Biocatalytic synthesis of nostoc anticancer agents
A compound and epoxide technology, applied in the fields of drug combination, organic chemistry, anti-tumor drugs, etc., can solve the problems of leading compound synthesis hindering exploration and other problems
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Embodiment 1
[0108] Materials and Methods
[0109] Chemical reagents and solvents were purchased from EMD Millipore, Sigma-Aldrich, Oakwood, Combi blocks, Chem impex and Thermo-Fisher Scientific unless otherwise stated. Kanamycin sulfate and isopropyl-beta-D-thiogalactoside (IPTG) were obtained from Gold Biotechnology. Lysozyme was purchased from RPI. Imidazole was purchased from AK Scientific. Amicon Ultra centrifugal filters for protein concentration were purchased from GE Healthcare.
[0110] Deionized water was obtained from a Milli-Q system (EMDMilipore) using a Q-Gard 2 / Quantum Ex Ultrapure organex column. Media components for E. coli growth were purchased from EMD Milipore, Sigma-Aldrich and Thermo-Fisher Scientific. Glycerol was purchased from BDH via VWR. LB broth and LB agar (Miller) were purchased from EMD Millipore in pre-granulated form. TB broth was prepared from separately purchased components and consisted of 4% v / v glycerol. Autoclave or sterile filter media and sol...
Embodiment 2
[0116] chemical synthesis
[0117] 1. Unit A synthesis
[0118] like image 3 As shown in B, compound 2 was synthesized in two steps from commercially available S1. All spectra are consistent with previous literature reports. 1,2
[0119] (R)-4-benzyl-3-((2R,3S)-3-hydroxy-5-((4-methoxybenzyl)oxy)-2vinylvaleryl)oxa oxazolidin-2-one (S3).
[0120] To a three-necked flask with an internal temperature probe was added 1 (7.502 g, 30.58 mmol, 1 equiv) in CH 2 Cl 2 (305 mL, 0.1 M) and cooled to -78 °C. This was treated with dibutylboron triflate (1 M in DCM, 33.64 mL, 33.64 mmol, 1.1 equiv) and Et 3 Treat with N (6.02 mL, 42.8 mmol, 1.4 equiv). After 1 hour at -78°C, the reaction was warmed to 0°C and stirred for 30 minutes. The solution was re-cooled to -78 °C and treated with aldehyde 2 (8.31 g, 42.81 mmol, 1.4 equiv) in CH 2 Cl 2 The solution in (25 mL) was worked up and stirred for 1 hour, warming to 0°C. After 1 hour at 0°C, sodium phosphate buffer (pH 7, 500 m...
Embodiment 3
[0252] Synthesis of Ring-Opening Candida Chain-Extension Intermediates.
[0253]To test the substrate scope of CrpTE and to generate novel candida macrolides, a scalable synthesis of NAc-activated ring-opening chain extension intermediates was developed, which is suitable for late diversification of unit A aryl groups. The analogs were synthesized convergently using two key intermediates including the unit AB and the unit CD-NAc. Unit AB was generated using chiral-assisted chemistry as well as the previously reported Suzuki coupling strategy. 38 Finally, Horner-Wadsworth-Emmons olefination (HWE) is used to form the key connection between units A and B. The unit CD with the NAc recognition element is generated by peptide coupling of commercially tractable amino acid derivatives.
[0254] For this, unit A ( image 3 ), which gave excellent yields and high dr (>20:1) to afford the desired (2R,3S) adduct. Subsequent silation with TBS triflate yields 3, and reductive cleavage o...
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