Convergent solid phase peptide synthesis vi : synthesis by the fmoc procedure with a modified protocol of two protected segments, sequence 5-17 and 18-31 of the neurotoxin ii of the scorpion androctonus australis hector.

Synthesis of two protected peptides thirteen and fourteen residues long, sequence 5-17, i.e. Fmoc-Tyr(cHex)- Ile-Val-Asp(Bzl)-Asp(Bzl)-Val-Asn-Cys(Acm)-Thr(Bzl)-Tyr(cHex)- Phe-Cys(Acm)-Gly-OH, and 18-31, i.e. Fmoc-Arg (Tos)-Asn-Ala- Tyr(cHex)-Cys(Acm )-Asn-Glu(Bzl)-Glu(Bzl)-Cys(Acm)-Thr(Bzl)- Lys(Z)-Leu-Lys(Z)-Gly-OH, of the scorpion neurotoxin II from , was performed by the solid phase method. The hydroxymethylphenoxymethyl copoly(styrene - 1% -divinylbenzene) type resin was used in combination with Fmoc-amino acids for both syntheses. A general protocol minimizing side reactions has been developed for the use of the base labile Fmoc--amino protecting group. The time of reaction with piperidine (50% in N,N'-dimethylformamide) has been shortened to three times one minute and coupling was performed mainly in methylene chloride with just dicyclohexyl or diisopropyl-carbodiimide. The side chain protecting groups of the Fmoc--amino acids were of the hydrogen fluoride labile type, which permitted, after trifluoroacetic acid cleavage of the peptide to resin ester bond, obtainment of protected peptides. The crude segments, precipitated from N,N'-dime- thylacetamide with water, were highly purified by HPLC and chemically characterized for future use in convergent solid phase assembling.     

Synthesis of a putative subtype specific antigenic heptapeptide from Escherichia coli K88 ad protein fimbriae

The heptapeptide methyl ester Phe-Asn-Glu-Asn-Met-Ala-Tyr-OMe covering the amino acid sequence of the region 213-219 of Escherichia Coli K88 ad protein fimbriae is synthesized using N alpha-t-butyloxycarbonyl-protection and benzyl groups for side-chain-protection. All condensation reactions are performed in 84-97% yield by preactivation of the protected amino acids by dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt), and reaction of the resulting active ester with amine in the presence of 4-methylmorpholine (NMM). A mechanism is proposed for the nitrile formation in the side-chain of activated asparagine, and the suppression of this side-reaction is investigated. The repetitive deprotection is performed in a mixture of trifluoroacetic acid (TFA), phenol and p-cresol to give the TFA salts in virtually quantitatively yields. The final deprotection of the heptapeptide is carried out in a mixture of 25% hydrogen fluoride (HF) and dimethyl sulfide (DMS) in an overall yield of 48%. The serological and conformational properties of the synthetic peptide are under investigation.     

Solid phase synthesis and hplc purification of the protected 1-12 sequence of apamin for rapid synthesis of apamin analogues differing in the c-terminal region

Apamin is a bee neurotoxin, active in the central nervous system. It is an 18-peptide whose amino acid residues 13 and 14 play an essential role for binding to its receptor and for displaying toxicity. In order to accelerate the preparation of apamin analogues differing in the C-terminal region, a new strategy was set up involving solid phase synthesis of the 1-12 segment, which, after purification, can be solid phase coupled with different 13-18 sequences. The formula of the 12-membered protected peptide is: Boc-Cys(Acm)-Asn-Cys(Acm)-Lys(Z)-Ala-Pro-Glu(Bzl)-Thr(Bzl)-Ala-Leu- Cys(Acm)-Ala-OH. It has been assembled on the photosensitive resin, α-(4-bromomethyl-3-nitro-benzamido)benzylcopoly(styrene-1%divinyl- benzene) by conventional solid phase technique with Boc-amino acids. Boc-Leu was coupled by the method of Suzuki. Photolysis of batches of 1 gram of peptide-resin In trifluoroethanol/methylene chloride (20:80) yielded 89% of cleavage. The procedure for segment purification: organic extractions (ether, chloroform and precipitation from DMF with water), gel filtration on Sephadex LH-60, and finally semi-preparative HPLC on C₁₈ in DMF/H₂O (82:18) gave excellent results and an overall purification yield of 55%.After characterization, the purified 1-12 segment was coupled with three analogous 13-18 apamin sequences assembled on benzhydrylamine resins with yields of 77, 94, and 96%.After HF cleavage, deprotection and oxidation of the cysteines, the three peptides, apamin, p-aminophenylalanine-13- apamin, and p-aminophenylalanine-14-apamin were purified on carboxy-methylcellulose CM-52 and C₁₈ HPLC. The purified peptides (yield 14-17%), after chemical characterization, were tested for toxic activity on mice and binding on synaptic membranes. The two analogues were about 100 times less toxic to mice than apamin and about 1000 times less potent in the binding assay.     

β-(3,4-二羟基苯基)-α-羟基丙酸异丙酯/冰片酯合成研究

以3,4-二羟基苯甲醛为起始原料, 经苄基保护、Darzens环氧化、Lewis酸开环、NaBH4还原、催化加氢脱保护得到β-(3,4-二羟基苯基)-α-羟基丙酸异丙酯和β-(3,4-二羟基苯基)-α-羟基丙酸冰片酯, 所得化合物的结构通过1H NMR、13C NMR, IR, MS证实. 该方法操作简单、毒性低、产物易于纯化.     

Enzymatic Synthesis of Oligopeptide. Part I. Papain-Catalyzed Synthesis of Dipeptide,Tripeptide and Tetrapeptide

Eighteen Z-X-Y-OTNB⁺ type dipeptides, four Z-Val-Cys(Bzl)-X-OTMB tripeptides and a tetrapeptide Z-Val-Cys(Bzl)-Cys(Bzl)-Asn-OTMB have been synthesized by papain-catalyzed reaction in reasonable yield after recystallization. Z-DL-Ala-OH has been resolved through papain-catalyzed synthesis of Z-L-Ala-Leu-OTMB with an optical purity as high as 98.6%. These results show that papain is a good catalyst for oligopeptide synthesis.     

Migrastatin母核9-羟基的衍生化

为了将示踪元素引入Migrastatin母核并用于肿瘤诊断和靶向治疗,以2,6-二烯庚酸-5-(叔丁基二甲硅氧基)-6-甲氧基-2,4-二甲基-2,7-二烯酯为起始原料,经过脱TBS保护、酯化和烯烃复分解反应,成功地合成了Migrastatin母核9-甲磺酸酯,总收率15.3%,其结构经1H NMR和ESI-MS表征。     

Synthesis of Taiwan Cobra Venom Cardiotoxin II Synthesis of Protected Hexapeptide,Sequence 44-49 and Protected Tripeptide,Sequence 50-52

The protected hexapeptide (sequence 44-49) and the protected tripeptide (sequence 50-52) of Taiwan Cobra (Naja naja atra) venom cardiotoxin were synthesized by stepwise coupling and fragment coupling methods. The protected hexapeptide is Nps-Lys(Z)-Ser-Ser-Leu-VaI-Leu-OMe and the protected tripeptides are Nps-Lys(Z)-Tyr(Bzl)-Val-OMe and Boc-Lys(Z)-Tyr(Bzl)-VaI-OMe.     

Ca-mediated thiolysis of peptide–resin linkage as an option for preparing protected peptide thioesters

A mild new procedure for preparing protected peptide thioesters, based on Ca²⁺-assisted thiolysis of peptide–Kaiser oxime resin (KOR) linkage, is described. Ac-Ile-Ser(Bzl)-Asp(OcHx)-SR (Ac: acetyl; Bzl: benzyl; cHx: cyclohexyl), model peptide, was readily released from the resin by incubating the peptide–KOR at 60 °C in mixtures of DMF with n-butanethiol [R = (CH₂)₃CH₃] or ethyl 3-mercaptopropionate [R = (CH₂)₂COOCH₂CH₃] containing Ca(CH₃COO)₂. After serine and aspartic acid side-chain deprotection under acid conditions, Ac-Ile-Ser-Asp-S(CH₂)₂COOCH₂CH₃ was successfully obtained with good quality and high yield. This type of C-terminal modified peptide may act as an excellent acyl donor in peptide segment condensation by the thioester method, native chemical ligation and enzymatic methods.     

Conventional and Microwave Assisted Hydrogenolysis Using Zinc and Ammonium Formate

Abstract

The selective deprotection of several N‐Bzl amino derivatives to the corresponding amines and the removal of S‐Bzl and O‐Bzl groups from the protected amino acids with ammonium formate and commercial zinc dust are reported. Many other reducible or hydrogenolysable substituents such as halogens, methoxy, phenol, ester, acid, ethene, and Boc groups are unaffected.     

Improved synthesis of a functionalized 2,8-ethanonoradamantane derivative

An improved preparation of a functionalized 2,8-ethanonoradamantane derivative, which avoids two protection/deprotection steps while deprotection of a benzyloxymethyl protecting group takes place during an acid-catalyzed dehydration, is described. Altogether the synthesis has been reduced in five steps (from 16 to 11 steps) with an increase in the global yield from 5.8 to 7.2%.     

三肽N-o-Ns-Gly-N-Me-D-Phe-L-Pro-OMe的合成

以L-脯氨酸、D-苯丙氨酸和甘氨酸为原料,经酯化、Boc保护、N-甲基化、偶合、酯化、邻硝基苯磺酰基保护、水解、酰化、脱Boc保护、偶合等十步反应,合成了三肽N-o-Ns-Gly-N-Me-D-Phe-L-Pro-OMe,总收率为22·3%(以L-脯氨酸计)。     

Synthese eines dekapeptid-derivates mit der sequenz b 21–30 des rinderinsulins

The synthesis of the benzyltype protected bovine insulin fragment B 21–30 Boc-Glu(OBzl)-Arg(H+)-Gly-Phe-Phe-Tyr(Bzl)-Thr(Bzl)-Pro-Lys(Z)-Ala-OBzl following the route 3 + 3 + 4 is described. In addition, the solid phase technique is applied to the synthesis of the corresponding protected sequence B 24–30.     

爱滋病病毒中肽段的酶促合成

为了进一步研究酶促合成在多肽合成中的实际应用,选择合成了爱滋病病毒(人类免疫缺损病毒,HIV-I)的gp41中氨基酸序列598-609的三个肽段,该部分是HIV-I中的2个抗原决定簇部分,H-Leu-Glg-Leu-Trp-Glg-cgs-Ser-Glg-Lgs-Leu-Ile-Cgs-OH可以作为抗原来检测HIV抗体.     

First total synthesis of (±)-abyssinoflavanone V

The total synthesis of (±)-abyssinoflavanone V was first achieved through C-prenylation, selective protection of phenolic hydroxyl group, aldol condensation, cyclization and deprotection starting from cheap 4-hydroxybenzaldehyde and 2,4,6-trihydroxyacetophenone, with total yield 24%. All structures of new compounds were confirmed by IR, 1H NMR and MS.     

(±)-Abyssinone Ⅰ的全合成

以对羟基苯甲醛和2,4-二羟基苯乙酮为起始原料,经过C-异戊烯基化、选择性的保护酚羟基、羟醛缩合、催化环化、去保护基等步骤,以25%的总收率首次完成了天然产物(±)-AbyssinoneⅠ(1)的全合成。其中新化合物4,7,8和1的结构经1H NMR,IR和MS表征。     

克拉霉素的合成新方法

以醚化剂1-乙氧基环己烯和硅烷化试剂1,1,1,3,3,3-六甲基二硅氨烷为保护试剂, 采用醚化-硅烷化保护法制备了克拉霉素. 以红霉素A肟为原料计算, 经肟羟基醚化、2',4"-OH硅烷化、6-OH选择性甲基化、脱保护至克拉霉素, 四步反应总收率为49.5%.     

First total synthesis of （±）-abyssinoflavanone V

The total synthesis of （±）-abyssinoflavanone V was first achieved through C-prenylation, selective protection of phenolic hydroxyl group, aldol condensation, cyclization and deprotection starting from cheap 4-hydroxybenzaldehyde and 2,4,6- trihydroxyacetophenone, with total yield 24%. All structures of new compounds were confirmed by IR, 1^H NMR and MS.     

Facile synthesis of suvorexant,an orexin receptor antagonist,via a chiral diazepane intermediate

A facile synthesis of suvorexant,an orexin receptor antagonist,is described.The key intermediate 6 was prepared from R-3-aminobutyric acid through protection,condensation,deprotection,cyclization,and hydrogenation steps.The title product was obtained with a total yield of 31%(>99%ee) after eight linear steps using commercially available raw materials.     

1-羟基异喹啉及羟基Fasudil的合成

首先以异喹啉为原料,经氧化生成氮氧化物后与苯甲酰氯和水作用,得到1-羟基异喹啉,收率为73.3%.以Fasudil为原料,经氨基保护、氧化,在相转移催化剂的存在下,于二氯甲烷和水的两相体系中与苯甲酰氯和水作用,合成羟基Fasudil,HPLC纯度大于99%,总收率为46.8%,从而建立了一条条件温和、操作简便的羟基Fasudil的合成工艺路线.     

熊去氧胆酸的合成

通过廉价易得的猪去氧胆酸为起始原料,以Shapiro反应为关键步骤,经酯化、选择性氧化、环氧化、脱保护等一系列反应成功合成了熊去氧胆酸,总产率为25.8%。在此基础上对该法进行了改良,使用硅基保护、Rubuttom氧化和Clemmensen还原来缩短反应路线,总产率达到28.8%。产物结构经1H NMR、13C NMR和HRMS确认。通过芘荧光探针法对结构相近的胆酸盐的聚集行为进行探究,可以推测临界胶束浓度只与结构中羟基的数量有关,而与羟基的构型没有直接联系。