Pyrrolidine derivatives diastereoselective synthesis

This type of diastereoselective Petasis reaction was elaborated by Nanda et al in pyrrolidine-derived arylglycine synthesis (Scheme 8.4) [16]. 

Diastereoselective synthesis of pyrrolidine derivatives using chiral and non-racemic A-cyanomethyloxazolidines 99CSR383. 

Chiral and nonracemic A-cyanomethyloxazolidines in diastereoselective synthesis, particularly of pyrrolidine and piperidine derivatives 99CSR383. 

Pyrrolo[l,2- ][l,2]oxazines are a class of compounds with very few references regarding synthesis and reactivity. An interesting preparation has been described by intramolecular cyclization of IV-hydroxy pyrrolidines carrying a methoxyallene substituent at C-2 (242, Scheme 32). These compounds were obtained by addition of a lithiated allene to chiral cyclic nitrones 241. Cyclization occurred spontaneously after some days at relatively high dilution (0.05 M). Compounds 243 (obtained with excellent diastereoselectivity) can be submitted to further elaboration of the double bond or to hydrogenolysis of the N-O bond to form chiral pyrrolidine derivatives (Section 11.11.6.1) <2003EJ01153>. 

Chiral enamine derivatives have also been used as electron-rich alkenes. The oxazoline derivative 17 reacted with benzaldehyde to yield the two stereoiso-meric oxetanes 18a and 18b with a diastereomeric excess of 67% (Scheme 5) [12]. A significantly higher diastereoselectivity was observed in the case of the reaction of the pyrrolidine derivatives 19 where the enamine function is localized inside the five membered ring [13]. Then the oxetane 20a (R — n-Cgil g) was used in an asymmetric synthesis of the antifungal alkaloid (+ )-preussin. The approach of the 3n,7T excited ketone preferentially occurred syn with respect to... 

A multigram-scale diastereoselective synthesis of 1,2-dioxanes involved a Mn(III)-promoted [2 + 2 + 2] cycloaddition reaction of P-keto esters, 1,1-disubstituted alkenes, and molecular oxygen (14EJO1607). The same catalyst was used in the aerobic oxidation of 3-alkyl-substituted pyrrolidin-ediones in the presence of 1,1-diarylethenes to provide 1,2-dioxane derivatives in high yields (Scheme 83) (14JHC579). 

In the course of an attempt to synthesize pyrrolidine-derived arylglycines, in 2005, Nanda and Trotter reported a diastereoselective synthesis of such compounds, applying the Petasis-Akritopoulou reaction, where the use of HFIP as cosolvent dramatically reduces the reaction times from several days to less than 24h. High diastereoselectivities were achieved (Figure 6.3) [59]. 

Scheme 8.4 Diastereoselective synthesis of pyrrolidine-derived arylgtycine methylester 6...

In 2004, Wolfe et al. used a carboamination reaction for the first time for the stereoselective synthesis of substituted pyrrolidine derivatives via a Pd-catalyzed intermolecular iV-arylation followed by intramolecular cyclization reaction sequences. The reaction proceeds via an innersphere mechanism with the formation of the Pd(Ar)(NRR ) complex. In this reaction, a -(A-arylamino) alkene was treated with an aryl or heteroaryl bromide in the presence of NaO Bu as the base and Pd catalyst the corresponding 2,3- or 2,5-disubstituted pyrrolidine derivatives (Scheme 40.4) were obtained in good yields and excellent diastereoselectivity. ... 

Scarborough and Stahl also described a carboamination reaction for the synthesis of pyrroUdine derivatives. They used iV-tosyl allylamines and vinyl ether or styrene derivatives as the electrophiUc carbon source in place of aryl bromide to obtain 2,4-disubstituted pyrrolidine derivatives in good yield and moderate diastereoselectivity (Scheme 40.7). This reaction was performed in the presence of Cu(II) salt and molecular O2 as the co-catalyst for the reoxidation of Pd(0) to Pd(II). ... 

Earlier in 2006, Bertrand and Wolfe reported on the synthesis of (-l-)-preussin starting from decanal 103 (Scheme 40.22). After seven steps, the key intermediate 108 was obtained in 97% ee and 30% overall yield. 108 underwent Pd-catalyzed C N alkylative cyclization to afford the pyrrolidine derivative 109 with excellent diastereoselectivity. Derivative 109 under lithium aluminum hydride (LAH) reduction followed by alkaline workup produced (+)-preussin 100 in excellent yield. 

R)-(-)-2,2-Diphenylcyclopentanol (1) is a highly effective chiral auxiliary in asymmetric synthesis. Hydrogenation of chiral 0-acetamidocrotonates derived from this alcohol has afforded the corresponding 0-amido esters with high diastereoselectivity (96% de).6 In addition, (R)-1 has been used as a chiral auxiliary in Mn(lll)-based oxidative free-radical cyclizations to provide diastereomerically enriched cycloalkanones (60% de).7 Our interest in (R)-(-)-2,2-diphenylcyclopentanol is its utility as a chiral auxiliary in Lewis acid-promoted, asymmetric nitroalkene [4+2] cycloadditions. The 2-(acetoxy)vinyl ether derived from alcohol (R)-1 is useful for the asymmetric synthesis of 3-hydroxy-4-substituted pyrrolidines from nitroalkenes (96% ee).8 In a similar fashion, a number of enantiomerically enriched (71-97% ee) N-protected, 3-substituted pyrrolidines have been prepared in two steps from 2-substituted 1-nitroalkenes and (R)-2,2-diphenyl-1-ethenoxycyclopentane (2) (see Table).9... 

Synthesis of Substituted Pyrrolidines. A cycloaddition/red-uction sequence between nitroalkenes and vinyl ethers derived from DCP, i.e., 2 can effect the enantioselective synthesis of substituted pyrrolidines. 2-Substituted 1-nitroalkenes undergo highly efficient and diastereoselective Lewis-acid-promoted [4 + 2] cycloaddition with DCP-derived vinyl ethers to afford cyclic ni-tronates 5 in high yields. Subsequent reduction with Pt02 (7.5 mol%), under 160 psi of H2 at room temperature for 24 h, affords the optically active 3-substituted pyrrolidines (6) (71-97%, both as the free base and V-protected derivatives), and the chiral auxiliary 1 (eq 3). 

R.A. Batey and co-workers developed a modification of the Petasis-boronic acid-Mannich reaction that occurs via N-acyliminium ions derived from A/-protected-2,3-dihydroxypyrrolidine and 2,3-dihydroxypiperidine derivatives. This method was utilized in the total synthesis of (+)-deoxycastanospermine. The formation of the A/-acyliminium ion was achieved by treating A/-Cbz-2,3-pyrrolidine with BF3-OEt2. ° Subsequent vinyl transfer from the alkenylboronic ester provided the product with excellent yield and diastereoselectivity. 

Gallc er and co-workers devised a formal enantioselective synthesis of ( — )-3 in wduch the stereogenic center at C-6 was derived fiom Cbz-protected (S)-2-amino-4-pentenoic acid (36) (44). Acylation of 3,3-dimethoxy-pyrrolidine (37) with this acid yielded amide 38, which was converted into aldehyde 39 by cleavage of the terminal alkene vnth osmium tetroxide and sodium periodate (Scheme 5). The indolizidine nucleus was constructed from 39 by a problematic intramolecular aldol condensation, which was eventually optimized by using 2,2,6,6-tetramethylpiperidine as base followed by adsorption onto, and elution from, silica gel (45). Diastereoselective reduction of the ketone group of the aldol product 40 was accomplished in better than 95% enantiomeric excess (ee) with the Corey... 

Addition of the titanium enolate of Af-acetyl-4-isopropyl-l,3-thiazohdme-2-thione 150 to the A-acyl iminium ions from 151 furnishes the corresponding Mannich-type adducts 152 and 153 with good diastereoselectivity <05JOC4214>. A similar diastereoselective addition of the titanium enolate derived from Af-4-chlorobutyryl-l,3-thiazolidine-2-thione 154 to A -Boc-2-methoxypyrrohdine 155 has been used to provide 2-substituted pyrrolidine 156, a key intermediate in the synthesis of (+)-isoretronecanol <05TL2691>. 

Ring closure is expected for a radical precursor set with an unsaturation four bonds away when such a compound is treated with BusSnH-AIBN. The versatility of such cyclizations is derived from allowance of many varieties of substitution patterns and heteroatoms between the reactive centers. Furthermore, as shown in a synthesis of 2,4-disubstituted pyrrolidines, diastereoselectivity may be controlled in certain cases. 

Diastereoselectivity is also observed in reactions of carbanions derived from imines and hydrazones, when those species contain a chiral center or a chiral auxiliary (sec. 9.4.F). Asymmetric imines can be used, and chiral oxazoline derivatives have also been prepared and used in the alkylation sequence (sec. 9.3.A). Meyers showed that chiral oxazoline 478 could be alkylated to give the ethyl derivative, 479. A second alkylation generated the diastereomeric product 480, and hydrolysis provided the chiral lactone (481) in 58% yield and with a selectivity of 70% ee for the (R) enantiomer. 53 As pointed out in Section 9.4.F.ii, hydrazone carbanions can be used for alkylation or condensation reactions. In a synthesis of laurencin. Holmes -l prepared the asymmetric hydrazone 483 (prepared by Enders by reaction of cycloheptanone and the chiral hydrazine derivative called SAMP, 482-A-amino-(2S)-(methoxymethyl)pyrrolidine)- - and showed that treatment with LDA and reaction with iodomethane gave an 87% yield of the 2-ethyl derivative in >96% de. Ozonolysis cleaved the SAMP group to give (/ )-2-ethylcycloheptane (484) in 69% yield. The enantiomer of 482 is also known (it is called RAMP, A-amino-(27 )-(methoxymethyl)pyrrolidine). 

Two total syntheses of pyrrolidine alkaloids have been reported. (—)-Codonopsinine (85), an imino-pentitol which exhibits antibiotic and hypotensive activity, has been synthesized in seven steps in 16% overall yield from dihydropyrrole 84. The enantioselective synthesis of the potent antifungal agent (-l-)-preussin (87) has also been achieved from L-phenylalanine derivative 86. The pyrrolidine skeleton was established by hydrogenolysis of an intermediate oxazoline and subsequent diastereoselective reductive cyclization of the resultant aminoketone using Pearlman s catalyst. ... 

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