Racing against unwanted isomerization

doi:10.1126/science.abf8851

GSTDTAP > 气候变化

DOI	10.1126/science.abf8851
	Racing against unwanted isomerization
	Steven J. Malcolmson
	2021-01-22
发表期刊	Science
出版年	2021
英文摘要	Carbon-carbon double bonds are found in a diverse array of natural products as well as synthetic pharmaceuticals and agrochemicals. A common substitution pattern is for each carbon to bear one proton and one other functional group. Because the double bond lacks free rotation, the coplanar geometry creates two possible stereochemical isomers. The lower-energy trans ( E ) isomer has protons on opposite sides of the double bond, and the higher-energy cis ( Z ) isomer has the protons on the same side of the double bond. Often the Z isomer is desired, but its higher energy can hamper its chemical synthesis, and when present in a molecule, given the chance, it can (and usually will) isomerize to the lower-energy E isomer (see the figure, top). On page 380 of this issue, Jiang et al. ([ 1 ][1]) report the catalytic substitution of ( Z )-alkene–containing allylic acetates wherein the ( Z )-alkene is retained in the products. Allylic substitution is a hallmark reaction in modern organic synthesis ([ 2 ][2]–[ 4 ][3]). The transformation can be promoted by transition metal catalysts containing either early transition metals such as molybdenum or late transition metals such as palladium and iridium (see the figure, bottom). This reaction has been used to form a large variety of chemical bonds, including the carbon-carbon bonds that provide the skeletal backbone of organic molecules. Single-enantiomer catalysts (one of two possible mirror-image isomers) have been used in forming single-enantiomer products composed of stereogenic carbons (those with four different groups attached at one carbon). Much less attention has been paid to controlling the alkene stereochemistry of the products. ![Figure][4] How to catch some (Z)-alkenes Cis or (Z)-alkenes are the disfavored higher-energy isomer, but a new catalytic route can retain this isomer. GRAPHIC: JOSHUA BIRD/ SCIENCE Many allylic substitutions generate cyclic alkenes, which impart a geometric constraint for ( Z )-alkene formation. However, in acyclic systems, when stereoisomers might be formed, it is the ( E )-alkene that is typically observed. The favoring of the ( E )-alkene can be understood in terms of two key mechanistic steps: the displacement of the leaving group (ionization) by the transition metal catalyst to form a metal–π-allyl complex, and the subsequent attack of a nucleophile upon this electrophilic intermediate to furnish the product. Unlike the alkenes of the starting materials and products, the metal–π-allyl intermediate itself is not geometrically static but can exist as two stereoisomers that may readily equilibrate. Thus, the lower-energy isomer, called the syn –π-allyl, if not formed kinetically by the metal catalyst in the leaving-group ionization step, may be garnered by isomerization of the higher-energy anti –π-allyl complex. The unimolecular isomerization of the π-allyl complex might be expected to be faster on an entropic basis than its bimolecular coupling with the nucleophile. However, Jiang et al. illustrate that two related classes of single-enantiomer iridium-based catalysts belie this logic. From ( Z )-alkene–containing substrates, these researchers show that catalyst displacement of either a trifluoroacetate or acetate leaving group kinetically delivers the expected anti –π-allyl complex, but this intermediate is then trapped intermolecularly by nucleophiles faster than its isomerization to the syn –π-allyl can occur, leading to ( Z )- rather than ( E )-alkene products ([ 5 ][5]). In a series of experiments wherein both π-allyl isomers could be observed spectroscopically, they convincingly demonstrate that it is this difference in relative reaction rates in these two critical steps that is responsible for ( Z )-retention. An important factor in the observed retention of ( Z )-stereochemistry is that the nucleophiles studied undergo attack at the carbon bearing the greater number of protons within the anti –π-allyl to afford the linear product. This finding is astounding in that these iridium catalysts typically lead to nucleophilic attack at the carbon with fewer protons within the syn –π-allyl complex and deliver the branched product with an alkene that lacks stereochemistry ([ 4 ][3], [ 6 ][6]). The reason for this uncommon positional selectivity is unclear at this time ([ 7 ][7]). Two different classes of nucleophiles are shown to generate ( Z )-alkene products with accompanying high enantiomer ratios: Tryptamines and tryptophols afford tricyclic products, and α–amino acid derivatives furnish valuable α,α-disubstituted amino acids. The ( Z )-retentive allylic substitution strategy disclosed by Jiang et al. does rely on pre-installation of the higher-energy ( Z )-alkene, and so it does not constitute de novo synthesis of this functionality, as does ( Z )-selective cross-metathesis ([ 8 ][8], [ 9 ][9]). Still, unlike metal-catalyzed cross-coupling reactions, which are far less prone to alkene isomerization, the resistance toward alkene stereochemical isomerization discovered by Jiang et al. in iridium-catalyzed allylic substitution is remarkable. That two disparate classes of nucleophiles show the same ( Z )-retentive reactivity suggests the exciting possibility that this phenomenon is widely applicable. Given the overall worth of allylic substitution in chemical synthesis, this finding is perhaps just the first step toward new pathways for chemists to access highly valuable ( Z )-alkenes. 1. [↵][10]1. R. Jiang, 2. L. Ding, 3. C. Zheng, 4. S.-L. You , Science 371, 380 (2021). 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领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/312354
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Steven J. Malcolmson. Racing against unwanted isomerization[J]. Science,2021.
APA	Steven J. Malcolmson.(2021).Racing against unwanted isomerization.Science.
MLA	Steven J. Malcolmson."Racing against unwanted isomerization".Science (2021).