环状β氨基酸cispentacin的合成研究
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摘要
环状β氨基酸cispentacin是种抗生素、抗菌素，在医药合成上是种重要的中间体。本论文通过广泛的查阅资料，确定了合成cispentacin的方法为Palmieri研究小组的还原氨化法。该方法起始原料价格低廉易得，所生成的非对映体和顺／反对映体的选择性通过改变还原条件可以得到进一步的改善。这种方法的唯一缺点是得到的产物需要用色谱仪纯化分离。但是研究发现：最后生成的主要的非列应体1(R，S，S)或它的对映体能够从反应混合物中以HBR盐的形式分离出来，并得到很高的产率和光学纯度。另外论文对合成已二酸二乙酯的催化剂进行了选择，确定了该反应的最佳时间、醇酸配比、带水剂的最佳用量、催化剂的最佳用量。用还原氨化法合成了原料(+)α—苯基乙胺。确定合成cispentacin的原料2-oxo-cyclopentanecarboxylate的催化剂为钠，溶剂为甲苯及它们的用量。
Annular β amino acid cispentacin is a kind of antifungal
antibiotic. It ;s an important pharmaceutical intermediate in the synthesization of many Pharmaceuticals. After consulting many literatures , we chose the following way to synthesize cispentacin :diastereoselective reductive amination of 2-oxo-cyclopentanecarboxylate with a -methylbenzylamine.This method reported by Palmieri utilizes inexpensive and readily available starting materials .The only drawback of this method is the necessity of a chromatographic purification to isolate the desired diastereomer .This thesis also reports some research work on the synthesization of di-Et adipate and gets the conclusion of the most reasonable time,the best proportion of acid and alcohol,the most reasonable quality of catalyzer in this.chemical reaction.And also synthesizes the a-methylbenzylamine
and 2-oxo-cyclopentanecarboxylate,,
Annular β amino acid cispentacin is a kind of antifungal
antibiotic. It ;s an important pharmaceutical intermediate in the synthesization of many Pharmaceuticals. After consulting many literatures , we chose the following way to synthesize cispentacin :diastereoselective reductive amination of 2-oxo-cyclopentanecarboxylate with a -methylbenzylamine.This method reported by Palmieri utilizes inexpensive and readily available starting materials .The only drawback of this method is the necessity of a chromatographic purification to isolate the desired diastereomer .This thesis also reports some research work on the synthesization of di-Et adipate and gets the conclusion of the most reasonable time,the best proportion of acid and alcohol,the most reasonable quality of catalyzer in this.chemical reaction.And also synthesizes the a-methylbenzylamine
and 2-oxo-cyclopentanecarboxylate,,
引文
1．徐寿昌：《有机化学》，β-二羰基化合物 1981：352～354
2．立功 王东华 宋传君等编著《药物中间体合成工艺》化学工业出版社 精细化工出版中心
3. Daqiang Xu~* Kapa Prasad,O ljan Repic andThomas J.Biacklock, A practical synthesis of enantiopure ethyl cis-2-amino-1-cyclohexanecarboxylatevia asymmetric reductive amination methodology, Tetrahedron: Asymmetry, 8, 9, 1997: 1445～1451
4. Ilaria D,Acquarica Francesco Gasparrini et al, Application of a new chiral stationary phase containing the glycopeptide antibiotic, A-40,926 in the direct chromatographic resolution of β-amino acids。Tetrahedron.Asymmetry, 11, 2000: 2375～2385
5. Ault,A, Resolution of D,L-α phenylethylamine, Journal of Chemical Education, 42, 1965:269～272
6. Jacobus,J,and Raban,M, An NMR Determination of Optical Purity, Journal of Chemical Education, 46, 1969:351～354
7. Ferenc Fulop, Alicyclic β-amino acids:useful synthons in drag resourchIL FARMACO55, 2000: 181～183
8．国家标准总局，增塑剂酸值的测定 (一)，中华人民共和国国家标准，1982：224～225
9．合编，已二酸二乙酯，有机化合物合成手册 342
10．王伯康，已二酸的制备，综合化学实验，280
11. Ferenc Fulop.et al, Synthesis of all four enantiomers of 1-aminoindane-2-carboxylic acid,a new cispentacin benzologue, Tetrahedron.Asymmetry, 11, 2000:4179～4187
12. Stephen G.DaviesOsamu Ichltrara et al Asymmetric synthesis of (-)- (1R,2S)-Cispentacin and Related cis-and trans -2-Amino Cyelopentane -and Cyclohexane-1-carboxylic Acids,Journal of chemical society 1,1994,1411～1415
13. Peter Csomos Liisa T Kanerva Gabor Bernath Ferenc Fulop,Biocatalysis for the Preparation of Opiticall Active β-Lactam Precursors of Amino Acids,Pergamon 1789～1796
14. Liisa T Kanerva Peter Csomos et al,Approaeh to highly enantiopure β-amino acid by using lipase catalysis in organic media,Tetrahedron: Asymmetry 第 7
卷，6．1996，1705～1716
15. Naomi Shida Tadao Uyehara and Yoshinori Yamamoto,Asymmetric Cyclization via Tandem Conjugate Addition by Using Metal Amide Reagents.Importance of the Folded Orientation of Two Enoate Moieties,Journal of chemical society,57,1992,5049～5051
16. Cristina Cimarelli and Gianni Palmieri,Diastereo and Enantioselective Entry to β-Amino Esters by Hydride Reduction of Homochiral β-Enamino Esters,Tetrahedron: Asymmetry 第5第, 8, 1994, 1455～1458
17. Haase,Hans Joachim Ger often 2,055,009 (cl,c 07c)10 May 1972 Appl P 2O55 009,8,09 Nov 1970 7pp
18．俞善信，《硫酸铜的催化酯化作用》，精细石油化工，3，1995，45～47
19．合编， (十，-)-α-苯基乙胺的合成，现代有机化学实验技术导论 354～357
20．(+，-)-α-苯基乙胺的拆分，有机化学实验技术综述，357～358
21. R.GRAF, Reactions with N-Carbonylsulfamoly Chloride, Angew.Chem.Internat.Edit 第7卷，3，1968，172～182
22．邹德琴 周宁章，顺丁烯二酸二异辛酯的合成，《辽宁化工》5，1996，36～37
23．吴庆银 宋玉林 王恩波，钨锗酸催化酯化反应的研究《精细石油化工》3，1992，13～15
24．梁梦兰，己二酸双酯香精控制剂的研究，精细石油化工 4，1989，29～32
25．俞善信 唐艳春 梁哲辉，以对甲苯磺酸为催化剂合成乙酸异戊酯，精细石油化工2，1996，31～32
26．赵女琪 林进，十二水合硫酸铁铵催化合成已二酸二乙酯的研究，有机化学，第20卷3，2000，407～409
27．樊能廷，已二酸二乙酯，有机合成事典
28．北大化学系普化教研室，实验技术，普通有机化学实验
31. Abdel-MagidA.F Cohen J.H Maryanoff C. A, Curt Med Chem, 6, 1999,955
32. F GAIZER and L.GERA, Protonation and Complex Formation of the cis and trans Isomers of Alicyclic β-Amino Acids, Polyhedron 第5第, 6, 1986, 1149～1156
33. Toshimasa Yamazaki Yun-Fei Zhu etal, Probing a Molecular Model
ofTaste Utilizing Peptidomimetic Stereoisomers of 2～Aminocyclopentanecarboxylic Acid Methyl Ester, Jourany of Orgnic Chemistry, 56, 23, 1991, 6644～6655
34. Cristina Cimarelli and Gianni Palmieri, Stereoselective Reduction of Enantiopure β-Enamino Esters by Hydride: A Convenient Synthesis of Both Enantiopure β-Anamino Esters Jourany of Orgnic Chemistry 61, 1996, 5557～5563
35. Darek R Boyd etal, Terochemical and Mechanistic Aspects of the Base-catalysed Decomposition of N-ALkyloxaziridines to form NH Ketimines, Chemical Society Perkin Trans 11, 1986, 867～872
36. David M.Pond and Robert L Cargill, Alkyation of 2-Carbethoxycyclopentanone in Dimethyl Sulfoxide, 32, 1967, 4064～4065
37. Norikazu Tamura Yasuhiko Kawano etal, An efficient Synthesis of a Key Intermediate for Optically Active5,6-cis Carbapenem Antibiotics, Tetrahedron letters 第 27 卷32, 1986, 3749～3752
38. Non-haemolytic β-Amino Acid oligomers, Nature, 404, 4, 2000:565
39. Brent Llverson, Betas are brought into the fold, Nature, 385, 9, 1997:113
40. S.M Roberts, The use of enzymes for the catalysis of key reactions in the synthesis of biologically active natural products and analogues, Pure &ppl.hem, 第64卷, 12, 1992, 1933～1937
41. Susumu Kobayashi Keiji Kamiyama, Creation of novel chiral synthons with enzymes and applications to natural product synthesis, Tetrahedron letters第 25 卷, 24, 1984, 2557～2560
42. Chris evans, Whole cell catalysed kinetic resolution of 6_azabicyclo[3.2.0] hept-3-en-7-one:synthesis of (-)-cispentacin (fr109615), Chemical Society Perkin Trans 1, 1991, 2276～2277
43. J T Edward, The dielectric increments of amino acids, Journal of the Amenican Chemical Society, 6, 1974, 902～906
44. A Peter and G, Effect of temperature on retention of cyclic β-Amino Acid enantiomers on a chiral crown ether stationary phase, Journal of Chromatographic Science, 36, 1998, 311～317
45. Synthesis and structure determination of (fr109615),a new antifungal antibiotic, Journal of Antibiot, 43, 5, 1990, 513～518
46. a new antifungal antibiotic from streptomyces setonic taxonomy fermentation isolation physico-chemical properties and biological activity, Journal of Antibiot, 43, 1, 1990, 1～7
47. Cispentacin, a new antifungal antibiotic in vitro and in vivo antifungal activities, Journal ofAntibiot, 42, 12, 1989, 1752～62
48. Mkonishi ETAL, Journal of Antibiot, 42, 1989, 1749
49. T.Iwamoto, Journal of Antibiot, 43, 1, 1990
50. Kkawabata Y.Inamono, Journal of Antibiot, 43, 1990, 513
51. Ktomatsu, Journal of Antibiot, 42, 1989, 1756
52. Journal of chemical education,42 (1965),269
53. Journal of chemical education,46 (1969)351
54．周科衍 吕俊民 实验技术，有机化学实验 1984，268～269
55 P. S.PinKney 2-carbethoxycyclopentanone organic syntheses,CV2,116
56 M. P. UnanyanandS. I. Zav valov (Inst. Org. Khim. im. Zelinskogo, Moscow). Izv, Akad. Nauk SSSR, Ser. Khim. 1967 (9), 2112 (Russ)
2．立功 王东华 宋传君等编著《药物中间体合成工艺》化学工业出版社 精细化工出版中心
3. Daqiang Xu~* Kapa Prasad,O ljan Repic andThomas J.Biacklock, A practical synthesis of enantiopure ethyl cis-2-amino-1-cyclohexanecarboxylatevia asymmetric reductive amination methodology, Tetrahedron: Asymmetry, 8, 9, 1997: 1445～1451
4. Ilaria D,Acquarica Francesco Gasparrini et al, Application of a new chiral stationary phase containing the glycopeptide antibiotic, A-40,926 in the direct chromatographic resolution of β-amino acids。Tetrahedron.Asymmetry, 11, 2000: 2375～2385
5. Ault,A, Resolution of D,L-α phenylethylamine, Journal of Chemical Education, 42, 1965:269～272
6. Jacobus,J,and Raban,M, An NMR Determination of Optical Purity, Journal of Chemical Education, 46, 1969:351～354
7. Ferenc Fulop, Alicyclic β-amino acids:useful synthons in drag resourchIL FARMACO55, 2000: 181～183
8．国家标准总局，增塑剂酸值的测定 (一)，中华人民共和国国家标准，1982：224～225
9．合编，已二酸二乙酯，有机化合物合成手册 342
10．王伯康，已二酸的制备，综合化学实验，280
11. Ferenc Fulop.et al, Synthesis of all four enantiomers of 1-aminoindane-2-carboxylic acid,a new cispentacin benzologue, Tetrahedron.Asymmetry, 11, 2000:4179～4187
12. Stephen G.DaviesOsamu Ichltrara et al Asymmetric synthesis of (-)- (1R,2S)-Cispentacin and Related cis-and trans -2-Amino Cyelopentane -and Cyclohexane-1-carboxylic Acids,Journal of chemical society 1,1994,1411～1415
13. Peter Csomos Liisa T Kanerva Gabor Bernath Ferenc Fulop,Biocatalysis for the Preparation of Opiticall Active β-Lactam Precursors of Amino Acids,Pergamon 1789～1796
14. Liisa T Kanerva Peter Csomos et al,Approaeh to highly enantiopure β-amino acid by using lipase catalysis in organic media,Tetrahedron: Asymmetry 第 7
卷，6．1996，1705～1716
15. Naomi Shida Tadao Uyehara and Yoshinori Yamamoto,Asymmetric Cyclization via Tandem Conjugate Addition by Using Metal Amide Reagents.Importance of the Folded Orientation of Two Enoate Moieties,Journal of chemical society,57,1992,5049～5051
16. Cristina Cimarelli and Gianni Palmieri,Diastereo and Enantioselective Entry to β-Amino Esters by Hydride Reduction of Homochiral β-Enamino Esters,Tetrahedron: Asymmetry 第5第, 8, 1994, 1455～1458
17. Haase,Hans Joachim Ger often 2,055,009 (cl,c 07c)10 May 1972 Appl P 2O55 009,8,09 Nov 1970 7pp
18．俞善信，《硫酸铜的催化酯化作用》，精细石油化工，3，1995，45～47
19．合编， (十，-)-α-苯基乙胺的合成，现代有机化学实验技术导论 354～357
20．(+，-)-α-苯基乙胺的拆分，有机化学实验技术综述，357～358
21. R.GRAF, Reactions with N-Carbonylsulfamoly Chloride, Angew.Chem.Internat.Edit 第7卷，3，1968，172～182
22．邹德琴 周宁章，顺丁烯二酸二异辛酯的合成，《辽宁化工》5，1996，36～37
23．吴庆银 宋玉林 王恩波，钨锗酸催化酯化反应的研究《精细石油化工》3，1992，13～15
24．梁梦兰，己二酸双酯香精控制剂的研究，精细石油化工 4，1989，29～32
25．俞善信 唐艳春 梁哲辉，以对甲苯磺酸为催化剂合成乙酸异戊酯，精细石油化工2，1996，31～32
26．赵女琪 林进，十二水合硫酸铁铵催化合成已二酸二乙酯的研究，有机化学，第20卷3，2000，407～409
27．樊能廷，已二酸二乙酯，有机合成事典
28．北大化学系普化教研室，实验技术，普通有机化学实验
31. Abdel-MagidA.F Cohen J.H Maryanoff C. A, Curt Med Chem, 6, 1999,955
32. F GAIZER and L.GERA, Protonation and Complex Formation of the cis and trans Isomers of Alicyclic β-Amino Acids, Polyhedron 第5第, 6, 1986, 1149～1156
33. Toshimasa Yamazaki Yun-Fei Zhu etal, Probing a Molecular Model
ofTaste Utilizing Peptidomimetic Stereoisomers of 2～Aminocyclopentanecarboxylic Acid Methyl Ester, Jourany of Orgnic Chemistry, 56, 23, 1991, 6644～6655
34. Cristina Cimarelli and Gianni Palmieri, Stereoselective Reduction of Enantiopure β-Enamino Esters by Hydride: A Convenient Synthesis of Both Enantiopure β-Anamino Esters Jourany of Orgnic Chemistry 61, 1996, 5557～5563
35. Darek R Boyd etal, Terochemical and Mechanistic Aspects of the Base-catalysed Decomposition of N-ALkyloxaziridines to form NH Ketimines, Chemical Society Perkin Trans 11, 1986, 867～872
36. David M.Pond and Robert L Cargill, Alkyation of 2-Carbethoxycyclopentanone in Dimethyl Sulfoxide, 32, 1967, 4064～4065
37. Norikazu Tamura Yasuhiko Kawano etal, An efficient Synthesis of a Key Intermediate for Optically Active5,6-cis Carbapenem Antibiotics, Tetrahedron letters 第 27 卷32, 1986, 3749～3752
38. Non-haemolytic β-Amino Acid oligomers, Nature, 404, 4, 2000:565
39. Brent Llverson, Betas are brought into the fold, Nature, 385, 9, 1997:113
40. S.M Roberts, The use of enzymes for the catalysis of key reactions in the synthesis of biologically active natural products and analogues, Pure &ppl.hem, 第64卷, 12, 1992, 1933～1937
41. Susumu Kobayashi Keiji Kamiyama, Creation of novel chiral synthons with enzymes and applications to natural product synthesis, Tetrahedron letters第 25 卷, 24, 1984, 2557～2560
42. Chris evans, Whole cell catalysed kinetic resolution of 6_azabicyclo[3.2.0] hept-3-en-7-one:synthesis of (-)-cispentacin (fr109615), Chemical Society Perkin Trans 1, 1991, 2276～2277
43. J T Edward, The dielectric increments of amino acids, Journal of the Amenican Chemical Society, 6, 1974, 902～906
44. A Peter and G, Effect of temperature on retention of cyclic β-Amino Acid enantiomers on a chiral crown ether stationary phase, Journal of Chromatographic Science, 36, 1998, 311～317
45. Synthesis and structure determination of (fr109615),a new antifungal antibiotic, Journal of Antibiot, 43, 5, 1990, 513～518
46. a new antifungal antibiotic from streptomyces setonic taxonomy fermentation isolation physico-chemical properties and biological activity, Journal of Antibiot, 43, 1, 1990, 1～7
47. Cispentacin, a new antifungal antibiotic in vitro and in vivo antifungal activities, Journal ofAntibiot, 42, 12, 1989, 1752～62
48. Mkonishi ETAL, Journal of Antibiot, 42, 1989, 1749
49. T.Iwamoto, Journal of Antibiot, 43, 1, 1990
50. Kkawabata Y.Inamono, Journal of Antibiot, 43, 1990, 513
51. Ktomatsu, Journal of Antibiot, 42, 1989, 1756
52. Journal of chemical education,42 (1965),269
53. Journal of chemical education,46 (1969)351
54．周科衍 吕俊民 实验技术，有机化学实验 1984，268～269
55 P. S.PinKney 2-carbethoxycyclopentanone organic syntheses,CV2,116
56 M. P. UnanyanandS. I. Zav valov (Inst. Org. Khim. im. Zelinskogo, Moscow). Izv, Akad. Nauk SSSR, Ser. Khim. 1967 (9), 2112 (Russ)