Homochiral epoxide

The first issue confronted by Myers was preparation of homochiral epoxide 7, the key intermediate needed for his intended nucleophilic addition reaction to enone 6. Its synthesis began with the addition of lithium trimethylsilylacetylide to (R)-glyceraldehyde acetonide (Scheme 8.6).8 This afforded a mixture of propargylic alcohols that underwent oxidation to alkynone 10 with pyridinium dichromate (PDC). A Wittig reaction next ensued to complete installation of the enediyne unit within 11. A 3 1 level of selectivity was observed in favour of the desired olefin isomer. After selective desilylation of the more labile trimethylsilyl group from the product mixture, deacetalation with IN HC1 in tetrahydrofuran (THF) enabled both alkene components to be separated, and compound 12 isolated pure. 

The BF3-OEt2-promoted [3 + 2]-cycloaddition of l-morpholino-2-trimethylsilylethyne to homochiral epoxides is very valuable for direct asymmetric synthesis of 7-butanolides (Equation (4)).36 The initial product, a 4-sily 1-2,3-dihydrofuran, may be formed by ring closure of the /3-silylcarbenium ion generated from a BF3-activated epoxide and... 

The stereocontrolled enantioselective synthesis of an advanced B-ring synthon of bryostatin 1 was achieved in the laboratory of K.J. Hale. " The key step was a Smith-Tietze coupling of 2-lithio-2-TBS-1,3-dithiane with a homochiral epoxide in the presence of HMPA. The resulting dithiane alkoxide was trapped with TBSCI in situ followed by deprotection of the dithiane moiety to give a Crsymmetrical ketone. This ketone was then further elaborated into the target B-ring synthon. 

Homochiral epoxides are versatile intermediates for the synthesis of a variety of natural products. The four-carbon bifiinctional chiron (i )-l- erNbutyldimethylsilyl-3,4-epoxybut-l-yne (228) is conveniently prepared from 141 as shown in Scheme 53. The conversion of 141 to chloride 225 followed by base-induced chloride elimination in liquid ammonia proceeds without any detectable epimerization (as determined by both hplc and nmr analysis of the corresponding Mosher ester) to provide the i -alcohol 226 in good yield. Subsequent silyl protection followed by treatment with boron tribromide results in a highly stereoselective bromination, together with simultaneous debenzylation to the bromohydrin 227, which under mild basic conditions is converted to epoxide 228. The optical purity of 228 (ee = 99%) demonstrates the high selectivity in this new bromination reaction [80,81]. 

To look at substrate-controlled epoxide reactions providing high configurational flexibility, divinyl carbinol 34 is certainly a good choice as there is easy access to the homochiral epoxide 35, which additionally smoothly undergoes the Payne rearrangement to furnish epoxide 36 as the major component in a 97 3 equihbrium... 

The best method to liberate the homochiral epoxide 71 from this benzoate without isomerization turned out to be a mild DIBAH reduction followed by acid hydrolysis finally, inversion at Cj can be accomplished with the well-estabhshed Mitsunobu reaction. 

The configuration at the sulfur atom directs the incoming nucleophile to form the P-alcohol 482, which after reduction of the sulfoxide and alkylation can easily be converted into the homochiral epoxide 483 [170]. 

Homochiral thiiranium and aziridinium ion intermediates formed by Lewis acid-induced rearrangement of l-hetero-2, 3-epoxides 97SL11. 

In recent years, enantioselective variants of the above transannular C-H insertions have been extensively stiidied. The enantiodetermining step involves discrimination between the enantiotopic protons of a meso-epoxide by a homochiral base, typically an organolithium in combination with a chiral diamine ligand, to generate a chiral nonracemic lithiated epoxide (e.g., 26 Scheme 5.8). Hodgson... 

Scheme 7-16 shows that a similar synthetic route leads to the asymmetric synthesis of optically active 62. The synthesis that began from homochiral aldehyde (—)-52 used this newly discovered asymmetric epoxidation three times, 52 —> 58, 58 —> 68, and 68 —> 61, finishing the conversion from 52 to 61 by following a shortened route. The last chiral center to be built is C-27, and the addition of allyltin to the aldehyde derived from 61 proceeds with high stereoselectivity to give the chiral aliphatic segment 62. 

Kureshy, R. I. Singh, S. Khan, N. H. Abdi, S. H. R. Ahmad, I. Bhatt, A. Jasra R. V. (2005) Improved catalytic activity of homochiral dimeric cobalt salen complex in hydrolytie kinetic resolution of terminal racemic epoxides.. Chirality, 17 590-594. 

Rearrangement of an achiral epoxide to give an optically active allyl alcohol, e.g., 1, induced by enantioselective deprotonation with a homochiral base (see p 436 for the determination of absolute configuration)55. 

The homochiral ferrocenyl 1,4-thiazepines 72 were used for the asymmetric transformation of aldehydes into epoxides 74. The reaction involved the formation of an intermediate sulfur ylide 73. The ee s were up to 94%, although the diastereoselectivity remains to be controlled, being 60 40-82 18 in favor of the trans-oxirane 74 (Scheme 8) <2004TA3275>. 

Advantageous use of homochiral cyclohexadiene-cis-l,2-diol, available by means of biocatalytic oxidation of chlorobenzene with toluene dioxygenase, has enabled the synthesis of all four enantiomerically pure C18-sphingosines (Nugent, 1998), which are known inhibitors of protein kinase C and important in cellular response mediation for tumor promoters and growth factors. The four requisite diastere-omers of azido alcohol precursors were accessed by regioselective opening of epoxides with either azide or halide ions. 

The mechanism of the polyleucine-catalyzed epoxidation is still under investigation [74]. Kinetic studies indicate that the reaction proceeds via the reversible addition of chalcone to a polyleucine-bound hydroperoxide [75]. Recent discussions have included studies of asymmetric amplification polyleucine derived from non-enantiopure amino acid shows highly amplified epoxide enantiomeric excess, and the results fit a mathematical model requiring the active catalyst to have five terminal homochiral residues, as rationalized by molecular modeling studies [76]. 

In cases where the epoxide is chiral, an optically pure form is used to ensure that the resulting ligand is homochiral. These ligqnds assemble into a cone conformation upon complexation with a cavity that varies from being negligible in 93 and 94 (101, 102), to saucer-shaped in 95 (103, 104), to quite deep in 96 and 97 (100, 105). The dimensions and shape of the cavity can be varied according to the ionic radius of the metal ion that is incorporated (103, 104). With Cd(II), the cavity that is created with ligand 96 is an effective receptor site for aromatic anions such as p-toluenesulfonate (100), p-nitrophenolate (100,105-107), (L)-phenylalaninate (106), and p-aminobenzoate (106), all of... 

The literature has been reviewed through 1989 for the purposes of preparing this chapter but the documentation herein is not intended to be comprehensive. Other reviews have covered various aspects of asymmetric epoxidation including synthetic applications through 1984, a thorough compilation of uses through early 1987 and an extensive discussion of the mechanism of the reaction. Use of homochiral epoxy alcohols in the synthesis of polyhydroxylated compounds, e.g. sugars, and for the preparation of various synthetic intermediates has been reviewed.A personal account of the discovery of titanium-catalyzed asymmetric epoxidation has been recorded." A comprehensive review of titanium-catalyzed asymmetric epoxidation is planned."... 

S)-rra/if-verbenol when (+)-DIPT is used in Ae catalyst. For allylic alcohols with an exocyclic double bond, kinetic resolution gives 2-methylenecyclohexanol (78) with 80% ee and a 46% yield when (-)-DIPT is used. Epoxidation of the homochiral 4-methylene-Sa-cholestan-3P-ol (79) is reported to be much faster with catalyst derived from (-( )-DET than from (-)-DET. The variable enantioselectivities seen in these results likely stem from conformational restraints imposed by the cyclic structures which prevent the allylic alcohols from attaining an ideal conformation for the epoxidation process (see Section 3.2.6 and Figure 5 for the proposed ideal conformation). 

Preparation. A number of methods have been reported for both the racemic and asymmetric preparations of l-amino-2,3-dihydro-lH-inden-2-ol (1), most commonly starting from inexpensive and readily available indene. These methods have been described in detail in recent reviews. The valuable properties of 1 as both a component of a medicinally active compound and as a chirality control element, derive primarily from its rigid and well-defined stereochemical structure. As a result, the compound is most desirable in enantiomerically pure form. One of the most efficient asymmetric syntheses of 1, which may be employed for the synthesis of either enantiomer of the target molecule, involves an asymmetric epoxidation (89% yield, 88% ee) of indene to give epoxide 2 using the well-established Jacobsen catalyst. This is followed by a Ritter reaction using oleum in acetonitrile resulting in conversion to the oxazoline (3) which is subsequently hydrolysed to the amino alcohol. Fractional crystallization with a homochiral diacid permits purification to >99% ee (eq 1). ... 

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