Synthetic methods and compounds related thereto
Inventors
Green, Thomas K. • Dai, Zhipeng
Assignees
University of Alaska Fairbanks
Publication Number
US-9133488-B2
Publication Date
2015-09-15
Expiration Date
2033-12-30
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Abstract
Disclosed herein are synthetic methods and compounds related to the compounds that are useful as or in the production of biologically active compounds. Stereoselective and stereospecific synthetic methods are disclosed to produce compounds, such as, for example, γ,δ-unsaturated-β-hydroxyesters and aminated derivatives thereof, at high yields with desired stereochemistry. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
Core Innovation
The invention relates to synthetic methods and compounds for producing biologically active compounds, specifically providing stereoselective and stereospecific routes to obtain γ,δ-unsaturated-β-hydroxyesters and aminated derivatives in high yields with defined stereochemistry. The methods use ketoreductase enzymes to enable the selective reduction of corresponding β-ketoesters, allowing synthesis of enantiomerically pure products, which are important intermediates in the preparation of various pharmaceutical and biologically active molecules.
A central problem addressed by this invention is the low stereospecificity observed in previously established synthetic approaches, particularly those utilizing protected serine aldehydes, which led to mixtures of threo and erythro products and necessitated chiral separation. Traditional chemical methods for asymmetric preparation of β-hydroxyesters suffered from limitations such as expensive catalysts, low chemoselectivity, strict reaction conditions, and incompatibility with certain functionalities.
This invention overcomes these limitations by employing biocatalysis with isolated ketoreductases, providing high enantioselectivity, broad substrate scope, mild and environmentally friendly reaction conditions, and easy product separation. The invention further discloses methods for transforming these hydroxyesters into sphingosine analogs and related compounds through aminating, reducing, protecting, and cleaving steps, maintaining the desired stereochemistry throughout the process.
Claims Coverage
The patent includes three independent synthetic method claims, each defining inventive features for the preparation of stereoselective hydroxyesters and their derivatives using specific enzymatic and chemical steps.
Stereoselective reduction of β-ketoesters using ketoreductases
A synthetic method comprising: 1. Providing a first compound having a specified structure with defined R1A, R1B, R1C, R2, and R7 substituents. 2. Reacting the first compound in the presence of a ketoreductase selected from the group: 101, 119, 130, NADH-101, NADH-110, P1-B02, P1-B05, P1-B10, P1-B12, P1-C01, P1-H08, P2-B02, P2-C11, P2-D03, P2-D11, P2-D12, P2-G03, P3-G09, and P3-H12. 3. Forming a second compound with specified structure and defined substituents, at high enantiomeric excess.
Amination of stereoselective hydroxyester intermediates
A synthetic method comprising: - Aminating a second compound of specified structure (as in the reduction product above). - Forming a third compound having an aminated structure, where multiple R groups and amine protecting groups are explicitly defined and retained.
Complete multi-step synthesis including reduction, protection, and N—N bond cleavage
A synthetic method comprising: 1. Providing a first compound with the defined structure and substituents. 2. Reacting in the presence of a ketoreductase (130, NADH-101, P3-G09, or P3-H12) to obtain a hydroxyester. 3. Aminating the hydroxyester to a protected hydrazine (third compound). 4. Reducing the ester in said compound to an alcohol (fourth compound). 5. Protecting the alcohols to yield a fifth compound. 6. Cleaving the N—N bond in the protected compound, producing a sixth compound with defined R3, R4, R5, and R6 substituents.
The inventive features cover a comprehensive suite of steps for enantioselective enzymatic synthesis of functionalized hydroxyesters, extending through multiple chemical transformations while retaining stereochemical purity and providing flexibility in substituent scope.
Stated Advantages
The synthetic methods produce enantiomerically pure compounds with high diastereomeric and enantiomeric excess (e.g., >99% ee).
The process enables broader substrate acceptance, mild and environmentally friendly reaction conditions, as well as tolerance of organic solvents.
Conversion and purification of the synthesized compounds can be achieved economically, safely, and readily.
The biocatalytic approach provides high enantioselectivity and easy product separation.
The strategy permits preparation of either enantiomer of sphingosine derivatives and accommodates incorporation of various substituents at key positions.
Documented Applications
Serving as chiral building blocks for the synthesis of biologically active compounds, pharmaceutical products, and their intermediates, such as (−)-CP2-Disorazole C1, turnagainolides A and B, epothilone, and seimatopolide A.
Preparation of sphingosine analogs and derivatives relevant to anticancer research and other biological activity.
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