Cyclic hemiacetals synthesis

Kluge, M. and Sicker, D. 1996. Double diastereoselective glucosidation of cyclic hemiacetals synthesis of the 1,4-benzoxazinone acetal glucosides GDIBOA and GDIMBOA from Gramineae. Tetrahedron 52, 10389-10398... 

Structural drawings of carbohydrates of this type are called Haworth formulas, after the British chemist Sir Walter Norman Haworth (St Andrew s University and the University of Birmingham) Early m his career Haworth contributed to the discovery that carbohydrates exist as cyclic hemiacetals rather than m open chain forms Later he col laborated on an efficient synthesis of vitamin C from carbohydrate precursors This was the first chemical synthesis of a vitamin and provided an inexpensive route to its prepa ration on a commercial scale Haworth was a corecipient of the Nobel Prize for chem istry m 1937... 

O-protected cyclic or acyclic carbon frameworks. The choice of acetals or ethers as derivatives allows a systematic manipulation of diols and polyols. Kinetic control and a lesser affinity for protonation on sulfur compared with oxygen allows the transformation of cyclic hemiacetals into acyclic dialkyl dithioacetals. Acetal, ether, and dithioacetal derivatives are some of the pivotal intermediates needed to explore various applications of carbohydrates in synthesis. 

The synthesis of 3-methylsulfinylchroman-4-one (600) from ethyl salicylate follows a related pathway (72JHC171), whilst the triketone (601), derived from pentane-2,4-dione and the benzoate ester, exists as the substituted chromanone, a cyclic hemiacetal (81JOC2260). 

An excellent example of the use of the TB moiety as a chiral auxiliary in asymmetric synthesis is the preparation of the above-mentioned fullerene TB derivative 71a. The high asymmetric induction in the addition of 72 to fullerene C60 was attributed to the relatively large distance between the two reacting fullerene bonds spanned by the TB tether (04AG(E)1738). Sicker et al. used 1 for discrimination of enantiomeric cyclic hemiacetals and methylacetals finding a weakly discriminating effect (94MRC727). 

A stable tetrahedral intermediate is more likely in the reduction of lactones, and DIBAL is most reliable in the reduction of lactones to lactols (cyclic hemiacetals), as in E.J. Corey s synthesis of the prostaglandins. The key step, the hydride transfer from Al, is shown in the green frame. 

A particularly successful synthesis of Epothilone A is based on two DERA-cata-lyzed steps. In these two of the seven stereocentres of Epothilone A were established. When a racemic aldehyde was released in situ from its acetal, DERA converted only the R-enantiomer into the stable cyclic hemiacetal. This is a combined kinetic resolution and carbon-carbon bond formation yielding a building block with two chiral centers. Since the alcohol function was oxidized, the optical information obtained from the kinetic resolution was lost. Thus, for the overall yield it would have been better if DERA had displayed no stereoselectivity towards the acceptor (Scheme 5.32). In the DERA-catalyzed synthesis of another part of Epothilone A DERA is again highly stereoselective. Fortunately its preference is for the S-enan-tiomer of the acceptor aldehyde, the enantiomer that has to be submitted to the carbon-carbon bond formation in order to obtain the desired building block, again a stable hemiacetal (Scheme 5.32). Indeed, both DERA-catalyzed reactions yield open chain products that form stable cyclic hemiacetals. This ensures that the equilibria of these aldol reactions are shifted towards the desired products. Further synthetic manipulations converted these intermediates into Epothilone A [55]. 

A particularly elegant application of DERA is the sequential synthesis of thermodynamically stable cyclic hemiacetal. Two DERA-catalyzed aldol reactions convert one equivalent of acceptor and two equivalents of acetaldehyde into this stable compound. A mild subsequent oxidation yielded the corresponding lactone in ex-... 

In the synthesis of verrucarin J (55) by Fraser-Reid and coworkers [62], triol 109 was treated with pyridiniura dichromate (PDC) for 3 days, resulting in oxidative cleavage of the adjacent diol to the corresponding aldehyde and further oxidation of the presumed cyclic hemiacetal intermediate gave 55 in 50% yield (Scheme 37). 

The challenge in the synthesis of an aglucone like e.g. DIMBOA consists in accomplishing the direct combination of a cyclic hydroxamic acid with a cyclic hemiacetal unit together with a donor substituent in para position to the N atom keeping in mind the principle tendency of the 2,4-di-hydroxy-2//-l,4-benzoxazin-3(4//)-one skeleton to undergo in solution degradation to a benzoxazolin-2(3/7)-one as discussed recently [108] and above. 

Glucuronic acid pathway. The first part consists of synthesis of UDP-glucuronic acid and release of free D-glucuronic acid. The second part is the metabolism of D-glucuronic acid. D-Glucuronic acid is written as both the cyclic hemiacetal and the open-chain aldohexose and two orientations of L-gulonic acid and D-xylulose are shown. P = phosphate. 

Mono-enolisation of a 1,5-diketone, then the formation of a cyclic hemiacetal, and its dehydration, produces 4//-pyrans, which require only hydride abstraction to arrive at the pyrylium oxidation level. The diketones are often prepared in situ by the reaction of an aldehyde with two moles of a ketone (compare Hantzsch synthesis, 8.14.1.2) or of a ketone with a previously prepared conjugated ketone - a chalcone in the case of aromatic ketones/aldehydes. It is the excess chalcone that serves as the hydride acceptor in this approach. 

In the key step of a synthesis of spironolactone (an aldosterone antagonist, used as a diuretic) reductive carbonylation of the optically active steroidal alkynol ethisterone yields a saturated cyclic hemiacetal (lactol) 15 with rhodium(II) acetate dimer/triphenylphosphane in 90% yield173. This reaction proceeds without loss of optical information and is interpreted as a combination of hydroformylation and hydrogenation173. 

A number of steps are required for the conversion of rac-12 into the cyclic hemiacetal rac-14 (Scheme 3). This compound is important to the rest of the synthesis, since it cannot only be prepared from tryptamine (3) and dimethyl 2-ketoglutarate (4), but can also be obtained readily in substantial amounts and in enantiomerically pure form by degradation of strychnine. As soon as enough of this relay hemiacetal has been secured, assembly of the G ring can be tackled. 

A stable tetrahedral Intermediate Is more likely In the reduction of lactones, for the same reasons that cyclic hemiacetals are more stable than acyclic ones. DIBAL Is most reliable In the reduction of lactones to cyclic hemiacetals (also known as lactols), as In this reaction from E. J. Corey s synthesis of the prostaglandins. 

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