Cyclization of Open-Chain Sugars

The main drawback of this strategy is the low yield of the carbocyclization step, because of the competition between addition to the carbonyl and substitution of the iodide. To circumvent this problem, an alternate pathway incorporating the malonate moiety prior to the transformation of the primary hydroxyl group into a leaving group was explored. This alternative method was used for 

SCHEME 8.5 Synthesis of carba-sugars using malonates. 

SCHEME 8.6 Improved synthesis of a carba-sugar using malonates. 

SCHEME 8.7 Synthesis of a carba-furanose using malonates. 

SCHEME 8.8 Synthesis of carba-pyranoses using a nitro group. 

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Hemiacetals that can be formed by intramolecular cyclization of an alcohol on to an aldehyde are also often stable, especially if a five- or six-membered ring is formed. You met this in Chapter 6— many sugars (for example, glucose) are cyclic hemiacetals, and exist in solution as a mixture of open-chain and cyclic forms. 

Phenylalanine, tyrosine, and tryptophan are synthesized by a common pathway in E. coli (Figure 24.13). The initial step is the condensation of phosphoenolpyruvate (a glycolytic intermediate) with erythrose 4-phosphate (a pentose phosphate pathway intermediate). The resulting seven-carbon open-chain sugar is oxidized, loses its phosphoryl group, and cyclizes to 3-dehydroquinate. Dehydration then yields 3-dehydroshikimate, which is reduced by N ADPH to shikimate. The phosphorylation of shikimate by ATP gives shikimate 3-phosphate, which condenses with a second molecule of phosphoenolpyruvate. The resulting 5-enolpyruvyl intermediate loses its... 

OZTs from aldoses and ketoses. The second and the oldest-as well as the less studied—method is based on the condensation of O-unprotected sugars with thiocyanic acid, generated in situ from potassium thiocyanate and a protic acid. The reaction involves the free anomeric position and a y- or (5-hydroxyl group able to promote intramolecular cyclization of a transient open-chain isothiocyanate, to form the thermodynamically most stable OZT. The first results obtained by Zemplen in d-gluco and D-Fru series reported the formation of OZTs fused to pyran backbones (Scheme 20).42... 

The predominant forms of ribose, glucose, fructose, and many other sugars in solution are not open chains. Rather, the open-chain forms of these sugars cyclize into rings. In general, an aldehyde can react with an alcohol to form a... 

Another route to thioglycosides from hemiacetals involving a cyclization of an open-chain sulfide has been described recently. A Wittig-Horner reaction afforded the Q ,/3-unsatu-rated thiophenyl derivative, which then was treated with iodonium reagents to induce cyclization to afford 2-iodo-l-thioglycosides, which are good precursors for 2-deoxy-sugars (O Scheme 13) [167]. 

The reaction between tri-O-acetyl-D-glucal 7 and chlorosulfonyl isocyanate has been studied in the past, but neither formation of a cycloadduct nor of a rearranged product has been observed. Isocyanate acted only as acid catalyst causing decomposition of sugar material. On the other hand, [2+2]cycloaddition of active isocyanates to dihydro-2H-pyran and to its derivatives has been widely investigated, under a variety of conditions. The reaction of tosyl isocyanate with dihydro-2H-pyran 1 at low temperature (0 ) led to the formation of bicyclic p-lactam 2. Elevation of the cyclization temperature resulted in the rearrangement of the four-membered ring to the open-chain amide 3 (Scheme 4). 

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