Hemiketalization/nucleophilic addition

As nucleophihc ring-opening of epoxides is analogous to nucleophihc substitutions, the latter will not be described in this section. In addition, the hemiketalization/nucleophilic addition sequence involving the creation of a C—C bond through a nucleophihc addition onto an oxocarbenium intermediate wiU be described in the Section 3. 

Finally, reactions of flavonoid and nonflavonoid precursors are affected by other parameters like pH, temperature, presence of metal catalysts, etc. In particular, pH values determine the relative nucleophilic and electrophilic characters of both anthocyanins and flavanols. Studies performed in model solutions showed that acetaldehyde-mediated condensation is faster at pH 2.2 than at pH 4 and limited by the rate of aldehyde protonation. The formation of flavanol-anthocyanin adducts was also limited by the rate of proanthocyanidin cleavage, which was shown to take place at pH 3.2, but not at pH 3.8. Nucleophilic addition of anthocyanins was faster at pH 3.4 than at pH 1.7, but still took place at pH values much lower than those encountered in wine, as evidenced by the formation of anthocyanin-caffeoyltartaric acid adducts, methylmethine anthocyanin-flavanol adducts,and flavanol-anthocyanin adducts. The formation of pyranoanthocyanins requiring the flavylium cation was faster under more acidic conditions, as expected, but took place in the whole wine pH range. Thus, the availability of either the flavylium or the hemiketal form does not seem to limit any of the anthocyanin reactions. 

It is likely that protonation of the ketone-carbonyl in 5 facilitates an internal nucleophilic attack by either of the hydroxyls that ultimately form part of the bicyclic acetal array. Initially nucleophilic addition will afford a hemiketal whose exo-hydroxyl can protonate and ultimately be lost as water. This would lead to a stabilised oxonium ion that could cyclise to 4. In Scheme 7.9, we present one mechanism which satisfies the above discussion, but we emphasise that a myriad of mechanistic pathways can potentially operate. 

The reaction mechanism involves the nucleophilic addition of one molecule of alcohol to form a hemiacetal or hemiketal. Elimination of water occurs to form an oxonium ion and a second molecule of alcohol is then added ... 

The intermediate formed from this first nucleophilic addition is known as hemiacetal. When ketone is the starting material, the structure obtained is a hemiketal. Once the hemiacetal is formed, it is protonated and water is eliminated by the same mechanism described in the formation of imines with the only difference that oxygen donates a lone pair of electrons to force the removal of water rather than nitrogen (Following fig.). The resulting oxonium ion is extremely electrophilic and a second nucleophilic addition of alcohol to forms the acetal. 

The formation in red wines of anthocyanin-flavanol adducts had been early hypothesised by Jurd (1967,1969). Two types of adducts seem possible, (1) F-A derivatives resulting from the nucleophilic addition of the hemiketal form of an anthocyanin through their C-8 or C-6 positions at C-4 of a carbocation resulting from the cleavage of a procyanidin, and (2) A-F derivatives from the electrophilic substitution of the anthocyanin flavylium form (C-4) by a flavanol (C-8 or C-6). The former... 

Glucose is a six-carbon aldohexose. The straight chain hexose structures can become cyclic. When aldehydes and ketones undergo reactions with alcohols, hemiacetals or hemiketals are formed. In aldohexoses, the eyclic structure is formed when the hydroxyl group in the fifth carbon reacts (nucleophilic addition) with the carbonyl carbon of the aldehyde group. The product formed is a hemiacetal. The cyclization is represented in Figure 29-4. 

Alcoholate anions in alcohol solutions react with aldehydes and ketones forming ketals and acetals, or hemiacetals and hemiketals. The rates of nucleophilic additions on the carbonyl group are enhanced by protonation of the carbonyl oxygen, so these reactions are acid catalysed. 

As inert as the C-25 lactone carbonyl has been during the course of this synthesis, it can serve the role of electrophile in a reaction with a nucleophile. For example, addition of benzyloxymethyl-lithium29 to a cold (-78 °C) solution of 41 in THF, followed by treatment of the intermediate hemiketal with methyl orthoformate under acidic conditions, provides intermediate 42 in 80% overall yield. Reduction of the carbon-bromine bond in 42 with concomitant -elimination of the C-9 ether oxygen is achieved with Zn-Cu couple and sodium iodide at 60 °C in DMF. Under these reaction conditions, it is conceivable that the bromine substituent in 42 is replaced by iodine, after which event reductive elimination occurs. Silylation of the newly formed tertiary hydroxyl group at C-12 with triethylsilyl perchlorate, followed by oxidative cleavage of the olefin with ozone, results in the formation of key intermediate 3 in 85 % yield from 42. 

Aldehydes and ketones react with alcohols to form hemiacetols and hemiketah, respectively. In this reaction the alcohols react in typical fashion as the nucleophile. When aldehydes and ketones are attacked by a nucleophile, they undergo addition. Aldehydes and hemiacetals, and ketones and hemiketals, exist in equilibrium when an aldehyde or ketone is dissolved in an alcohol however, usually the hemiacetal or hemiketal is too unstable to isolate unless if exists as a ring structure. If a second molar equivalent of alcohol is added, an oceiuf is formed from a hemiacetal, or a ketal is formed from a hemiketal. 

H20 or alcohols as nucleophiles give low molecular weight compounds when they add to the C=0 double bond of carbonyl compounds. These addition products are called aldehyde or ketone hydrates (Section 9.1.1) and hemiacetals or hemiketals (Section 9.1.2), respectively, depending on whether they result from the addition to an aldehyde or a ketone. Today, one no longer distinguishes systematically between hemiacetals and hemiketals, but the expression hemiacetal is frequently used to cover both. 

As already mentioned, <5-hydroxyfeto s may be present in the open-chain form or as an isomeric cyclic hemiketal, depending on their substitution pattern. For example, a polyhy-droxylated 5-hydroxyketone, D-fructose, is present exclusively in the form of hemiketals (Figure 9.7). Responsible for this equilibrium position is the fact that the carbonyl group involved contains an electron-withdrawing group in both a-positions, which favors the addition of nucleophiles (see Section 9.1.1). 

Cyclopropanone ethyl hemiketal was converted to the vinyltrimethylsiloxy cyclopropane by the addition Of the acetylenic nucleophile 153, followed by the steps shown in equation 38 and Sehettie 58. Thermal ring enlargement provided the 3-substituted... 

In acidic media, polarized multiple bonds often undergo acid catalyzed addition, and a common mode of addition is the Ad 2. Deprotonation of the nucleophile by solvent gives the neutral compound. Common examples of this easily reversible Adg2 reaction are the formation of hydrates (NuH is H2O) and, if NuH is ROH, hemiacetals (from aldehydes) and hemiketals (from ketones). Usually this reaction favors reactants. 

The Ad]q2 addition creates a hemiorthoester that is just an ester version of a hemiketal. The tetrahedral intermediate is too hindered to serve as a nucleophile, and if it is protonated it yields a species that is uphill in energy from the starting ester. A AH calculation shows that a stronger carbonyl double bond (177 kcal/mol) was replaced with two C-O single bonds (2 x 86 = 172 kcal/mol), so this reaction is expected to be uphill by about 5 kcal/mol. Since this equilibrium will favor reactants, we should explore further. 

Figure A.4 The reaction cube for the addition of a nucleophile to a carbonyl in protic media (for hemiketal/hemiacetal, NuH = ROH) where O p.t. is proton transfer to oxygen and Nu p.t. is proton transfer to the nucleophile. (Modified with permission from P. H. Scudder, J. Org. Chem., 1990, 55,4238-4240. Copyright 1990 by the American Chemical Society.)...

A possible biogenesis of the macroline-cabucraline dimers derives from a Michael reaction of the nucleophilic C(IO ) of cabucraline (299) with the unsaturated aldehyde 300 (which may be regarded as an opened form of talcarpine) to give an addition product 301, which on subsequent hemiketalization or ketalization furnishes the dimeric compounds 296 and 297 [83]. 

In this reaction, both the flavanol and the anthocyanin act as nucleophiles while the protonated form of the aldehyde is the electrophilic species. It must be noted that the flavylium form of the anthocyanin is an electrophilic entity while the hydrated hemiketal form is a nucleophilic entity. During the addition process, the anthocyanin acts thus as a nucleophile in its hydrated hemiketal form and the obtained adduct is then dehydrated to the corresponding flavylium (Figure 3). 

In the domain of synthetic inhibitors, chloromethylketone derivatives of specific substrates are potent irreversible covalent inhibitors of the serine proteases, alkylating the active-center histidine at N-2. X-ray crystallographic studies led to the suggestion that, in addition to the above alkylation, there was also nucleophilic attack by the active-center serine hydroxyl to form a hemiketal, which is stereochemically analogous to the tetrahedral intermediate purported to occur during catalysis. 

The addition of a nucleophile on an oxocarbenium intermediate is also an efficient way to access 2,6 ds-THPs and 2,6 tra 5-THPs depending on the substitution pattern of the hemiketal/ketal and on the conditions. An axial attack of the nucleophile on the six-membered half-chair G occurred from the side that favors the low-energy chair transition state rather than the twist-boat transition state (Scheme 35). 

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