Acyloxy esters

Esters of swainsonine appear to offer therapeutic advantages in terms of specificity for Golgi a-mannosidase II, improved pharmacokinetics, and diminished side effects (143). Although 2- and 8-acyloxy esters of swainsonine were two to three orders of magnitude less active as a-mannosidase inhibitors in vitro than the parent alkaloid, the 2-butanoyl, 2-octanoyl, and 2-p-nitrobenzoyl esters, which are soluble enough to enter viable tumor cells, were as effective as swainsonine in vivo, apparently because they are hydrolyzed to swainsonine with intracellular esterases. These compounds may thus be advantageous as prodrugs. 

Sterically demanding a-substituted p-acyloxy esters were resolved using an Aspergillus sp. lipase (see Scheme 2.69). Again, introduction of a fhioacetate as the acyl moiety improved the selectivity dramatically [479], The diastereomeiic sy /a n -conformation of the substrate was of critical importance due to the fact that, in contrast to the sy -substrates, only the an/j-derivatives were resolved with high selectivities. 

Scheme 2.69 Resolution of a-substituted [l-acyloxy esters by Aspergillus sp. lipase...

Chiral hydroxyesters would be accessible via enzymatic hydrolysis of their acyloxy esters, but a disadvantage which is commonly encountered in such resolutions is an undesired side reaction involving the hydrolysis of the carboxyl ester moiety which leads to the formation of hydroxyacids as byproducts. Thus, low... 

In peptide syntheses, where partial racemization of the chiral a-carbon centers is a serious problem, the application of 1-hydroxy-1 H-benzotriazole ( HBT") and DCC has been very successful in increasing yields and decreasing racemization (W. Kdnig, 1970 G.C. Windridge, 1971 H.R. Bosshard, 1973), l-(Acyloxy)-lif-benzotriazoles or l-acyl-17f-benzo-triazole 3-oxides are formed as reactive intermediates. If carboxylic or phosphoric esters are to be formed from the acids and alcohols using DCC, 4-(pyrrolidin-l -yl)pyridine ( PPY A. Hassner, 1978 K.M. Patel, 1979) and HBT are efficient catalysts even with tert-alkyl, choles-teryl, aryl, and other unreactive alcohols as well as with highly bulky or labile acids. 

Ester groups in R —CO—OR compounds are named (1) by the prefix alkoxycarbonyl- or aryloxycarbonyl- for —CO—OR when the radical R contains a substituent with priority for citation as principal group or (2) by the prefix acyloxy- for R —CO—O— when the radical R contains a substituent with priority for citation as principal group. Examples are... 

When the ester function is named as a substituent, it is indicated by alkoxycarbonyl or acyloxy depending on the connection to the —C=0 group ... 

The (acyloxy)borane complex 9, readily available from tartaric acid derivative 8, also catalyzes aldol additions of silyl enol ethers34 and silylketene acetals3 5 in an enantioselective manner. Thus,. u -ketones 10 and /Thydroxy esters 12 are available34, as well as a-unsubstituted ketones 1135. 

The hyponitrites (16), esters of hyponitrous acid (HO N=N OH), are low temperature sources of alkoxy or acyloxy radicals. A detailed study of the effect of substituents on k4 for the hyponitrite esters has been reported by Quinga and Mendenhall,114... 

In general, aliphatic diacyl peroxide initiators should be considered as sources of alkyl, rather than of aeyloxy radicals. With few exceptions, aliphatic acyloxy radicals have a transient existence at best. For certain diacyl peroxides (36) where R is a secondary or tertiary alkyl group there is controversy as to whether loss of carbon dioxide occurs in concert with 0-0 bond cleavage. Thus, ester end groups observed in polymers prepared with aliphatic diaeyl peroxides are unlikely to arise directly from initiation, but rather from transfer to initiator (see 3.3,2.1.4),... 

The high rate of decarboxylation of aliphatic acyloxy radicals is also the prime reason behind low initiator efficiencies (see 3.3.2.1.3). Decarboxylation occurs within the solvent cage and recombination gives alkane or ester byproducts. Cage return for LPO is 18-35% at 80 °C in -octane as compared to only 4% for BPO under similar conditions.144... 

Sulfonate esters and halides can also migrate in this reaction. a-Halo and a-acyloxy epoxides undergo ready rearrangement to a-halo and a-acyloxy ketones,... 

The mechanism of the ester formation would seem to be either an S i decomposition of the peroxide to give the ester directly, or a front side reaction between two acyloxy radicals. 

A-Acyloxy-A-alkoxyamidcs 20 are synthesised from A-chlorohydroxamic esters 22 by replacement of chlorine by a carboxyl group (Scheme 3). Initially we employed silver acetate in anhydrous ether to make A-acetoxy derivatives.47 However, most have been made using sodium carboxylates in dry acetone by analogy with Finkelstein chemistry.5,38 40>42,43,46,48,49,i05 reacti0ns can be monitored conveniently by thin layer chromatography and A-acyloxy-A-alkoxyamides generally... 

Carbonyl stretch frequencies, carbonyl 13C and amide 15N chemical shifts for a wide range of A-acyloxy-A-alkoxyamides are listed in Table 2 together with those of the precursor hydroxamic esters. Spectroscopically, mutagens can be categorised into six types ... 

A -Acyloxy-A -alkoxyamides are characterised by two high frequency double bond absorptions corresponding to the stretching modes of the ester and amide carbonyls. 

Table 2 Infrared carbonyl absorption frequencies (CHC13), 13C and selected 15N chemical shiftsa (CDC13) for 7V-acyloxy-7V-alkoxyamides (R1ON(OCOR2)COR3) and precursor hydroxamic esters... 

C NMR spectroscopy. 13C NMR resonances for both carbonyls of the TV-acyloxy-V-alkoxyamides and that of the parent hydroxamic ester are given for most compounds in Table 2. 

With the exception of para-substituted benzyloxy-/V-acyloxy-V-alkoxyamides, amide carbonyl 13C NMR values of 56 congeners differ from those of their precursor hydroxamic esters by on average +8.0( + 0.6)ppm. Steric and electronic effects influence hydroxamic esters and N- a c y 1 o x y - A- - a 1 k o x y a m i dc s similarly. This includes substrates with branching a to the amide carbonyl. Two classes of A -acy 1 o x y- A -a 1 koxyamides are worthy of mention ... 

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