Y-hydroxy lactol

Fig. 7. Nicolaou s total synthesis oxidation to the y-hydroxy lactol. PDC = pyridinium dichromate, DMP = Dess-Martin periodinane.

These enol carbamates are stable to acid, but undergo methanolysis in the presence of methanesulfonic acid and Hg(OAc)2 to form y-lactol methyl ethers, with retention of configuration at C, and C4. These products can be oxidized (8, 97) to -y-lactones. The overall process thus provides a route to protected -y-hydroxy aldehydes. 

The application of resin-supported peptides for the asymmetric Michael addition was further investigated by the group of Kudo for the preparation of p-substituted y-lactones via addition of boronic acids to y-hydroxy-a,p-un-saturated aldehydes followed by an additional oxidation step. Intense screening of resin-supported peptide catalysts gave the desired intermediate lactols in moderate to excellent yield and enantioselectivity. ROESY and CD spectra of related peptides indicated that both the p-turn as well as a partial helicily of the peptide are important for the high enantioselectivity of the catalyst. 

Finally, Kim reported the asymmetric conjugate addition of organoboronic acids to y-hydroxy a,p-unsaturated aldehydes catalysed by diarylprolinol silyl ethers, which afforded the corresponding p-substituted y-lactols in good yields. High enantioselectivities of up to 91% ee were obtained in the case of... 

Tsuchihashi has studied additions to y-hydroxy aldehydes, which are found in their hemiacetal forms (Equation 14) [86, 87]. The addition of MeTiCl3 or MeTi(Oi-Pr)j to lactol 145 proceeded with high selectivity. The major product corresponded to the 1,4-syw diol 146, in contrast to the 1,4-anti diol product 143 obtained from additions to the acyclic O-benzyloxy aldehyde 141 above [86]. 

Reduction of lactones leads to cyclic bemiacetals of aldehydes. With a stoichiometric amount of lithium aluminum hydride in tetrahydrofuran at —10° to —15° and using the inverse technique, y-valerolactone was converted in 58% yield to 2-hydroxy-5-methyl tetrahydrofuran, and a-methyl-5-caprolac-tone in 64.5-84% yield to 3,6-dimethyl-2-hydroxytetrahydropyran [1028]. Also diisobutylaluminum hydride in tetrahydrofuran solutions at subzero temperatures afforded high yields of lactols from lactones [7024]. 

A more useful way of reducing esters to ethers is a two-step procedure applied to the reduction of lactones to cyclic ethers. First the lactone is treated with diisobutylaluminum hydride in toluene at —78°, and the product - a lactol - is subjected to the action of triethylsilane and boron trifluoride etherate at —20° to —70°. y-Phenyl-y-butyrolactone was thus transformed to 2-phenyltetrahydrofuran in 75% yield, and 5-lactone of 3-methyl-5-phenyl-5-hydroxy-2-pentenoic acid to 4-methyl-2-phenyl-2,3-dihydropyran in 72% yield [1034]. 

It has been demonstrated by Pancrazi, Ardisson and coworkers that an efficient kinetic resolution takes place when an excess (2 equivalents) of the racemic titanated alkenyl carbamate rac-334a (R = Me) is allowed to react with the enantiopure )-hydroxyaldehyde 341 or alternatively the corresponding y-lactol 340, since the mismatched pair contributes to a lower extent to the product ratio (equation 91) . Under best conditions, the ratio of the enantiomerically pure diastereomers 3,4-anti-4,5-syn (342) and 3,4-anti-4,5-anti (343) is close to 14 1. Surprisingly, approximately 9% of the iyw,iyw-diastereomer 344 resulted when the starting (ii)-crotyl carbamate was contaminated by the (Z)-isomer. The reasons which apply here are unknown. Extra base has to be used in order to neutrafize the free hydroxy group. The pure awft, awfi-product 345 was obtained with 85% yield from the reaction of the (W-oxy-substituted titanate rac-334b and lactol 340. 345 is an intermediate in the asymmetric synthesis of tylosine . ... 

If the 4-hydroxy group is free, then when using methanol as solvent, anomeric lactol ethers 356 are formed with high yields (equation 95). Oxidation by the Grieco method leads to y-substituted y-lactones 357 (equation 95)209,224,231,243,249,260 ... 

To a solution of 0.50 g of (-)-3a,5a-dihydroxy-2p-[(3RS)-3-hydroxy-3-methyl-trans-octenyl]cyclopentane-la-acetic acid - lactone 3-benzoate in 15 ml of tetrahydrofuran at -78°C under nitrogen was added 10 ml of 10% diisobutylaluminum hydride in toluene. After a gas evolution was ceased, the reaction was quenched by addition of 10 ml of saturated aqueous ammonium chloride. The resulting mixture was stirred at room temperature, filtered through Celite, and extracted with ethyl acetate. Extract was evaporated to give 0.48 g of (-)-3a,5a-dihydroxy-2p-[3-(RS)-3-hydroxy-3-methyl-trans-octenyl]cyclopentane-l-a-acetaldehyde y-lactol 3-benzoate as an oil. 

Five- or six-membered cyclic hemiketals, which are also referred to as lactols, can form from y- or 8-hydroxy kefones. However, hemiketals of this type are not necessarily more stable than the acyclic hydroxyketone isomers because ketones are less thermodynamically suitable to add nucleophiles than are aldehydes (Section 9.1.1). 

Fig. (10). Reductive generation of the lactol unit from a lactone A general synthesis for the 2-hydroxy-2/f-1,4-benzoxazin-3(4/y)-one skeleton...

It has been demonstrated by Pancrazi, Ardisson et al.,that an efficient kinetic resolution takes place when an excess of the racemic titanoalkenyl carbamate 266a is allowed to react with the enantiopure oo-hydroxy-aldehyde 300 or alternatively the corresponding y-lactol 299, since the mismatched pair contributes to a lower extent to the product ratio [Eq. (88)] [198]. 

As a special case, the formation of hemiacetals 2 (lactolization) during the hydroformylation of hydroxy-functionalized olefins, such as allyl or homoallyl alcohols, has to be mentioned (1, Y= O, Scheme 5.70). With these substrates, the reaction occurs in an intramolecular manner. In the presence of an external alcohol, the cyclic hemiacetal can further react to give a nonsymmetric cyclic acetal 3. Hemiacetals can be subjected to hydrogenation to afford diols 4. Under reducing conditions and in the presence of amines, amino alcohols 5 are formed both are valuable building blocks in fine chemistry. Alternatively, oxidation gives lactones 6 [5]. By dehydration of hemiacetals, cychc vinyl ethers 7 are formed. The same transformation with allylamines (Y=NR) gives cyclic hemiaminals, A/ ,0-acetals, lactames, or vinyl amines. 

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