Science
Epoxidation advance may spur its industrial use Asymmetric epoxidation of allylic alcohols finally has been made tru ly catalytic [/. Org. Chem., 51, 1922 (1986)]. This advance may acceler ate industrial use of the reaction to make optically pure intermediates for drugs and pheromones. Engineers at Upjohn already have used the stoichiometric version of the reaction to convert (2£)-octenl-ol to (3S)-pentyloxirane-(2S)-methanol on a multikilo scale. In the future, Upjohn may switch to the catalytic version. Aldrich Chemical offers enantiomers of eight substi tuted glycidols and their esters made with the catalytic version. And Arco Chemical plans to use it to produce the two enantiomers of glycidol. Invented by organic chemistry professor K. Barry Sharpless at Stanford University in 1980, asym metric epoxidation uses titanium(IV) isopropoxide and diethyl (+)- or (-)-tartrate to effect reaction of tertbutyl hydroperoxide with allylic al cohol substrates. Chemists can pre dict and direct the enantiomer to be made by sketching the geometry of the substrate and choosing be tween (+)- and (-)-tartrate. But formerly the procedure re quired costly titanium and tartrate reagents in amounts equimolar with allylic alcohol. Otherwise, reactions were slow, optical purities were only 40 to 80%, and reactions stopped at 50 to 60% conversion. Although yields and enantiomeric excesses of substituted allyl alcohols were high, allyl alcohol itself reacted with a yield of only 10 to 15%.
Now at Massachusetts Institute of Technology, Sharpless and postdoc toral fellow Robert M. Hanson re port that adding molecular sieves to the reaction mixture reduces the need for titanium-tartrate complex to only 5 mole %. Moreover, con centrations of substrate can be 0.5 to 1M, whereas the old procedure limited them to 0.1 to 0.3M. Also, the amount of tert-butyl hydroper oxide can be 1.5 equivalents, com pared with 2 equivalents before. And with smaller quantities of tita nium and tartrate compounds in the reaction mixture, product isolation is simpler. Supported by the National Insti tutes of Health and Eli Lilly & Co., Sharpless and Hanson demonstrated the catalytic method with detailed instructions for epoxidizing undecenol, a trisubstituted allylic alcohol, and geraniol, a tetrasubstituted com pound. They also told how to make and standardize 5 to 6M stock solu tions of anhydrous tert-butyl hydro peroxide in methylene chloride or isooctane on a 2.5-L scale. In other work with graduate stu dents Janice M. Klunder and Soo Y. Ko, Sharpless used cumyl hydro peroxide to epoxidize allyl alcohol itself catalytically. The older meth od gave poor yields with this sub strate. They used each enantiomer of glycidol in different routes to (2S)-propranolol, the active isomer of a drug important in treating heart disease and hypertension. Senior research scientist Joseph M. Timko of Upjohn says the com
pany has used the earlier stoichio metric version of the reaction to epoxidize 8 kg of (2E)-octen-l-ol to the (2S,3S)-epoxy alcohol with a yield of 80% and enantiomeric ex cess greater than 98%. Upjohn is in terested in producing large amounts of analogs of naturally occurring metabolites of arachidonic acid such as p r o s t a g l a n d i n s , prostacyclin, thromboxanes, and leukotrienes (C&EN, Aug. 16, 1982, page 30). The eight-carbon epoxy alcohol could be come the C-13 through C-20 seg ment of those molecules. Project manager Howard Brainard of Arco Chemical's new busi ness development department says he is talking to potential custom ers for enantiomeric glycidyl alco hol. However, he emphasizes that Arco also will make glycidyl deriv atives or other enantiomeric epoxy alcohols, depending on market in terest. Products, plant location and scale, and process details have not been decided on, Brainard points out. Aldrich offers eight epoxy alco hols and esters with purity of 97 to 98% and enantiomeric excess of 90% to greater than 98% at prices from $14 to $19 per g. Included among Aldrich products are glycidyl 4-toluenesulfonates and 4-nitrobenzoates, 3-methylglycidyl and 3,3-dimethylglycidyl 4-nitrobenzoates, 3-phenylglycidols, 3-(4-nitrophenyl)glycidols, 2-methyl-3-phenylglycidols, and 3-(4-bromophenyl)glycidols. Up john, Arco, and Aldrich have all licensed the Stanford patent on the Sharpless reaction. Steve Stinson, New York
Catalytic asymmetric epoxidation yields two routes to drugs CH =CHCH 9 OH
+ °iKc (2fl)-Glycidol CHJDH
Κ
CH2OSO?
ChL OH
(2S)-Glycidyl p-toluenesulfonate
4^^NHCH(CH3)2 (2S)-Propranolol
24
June 2, 1986 C&EN
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p
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