Fragmentation hemiacetals

The reducing-end units (see Fig. 8) are highly labile in alkaline solutions. After an initial attack by hydroxide ions at the hemiacetal function, C-1, a series of enoHzations and rearrangements leads to deoxy acids, ie, saccharinic acids, and fragmentation. Substituents on one or more hydroxyl groups influence the direction, rate, and products of reaction. 

Base-catalyzed fragmentation also occurs on treatment of 5,6j9-epoxy-19-aldehyde (hemiacetal, hemiacetal-acetate or 3)5,6/ -acetal) accessible from nitrous acid-acetic acid treatment of 5a-bromo-6jS-hydroxy-19-oximes followed by mild base hydrolysis (yield not reported)... 

Scheme 8.52 Retro-aldol fragmentation of an epoxide-derived hemiacetal.

A retroaldol fragmentation subsequent to the addition of p-TsOI I and a small amount of water to epoxide 206, obtained by oxidation of enol ether 205 with DMDO, resulted in the direct formation of dialdehyde hydrate 208, possessing the spirostructure necessary for the construction of the fused-rings core of ( )-ginkoli-de B. Apparently, hydrolysis of the epoxide produces the hemiacetal 207, which undergoes retroaldol fragmentation of the cydobutane to afford the dialdehyde, which forms the stable hydrate 208 (Scheme 8.52) [94]. 

Similarly, bicyclic hemiacetals fragment to medium-size lactones. 

Three possible mechanistic schemes can be suggested for this process. One involves elimination of the proton attached to the p-C atom of nitronate A or A followed by elimination of the OSi group from the intermediate anion (cf. Scheme 3.93). Another mechanism is associated with a 1,4-C,O-transfer of the proton from the p-C atom of nitronate A to the oxygen atom of the N—>0 fragment followed by elimination of silanol from hemiacetal B. The third mechanism is based on the concerted elimination of silanol from the minor cis isomer of SENA. 

In fact, other studies have shown that TMSOTf catalyzes the glycosylation of a silylated acceptor with a silylated hemiacetal donor [49]. Nudel man s procedure was applied to the synthesis [1-glucuronide 30, isolated in 57% yield. Kiyoi and Kondo have applied the TMSOTf activation protocol to protected L-fucose hemiacetal donors for glycopeptide synthesis and obtained glycopeptide fragment 31 in 74% yield (a p, 20 1) [50], Posner and Bull have developed a procedure that uses excess TMSOTf in the presence of molecular sieves (SYLOSIV A4) to synthesize various l.l -linked disaccharides such as the galactopyranose dimer 32 [51,52]. 

A mechanism was proposed in which the perferryl iron-oxeme, resulting from heterolytic cleavage of the 0-0 bond of the iron-peroxy intermediate, abstracts an electron from the 0=0 double bond of the carbonyl group of the aldehyde. The reduced perferryl attacks the 1-carbon of the aldehyde to form a thiyl-iron-hemiacetal diradical. The latter intermediate can fragment to form an alkyl radical and thiyl-iron-formyl radical. The alkyl radical then abstracts the formyl hydrogen to produce the hydrocarbon and C02 (Reed et al 1995). 

The C2g-C34 fragment of FK-506 and (-)-shikimic acid required the hemiacetal 63 having the same framework which was obtained from (+)-26 by convex-face 1,4-addition and acetal cleavage. The C28-C34 fragment was obtained through 63-65 (R=Me) on sequential RCM and hydrogenation.25... 

Just as protonated carbonyl groups are much more electrophilic than unprotonated ones, these oxonium ions are powerful electrophiles. They can react rapidly with a second molecule of alcohol to form new, stable compounds known as acetals. An oxonium ion was also an intermediate in the formation of hemiacetals in acid solution. Before reading any further, it would be worthwhile to write out the whole mechanism of acetal formation from aldehyde or ketone plus alcohol through the hemiacetal to the acetal, preferably without looking at the fragments of mechanism above, or the answer below. 

---