Proline pyrrolidine derivative from

A chiral example of phosphazene bases was synthesized by treatment of (5)-2-(dialky-laminomethyl)pyrrolidine derived from 5-oxo-(5)-proline, with phosphorus pentachloride and subsequent addition of gaseous ammonia. The phosphazenes were isolated as HBF4 salts in high yields and fully characterized by H, and P NMR spectroscopy, various ID and 2D NMR experiments and mass spectrometry (El). The molecular structure and the absolute configuration of the HBF4 salts were determined by X-ray analysis [16]. 

The enantioselectivity of Sn(II) enolate reactions can be controlled by chiral diamine additives. These reagents are particularly effective for silyl thioketene acetals.162 Several diamines derived from proline have been explored and l-methyl-2-(l-piperidinomethyl)pyrrolidine 21 is an example. Even higher enantioselectivity can be achieved by attachment of bicyclic amines to the pyrrolidinomethyl group.163... 

As with the above pyrrolidine, proline-type chiral auxiliaries also show different behaviors toward zirconium or lithium enolate mediated aldol reactions. Evans found that lithium enolates derived from prolinol amides exhibit excellent diastereofacial selectivities in alkylation reactions (see Section 2.2.32), while the lithium enolates of proline amides are unsuccessful in aldol condensations. Effective chiral reagents were zirconium enolates, which can be obtained from the corresponding lithium enolates via metal exchange with Cp2ZrCl2. For example, excellent levels of asymmetric induction in the aldol process with synj anti selectivity of 96-98% and diastereofacial selectivity of 50-200 116a can be achieved in the Zr-enolate-mediated aldol reaction (see Scheme 3-10). 

By surveying 72 catalysts from the proline family, including piperidine- and pyrrolidine-derived catalysts, amino acids and diamines investigated over the past decade (Appendices 7.B-D), we may better understand both the structural features that are compatible with a successful catalyst and those which are detrimental and preferably avoided. 

A simple pyrrolidine imide (10), derived from L-proline, brings about the direct formation of a -unsaturated ketones from unmodified ketones and aldehydes under mild conditions.31 Mechanistic investigation suggests a Mannich elimination process, rather than an aldol route. 

Organocatalyst (56), a pyrrolidine sulfonamide derived from L-proline, catalyses the direct Michael addition of aldehydes to nitrostyrene with high ee and de, apparently exploiting its bifunctional (acid-base) nature.220 ... 

Of the several studies made of enolates derived from such a-aminoke-tones,37 the most interesting one from the point of view of this work came from Holladay and co-workers who studied alkylation reactions of pyrrolidine enamine 40 derived from protected 4-keto-L-proline 41 with allyl bromide (Scheme 10).38 A 44% yield of two diastereoisomers of allylated material 42 was obtained with a quoted isomer ratio of trans cis of 2 1. 

The existence of the enamine intermediate of proline-catalyzed reaction with acetone as a donor was detected by mass analysis [54], but not by aH NMR. The formation of the presumed enamine intermediate generated from pyrrolidine-acetic acid and isobutyraldehyde was confirmed by 1H NMR [29a]. In this study, the enamine formation in the presence of pyrrolidine-acetic acid was observed within 5 min, but the enamine was shown to form only very slowly in the absence of acid. In these pyrrolidine derivative-acid combination catalysts, the acid component was shown to be important both for faster enamine formation and for the stereocontrol in the C-C bond-forming step. These catalyst systems are essentially split-proline systems that allow for the contributions of the pyrrolidine and carboxylate functionalities of proline to be probed independently. 

The effectiveness of various precursors of these compounds was investigated quantitatively by Ottinger and Hofmann.283 Hexose-derived cyclotene was the common precursor for both 33 and 35, as well as 34 and 36. The formation of each compound is very much determined by the nature of the N-containing precursor. Thus, for example, pyrrolidine (e.g., formed by thermal decarboxylation of proline) plus cyclotene produced 33 and 35 only, whereas 1-pyrroline (derived from proline... 

When chiral thiocarbonyl S-oxides derived from (S)-proline, prepared from the appropriate l-(trimethylsilylalkylsulfonyl)-2-(alkoxymethyl)pyrrolidine, are subjected to Diels-Alder reaction with 2,3-dimcthyl-l,3-butadiene, the 2-substituted 2-[(2-alkoxymethyl-l-pyrrolidinyl)sul-fonyl]-3,6-dihydro-4.5-dimethyl-2/f-thiopyran 1-oxides 10A and 10B are formed as a mixture of diastereomers. Their ratio depends on the nature of the substituents R1 and R2 as well as on the reaction temperature. The diastereomeric excess values, determined by H NMR in the presence of Yb(tfc)3 or by HPLC, vary from 0 to 41 % 84. 

Simple L-alanine, L-valine, L-norvaline, L-isolecucine, L-serine and other linear amino acids [ 121 ] or chiral amino acids with a binaphthyl backbone [ 122] and peptides have also been used as asymmetric catalysts [123,124,125,126]. Solid-supported proline-terminated peptides have been used for heterogeneous catalysis of the asymmetric aldol reaction [ 127]. Apart from proline and derivatives, other cyclic compounds such as 5,5-dimethyl thiazolidinium-4-car-boxylate (DMTC) [128], 2-fert-butyl-4-benzyl imidazolidinones [129], (l/ ,25)-2-aminocy-clopentanecarboxylic acid [130], (5 -5-(pyrrolidin-2-yl)tetrazole, (5)-l,3-thiazolidine-4-car-boxylic acid, (5)-5,5-dimethyl-l,3-thiazolidine-4-carboxylic acid, and (5)-hydroxyproline are effective catalysts in asymmetric aldol reactions [126,131,132,133,134,135]. 

Chiral auxiliaries derived from (S)-proline appeared to be particularly attractive since they possess conformationally rigid pyrrolidine ring(s), a prerequisite to the above specified criteria. In this chapter highly stereoselective asymmetric reactions, employing the chiral diamines 1 and chiral diamino alcohols 2 and 3 (Fig. 1),... 

According to a recent report, however, the carbonyl ylides formed under these conditions may isomerize and lead to adducts different from those normally expected87. Thus, (5)-l-acetyl-2-(diazoacetyl)pyrrolidine (8). derived from /V-acetyl-i.-proline, upon treatment with dimethyl butynedioate in the presence of a catalytic amount of rhodium(II) acetate dimer at 25 °C affords only 10% of the expected adduct dimethyl 5,8-epoxy-2,3,5,8,9,9a-hexahydro-5-methyl-9-oxo-lH-pyrrolo[l, 2-o]azepine-6,7-dicarboxylate (9). Instead, dimethyl 1,2,8,9-tetrahydro-5-methyl-l-oxo-3a//,7//-furo[3,2-g]pyrrolizine-3a,4-dicarboxylate (10) is obtained in 87% yield. The formation of this product is explained via an isomeric ylide87 and thus occurs with complete loss of chiral information. 

The application of this cycloaddition strategy to the synthesis of norsecurinine was then undertaken. Thus the oxazole-pyrrolidine derivative 188 was prepared in four steps from o-proline (Fig. 3.57). Coupling 188 with enynone 189, prepared in four steps from maleic anhydride, afforded a near-quantitative yield of the acetylenic ketone 190 as a 2 1 mixture of C-7 epimers. After refluxing for 30 min in mesitylene, 190 underwent cycloaddition to produce a 2 1 mixture of the tricyclic furano-ketone 191 and the C-7 epimer in 50% overall yield from 189. The undesired epimer could be recycled by epimerizing with sodium carbonate to give a 1 1 mixture of epimers. The tricyclic furano-ketone 191 was then converted to (-)-norsecurinine in six steps. (+)-Norsecurinine was synthesized using an identical route starting with L-proline. 

Propargylic alcohok The highly enantioselective aldol reaction of Mukaiyama can also be used to obtain optically active propargylic alcohols by reaction of acetylenic aldehydes with a silyl enol ether. The most effective chiral catalyst is obtained by a combination of tin(II) triflate with a diamine derived from (S)-proline, (S)-l-methyl-2-[N-naphthylamino)methyl]pyrrolidine (1). Thus the reaction of an acetylenic aldehyde... 

The synthesis of various proline derivatives has received attention this year. A route to proline itself from pyrrolidine in 45% overall yield has been reported, which appears to be an improvement on previous multistage methods.A one-pot synthesis of racemic 4-hydroxyproline in 30—40% yield from glyoxal and oxaloacetic acid has been developed, and a total synthesis of all four dias-tereoisomers of 3-hydroxy-5-methylproline has been achieved. An asymmetric synthesis of prolines is by addition of malonate carbanions to chiral aziridines derived from amino-acids. ... 

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