Taxol amino acid side chain

Synthetic applications of AD which have already appeared and which are of potential industrial interest include the synthesis of propranolol (9) [48], diltiazem (10) [49], carnitine, and 4-amino-3-hydroxybutyric acid (11) [50], azole anti-fungals (12) [51], chloramphenicol (13) [52], reticuline intermediates (14) [53], camptothecin analogs (15) [54], khellactone (16) derivatives [55], taxol C-13 side chain (17) [56], halosarin [64], dehydro- xo-brevicomin [65], and antimalar-ial active cyclopenteno-l,2,4-trioxanes [57], as summarized in Figure 4. 

Amino-Hydroxylation. A related reaction to asymmetric dihydroxylation is the asymmetric amino-hydroxylation of olefins, forming v/c-ami noalcohols. The vic-hydroxyamino group is found in many biologically important molecules, such as the (3-amino acid 3.10 (the side-chain of taxol). In the mid-1970s, Sharpless76 reported that the trihydrate of N-chloro-p-toluenesulfonamide sodium salt (chloramine-T) reacts with olefins in the presence of a catalytic amount of osmium tetroxide to produce vicinal hydroxyl p-toluenesulfonamides (Eq. 3.16). Aminohydroxylation was also promoted by palladium.77... 

Polyamino acids are easy to prepare by nucleophUe-initiated polymerisation of amino acid JV-carboxyanhydrides. Polymers such as poly-(L)-leucine act as robust catalysts for the epoxi-dation of a wide range of electron-poor alkenes, such as y-substituted a,Ji-unsaturated ketones. The optically active epoxides so formed may be transformed into heterocyclic compounds, polyhydroxylated materials and biologically active compounds such as dUtiazem and taxol side chain. 

Besides the large number of a-amino acids found in nature, )3-amino acids are gaining an ever increasing attention [100]. Amino acids are e.g. found in the side chain of the cancerostatic taxol [101] as well as the new antibiotics sperabillin and TAN 1057 A/B [102]. The simple deprotection of 2 -substituted cyclopropylacetic acid derivatives 196-R by hydrogenolysis (and hydrolysis for the methyl esters 196b,i,j,m-Me) yielded enantiomerically pure 2-(r-amino-cyclopropyl)acetic acids (Scheme 59) [10]. 

Several valued terpene alkaloids [86] from Taxaceae bear / -Phe 8 or a-hydroxy-/ -Phe (phenylisoserine) side-chains at C13 and C5. Often these aromatic //-amino acids are N-methylated, as exemplified by a-hydroxylated Wintersteirfs acid, found to be a side-chain of taxine A 42 (Scheme 1.5.7). The N-benzoylphenylisoserine ester moiety of paclitaxel (taxol) has been found to be essential for its crucial mi-crotubuli-stabilizing activity. Accordingly synthetic taxol derivatives [97] that have already reached the market (e.g. non-natural docetaxel (40, taxotere)) or are still undergoing clinical/preclinical trials, e.g. non-natural BAY 59-8862/IDN5109 41... 

Sih, CJ. (1997) Chemoenzymatic synthesis of the side chain of taxol, in Enantiosdective Synthesis of -Amino Acids (ed. E. Juaristi), Wiley-VCH Verlag GmbH, Weinheim, pp. 433-442. 

Further examples of acyclic stereocontrol in related amino acid systems make use of chiral and nonracemic oxaziridine reagents to induce high levels of stereocontrol. In 1992, Davis and coworkers synthesized the methyl ester of the Taxol C13 side chain using this method.30 Following enolization, the dianion of 44 was reacted with the Davis reagent 5 to yield the a-hydroxy (5-amino acid 45 in 49% yield. While the yield was marginal in this particular example, the 86 14 ratio of stereoisomers produced is impressive in this acyclic system. 

The C-7 hydroxyl group is in many ways the most accessible functional group on the taxane ring system, and is second in reactivity only to the C-2 hydroxyl group in the side chain. For this reason its chemistry has been studied fairly extensively, and many simple derivatives have been prepared. Thus the acetyl derivative 4.1.1.1 (140,141), benzoyl derivative 4.1.1.2 (142), glutaiyl derivative 4.1.1.3 (143), amino acid derivatives 4.1.1.4-4.1.1.6 (144), chloroacetyl derivative 4.1.1.7 (145), and a docosahexaenoic acid derivative 4.1.1.8 (146) have all been prepared and found to have comparable activity to taxol. 

Various ether derivatives of taxol have also been prepared. Simple C-7 silyl ethers have poor in vitro cytotoxicity (148 but other ether derivatives sometimes have improved activity. Thus treatment of 2 -protected taxol derivatives with chloromethyl methyl ether followed by deprotection yields the acetal derivative 4.1.1.19 (757), while treatment of baccatin III with dimethyl sulfide in the presence of benzoyl peroxide followed by coupling with side chain gives thiomethyl derivatives such as 4.1.1.20 (158). This latter compound has been selected for development by Bristol-Myers Squibb, and is currently in clinical trials (759). Other ethers such as the amino acid derivative 4.1.1.21 have also been prepared by treatment of 4.1.1.20 with chloroacetic acid, N-iodosuccinimide, and silver triflate followed by N-methylpiperazine (158). 

Recently, Ueno et al used the chiral zirconium catalyst 7.4.4 for asymmetric induction. Thus, reaction of imine 7.4.5 and silyl enol ether 7.4.6 in the presence of 10 mol% S-IAA gave the desired phenyl isoserine derivative 7.4.7 in 94% ee and 95% yield. The a-hydroxy-phenylamine which was required for the catalytic asymmetric induction was then cleaved oxidatively using CAN after being converted to an a-methoxy-phenylamine derivative. Aqueous hydrolysis of the resulting aminoester 7.4.8 yielded the amino acid quantitatively, which was benzoylated to give the taxol side chain (269). 

Although not specifically related to the taxol side chain, two other publications deserve mention. Williams and his colleagues have developed a general stereocontrolled asymmetric synthesis of a-hydroxy-/ -amino acids (558) while Verdine has published a concise stereoselective synthesis of a-hydroxy-a-methyl-/ -amino acids (559). 

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). 

In a related fashion, asymmetric amination of ( )-cinnamic acid yields L-phenylalanine using L-phenylalanine ammonia lyase [EC 4,3,1,5] at a capacity of 10,000 t/year [1274, 1601], A fascinating variant of this biotransformation consists in the use of phenylalanine aminomutase from Taxus chinensis (yew tree), which interconverts ot- to p-phenylalanine in the biochemical route leading to the side chain of taxol [1602], In contrast to the majority of the cofactor-independent C-0 and C-N lyases discussed above, its activity depends on the protein-derived internal cofactor 5-methylene-3,5-dihydroimidazol-4-one (MIO) [1603], Since the reversible a,p-isomerization proceeds via ( )-cinnamic acid as achiral intermediate, the latter can be used as substrate for the amination reaction. Most remarkably, the ratio of a- vs, 3-amino acid produced (which is 1 1 for the natural substrate, R = H) strongly depends on the type and the position of substituents on the aryl moiety While o-substituents favor the formation of a-phenylalanine derivatives, / -substituted substrates predominantly lead to p-amino analogs, A gradual switch between both pathways occurred with m-substituted compounds. With few exceptions, the stereoselectivity remained exceUent (Scheme 2,215) [1604, 1605],... 

The enantioselective synthesis of taxol side chain and (-)-epi-cytoxazone were then accomplished with this type of dual catalytic asymmetric multicomponent reaction [120]. Starting with the recrystalUzed P-amino-a-hydroxyl acid derivatives 318, a relatively concise synthesis of taxol side chain 319 was carried out in 18% overall yield with >99% ee, while (-)-epi-cytoxazone 320 was synthesized in four steps from corresponding intermediates with 32% overall yield (Scheme 2.87). 

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