- Michael-type addition of phthalimide salts to chiral α,β-unsaturated imides
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The synthesis of (R)-(-)-3-aminobutanoic acid starting from chiral α,β- unsaturated imide 1b is described, by means of the nucleophilic attack of several phthalimido derivatives in the presence of a Lewis acid. The reaction was studied in some details and chloromagnesium phthalimide afforded the better results with 95:5 diastereomeric ratio and 90% yield. Furthermore the resulting enolate was trapped performing the reaction in the presence of benzenesulfonyl bromide and the 2-bromo-3-phthalimido derivative 4 was obtained in good yield and high diastereoselectivity and successively transformed into the corresponding 2-azido-3-phthalimido derivative 6 by displacement of the bromide with sodium azide.
- Cardillo, Giuliana,De Simone, Angela,Gentilucci, Luca,Sabatino, Piera,Tomasini, Claudia
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Read Online
- Converting aspartase into a β-amino acid lyase by cluster screening
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Aspartase, despite being one of the most specific enzymes known, shows potential for application in β-amino acid synthesis. The substrate binding pocket of AspB from Bacillus sp. YM55-1 was reshaped by enzyme engineering to accommodate crotonic acid. The mutant enzyme BSASP-C6 yielded enantiopure (R)-3-aminobutyrate from crotonic acid and ammonia. To obtain this mutant, a high-throughput screening in combination with a focused permutational library was decisive for the success in this project. We achieved this by simultaneous randomisation of four residues within the substrate binding pocket and cluster screening in mixed population. Screening of 300 000 clones was necessary to find the BSASP-C6 mutant which has β-amino acid lyase activity. This exemplifies the need for efficient search and screening strategies in creating novel enzyme activities. The BSAPS-C6 enzyme developed here surpasses the natural substrate functionality of aspartase and thus represents the proof-of-concept of application of this novel synthetic route to a broader set of β-amino acids. β-Amino acids with aspartase mutants: Aspartase, despite being one of the most specific enzymes known, shows potential for application in β-amino acid synthesis. By applying a combination of focused library design and cluster screening, we created an aspartate mutant with β-amino acid lyase activity and thus open up a new platform to synthesize this interesting and important compound class. BSASP-C6= Mutant of AspB from Bacillus sp. YM55-1.
- Vogel, Andreas,Schmiedel, Ramona,Hofmann, Ute,Gruber, Karl,Zangger, Klaus
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Read Online
- Preparation method of 3-aminopropanol or 3-aminopropionic acid derivative
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The invention provides a preparation method of an optically active 3-aminopropanol or 3-aminopropionic acid derivative, and belongs to the technical field of organic synthesis. A compound having a structure as shown in a formula II and a formula III is used as a raw material, and the optically active 3-aminopropanol or 3-aminopropionic acid derivative is obtained through four basic steps, namely dehydration condensation, hydrogenation reduction, reduction and hydrolysis. The raw materials adopted in the preparation method are easy to obtain and low in cost; as a chiral phosphine-transitional metal catalyst is used in the hydrogenation reduction reaction, the optically active 3-aminopropanol or 3-aminopropionic acid derivative is efficient, high in selectivity, low in cost and suitable forlarge-scale production. Compared with existing chemical resolution and chiral introduction, the asymmetric hydrogenation synthesis method provided by the invention only produces one chiral product, ishigh in yield, and has relatively high advantages in economy and raw material utilization rate.
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Paragraph 0150; 0163-0165; 0168
(2018/10/11)
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- A optically active 3 - amino butanol and 3 - aminobutyric acid preparation method (by machine translation)
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The invention discloses a method of optically active 3 - amino butanol and 3 - aminobutyric acid preparation method. Wherein optically active 3 - amino butyl alcohol preparation method comprises the following steps: in a solvent, in the borohydride reducing agent and a Lewis acid under the action of the, shown as 65 shown in the reduction reaction of compound, production like type 14 indicated by the compound. Optically active 3 - aminobutyric acid preparation method comprises the following steps: shown as 64 a compound represented by the hydrolytic reaction, production like type 65 compound of formula. Preparation method of this invention the raw material is cheap, simple operation, the process route is short, the raw material is not hazardous, high yield, produce little material waste, is beneficial for the protection of the environment, high conversion rate of raw materials, product chemical purity and high optical purity, and is easy to realize industrial. (by machine translation)
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Paragraph 0119; 0120
(2017/07/01)
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- Cyclombandakamines A1 and A2, Oxygen-Bridged Naphthylisoquinoline Dimers from a Congolese Ancistrocladus Liana
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Cyclombandakamines A1 (1) and A2 (2), both with an unprecedented pyrane-cyclohexenone-dihydrofuran sequence and six stereocenters and two chiral axes, are the first oxygen-bridged dimeric naphthylisoquinoline alkaloids. They were isolated from the leaves of an as yet unidentified Congolese Ancistrocladus species. Their stereostructures were established by spectroscopic, chemical, and chiroptical methods in combination with DFT and TDDFT calculations. They apparently originate from a cascade of oxidative cyclization reactions of open-chain naphthylisoquinoline dimers and exhibit significant antiprotozoal activities.
- Lombe, Blaise Kimbadi,Bruhn, Torsten,Feineis, Doris,Mudogo, Virima,Brun, Reto,Bringmann, Gerhard
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supporting information
p. 1342 - 1345
(2017/03/23)
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- Acylation of β-Amino Esters and Hydrolysis of β-Amido Esters: Candida antarctica Lipase A as a Chemoselective Deprotection Catalyst
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N-Acylation by lipase A from Candida antarctica (CAL-A) in ethyl butanoate was applied to the kinetic resolution of tert-butyl esters of 3-amino-3-phenylpropanoic acid (E>100), 3-amino-4-methylpentanoic acid (E>100) and 3-aminobutanoic acid (E=60) on 1.0-2.0 m scale. With the N-acylated resolution products, the exceptional ability of CAL-A to hydrolyse amides and bulky tert-butyl esters was then studied. In all N-acylated tert-butyl esters, chemoselectivity favoured the amide bond cleavage. The tert-butyl ester bond was left intact with 3-amino-3-phenylpropanoate, whereas with 3-amino-4-methylpentanoate and 3-aminobutanoate the CAL-A-catalysed hydrolysis of tert-butyl ester followed the amide hydrolysis.
- M?enp??, Harri,Kanerva, Liisa T.,Liljeblad, Arto
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p. 1226 - 1232
(2016/04/05)
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- METHOD FOR OBTAINING OPTICALLY PURE AMINO ACIDS
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This invention relates to a method for obtaining optically pure amino acids, including optical resolution and optical conversion. This method significantly shortens the time taken for optical transformation, and enables the repeated use of an organic solution containing a enantioselective receptor, to thereby obtain optically pure amino acids in a simple and remarkably efficient manner, and to enable the very economical mass production of optically pure amino acids.
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Page/Page column 7
(2012/02/01)
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- METHOD FOR OBTAINING OPTICALLY PURE AMINO ACIDS
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This invention relates to a method for obtaining optically pure amino acids, including optical resolution and optical conversion. This method significantly shortens the time taken for optical transformation, and enables the repeated use of an organic solution containing a enantioselective receptor, to thereby obtain optically pure amino acids in a simple and remarkably efficient manner, and to enable the very economical mass production of optically pure amino acids.
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Page/Page column 10-11
(2012/02/14)
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- Formation and hydrolysis of amide bonds by lipase A from Candida antarctica; Exceptional features
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Various commercial lyophilized and immobilized preparations of lipase A from Candida antarctica (CAL-A) were studied for their ability to catalyze the hydrolysis of amide bonds in N-acylated α-amino acids, 3-butanamidobutanoic acid (β-amino acid) and its ethyl ester. The activity toward amide bonds is highly untypical of lipases, despite the close mechanistic analogy to amidases which normally catalyze the corresponding reactions. Most CAL-A preparations cleaved amide bonds of various substrates with high enantioselectivity, although high variations in substrate selectivity and catalytic rates were detected. The possible role of contaminant protein species on the hydrolytic activity toward these bonds was studied by fractionation and analysis of the commercial lyophilized preparation of CAL-A (Cat#ICR-112, Codexis). In addition to minor impurities, two equally abundant proteins were detected, migrating on SDS-PAGE a few kDa apart around the calculated size of CAL-A. Based on peptide fragment analysis and sequence comparison both bands shared substantial sequence coverage with CAL-A. However, peptides at the C-terminal end constituting a motile domain described as an active-site flap were not identified in the smaller fragment. Separated gel filtration fractions of the two forms of CAL-A both catalyzed the amide bond hydrolysis of ethyl 3-butanamidobutanoate as well as the N-acylation of methyl pipecolinate. Hydrolytic activity towards N-acetylmethionine was, however, solely confined to the fractions containing the truncated form of CAL-A. These fractions were also found to contain a trace enzyme impurity identified in sequence analysis as a serine carboxypeptidase. The possible role of catalytic impurities versus the function of CAL-A in amide bond hydrolysis is further discussed in the paper. The Royal Society of Chemistry 2010.
- Liljeblad, Arto,Kallio, Pauli,Vainio, Marita,Niemi, Jarmo,Kanerva, Liisa T.
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scheme or table
p. 886 - 895
(2010/06/20)
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- Burkholderia cepacia lipase and activated β-lactams in β-dipeptide and β-amino amide synthesis
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The work describes fluorine-activated and N-Boc-activated β-lactams as acyl donors to N-nucleophiles in the presence of Burkholderia cepacia lipase (lipase PS-D). Fluorine activation at the β-lactam ring causes the ring to open in high enantioselectivity
- Li, Xiang-Guo,Laehitie, Maria,Kanerva, Liisa T.
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p. 1857 - 1861
(2008/12/21)
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- Parallel synthesis of homochiral β-amino acids
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The parallel asymmetric synthesis of an array of 30 β-amino acids of high enantiomeric purity using the conjugate addition of homochiral lithium N-benzyl-N-(α-methylbenzyl)amide as the key step is accomplished. The experimental simplicity and highly practical nature of the protocol is demonstrated by the efficient parallel conversion of 15 α,β-unsaturated esters to both enantiomeric series of the corresponding β-amino acids in high overall yields and selectivities with minimal purification involved in each step of the reaction protocol.
- Davies, Stephen G.,Mulvaney, Andrew W.,Russell, Angela J.,Smith, Andrew D.
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p. 1554 - 1566
(2008/02/09)
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- Homochiral lithium amides for the asymmetric synthesis of β-amino acids
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Secondary homochiral lithium amides derived from α-methylbenzylamine undergo highly diastereoselective conjugate additions to a range of α,β-unsaturated esters. The corresponding β-amino acids are readily liberated by successive N-debenzylation and ester hydrolysis, furnishing (R)-β-amino butyric acid, (R)-β-amino pentanoic acid, (S)-β-leucine, (R)-β-amino octanoic acid, (S)-β-phenylalanine, (S)-β-tyrosine methyl ether, (S)-β-tyrosine hydrochloride and (S)-β-(2-methoxyphenyl)-β-amino propanoic acid in high yields and high ee. The application of this procedure to the synthesis of the natural products (R)-β-DOPA and (R)-β-lysine is demonstrated. The development of a simplified one-pot reaction protocol applicable to the multi-gram scale synthesis of homochiral β-amino esters is also delineated.
- Davies, Stephen G.,Garrido, Narciso M.,Kruchinin, Dennis,Ichihara, Osamu,Kotchie, Luke J.,Price, Paul D.,Mortimer, Anne J. Price,Russell, Angela J.,Smith, Andrew D.
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p. 1793 - 1811
(2007/10/03)
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- An improved synthesis of enantiopure β-amino acids
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An improved method for the preparation of both the enantiopure β-amino acids is presented. The diastereomer benzyl β-amino esters, obtained by stereoselective reduction of β-enamino esters, were separated and hydrogenolyzed to the free enantiopure β-amino acids.
- Cimarelli,Palmieri,Volpini
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p. 2943 - 2953
(2007/10/03)
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- Enantioselective conjugate addition of hydroxylamines to pyrazolidinone acrylamides
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(Matrix Presented) Chiral relay templates provide amplification of selectivity in conjugate addition reactions. Reversal of stereochemistry of the product isoxazolidinones has also been demonstrated by a simple change of the Lewis acid.
- Sibi, Mukund P.,Liu, Mei
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p. 4181 - 4184
(2007/10/03)
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- 104. The enantioselective synthesis of β-amino acids, their α-hydroxy derivatives, and the N-terminal components of bestatin and microginin
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L-Aspartic acid by tosylation, anhydride formation, and reduction with NaBH4 was converted into (3S)-3-(tosylamino)butan-4-olide (8; Scheme 1). Treatment of 8 with ethanolic trimethylsilyl iodide gave the N-protected deoxy-iodo-β-homoserine ethyl ester 9. The latter, on successive nucleophilic displacement with lithium dialkylcuprates (→ 10a-e), alkaline hydrolysis (→ 11a-e), and reductive removal of the tosyl group, produced the corresponding 4-substituted (3R)-3-aminobutanoic acids 12a-e (ee >99%). Electrophilic hydroxylation of 8 (→ 19; Scheme 3), subsequent iodo-esterification (→ 21; Scheme 4), and nucleophilic alkylation and phenylation afforded, after saponification and deprotection, a series of 4-substituted (2S,3A)-3-amino-2-hydroxybutanoic acids 24 including the N-terminal acids 24e (= 3) and 24f (= 4) of bestatin and microginin (de >95%), respectively.
- Jefford, Charles W.,McNulty, James,Lu, Zhi-Hui,Wang, Jian Bo
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p. 1203 - 1216
(2007/10/03)
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- Enantioselektive Synthese von β-Aminosaeuren - TMS-SAMP als chirales Ammoniak-Aequivalent in der azaanalogen Michael-Addition an α,β-ungesaettigte Ester
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Stichworte: Aminosaeuren * Asymmetrische Synthesen * Chirale Hilfsstoffe * Michael-Additionen
- Enders, Dieter,Wahl, Heiner,Bettray, Wolfgang
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p. 527 - 529
(2007/10/02)
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- An enantiospecific synthesis of β-amino acids
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L-Aspartic acid by regioselective modification of the α-carboxylic acid group, namely N-tosylation, anhydride formation, reduction, iodo-esterification, alkylation, and deprotection afforded a series of γ-alkyl β-aminobutyric acids of the R configuration (ee > 99%).
- Jefford,Wang
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p. 1111 - 1114
(2007/10/02)
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- USE OF CHIRAL AMIDALS IN THE SYNTHESIS OF 6-METHYLPERIHYDROPYRIMIDIN-4-ONES, PROTECTED FROM OF β-AMINO ACIDS
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The synthesis of 6-methylperihydropyrimidin-4-ones (7a and 7b) is described by mercury cyclization of the β,γ-unsaturated amidal (3).After reduction of the intermediate organomercury compound (6) and separation of the diastereomeric mixture, the perihydropyrimidin-4-ones (7a and 7b) have been obtained.Their structure has been fully characterized by means of 1H NMR spectroscopy and, after acid hydrolysis, the 3-aminobutyric acids (8a and 8b) have been obtained.
- Amoroso, Rosa,Cardillo, Giuliana,Tomasini, Claudia
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p. 349 - 355
(2007/10/02)
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- Enantioselective Synthesis of β-Amino Acids. 2. Preparation of the like Stereoisomers of 2-Methyl- and 2-Benzyl-3-aminobutanoic Acid
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An improved procedure for the preparation of (R)- and (S)-3-aminobutanoic acids (2a) through diastereomer separation of the corresponding (1'S)-N-phenethyl derivatives 1 is reported.From 2a, the four possible stereoisomeric perhydropyrimidin-4-ones 4 were prepared through the amide 2c and the Schiff base 3.In the cyclization of 3, the cis products 4 predominate ca. 95:5.These heterocycles can be alkylated (LDA, RX), as demonstrated by methylation and benzylation, with formation of a single diastereoisomer (5, 6).Hydrolysis (6 N aqueous HCl) of these 5,6-dialkylperhydropyrimidin-4-ones leads to the free amino acids 7-10.
- Juaristi, Eusebio,Escalante, Jaime,Lamatsch, Bernd,Seebach, Dieter
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p. 2396 - 2398
(2007/10/02)
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- Efficient EPC Synthesis of β-Aminobutanoic Acid
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A practical approach to enantiomerically pure (R)-3-aminobutanoic acid (6) from L-asparagine is presented.The key step of the synthesis is the chemoselective reduction of the β-homoserine derivative 2.
- Gmeiner, Peter
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p. 501 - 502
(2007/10/02)
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- ASYMMETRIC SYNTHESIS OF R-β-AMINO BUTANOIC ACID AND S-β-TYROSINE: HOMOCHIRAL LITHIUM AMIDE EQUIVALENTS FOR MICHAEL ADDITIONS TO α,β-UNSATURATED ESTERS.
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Michael addition of the lithium amide derived from R-N-(α-methylbenzyl)benzylamine to benzyl E-crotonate is highly stereoselective (95percent d.e.) giving after debenzylation and crystallisation homochiral R-β-amino butanoic acid.A similar addition to methyl E-(p-benzyloxy)cinnamate is completely stereoselective giving after debenzylation and acid hydrolysis homochiral S-β-tyrosine as its HCl salt.
- Davies, Stephen G.,Ichihara, Osamu
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p. 183 - 186
(2007/10/02)
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- 194. Diastereoselecktive Alkylation of 3-Aminobutanoic Acid in the 2-Position
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The enantiomerically pure 3-aminobutanoic acids (R)- and (S)-6 are readily available by preparative HPLC separation of the two diastereoisomers 5 obtained from addition of (S)-phenethylamine to methyl crotonate and subsequent hydrogenolysis (Scheme 2). (S)-methyl 3-(benzoylamino)butanoate ((S)-3) is also available by enzymatic kinetic resolution with pig-liver esterase.The N-benzoyl- and N-benzyloxycarbonyl derivatives rac-3, 8,and 9 of 3-aminobutanoates are doubly deprotonated with LDA and alkylated or aminated in high selectivity (17 examples, relative topicity like; see Tables 1 and 2).The configuration of three of the products is assigned (Schemes 4-6), and in four cases, the free α-substituted β-amino acid is prepared by acidic hydrolysis (see Table 3).It is shown that the doubly lithiated β-amino-acid derivative is solubilized, and its reactivity may be strongly influenced by the presence of 3 equiv. of LiCl.
- Estermann, Heinrich,Seebach, Dieter
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p. 1824 - 1840
(2007/10/02)
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- Herstellung enantiomerenreiner Derivate von 3-Amino- und 3-Mercaptobuttersaeure durch SN2-Ringoeffnung des β-Lactons und eines 1,3-Dioxanons aus der 3-Hydroxybuttersaeure
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From (S)-4-methyloxetan-2-one (1), the β-butyrolactone readily available from the biopolyner (R)-polyhydroxybutyrate (PHB) and various C,N,O and S nucleophiles, the following compounds are prepared: (S)-2-hydroxy-4-octanone (3), (R)-3-aminobutanoic acid (7) and its benzyl derivative 5, (R)-3-azidobutanoic acid (6), (R)-3-mercaptobutanoic acid (10), (R)-3-(phenylthio)butanoic acid (8) and its sulfoxide 9.The (6R)-2,6-dimethyl-2-ethoxy-1,3-dioxan-4-one (4) from (R)-3-hydroxybutanoic acid undergoes SN2 ring opening with benzylamine to give the N-benzyl derivative (ent-5) of (S)-3-aminobutanoic acid in 30-40percent yield.
- Griesbeck, Axel,Seebach, Dieter
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p. 1326 - 1332
(2007/10/02)
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