- Molecular Iodine-Mediated α-C-H Oxidation of Pyrrolidines to N,O-Acetals: Synthesis of (±)-Preussin by Late-Stage 2,5-Difunctionalizations of Pyrrolidine
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We previously reported an iterative synthesis of unsymmetrical 2,5-disubstituted pyrrolidines from pyrrolidine by two rounds of redox-triggered α-C-H functionalization. Although this approach can be used to introduce substituents at the 2- and 5-positions, it is lengthy because the redox auxiliary must be removed and then reinstalled. Therefore, we sought to develop a method to oxidize 2-functionalized pyrrolidine to cyclic N,O-acetal which could then react with a nucleophile for introduction of the 5-substituent. In this work, we found that molecular iodine can mediate the preferential oxidation of secondary over tertiary α-C-H bonds of α-substituted pyrrolidines to form cyclic N,O-acetals, improving the step economy of our previously reported method. With this strategy, (±)-preussin and its C(3) epimer were synthesized from (±)-pyrrolidin-3-ol.
- Rong, Hao-Jie,Yao, Jun-Jun,Li, Ji-Kun,Qu, Jin
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- Alkoxyallene-based syntheses of preussin and its analogs and their cytotoxicity
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Short syntheses of oxa-preussin, racemic preussin and (-)-preussin are reported. Starting from a racemic 3-nonyl-substituted methoxyallene derivative, its lithiation and addition to phenylethanal provided the corresponding allenyl alcohol that was converted into two diastereomeric dihydrofuran derivatives by silver nitrate-catalyzed 5-endo-trig cyclization. The acid hydrolysis of the enol ether moiety gave heterocyclic ketones and subsequent highly stereoselective reductions with l-selectride furnished 2-benzyl-5-nonylfuran-3-ol derivatives in good overall yield. The major all-cis-diastereomer has the skeleton and relative configuration of preussin and is hence called oxa-preussin. An analogous sequence with the same allene, but an N-sulfonyl imine as the electrophile, finally led to racemic preussin. The stereoselectivities of the individual steps are discussed in detail. With an enantiopure 2-benzyl-5-nonylpyrrolidin-3-one intermediate the preparation of (-)-preussin with an enantiomeric ratio of >95:5 could be accomplished in a few steps. The sign of the optical rotation of this product finally proved the absolute configurations of its precursors and demonstrated that our chiral auxiliary-based route led to the antipode of the natural product. The cytotoxicity of several of the prepared heterocycles against MCF-7 tumor cells was investigated and five compounds, including racemic and enantiopure (-)-preussin, were identified as highly cytotoxic with IC50 values in the range of 3-6 μM.
- Hausherr, Arndt,Siemeister, Gerhard,Reissig, Hans-Ulrich
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- A concise and efficient synthesis of (+)-preussin
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A novel and efficient synthesis of (+)-preussin (7) starting from N-butoxycarbonyl-L-phenylalaninal (1) is described. This natural product was synthesized under mild conditions and with good overall yield.
- Arevalo-Garcia, Enzo B.
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- An efficient approach to trans-4-hydroxy-5-substituted 2-pyrrolidinones through a stereoselective tandem Barbier process: divergent syntheses of (3R,4S)-statines, (+)-preussin and (?)-hapalosin
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A diastereoselective approach to trans-4-hydroxy-5-substituted 2-pyrrolidinones 1 (P1 = TBS, P2 = H) has been developed through a stereoselective tandem Barbier process of (R,SRS)-8 with alkyl and aryl bromide. The stereochemistry at the C-5 stereogenic center of the trans-4-hydroxy-5-substituted 2-pyrrolidinones was solely controlled by α-alkoxy substitution. This effective approach was successfully used to prepare a variety of substituted (3R,4S)-statines 2. In addition, two bioactive natural products of (+)-preussin 4 and hapalosin 5 were effectively synthesized through this stereoselective tandem Barbier process.
- Si, Chang-Mei,Shao, Lu-Ping,Mao, Zhuo-Ya,Zhou, Wen,Wei, Bang-Guo
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p. 649 - 661
(2017/01/25)
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- Three-step synthesis of (±)-preussin from decanal
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A straightforward and stereoselective synthesis of the alkaloid preussin is described starting from decanal and diethyl 3-diazo-2-oxopropylphosphonate. The key steps are an aza-Michael reaction from an α,β-unsaturated diazoketone followed by a highly stereoselective Cu-catalyzed ylide formation and then a [1,2]-Stevens rearrangement. This strategy is feasible for extension to preussin analogues, demonstrating its utility for the rapid construction of all-cis-substituted pyrrolidines.
- Rosset, Isac G.,Dias, Rafael M. P.,Pinho, Vagner D.,Burtoloso, Antonio C. B.
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p. 6748 - 6753
(2014/08/05)
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- Asymmetric synthesis of 2,5-disubstituted 3-hydroxypyrrolidines based on stereodivergent intramolecular iridium-catalyzed allylic aminations
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Intramolecular iridium-catalyzed allylic aminations of homochiral (E)-6-N-nosylaminohept-2-en-1-yl methyl carbonates were investigated. The relative position of the 2,5-substituents of the resulting pyrrolidines was found to be controlled by using both enantiomers (4 and 5) of the appropriate chiral ligand, demonstrating a simple and highly stereodivergent synthetic protocol. Selected trans- and cis-2,5-disubstituted 3-hydroxypyrrolidines (2a and 18a) were converted to (+)-bulgecinine (6) and (+)-preussin (7), respectively.
- Natori, Yoshihiro,Kikuchi, Shunsuke,Kondo, Takahiro,Saito, Yukako,Yoshimura, Yuichi,Takahata, Hiroki
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p. 1983 - 1994
(2014/03/21)
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- An efficient method for the preparation of 3-hydroxyl-5-substituted 2-pyrrolidones and application in the divergent synthesis of (-)-preussin and its analogues
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An asymmetric method to (S,R)-α-hydroxyl-γ-amino alcohols 12 through a diastereoselective addition of Grignard reagents to β-chiral aldimines 11 is described. Subsequent oxidation/cyclization with Sarett reagent provided a novel approach to lactams 14, a flexible building block whose utility was demonstrated in the divergent synthesis of antifungal agent (-)-preussin 5 and its three analogues 23, 24, 25.
- Zhou, Qian-Ru,Wei, Xiao-Yun,Li, You-Qin,Huang, Danfeng,Wei, Bang-Guo
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p. 4799 - 4808
(2014/06/24)
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- A concise and stereoselective synthesis of hydroxypyrrolidines: Rapid synthesis of (+)-preussin
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A convergent and stereoselective synthesis of 2,5-disubstituted 3-hydroxypyrrolidines has been developed that involves reductive annulation of β-iminochlorohydrins, which are readily available from β- ketochlorohydrins, and provides rapid access to a variety of 2,5-syn-pyrrolidines. Application of this process to the concise (three-step) synthesis of the fungal metabolite (+)-preussin and analogues of this substance is reported.
- Draper, Jason A.,Britton, Robert
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supporting information; experimental part
p. 4034 - 4037
(2010/11/05)
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- Versatile one-pot reductive alkylation of lactams/amides via amide activation: Application to the concise syntheses of bioactive alkaloids (±)-bgugaine, (±)-coniine, (+)-preussin, and (-)-cassine
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Direct entry: One-pot reductive alkylation of lactams/amides with Grignard reagents has been realized via lactam/amide activation with Tf2O. This method opens a direct entry to α-alkylated amines. The versatility of the method is illustrated by the concise syntheses of bioactive alkaloids (±)-bgugaine, (±)-coniine, (+)-preussin, and (?)-cassine.
- Xiao, Kai-Jiong,Wang, Yu,Ye, Ke-Yin,Huang, Pei-Qiang
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supporting information; experimental part
p. 12792 - 12796
(2011/02/22)
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- Asymmetric synthesis of cis- and trans-2,5-disubstituted pyrrolidines from 3-oxo pyrrolidine 2-phosphonates: Synthesis of (+)-preussin and analogs
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(Chemical Equation Presented) Pyrrolidine enones, derived from 3-oxo pyrrolidine 2-phosphonates and a HWE reaction with aldehydes, on Luche reduction give pyrrolidine allylic alcohols. The alcohols on hydrogenation (Pd/H 2) give cis-2,5-disubstituted pyrrolidines and on treatment with TFA-NaBH3CN undergo a hydroxy directed reduction to trans-2,5-disubstituted pyrrolidines.
- Davis, Franklin A.,Zhang, Junyi,Qiu, Hui,Wu, Yongzhong
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body text
p. 1433 - 1436
(2009/04/10)
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- A concise stereoselective synthesis of Preussin, 3-epi-Preussin, and analogues
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A new stereoselective synthesis of the antifungal and antitumor agents Preussin and 3-epi-Preussin via a Pd-catalyzed carboamination of a protected amino alcohol is described. The key transformation leads to simultaneous formation of the N-C2 bond and the C1′-aryl bond, and allows installation of the aryl group one step from the end of the sequence. This strategy permits the facile construction of a variety of preussin analogues bearing different aromatic groups.
- Bertrand, Myra Beaudoin,Wolfe, John P.
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p. 2353 - 2356
(2007/10/03)
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- A concise total synthesis of antifungal antibiotic (+)-preussin
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A short synthesis of the pharmacologically important natural product (+)-preussin is described. Two asymmetric C-C bond-formation reactions mediated by binaphthol-derived asymmetric catalysts have been applied to control the stereo-chemistry of its three stereocenters. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Gogoi, Naminita,Boruwa, Joshodeep,Barua, Nabin C.
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p. 1722 - 1725
(2007/10/03)
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- Total synthesis of (+)-preussin: Control of the stereogenic centers by enantioselective allyltitanations
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(+)-Preussin was synthesized in ten steps with an overall yield of 6.4% from phenylacetaldehyde. The three stereogenic centers were controlled by enantioselective allyltitanations of aldehydes.
- Canova, Sophie,Bellosta, Véronique,Cossy, Janine
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p. 1811 - 1813
(2007/10/03)
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- Asymmetric synthesis of (+)-preussin from N-sulfinyl δ-amino β-ketoesters
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The efficient asymmetric synthesis of the antifungal pyrrolidine alkaloid (+)-preussin (2) was accomplished via the stereoselective reduction of a 5-substituted 3-oxo proline. The oxo proline was prepared from an N-sulfinyl δ-amino β-ketoester, a sulfinimine derived polyfunctionalized chiral building block.
- Davis, Franklin A.,Deng, Jianghe
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p. 5111 - 5115
(2007/10/03)
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- A novel and stereospecific synthesis of (+)-preussin
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A novel and stereospecific approach to (+)-preussin that would permit the synthesis of analogs for structure activity relationship studies, is disclosed. The key step includes the regio- and stereoselective elaboration of a bromohydrin via intramolecular sulfinyl group participation.
- Raghavan, Sadagopan,Rasheed, M. Abdul
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p. 10307 - 10312
(2007/10/03)
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- A Flexible Approach to (S)-5-Alkyl Tetramic Acid Derivatives: Application to the Asymmetric Synthesis of (+)-Preussin and Protected (3S,4S)-AHPPA
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(Equation presented) A flexible asymmetric approach to 5-alkyl tetramic acid derivatives is described, which is based on the use of 9 as the first synthetic equivalent to chiral nonracemic tetramic acid 5-carbanionic synthon 9b. The existence of the carbanion intermediate 9b was proven by trapping with trimethylchlorosilane. Application of the present method to the synthesis of antifungal alkaloid (+)-preussin, as well as protected (3S,4S)-AHPPA 6, is also described.
- Huang, Pei-Qiang,Wu, Tian-Jun,Ruan, Yuan-Ping
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p. 4341 - 4344
(2007/10/03)
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- Short-step syntheses of all stereoisomers of preussin and their bioactivities
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All the eight stereoisomers of (+)-preussin (1b), an antifungal agent inhibiting the growth of fission yeast and human cancer cells, were synthesized in two steps by non-stereoselective reactions and chromatographic separation, starting from L- and D-N-pr
- Okue, Masayuki,Watanabe, Hidenori,Kasahara, Koji,Yoshida, Minoru,Horinouchi, Sueharu,Kitahara, Takeshi
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p. 1093 - 1096
(2007/10/03)
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- Efficient stereoselective synthesis of (2s,3s,5r)-(+)-preussin
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Allyltrimethylsilane reacted with N-carbobenzoxy-L-phenylalaninal to afford with high diastereoselectivity syn-adduct which was subsequently transformed into (2S, 3S, SR)-(+)-preussin.
- Krasiński, Antoni,Gruza, Henryk,Jurczak, Janusz
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p. 581 - 584
(2007/10/03)
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- A concise synthesis of (+)-preussin
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A concise synthesis of (+)-preussin (1), an antifungal agent and a growth-inhibitor of fission yeast and human cancer cells, was accomplished employing a stereoselective aldol reaction between the zinc enolate of 2-undecanone and N-protected-L-phenylalaninal followed by reductive pyrrolidine formation as key steps.
- Okue, Masayuki,Watanabe, Hidenori,Kitahara, Takeshi
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p. 4107 - 4110
(2007/10/03)
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- A sulfone-mediated synthesis of (+)-preussin
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The synthesis of the antifungal pyrrolidine (+)-preussin is described, utilising the 5-endo-trig cyclisatian of a vinylic sulfone generated in situ to give the requisite pyrrolidine nucleus.
- Caldwell,Craig,East
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p. 1602 - 1604
(2007/10/03)
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- The synthesis of (+)-preussin and related pyrrolidinols by diastereoselective Paterno-Buechi reactions of chiral 2-substituted 2,3-dihydropyrroles
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The N-alkoxycarbonyl substituted 2,3-dihydropyrroles 3 and 8 are converted to 2-benzyl-3-pyrrolidinols by the Paterno - Buechi reaction followed by hydrogenolysis. Since the addition of the photoexcited benzaldehyde at the unsaturated heterocycle proceeds in a syn fashion, the benzyl group at C-2 and the hydroxy group at C-3 of the product are cis oriented. The simple and facial diastereoselectivities of the Paterno -Buechi reaction were studied more closely and the relative configuration of the products was elucidated. The thermodynamically less stable endo product is formed as a result of simple diastereo-selection. The face differentiation in 2-substituted 2,3-dihydropyrroles is presumably due to the nonplanarity of these heterocycles, which forces attack of the carbonyl group on the face with the existing substituent. All-cis-pyrrolidinols are consequently formed after hydrogenolysis. Following this route, a total synthesis of the pyrrolidinol alkaloid (+)-preussin (1) was conducted, which yielded the target compound in a total yield of 11% over nine steps starting from L-pyroglutaminol (11).
- Bach, Thorsten,Brummerhop, Harm,Harms, Klaus
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p. 3838 - 3848
(2007/10/03)
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- Facile and efficient total synthesis of (+)-preussin.
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[structure] The enantioselective total synthesis of (+)-preussin, a potent antifungal agent, has been achieved. The key steps are a Pd(0)-catalyzed oxazoline-forming reaction from L-phenylalanine, hydrogenolysis, and subsequent diastereoselective reductive cyclization of the intermediate aminoketone to pyrrolidine using Pearlman's catalyst.
- Lee,Kim,Oh,Ham
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p. 4041 - 4042
(2007/10/03)
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- Desymmetrization of 3-dimethyl(phenyl)silyl glutaric anhydride with Evans' oxazolidinone: An application to stereocontrolled synthesis of the antifungal agent (+)-preussin
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A stereoselective total synthesis of (+)-preussin (1) has been achieved from the a-symmetric 3-dimethyI(phenyl)silyl substituted glutaric anhydride 4 featuring its desymmetrization using Evans' oxazolidinone 10. The first homochiral intermediate, the glutarate half-ester 9 was obtained from both the diastereoisomeric acids lia, and 12a in a convergent fashion. The dimethyl(phenyl)silyl group is not only acting as a masked hydroxy group but also restricts elimination reactions, and facilitates Curtius reaction. It also stereodirects ester enolate alkylation of 18, and hydrogenation of intermediate Δ1-pyrroline 5.
- Verma, Rekha,Ghosh, Sunil K.
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p. 265 - 270
(2007/10/03)
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- Practical asymmetric approach to pyrrolidinones: Efficient synthesis of (+)-preussin and (-)-AHPPA
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A novel, dichloroketene-chiral enol ether cycloaddition-based synthesis of enantiopure (+)-preussin and (-)-AHPPA has been realized. The efficient, highly stereoselective approach, which involves a Beckmann ring expansion reaction to access the key pyrrolidinone, proceeds in ca. 16% overall yield for each of the compounds.
- Kanazawa, Alice,Gillet, Sandra,Delair, Philippe,Greene, Andrew E.
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p. 4660 - 4663
(2007/10/03)
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- A silicon controlled total synthesis of the antifungal agent (+)-preussin
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A stereoselective total synthesis of (+)-preussin has been achieved from a meso anhydride featuring a dimethyl(phenyl)silyl group as a masked hydroxy group which also restricts elimination reactions, stereodirects hydrogenation and ester enolate alkylation, and facilitates Curtius reaction.
- Verma, Rekha,Ghosh, Sunil K.
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p. 1601 - 1602
(2007/10/03)
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- An epoxide-based enantioselective synthesis of the antifungal antibiotic (+)-preussin
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The enantioselective total synthesis of (2S,3S,5R)-1-methyl-5-nonyl-2-(phenylmethyl)-3-pyrrolidinol, (+)-preussin 1, from (S)-phenylalanine is described. Key steps involve ring-opening of a (1-amino-alkyl) epoxide 5 by an allyl anion, [2,3]-sigmatropic rearrangement of 9 and cyclization of aminoepoxide 11 to give the pyrrolidine unit 12 with the correct stereochemistry.
- Beier,Schaumann
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p. 1296 - 1300
(2007/10/03)
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- Novel route to the synthesis of hydroxylated pyrrolidine derivatives via the intramolecular reaction of γ-aminoallylstannane with aldehyde. Total synthesis of (+)-preussin
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The thermal cyclization of γ-aminoallylstannane (8) having an aldehyde group gave β-hydroxypyrrolidine derivative (9a) as a sole product. This methodology was applied successfully to the total synthesis of (+)-preussin.
- Kadota, Isao,Saya, Shioko,Yamamoto, Yoshinori
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p. 335 - 348
(2007/10/03)
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- A novel stereoselective synthesis of enantiomerically pure antifungal agent, (+)-preussin
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An efficient and novel process is described for the asymmetric synthesis of (2S, 3S, 5R)-1-methyl-5-nonyl-2-(phenylmethyl)-3-pyrrolidinol, (+)-preussin employing reductive deoxygenation of a functionalized quaternary α-hydroxy N-Boc pyrrolidine obtained by stereocontrolled elaboration of tri-O-benzyl-β-D-arabinofuranose. The synthetic strategy involves no separation of stereoisomers through the entire sequence.
- Yoda, Hidemi,Yamazaki, Hiroyasu,Takabe, Kunihiko
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p. 373 - 374
(2007/10/03)
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- A Concise Synthesis of the Antifungal Agent (+)-Preussin
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The antifungal agent (+)-preussin (1) was synthesized in five efficient transformations from t-Boc-(S)-phenylalanine.The key step involved the Hg(II)-mediated ring closure of ynone 4, a 5-endo-dig process.
- Overhand, Mark,Hecht, Sidney M.
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p. 4721 - 4722
(2007/10/02)
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- Enantioselective total synthesis of either enantiomer of the antifungal antibiotic preussin (L-657,398) from (S)-phenylalanine
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Enantioselective total syntheses of the antifungal agent (+)-preussin (1) and its enantiomer (-)-1 from (S)-phenylalanine are described. The central transformations are protic acid-promoted aza-Cope rearrangement - Mannich cyclization reactions (12 → 19 and 13 → 27). Retro-Mannich fragmentation-Mannich cyclization (27 → 28) is key to the formation of (-)-1. This study demonstrates, for the first time, that enantioenriched substituted pyrrolidines can be prepared using the aza-Cope-Mannich rearrangement.
- Deng,Overman
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p. 11241 - 11250
(2007/10/02)
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- Synthesis Of (+)-Preussin
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A total synthesis of (+)-preussin (1), a novel antifugal agent, was achieved via asymmetric 1,3-dipolar cycloaddition of decyl methyl nitrone (2) with (-)-1-phenyl-3-buten-2-ol (3) as a key reaction.
- Shimazaki, Makoto,Okazaki, Fumiaki,Nakajima, Fumihiro,Ishikawa, Tetsuya,Ohta, Akihiro
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p. 1823 - 1836
(2007/10/02)
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- Synthetic applications of imidotitanium-alkyne [2 + 2] cycloadditions. A concise, stereocontrolled total synthesis of the antifungal agent (+)-preussin
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An efficient stereoselective total synthesis of (+)-preussin, (2S,3S,5R)-1-methyl-5-nonyl-2-(phenylmethyl)-3-pyrrolidinol (1), was achieved by way of a convergent, intramolecular imidotitanium-alkyne [2 + 2] cycloaddition-acyl cyanide condensation sequence.
- Leo McGrane,Livingbouse, Tom
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p. 11485 - 11489
(2007/10/02)
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