2.4- Pentanediol chiral acetals

A third route to nonracemic a-alkoxy and a-hydroxy stannaries employs the chiral acetal 73 prepared from (f ,f )-2,4-pentanediol (Scheme 30)66. Addition of various Grignard reagents to this acetal in the presence of TiCLt results in selective displacement yielding (S )-a-alkoxy stannanes. The corresponding a-hydroxy derivatives can be obtained after oxidation and mild base treatment. Organocuprates can also be employed to cleave this acetal but with somewhat lower selectivity67. 

Chiral acetals/ketals derived from either (R,R)- or (5,5 )-pentanediol have been shown to offer considerable advantages in the synthesis of secondary alcohols with high enantiomeric purity. The reaction of these acetals with a wide variety of carbon nucleophiles in the presence of a Lewis acid results in a highly diastereoselective cleavage of the acetal C-0 bond to give a /1-hydroxy ether, and the desired alcohols can then be obtained by subsequent degradation through simple oxidation elimination. Scheme 2-39 is an example in which H is used as a nucleophile.97... 

H) [a]D -64.1° (CHCI3), c 1.0). The optical purity of this adduct was 95% as determined by 200 MHz 1H NMR spectroscopy and GC analysis (capillary column PEG, 0.25 mm x 25 m, purchased from Gaskuro Kogyo Company, Ltd. in Japan) after conversion to the corresponding chiral acetal as follows A solution of the adduct, (2R,4R)-(-)-pentanediol (1.2 equiv, obtained from Wako Pure Chemical Industries), triethyl orthoformate (1.2 equiv), and p-toluenesulfonic acid monohydrate (as a 5 mM solution) in dry benzene is stirred at ambient temperature for 3 hr. The mixture is poured into saturated sodium bicarbonate and the product is extracted with ether. The... 

Asymmetric induction in the cyclopropanations of unsaturated substrates with methylene has been extensively investigated. A propensity of the Simmons-Simth and related reagents to make coordination to basic atoms is most frequently exploited. Treatment of a,/J-unsaturated aldehyde acetals derived from the aldehydes and chiral dialkyl tartrates or 2,4-pentanediol, with diiodomethane/diethylzinc in hexane, produces cyclopro-panecarboxaldehyde acetals with high diastereoselectivity (equation 69)109 110. Uniformly good diastereoselectivity has also been realized in the cyclopropanations of chiral acetals... 

Chiral hydroxy carboxylic acids The chiral acetals 2, available from (2R, 4R)-pentanediol (12,375-378), couple with ketene f-butyl f-butyldimethylsiiyl acetal (3) in the presence of TiCl4 (0.5 equiv.) to give adducts that are hydrolyzed by TFA-H20 to 4 and 5. The mixture is converted on oxidation and p-elimination into essentially pure (3R)-p-hydroxy carboxylic acids (6). 

Reaction with chiral acetals. The chiral ketals derived from (2R,4R)-(-)-2,4-pentanediol (1) can be cleaved with high diastercoselectivity by aluminum hydride reagents, in particular DIBAH, CI2AIH, and Br,AlH. Oxidative removal of the chiral auxiliary affords optically active alcohols. This process provides a useful method for highly asymmetric reduction of dialkyl ketones. ... 

Aldol coupling of chiral acetals. The acetals (2) prepared from an aldehyde and (2R,4R)-pentanediol react with a-silyl ketones orenol silyl ethers in the presence of TiCI, to form aldol ethers 3 and 4 with high diastereoselectivity (>95 5). Removal of the chiral auxiliary usually results in decomposition of the aldol, but can be effected after reduction... 

Kinetic resolution of chiral acetals has been effected by use of some organoaluminum reagents [84], On treating a chiral acetal 88, derived from (2, 4/ )-(-)-pentanediol, with -Bu3A1 at room temperature, one diastereomer was found to react much faster than the other, and the residu enol ether is transformed into optically pure ketone. The efficiency of this method is demonstrated by a concise synthesis of (5)-(-)-5-hexadecan-l,5-lactone (89), the pheromone of Vespa orientalis, as shown in Sch. 56. 

Chiral acetals derived from (R,R)-2,5-pentanediol 1.38 (R = Me. Y = R ) react with Me3SiCN in the presence of TiC. After appropriate treatment, (/O-cya-nohydrins are obtained in a good enantiomeric excess [213] (Figure 6.27). Following quatemization with Mel, cyclic N, O-acetals 6.32 derived from (1R, 25)-ephedrine 1.61 (R = Me) suffer stereoselective ring opening by NaCN in DMSO at 130°C [1158], (R)-a-Hydroxyacids are obtained with an excellent enantiomeric excess after quatemization and treatment with HC1 (Figure 6.27). 

Aside from the type III cyclizations described above, acetals have seen limited use in intermolecular Prins reactionsand extensive use as initiators for cation-alkene cyclizations.Only limited success has been achieved in Lewis acid catalyzed addition of acetals to alkenes. Better success has been achieved in the synthesis of C-glycosides by Lewis acid catalyzed addition of glycosyl acetates or glycals to alkenes. Johnson has extensively developed the use of acetals as initiators for cation-alkene cyclizations. Recent studies have shown that excellent asymmetric induction can be obtained using chiral acetals derived from optically active 2,3-butanediol or 2,4-pentanediol. - ... 

Pentanediol [(R,/ )-28] has been used for the formation of chiral acetals and as a precursor for chiral alkenes (Sections D.1.5.1. and 1.6.1.5.). The original procedure for the resolution of the phenylboronic acid derivative with brucine39 was impractical, but recently a kinetic resolution by lipase-catalyzed esterification and hydrolysis has been developed40. In addition, a good method for catalytic reduction of 1,3-diketones with Raney nickel modified with sodium bromide and tartaric acid (for a procedure, see Section D.2,3.1.) allowed the production for commercial purposes41. Similarly, sterically more hindered and less water-soluble 2,6-dimethyl-3,5-heptanediol (29) has been introduced for the same purpose. It is obtained in the same way from the diketone and separated from the meio-compound by simple recrystallization42. 

Polymer-bound diene 25 was subjected to a Diels-Alder reaction with tiglic aldehyde 26 in the presence of tetrame-thylsilane (TMS)-triflate for the construction of the bicyclic core structure (Scheme 16.4). Cycloadduct 27 was obtained as a mixture of four isomers that were formed in a ratio of 67 16 16 1 endolendo lexolexo ) with the desired endo isomer predominating. To improve the stereoselectivity, tiglic aldehyde was converted into the quasi-Ca-symmetric chiral acetal 28 derived with (R,R)-2,4-pentanediol. This chiral dienophile underwent an asymmetric Diels-Alder reaction at -78°C. Removal of the chiral auxiliary from the acetal 29 resulted in the cycloadduct 27 as a mixmre of the four isomers in a ratio of 87 4 9 0.1 endolendo lexolexo ), demonstrating that the stereoselectivity of the main isomer increased from 67% to 87%. ... 

The chiral catalyst was made from Raney nickel, which was prepared by addition in small portions of 3.9 g Raney nickel alloy to 40 ml water containing9 g NaOH. The mixture was kept at 100 C for 1 h, and then washed 15 times with 40 ml water. Chirality was introduced by treatment of the Raney nickel for I h at lOO C with 178 ml water adjusted to pH 3.2 with NaOH and containing 2g (S,S)-tartaric acid and 20 g NaBr. The solution was then decanted, and the modifying procedure was twice repeated. Hydrogenation over this catalyst of acetylacctone (100 atm, 100" C) in THF containing a small amount of acetic acid gave an isolated yield of chiral pentanediol of 44% (99.6% optical purity). 

The combination of the enantiomerically pure 7V-methylephedrine derived silylketene acetal l-[(l/ ,2S)-2-dimethylamino-1-phenylpropoxy]-l-triniethylsilyloxy-l-propene with the chiral aldehyde (,R)-3-benzyloxy-2-methylpropanal leads, after reduction with lithium aluminum hydride, to the formation of a single 1,3-pentanediol 9 ( matched pair ). 

Chiral ketals of 4-alkylcyclohexanones and of m-3,5-dimethylcyclohexanone with (/ ,/ )-2,4-pentanediol are converted, on treatment with triisobutylaluminum in dichloromethane at 0°C and subsequent acetylation of the first formed alcohol with acetic anhydride, to chiral enol ethers with high yield and good diastereoselectivity82. 

Cleavage of acetals. The acetals derived from (2R,4R)-2,4-pentanediol (this volume) are cleaved by organotitanium reagents of the type RTiCI, or R,TiCf. with high chemo- and stereoselectivity. Removal of the chiral auxiliary gives chiral secondary alcohols in high purity. Acetals complexed with TiCb arc also cleaved by treatment with an alkyllithium. 

Chiral cyanohydrines The TiCU-catalyzed reaction of (CH,),SiCN with (2R,4R)-pentanediol acetals (2) gives cyanohydrin ethers (3) with high diastereoselectivity (-95% de). 

Pentanediol is often superior to other diols such as 2,3-butanediol for these reactions because of higher distereoselectivities in reactions with nucleophiles and the more facile cleavage of the resulting hydroxy ether by oxidation-p-elimination. Removal of the chiral auxiliary is usually carried out with Pyri-dinium Chlorochromate oxidation followed by p-elimination using KOH, K2CO3, piperidinium acetate, dibenzylammonium trifluoroacetate, " or DBU. In some cases, 1,3-butanediol is preferred because the final 3-elimination may be effected under milder conditions. ... 

Reduction of Acetals. Reductions of acetals of 2,4-pentanediol can provide (after removal of the chiral auxiliary by oxidation and 3 elimination) secondary alcohols with good enan-tioselectivity. The choice of reagents dictates the configuration of the final product. Use of Dibromoalane gives products from selective syn cleavage of the acetal while Triethylsilane/Titanium(IV) Chloride gives the more usual anti cleavage products (eq 2). ... 

Acetals as Chiral Auxiliaries. There have been many applications of acetals of 2,4-pentanediol as chiral auxiliaries to control the diastereoselectivity of reactions on another functional group. Examples include cyclopropanation of alkenyl dioxanes, lithium amide-mediated isomerization of epoxides to allylic alcohols, and addition of dioxane-substituted Grignard reagents or organolithiums to aldehydes. 

Acetals prepared from chiral diols and carbonyl compounds serve as a chiral synthetic equivalent of aldehydes or ketones. 1,3-Dioxanes synthesized from chiral 2,4-pentanediols are especially useful, and high asymmetric inductions are observed in the Lewis acid promoted reactions of a variety of organometallic compounds. After the removal of the chiral auxiliary by the oxidation and -elimination procedures, optically active alcohols are obtained. Optically active propargylic alcohols and cyanohydrins are synthesized from organosilane compounds, TMS-C CR or TMS-CN in the presence of TiCU (Scheme 24). 1 6-138 Reactive wganometals such as alkyl-lithiums, -magnesiums or -coppers also react with chiral... 

Application of 2.4-pentanediol (PD) and its homoloeues for new diastereo-differentiatinv reactions as chiral auxiliaries-. In the early 80 s, optically pure PD prepared by our siiiqile procedures became available in a practical scale and various types of use were proposed shortly thereafter. One of the most extensively studied uses is as a chiral auxiliary built in the prochiral ketone or aldehyde as an acetal. The diastereo-differentiating attacks of various nucleophiles on the PD acetals activated by the Lewis acid, proceeds effectively giving the PD mono-ether of chiral alcohols in 80-95 % d.e. After the reaction, removing the PD unit from the mono-ether can easily be carried out by oxidation of the hydroxy group and mild base treatment. Because of good d.e. s. of the... 

In their second approach (Scheme 12), Johnson and his co-workers used the acetal 96 derived from (3S)-butane-l,3-diol instead of from (/ ,/ )-2,4-pentanediol (22). As in the earlier work, the Mukaiyama aldol condensation of acetal 96 with acetone trimethylsilyl ether gave a mixture of diastereoisomers 97 and 98 in a ratio of 96 4. In contrast, however, the removal of the chiral auxiliary was achieved without the need for first reducing the ketone group. Oxidation of the aldol... 

Yamamoto could resolve a number of 2-alkylcyclohexanones through a diastereoselective opening of the chiral dioxolanes made with (-)-(2R,4R)-2,4-pentanediol 146 [90]. As an example, treatment of the diastereomers 147 with 2 equiv of tri-isobutylaluminium (TIBA) (i-BUjAl) afforded the enol ether 148 (34%, >98% de) along with the recovered, diastereomericaUy enriched acetal 147 (62%). Separation... 

Asymmetric Buchner reactions using chiral auxiliary have also been undertaken. The diazoketo substrate 126 for the chiral tethered Buchner reaction is prepared from optically pure (2/ ,4/f)-2,4-pentanediol in three steps the Mitsunobu reaction with 3,5-dimethylphenol, esterification with diketene, and diazo formation/deacetylation. Treatment of 126 with rhodium(II) acetate results in a quantitative yield of 127 with more than 99% ee. This compound is reduced with lithium aluminium hydride, and the resulting diol 128 undergoes epoxidation and concurrent acetal formation to give 129 as a single diastereomer. Hydrogenation of 129 with Raney nickel proceeds stereoselectively to yield saturated diol 130, which is converted to aldehyde 132 via acid hydrolysis followed by oxidation. Compound 132 is a versatile intermediate for natural product synthesis. 

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