Monoprotected diols

A variety of cyclic ortho esters,including cyclic orthoformates, have been developed to protect czs-1,2-diols. Cyclic ortho esters are more readily cleaved by acidic hydrolysis (e.g., by a phosphate buffer, pH 4.5-7.5, or by 0.005-0.05 M HCl) than are acetonides. Careful hydrolysis or reduction can be used to prepare selectively monoprotected diol derivatives. 

Coxon and Stoddart have directed their attention to the formation of penta-erythritol-derived cryptands. With these molecules, the strategy was to block one pair of hydroxyl groups as an acetal and form a crown from the remaining diol. In the first of the two reports cited above, this was accomplished by treating the 0-benzylidine derivative of pentaerythritol with base and diethylene glycol ditosylate. The crown was then treated with a mixture of UAIH4 and BF3 which gives partial reduction of the acetal as shown in (8.9), above. The monoprotected diol could now be treated in a fashion similar to that previously described and the benzyloxy cryptand (77) would result. The scheme is illustrated below as Eq. (8.10). 

As with the benzylidene ketals, the carbonate can be opened to give a monoprotected diol. ... 

The construction of the heterocycle 3 started with enantiomerically-pure ethyl lactate. Protection, reduction and oxidation led to the known aldehyde 6. Chelation-controlled allylation gave the monoprotected-diol 7. Formation of the mixed acetal with methacrolein followed by intramolecular Grubbs condensation then gave 3. The dihydropyran 3 so prepared was a 1 1 mixture at the anomeric center. 

The monographs (8,9) also present clear expositions of methods of synthesis. A recent communication addressing a short approach to both symmetrical and unsymmetrical tetrahydrofurofuran lignans is outlined in Scheme 32 (149). Michael addition of the sodium salt of the silyl monoprotected diol (155) to the a-sulfonylcinnamate (156) gave the ether (157) which on desulfurization and hydrolysis gave the hydroxy acid (158). Lactonization of (158) by the Mukaiyama method... 

One of the key steps during the first total synthesis of (-)-aspinolide B by A. de Meijere and co-workers was the NHK reaction to form the ten membered lactone ring. The precursor for this key macrocyclization step was prepared by forming an ester from a three-carbon monoprotected diol fragment and a seven-carbon vinyl iodide fragment. Deprotection of the primary alcohol and its subsequent oxidation afforded the desired vinyl iodide aldehyde precursor. Exposure of this precursor to 15 equivalents of CrCl2 doped with 0.5% of NiCb at high dilution in DMF afforded the desired diastereomer in a 1.5 1 ratio. 

The enantioselective discrimination of one of the hydroxyl groups of meso-diols can give chiral monoprotected diols, which serve as versatile intermediates for asymmetric organic synthesis. In addition to the enzymatic methods, a number of chemical approaches have been reported using chiral 1,2-diamine catalysts, chiral phospholane-based catalysts, planar chiral DMAP derivatives, and oligopeptide-based catalysts [2,28], Surprisingly, however, relatively a few publications are devoted to this reaction with cinchona-based organocatalysts. 

Trost chose to exemplify the utility of organopalladium coupling reactions for carbon-carbon bond formation by use of this process for the ring closure step in a synthesis of 1 (Scheme 1.9) To this end, monoprotected diol 31 was oxidized and chain extended to form the a,p-unsaturated ester 32. Reduction to the allylic alcohol followed by acetylation and desilylation gave 33 in 53% overall yield from 31. Carboxylic acid 35 was then obtained via a two-step sequence from bromo ester 34 (84%) by alkylation with methyl... 

Dihydropyran, I2, 0.5-3.5h, CH2CI2, rt, 83-92% yield. In situ generated HI is most likely the actual catalyst. This method modified by microwave heating has been used to monoprotect diols with modest selectivity. ... 

Sarma [49] studied the monotetrahydropyranylation of symmetrical diols catalyzed by iodine. Monoprotected diols were obtained in 75% yield within 3 min on irradiation in a microwave oven. When the same reaction was performed under reflux, however, the conversion was quantitative within 30 min now the selectivity was very poor (mono diether yield 43% 51%) (Fig. 5.15). Even at room temperature, the reaction proceeded slowly with no selectivity (mono diether ratio 1 1) [49]. 

Selective monotetrahydropyranylation of symmetrical 1, -diols 16 with DHP was achieved under MWI for 3 min in the presence of iodine as a catalyst to give the monoprotected diol 17 in 75% yield. The same reaction by conventional heating under reflux led to very poor selectivity whereby 43% yield of mono-THP-ether 17 and 51% yield of di-THP-ether 18 were obtained (Scheme 4) (01JOC1947). 

Very recently. Steward and Johnson developed the DKR of jS-silyloxy-a-keto esters, previously prepared through a cyanide-catalysed benzoin-type reaction between silyl glyoxylates and aldehydes. The asymmetric transfer hydrogenation was performed in the presence of TEA as the base, formic acid as the hydride source, and a ruthenium catalyst bearing a chiral 1,2-diamine, providing the corresponding enantioenriched monoprotected diols with moderate diastereo- and enantioselectivities of up to 66% de and 52% ee, respectively. 

Cyclocarbonylation of the monoprotected diol 6.81 gave a carboxylic acid 6.82 with complete stereocontrol (Scheme 6.29) This acid could be converted to the natural product, diospongin A 6.83, by Stille coupling... 

Nevertheless, ben2yl-chloromethylether reacts with this ketone in the presence of Sml2 to give the monoprotected diol 394 in nearly quantitative yield. It is certainly worth mentioning that a reduction (94%)-oxidation (93%) sequence transforms this alkylation product into hydroxyaldehyde 395. 

Nanda et al. applied an alcohol DKR methodology to the total synthesis of a natural product, stagonolide-C, which exhibited antibacterial and antifungal activities (Scheme 5.47) [69]. In this synthesis, the DKRs of two monoprotected diols rac-33 and rac-36 were performed with CAL-B (Novozym 435) and Ru catalyst 5, followed by... 

Sometimes the hydroxy and carboxy groups of p-hydroxyisobutyric acid are simultaneously protected by the same protective group and the resultant protected p-hydrox-yisobutyrate esters are similarly reduced to monoprotected diols. 

---