N-Benzoyl-3-phenylisoserine

An introduction to Taxol (Bristol-Myers Squibb) is presented in Exhibit 3.4. The active pharmaceutical ingredient (API) is paditaxel. The chemical name is 5j8,20-epoxy-l,2a,4,7)3,10i3,13a-hexahydroxytax-ll-en-9-one 4,10-diacetate 2-benzoate 13 ester with 2R, 3S)-N-benzoyl-3-phenylisoserine. 

It was originally suggested by Swindell that acylation of baccatin III with protected N-benzoyl-3-phenylisoserine proceeds through an oxazinone intermediate (286). He then developed a synthesis of the side chain methyl ester by hydrolysis of a protected oxazinone intermediate 7.6.3, which was itself prepared in 70% yield by a Diels-Alder type reaction between the imine 7.6.1 and the chiral ketene acetal 7.6.2. Hydrolysis of 7.6.3 and removal of protecting groups gave the side chain methyl ester in 93% yield (287). 

Nandanan E, Phukan P, Sudalai A (1999) Regio and Stereoselective Opening of Chiral Cyclic Sulfates with MgBr2-Et20 a Practical Strategy for the Synthesis of (—)-N-Benzoyl-3-phenylisoserine Ethyl Ester (Taxol Side Chain). Indian J Chem Sect B Org Chem Incl Med Chem 38B 283... 

Mukai C, Kim I, Hanaoka M (1992) An Optically Active Chromium(0)-Complexed Benzaldehyde in Organic Synthesis a Highly Stereocontrolled Asymmetric Synthesis of (2R,3S)-(—)-N-Benzoyl-3-phenylisoserine Methyl Ester, the Taxol C-13 Side Chain analogue. Tetrahedron Asymmetry 3 1007... 

Some approaches for the semisynthesis of taxol are based on relatively economically priced 10-deacetylbaccatin III, obtained from leaves of the European yew Taxus baccata. The leaves are able to regenerate by growing again, whereas removal of the bark of the Pacific yew Taxus brevijblia, which contains taxol, kills the tree. The semisyntheses of Denis and Greene from 1988 [190] and 1994 [191] are discussed here. 10-Deacetylbaccatin III 257 is first protected at the 7-position with a triethyl-silyl residue and acetylated at the 10-position with acetyl chloride. The resulting 7-TES-baccatin III 258 is coupled with O-protected N-benzoyl-3-phenylisoserine using a sixfold excess of dipyridyl carbonate (DPC) to afford 2 -0-ethoxyethyl-7-TES-taxol 259, which is deprotected with 0.5% hydrochloric acid to afford taxol 241 [190]. 

Paditaxel, a complex terpene molecule with antimitotic activity (commercialized as Taxol ), is used for various cancer treatments, including ovarian and breast cancer treatments. The isolation of this naturally occurring compound requires the harvesting of a large amount of trees and involves difficult purification. A semisynthetic route has been developed based on the coupling of baccatin III (a diterpenoid that can be isolated from yew leaves) with the chiral side-chain (2R,3S)-N-benzoyl-3-phenylisoserine ethyl ester. The latter could be obtained from the diastereoselective microbial reduction of racemic 2-keto-3-(N-benzoylamino)-3-phenylpropionic acid ethyl ester using whole cells of Hansemda sp. (Figure 13.12). Despite concomitant production of the undesired anti diastereomers (2R,3R)-N-benzoyl-3-phenylisoser-ine ethyl ester and (2S,3S)-N-benzoyl-3-phenylisoserine ethyl ester (up to 20%) due to nonperfect selectivity, the C-13 side-chain synthon required for paclitaxel... 

Figure ll.lOf shows the synthesis of chiral C-13 paclitaxel side chain, key precursor for the paclitaxel S5mthetic process by a preparative-scale reduction of aminoketoester by Hansenula fabianii SC 13894 2R,3S)- N-benzoyl-3-phenylisoserine ethyl ester was obtained in 88% yield with 95% ee [63]. 

Several p-amino acids occur naturally as free metabolites in metabolic pathways or as key intermediates in biosynthetic products. p-Alanine is the simplest p-amino acid that appears in pantothenic acid, a precursor of the coenzyme A. Further examples are (2R,3S)-N-benzoyl-3-phenylisoserine derived from (R)-p-phenylalanine, a compound in the antitumor agent paclitaxel from Taxus brevifolia [89], or as building blocks for p-lactam antibiotics [90] and in jasplakinolide, an antifungal compound [91] (Scheme 29.12). 

Wroblewski AE, Piotrowska DG (1998) Phosphonate Analogs of iV-benzoyl- and N-Boc-3-phenylisoserine, the Taxol C-13 Side Chain. Tetrahedron 54 8123 Wroblewski AE, Piotrowska DG (1999) Enantiomeric Phosphonate Analogs of the Paclitaxel C-13 Side Chain. Tetrahedron Asymmetry 10 2037... 

Gou, D.M., Liu, Y.C., Chen, C.S. (1993) A Practical Chemoenzymatic Synthesis ofthe Taxol C-13 Side Chain N-Benzoyl-(2R,3S)-3-phenylisoserine. Journal of Organic Chemistry, 58, 1287-1289. 

Esterification.1 This reagent in combination with a catalytic amount of 4-dimethylaminopyridine (DMAP) is very effective for esterification of carboxylic acids with alcohols or thiols at room temperatures. However, reaction of aromatic and hindered acids requires several days at room temperature. French chemists report that only this method is useful for esterification of the protected baccatin III derivative (2) with (2R,3S)-N-benzoyl-0-(l-ethoxyethyl)-3-phenylisoserine (3) to provide the protected taxol derivative (4). A reaction conducted at 73° for 100 hours with 6 equiv. of 1 and 2 equiv. of DMAP produced 4 in 80% yield. Natural taxol, a cancer chemotherapeutic agent, is obtained by removal of the protective groups at C2 and C7 of 4. 

Taxol is a natural product isolated in very low yield from Taxus brevifolia and is used in the treatment of cancer (110). The extreme chemical complexity of Taxol makes production by total synthesis uneconomical. However, a semisynthetic approach using the naturally derived 10-deacetylbaccatin III (66) condensation with iST-benzoyl-(2J2, 3S)-3-phe-nylisoserine (67) does provide an alternative and economic approach (111). N-benzoyl-(2J2, 3S)-3-phenylisoserine (67) is also commonly known as the Taxol side-chain and has been prepared in optically active form using chiral auxiliaries or resolving agents (112). It has been shown that the Taxol side-chain is a conglomerate and can therefore be cheaply and... 

Georg GI, Cheruvalath ZS, Velde DV, Ye Q-M, Mitscher LA, Himes RH, Mejillano MR (1993) Semisynthesis and Biological Evaluation of Brevifoliol 13-[N-Benzoyl-(2 R,3 S)-3 -phenylisoserinate]. Bioorg Med Chem 3 1349... 

The stereoselective synthesis of a-hydroxyl-p-amino acids such as N-benzoyl-(2i ,35)-(-)-3-phenylisoserine, the C13 side-chain (57) of taxol, has been described by Davis [39]. The pivotal step in the synthetic procedure involves addition of an ester enolate to the chiral N-alkylidene sulfinamide (55) (Scheme 4.29). 

Ojima I, Habus I, Zhao M (1991) Efficient and practical asymmetric synthesis of the taxol C-13 side chain, N-benzoyl-(2R, 3S)-3-phenylisoserine, and its analogues via... 

Taxol, the drug of choice for treating certain types of ovarian and breast cancers, contains an N-benzoyl (2R,35)-phenylisoserine unit as the side chain. A precursor of the ethyl ester of this unit (2R,35)-135 is ethyl (25,3R)-2-chloro-3-hydroxy-3-phenylpropanoate 134 (Scheme 57.40), which has been prepared with very high yield (91 %) by means of the DYRKR of rac-133 mediated by the reductase YDL124w (a Saccharomyces cerevisiae reductase). " The facile enolization of the substrate under the reaction conditions (30°C, pH constant of 5.6) in addition... 

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