Enantioselective reduction allylic alcohol epoxidation

In connection with the synthetic work directed towards the total synthesis of polyene macrolide antibiotics -such as amphotericin B (i)- Sharpless and Masamune [1] on one hand, and Nicolaou and Uenishi on the other [2], have developed alternative methods for the enantioselective synthesis of 1,3-diols and, in general, 1, 3, 5...(2n + 1) polyols. One of these methods is based on the Sharpless asymmetric epoxidation of allylic alcohols [3] and regioselective reductive ring opening of epoxides by metal hydrides, such as Red-Al and DIBAL. The second method uses available monosaccharides from the "chiral pool" [4], such as D-glucose. 

Much of the experimental success of asymmetric epoxidation lies in exercising proper control of Eq. 6A.4 [6]. Both TI(OR)4 and Ti(tartrate)(OR)2 are active epoxidation catalysts, and because the former is achiral, any contribution by that species to the epoxidation will result in loss of enantioselectivity. The addition to the reaction of more than one equivalent of tartrate, relative to Ti, will have the effect of minimizing the leftward component of the equilibrium and will suppress the amount of Ti(OR)4 present in the reaction. The excess tartrate, however, forms Ti(tartrate)2, which has been shown to be a catalytically inactive species and will cause a decrease in reaction rate that is proportional to the excess tartrate added. The need to minimize Ti(OR)4 concentration and, at the same time, to avoid a drastic reduction in rate of epoxidation is the basis for the recommendation of a 10-20 mol % excess of tartrate over Ti for formation of the catalytic complex. After the addition of hydroperoxide and allylic alcohol to the reaction, the concentration of ROH will increase accordingly, and this will increase the leftward pressure on the equilibrium shown in Eq. 6A.4. Fortunately, in most situations this shift apparently is extremely slight and is effectively suppressed by the use of excess tartrate. A shift in the equilibrium does begin to occur, however, when the reaction is run in the catalytic mode and the amount of catalyst used is less than 5 mol % relative to allylic alcohol substrate. Loss in enantioselectivity then may be observed. This factor is the basis of the recommendation for use of 5-10 mol % of Ti-tartrate complex when the catalytic version of asymmetric epoxidation is used. 

Thus, the allylic alcohol (S)-2 could be obtained in high yield (89%) with 94% ee by using only 20 mol% chiral lithium base 14 (Scheme 69a). Reduction of the amount of chiral base to 5 mol% lowered the ee to 85%. Interestingly, epoxides such as 99, which previously had rearranged with low enantioselectivity, were deprotonated with high enantioselectivity under such catalytic conditions (Scheme 69c). 

The classical method for the synthesis of epoxy alcohols is the epoxidation of allylic alcohols, the latter accessible by reduction of allylic hydroperoxides or other more traditional methods. One of the most valuable reactions for preparative purposes is the Sharpless method82 83, in which, for chiral allylic alcohols, the epoxy alcohols are produced diastereoselectively and, in the presence of chiral ligands, also in high enantioselectivity (see Section D.4.5.1.). 

After reduction of the enal with diisobutylaluminium hydride, the Wittig olefination of D-glycer-aldehyde acetonide (7 )-24 with Ph3P=CHCHO gives the ( )-allylic alcohol 129. The Katsuki-Sharpless enantioselective epoxidation [89] applied to 129 allows the preparation of D-arabinitol (= D-lyxitol) and ribitol, a meso alditol (Scheme 13.47). Similarly, Wittig olefination of R)-2A with Ph3P=CHCH(OEt)2, followed by acidic hydrolysis of the diethyl acetal and subsequent reduction of the enal with diisobutylaluminium hydride, provides the (Z)-allylic alcohol 130. Diastereoselective epoxidation and hydrolysis leads to D-arabinitol or xylitol, another meso alditol [90a]. 

Another method, where a different reduction methodology is employed, can be used to generate secondary and tertiary allylic alcohols from primary ones, and when this method is used in combination with Sharpless asymmetric epoxidation enantioselectivity may even be achieved (Scheme 11). ... 

The. V-alkylation of ephedrine is a convenient method for obtaining tertiary amines which are useful as catalysts, e.g., for enantioselective addition of zinc alkyls to carbonyl compounds (Section D. 1.3.1.4.), and as molybdenum complexes for enantioselective epoxidation of allylic alcohols (Section D.4.5.2.2.). As the lithium salts, they are used as chiral bases, and in the free form for the enantioselective protonation of enolates (Section D.2.I.). As auxiliaries, such tertiary amines were used for electrophilic amination (Section D.7.I.), and carbanionic reactions, e.g., Michael additions (Sections D. 1.5.2.1. and D.1.5.2.4.). For the introduction of simple jV-substituents (CH3, F.t, I-Pr, Pretc.), reductive amination of the corresponding carbonyl compounds with Raney nickel is the method of choice13. For /V-substituents containing further functional groups, e.g., 6 and 7, direct alkylations of ephedrine and pseudoephedrine have both been applied14,15. 

The epoxidation reaction is normally best carried out with only 5-10 mol% of the titanium catalyst in the presence of activated molecular sieves. These conditions avoid the traditional use of stoichiometric catalyst and provide a mild and convenient method (although often at the expense of a slight reduction in enantioselectivity and rate of reaction). Numerous examples of highly enantioselective epoxidations of allylic alcohols by this procedure have been reported. For example, the allylic alcohol 44 was converted selectively into the epoxides 45 and 46 (5.56). 

Another modification of Route B requires enantioselective reduction of ketones (E)-27 or stereoselective carbon-carbon bond formation at C-1 of (E)-27 (R = H) with appropriate organometallic species in the presence of chiral additives, both of which successfully supply the optically active (E)-26. The resulting chiral allylic alcohols (E)-26 are subjected to hydrogen bond-directed epoxidation with mCPBA, leading to the diastereoselective formation of syn-epoxy alcohols. In conplementary fashion, antz-selective epoxidation is possible using the Sharpless protocol. ... 

Umani-Ronchi adapted the Furstner protocol to achieve the first catalytic, enantioselective variant of this reaction. The chiral chromium salen complex was prepared from the in situ reduction of the anhydrous CrCb to CrCl2 with an excess of manganese metal, followed by complexation with the salen ligand 8 in the presence of catalytic triethylamine." Then the addition of allylic chloride (9) to aldehydes 10 to give the allylic alcohols 11 in moderate yields and in up to 95% ee. The same groups employed the same conditions for the addition of 2-butenyl bromides to aldehydes to achieve up to 83 17 syn/anti of allylic alcohol products and for the addition of 1,3-dichloropropene to aromatic aldehydes to obtain the syn chlorohydrin adduct in modest yield which were further converted to optically active vinyl epoxides. The [Cr(salen)]-catalyzed addition of propargyl halides to aromatic aldehydes allowed the synthesis of enantiomerically enriched homopropargyl alcohols in moderate yields with up to 56% ee. ... 

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