DICHED boronic esters

Hydrolysis of 1,3,2-dioxaborolanes is thermodynamically disfavored, no doubt as a result of the same kinds of entropic factors that favor formation of cyclic acetals in preference to acyclic acetals. Hydrolysis of a 1,3,2-dioxaborolane (1) converts three molecules to two, but hydrolysis of a boronic acid dimethyl ester keeps the total number of molecules at three (Scheme 5). (It m be noted that hydrolysis of a cyclic acetal with one molecule of water keeps the number of reactant and product molecules equal at two, and hydrolysis of an acyclic acetal converts two molecules to three.) Adding base does almost nothing to the equilibrium, since hydroxide ion coordinates to the boronic ester 1 as well as to the boronic acid product. Furthermore, it spears that the trans R° substituents in 1 further stabilize the stmcture. Chiral boronic esters of this series are harder to hydrolyze than pinacol boronic esters, and treatment of pinacol boronic esters with DICHED results in liberation of the pinacol and formation of the DICHED boronic ester. 

The chemistry of boronic esters that have cyano substituents closely resembles that of boronic esters with carboxylic ester substituents. The same rules apply to the requirements for separation between the boron atom and the substituent. Lithioace-tonitrile reacts with (a-haloalkyl)boronic esters in the same maimer as does tert-butyl lithioacetate, but the less bulky nitrile function encounters fewer steric obstacles. Some examples of sterically hindered compounds that can be made in this way include pinanediol ester 97 [46], (J )-DICHED ester 98 [54], and the (a,a-dimethyl-P-cyanoethyl)boronic ester 99 (Scheme 8.22) [37]. 

The first application of the alkyltrifluoroborate salts was the conversion into alkyldihaloboranes by silyl hahdes and subsequent reaction with alkyl azides [77]. An example of a usefid synthesis was the preparation of (S)-2-phenylpyrrolidine (141) (Scheme 8.32). (S)-DICHED (3-bromopropyl)boronate (13S) was converted into the 3-azido derivative 136 at reflux temperature under phase-transfer conditions. The usual reaction with (dichloromethyl)lithium followed by phenylmagnesium bromide to form DICHED ester 137 was followed by treatment with potassium bifluoride in aqueous methanol to provide the alkyltrifluoroborate salt 138. Neither boronic esters nor alkyltrifluoroborate salts react with alkyl azides. Reaction of 138 with trimethylsi-lyl chloride yielded (S)-2-phenylpyrrolidine (141), but reaction with silicon tetrachloride proved much faster and more efficient. At first it was thought that the intermediates 139 and 140 were probably difluoroboranes in accord with literature precedent [76], but careftil reinvestigation has revealed that reaction of alkyltrifluoroborate salts with silicon tetrachloride in coordinating solvents yields alkyldichloroboranes [78]. 

The reaction of (a-chloroalkyl)boronic esters with silicon tetrachloride does not epimerize (a-chloroalkyl)boron groups. As a test, (S)-DICHED (1-chloropentyl)-boronate (142) with potassium bifluoride was converted into potassium (1-chloro-pentyl)trifluoroborate (143), which was treated with silicon tetrachloride in THF to form (l-chloropentyl)dichloroborane (144). The dichloroborane was converted into the stable pinacol ester 145, which was transesterified to the (R)- and (5)-pinanediol esters 146 and 147, respectively (Scheme 8.33). H NMR spectra of these two di-astereomers differ sufficiently to show that each was pure and free from more than 1-2% of the other. Compound 144 was shown to react readily with diethylzinc followed by base and finally hydrogen peroxide to yield the expected (S)-3-heptanol, but this chemistry awaits further development to achieve efficient synthetic procedures. 

Scheme8J3 Conversion of a DICHED (a-chloroalkyl)boronic ester into an (a-chloroalkyl)dichloroborane without loss of stereopurity. Yields for these transformations, though generally good, were not optimized and were not reported.

There are several situations where cleavage of a 1,3,2-dioxaborolane to the boronic acid and diol is useful. One of these is for removal of a chiral director and replacement by its enantiomer. The first time we encountered this problem, a pinanediol ester was converted to the boronic acid via destructive cleavage of the pinanediol with boron trichloride (14). More recently, it has proved possible to convert an (R)-DICHED a-benzyloxy boronate (20) to the free bororric acid (23) with the aid of sodium hydroxide and a tris(hydroxymethyl)methane to form water soluble derivative 21 (R = CH2OH or NH(CHi)3S03 ) plus water insoluble (R)-DICHED (22). Treatment of 23 with (S)-DICHED (24) then yielded diastereomer 25 (76%, 97-98% diastereomeric purity). Further chain extension and alkylation led to 26 and 27, and deboronation yielded 28, all of which are stereoisomers that could not be accessed directly with a single chiral director (Scheme 6). 

Mild methods were known in some other specific instances. The (R,J )-2,3-butane-diol ester of (l-chloro-2-methylpropyl)boronic acid with diethanolamine yielded the crystalline diethanolamine ester [13]. DICHED (a-benzyloxyalkyl)boronates have been cleaved with TAPS buffer [a water-soluble gem-tris(hydroxymethyl) compound] and excess base [74]. However, these methods were inefficient and not general. 

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