Enantiomerically pure diols

The enantioselective addition of organometallic reagents to, V-(trimethylsilyl)benzaldehyde imine (1) in the presence of enantiomerically pure modifiers has been investigated. The best result is obtained with butyllithium (the corresponding Grignard reagent affords both lower yield and selectivity, 1 fails to react with diethylzinc) and two equivalents of the enantiomerically pure diol 2 in diethyl ether. It should be noted that the choice of the solvent is crucial for the stereoselectivity of the reaction1 2 3 5 7 8 9. 

Acetals of A. A -dimethyl hydrazones 4, derived from glyoxal (1) and various enantiomerically pure diols (c.g., 3a-f)24, are readily prepared by transacetalization of 2. Addition of methyl-or butyllithium to 4 provides the corresponding hydrazines in good yield (70-88%) and moderate to excellent diastereoselectivity (see Table 3)4,5. 

Chirality transfer in catalytic asymmetric hydrogenation can be achieved not only by using powerful chiral ligands such as BINAP or DuPhos but also by the formation of a dynamic conformational isomer. The availability of many enantiomerically pure diols allows the production of electron-deficient, bi-dentate phosphate in the form of 27. The backbone O-R -O can define the chirality of the 0-R2-0 in complex 28, hence realizing the chirality transfer.44... 

As this synthesis started from an achiral starting material, compound 199 must be resolved to secure enantiomerically pure intermediates for the synthesis of taxol. Treatment of (+ )-diol 199 with excess ( lA)-( )-camphanic chloride in methylene chloride in the presence of Et3N forms two diastereomeric monoesters for chromatographic separation. Enantiomerically pure diol 199 can be regenerated from the ester in 90% yield with a specific rotation of +187 (c = 0.5, CHC13). 

Continuing the synthesis of rac-6 with enantiomerically pure diols 12 and ent-l2 (after saponification of 15 with KOH), both enantiomers 6 and ent-6 were accessible. This allowed for an enantioselective synthesis of natural kel-soene (1) and its enantiomer (ent-l) (see below) with only one additional step as compared to the synthesis of the racemate (rac-l). 

Diastereoselective cleavage of propynyl acetals of enantiomeric pure diols with organocopper(I) reagents leads to alkoxyallenes with high diastereomeric purity, in which the chiral auxiliary is included... 

Details for the large-scale synthesis of (R,R) 1,2-diphenyl-1,2-ethanediol by using the DHQD-CLB/NMO variation of catalytic AD have been published [47]. Under these conditions the crude diol is produced with 90% ee and upon crystallization, essentially enantiomerically pure diol is obtained in 75% yield. Subsequent improvements in the catalytic AD process now allow this dihydroxylation to be achieved with >99.8% ee (entry 20, Column 9) however, the Organic Synthesis procedure [47] is still an excellent choice for preparing large amounts of the... 

Last but not least, from the process improvement point of view, a research group at Sepracor led by Yun Gao has developed an extremely effective electrocatalytic version of the catalytic AD process (see Section 6D.2.2) [37]. As symbolized in Figure 6D.3, this electrocatalytic approach to AD appears to be ideal. Enantiomerically pure diols arise from electricity, water, and olefins compounds, with hydrogen gas and a little water over the dam as the only byproducts. 

Finally, it should be noted that achiral dioxiranes can be used to generate chiral hydroxyketones from enantiomerically pure diols or acetals [140, 141]. 

Fig. 17.43. Regioselective reduction of enantiomerically pure epoxy alcohols to enantiomerically pure diols. 1,3-Diols are formed with Red-Al and 1,2-diols are formed with DIBAL...

Diastereomeric mixtures (three isomers) of 2,2 -biphospholes 162-164 were synthesized by asymmetric alkylation of 2,2 -biphospholyl anion 161 with enantiomerically pure diol ditosylates. The generated 2,2 -biphospholes were converted into the more stable disulfide derivatives 58, 165, and 166 <2005OM5549, 2003CC1154>. Dianion 161 was generated in two steps from l-phenyl-2,3-dimethylphosphole 159 by pyrolysis and subsequent treatment of the formed phosphole tetramer 160 with sodium naphthalene. Structures of the diastereomers of disufides 58 and 165 were established by the X-ray crystallographic data. 

Furthermore, when the enantiomerically pure diol 5 is treated with /V-iodosuccinimide in acetonitrile in the dark at 20 C for 16 hours, smooth cyclization gives (17 ,2 S, 4 S,)-l-iodomethyl-3,3-dimethyl-7-oxabicyclo[2.2.1]heptan-2-ol (6) in 76% yield. Recrystallization affords an optically pure sample109. 

We prepared and purified the air- and moisture-sensitive complex 43 to carry out these studies. We have also found that it is possible to generate this complex in situ, with the starting ArOH (two equivalents) and two equivalents of BuLi, followed, at it, by TiCU, and then at -18° by the diene and two more equivalents of BuLi. The cyclization results are the same as with the preprepared complex 43. We will use this latter approach to quickly screen a variety of other alcohols and diols, including enantiomerically pure diols such as BINOL (1,1 -bi-2-naphthol) and Taddol (a,a,a, a -tetraaryl-l,3-dioxolane-4,5-dimethanol), in this cyclization. 

Both the chiral centres in diol 90 have the R configuration. We see perhaps the most revealing result when enantiomerically pure diol 90 is dihydroxylated with 0s04 using an achiral ligand - quinuclidine. This is important because it tells us how the substrate likes to react with osmium tetroxide. There is a 3 97 product ratio in favour of the me so compound 92 rather than the C2 symmetric compound 91. In other words, the molecule with two R chiral centres prefers the reaction that leads to the formation of two new chiral centres of opposite configuration - S. 

The high regioselectivity observed in the transformation of some chiral diols into halohydrins allows various selective reactions to be performed on these intermediates. For example, the reduction of the hahde substituent affords an easy entry into optically active carbinols (Scheme 54). This methodology was used by Keinan [134] in his approach towards aspicilhn 213. Thus, the enantiomerically pure diol 210 was transformed into the bromohydrin 211 which was reduced to... 

An alternative approach to vinyl ether 3 was designed, which relied on a quaternary ammonium bicyclic acetal undergoing a Hofmann elimination. A requisite synthon for this process was aminodiol 44 (Scheme 14). An asymmetric dihydroxylation of styrene 41 afforded the corresponding enantiomerically pure diol 42. Activation and ethanolamine addition afforded crystalline 44. The single stereocenter contained in this substrate was the stereocontrol element for subsequent asymmetric induction. 

This method, developed in 1980 by Barry Sharpless, has proven to be useful for the synthesis of a wide variety of enantiomerically pure compounds, because an epoxide can easily be converted into a compound with two adjacent asymmetric carbons, since epoxides are very susceptible to attack by nucleophiles. In the following example, an allylic alcohol is converted into an enantiomerically pure epoxide, which is used to form an enantiomerically pure diol. 

The dienophile may also be activated by hydrogen bonding of the carbonyl oxygen with suitable protic molecules and it has been observed that Diels-Alder reactions are accelerated when performed in protic solvents such as 2-butanol. Thus the opportunity exists for the development of an enantioselective alcohol-catalysed asymmetric Diels-Alder reaction. Indeed, Rawal and coworkers have recently discovered that the use of catalytic amounts of the enantiomerically pure diol a,a,a, a -tetraaryl-l,3-dioxolane-4,5-dimethanol (TADDOL) (8.113) in the Diels-Alder reaction of aminosilyloxydiene (8.114) with 2-substituted acroleins such as (8.24), results in the formation of the cycloadduct (8.115) with high ee. Simiharly, the strong Bronsted acid (8.116) effectively catalyses the Diels-Alder reaction of sUyloxydienes such as (8.117) with a,P-enone (8.105). ... 

Finally, using a similar strategy, the protected functionalized cyclohexadienediol was used as starting material in the synthesis of ( )-, (+)-, and (-)-Conduritol C (Scheme 20) Enzymatic hydrolysis of the diacetate produced enantiomerically pure (-)-diol and (+)-diacetate. Subsequent hydrolysis of the diol and diacetate afforded (+)-and (-)-Conduritol C, respectively. 

Optically active allylboronates bearing chiral auxiliary located at the boron atom found widespread applications in asymmetric synthesis. Enantiomerically enriched a-alkylidene-y-lactones and lactams can also be synthesized following such a synthetic approach. VUlieras et al. (41, 45] demonstrated the potential of chiral allylboronates derived from 2-phenyl-2,3-bomanediol, ephedrine, or norephedrine for this purpose. Chiral allylboronates 46a,b were obtained in a sequence of reactions involving transformation of achiral precursors 32 into the corresponding boronic acids 44 followed by their esterification with enantiomerically pure diol or 1,2-aminoalcohol 45 (Scheme 4.10). In the case of methyl-substituted derivatives 32b (R = Me), initial composition of E- and Z-isomers was transferred to the target allylboronates 46b. Importantly, the isomeric mixture was separated by means of the column chromatography. 

Several boron-containing species have been used as chiral NMR derivatizing agents for the analysis of primary amines or diols. " Most noteworthy among these is 2-for-mylphenylboronic acid 61, which is commercially available. Reaction of 61 with an amine and diol forms a borate-imine as shown in Scheme 50.1. The reaction can be run using an enantiomerically pure amine such as PEA to determine the enantiomeric purity of the diol, or using an enantiomerically pure diol such as BINOL to determine the enantiomeric purity of the amine.The system has been used to determine the enantiomeric purity of amines with remote chiral centers such as l-amino-4-5 ec-butylbenzene and the methyl ester of 2-methyl-5-aminopentanoic acid. 

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