Methyl shikimate synthesis

Nucleophilic additions to (cyclohexadienone)Fe(CO)3 complexes (218) occur in a dia-stereospecific fashion (Scheme 56)197. For example, the Reformatsky reaction of ketone (218a) affords a simple diasteromeric alcohol product19715. The reduction of (1-carbo-methoxycyclohexa-l,3-dien-5-one)Fe(CO)3 (218b) to give 219 has been utilized in the enantioselective synthesis of methyl shikimate. In a similar fashion, cycloadditions of (2-methoxy-5-methylenecyclohexa-l,3-diene)Fe(CO)3 (220) occur in a diastereospecific fashion198. 

As an example of conversion of complex 111 to 113, optically pure complex 126 was used for the enantioselective total synthesis of shikimic acid (129) [30]. The hydroxy-substituted diene complex 127 was prepared from 126. Silylation and decomplexation of 127 gave 128. Stereoselective dihydroxylation of the more reactive double bond of the decomplexed silyl ether derivative 128, followed by desilylation afforded (—)-methyl shikimate (129). 

Prtvost reaction. A short synthesis of methyl shikimate (5) involves base-promoted cleavage of 1, obtained by a Diels-Alder reaction of furane with methyl acrylate (11,... 

Mirza, S., and Vasella, A., Deoxy-nitrosugars. Part J. Synthesis of methyl shikimate and of diethyl phosphashikimalc from D-ribose, Helv. Chim. Acta, 67, 1562, 1984. 

Methyl shikimate 116 has been made using a strategy with iodolactonisation at its heart.26 Note that shikimate has three chiral centres. Interestingly, these three centres are controlled in the synthesis by a centre that is finally destroyed. The first steps are iodolactonisation of 103 and subsequent elimination and epoxidation to give 109 as described above. 

Epoxide 109 is opened with Me3SiBr (Ph3P-catalysed) and another elimination with DBU gives the allylic alcohol 117. The epoxidation that follows is controlled in a couple of ways. Firstly, the axial alcohol can direct the reagent (the same peroxyacid used to make 109) to the bottom face of the six-membered ring which is also the less hindered side of the molecule (opposite the lactone bridge) 118. The synthesis is completed with basic methanolysis of the lactone 118 to give racemic methyl shikimate 116. 

Brief synthesis of ( )-methyl shikimate, ( )-methyl epishikimate and structural variants. Tetrahedron 40 2461-2470. 

As a more practical route to EPSP, we elected to pursue a partial synthesis, starting with methyl shikimate acetonide (20) which is readily available from shikimic acid itself. While our work on this transformation was in progress,... 

Example 16 the synthesis of (-)-shikimate-3-phosphate by Shin and Wu [44] using dibenzyl-iV,N-diisopropylphosphoroamidite and subsequent oxidation by CPBA (steps a and b) involves the deprotection of the final triester phosphate by trimethylbromosilane (TMBS) which allows simultaneous removal of benzyl 2,2,3,3-tetramethoxybutane and methyl groups (steps c and d). 

The simultaneous and selective protection of the two equatorial hydroxyl groups in methyl dihydroquinate [11L1, Scheme 3.111 j as the butane-2,3-diace-tal 111 2 was a key strategic feature in a synthesis of inhibitors of 3-dehydroqui-nate synthase.205 Later in the synthesis, deprotection of intermediate 111.4 required three steps (a) hydrolysis of the trimethylsilyl ether and the butane-2,3-diacetal with trifluoroacetic acid (b) cleavage of the isopropyl phosphonate with bromotrimethylsilane and (c) hydrolysis of the methyl ester with aqueous sodium hydroxide. Compound 111 1 has also been used in the synthesis of inhibitors 3-dehydroquinate dehydratase206 and influenza neuraminadase207-208 as well as shikimic add derivatives.209 210... 

In reporting a new synthesis of ( )-shikimic acid methyl ester (4), Grewe and Hinrichs noted that this substance is convertible in high yield into the cyclohexylidene derivative (5), an oil (—)-shikimic acid methyl ester afforded a crystalline derivative, m.p. 61°. A mixture of 6 g. of the ester, 6.6 ml. of cyclohexanone. 

A good illustration of many aspects of this chemistry comes from Koreeda s synthesis of shikimic acid.22 The silyl diene 123 adds cleanly to methyl acrylate to give essentially one isomer of the adduct 124 (9 1). Dihydroxylation with catalytic 0s04 and the stoichiometric oxidant NMO (A-methylmorpholine-A-oxide) occurs on the opposite face to all three substituents. The alkene 124 is an allylic acetate but this group has no attractive interaction with the reagent. 

Cycloadduct (195) has been used in the synthesis of the C-nucleosides d-showdomycin (201) and D-3,4-0-isopropylidene-2,5-anhydroallose (202) via the common intermediate (203) (Scheme 5.66) [168]. The Diels-Alder endo cycloadduct (204), prepared in 50% yield and 92% diastereomeric excess by the reaction of (5 )-3-(2-pyridylsulfinyl)acrylate (194) with 3,4-dibenzyloxyfuran, was converted into the secondary metabolite (-)-shikimic acid (205) in six steps [169]. Cycloadduct (195), prepared as shown in Scheme 5.64, has also been transformed into (+)-methyl 5-epi-shikimate (206) [170] (Scheme 5.66). 

Chrysophanol (XXIII), an anthraquinone isolated from the leaves of Rumex alpinus (Polygonaceae), is also formed from acetate (and presumably therefore derived via the acetate-malonate pathway) (Leistner and Zenk, 1969) and not, as previously considered, from shikimic acid and mevalonate. Only anthraquinones such as alizarin lacking a C-methyl group and not hy-droxylated in ring A are made in this way, despite an apparent similarity in structure thus at least two independent routes also exist for the synthesis of these compounds and reflect the diversity available for the biogenesis of multiringed phenols in plants. 

Occasionally, however, a ring methyl group arises from the carboxyl carbon after total reduction, as in the formation of bamol (XXVIII) (Mosbach and Ljungcrantz, 1965) or javanicin (XXIX) (Gatenbeck and Bentley, 1%5). Only the methyl groups marked with an asterisk in these structures are derived from methionine (see also Scheme 2). It should also be remembered that alkylation may occur at nucleophilic positions of aromatic precursors in susceptible products of shikimic acid origin, as in the synthesis, for example, of plastoquinone and ubiquinone (Threlfall et al., 1968). 

A highly specialized synthesis converted (-)-shikimic acid 7.169) to 7.170. Reaction with azide and catalytic hydrogenation gave 5-aminoshikimate 7.171, methyl 5-amino-3,4-dihydroxy-l-cyclohexene carboxylate) in 21% overall yield. Amino acid 7.171 is an inhibitor of EPSP synthetase, and can be used as an herbicide,... 

Feeding experiments using total plants revealed that phylloquinone is formed in leaves from shikimate /20/ and 2-succinylbenzoate /21/. Just recently Leistner s group provided evidence from studies on E. coli /22/ that isochorismate and not chorismate reacts with 2-oxoglutarate to form 2-succinylbenzoate. The results from studies on cell cultures /23,24/ and chloroplasts /25,26/ are summarized in Fig. 5. The chloroplast envelope is the site of prenylation /25/ and the thylakoid membrane of methylation reaction /26/, however, compartmentation of the other reactions remains still unclear. The synthesis in plants resembles the microbial one /27/ though phytyl-PP is preferred as prenyl donor in plants /25/. 

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