Semisynthetic approaches

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]. 

2-Trichloroethyl chloroformate (Troc-Cl) has been used for the 0-protection of the C-7, C-10, and C-19 positions of lO-deacetyl-19-hydroxybaccatin III 262, a novel baccatin derivative which is reacted with the N-Boc-3-phenylisoserine 264 in the presence of DCC/DMAP to form, after further steps, the novel 19-hydroxy-docetaxel 265 [192], The analogue 265 exhibits a high level of in vitro cytotoxicity 

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Levodopa Levodopa, (-)-3-(3,4-dihydroxyphenyl)-L-alanine (10.1.1), is a levorotatory isomer of dioxyphenylalanine used as a precursor of dopamine. There are a few ways of obtaining levodopa using a semisynthetic approach, which consists of the microbiological hydroxylation of L-tyrosine (10.1.1) [1,2], as well as implementing a purely synthetic approach. 

Semisynthetic approaches can also be used to place unnatural amino acids into biologically synthesized proteins through the use of suppressor transfer RNAs (Chapter 29).306... 

After the first successful attempts in 1928 to identify the active biochemicals found in antibacterial molds, followed the rediscovery of penicillin by Fleming, identification of its chemical structure by Hodgkin, and subsequent synthesis by Chain, Heatley, and Florey, which led to the commercial production of penicillin in the mid 1940s [1], Since then, other families of (3-lactam antibiotics have been developed [2, 3], and their massive use worldwide continues to be a forefront line of action against infectious pathogens [4-6]. In recent years, (3-lactams have found other biomedical applications, such as inhibitors of serine protease ([7, 8] for a review, see [9]) and inhibitors of acyl-CoA cholesterol acyltransferasa (ACAT) [10]. Encouraged by their bioactivity, the synthesis and chemistry of (3-lactam antibiotics have been the focus of active research, and chemical modification of some basic structures available from biosynthesis (semisynthetic approaches) as well as the discovery of fully chemical routes to de novo synthesis of (3-lactam... 

To optimize the photoswitchable bioelectrocatalytic features of the protein, site-specific functionalization or mutation of the active site microenvironment is essential. This was accomplished by a semisynthetic approach involving the reconstitution of the flavoenzyme-glucose oxidase with a semisynthetic photoisomerizable FAD cofactor (Scheme 9).1511 The photoisomerizable nitrospiropyran carboxylic acid (24) was covalently coupled to N6-(2-aminoethyl)-FAD (25), to yield the synthetic photoisomerizable nitrospiropyran-FAD cofactor 26a (Scheme 9(A)). The native FAD cofactor was removed from glucose oxidase, and the synthetic photoisomeriz-able-FAD cofactor 26a was reconstituted into the apo-glucose oxidase (apo-GOx), to yield the photoisomerizable enzyme 27a (Scheme 9(B)). This reconstituted protein... 

A number of kainoids have been isolated from the poisonous Japanese mushroom, Clitocybe acromelalga. Acromelic acid A 5 and acromelic acid B 6 were isolated from this source by Shirahama and co-workers6 in 1983, their structures being confirmed from total syntheses by Takano et al.7,8 and semisynthetic approaches by Shirahama.9-11 More recently, an additional three acromelates have been isolated acromelic acids C... 

Because of the complexity of the molecular architecture of glycopeptides, total synthesis as a tool for SAR studies is devoid of applicability. Better chances offer semisynthetic approaches, albeit a relatively limited number of modifications can be introduced. An attempt to subdivide these modifications is the alteration or modification of amino acid residues, or alternatively the attachment of molecules to the C- terminus, the V-terminus, or variations at the carbohydrate moieties (Scheme 2-9). The latter modifications mostly comprise deglycosylation reactions and alterations of... 

Modification ofAA4 and AA5 The phenolic group of " Hpg serves as the carbohydrate attachment site, and in semisynthetic approaches, this group has been deriva-tized by protecting groups. Besides these modifications, other glycopeptide derivatives do not exist. This is similarly the case for Hpg, where some naturally occuring derivatives are known, which are chlorinated in the o-position of the... 

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... 

These semisynthetic approaches also provide access to analogs with potential advantages over paclitaxel itself Structure-activity studies have shown that, although the oxetane ring appears to be essential for activity, wide variation in the nature and stereochemistry of... 

Access to analogues with varied side-chains at the 7-position initially posed a problem. Unlike penicillins, it proved impossible to obtain cephalosporin analogues by fermentation. Similarly, it was not possible to obtain the 7-ACA (7-aminocephalosporinic acid) skeleton (Fig. 10.44) either by fermentation or by enzymic hydrolysis of cephalosporin C, thus preventing the semisynthetic approach analogous to the preparation of penicillins from 6-APA. 

The diterpene taxol is used as a potent chemotherapeutic agent in cancer treatment. The hmited supply of the drug from the natural source, the bark of the Pacific Yew (Taxus brevifolia), was overcome by a semisynthetic approach. Taxol is presently manufactured by coupling the advanced naturally occurring taxoid 10-deacetylbaccatin 111, isolated from needles of the more abundant Tdxus baccata, to a synthetic side-chain precursor. 

Cabri W, Curini M, Marcotullio MC, Rosati O (1996) A High Yield Semisynthetic Approach to 2 -epi-Taxol. Tetrahedron Lett 37 4785... 

These semisynthetic approaches resolve inherent problems in the analysis of posttranslationally modified proteins, where recombinant production of normative structures is either difficult or impossible. The constructed prenylated Rab protein probes were then further used to study the thermodynamics and kinetics of their interaction with regulatory proteins (see Section 6.4.1). 

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