Internal acetal functionality

As noted above, one difficulty which prevents versatile use of levoglucosenone 1 is its sturdy internal acetal functionality. We, therefore, designed12 a levoglucosenone carrying a handle on an appropriate position such as 6-alkoxymethyllevoglucosenone 20 so as to cleave the internal acetal functionality without difficulty. If 20 is available, its acetal linkage may be cleaved after conversion into a halomethyl derivative 21 to give a hemiacetal 22 under reductive conditions (Scheme 6). 

Subjection of intermediate 16 to the action of 3 n aqueous HC1 in THF results in the formation of monocyclic lactol 14. In the presence of aqueous acid, the internal acetal grouping in intermediate 16 is hydrolyzed and lactol 14 is produced after the liberated secondary hydroxyl group attacks the terminal aldehyde carbonyl positioned five atoms away (see intermediate 15). Protection of the free aldehyde function in 14 with 1,1-dimethylhydrazine proceeds smoothly under dehydrating conditions and affords intermediate 13 in an overall yield of 72 %. 

Internal acetals are found in several biological active natural products such as di-hydroclerodin [209] and aflatoxins as 6/2-70 [210]. An efficient formation of this functionality was described by Eilbracht and coworkers [211], using a hydroformylation of an enediol as 6/2-71 to give the tetrahydrofurobenzofurans 6/2-72 (Scheme 6/2.15). 

An ingenious new method for the preparation of Woodward s intermediate (97) by Pearlman70 constitutes another formal synthesis of reserpine. The essence of this new approach is an adaptation of the de Mayo reaction which allows the introduction of vicinal aldehyde and acetic ester functions on to a double-bond (Scheme 13). An internal [2tt + 27r] photocyclization of the diene (98) gave the tetracyclic cyclobutane derivative (99), which was converted into the ester (100) by standard procedures. Methanolysis of the acetate function with concomitant retro-aldol fission completed the introduction of the vicinal aldehyde and acetic ester functions obvious manipulation then gave the desired intermediate (97). 

In general, the chemical properties of nareline are those expected of a compound containing the complex functionality of (173), including the unusual hemiacetal unit formed from an aldehyde and a hydroxylamine derivative. However, the oxidation by chromic acid in acetic acid takes a course that would have been difficult to predict, and affords a product, oxonareline (175), which is presumably formed from (173) by oxidative fission of the 2, 3, Nb system to give an oxindole function (176), followed by internal acetal formation between oxygen attached to C-5 and a carbinolamine equivalent at C-3.98... 

Acetals are unique as chiral auxiliaries since the prochiral carbon atom is tetrahedral, not trigonal, as in all other examples.t l In the presence of a Lewis acid the acetal function becomes a powerful electrophile, capable of reacting with electron-rich double bonds. The origin of the selectivity is believed to be the preferential complexation of the Lewis acid with the less-hindered oxygen as in (102).[4i] Reaction takes place by Sn2 displacement with inversion at the electrophilic carbon to give (103). Of interest in this synthesis of the lactone portion of mevinolin (105)[42] is the use of 3-elimi-nation to remove the chiral auxiliary and internal chelation to reduce the ketone (104) stereoselectively, as already described in section... 

Oxygen functionalities, such as alcohols, ethers, and acetate groups, and halogens at the allylic position, deshield when the fluorine is at the terminal position and shield when it is at the internal 2-position (Scheme 3.43). 

This intermediate, like 6-APA, incorporates a primary amine that can be coupled with a host of side chains. The presence of an additional reactive function, the allylic acetate at the 3 position, provides an additional center that can be modified. The observation that both types of modifications provided unproved antibiotics has resulted in the synthesis of hundreds of analogues. The very few examples discussed below barely scratch the surface in this field. One of the earliest examples of a doubly derivatized 7-ACA derivative, cephalothin (19-1), is stUl widely used as an antibiotic. Acylation of (18-4) with 2-thiophenylacetyl chloride gives the corresponding amide (19-2). Heating that product with pyridine leads to the displacement of the allyl acetate by the basic nitrogen. The resulting product, cephalothin (19-3), is isolated as the internal betaine [23]. 

The dynamism of these systems is further illustrated in the chemistry of the adduct of vinyl acetate (Entry 12), where reversible coordination of the C=0 function dominates, but competes with electrophilic attack of the vinyl group of the ester moiety (Scheme 18).132 Irreversible proton transfer from the OH tautomer of this minor olefin adduct results in the expulsion of CeFsH and formation of the internally coordinated adduct shown as the eventual thermodynamic product in the reaction. A related chelating RC(=0)0R species results from the hydroboration of H2C=C(H)CH2CH2C(=0)0Et using HB(C6F5)2.30... 

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