PROCESAMIENTO DE DATOS DE LA ENCUESTA N° 01 DIRIGIDA A LAS ASOCIACIONES CULTURALES:

Although, the required Z?w(trimethylsilyl)diphenyl sulfone 132 was readily obtained, when it was treated with either tri-n-butyl borate or boron trifluoride etherate, the predicted product (133) was not isolated. In both cases, the same product, whose identity could not be elucidated, was obtained. Both the and NMR spectra provided evidence for a symmetrical product in which C- 6 and C-6' no longer bore hydrogen atoms. In the spectrum, there are three multiplets which correspond to six aromatic hydrogen atoms when compared to the singlet that represents two equivalent TMS groups. The spectrum contains, in addition to the TMS singlet, six resonances, three of which appeared to correspond to quaternary aromatic carbon atoms. On the basis of this information we postulated that this product might be the borinic anhydride 134. However, as the same

TMS •IMS

B-O-B

TMS TMS

134

product was isolated from the reaction of 2,2'-^w(trimethylsilyl)-6,6'-dilithiodiphenyl sulfone with diwopropoxyphenylborane, and the product did not contain boron (according to NMR spectroscopy), this structure had to be dismissed. Despite its structure not being known, the product was treated with TBAF, and was found to afford exclusively dibenzothiophene-5,5-dioxide 136. We concluded, therefore, that the unknown product thought at first to be 134 was in fact 4,6-è/5(trimethylsilyl)-dibenzothiophene-5,5-dioxide (135).

135, R = TMS 1

The mechanism by which 135 is formed from 132 when treated with n-BuLi is not known. The failure of this approach led us to abandon the attempted synthesis of borinic acid 82.

As has already been described, compound 82 could not be synthesised directly from diphenyl sulfone by the initial lithiation strategy (see Schemes 2.19 and 2.20). This may be because either the intermediate borinate formed during this reaction, or the borinic acid 82 that results from its hydrolysis, is so electrophilic that it is attacked by water, when the reaction is quenched, thereby causing the formation of boronic acid 108. Similar electronic effects may have prevented the synthesis of the diphenyl sulfone-derived phenyl borane (1 2 0); as already discussed, however, this may arise more as a result of the steric bulk of the phenyl group than because of the stability of the product, or the intermediate borinate.

The most unusual compounds to have been synthesised from all the above reactions are the ammonia (122) and hydroxylamine (128) adducts of the target diphenyl sulfone-derived methylborane (120). Why exactly ammonia complexes only to borane 120 is not understood as it is undoubtedly present during the quenching of many of the reactions discussed above.

2 .7 Design of Acyclic Borinic and Boronic Acids

A final set of target molecules, whose syntheses again we hoped would be easier than all of those previously described, were designed. The rationale for this came initially from an idea to synthesise a single compound that would resemble, as closely as possible, borinic acid 82. As has been demonstrated (by the syntheses of compounds 122 and 128), the co-ordinative bond formed between nitrogen- and boron-containing compounds can be very strong. On the basis of these considerations, compound 137 was designed.

HO OH

X = SOg: 137 X = S: 138 X = O: 139

Although we hoped that the sulfone present in boronic acid 137 could be generated from the oxidation of the sulfur atom in the analogous sulfide-containing boronic acid 138, were this not to prove possible 138 itself would still be a valid target compound. The oxygen-containing analogue (139) was also thought to be worthy of examination.

In addition to these pyridine-containing boronic acids, it was decided to try to synthesise the following two final sets of compounds:

• the sulfur- and oxygen-containing analogues (140 and 141) of the previously synthesised sulfone-containing boronic acid (108).

• three closely related borinic acids (142 - 144), differing only from the boronic acids 108,140 and 141 in the replacement of one of their hydroxyl groups with a methyl group.

1

V

u '

T "

X = SO2: 108 X = SO2: 142

X = S: 140 X = S: 143

X = O: 141 X = O: 144

It was intended that any inhibition of HIV-1 PR exhibited by boronic acids 140 and 141 could be compared directly with the cyclic borinic acids 83 and 84 (the compound obtained when borinic anhydride 117 is dissolved in aqueous solution) synthesised earlier. The purpose in making borinic acids 142-144 was to assess whether the borinic acid functionality might be better than the boronic acid group at binding to the catalytic aspartic acids even if the cyclic borinic acids 83 and 84 proved to be inactive. It was hoped that these more flexible acyclic analogues might be active on account of being able to adapt their conformations to complement the active site. The small methyl group was not expected to sabotage the interaction of the borinic acid group contained within these molecules with the active site. This premise was based on the earlier successful

development of inhibitors of the phosphonamidate methyl ester class by Camp and others within the Gani group at St Andrews (see page 2 9).^19,206

2 .8 Syntheses of Acyclic Borinic and Boronic Acids

2 .8 .1 Attempted Syntheses of Pyridyl-containing Boronic Acids

We intended to synthesise sulfide 137, the precursor to borinic acid 138, by treating sulfide 145 with n-BuLi, followed by reaction with a trialkyl borate [Scheme 2.29 (ii)].

a r * ^ Gc'D

145 138

Reagents and Conditions', (i) NaHCOg, DMF, 130 °C, 2 h, 54%; (ii) n-BuLi, THF, -70 °C, then B(OR)3, -70->25 °C.