Taxol side chain, synthesis

Sharpless asymmetric aminohydroxylation can also be used for taxol side chain synthesis. For example, using DHQ as a chiral ligand, asymmetric aminohydroxylation of methyl trau.v-cinnamatc provides compound 240 in high enantiomeric excess (Scheme 7-80).37... 

Kant J (1995) The Chemistry of the Taxol Side Chain Synthesis Modifications and Conformational Studies. In Farina V (ed) The Chemistry and Pharmacology of Taxol and its Derivatives. Elsevier Science B V, Amsterdam, p 255... 

Li G, Sharpless KB (1996) Catalytic Asymmetric Aminohydroxylation Provides a Short Taxol Side-chain Synthesis. Acta Chem Scand 50 649... 

Other examples of application of the SAD on achiral alkenes leading to natural products of small molecular weight are the synthesis of glycinol 114 and derivatives of combrestatin A-1 115 and acronycine 116 (Scheme 34.31). The reaction is also scalable on multikilogram scale as recently demonstrated for the synthesis of trrms-methyl cinnamate vicinal diol 117, which is an important intermediate for the taxol side chain synthesis (Scheme 34.31). ... 

The asymmetric epoxidation of electron-poor cinnamate ester derivatives was highlighted by Jacobsen in the synthesis of the Taxol side-chain. Asymmetric epoxidation of ethyl cinnamate provided the desired epoxide in 96% ee and in 56% yield. Epoxide ring opening with ammonia followed by saponification and protection provided the Taxol side-chain 46 (Scheme 1.4.12). 

Choudary, B.M., Chowdari, N.S., Mahdi, S., Kantam, M.L. (2003) A Trifimctional Catalyst for One-Pot Synthesis of Chiral Diols via Heck Coupling-N-Oxidation-Asymmetric Dihydroxyla-tion Application for the Synthesis of Diltiazem and Taxol Side Chain. Journal of Organic Chemistry, 6S, 1736-1746. 

Ill. Denis, J.N., Greene, A.E., Serra, A.A., Luche, M.J. (1986) An Efficient, Enantioselective Synthesis of the Taxol Side Chain. Journal of Organic Chemistry, 51, 46-50. 

Scheme 12.10 gives some examples of these oxidations. Entry 1 is one of several aryl-conjugated alkenes that were successfully epoxidized. Entry 2 is a reaction that was applied to enantioselective synthesis of the taxol side chain. Entry 3 demonstrates... 

Figure 7.15 Synthesis of the antipodes of A-benzoyl phenylisoserine Taxol side chain...

Jacobsen applied the salen-Mn(III) complex (J ,J )-121 in the synthesis of two antihypertensive agents 122 and 12386a (Scheme 4-41) and also the taxol side chain 124.8 6b... 

The structures of taxol and its polycyclic part baccatin III are shown in Figure 7-2, and the numbering of these two compounds is extensively used throughout the rest of this chapter. Because connecting the side chain to baccatin HI is just routine chemistry, we introduce only the synthesis of baccatin III and the taxol side chain. 

Several methods have been developed for the synthesis of the taxol side chain. We present here the asymmetric construction of this molecule via asymmetric epoxidation and asymmetric ring-opening reactions, asymmetric dihydroxylation and asymmetric aminohydroxylation reaction, asymmetric aldol reactions, as well as asymmetric Mannich reactions. 

Wang et al.36 have used the chiral catalyst (DHQ)2 PHAL (see Chapter 4 for the structure) for the asymmetric synthesis of the taxol side chain. Optically enriched diol was obtained at 99% ee via asymmetric dihydroxylation. Sub-... 

Commerqon et al.40 developed a method based on an Evans-type auxiliary-controlled aldol reaction. Subsequent treatment of the aldol product with base produced the standard epoxide compound for the asymmetric synthesis of the taxol side chain (Scheme 7-84). 

This chapter has introduced the asymmetric synthesis of several types of natural products erythronolide A, 6-deoxyerythronolide, rifamycin S, prostaglandins and baccatin III, the polycyclic part of taxol, as well as the taxol side chain. The... 

Keywords Polyamino acids. Optically active epoxyketones. Synthesis of dUtiazem and taxol side-chain. Asymmetric oxidation. 

A recent synthesis of the phenylisoserine side-chain of taxol is shown in Scheme 18. The enone 21 was obtained in high yield by condensation of benzal-dehyde with pinacolone. Employing the non-aqueous two-phase epoxidation protocol, epoxide 22 was obtained in 76% yield and 94% e.e. Recrystallisation of the epoxide furnished the desired enantiomer in 97 % e. e. Subsequent manipulations of the epoxy-ketone gave the taxol side-chain 23 with the required stereochemistry (Scheme 18). 

This reaction has been applied for the synthesis of the Taxol side chain from the frani-alkene (Rj = Ph, R2 = CH2OAC) (Table 8.20, entry 11, Fig. 8.9 Scheme 8.55). 

Adger, B.M., Barkley, J V. Bergeron, S., Cappi, M.W., Elowerdew, B.E., Jackson, M. R, McCague, R., Nugent, T.C. and Roberts, S.M. Improved Procedure for Julia-Colonna Asymmetric Epoxidation of a,/l-Unsaturated Ketones Total Synthesis of Diltiazem and Taxol Side-chain. J. Chem. Soc., Perkin Trans. 1 1997, 23, 3501-3507. 

Aggarwal and Vasse have applied asymmetric ylide aziridination to the synthesis of the taxol side chain 26 [75]. By using stoichiometric quantities of chiral sulfide, 26 was obtained in six steps and 16% overall yield (see Scheme 10.19, route A), while the catalytic variant allowed access to 26 in seven steps and 20% overall yield (see Scheme 10.19, route B). Both methods gave the key aziridine intermediates in excellent enantiomeric purity. Unfortunately, the benzoyl imine 25 did not work well in the catalytic reaction, and so a slightly longer synthetic route... 

The first application of the AA process was the short and efficient synthesis of the paclitaxel (Taxol) side chain 32 (Scheme 4) [58]. The hydroxysulfonamide 31 crystallized directly from the reaction mixture (69% yield, 82% ee) and was transformed to 32 in two steps. The procedure was further improved when the acetamide-AA was discovered [22]. The hydroxyactamide 33 was easily obtained in good yield (71%) and excellent ee (99% ee) and removal of the N-protecting group was nearly quantitative. A direct benzamide-AA gave 34, the isopropyl ester of 32, in a single step, though with lower yield (46%) than the acetamide-AA [24]. 

The enantioselective synthesis of 2-phenylisoserine derivatives is an attractive goal and several attempts, such as the application of acylase (36), lipase [37], and, more recently, bakers yeast reductase enzymes [38], were made to prepare the taxol side chain (see Section 15.1). No nitrile-converting enzymes have been investigated so far. The chemical instability of 2-hydroxy-3-amino-3-phenylpropionitrile (a cyanohydrin) in aqueous solution afforded the preparation of the cyclic protection products tron.s-( )-8a and ds-( )-9a (Figure 15.2). 

Synthesis of the taxol side chain involves the asymmetric aminohydroxylation reaction (Scheme 1.16). 

Besides the investigations treated so far concerning the synthesis of the taxane skeleton, some groups have also reported on the synthesis of particular building blocks. Synthesis of the taxol side chain 30 (57) has already been introduced in Section V,B. A Swedish group presented an enantiospecific synthesis of a functionalized ring A derivative 105,106). Starting from L-arabinose, 136 (Scheme 33) was made in 20 steps and could be transformed by three further steps into 137. 

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... 

Rossi, F. M., Powers, E. T., Yoon, R., Rosenberg, L., Meinwald, J. Preparation of 2,3-diamino acids stereocontrol led synthesis of an aminated analog of the taxol side chain. Tetrahedron 1996, 52, 10279-10286. 

Several other chiral boron reagents are available for asymmetric aldol reactions however, each of these compounds must be synthesized in the laboratory. In certain situations, some will give higher stereocontrol than the Ipc ligands, and hence for a given reaction their application could be pursued. Chiral reagents 53 and 54 have been used in the synthesis of bryostatin 7 [36] and the Taxol side-chain [37], respectively, while bis-sulfonamide 55 has been used in the synthesis of a C24-C35 segment of FK-506 (Scheme 9-18) [38]. 

Patel RN, Baneijee A, HoweU JM, et al. Stereoselective microbial reduction of 2-keto-3-(Al-benzoylamino)-3-pheny propionic acid ethyl ester. Synthesis of taxol side-chain synthon. Tetrahedron Asymmetry A, 2069, 1993. 

Scheme 24 Use of 132 as a chiral building block for the synthesis of (+)-goniofufurone (134) and the taxol side chain analog 135 according to Hanaoka...

A highly stereoselective hetero Diels-Alder reaction of achiral N-acylimines with chiral enolethers derived from 8-phenylmenthol has been applied to the synthesis of the taxol side chain as outlined below. 

Several other groups have reported effective dioxirane systems employing Oxone as the terminal oxidant. For example, Armstrong et al. have developed a spirocyclic iV-carbethoxy-azabicyclo[3.2.1]octanone precatalyst, which affords up to 91.5% ee in the epoxidation of stilbenes (eq 102). Shing et al. have developed an arabinose-derived ketone and employed this in the enantioselective synthesis of the Taxol side chain however, enantioselectivities for the epoxidation were only up to 68% (eq 103). Bortolini et al. have also described the epoxidation of alkenes with the stoichiometric keto bile acid-Oxone system, a range of ee values were observed over several substrate types but up to 98% was observed for the epoxidation of tran -stilbene, although the yield was only 50% (eq 104). ... 

Synthesis of Taxol and Taxol Side Chain Analogs from Baccatin III. ... 126... 

The synthesis of 1-deoxytaxol analogs was eventually achieved by a sequence starting from baccatin VI (3.5.4). Baccatin VI has most of the key structural features of baccatin III, but importantly it lacks the C-1 hydroxyl group. Selective hydrolysis of baccatin VI followed by acylation with the taxol side chain by the / -lactam method gave various 1-deoxytaxol analogs such as 3.5.5 and 3.5.6 126). Both analogs were approximately one half as active as taxol in tubulin assembly and cytotoxicity assays. 

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