A-Isomer

The commercial product, m.p. 53-55°, may be used. Alternatively the methyl -naphthyl ketone may be prepared from naphthalene as described in Section IV,136. The Friedel - Crafts reaction in nitrobenzene solution yields about 90 per cent, of the p-ketone and 10 per cent, of the a-ketone in carbon disulphide solution at — 15°, the proportions ore 65 per cent, of the a- and 35 per cent, of the p-isomer. With chlorobenzene ns the reaction medium, a high proportion of the a-ketone is also formed. Separation of the liquid a-isomer from the solid p-isomer in Such mixtures (which remain liquid at the ordinary temp>erature) is readily effected through the picrates the picrate of the liquid a-aceto compound is less soluble and the higher melting. 

All the ring substituents m p D glucopyranose are equatorial m the most stable chair conformation Only the anomenc hydroxyl group is axial m the a isomer all the other substituents are equatorial... 

The optical rotations just cited for each isomer are those measured immediately after each one is dissolved m water On standing the rotation of the solution containing the a isomer decreases from +112 2° to +52 5° the rotation of the solution of the p isomer increases from +18 7° to the same value of +52 5° This phenomenon is called mutarotation What is happening is that each solution initially containing only one anomeric form undergoes equilibration to the same mixture of a and p pyranose forms The open chain form is an intermediate m the process... 

The mechanism for formation of the 3 methyl glycoside is shown The mechanism for for mation of the a isomer is the same except that methanol approaches the carbocation from the axial direction... 

The commercial tricresyl phosphate product is essentially a -isomer mixture. Typical products of this class are Ak2o s Lindol [1330-78-5] ... 

Methods (25,26) to iacrease the ratio of the desired a-isomer (1) versus the unsweet -isomer [22839-61-8] (3) exist and are proprietary. The isomers can be separated by subjecting the solution of the final step to hydrochloric acid. The desired a-isomer hydrochloride salt crystallines out of the solution the P-isomer remains. There are many patented synthetic processes. The large-scale synthesis of aspartame has been discussed (27—47). 

Later investigations led to improved synthetic routes and analogues such as those shown in Figure 3 (51). Conversion of the mixed imide (24) to the bromide (25) provided a mixture of a- and (3-bromomethylpenicilLins in which the a-isomer predominated. 

The isolation of the 6-deoxytetracyclines (44) led to other chemical modifications of (1). 6P-Deoxytetracycline [5614-03-9] (13), prepared by catalytic hydrogenolysis of tetracycline (1), resulting ia an iaversion (45) of the configuration at the C-6 position, but retention of antibacterial activity. Catalytic reduction (7,8) of the 6-methylene derivative (14) yields both the 6a-methyl (15) and 6P-methyl compound (13). The 6a-isomer (15) is reported (7,45) to be more active than the 6P isomer (13). The a-isomer, doxycycline (6), is an example of a semisynthetic tetracycline that has become commercially useful. 

The fundamental subject of this section is the transformation of A -pyrazolines into cyclopropanes (Buchner-Curtius and Kishner cyclopropane syntheses). The cyclopropane is often accompanied by alkenes (67HC(22)l). When applied to A -pyrazolines the reaction occurs via the A isomers (Scheme 37). 

Dinitrofluorobenzene, DABCO, DMF, 85% yield. When this group was used to protect an anomeric center of a carbohydrate, only the /3-isomer was formed, but this could be equilibrated to the a-isomer in 90% yield with K2CO3 in DMF. 

Gaseous hydrogen chloride is bubbled through a solution of 0.8 g of 22,23-dibromoergost-8(14)-en-3/3-yl acetate in 25 ml of chloroform at 0° for 2 hr. The solvent is removed by evaporation and the solid mixture of A8(i4) A -isomers is hydrogenated over platinum oxide (0-2 g) in ether... 

The bromination of 4,5-j -dihydrocortisone acetate in buffered acetic acid does not proceed very cleanly (<70%) and, in an attempt to improve this step in the cortisone synthesis, Holysz ° investigated the use of dimethylformamide (DMF) as a solvent for bromination. Improved yields were obtained (although in retrospect the homogeneity and structural assignments of some products seem questionable.) It was also observed that the combination of certain metal halides, particularly lithium chloride and bromide in hot DMF was specially effective in dehydrobromination of 4-bromodihydrocortisone acetate. Other amide solvents such as dimethylacetamide (DMA) and A-formylpiperidine can be used in place of DMF. It became apparent later that this method of dehydrobromination is also prone to produce isomeric unsaturated ketones. When applied to 2,4-dibromo-3-ketones, a substantial amount of the A -isomer is formed. 

Thionyl chloride behaves in some circumstances as though it dehydrates by tran -diaxial elimination, as described for phosphorous oxychloride. For example, the 5a-alcohol (102) undergoes anti-Saytzelf elimination to give the A" -olefin. In this particular example, phosphorous oxychloride-pyridine does not work, and acetic anhydride-sulfuric acid gives the A -isomer (ref. 185, p. 199). 

The pure olefin is best prepared via the bromohydrin (131) a more direct route from the tosylate (129) yields a mixture of (132) and its A -isomer. The indirect method is most suitable for preparing A -olefins in the 5jS-series. 

Unsubstituted 20-ketones readily form enol acetates. Reaction with isopropenyl acetate yields the kinetic A -isomer (86, R = CH3CO) which is equilibrated to the A -enol acetate (85, R = CH3CO) on exposure to acetic anhydride-/7-toluenesulfonic acid. Treatment of the 20-ketone according to the latter conditions gives the A -enol acetate directly. 

The reactions of A -steroids with nitrosyl fluoride parallel those of their A -isomers. Thus, 17 -acetoxyandrost-4-ene (37) is converted to the nitrimine (38), in 67 % yield and thence to the 4-ketone (39), which can be dehydrofluorinated to the A -4-ketone (40) with lithium bromide in di-methylformamide. In the corresponding 19-nor series the nitroso dimer is also formed. 

Malhotra et al. (5pyrrolidine enamine of 3-methyl-cyclohexanone, prepared under equilibrating conditions, is a 3 7 mixture of A and A isomers (67 and 68) on the basis of NMR spectral data. The preponderance of the A isomer in the mixture was attributed to strain between the equatorial methyl group and the vinylic hydrogen atom... 

In the steroidal series Heyl and Herr (40) have reported that the pyrrolidine enamine of 5a-cholestan-3-one consisted of a mixture of and A isomers (78),... 

Interestingly the pyrrolidine enamine of 3-t-butylcyclohexanone (41) consists of a 3 2 mixture of A and A isomers (79 and 80). The preference for the A isomer in this case is due to the relief of two of the four skew butane interactions, which are present in the isomer. The A isomer, owever, contains two additional interactions, i.e., one modified skew utane interaction 0.4 kcal/mole (42) and one interaction between c C-2 vinylic hydrogen atom and the ethyl portion of the t-butyl group hich is pointed toward it. 

The enamine formed by dehydrogenation of indollzidine was considered to be a mixture of Zl (54) and Zl (55) isomers because of infrared spectra (126). According to the NM R spectrum, the A isomer Isthe majorconstituent. This is demonstrated by comparison of this spectrum with the spectra of compounds 56 and 57 containing fixed double bonds. 

---