Improved Synthesis Of The Taxol Through Asymmetric Dihydroxylation (AD) And Asymmetric Aminohydroxylation (AA) Of Olfins

Paclitaxel (Taxol), isolated from the bark of the Pacific yew, is considered one of the most promising new drugs in cancer chemotherapy and has recently been approved for treatment of various types of cancers. Taxol has become the first-elected anti-tumor drug in clinic because of its high effect and low toxicity. However, the large-scale clinical usage of taxol has been prevented by its limited supply.At present, taxol was obtained mostly from the extraction of the stem bark of the yew trees. The yew trees grow slowly and the loss of stem bark will lead to the death of yew trees. In addition, the output of taxol is quite low due to the low content of taxol in stem bark of yew trees (about 0.01%). It means that about 10000kg tree barks would be consumed to obtain lkg paclitaxel, which will eventually destroy plant resources and natural environment in the world. Therefore, the supply of taxol through natural resources cannot satisfy with the increasingly clinical need in the long term. Nowadays, the total synthesis of taxol has been achieved, but the complicated synthetic steps, too low total yields and high costs make it impossible to produce the taxol in a large scale at the moment.A viable approach for the preparation of taxol is to utilize more accessible 10-deacetylbaccatin-â…¢ (fig. 1) as precursors via a semisynthetic route. The more readily available taxol precursor 10-deacetylbaccatin-â…¢ can be easily obtained (1g/kg) by extraction from the leaves of taxus (European yew) with a high yield and can be supplied continuously without threatening the survival of the yew species, but its anti-cancer activity is not as effective as taxol. Fortunately, 10-deacetylbaccatin-â…¢ has been converted to taxol viacoupling with the appropriately protected the (2R, 3S)-N-benzoyl-3-phenylisoserine side chain (C₁3(fig 1). Thus, the development of short and practiceal synthetic routes to the taxol C₁3 side chain, which are adaptable for Industrial-scale production, have become very important.Much effort has been made in the preparation of enantiomerically enriched (2R,3S)-N-benzoyl-3-phenylisoserine. The project reported in this paper aims at developing easily manipulated, lowly costed ways to obtain the C₁3 side chain with high yields. We accomplished synthesis of taxol C₁3 side chain on the basis of the Sharpless asymmetric dihydroxylation (AD) and aminohydroxylation (AA) of olefins. At last taxol was successfully generated by union of the two parts, deprotection and N-benzoylation.The chiral osmium catalyst is generated in situ by the chiral ligand complexing with OSO₄ in the reaction. Although AD and AA reaction can be widely applied to the synthesis of pharmaceuticals, natural products and fine chemicals, the high cost of osmium and chiral ligands has restricted its use in industry. So exploration of the recovery and reuse of the ligands for AD and AA reaction is urgent. This project aims at the development of economical, simple and highly effective recoverable and reusable free ligands for the AD and AA reaction of olefins, and has made following progress.1. Design and synthesis of one recoverable and reusable freebis-cinchona alkaloid derivativesTreatment of 1,4-difluoroanthraquinone with quinine provided (QN)₂AQN. then (QN)₂AQN was oxidezed in the presence of OSO₄ and NMO to give ligand 1(fig 1).2. Evaluation of one free bis-cinchona alkaloid derivativesLigand 1 was applied to the homogeneous AD reaction of nine olefins respectively in two system. Furthermore, ligand 1 was applied to the homogeneous AA reaction of four olefins. When the reaction was finished, the ligand was extracted with CH₂Cl₂ and precipitated upon addition of diethyl ether followed by filtration.(1) In BuOH-H₂O (1:1) system.Ligand 1 deliver excellent enantiosel ectivity (84-99 %e.e.) and good yield (80-93 %) for nine olefins.(2) In Me₂CO-H₂O (9:1) system.Ligand 1 deliver excellent enantiose letivity (83-99 % e.e.) and Good yields(81⁹5 %) for nine olefins. especially for the trans-disubstituted(93⁹9% e.e.).(3) With ethyl trans-cinnamate as substrate of the AD reaction, the recovered ligand 1 was reused in.BuOH-H₂O (1:1) system. No significant decrease in activity and enatioselectivity wasobserved within the first four recycles. Recovery rate was 92-95%.(4) With ethyl trans-cinnamate as substrate of the AD reaction, ligand1 was reused in Me₂CO-H₂O(1:1) system for nine times to show very good yields and excellent enantioselectivity with only 20% of OsO₄ addition for each recycle.(5) Ligand 1 was applied to AA reaction of four olefins respectivelyin good yields (46⁶0%) and excellent enatioselectivity (91⁹7%e.e.).(6) With ethyl trans-cinnamate as substrate of the AA reaction, the recovered ligand 1 was reused for three times. No significant decrease in activity and enatioselectivity was observed. Recovery rate was 92-93%.(7) Ligand 1 was applied to asymmetric aminohydroxylation (AA) of trans-cinnamate with N-bromobenzamide as an Oxidant /nitrogen reagent in the presence of K₂[OsO₂(OH)₄] to give highly enantioselective(99%) and yield(41%, 43%) C₁3 side chain . Although this way provide a direct route to synthesise C₁3 side chain, the high cost makes it impossible to be utilized in a large scale.(8) The C₁3 side chain also could be prepared through 3 steps from asymmetric dihydroxylation of trans-cinnamate in the yield of 52-54%, which needs less steps than Sharpless method through AD reaction does. This simple way is more economical and practical because free ligands 1 can be recorved and resued for several runs and the column chromatography is avoided in the whole procedure.3. Synthesis of taxolTaxol was successfully generated by union of the protected taxolC₁3 side chain B and protected baccatin-â…¢, deprotection and N-benzoylation.