With a One-Carbon Substituent at

Compound 874, as a representative of derivatives with an electron-withdrawing substituent at C-[1 of the vinyl group, is easily prepared by elimination of one benzotriazole from 2,2-/fo(benzotriazol-l-yl)ethyl methyl ketone 873. The stereoselective elimination catalyzed by NaOH gives exclusively the (E) isomer of derivative 874. Addition of nucleophiles to the double bond of vinyl ketone 874 followed by elimination of benzotriazole leads to a,P unsaturated ketones 875. Amines used as nucleophiles do not need any catalysis, but reactions with carbon and sulfur nucleophiles require addition of a base. The total effect is nucleophilic substitution of the benzotriazolyl group at the i-carbon of orji-iinsaturatcd ketone (Scheme 142) <1996SC3773>. 

Cycloalkenones are ubiquitous as reactive intermediates and bioactive materials. Modification of a simple cycloalkenone by addition of a carbon substituent at the o-position should be a useful transformation, but one that is not readily accomplished by conventional enone chemistry. a-Substituted cycloalkenones could of themselves be of interest, but perhaps, of more general importance would be their use as intermediates for the production of substituted cycloalkanones or a, 5-disubstituted cycloalkanones by a subsequent conjugate addition procedure.2 These strategies avoid many of the limitations attendant to the trapping of enolates with carbon electrophiles. The method of Kim involving treatment of enones with the combination of a dimethyl acetal, pyridine and trimethylsilyl triflates results in a-(1-methoxyalkyljenones.3 The metallation of a-bromoenones masked as ketals for [Pg.184]

An evolution from Noyori s approach leads to one where a diethylaminomethyl substituent is used to give a one-carbon start to the a-chain. From this synthon there is much flexibility because the co- and a-chains can be added in either order, and synthesis of the single isomer synthon can start with a Sharpless epoxidation. This route is shown in Scheme 30.6.23 For completeness, we note that there is another variant of the general enone approach identified by Danishefsky, in which the C-9 and C-ll carbon oxidation states are inverted (ketone at what is to become C-ll) where the a-chain is added first as a nucleophile, and then the co-chain is added second as an electrophile.24... 

Di-0-methyleneallitol (LI, R = H) is a representative of the most stable of all such acetals, those with two equatorial residues. Substituents at acetal carbon atoms will have the configurations shown. The trans bicyclic system with one equatorial residue (LII) will occur in 1,3 2,4-... 

The stereochemistry uf the tetracyclines is very complex. Carbon atoms 4. 4a.. S.. Na. 6. and 12a arc potentially chiral, depending on substitution. Oxytctracyclinc and doxycyclinc. each with a Sa-hydroxyl substituent, have six asymmetric centers the others, lacking chirality at C-. >. have only five. Determination of the complete, absolute stcreochemi.stry of the tetracyclines w.as a difficult problem. Detailed x-ray diffraction analysis c.siablished the stereochemical formula shown in Table 10-6 as the orientations found in the natural and semisynthetic tetracyclines. Tlic.se studies also confirmed that conjugated systems exist in the structure from C-10 through C-12 and from C-1 through C-.T and that the formula represents only one uf. several canonical forms exi.st-ing in those portions of the molecule. 

The introduction of a one-carbon fragment into a pyrazin-2-amine carrying a C—N substituent at the 3-position is a relatively common reaction with wide applicability. Often, however, reduced pteridines are produced which require subsequent oxidative aromatization. 

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