Sharpless asymmetric dihydroxylation

Enantioselective c -dihydroxylation of olefins using osmium catalyst in the presence of cinchona alkaloid ligands. 

The catalytic cycle is shown on page 539 (the secondary cycle is shut off by maintaining a low concentration of olefin)  

A Reaction under Scrutiny, in Chem. Eng. News 1997, November 3, 23. (Review, Mechanism). 

Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024. (Review, Nobel Prize Address). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 233, Springer-Verlag Berlin Heidelberg 2009 

AD-mix p, 1 mol% OSO4 5 mol% (DHQDjgPHAL CH3SO2NH2 (2 equiv) K2S2O8 (2 equiv) f-Bu0H/H20 (1 1) 

The key component of the cell wall lipopolysaccharide of Gram-negative bacteria, KDO (3-deoxy-D-manno-2-octulosonic acid), was synthesized by S.D. Burke and co-workers. One of the key transformations in the synthetic sequence was a doubie SAD of a 6-vinyldihydropyran-2-carboxylate template. This 1,4-diene was cleanly converted to a mixture of two C7 epimeric tetraols in a 20 1 ratio. The endocyclic olefin had an intrinsic preference for dihydroxyiation from the 3-face and not from the desired a-face. This stereofacial bias was impossible to override with any ligand normally used in the SAD, so later in the synthesis these two stereocenters had to be inverted in order to give the required stereochemistry at C4 and C5. 

The source of enantioselectivity can be discerned from the structure of the osmium complex. O An X-ray crystal structure of the OSO4 complex of (dimethylcarbamoyl) dihydroquinidine (263) has been published. Using 263 as a guide, the osmium complex of stilbene can be represented as 264 (the p-methoxy ester was used in this case), which may not be the active complex but it illustrates how selectivity arises in the reaction. 

Stilbene coordinates with osmium in a manner that minimizes any interaction of the phenyl groups with the azabicyclo[2.2.2]octane moiety and/or with the methylquinoline ring. As seen in 264, 01 appears to be significantly more hindered than 02. The phenyl rings of the stilbene molecule are oriented so that those rings are 

Asymmetric Epoxidations, Pergamon Press, Oxford too o nP ehensive Organic Synthesis, Vol. 7, Chapter 3.2, 

In a simple synthetic example, Jung used AD-mix-P to convert 267 to 268 in quantitative yield and 93% ee, as part of study using dialkyl aminals in asymmetric induction.374 Similarly, Corey used AD-mix-a with 269 as part of synthesis of eicosanoid (11/ , 125)-oxidoarachidonic acid, [,yt the initial diol (270) was not isolated. Internal transesterification led to the hydroxy-lactone 271 in 70% yield and 88% ee. After crystallization, 271 was obtained in 86% yield and 94% ee after crystallization. A comparison of 268 and 271 shows that the different catalysts have produced diols with the opposite absolute configuration. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 249, Springer International Publishing Switzerland 2014 

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Sharpless Asymmetric Dihydroxylation (AD) - Ligand pair are really diastereomers ... 

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. 

R,8S)-(+)-Disparlure (12) is the female sex pheromone of the gypsy moth (Lymantria dispar). Advent of Sharpless asymmetric dihydroxylation (AD) allowed several new syntheses of 12 possible. Sharpless synthesized 12 as shown in Scheme 17 [27]. Scheme 18 summarizes Ko s synthesis of 12 employing AD-mix-a [28]. He extended the carbon chain of A by Payne rearrangement followed by alkylation of an alkynide anion with the resulting epoxide to give B. Keinan developed another AD-based synthesis of 12 as shown in Scheme 19 [29]. Mit-sunobu inversion of A to give B was the key step, and the diol C could be purified by recrystallization. 

Z,9S,10 )-9,10-Epoxyhenicos-6-ene (13) is the female sex pheromone of moths such as ruby tiger moth (Phragmatobiafuliginosa), fruit-piercing moth (Oraesia excavata), and painted apple moth (Teia anartoides). Scheme 23 summarizes Shi s synthesis of 13 based on Sharpless asymmetric dihydroxylation (AD) [36]. Mori synthesized 13 employing lipase to prepare A (Scheme 24) [37]. Alkylation of the acetylide anion C was possible neither with tosylate nor with iodide, but triflate B could alkylate C to give D. 

Scheme 69 summarizes Mori s synthesis of 45, in which was employed Sharpless asymmetric dihydroxylation (A B) as the key-step [101]. 

Sharpless asymmetric dihydroxylation has been successfully applied to (1-cyclopentenyl)acetonitrile. Using (DHQ)PHN as a ligand in place of (DHQ)2PHAL, one of the components of AD-mix-a, (A, A)-(l, 2-dihydroxycy-clopentyl)acetonitrile was obtained after two recrystallizations, in 50% yield... 

Sharpless asymmetric dihydroxylation procedure was applied to the synthesis of the side chain of azinomycin A (equation 26)43. Horner-Emmons condensation of phospho-nate 36 with a /J-aziridine substituted acrolein afforded dehydroamino acid diene 37. Treatment of the diene with catalytic amounts of an osmium reagent and dihydroquini-dine (DHQD) p-chlorobenzoate resulted in asymmetric dihydroxylation, producing diol 38. Diol 38 was further converted to the naphthyl ester. 

In studies directed toward the total synthesis of tedanolide [38], the addition of y-substituted ketene acetal 60 to aldehyde 84 generated unsaturated ester 85 in 62% yield (Scheme 30). The resulting double bond could be further functionalized by applying Sharpless asymmetric dihydroxylation conditions. Hence diol 86, which represents the mismatched case due to unfavorable... 

Reactions have been carried out adjacent to the epoxide moiety in order to examine the effects, if any, that the epoxide has on subsequent reactions with respect to the regio- and stereochemical outcome. Dihydroxylation using osmium tetraoxide and Sharpless asymmetric dihydroxylation reactions have been extensively studied using substrates 29 and 31. Initial studies centred on the standard dihydroxylation conditions using AT-methylmorpholine-AT-oxide and catalytic osmium tetraoxide. The diastereomeric ratios were at best 3 2 for 29 and 2 1 for 31, indicating that the epoxide unit had very little influence on the stereochemical outcome of the reaction. This observation was not unexpected, since the epoxide moiety poses minimal steric demands (Scheme 21). 

More recently, in light of the development of the Sharpless asymmetric dihydroxylation protocol [20], we have approached the synthesis of diols such as 14 (Scheme 2) from the alkene. Thus, treatment of the alkenyl D-glucosides 15 vmder the conditions of the Sharpless dihydroxylation gave a range of diols 16 with varying diastereoisomeric excesses (Table 1). One of these mixtures of diols, upon recrystallization, yielded the pure diastereoisomer, namely the diol 14. This procedure now gives a very rapid and efficient entry into one of the precursor diols for the synthesis of the optically-pure epoxides [21]. 

It was of obvious interest to prepare the inhibitors 60 as their pure dia-stereoisomers, 66 and 67. Following on from our successful treatment of alkenyl D-glucosides under Sharpless asymmetric dihydroxylation conditions [21], we treated the alkenes 64 with the a-AD - and AD -mLxes - the results are summarized in Table 2. In no case did we ever obtain a satisfactory diastereo-isomeric excess of the diol 68 over the diol 69, or vice versa. A similar lack of stereoselectivity was also obtained with the triol 70 and the amine 71 [48]. 

The quinoline portion of the target alkaloids was prepared by condensing p-anisidine 9 with ethyl propiolate, followed by bromination. Coupling of 10 with the boronic ester 8 proceeded to give 11, the intermediate for the synthesis of both 1 and 2. Selective direct epoxidation of 11 using the usual reagents failed, but Sharpless asymmetric dihydroxylation was successful, providing the diol in > 96 4... 

The Sharpless asymmetric dihydroxylation has played a prominent role in enantioselecitve organic synthesis. Two groups have recently reported improvements in the procedure. Osmo E.O. Horni of the University of Oulu, Finland has found (J. Org. Chem. 2004,69,4816) that sodium chlorite is a more efficient reoxidant than is the usual K,[Fe(CN)J. Carlos A.M. Alfonso of the Instituto Superior , Lisbon has reported (J. Org. Chem. 2004,69,4381) that the asymmetric dihydroxylation can... 

Salinosporamide synthesis 196 Sharpless asymmetric dihydroxylation (see also Osmylation) 84,89, 141, 189 Sharpless asymmetric epoxidation 32,141 Silane, allylic synthesis 43 Sonogashira coupling (see Pd)... 

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