Epoxides enantioenrichment

The application of the AE reaction to kinetic resolution of racemic allylic alcohols has been extensively used for the preparation of enantiomerically enriched alcohols and allyl epoxides. Allylic alcohol 48 was obtained via kinetic resolution of the racemic secondary alcohol and utilized in the synthesis of rhozoxin D. Epoxy alcohol 49 was obtained via kinetic resolution of the enantioenriched secondary allylic alcohol (93% ee). The product epoxy alcohol was a key intermediate in the synthesis of (-)-mitralactonine. Allylic alcohol 50 was prepared via kinetic resolution of the secondary alcohol and the product utilized in the synthesis of (+)-manoalide. The mono-tosylated 3-butene-1,2-diol is a useful C4 building block and was obtained in 45% yield and in 95% ee via kinetic resolution of the racemic starting material. 

From the standpoints of both cost and atom economy, water is the ideal nucleophile for synthesis of enantioenriched C2-symmetric 1,2-diols from meso-epoxides. 

Although the enantioselective intermolecular addition of aliphatic alcohols to meso-epoxides with (salen)metal systems has not been reported, intramolecular asymmetric ring-opening of meso-epoxy alcohols has been demonstrated. By use of monomeric cobalt acetate catalyst 8, several complex cyclic and bicydic products can be accessed in highly enantioenriched form from the readily available meso-epoxy alcohols (Scheme 7.17) [32]. 

Two recent reports described addition of nitrogen-centered nucleophiles in usefully protected fonn. Jacobsen reported that N-Boc-protected sulfonamides undergo poorly selective (salen) Co-catalyzed addition to racemic epoxides. However, by performing a one-pot, indirect kinetic resolution with water first (HKR, vide infra, Table 7.1) and then sulfonamide, it was possible to obtain highly enantiomer-ically enriched addition products (Scheme 7.39) [71]. These products were transformed into enantioenriched terminal aziridines in straightforward manner. 

Although several interesting nitrogen-centered nucleophiles have been developed with ARO reactions of epoxides (vide supra), kinetic resolutions with such reagents are unlikely to be of practical value for the recovery of enantioenriched terminal epoxides. This is due to the fact that these nucleophiles are too valuable to be discarded in a by-product of the resolution, are generally not atom-economical, and, particularly in the case of azide, may represent safety hazards. 

Previous syntheses of terminal alkynes from aldehydes employed Wittig methodology with phosphonium ylides and phosphonates. 6 7 The DuPont procedure circumvents the use of phosphorus compounds by using lithiated dichloromethane as the source of the terminal carbon. The intermediate lithioalkyne 4 can be quenched with water to provide the terminal alkyne or with various electrophiles, as in the present case, to yield propargylic alcohols, alkynylsilanes, or internal alkynes. Enantioenriched terminal alkynylcarbinols can also be prepared from allylic alcohols by Sharpless epoxidation and subsequent basic elimination of the derived chloro- or bromomethyl epoxide (eq 5). A related method entails Sharpless asymmetric dihydroxylation of an allylic chloride and base treatment of the acetonide derivative.8 In these approaches the product and starting material contain the same number of carbons. 

A cuprate prepared in situ from tBuPh2SiLi and Cul has been found to react with alkynyl epoxides to afford allenylsilanes (Eq. 9.43) [50]. Enantioenriched alkynyl epoxides, which are readily prepared in high yield through Sharpless asymmetric epoxidation [51], afford chiral allenylsilanes with anti stereoselectivity. 

Reaction in organic solvent can sometimes provide superior selectivity to that observed in aqueous solution. For example, Keeling et al recently produced enantioenriched a-trifluoromethyl-a-tosyloxymethyl epoxide, a key intermediate in the synthetic route to a series of nonsteroidal glucocorticoid receptor agonist drug candidates, through the enan-tioselective acylation of a prochiral triol using the hpase from Burkholderia cepacia in vinyl butyrate and TBME (Scheme 1.59). In contrast, attempts to access the opposite enantiomer by desymmetrization of the 1,3-diester by lipase-catalysed hydrolysis resulted in rapid hydrolysis to triol under a variety of conditions. 

Typically chiral metal complexes catalyzed asymmetric ring opening of achiral / racemic and chiral epoxides with various nucleophiles conveniently produce enantioenriched 1,2-... 

Jacobsen et al. [48], in 1997 for the first time demonstrated KR of racemic terminal epoxides with water as nucleophile for the production of optically pure epoxides and corresponding 1,2-diols. Since then, various other nucleophiles viz., carboxylic acids, phenols, thiols, amines, carbamates and indols were used in KR to produce optically pure epoxides with concomitant production of corresponding enantioenriched l,2-bifimctional moieties [49-52]. 

The tra x-[Ru (0)2(por)] complexes are active stoichiometric oxidants of alkenes and alkylaro-matics under ambient conditions. Unlike cationic macrocyclic dioxoruthenium I) complexes that give substantial C=C bond cleavage products, the oxidation of alkenes by [Ru (0)2(por)] affords epoxides in good yields.Stereoretentive epoxidation of trans- and cw-stilbenes by [Ru (0)2(L)1 (L = TPP and sterically bulky porphyrins) has been observed, whereas the reaction between [Ru (0)2(OEP)] and cix-stilbene gives a mixture of cis- and trani-stilbene oxides. Adamantane and methylcyclohexane are hydroxylated at the tertiary C—H positions. Using [Ru (0)2(i)4-por)], enantioselective epoxidation of alkenes can be achieved with ee up to 77%. In the oxidation of aromatic hydrocarbons such as ethylbenzenes, 2-ethylnaphthalene, indane, and tetrahydronaphthalene by [Ru (0)2(Z>4-por )], enantioselective hydroxylation of benzylic C—H bonds occurs resulting in enantioenriched alcohols with ee up to 76%. ... 

Astonishingly enough, enantioenriched lithiated cyclooctene oxides 142, originating from (—)-sparteine-mediated lithiation of 124 by i-BuLi/(—)-sparteine (11), could be trapped by external electrophiles, resulting in substituted epoxides 143 (equation 31) ° . Again, the use of i-PrLi furnished better enantioselectivities (approx. 90 10). Lithiated epoxides, derived from tetrahydrofurans and A-Boc-pyrrolidines, undergo an interesting elimination reaction . ... 

The asymmetric lithiation/substitution of Af-Boc-Af-(3-chloropropyl)-2-alkenylamines 395 by w-BuLi/(—)-sparteine (11) provides (5 )-Af-Boc-2-(alken-l-yl)pyrrolidines 397 via the allyllithium-sparteine complexes 396 (equation 106) . Similarly, the piperidine corresponding to 397 was obtained from the Af-(4-chlorobutyl)amine. Intramolecular epoxide openings gave rise to enantioenriched pyrrolidinols. Beak and coworkers conclude from further experiments that an asymmetric deprotonation takes place, but it is followed by a rapid epimerization a kinetic resolution in favour of the observed stereoisomer concludes the cyclization step. 

Much activity continues to be centered around the preparation of enantioenriched epoxides using chiral Co(III)-, Mn(III)- and Cr(III)-salen complexes, particularly in the area of innovative methods. A recent brief review <02CC919> focuses on the synthesis, structural features, and catalytic applications of Cr(III)-salen complexes. In an illustrative example, Jacobsen and coworkers <02JA1307> have applied a highly efficient hydrolytic kinetic resolution to a variety of terminal epoxides using the commercially available chiral salen-Co(III) complex 1. For example, treatment of racemic m-chlorostyrene oxide (2) with 0.8 mol% of catalyst 1 in the presence of water (0.55 equiv) led to the recovery of practically enantiopure (> 99% ee) material in 40% yield (maximum theoretical yield = 50%). This method appears to be effective for a variety of terminal epoxides, and the catalyst suffered no loss of activity after six cycles. 

The hydrolytic kinetic resolution of racemic terminal epoxides using metal salen catalysts is one of the premier methods for the formation of enantioenriched oxiranes and/or 1,2-diols, e.g., <1997SCI936, 1998JOC6776, 2000AGE3604, 2002JA1307>. 

Chiral dioxiranes continue to be examined for the synthesis of enantioenriched epoxides. An interesting report details the use of a dioxirane derived from oxazolidinone 7 for the... 

The bromomandelation of terminal alkenes provides a facile and convenient method for the synthesis of enantioenriched terminal epoxides <07JOC431>. Reaction of terminal alkenes with mandelic acid and NBS provides a 1 1 mixture of bromomandelates 15 and 16,... 

Chiral bis(oxazolines) 51 with an oxalylic acid backbone were used for the Ru-catalyzed enantioselective epoxidation of tran5-stilbene yielding franx-l,2-diphenyloxirane in up to 69% ee [24]. The asymmetric addition of diethylzinc to several aldehydes has been examined with ferrocene-based oxazoline ligand 52 [25], resulting in optical yields from 78-93% ec. The imide 53 derived from Kemp s triacid containing a chiral oxazoline moiety was used for the asymmetric protonation of prochiral enolates [26]. Starting from racemic cyclopentanone- and cyclohexanone derivatives, the enantioenriched isomers were obtained in 77-98 % ee. 

Epoxide formation using biocatalysis is a useful process for the formation of chiral oxiranes (Scheme 29). The synthesis of enantioenriched epoxides using enzymes has been reviewed <1995BCSF769>. Chloroperoxidase has been examined for the oxidation of 2-methyl-l-alkenes, among other alkenes. The yields in some cases can be low, but the enantioselectivities can be high <1995JA6412, 1997JA443>. This enzyme has been used in a synthesis of... 

D-Fmctose-derived ketone 50 (also available in its enantiomeric form from L-sorbose) was introduced as a catalyst for the asymmetric epoxidation of trans- and trisubstituted olefins, and as such was successful in the preparation of enantioenriched substituted cycloalkene oxides (Table 5, entries 1-5) <1996JA9806, 1997JA11224, 2001T5213>. 

In 1997, Tokunaga et al. reported the hy-drolytie kinetie resolution of raeemie terminal epoxides using a Co(III)-Salen eatalyst (164). This remarkably general proeess uses only water as the nucleophile and provides the synthetically useful chiral epoxides and diols in highly enantioenriched form. The catalyst can be recycled and the reactions conducted under solvent-free conditions. 

Schaus, S. E., Brandes, B. D., Larrow, J. F., Tokunaga, M., Hansen, K. B., Gould, A. E., Furrow, M. E., Jacobsen, E. N. Highly Selective Hydrolytic Kinetic Resolution of Terminal Epoxides Catalyzed by Chiral (salen)Colll Complexes. Practical Synthesis of Enantioenriched Terminal Epoxides and 1,2-Diols. J. Am. Chem. Soc. 2002, 124, 1307-1315. 

S. E. Schaus, B. D. Brandes, J. F. Larrow, M. Tokunaga, K. B. Hansen, A. E. Gould, M. E. Furrow, E. N. Jacobsen, Highly selective hydrolytic kinetic resolution of terminal epoxides cataly zed by chiral (salen)Co complexes. Practical synthesis of enantioenriched termmal epoxides and... 

Aldehydes can also be converted to enantioenriched chiral epoxides through the Darzens reaction. Thus, haloimides (e.g., 47) react with benzaldehyde in the presence of a novel phase transfer catalyst 45 derived from BINOL to give 1,2-disubstituted epoxides in good yields with... 

The hydrolytic kinetic resolution (HKR) of racemic terminal epoxides catalyzed by chiral (salen)-Co(III) complexes provides efficient access to epoxides and 1,2-diols, valuable chiral building blocks, in highly enantioenriched forms. While the original procedure has proved scalable for many substrates, several issues needed to be overcome for the process to be industrially practical for one of the most useful epoxides, epichlorohydrin. Combined with kinetic modelling of the HKR of epichlorohydrin, novel solutions were developed which resulted in linearly scalable processes that successfully addressed issues of catalyst activation, analysis and reactivity, control of exothermicity, product isolation, racemization, and side-product formation. 

The [Mn(salen)]-catalyzed epoxidation of chromene derivatives was discovered to occur with exceptional enantioselectivity [74]. Chromene derivatives bearing 2,2-disubstitution appear to combine all the important substrate characteristics required for a highly enantioselective epoxidation. The synthetic utility of the enantioenriched epoxychroman products is increased by the predictable regio- and stereochemical outcome of epoxide ring opening with a variety of nucleophiles. These two features were highlighted in the synthesis of the selective potassium channel activator BRL 55834 [78]. Catalyst loadings as low as... 

Schaus SE, Brandes BD, Larrow JF et al (2002) Highly selective hydrolytic kinetic resolution of terminal epoxides catalyzed by chiral (salen)Co-III complexes. Practical S5Uithesis of enantioenriched terminal epoxides and 1,2-diols. J Am Chem Soc 124 1307-1315... 

Hydroxy-ketones have also been obtained very conveniently by epoxidation or dihydroxylation of silyl enol ethers (derived from ketones with either kinetic or thermodynamic control), for example with mCPBA or osmium tetroxide and N-methylmorpholine-A-oxide. Asymmetric dihydroxylation, for example with AD-mix-a or -(3 (see Section 5.3), can provide highly enantioenriched products (6.56). ... 

The first configurationally stable l-oxy-2-alkenyllithium 253 was reported in 1986 by Hoppe and Kramer [Eq. (70)] [8]. It was generated by deprotonation of the enantioenriched allyl carbamate 252, obtained fi om the corresponding alcohol via kinetic resolution through Sharpless epoxidation. More conveniently accessible are the 1-methyl derivatives 254 and analogues either from (R)- or (S)-lactaldehydes via Wittig olefination [154]. Kinetic resolution of rac-254 during deprotonation is also possible [155-157]. 

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