Dihydroxylation diastereoselectivity

A catalytic enantio- and diastereoselective dihydroxylation procedure without the assistance of a directing functional group (like the allylic alcohol group in the Sharpless epox-idation) has also been developed by K.B. Sharpless (E.N. Jacobsen, 1988 H.-L. Kwong, 1990 B.M. Kim, 1990 H. Waldmann, 1992). It uses osmium tetroxide as a catalytic oxidant (as little as 20 ppm to date) and two readily available cinchona alkaloid diastereomeis, namely the 4-chlorobenzoate esters or bulky aryl ethers of dihydroquinine and dihydroquinidine (cf. p. 290% as stereosteering reagents (structures of the Os complexes see R.M. Pearlstein, 1990). The transformation lacks the high asymmetric inductions of the Sharpless epoxidation, but it is broadly applicable and insensitive to air and water. Further improvements are to be expected. 

Scheme 20. Synthesis of aldehyde 68 the diastereoselective dihydroxylation of 82 and synthesis of 87.

Usually, the polarity of compounds increases by dihydroxylation to such an extent that re-entry into the active site of dioxygenases is not possible and only single microbial biooxygenation is observed. Ho vever, vhen diols are masked in the form of lipophilic acetonides, a second biooxygenation reaction is possible the diastereoselectivity of both cis-diol systems vas reported to be trans (Scheme 9.30) [240]. 

The masked propargylic anfz-l,3-diols obtained in these reactions are useful precursors to more functionalized systems. Lindlar reduction of alkyne 171 generated the (Z)-allylic diol 172, which underwent diastereoselective osmium tetraoxide-catalyzed dihydroxylation to provide the partially protected tetraol 173 (Scheme 28). The propargylic anfz-l,3-dioxane 175,obtained in 88% yield from... 

Various other chiral diamines have also been explored for use with 0s04, some of which are illustrated in Scheme 12.8. They presumably function by forming hexaco-ordinate chelates with 0s04. The reactant in Entry 3 also raises the issue of diastereo-selectivity with respect to the allylic substituent. Normally, the dihydroxylation is anti toward such substituents.52 There are thus matched and mismatched combinations with the chiral osmium ligand. The R, 7 -diamine shown gives the matched combination and leads to high diastereoselectivity, as well as high enantioselectivity. 

Chart 3.4 Proposed substrate-reagent assembly for the diastereoselective dihydroxylation of 55... 

Cyclohexenones 34 also undergo a highly diastereoselective dihydroxylation to give cii-diols 39 (Scheme 11).22 These diol amides are converted to hydroxylactones 40 by an acid-catalyzed process involving retro aldol-realdolization prior to transacylation. The enantiomers of hydroxylactones 40 are obtained from iodolactones 35 by iodide exchange with 2,2,6,6-tetramethylpiperidin-l-yloxy free radical (TEMPO) followed by reductive cleavage of the TEMPO derivative with Zn in ElOAc. The enantiomeric purity of the hydroxylactones prepared by either route is 95-98% ee. 

Landais has extended his desymmetrization of dienes from dihydroxylation approaches to a cyclopropanation reaction. A Cu-pybox complex provides the highest enantioselectivities and good diastereoselectivity in the asymmetric cyclopropanation of the silyl-substituted cyclopentadiene 210 ... 

The protected diol side-chain of 456 is introduced by asymmetric dihydroxylation and directs diastereoselectivity in the formation of 457 and 458 by lithiation. The most acidic position of 456, between the two methoxy groups, is first protected by silylation. Suzuki coupling of 459 with the boronic acid 460 gives the kinetic product 461—the more severe hindrance to bond rotation in this compound does not allow equilibration to the more stable atropisomer of the biaryl under the conditions of the reaction. 

Stilbene diols such as 3 are gaining prominence both as synthetic intermediates and as effective chiral auxiliaries. While the diols can be prepared in high by Sharpless dihydroxylation, it would be even more practical to prepare them by direct asymmetric pinacol coupling. N. N. Joshi of the National Chemical Laboratory in Pune reports (J. Org. Chem. 68 5668,2003) that 10 mol % of the inexpensive Ti salen complex 2 is sufficient to effect highly enantioselective and diastereoselective pinacol coupling of a variety of aromatic aldehydes. Most of the product diols are brought to >99% by a single recrystallization. 

Additionally, 1,2-dihydroxyethylene dipeptide analogues without the C-terminal carboxylic acid have been used to obtain aspartyl proteases inhibitors.[641 These efforts include stereoselective alkylation of imines, one-pot reductive amination of epoxy ketones, ring opening of epoxides with sodium azide, diastereoselective dihydroxylation of allylic amines, and enzymatic resolution and stereocontrolled intramolecular amidation. 

Asymmetric induction also occurs during osmium tetroxide mediated dihydroxylation of olefinic molecules containing a stereogenic center, especially if this center is near the double bond. In these reactions, the chiral framework of the molecule serves to induce the diastereoselectivity of the oxidation. These diastereoselective reactions are achieved with either stoichiometric or catalytic quantities of osmium tetroxide. The possibility exists for pairing or matching this diastereoselectivity with the face selectivity of asymmetric dihydroxylation to achieve enhanced or double diastereoselectivity [25], as discussed further later in the chapter. 

The ratio of diols 61 62 from dihydroxylation with osmium tetroxide alone is 2.8 1, whereas with (DHQD)2-PHAL the ratio is 39 1, and with (DHQ)2-PHAL the ratio is 1 1.3, which shows the cumulative effect that can be achieved by matching diastereoselectivities and also reveals that AD may not be as reliable as is asymmetric epoxidation (Chapter 6A) for attaining good results when diastereoselectivities are mismatched. 

Other comparisons of diastereoselective osmylations in the absence and in the presence of chiral ligands have been reported. A study of the dihydroxylation of unsaturated side chains... 

The alkylation products are synthetically useful because simple subsequent transformations furnishes precursors of important natural products as illustrated in Scheme 8E.23. Simple oxidative cleavage of allylic phthalimide 45 generates protected (5)-2-aminopimelic acid, whose dipeptide derivatives have shown antibiotic activity. The esterification via deracemization protocol is not limited to the use of bulky pivalic acid. The alkylation with sterically less hindered propionic acid also occurs with high enantioselectivity to give allylic ester 116, which has been utilized as an intermediate towards the antitumor agent phyllanthocin and the insect sex excitant periplanone. Dihydroxylation of the enantiopure allylic sulfone gives diol 117 with complete diastereoselectivity. Upon further transformation, the structurally versatile y-hydroxy-a,(f-un-saturated sulfone 118 is readily obtained enantiomerically pure. 

In the synthesis of polyhydroxylated polyenes, osmium tetroxide induced dihydroxylation of an alkene adjacent to a coordinated iron atom has been used as the key synthetic step115. The reaction has been shown to be highly diastereoselective for E-alkenes and diastereospecific for Z-alkenes. With both types of alkene, the reaction occurs anti to the coordinated iron group (equation 18). 

Permanganese is a common oxidative reagent, the application of which to the asymmetric oxidative cyclization of 1,5-dienes has been reported by Brown (Scheme 3.14). The addition of acetic acid is quite important for the reaction to proceed, and highly functionalized tetrahydrofurans are obtained in a range of 58 to 75% ee, in diastereoselective manner [35]. Another oxidative transformation using KMn04 with a chiral ammonium salt has been investigated. Scheme 3.15 illustrates the asymmetric dihydroxylation of electron-deficient olefins to chiral diols in the... 

When dienones such as 55 are subjected to the epoxidation conditions the electron-poorer C=C double bond is selectively epoxidized. The other C=C bond can be functionalized further, for example, it can be dihydroxylated, as shown in the synthesis of the lactone 56 (Scheme 10.11) [82]. Stannyl epoxides such as 57 (Scheme 10.11, see also Table 10.8, R1 = n-Bu3Sn) can be coupled with several electrophiles [72], reduction of chalcone epoxide 58 and ring opening with alkyl aluminum compounds provides access to, e.g., the diol 59 and to phenylpropionic acids (for example 60). Tertiary epoxy alcohols such as 61 can be obtained with excellent diastereoselectivity by addition of Grignard reagents to epoxy ketones [88, 89]. 

LiBr has been reported to catalyse the dihydroxylation of alkenes (1) to afford syn-and anh -diols (2/3) with excellent diastereoselectivity, depending on the use of NaKTt (30 mol%) or PhI(OAc)2 (1 equiv.), respectively, as the oxidant.28 The authors claim that oxidation of non-benzylic halides was achieved for the first time to afford the corresponding diols in excellent yields 28 is not really justified as the development of the silver-free Prevost-Woodward dihydroxylation for non-benzylic substrates had... 

A similar cyclisation of an alkene derived from geranyl acetate 24 by dihydroxylation and formation of the epoxide 26 leads to a substituted cyclohexane 28. The Lewis acid ZrCU is used to open the epoxide and the alkene attacks intramolecularly 27 to give eventually the ryn-compound 28 with both substituents equatorial. The alignment of the alkene and the epoxide in a chair conformation 27a is responsible for the diastereoselectivity Note the regioselectivity the less substituted end of the alkene attacks the more substituted end of the epoxide 27. These are just two examples of the very many ordinary ionic reactions that can be used to make six-membered rings. 

The examples mentioned above illustrate the progress in the field of stereocontrolled cyclopropanation. Nowadays, the asymmetric Simmons Smith cyclopropanation may well be mentioned in the line with other asymmetric reactions like epoxidation or dihydroxylation. Fligh enan-tioselectivity and diastereoselectivity can be... 

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