Synthesis of the Side Chains

35 Zaragozic Acid A/Squalestatin S1 35.3.4 Synthesis of the Side Chains 

5 Coupling of Key Intermediates and Completion of the Total Synthesis of Zaragozic Acid A/Squalestatin SI 

American Heart Association. 1991 Heart and Stroke Facts. American Heart Association, Dallas, 1991. 

(a) Lipid Research Clinics Program, J. Am. Med. Assoc. 1984, 251, 351 (b) Lipid Research Clinics Program, ibid. 1984, 251, 365. 

The Logic of Organic Synthesis, John Wiley Sons New York, 1989, p. 205. 

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Modification of the synthesis of the side chain by reaction of 73 with isopropyl amine rather than diethylamine gives eventually the haloamine, 94. Alkylation of the aminoquinoline (92)... 

Scheme 9. Synthesis of the side chain of a-tocopherol by Noyori et al.

The total synthesis of taxol (52) has been described in Chapter 34. Clearly, total synthesis cannot hope to meet the demand for taxol at the present time, and supplies are currently procured by semisynthesis. This approach uses baccatin III (derived from yew tree needles) and the C-13 side chain 51, made synthetically (Scheme 13). A practical synthesis of the side chain is necessary,... 

V-bromo-benzamide is a useful method for the synthesis of the side chain of paclitaxel (taxol) from isopropyl cinnamate.219... 

Sharpless asymmetric dihydroxylation procedure was applied to the synthesis of the side chain of azinomycin A (equation 26)43. Horner-Emmons condensation of phospho-nate 36 with a /J-aziridine substituted acrolein afforded dehydroamino acid diene 37. Treatment of the diene with catalytic amounts of an osmium reagent and dihydroquini-dine (DHQD) p-chlorobenzoate resulted in asymmetric dihydroxylation, producing diol 38. Diol 38 was further converted to the naphthyl ester. 

This enantioselective preparation of allylic alcohols has been applied to the synthesis of the side chain of prostaglandins . The addition to functionalized aldehydes, such as 483, allows the synthesis of C2-symmetrical 1,4-diols, such as 484, with excellent diastereoselectivity and enantioselectivity . An extension of this method allows the synthesis of C3-symmetrical dioF . Aldol-type products result from the catalytic enantioselective addition of functionalized dialkylzincs to 3-TIPSO-substituted aldehydes, such as 485, followed by a protection-deprotection and oxidation sequence affording 486 in 70% yield and 91% ee (Scheme 118) . The addition to a-alkoxyaldehydes provides a... 

This reaction has recently been applied to the synthesis of the side chains of mycolac-tones A and 147 (Scheme 48). 

SCHEME 48. Synthesis of the side chains of mycolactones A and via Pd-catalyzed stepwise double substitution... 

Montelukast sodium (3) has the (R) absolute configuration and its synthesis was first descnbed by Labelle et The synthesis of the side-chain commenced with... 

Scheme 11 Examples for stereoselective synthesis of the side chain units...

Various unsaturated compounds, such as CO2, isocyanates and aldehydes, undergo Pd-catalysed cycloaddition with vinyl epoxides. Reaction of CO2 with 127 affords cyclic carbonates 128 with retention of the configuration at C(3), offering a method of cis hydroxylation of epoxides [66], and has been used for the synthesis of the side-chain unsaturated (—)-exo-brevicomin (129) [67], The tetrahydrofuran 131 was prepared by [3+2] cycloaddition of activated alkenes such as benzylidene malononitrile (130) with vinyl epoxide via Michael addition and allylation [68],... 

This ene reaction can be used to effect synthesis of the side chain present in the plant growth brassinosteroids (equation I). 

Synthetic statins are important lipid regulating drugs for the treatment of atherosclerosis and other diseases related to hyperlipidaemia, especially coronary heart disease. As the pharmacophore, all synthetic statins contain a saturated or partially unsaturated syn-3,5-dihydroxy C7-carboxylate. An important building block for the synthesis of the side chain is represented by 4-chloro-3-hydroxybutanoate esters (CHBE). Both enantiomers can be obtained by enzyme-catalyzed reduction of the (1-keto ester. The group of Kataoka and Shimizu found that an aldehyde reductase of Sporobolomyces salmonicolor [161] and a carbonyl reductase of Candida... 

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. 

This methodology also enables stereospecific synthesis of the side-chain of taxol [56]. The A-benzoyl-3-phenylisoserine side chain at C-13 of the taxol molecule is essential for its antitumor activity. The stereoselectivity in this reaction depends on the geometry of the silyl ketene acetal (Eq. 77). The reaction of the (E)-ketene acetal with (i )-27 produces the anti adduct with high stereoselectivity anttsyn = 98 2, 92 % de anti). In contrast, the reaction of the (Z)-silyl ketene acetal with S)-27 produces the enantiomerically pure syn adduct (symanti = > 99 1, > 99 % de syn). Aus, our methodology provides the first practical and efficient route for the preparation of both diastereomers of an a-hydroxy /3-amino ester. The syn adduct 52 is transformed to the desired A-benzoyl-(27 ,35)-phenylisoserine methyl ester by hydrogenolysis over a palladium catalyst then the Schotten-Baumann reaction. 

That this asymmetric reaction has vast potential in natural product synthesis is illustrated by the short synthesis of the side-chain alcohol present in the biologically important vitamins E and K (Sch. 55). 

A stereocontrolled synthesis of the side-chain acid 186 of isoharringtonine from (R,R)-(-l-)-tartaric acid was reported by Zhang etal. (63) (Scheme 30). Dimethyl (2R, 3i )-tartrate acetonide (182) was allylated in the presence of lithium diisopropylamide to give 183, which underwent base-catalyzed epimerization to 184. Catalytic hydrogenation, followed by hydrolysis and by treatment with methanol in the presence of sulfuric acid, yielded the half ester 185, which was treated with aqueous trifluoroacetic acid to provide the side-chain acid of isoharringtonine (186) with the appropriate stereochemistry. 

Fig. 6 Typical lab-scale synthesis of the side-chain of RRR-3 involving two enantioselective hydrogenation steps.

The total synthesis of a-tocopherol in the naturally occurring R,R,R)-configa-ration (26, Scheme 5) was a potent promoter for establishing enantioselective catalytic methodologies at Roche. Based on the fundamental work of Noyori and Takaya on the Ru(BINAP)-catalyzed hydrogenation of allylic alcohols [20] the synthesis of the side-chain alcohol 25 was realized in our laboratories as outlined in Scheme 5. The hydrogenations of 20 and 24 proceeded extremely well with Ru(MeOBIPHEP)(tfa)2 catalysts TON s of 20,000 and 100,000 and ee s of... 

Other approaches to produce synthons for an efficient stereoselective synthesis of the side chain of natural a-tocopherol have been made by reducing phenylpentene aldehydes with baker s yeast liberating optically active C5 units or C5 derivatives by ozonolysis of the C-4 double bond and reductive workup30. 

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