Sharpless epoxidation stereochemistry

The stereochemistry of the first step was ascertained by an X-ray analysis [8] of an isolated oxazaphospholidine 3 (R = Ph). The overall sequence from oxi-rane to aziridine takes place with an excellent retention of chiral integrity. As the stereochemistry of the oxirane esters is determined by the chiral inductor during the Sharpless epoxidation, both enantiomers of aziridine esters can be readily obtained by choosing the desired antipodal tartrate inductor during the epoxidation reaction. It is relevant to note that the required starting allylic alcohols are conveniently prepared by chain elongation of propargyl alcohol as a C3 synthon followed by an appropriate reduction of the triple bond, e. g., with lithium aluminum hydride [6b]. 

Asymmetric epoxidation, dihydroxylation, aminohydroxylation, and aziridination reactions have been reviewed.62 The use of the Sharpless asymmetric epoxidation method for the desymmetrization of mesa compounds has been reviewed.63 The conformational flexibility of nine-membered ring allylic alcohols results in trans-epoxide stereochemistry from syn epoxidation using VO(acac)2-hydroperoxide systems in which the hydroxyl group still controls the facial stereoselectivity.64 The stereoselectivity of side-chain epoxidation of a series of 22-hydroxy-A23-sterols with C(19) side-chains incorporating allylic alcohols has been investigated, using m-CPBA or /-BuOOH in the presence of VO(acac)2 or Mo(CO)g.65 The erythro-threo distributions of the products were determined and the effect of substituents on the three positions of the double bond (gem to the OH or cis or trans at the remote carbon) partially rationalized by molecular modelling. 

Sharpless epoxidation of alkenylsilanols.1 Allylic silanols also undergo highly enantioselective Sharpless epoxidation. This reaction furnishes simple epoxides such as styrene oxide in high optical purity. Thus reaction of fram-(3-lithiostyrene il) with ClSi(CH,)2H gives 2, which can be oxidized to the alkenylsilanol 3. ShaTp-less epoxidation of 3 gives the epoxide 4, which is converted to styrene epoxide 5 by cleavage with fluoride ion. The stereochemistry of epoxidation of 3 is similar to that of the corresponding allylic alcohol. 

The asymmetric Sharpless epoxidation allowed us to obtain the epoxide of desired stereochemistry by use of the proper catalyst, however, the selectivity was not high. Much more selective was the epoxidation process of a precursor of higher sugar p)ranosidic nucleosides 79, which provided only epoxide 80 with (-)-DET, while (+)-DET afforded exclusively the opposite stereoisomer 81 (O Scheme 24) [1]. 

Hydroxyalkylphosphonates have been prepared by reduction of the corresponding ketones. These include phosphonomalate esters by highly diastereose-lective reduction of 3-phosphonopyruvates with NHs.BHa and both 2-hydroxyalkyl-phosphonates, e.g. 178, and thiophosphonates by asymmetric hydrogenation using chiral ruthenium catalysts. An enantioselective synthesis, from 179, of both enantiomers of phosphonothrixin 180 and their absolute stereochemistry have been reported.The epoxide 179 was prepared from 2-methy -3-hydroxymethyl-1,3-butadiene via a Sharpless epoxidation. 

Asymmetric oxidations have followed the usual development pathway in which face selectivity was observed through the use of chiral auxiliaries and templates. The breakthrough came with the Sharpless asymmetric epoxidation method, which, although stoichiometric, allowed for a wide range of substrates and the stereochemistry of the product to be controlled in a predictable manner [1]. The need for a catalytic reaction was very apparent, but this was developed and now the Sharpless epoxidation is a viable process al scale, although subject to the usual economic problems of a cost-effective route to the substrate (see later) [2]. The Sharpless epoxidation has now been joined by other methods and a wide range of products are now available. The pow er of these oxidations is augmented by the synthetic utility of the resultant epoxides or diols that can be used for further transformations, especially those that use a substitution reaction (see Chapter 7) [1]. 

Workers at Lilly have reported the synthesis of 8,9-LTA3 (51), 8,9-LTC3 (52a), and 8,9-LTD3 (52b),leukotrienes that are reported to be produced from dihomo-y-linolenic acid in ionophore-stimulated murine mastocytoma cells. The natural stereochemistry was assumed to be (85,9/f,10,12 ,14Z) by analogy with arachidonic acid metabolism in the same cell system. The chiral synthesis was achieved (93% ee) via Sharpless epoxidation of an appropriate allylic alcohol (53) (Scheme 5.17). 

There are several efficient methods available for the synthesis of homochiral sulfoxides [3], such as asymmetric oxidation, optical resolution (chemical or bio-catalytic) and nucleophilic substitution on chiral sulfinates (the Andersen synthesis). The asymmetric oxidation process, in particular, has received much attention recently. The first practical example of asymmetric oxidation based on a modified Sharpless epoxidation reagent was first reported by Kagan [4] and Modena [5] independently. With further improvement on the oxidant and the chiral ligand, chiral sulfoxides of >95% ee can be routinely prepared by these asymmetric oxidation methods. Nonetheless, of these methods, the Andersen synthesis [6] is still one of the most widely used and reliable synthetic route to homochiral sulfoxides. Clean inversion takes place at the stereogenic sulfur center of the sulfinate in the Andersen synthesis. Therefore, the key advantage of the Andersen approach is that the absolute configuration of the resulting sulfoxide is well defined provided the absolute stereochemistry of the sulfinate is known. 

One of the most important asymmetric syntheses is the Sharpless epoxidation. In this reaction, an allylic alcohol is transformed, by reaction with rerf.-butyl hydroperoxide (TBHP) in the presence of titanium tetra-wo-propoxide (Ti(/-PrO)4) and diethyl tartrate (DET), to the corresponding epoxy alcohol, with high enantiomeric purity. By the application of either (+)- or (-)-DET, the reaction product with the desired stereochemistry can be obtained [1,2] (Scheme 1). "O" (-)-DET... 

Preparation of another fragment began with 182 [75]. The asymmetry of the secondary hydroxyl groups of 183 and that of the tertiary one of 184 was derived from Sharpless epoxidation and Sharpless dihydroxylation. Acidic treatment to remove the acetonide group afforded tricychc spiroacetal 185. The stereochemistry was confirmed by NOE observed in the dithiane 169. 

The target molecule must first be rotated to fit the Sharpless asymmetric epoxidation model (need to have allylic alcohol group in bottom right position). The retrosynthesis of the epoxide leads to an alkene with the stereochemistry shown. Since the oxidation has occurred at the top face, the (+) enantiomer of diethyl tartrate (DET) is required. Note that only the alkene with the aUyUc hydroxyl group is oxidized in the Sharpless epoxidation. 

When predicting the stereochemistry of a Sharpless epoxidation product, you will find it helpful to draw the allylic alcohol in the same orientation each time, as shown in the margin, for example. 

Use of the Sharpless epoxidation allows access to optically active alkenyl epoxides and both the reaction with diiron nonacarbonyl under sonolytic conditions and the subsequent carbonylation proceed with retention of configuration, thus allowing us to predetermine the stereochemistry at of the 5-lactone at the C5-centre (Scheme 125). 

Stereochemistry Stereochemistry (the three-dimensional structure of molecules) is introduced early (Chapter 5) and reinforced often, so students have every opportunity to learn and understand a cracial concept in modem chanical research, drag design, and synthesis. Modern reactions While there is no shortage of new chemical reactions to present in an organic chemistry text, I have chosen to concentrate on new methods that introduce a particular three-dimensional arrangement in a molecule, so-called asymmetric or enanti-oselective reactions. Examples include Sharpless epoxidation (Chapter 12), CBS reduction (Chapter 20), and enantioselective synthesis of amino acids (Chapter 28). 

The ring opening of epoxides by inorganic azides is the initial step of a general synthetic route to aziridines. Because enantiopure epoxides are readily available by Sharpless epoxidation and other methods, their ring opening by azide ions provides one of the best approaches to the synthesis of enantiopure aziridines. The stereochemistry of the aziridines can be reliably predicted on the basis of the mechanisms of the steps involved. 

For asymmetric synthesis, we had to prepare the enantiomerically pure allene 55 with the proper relative stereochemistry. The allene moiety could be synthesized from epoxy propargyhc derivative 56 through SN2 -type reaction with a Grignard reagent. The epoxy propargylic substrate would be synthesized from allylic alcohol 57 via Sharpless epoxidation for introducing the appropriate stereochemistry of the protected allenyl alcohol. For the stereoselective synthesis of 56, the allylic alcohol 57 would be prepared enantioselectively (Scheme 16). 

Aldehyde 73 was prepared from aldehyde 70 using a Brown Allylation to control absolute stereochemistry in the preparation of 72. Bromide 68 was prepared using a Sharpless epoxidation to control absolute stereochemistry. Conversion of 73 to the corresponding enolate, alkylation with 68, and addition of more LDA to generate a new enolate (74) gave a reasonable yield of 75 (see Histrionicotoxin-8/9). 

Further variations on the epoxyketone intermediate theme have been reported. In the first (Scheme 9A) [78], limonene oxide was prepared by Sharpless asymmetric epoxidation of commercial (S)-(-)- perillyl alcohol 65 followed by conversion of the alcohol 66 to the crystalline mesylate, recrystallization to remove stereoisomeric impurities, and reduction with LiAlH4 to give (-)-limonene oxide 59. This was converted to the key epoxyketone 60 by phase transfer catalyzed permanganate oxidation. Control of the trisubstituted alkene stereochemistry was achieved by reaction of the ketone with the anion from (4-methyl-3-pentenyl)diphenylphosphine oxide, yielding the isolable erythro adduct 67, and the trisubstituted E-alkene 52a from spontaneous elimination by the threo adduct. Treatment of the erythro adduct with NaH in DMF resulted... 

More than a decade of experience on Sharpless asymmetric epoxidation has confirmed that the method allows a great structural diversity in allylic alcohols and no exceptions to the face-selectivity rules shown in Fig. 10.1 have been reported to date. The scheme can be used with absolute confidence to predict and assign absolute configurations to the epoxides obtained from prochiral allylic alcohols. However, when allylic alcohols have chiral substituents at C(l), C(2) and/or C(3), the assignment of stereochemistry to the newly introduced epoxide group must be done with considerably more care. 

Asymmetric oxidations have followed the usual development pathway where face selectivity was observed through the use of chiral auxiliaries and templates. The breakthrough came with the Sharpless asymmetric epoxidation method, which, although stoichiometric, allowed for a wide range of substrates and the stereochemistry of the product to be controlled in a predictable manner.4... 

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