Alcohols hindered

Mono MOM derivatives of diols can be prepared from the ortho esters by diiso-butylaluminum hydride reduction (46-98% yield). In general, the most hindered alcohol is protected. ... 

THF, Et3NHCe(ni) (N03)6, 50-100°, 8 h, 30-98% yield. Hindered alcohols give the lower yields. The method was also used to introduce the THP group with tetrahydropyran. 

A large number of silylating agents exist for the introduction of the trimethylsilyl group onto a variety of alcohols. In general, the sterically least hindered alcohols are the most readily silylated, but these are also the most labile to hydrolysis with either acid or base. Trimethylsilylation is used extensively for derivatization of... 

TBDMSCl, KH, 18-crown-6, THF, 0°-rt, 78% yield.This combination of reagents is very effective in silylating extremely hindered alcohols. 

CF3CO3H, 20°, 4 h, 83% yield. In this case a hindered alcohol was converted to the TFA derivative. The use of TFA failed to give a trifluoroacetate. This method is probably not general. 

Treatment with LiAlH4/AlCl3, BHa-NMea/AlCla, " BH3, THF, heat, or NaBH3CN/TMSCl, CH3CN results in cleavage at the least hindered side of the ketal, whereas treatment with NaBH3CN/HCl or NaBH3CN/TFA/DMF" results in formation of an MPM ether at the least hindered alcohol. 

In polyhydroxylated systems the regiochemical outcome is determined by initial reaction at the sterically less hindered alcohol. ... 

Carboxylic acids react with trifluoroacetic anhydride to give mixed anhydrides that are especially useful for the acylation of hindered alcohols and phenols ... 

The stereochemistry of reduction of 20-ketones with LiAlH4 is more influenced by substituents than that of other ketones. Usually reduction of the 20-ketone gives the more hindered -alcohol.208 stated that when C-17 has a substituent, the reduction yields almost quantitatively the 20)5-ol. However, the evidence on this point is conflicting Fukushima and Meyer claim that with a 17a-hydroxy present the 20a-ol is the predominant product except when an 11-ketone is being reduced simultaneously. Other results appear to support this conclusion, but... 

PhCH20CH2Cl, (/-Pr)2NEt, 10-20°, 12 h, 95% yield. Bu4N r can be added to increase the reactivity for protection of more hindered alcohols. 

NaH, /7-MeOQH4CH2Br, DMF, —5°, 1 h, 65%. Other bases, such as BuLi, ° dimsyl potassium," and NaOH under phase-transfer conditions," have been used to introduce the MPM group. The use of (n-Bu)4N I for the in situ preparation of the very reactive p-methoxybenzyl iodide often improves the protection of hindered alcohols." In the following example, selectivity is probably achieved because of the increased acidity of the 2 -hydroxyl group ... 

Me2BBr, TEA, BH3-THF, —78° warm to —20° over 1 h, 70-97% yield. These conditions cleave the benzylidene acetal, to leave the least hindered alcohol as a free hydroxyl. If diborane is omitted from the reaction mixture and the reaction is quenched with PhSH and TEA, the benzylidene group is cleaved to give an (9,5 -acetal [ROCH(SPh)Ph]. Acetonides are cleaved similarly." ... 

Nicolaou and co-workers established the severely strained A-ring oxazole (21) in their total synthesis of antitumor agent diazonamide A through initial oxidation of the hindered alcohol of intermediate 20 with TPAP and subsequent Robinson-Gabriel cyclodehydration of the resultant ketoamide with a mixture of POCI3 and pyridine (1 2) at 70°C. ... 

Hydrogen-bonding is more difficult in hindered alcohols. 

A Mitsunobu reaction for sterically hindered alcohols Qg% Tsudoda. T. Yamamiya, Y. Kawamura, Y. Ito, S. Tetrahedron Lett., 1995, 36, 2529... 

The inclusion of DMAP to the extent of 5-20 mol % in acylations by acid anhydrides and acyl chlorides increases acylation rates by up to four orders of magnitude and permits successful acylation of tertiary and other hindered alcohols. The reagent combination of an acid anhydride with MgBr2 and a hindered tertiary amine, e.g., ( -Pr)2NC2H5 or 1,2,2,6,6,-pentamethylpiperidine, gives an even more reactive acylation system, which is useful for hindered and sensitive alcohols.105... 

Compound (32) phosphorylates hindered alcohols in the presence of EtOH consistent with a dissociative mechanism involving a metaphosphate-like intermediate,since it proceeds with considerable racemization at phosphorus(Scheme 6). The extent of phosphoryl transfer which proceeds with retention of configuration is ca. 357, (i e. ca. 707. racemization) the excess of (S)p configuration would arise from transfer with configurational inversion, and might indicate a relatively free ... 

The lesser acidity of sterically hindered alcohols such as tert-butyl alcohol arises from solvation effects. 

The copper-catalyzed chiral reduction of -substituted ,/Tunsaturated lactones with PMHS and (S)-/ -Tol-BINAP in the presence of a hindered alcohol can be carried out in moderate to good yields with moderate ee values.599 The reaction is useful for both butenolides and pentenolides. Inferior results are realized with diphenylsilane as the reducing agent. Excellent results employing PMHS and the DTBM-SEGPHOS ligand are possible (Eq. 354).598... 

To address this problem, the authors devised two modifications. [30] The first one, two-stage glycosylation (Scheme 5.7), employed an initial, reversible trans-orthoes-terification step (12 —> 14, Scheme 5.7) in which the departing alcohol was removed either azeotropically or by molecular sieves [31]. The new orthoester 14 was then processed to give the glycoside (6) under the conditions developed in their previous work. The second variation consisted of the use of orthoacetates of hindered alcohols (isopropyl and tert-butyl) that minimize the return of the alcohol that is split off. 

ESTERIFICATION OF HINDERED ALCOHOLS tert-BUTYL p-TOLUATE, 51, 96 Esters, from diazoketones and organoboranes, 53, 82 Esters, a-deuterio-, 53, 82 Esters, y [Pg.59]

In most cases the identity of the reactive reducing species is not known with certainty. For example, the species initially formed by the reaction of lithium aluminum hydride (LAH) with alcohols may not be stable with respect to disproportionation. The degree of association of reducing species may be an important unknown factor in a particular case. Processes other than disproportionation or association may also make it difficult to predict the structure of the reagent formed from the reaction of LAH with sterically hindered alcohols (see Sect. II-A-1). 

Aside from the mixture of species 4 resulting from disproportionation, the reaction of LAH with highly hindered alcohols (or phenols) may lead to unexpected products. Refluxing a THF solution of lithium bis(2,6-di-/-butylphe-noxy)aluminum hydride (7) resulted in the reduction of THF to 1-butanol (41). 

In summary, the structure of a reagent formed from the reaction of LAH with an alcohol cannot be assumed on the basis of the stoichiometry of the reagents, because of the possibility of disproportionation. With very highly hindered alcohols or phenols, tricoordinate species may be formed. 

M. Safadi, R. Oliyai, V. J. Stella, Phosphoryloxymethyl Carbamates and Carbonates -Novel Water-Soluble Prodrugs for Amines and Hindered Alcohols , Pharm. Res. 1993, 10, 1350-1355. 

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