Intramolecular hemiacetals

The reaction of the carbinol 198 with acetone leads to dienic 1,3-dioxolanes 200 as a result of the intramolecular addition of the hydroxyl group of the intermediate hemiacetal 199 to its triple bond (73ZOR1594). 

If the carbonyl and the hydroxyl group are in the same molecule, an intramolecular nucleophilic addition can take place, leading to the formation of a cyclic hemiacetal. Five- and six-membered cyclic hemiacetals are relatively strain-free and particularly stable, and many carbohydrates therefore exist in an equilibrium between open-chain and cyclic forms. Glucose, for instance, exists in aqueous solution primarily in the six-membered, pyranose form resulting from intramolecular nucleophilic addition of the -OH group at C5 to the Cl carbonyl group (Figure 25.4). The name pyranose is derived from pyran, the name of the unsaturated six-membered cyclic ether. 

The indium-mediated allylation of trifluoroacetaldehyde hydrate (R = H) or trifluoroacetaldehyde ethyl hemiacetal (R = Et) with an allyl bromide in water yielded a-trifluoromethylated alcohols (Eq. 8.56).135 Lanthanide triflate-promoted indium-mediated allylation of aminoaldehyde in aqueous media generated (i-airiinoalcohols stereoselectively.136 Indium-mediated intramolecular carbocyclization in aqueous media generated fused a-methylene-y-butyrolactones (Eq. 8.57).137 Forsythe and co-workers applied the indium-mediated allylation in the synthesis of an advanced intermediate for azaspiracids (Eq. 8.58).138 Other potentially reactive functionalities such as azide, enone, and ketone did not compete with aldehyde for the reaction with the in situ-generated organo-indium intermediate. 

It is well known that in the cyclization of a y-hydroxy aldehyde to form the corresponding six-membered ring hemiacetal through intramolecular cyclization the hemiacetal form always predominates (48). This might account for the fact that no noticeable carbonyl absorption has been observed in the IR and NMR spectra of 54. However, the equilibrium between the hemiacetal and the aldehyde forms might shift in favor of the aldehyde form as the borane reduction proceeds until 54 is completely transformed to 55. 

On the basis of these experimental results, a possible mechanism has been proposed for the reaction of 1-215 with Sml2 (Scheme 1.52). After formation of the syn-complex A, a rearrangement occurs to give the aldehyde B, which coordinates to the added aldehyde RCHO to afford complex C. Subsequent samarium-catalyzed nucleophilic attack of the secondary alcohol to the carbonyl of RCHO generates a hemiacetal, D. There follows an irreversible intramolecular 1,5-hydride transfer via... 

The aldehyde or ketone group of monosaccharides can undergo an intramolecular reaction with one of its own hydroxyl groups to form a cyclic, hemiacetal, or hemiketal structure, respectively (Figure 1.26). In aqueous solutions, this cyclic structure actually predominates. The open-chain aldehyde or ketone form of monosaccharides is in equilibrium with the cyclic form, but the open structure exists less than 0.5 percent of the time in aqueous environments. It is the... 

A novd example of a catalytic enantioselective domino process1201 is the inter-intramolecular nitro-aldol reaction described by Shibasaki et al which generates substituted indanones. As catalyst a praseodym-heterobimetallic complex with binaph-thol as chiral ligand is employed. Treatment of keto-aldehyde 41 with nitromethane in the presence of the catalyst 46 at -40 °C and successive warming to room temperature affords diredly the produd 42 in an overall yield of 41 % and 96 % ee after several recrystallizations (scheme 9). As intermediates the nitromethane adduct 43 and the hemiacetal 44 can be proposed. In a second aldol reaction 44 leads to 45 which isomerizes to the thermodynamically more stable epimer 42. 

The tetrahydroquinones referred to above are readily reduced to tetrahydro-l-naphthoquin-4-ol derivatives, the photochemistry of which is also of interest. In solution these materials, 117, undergo intramolecular (2 + 2) photocycloaddition to give products, 118, having the tetracyclo[5.3.0.02-604 2]decane ring skeleton. If their configuration permits, these products immediately convert into hemiacetals, 119. 

Fig. 6.25. Simplified mechanism of two degradation reactions between peptides and reducing sugars occurring in solids, a) Maillard reaction between a side-chain amino (or amido) group showing the formation of an imine (Reaction a), followed by tautomerization to an enol (Reaction b) and ultimately to a ketone (Reaction c). Reaction c is known as the Amadori rearrangement (modified from [8]). b) Postulated mechanism of the reaction between a reducing sugar and a C-terminal serine. The postulated nucleophilic addition yields an hemiacetal (Reaction a) and is followed by cyclization (intramolecular condensation Reaction b). Two subsequent hydrolytic steps (Reactions c and d) yield a serine-sugar conjugate and the des-Ser-peptide...

The proposed mechanism for the photochemical cleavage of nBn ethers (see Scheme 3) involves a n tt transition of the nitrogroup and an intramolecular, benzylic hydrogen abstraction by the excited nitro group. Rearrangement leads to a hemiacetal that decomposes to a free alcohol and to 2-nitrosobenzaldehyde that undergoes further thermal and photochemical reactions. 

Generally, carbonyl derivatives have to be protected during synthesis. In the case of carbohydrate synthesis, this is frequently done through the intramolecular formation of hemiacetals, followed by alkylation or acylation. In the first instance, glycosides are formed. Light-sensitive glycosides were discussed in Section 11,2. 

Ring-chain tautomerism in which a ring closure occurs via intramolecular addition of an OH group to a C=0 bond (Scheme 4) is observed widely in organic chemistry. This type of tautomerism is sometimes called ketolo-lactolic, keto-lactolic, or oxo-cyclo tautomerism. The ring tautomers are usually referred to as cyclic hemiacetals or hemiketals. 

Intramolecular transannular OH-group addition to the C=0 bond yields bicyclic hemiacetals of erythromycin [90JCS(P1)1409 91JCS(P2)1481] and related polyfunctional macrocycles. 

LiAlH4 as this avoids protonation of the enolate and the production of any over-reduction products. Cholest-4-en-3-one may be reduced to cholestanone (5a 5/8,1 19) with alkali-metal carbonyl chromates. The studies on intramolecular hydride shifts on hydroxy-ketones and -aldehydes have been extended. " The hydride shifts were examined in a number of y- and 5-hydroxy-carbonyI compounds by heating the substrates with alkaline alumina containing D2O. Exchange of protons on the carbon a to both oxygen functions signals the intramolecular hydride shift typically, the hemiacetals (95) and (96) each incorporate up to six deuterium atoms. The general conclusion, in common with literature precedent, is that, whereas 1,5-shifts are common, 1,4-shifts are rare. 

Reaction at the C atom of nitronate salts is known with a variety of electrophiles, such as aldehydes (Henry reaction) and epoxides (191-193). Thus the incorporation of the nitro moiety and the cyclization event can be combined into a tandem sequence. Addition of the potassium salt of dinitromethane to an a-haloaldehyde affords a nitro aldol product that can then undergo intramolecular O-alkylation to provide the cyclic nitronate (208, Eq. 2.17) (59). This process also has been expanded to a-nitroacetates and unfunctionalized nitroalkanes. Other electrophiles include functionalized a-haloaldehydes (194,195), a-epoxyaldehydes (196), a-haloenones (60), and a-halosulfonium salts (197), (Chart 2.2). In the case of unsubstituted enones, it is reported that the intermediate nitronate salt can undergo formation of a hemiacetal, which can be acetylated in moderate yield (198). 

The above dramatic dependence of regio- and stereoselectivity on the nature of the metal can be explained by the reaction mechanism shown in Scheme 11.49 (167). The nitrone cycloadditions of allylic alcohols are again magnesium-specific just like the nitrile oxide reactions described in Section 11.2.2. Magnesium ions accelerate the reaction through a metal ion-bound intramolecular cycloaddition path. On the other hand, zinc ions afford no such rate acceleration, but these ions catalyze the acetalization at the benzoyl carbonyl moiety of the nitrone to provide a hemiacetal intermediate. The subsequent intramolecular regio- and stereoselective cycloaddition reaction gives the observed products. 

The tandem transesterification/[3 + 2]-cycloaddition methodology is be a powerful synthetic tool, since it guarantees high diastereoselectivity even under thermal conditions. It has been successfully apphed to synthetic work of the N-terminal amino acid component of Nikkomycin Bz (Scheme 11.53) (173). Thus, the sugar-based oxime is condensed with a glyoxylate hemiacetal to produce a chiral nitrone ester, which is then reacted with ( )-p-niethoxycinnamyl alcohol in the presence of a catalytic amount of TiCU at 100 °C. After the intramolecular cycloaddition, the... 

The reactivity of the 2,5-anhydrides of aldoses is determined by two essential structural features that do not exist in the sugars, namely, the presence of an oxolane ring and of a carbonyl group (most frequently, free) a to the ring-oxygen atom. These two characteristics make the 2,5-anhydroaldoses closer to tetrahydro-2-furaldehyde than to the aldoses, where only in exceptional cases is the carbonyl group not masked by the formation of an intramolecular, five- or six-membered, hemiacetal ring. 

Instead of necessarily being the consequence of the formation of intramolecular hemiacetals, it seems likely that the mutarotation observed with the 2,5-anhydroaldoses could also be attributable to the formation of hydrates or of unstable hemiacetals with hydroxyl-ated solvents, or even to dimerization. Known examples in related series lend support to these suppositions. It is known, for example, that l,2-0-isopropylidene-5-aZdehydo-a-D-xt/lo-pentodialdo-l,4-fu-ranose (98) readily forms102 a dimer (99). Working with related com-... 

From prior attempts at FruA-catalyzed DHAP additions to glyoxal or glutaric dialdehyde no product had been isolated, probably because the dialdehydes can cause cross-linking of the protein and thereby irreversibly destroy its enzymatic activity. On the other hand, hydroxylated aldehydes were assumed to form stable intramolecular hemiacetals in aqueous solution, which may mask the reactivity of free dialdehydes. Using the branched-chain glutaric dialdehyde 38 as a potential precursor to carbon-linked disaccharide mimetics (Scheme 2.2.5.14), we... 

Hexane-1,6-diol was found to undergo an oxidation-cyclization process at elevated temperatures (250 °C) in the presence of a Cu-Cr catalyst supported on kieselguhr to yield 2,3,4,5-tetrahydrooxepin (68) (65JOC335). The final stage of the latter reaction involves a dehydration of the hemiacetal 2-hydroxyoxepane (75) as indicated in equation (38). An alternative type of base-induced cyclization (equation 39) involving intramolecular nucleophilic attack has been used in the synthesis of 4-ethoxycarbonyI-2,3,6,7-tetra-hydrooxepin (153) (73JOC1767). 

Mechanism. The first step is the typical acid-catalysed addition to the carbonyl group. Then the alcohol nucleophile attacks the carbonyl carbon, and forms a tetrahedral intermediate. Intramolecular proton transfer from nitrogen and oxygen yields a hemiacetal tetrahedral intermediate. The hydroxyl group is protonated, followed by its leaving as water to form hemi-acetal, which reacts further to produce the more stable acetal. 

Zinc bisenolate 136 (Figure 11) is prepared by the transmetallation of propiophenone lithium enolate with 0.5 equivalents of ZnBr2 136 reacts with aldehydes, both aliphatic and aromatic, in a domino aldol reaction which mimics the action of aldolases167. The first aldol reaction between 136 and the aldehyde produces zinc aldolate 137, which then undergoes a second intramolecular aldol addition to adduct 138. Spontaneous hemiacetalization affords 139, where all large substituents occupy equatorial positions168. 

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