Taxol, intermediate

Intermolecular cycloaddition of n-butyl-2-pyridone and 4-methoxy-2-pyridone gives 17 in 51% yield (Figure 1)P This has provided a platform to explore the reactivity of the photoproducts. A combination of the n-butyl substituent and an absence of symmetry results in good solubility properties for 17 compared with many simple pyridone photodimers. Some initial transformations of 17 are shown in Figure 31. In all cases the yields exceed 70% and in most cases are nearly quantitative. The simplest reaction is hydrogenation. The close analogy of 17 to the core of taxol intermediate 53 (Figures 18... 

The biosynthetic pathway to taxol is considered to involve 19 steps from primary plant metabolism, and only a small number of the 400 taxoid metabolites are relevant taxol intermediates [239]. Many others represent the consequences of promiscuous oxygenase and AT activities. Thus, any approach aimed at increasing the production yields of taxol and its immediate precursors must take into account these numerous and apparently diversionary taxoid biosynthetic side routes leading to the production of taxoids different from taxol. 

Nicolaou, K.C., Liu, J.J., Yang, Z. et al. (1995) Total Synthesis of Taxol. 2. Construction of A and C Ring Intermediates and Initial Attempts to Construct the ABC Ring System. Journal of the American Chemical Society, 117, 634-644. 

The first synthesis of Taxol was completed by Robert Holton and co-workers and is outlined in Scheme 13.53. One of the key steps occurs early in the synthesis in sequence A and effects fragmentation of 4 to 5. The intermediate epoxide 4 was prepared from a sesquiterpene alcohol called patchino. 35 The epoxide was then converted to 5 by a BF3-mediated rearrangement. 

Another epoxidation, followed by fragmentation gave the bicyclic intermediate that contains the eight-membered ring and bridgehead double bond properly positioned for conversion to Taxol (Steps B-2 and B-3). 

Huang, Q., Roessner, C.A., Croteau, R. and Scott, A.I. (2001) Engineering Escherichia coli for the synthesis of taxadiene, a key intermediate in the biosynthesis of Taxol. Bioorganic Medicinal Chemistry, 9, 2237-2242. 

By using an elegant 13C-labeling study that involved incubation of Phoma sp. with 1-13C and 1,2-13C acetate, Oikawa et al. [9], were able to isolate the proposed biosynthetic intermediate phomactatriene (or Sch 49026), with 13C incorporation from singly labeled acetate units as indicated by in Fig. 8.3. Phomactatriene is strikingly reminiscent of taxadiene, a biosynthetic intermediate for Taxol . The net biosynthesis for both involves geranylgeranyl diphosphate (GGDP) cyclization [9]. It is noteworthy that prior to isolation of phomactins, the only known related structure is cleomeolide, a diterpene from the herb Cleome viscosa [10] that remarkably resembles phomactin H. 

As this synthesis started from an achiral starting material, compound 199 must be resolved to secure enantiomerically pure intermediates for the synthesis of taxol. Treatment of (+ )-diol 199 with excess ( lA)-( )-camphanic chloride in methylene chloride in the presence of Et3N forms two diastereomeric monoesters for chromatographic separation. Enantiomerically pure diol 199 can be regenerated from the ester in 90% yield with a specific rotation of +187 (c = 0.5, CHC13). 

B) Synthesis of C ring Scheme 13.6.3 shows the synthesis of aldehyde 19, which contains the required C ring of taxol, from the previously reported intermediate 14. ... 

Scheme 13.6.8 shows how compound 38. which has the basic bicyclo[5.3.1]undecane ring system of taxol, can be prepared by this procedure from a taxusin intermediate readily available from camphor in either enantiomeric form [15b]. Compare the structure of 40 with a-patchoulene 5, in Scheme 1.1 (pag. 10). 

The Nntrasweet Corp. are now selhng L-phenylalanine, rather than just using it in-honse. They quote its potential as a chiral intermediate for the production of reimin inhibitors, HIV protease inhibitors, taxol and other pharmaceuticals. 

Chiral epoxyoxazolidines (39) undergo regio selective ling opening by sodium azide to products (40).35 Further appropriate manipulations of functional groups lead to chiral /1-ammo alcohols, which are intermediates for the enantioselective synthesis of bioactive products related to taxol. 

In this chapter, we describe an account of our research on the chemistry and biology of paclitaxel and taxoid anticancer agents (taxoid = taxol-like compound). The topics covered in this chapter include (i) the development of a practical and efficient method for the semisynthesis of paclitaxel and docetaxel using chiral 3-hydroxy-P-lactams as synthetic intermediates, (ii) structure-activity relationship (SAR) studies of various taxoids that led to the discovery of the extremely potent second-generation taxoids, and (iii) biological and conformational studies with the use of fluorine-containing taxoids as probes. ... 

With an increasing number of novel lead candidates that enter into preclinical development, considerable resources are needed to identify impurities. LC/MS-based approaches provide integrated sample cleanup and structure analysis procedures for the rapid analysis of impurities. This advantage was demonstrated during the preclinical development of TAXOL . LC/MS played an important role for the identification of impurities contained in extracts and process intermediates from Taxus brevifolia and T. baccata biomass. Because drugs derived from natural sources often have a very diverse set of structural analogs, it is important to determine which... 

To better appreciate the standard by which inequitable conduct is measured, let s review an actual recent court opinion, Bristol-Myers Squibb Company v. Rhone-Poulenc Rorer, Inc.,1% where this issue was heard. This case serves to explain how materiality and intent are inextricably related. Perhaps less abstractly, it will also show why it is important for the scientists to pay close attention to what they publish as well as to documents that they are asked to review.79 This decision arose from an appeal from theU.S. District Court for the Southern District of New York (D-SDNY), which held the Rhone-Poulenc Rorer (RPR) patent relating to methods of preparing Taxol (hereinafter referred to by its generic name paclitaxel) as well as claiming key intermediates in the paclitaxel synthesis to be unenforceable due to inequitable conduct. A brief review of the facts of the case is presented next. 

---