总合成和结构确认的化氨酸A
Stephen Hanessian1, Juan R Del Valle, Yafeng Xue
1Department of Chemistry, Université de Montréal, C.P. 6128, Station Centre-ville, Montréal, P.Q., H3C 3J7 Canada.
Journal of the American Chemical Society
|August 10, 2006
概括
研究人员首次实现了化素A的全合成,这是一个强大的海洋天然产品. 这一突破使其结构和强大的酶抑制特性能够进一步研究.
科学领域:
- 自然产品的合成自然产品的合成
- 药用化学 医学化学
- 生物化学 生物化学
背景情况:
- 氨酸A是一种海洋海绵代谢产物,属于空气氨酸家族.
- 众所周知,它是参与血液凝固的关键人体血清蛋白酶的强有力的抑制剂.
- 在这项工作之前,精确的结构和立体化学,特别是新型氨酸残留物,尚未完全阐明.
研究的目的:
- 为了实现第一个enantio控制的A. 化的总合成.
- 确认氨酸A的结构和绝对配置,包括新的2S,3R-3-chloroleucine残留物.
- 为了评估化素A作为一种与血液静止相关的血清蛋白酶抑制剂.
主要方法:
- 为2S,3R-3-chloroleucine片段开发一个简洁,立体控制的合成.
- 执行乙醇控制的化氨酸A的总合成.
- 合成罗迪西诺辛A与血栓结合的X射线共晶学,用于结构确认.
主要成果:
- 成功实现了罗西诺辛A的对抗控制的总合成.
- X射线共晶结构证实了拟议的结构和绝对配置.
- 化素A证明对血栓素,VIIa因子和XA因子有强烈的抑制作用.
结论:
- 总合成提供了化素A的最终结构和立体化学赋值.
- 氨酸A是主要凝固蛋白酶的已知最强大的抑制剂.
- 这项工作有助于进一步研究氨酸A及其相关化合物的治疗潜力.
相关概念视频
Acid Strength and Molecular Structure
Binary Acids and Bases
In the absence of any leveling effect, the acid strength of binary compounds of hydrogen with nonmetals (A) increases as the H-A bond strength decreases down a group in the periodic table. For group 17, the order of increasing acidity is HF < HCl < HBr < HI. Likewise, for group 16, the order of increasing acid strength is H2O < H2S < H2Se < H2Te. Across a row in the periodic table, the acid strength of binary hydrogen compounds increases with increasing...
In the absence of any leveling effect, the acid strength of binary compounds of hydrogen with nonmetals (A) increases as the H-A bond strength decreases down a group in the periodic table. For group 17, the order of increasing acidity is HF < HCl < HBr < HI. Likewise, for group 16, the order of increasing acid strength is H2O < H2S < H2Se < H2Te. Across a row in the periodic table, the acid strength of binary hydrogen compounds increases with increasing...
Carboxylic Acid Derivatives: Overview
Carboxylic acid derivatives are formed by replacing the hydroxyl group of carboxylic acids with a different functional group. The most common carboxylic acid derivatives are:
Structures of Carboxylic Acid Derivatives
Structure of Carboxylic Acid Derivatives
Carboxylic acid derivatives contain an acyl group attached to a heteroatom such as chlorine, oxygen, or nitrogen. The carbonyl carbon and oxygen are both sp2-hybridized with an unhybridized p orbital.
The three sp2 orbitals of the carbonyl carbon form three σ bonds, one each with the carbonyl oxygen, the α carbon, and the heteroatom, whereas the other two sp2 orbitals of the carbonyl oxygen are occupied by the lone pairs. Further, the unhybridized p...
Carboxylic acid derivatives contain an acyl group attached to a heteroatom such as chlorine, oxygen, or nitrogen. The carbonyl carbon and oxygen are both sp2-hybridized with an unhybridized p orbital.
The three sp2 orbitals of the carbonyl carbon form three σ bonds, one each with the carbonyl oxygen, the α carbon, and the heteroatom, whereas the other two sp2 orbitals of the carbonyl oxygen are occupied by the lone pairs. Further, the unhybridized p...
Acid Halides to Amides: Aminolysis
Aminolysis is a nucleophilic acyl substitution reaction, where ammonia or amines act as nucleophiles to give the substitution product. Acid halides react with ammonia, primary amines, and secondary amines to yield primary, secondary, and tertiary amides, respectively.
In the first step of the aminolysis mechanism, the amine attacks the carbonyl carbon of the acyl chloride to form a tetrahedral intermediate. In the second step, the carbonyl group is re-formed with the elimination of a chloride...
In the first step of the aminolysis mechanism, the amine attacks the carbonyl carbon of the acyl chloride to form a tetrahedral intermediate. In the second step, the carbonyl group is re-formed with the elimination of a chloride...
Preparation of Acid Anhydrides
One of the methods for preparing symmetrical or unsymmetrical acid anhydrides involves the treatment of acid chlorides with the sodium salt of carboxylic acids. The reaction proceeds via a nucleophilic acyl substitution.
The carboxylate ion acts as a nucleophile that attacks the carbonyl carbon of the acid chloride to form a tetrahedral intermediate. Subsequently, the re-formation of the carbonyl group with the loss of the chloride ion as a leaving group leads to the formation of an acid...
The carboxylate ion acts as a nucleophile that attacks the carbonyl carbon of the acid chloride to form a tetrahedral intermediate. Subsequently, the re-formation of the carbonyl group with the loss of the chloride ion as a leaving group leads to the formation of an acid...
Structure of Amines
The hybridized nitrogen atom in amines possesses a lone pair of electrons and is bound to three substituents with a bond angle of around 108°, which is less than the tetrahedral angle of 109.5°. However, the C–N–H bond angle is slightly larger at 112°, with a carbon–nitrogen bond length of 147 pm. This carbon–nitrogen bond length of of amines is longer than the carbon–oxygen bond of alcohols (143 pm) but shorter than alkanes’ carbon–carbon bond (154 pm). These aspects are illustrated in Figure...


