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http://www.zzone.cn 中国.中学政治教学网崇尚互联共享
Scheme 6
Koseki et al utilized D-ribose derivative, which was turned into the Grignard adducts. The two-step oxidation afforded the lactone. Hydrogenation followed by the DCC coupled addition afforded the amide. The diol reacted with sodium azide and reducted to Bestatin. The process features the region-selective N3- nucleophile substitution with the 2-fluoropyridinium salt as the activating regent. The total yield from D-ribose is only 4%. Koseki,K, Ebata, T, Matsushita, H Biosci, Biotech, Biochem 1996 60(3) 534.
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
Kinds of chiral synthons used to synthesize Bestatin
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
routes
For the synthesis of Bestatin, the most popular avenue has been the utilization of optically pure starting materials like amino acids and sugars. Typically, these homochiral synthons undergo non-epimerizable reactions to form a mixture of diastereomers that can be separated by standard methods (flash chromatograph y,recrystallization, etc.) to yield an optically pure product.
also contains in other bioactive compounds.
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
Many methods have been developed to afford the desired stereochemistry chiral starting materials like amino acids and sugars Routes and strategies to Bestatin
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
The challenging element of this synthesis is the isolation of optically pure 3-amino-2hydroxy-4-phenylbutanoic
acid (AHPBA/AHPA), which
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
Scheme 3 Ohno et al used D-phenylalanine ethyl ester to make chiral allylamine by reduction and Witting reaction. The protected amine reacted with iodine affording the trans-iodocarbamates (trans: cis=6.7:1).The iodide was converted to alcohol and was oxidized, and the ring was opened and reacted with L-Leu-OBz to afford the Bestatin after the final hydrogenation. The total yield of this routine is 14% from the D-phenylalanine ethyl ester and the key step is the formation of trans-iodocarbamate.
Koboyashi, S; Isobe, T; Ohno, M; Tetrahedron Lett., 1984, 22(44), 5079.
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
Scheme 4 Jefford et al reported that L-aspartic acid underwent tosylation, anhydride formation, and reduction. The lactone underwent hydroxylation, iodoesterification, alkylation and a two-step deprotection giving (2S, 3R)-AHPA with an overall yield of 27% from L-aspartic acid. The key steps are the highly diastereoselective α-hydroxylation of the lactone. The high diastereoselectivity was due to the bulkiness of the amino substituent.
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
(Scheme 1)
Umezawa et al. was the first to synthesize Bestatin by using Cbz-protected D-phenylalanine, which was coupled with pyrazole, then reacted with lithium aluminum hydride. The bisulfite adduct was turned into cyanohydrin. After the acidic hydrolysis, the diastereomeric acid mixture was separated by chromatography to afford (2S, 3R)-AHPA (2). This was reprotected and then coupled to benzyloxycarbonyl protected L-leucine and the final hydrogenation afforded Bestatin (1). The total yield of 1 is less than 10%, and the most difficult steps are the resolution and the condensation. Suda, H; Takita, T; Aoyagi, T; Umezawa, H; J. antibiot., 1976, 29(1),102.
untilization of chiral auxiliary groups
asymmetric catalysis using catalysts
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
Kinds of chiral synthons used to synthesize Bestatin
C W. Jefford, J McNulty. et al. Helvetica Chimica Acta 1996, 79(4), 1203-1216.
http://www.zzone.cn 中国.中学政治教学网崇尚互联共享
Scheme 5
The Seki group also utilized the L-aspartic acid, which was converted into the oxazolidinone, then reacted with BnBr. After the hydrogenation, the Mitsunobu reaction was introduced to realize the inversion. The reduction gave the protected-2 and Bestatin was obtained through the general method. The overall yield from Laspartic acid is 5.4% with 13 steps, and besides the Mitsunobu inversion, other procedures are simple and the starting material is inexpensive. Seki, M, Nakao,K. Biosci. Biotech.Biochem. 1999,63(7),1304.
The overview of the synthesises of Bestatin and AHPAs
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
contwenku.baidu.comnts
1
Bestatin: Three Decades of Synthetic Strategies written by Feske
2
the synthesis of AHPAs with other configurations
introduction
routes
summary
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
introduction Bestatin (ubenimex) was extracted from Streptomyces olivoreticuli in 1975 is a dipeptide that can treat a variety of diseases. Much attention has been paid to its total synthesis.
http://www.zzone.cn 中国.中学政治教学网崇尚互联共享
scheme 2
The Park group also utilized a D-phenylalanine derivative beginning with an alkyne Grignard reaction, resulting in predominately syn-product (syn:anti=9.5:1).The alkyne was oxidized. The acid underwent a DCC coupling to produce protected-Bestatin. The CH-π interaction and chelation control in aromatic aminoaldehydes are utilized to effect a highly diastereoselective addition to afford optically active syn-aminoalcohols. The overall yield is 65% from the αaminoaldehyde. Lee, B. W; Lee, J. H; Jang, K. C et al. Tetrahedron lett., 2003, 44, 5905.
Scheme 6
Koseki et al utilized D-ribose derivative, which was turned into the Grignard adducts. The two-step oxidation afforded the lactone. Hydrogenation followed by the DCC coupled addition afforded the amide. The diol reacted with sodium azide and reducted to Bestatin. The process features the region-selective N3- nucleophile substitution with the 2-fluoropyridinium salt as the activating regent. The total yield from D-ribose is only 4%. Koseki,K, Ebata, T, Matsushita, H Biosci, Biotech, Biochem 1996 60(3) 534.
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
Kinds of chiral synthons used to synthesize Bestatin
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
routes
For the synthesis of Bestatin, the most popular avenue has been the utilization of optically pure starting materials like amino acids and sugars. Typically, these homochiral synthons undergo non-epimerizable reactions to form a mixture of diastereomers that can be separated by standard methods (flash chromatograph y,recrystallization, etc.) to yield an optically pure product.
also contains in other bioactive compounds.
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
Many methods have been developed to afford the desired stereochemistry chiral starting materials like amino acids and sugars Routes and strategies to Bestatin
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
The challenging element of this synthesis is the isolation of optically pure 3-amino-2hydroxy-4-phenylbutanoic
acid (AHPBA/AHPA), which
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
Scheme 3 Ohno et al used D-phenylalanine ethyl ester to make chiral allylamine by reduction and Witting reaction. The protected amine reacted with iodine affording the trans-iodocarbamates (trans: cis=6.7:1).The iodide was converted to alcohol and was oxidized, and the ring was opened and reacted with L-Leu-OBz to afford the Bestatin after the final hydrogenation. The total yield of this routine is 14% from the D-phenylalanine ethyl ester and the key step is the formation of trans-iodocarbamate.
Koboyashi, S; Isobe, T; Ohno, M; Tetrahedron Lett., 1984, 22(44), 5079.
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
Scheme 4 Jefford et al reported that L-aspartic acid underwent tosylation, anhydride formation, and reduction. The lactone underwent hydroxylation, iodoesterification, alkylation and a two-step deprotection giving (2S, 3R)-AHPA with an overall yield of 27% from L-aspartic acid. The key steps are the highly diastereoselective α-hydroxylation of the lactone. The high diastereoselectivity was due to the bulkiness of the amino substituent.
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
(Scheme 1)
Umezawa et al. was the first to synthesize Bestatin by using Cbz-protected D-phenylalanine, which was coupled with pyrazole, then reacted with lithium aluminum hydride. The bisulfite adduct was turned into cyanohydrin. After the acidic hydrolysis, the diastereomeric acid mixture was separated by chromatography to afford (2S, 3R)-AHPA (2). This was reprotected and then coupled to benzyloxycarbonyl protected L-leucine and the final hydrogenation afforded Bestatin (1). The total yield of 1 is less than 10%, and the most difficult steps are the resolution and the condensation. Suda, H; Takita, T; Aoyagi, T; Umezawa, H; J. antibiot., 1976, 29(1),102.
untilization of chiral auxiliary groups
asymmetric catalysis using catalysts
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
Kinds of chiral synthons used to synthesize Bestatin
C W. Jefford, J McNulty. et al. Helvetica Chimica Acta 1996, 79(4), 1203-1216.
http://www.zzone.cn 中国.中学政治教学网崇尚互联共享
Scheme 5
The Seki group also utilized the L-aspartic acid, which was converted into the oxazolidinone, then reacted with BnBr. After the hydrogenation, the Mitsunobu reaction was introduced to realize the inversion. The reduction gave the protected-2 and Bestatin was obtained through the general method. The overall yield from Laspartic acid is 5.4% with 13 steps, and besides the Mitsunobu inversion, other procedures are simple and the starting material is inexpensive. Seki, M, Nakao,K. Biosci. Biotech.Biochem. 1999,63(7),1304.
The overview of the synthesises of Bestatin and AHPAs
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
contwenku.baidu.comnts
1
Bestatin: Three Decades of Synthetic Strategies written by Feske
2
the synthesis of AHPAs with other configurations
introduction
routes
summary
http://www.zzone.cn
中国.中学政治教学网崇尚互联共享
introduction Bestatin (ubenimex) was extracted from Streptomyces olivoreticuli in 1975 is a dipeptide that can treat a variety of diseases. Much attention has been paid to its total synthesis.
http://www.zzone.cn 中国.中学政治教学网崇尚互联共享
scheme 2
The Park group also utilized a D-phenylalanine derivative beginning with an alkyne Grignard reaction, resulting in predominately syn-product (syn:anti=9.5:1).The alkyne was oxidized. The acid underwent a DCC coupling to produce protected-Bestatin. The CH-π interaction and chelation control in aromatic aminoaldehydes are utilized to effect a highly diastereoselective addition to afford optically active syn-aminoalcohols. The overall yield is 65% from the αaminoaldehyde. Lee, B. W; Lee, J. H; Jang, K. C et al. Tetrahedron lett., 2003, 44, 5905.