R -synthons

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

Treatment of O-silyl enols with silver oxide leads to radical coupling via silver enolates. If the carbon atom bears no substituents, two such r -synthons recombine to symmetrical 1,4-dicarbonyl compounds in good vield (Y. Ito, 1975). 

In terms of synthons, the Grignard addition to the carbonyl group corresponds to the coupling of R R C (OH) and R synthons. The reverse polarity approach can also be achieved with organometallic reagents providing they bear a protected hydroxyl group. The majority of the conventional... 

R ) relative configuration stereosymbol, 360 r synthons. See Radical synthons Racemates, resolution of. See Optical resoiution Racemization prevention in peptide synthesis, 145, 231-232, 234... 

A saturated alkyl group does not exhibit functionality. It is not a d -synthon, because the functional groups, e.g. halide or metal ions, are lost in the course of the reaction. It functions as an alkyl synthon. Alkenyl anions (R. West, 1961) on the other hand, constitute d -synthons, because the C = C group remains in the product and may be subject to further synthetic operations. 

Dioxo compounds are deprotonated at C-2 and C-4 by two equivalents of strong bases (e.g. LDA or BuLi). Carbon atom C-4 of those dianions is much more nucleophilic than the less basic center C-2 (Hauser s rule C.R. Hauser, 1958 K.G. Hampton, 1965). The formation of some typical d -synthons and their pA values are given below. 

Benzylic anions, ArCHj, are of little importance in the construction of carbon skeletons, and allylic anions, R C—CR—CR", are discussed in the d -synthons section below. 

It is also possible to convert carbonyl groups into oxirane rings with cenain carbenoid synthons. The classical Darzens reaction, which involves addition of anions of a-chloroacetic esters, has been replaced by the addition of sulfonium ylides (R. Sowada, 1971 C.R. Johnson, 1979). 

The addition of acetylides to oxiranes yields 3-alkyn-l-ols (F. Sondheimer, 1950 M.A. Adams, 1979 R.M. Carlson, 1974, 1975 K. Mori, 1976). The acetylene dianion and two a -synthons can also be used. 1,4-Diols with a carbon triple bond in between are formed from two carbonyl compounds (V. Jager, 1977, see p. 52). The triple bond can be either converted to a CIS- or frans-configurated double bond (M.A. Adams, 1979) or be hydrated to give a ketone (see pp. 52, 57, 131). 

The addition of large enolate synthons to cyclohexenone derivatives via Michael addition leads to equatorial substitution. If the cyclohexenone conformation is fixed, e.g. as in decalones or steroids, the addition is highly stereoselective. This is also the case with the S-addition to conjugated dienones (Y. Abe, 1956). Large substituents at C-4 of cyclic a -synthons direct incoming carbanions to the /rans-position at C-3 (A.R. Battersby, 1960). The thermodynamically most stable products are formed in these cases, because the addition of 1,3-dioxo compounds to activated double bonds is essentially reversible. 

If a Michael reaction uses an unsymmetrical ketone with two CH-groups of similar acidity, the enol or enolate is first prepared in pure form (p. llff.). To avoid equilibration one has to work at low temperatures. The reaction may then become slow, and it is advisable to further activate the carbon-carbon double bond. This may be achieved by the introduction of an extra electron-withdrawing silyl substituent at C-2 of an a -synthon. Treatment of the Michael adduct with base removes the silicon, and may lead as well to an aldol addition (G. Stork, 1973, 1974 B R.K. Boeckman, Jr., 1974). 

The primary disadvantage of the conjugate addition approach is the necessity of performing two chiral operations (resolution or asymmetric synthesis) ia order to obtain exclusively the stereochemicaHy desired end product. However, the advent of enzymatic resolutions and stereoselective reduciag agents has resulted ia new methods to efficiently produce chiral enones and CO-chain synthons, respectively (see Enzymes, industrial Enzymes in ORGANIC synthesis). Eor example, treatment of the racemic hydroxy enone (70) with commercially available porciae pancreatic Hpase (PPL) ia vinyl acetate gave a separable mixture of (5)-hydroxyenone (71) and (R)-acetate (72) with enantiomeric excess (ee) of 90% or better (204). 

Cychc alcohols are excellent targets for enantioselective enzymatic acylations. For example, acylation of (65) with vinyl acetate catalyzed by Hpase SAM-II gives the (R),(3)-ester with 95% ee (81). Similarly (66), which is a precursor for seratonin uptake inhibitor, is resolved in a high yield and selectivity with Amano Hpase P (82). The prostaglandin synthon (67) is resolved by the same method into the optically pure alcohol in 35% yield (83). 

The 3- or 5-aminopyrazoles are the synthons used most frequently. The second heterocyclic ring is created between the amino group and the 1-position (if unsubstituted) or between the amino group and the 4-position. Thus 3-substituted 5-aminopyrazoles react with 1,3-difunctional compounds to afford pyrazolo[l,5-a]pyrimidine derivatives (538) (Table 34). Aminopyrazolinones (R = OH) can be used instead of aminopyrazoles. Similarly 3-aminoin-dazole yields pyrimido[l,2-h]indazoles (539). 

Only in a few instances, where both phenyl groups were sufficiently different in their substitution patterns, were 3,5-diarylisoxazoles prepared regiospecifically by the reaction of 1,3-diketones (302) (R = substituted phenyl) with hydroxylamine (45JA134). Accordingly, other CCC component synthons have been employed for the regiospecific synthesis of 3,5-diarylisoxazoles. 

J. Hutchinson and G. Sandford, in Organofluorine Chemistry. Techniques and Synthons (R. D. Chambers, ed.) [Topics in Current Chemistry, Vol. 193], p. 1. Springer-Verlag, Berlin, 1997. 

The enantioselective synthesis of the V-benzyl-substituted /3-lactam 274a (NR2 = PhCH2NH), a precursor for carbapenem antibiotics, was described starting from the chiral synthon 5(R)-menthyloxy-2(5//)-furanone 170 (Scheme 71)... 

Methyl-1,2-benzenediamine (215, R = Me) with the hydrate of 3,3,3-trifluoro-pyruvic acid gave a mixture of isomers (216, R = Me) and (217, R = Me) (dioxane, reflux, 30 min 98%) from which neither appears to have been isolated in a pure state in contrast, 4-nitro-1,2-benzenediamine (215, R = NO2) and the same synthon gave a mixture of 6-nitro- (216, R = NO2) and 7-nitro-3-trifluoromethyl-2(l//)-quinoxalinone (217, R = NO2) (dioxane, reflux, 4 h 95%), from which both isomers were isolable, albeit with... 

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