported using sugars as chiral pool building blocks. In these syntheses parts of the sugar backbone have been implemented into the preussin skeleton. All four pyrrolidine carbon atoms stem from the carbohydrate. As a consequence, the two carbon-nitrogen bonds (N/C-2 and N/C-5) of the pyrrolidine ring... 

A later one-step synthesis was designed as a biomimetic process (18). The N-methyl pyrrolidine ring in alkaloids such as nicotine is derived from ornithine via... 

The nicotine molecule consists of a pyrrolidine ring attached to a pyridine ring by a bond between carbon atoms in the two-ring systems. Nicotine was isolated in impure form from tobacco in 1809 by Louis Nicholas-Vauquelin (1763—1829). Vauquelin called the substance nicotianine. In 1826, Wilhelm Posselt (1806-1877) and Karl Ludwig Reimann (1804-1872), medical students at Heidelberg University, isolated pure nicotine and published dissertations on its pharmacology in 1828. Louis Henri Melsens (1814—1886) determined nicotines empirical formula. Ame Pictet (1857-1937) and P. Crepieux reported the synthesis of nicotine in 1903. 

Five- and six-membered heterocycles, containing either a nitrogen or oxygen atom, and in particular pyrrolidine rings, are very important in natural products synthesis. There are many methods by which all these compounds may be synthesized and new routes to this target are constantly being sought. 

The catalytic cycles are, however, different in the reaction sequence for formation of the enamines which are key intermediates in these aldol reactions. With the type I aldolase a primary amino function of the enzyme is used for direct formation of a neutral imine (Ha) whereas starting from L-proline enamine synthesis proceeds via a positive iminium system (lib) (Scheme 6.23). In this respect, investigations by List et al. on the dependence of the catalytic potential on the type of amino acid are of particular interest. In these studies it has been shown that for catalytic activity the presence of a pyrrolidine ring (in L-proline (S)-37) and the carboxylic acid group is required [69]. 

Other examples include CAN oxidation of silylmethyl amines and amides with the synthesis of aryl-fused piperidine and pyrrolidine ring derivatives.360... 

Azomethine ylides are organic 1,3-dipoles possessing a carbanion next to an im-monium ion [ 12]. Cycloadditions to dipolarophiles provide access to pyrrolidine derivatives, useful intermediates in organic synthesis with stereo- and regiochem-ical control. Azomethine ylides can be readily produced upon decarboxylation of immonium salts derived from the condensation of a-amino acids with aldehydes or ketones. When they are added to C60, a fulleropyrrolidine monoadduct is formed in which a pyrrolidine ring is fused to the junction between two six-memberedrings of afullerene [13-15].Very importantly,functionalized aldehydes lead to the formation of 2-substituted fulleropyrrolidines, whereas reaction with AT-substituted glycines leads to AT-substituted fulleropyrrolidines (Scheme 1). 

The combination of the characteristics of the fullerene skeleton with the fused pyrrolidine ring is of great importance for the construction and synthesis of materials with novel properties. The most attractive feature of fulleropyrrolidines is... 

The Ugi reaction followed by Mitsunobu condensation was applied to the synthesis of the pyrrolidine-fused 1,4-oxazocane 230 (Scheme 30) <2007JOC2151>. It was expected that the pyrrolidine ring in the precursor 229 could furnish a steric bias favoring the cyclization. Indeed, the compound 230 was formed in 70% yield (cf. Scheme 29). 

The racemic hydrochloride salt can be prepared in four steps and 70% overall yield (eq 1). The synthesis is carried out on 2 mmol scale and starts with commercially available 5-hexen-2-one. The key step involves a mercury-catalyzed intramolecular amidomer-curation to form the pyrrolidine ring. If desired, the racemate can be resolved via the salts of Mandelic Acid. ... 

---