Proline derivative, reaction with

This route relies on 1,3-dipolar cycloaddition reactions a series of dihydropyrrolizines 213 were synthesized by heating the proline derivatives 211 with dimethyl acetylenedicarboxylate (DMAD) at 130-140 °C in the presence of acetic anhydride. Reaction between 211 and AczO provides the mesoionic oxazalone intermediate 212 which adds to dimethyl acetylenedicarboxylate, giving a cycloadduct, which undergoes spontaneous decarboxylation leading to 213 (Scheme 50) <1998JME4744, 1977JME812>. 

Gryko and coworkers studied the influence of an acid additive in the aldol reaction catalyzed by a proline derivative equipped with an existing hydrogen bonding... 

Reaction of the proline derivative 8 with pivaldehyde (1) in CH2C12 catalyzed by TFA results in a single product (9). Treatment of 9 with MeLi and then with LDA furnishes the enolate a. Alkylation or reaction with aldehydes or acetone followed by acid hydrolysis furnishes enantiomerically pure 2-substituted 4-hy-droxyprolines (10), with retention of configuration.3... 

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. 

Alkylated prolines can be incorporated into synthetic peptides as mimics for the p-turn found in the conformation of folded proteins. One such compound9 combines a spirocyclic proline derivative 77 with tyrosine. The allyl group in 74 is oxidatively cleaved to give 75 and eventually coupled to the nitrogen atom of the amide in 76 by a Mitsunobu reaction. 

An in situ method for capturing nitrones too unstable for isolation involved reaction of allylic amines such as proline derivative 33 with A -methylhydroxylamine in basic formalin solution to give, in this instance, chiral oxadiazinane 34 (Equation 7) <1997TL8545>. 

Pyramidalization was explored as a direct stereoelectronic source of stereoselectivity in enamine reactions. Seebach and coworkers suggested that the remarkable stereoselectivity of pyrrolidino-enamines derived from proline in reactions with electrophiles originates from stereoelectronic assistance from the lone pair of pyramidalized enamine N-atoms (Figure 6.124). ° ... 

Aldehydes and ketones could be asymmetrically a-amino-oxylated [36, 37] or a-aminated [38] to corresponding poly-functional compounds 8 and 9 by proline-catalyzed reactions with nitrosobenzene or diethyl azodicarboxylate in molten imidazoUum salts (Scheme 22.5). As compared to those in common solvents, the yields of a-aminoxylation products 8 of both aldehydes and ketones improved significantly in the IL medium and the enantioselectivity was excellent Yields and enantiomeric enrichment of hydrazino-aldehydes 9 were somewhat lower. The ionic environment considerably accelerated the processes and the (S)-proline/IL system could be quantitatively recovered after completion of the aminoxylation reaction and reused (5-6 times) without any loss of catalytic performance. Aldehyde-derived products 8 and 9 (R = H) could be reduced to chiral 1,2-diol derivatives 10 or configurationally stable heterocycles 11, which are valuable intermediates in asymmetric synthesis. 

Similar stereoselectivities are achieved in the allylation of enantiomerically pure proline-derived a-oxoamides47. l-Bromo-3-methy]-2-butcne reacts with clean allylic inversion. Since pinacol-type coupling products are also produced under the reaction conditions, this was taken as evidence for a radical addition mechanism47. 

Thus the product in such cases can exist as two pairs of enantiomers. In a di-astereoselective process, one of the two pairs is formed exclusively or predominantly as a racemic mixture. Many such examples have been reported. In many of these cases, both the enolate and substrate can exist as (Z) or (E) isomers. With enolates derived from ketones or carboxylic esters, (E) enolates gave the syn pair of enantiomers (p. 146), while (Z) enolates gave the anti pair. Addition of chiral additives to the reaction, such as proline derivatives, or (—)-sparteine lead to product formation with good-to-excellent asynunetric induction. Ultrasound has also been used to promote asymmetric Michael reactions. Intramolecular versions of Michael addition are well known. ... 

Scheme 1.12 Test reaction with (5)-proline-derived sulfur-containing phosphine ligands.

The same system was used by Frechet s group of to achieve a multicomponent one-pot cascade reaction with mutually interfering acid and proline-derived pyrrolidine catalysts [31]. The concept is illustrated in Figure 5.1. The protonation of imidazo-lidone (3) by the immobilized PSTA (5) gives the desired iminium catalyst (6), while... 

A very important development in multicomponent domino reactions is the enan-tioselective approach using organocatalysts which has been recently discussed in an excellent review by Yus and Ramon [2c]. The latest great success in this field stem from Enders and coworkers, presence of an enantiopure proline derivative to give polyfunctionalized cyclohexenes with 99% ee [111]. 

Cycloaddition of the cyclic nitrone derived from proline benzyl ester with alkenes proceeds readily to give isoxazolidines with good regio-and stereoselectivity (Eq. 8.47).68 The reaction favors exo-mode addition. However, certain cycloadditions are reversible and therefore the product distribution may reflect thermodynamic rather than kinetic control. 

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

Isatin derivatives and proline react to give stereospecific formation of an azo-methine ylide intermediate via the decarboxylation route. The resulting 1,3-dipole undergoes a cycloaddition reaction with N-substituted maleimide (6), as a dipolaro-... 

In the study of Weber et al.,41 a series of proline-derived hydrazones were prepared, and the reactions of the hydrazones with organocerium reagents were examined. It is clear from the table in Scheme 2 24 that the diastereoselectivity of the examined reactions depends on the nature of the side chain. (S )-l-amino-2-(2-methoxyethoxymethyl) pyrrolidine (40) gave the highest selectivity for various nucleophiles. 

Proline has been often used in reactions with aldehydes to form 1-oxo perhydropyrrolo[l,2-f]oxazole structures <1998J(P1)3777, 2004PNA5839>. These compounds were used for the asymmetric synthesis of proline derivatives which are present in natural products or analogs (Scheme 49) <2005T10018, 2005TA2075, 2006JOC97>. 

The hexahydro-l//-pyrrolo[2,l-f][l,4]oxazin-l-one 82 (obtained by radical cyclization see Section 11.11.7.3) was transformed into the proline derivative 83 by hydrogenation in the presence of the Pearlman s catalyst and a stoichiometric amount of trifluoroacetic acid (TFA) (Scheme 10). This reaction led with high yield to the disub-stituted proline 83 in an enantiomerically pure form <2003SL1058>. In an analogous approach, the chiral (4/ ,7/ ,8aA)-methyl 6,6-dimethyl-l-oxo-4-phenylhexahydro-l//-pyrrolo[2,l-r-][l,4]oxazine-7-carboxylate 84 was hydrogenated on Pd(OH)2 in the presence of TFA to give enantiomerically pure 5,5-dimethylproline derivatives 85 <2001SL1836> (Scheme 10). 

Structurally rather complicated target molecules can be synthesized with the aid of thi-olate 1,6-addition reactions to acceptor-substituted dienes as well. For example, a richly functionalized proline derivative with a 2,4-pentadienal side chain was converted into the corresponding 6-phenylthio-3-hexen-2-one derivative by 1,6-addition of phenylthiolate, treatment of the adduct with methyl lithium and oxidation (equation 46)127. The product was transformed into acromelic acid A, the toxic principle of clitocybe acromelalga ichimura. Similarly, the 1,6-addition reaction of cesium triphenylmethylthiolate to methyl 2,4-pentadienoate served for the construction of the disulfide bridge of the macrobicyclic antitumor depsipeptide FR-901,228128. 

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