Ketal internal

This process, which predominates at low temperatures, causes migration of internal ketal stmctures along a chain but does not involve the dissociation to separate aryloxy radicals that occurs during the redistribution process. 

Some insect pheromones are internal ketals. We have already mentioned multistriatin (pp T 2 and 99) and frontalin p 193). Brevicomin (22) is another example. Disconnection of the ketal gives (23) containing a 1,2-diol. Among other syntheses, hydroxy-lation of protected enone (24) by epoxidation and acid catalysed rearrangement gives brevicomin stereo-specifically,... 

This prediction was borne out for reactions of 2,3-dioxabicyclo[2.2.2]octane 2 27) and the 7-substituted-[2.2.1]-peroxides 10201 and 1121) which afforded 62b-d respectively upon treatment with either methanolic KOH or triethylamine. The bismercurated-[3.3.2]-peroxide 47 reacted similarly with aqueous NaOH, but the resultant 5-hydroxycyclooctanone underwent further rearrangement to the internal hemi-ketal.49)... 

The reaction worked with both internal and terminal alkynes (except silylated alkynes) and in many solvents, even in the neat alcohol added [105]. The mechanism proposed involved two catalytic cycles first, gold catalysis would lead to dihydro-furan by a fast intramolecular reaction then, the subsequent slower intermolecular reaction would be produced by the addition of alcohol to the enol ether to deliver a ketal (Scheme 8.18). 

EthytidenationThe ketone (2) undergoes Wittig reaction with ethylidene-triphenylphosphorane in yields of only about 40%, with recovery of 2. The difficulty may be enolization promoted by the basic ylide. Use of the Grignard reagent from a-chloroethyltrimethylsilane results only in reduction of the carbonyl group. The problem is solved by use of 1, which reacts with 2 to give the internal ketal 3. Hydro-... 

The enone lactone 410 could also be obtained in a single operation from the ozonolysis in methanol of hemi-ketal [3 (118). In this reaction, 41 produced first the diketone 14 which underwent an internal aldol condensation to 415 which is nicely set up to give K) vi a the intermediate 416. 

A word about nomenclature. Once upon a time, chemists made a useful distinction between acetals (derived from aldehydes) and ketals (derived from ketones) which has since perished. The International Union of Pure and Applied Chemistry (IUPAC) decided (Rule C-331.1) that the term ketal is redundant and that the term acetal should now apply to all 1,1-to-ethers whether derived from aldehydes or ketones. Nevertheless, in A Guide to IUPAC Nomenclature of Organic Compounds, Recommendations 1993 (R. Panico, W.H. Powel, I-C Richter, Eds. Blackwell Science Oxford, 1993) the IUPAC graciously reinstated the term ketal , by popular demand, as a subclass of the generic term acetals (Rule R-5.6,4),... 

Alcohols add to alkynes under certain conditions to give vinyl ethers. In an excess of alcohol, and in the presence of a platinum catalyst, internal alkynes are converted to ketals. " The alcohol to alkyne addition reaction is quite useful for the preparation of heterocycles. Dihydrofurans, " furans, " benzofurans, " and pyran... 

Carbohydrates are either polyhydroxyaldehydes (aldoses, oses) or polyhydroxyke-tones (ketoses, uloses) there is an electron gap at their carbonyl carbon atom. Typically, aldehydes and ketones accept nucleophiles such as water to form hydrates or alcohols to form hemiketals (5.1 and 5.3) and hemiacetals (5.4 and 5.6), respectively. In pentoses, pentuloses, hexoses, hexuloses, and higher carbohydrates, one of the hydroxyl groups can play the role of internal nucleophile. Thus, open-chain structure (5.2 and 5.5) cyclizes into internal hemiacetals and ketals, all with either five- (5.1 and 5.3) or six- (5.4 and 5.6) membered cycles. 

Animal experiments indicate a sixfold increase in potency over EM on oral administration that is attributed to the absence of inactivation by internal ketalization. It is interesting that simpler oximie derivatives, although also stable, showed weaker antibacterial action. 

To recall some basic concepts, it may be useful to discuss a simple example the geometry of the idealized ketal fragment shown in Figure 2.1. The relative positions of the five nuclei are described by9(=3x5-6) internal coordinates. Taking these as bond distances and angles, we see immediately that the 4 bond distances are independent quantities - any one can be varied independently of the others. It follows... 

Table 2.2. Symmetry coordinates of a ketal fragment, based on the internal coordinates shown in Figure 2.1, and their irreducible representations...

A series of rapid chemical quench experiments under single enzyme turnover conditions using radiolabeled S3P or PEP revealed that the tetrahedral ketal phosphate enzyme intermediate was formed as a new peak upon HPLC analysis with detection of the radiolabel. The time course revealed that the formation of the tetrahedral intermediate species paralleled the disappearance of PEP substrate and formation of the EPSP product thus establishing that it was a kinetically competent species. Isolation of the tetrahedral ketal phosphate intermediate using C-2 PEP and S3P as substrates coupled with rapid chemical quench was carried out in conjunction with H-, C-, and P- NMR to provide a definitive structure proof Thus with these studies we have satisfied the criteria for a true reaction intermediate in terms of a chemically plausible mechanism, structure proof, and kinetic competence. Additional studies support the mechanism for EPSP synthase described (Scheme 4, pathway a) including observation of the intermediate bound to the enzyme at internal equilibrium using solution NMR and C-2 PEP as well as using rapid freeze-quench/solid-state NMR studies. ... 

Furthermore, it is difficult to incorporate the EPSP ketal as an intermediate in a chemically plausible reaction mechanism for converting S3P and PEP into EPSP and P . In the experiments described above using solution NMR and C-2 PEP to observe the tetrahedral intermediate on the enzyme at internal equilibrium with substrates and products, the EPSP ketal was formed over longer times as a dead-end breakdown product of tetrahedral ketal phosphate intermediate. " The formation of EPSP ketal most likely occurs through trapping of a protonated enol form of PEP using the 4-OH group of S3P as a nucleophile. It is believed that this side product is also observed in a solid-state NMR experiment."" ... 

The early macrolides of the erythromycin class are chemically unstable because of rapid acid-catalyzed internal cyclic ketal formation, leading to inactivity (Fig. 38.30). This reaction that occurs in the Gl tract is clinically important. Most acid-susceptible macrolides are administered in coated tablets to minimize this... 

The oxidation of phenol ethers containing the azido group as an internal nidogen nucleophile provides a useful methodology for the construction of nitrogen heterocycles [370-372], Kita and coworkers have reported an efficient synthesis of quinone imine ketals 308 from the substituted phenol ethers 307 bearing an alkyl azido side chain (Scheme 3.126) [371]. 

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