Development of enantioselective techniques continues at steady pace
Stephen C. Stinson, C&EN Northeast News Bureau ynthetic organic chemists continue to make progress in developing techniques for creating chiral mole cules. The newest advances in stereose lective methods were described at a symposium sponsored by the Division of Organic Chemistry. Some methods are designed to make single enantiomers of compound classes that have proven resistant to enantioselectivity, such as sulfoxides and hy droperoxides. Other advances are in the development of reagents to deliver reactants such as oxygen and ozone enantioselectively. And because stoichiomet ric reagents are costly to use on a molefor-mole basis, many chemists are seeking new asymmetric catalysts, individual molecules of which mediate thousands of enantioselective conversions each. Yet another trend is the design of cascade reactions, in which each suc cessive product in a chain of reactions becomes the starting material for the next reaction in the sequence, with faithful transmission of chirality and without further intervention by the practitioner. When commercially feasi ble, the cascade technique constructs complex molecules economically while minimizing the number of waste streams flowing out of a process. Chiral hydroperoxides are important
S
intermediates in inflammation reac tions. For example, (5S)-hydroperoxyeicosatrienoic acid from the en zyme-catalyzed reaction of oxygen with the polyunsaturated fatty acid arachidonic acid is a precursor to leukotrienes, which are mediators of in flammation. In addition, the (15S)hydroperoxy acid stimulates blood platelet aggregation. In another field of research, enantio meric methallyl cc-hydroperoxypropionate is a promising antibacterial agent. And in asymmetric synthesis, enantiomeric hydroperoxides could be enantioselective oxidizing agents. Graduate student Rainer T. Fell of the University of Wurzburg, Germany, told an audience in Chicago that the enzyme horseradish peroxidase in combination with guaiacol reduces one enantiomer of a racemic oc-hydroperoxy ester to the α-hydroxy compound, leaving the other hydroperoxide enantiomer in optically pure form. The selective reduction of one hydroperoxide enantiomer is bal anced by oxidation of guaiacol. Working with organic chemistry professor Waldemar Adam, food sci ence professor Peter Schreier, graduate student Ute Hoch, and research associ ate Chantu R. Saha-Moller, Fell made methyl (-)-(R)-oc-hydroperoxybutyrate in 97% enantiomeric excess by this method. The Wurzburg team deter mined the absolute configuration of this compound and the (-)-(S)-oc-hydroxybutyrate coproduct by synthesizing the coproduct independently from (+)-(S)-ocaminobutyric acid, whose absolute con figuration is known. Their work is sup ported by the Bavarian Research Society,
Enzyme catalyzes kinetic resolution of hydroperoxides Horseradish peroxidase
Racemic methyl a-hydroperoxybutyrate
the Chemical Industry Fund, and the Bayer Research Foundation. A second approach to stereoselective synthesis of hydroperoxides is that of organic chemistry professor Patrick H. Dussault of the University of Nebraska, Lincoln, whose work is supported by the American Cancer Society. Umesh R. Zope, a postdoctoral fellow at Ne braska, told attendees that the reaction of olefins with ozone yields carbonyl oxides of the form R 2 C=0->0. These carbonyl oxides react with al cohols such as methanol to form meth yl hydroperoxyacetals of the type CH 3 0-CR 2 -OOH. When substituted with a neighboring chiral group, the carbonyl oxide acetals show a diastereoselective preference of addition. For example, ozonolysis of racemic 3-phenyl-l-butene yields the carbonyl oxide of oc-phenylpropionaldehyde. Addition of methanol to this intermedi ate generates a new asymmetric center at the former carbonyl carbon atom and therefore a mixture of diastereoisomers. The ratio of the two diastereoisomers is 64:36. Thus, although Dussault's olefins are racemic, the Nebras ka results show that single enantiomers can lead to asymmetric induction. Inexpensive though it is, ozone is still a reagent needed in stoichiometric amounts to carry out reactions. Catalyt ic reactions are always more economi cal. And fewer asymmetric catalytic re actions are cleaner or more efficient than hydrogénation. According to organic chemistry professor Mark J. Burk of Duke University, asymmetric hydrogénation has received less attention than it deserves in recent years because many people think that it is a solved problem. "I'm very pleased that people thought it was a solved problem," Burk says, "because that has kept others away from the field." Working with postdoctoral fellows Michael F. Gross, T. Gregory P. Harper, José P. Martinez, Antonio J. Pizzano, and Judith A. Straub and graduate students Christopher S. Kalberg and Jeffrey R. Lee, Burk has optimized phosphine ligands for rhodium-based catalysts. The National Institutes of Health supports the work. The Duke studies extend research Burk did when he was a research chemist at DuPont. That company has developed a series of ligands—called DuPHOS—that are based on two molSEPTEMBER 4,1995 C&EN
4l
SCIENCE/TECHNOLOGY times less toxic than later transition metals/' Buchwald says. "We try to find exAlcohols add diastereoselectively to carbonyl oxides amples that titanium handles better than late transition metals." CH3O O O H HOO PCH3 In particular, the MIT workers have ChhOH o3 had the best results to date for today's most challenging task—reduction of CRHC 6 5 6 5 imines to enantiomeric amines. BuchC H 36% 64% 6 5 wald is working toward his ultimate Racemic Carbonyl 3 goal of bringing these reactions off at olefin oxide room temperature and 15 psig. a (S)-carbonyl oxide enantiomer shown to simplify diagram. Another means of controlling stereochemistry in asymmetric synthesis is use of chiral auxiliaries. These are enantioecules of a £nms-2,5-dialkylphospho- are not as space-filling as higher dialkyl meric compounds that form covalent bonds with substrates, guide the stereolane bonded to ortho positions of ben analogs. zene. Yet another series involves transConversely, the best results in re chemical courses of reactions on those dialkylphospholanes bonded to each duction of acetoacetates come from substrates, and are removable afterward. end of ethane. Changing the ligands more sterically demanding diisoproOrganic chemistry professor Philip among dimethyl-, diethyl-, or diisopro- pylphospholane-based catalysts. As a Garner of Case Western Reserve Unipylphospholane allows modulation of comparison, BINAP [2,2'-bis(diphenyl- versity, Cleveland, discussed the use of catalysts and optimization tailored to phosphino)-l,r-binaphthyl], a com sugar derivatives as generalized chiral specific substrates. monly used phosphine catalyst, gives auxiliaries for enantioselective free-radIn particular, the Duke workers have the same 98% enantiomeric excesses as ical reactions. He finds that asymmetric routes to enantiomeric β-branched phospholanes, but only 10% conversion induction by monosaccharides is so amino acids and β-hydroxyesters. of starting materials, versus 100% for powerful that it can override other inductive influences already in the subThese products come from hydrogéna- phospholanes. tion of α-acetaminoacrylic esters with Another innovator in exploiting the strate molecule. His work is supported rhodium catalysts and substituted ace- clean features of asymmetric hydrogéna- by the National Institute of General toacetate esters with ruthenium cata tion is chemistry professor Stephen L. Medical Sciences. lysts, respectively. For example, working with postdocBuchwald of Massachusetts Institute of The only β-branched amino acids that Technology. Buchwald summarized a toral fellows Philip Cox and Ray Leslie occur in proteins are valine, isoleucine, broad spectrum of work over the years and fellow faculty member Stephen and serine. So synthetic routes to other with graduate students Bain Chin, Ma- Klippenstein, Garner treats methyl (S)branched amino acids would furnish ad risa V. Troutman, and Christopher A. lactate with tri-O-benzyl-D-glucal. The ditional raw materials for peptide-type Willoughby and postdoctoral fellows free hydroxyl group of lactate adds drugs. But the bulky acetaminoacrylate Richard D. Broene, Nancy Lee, and Jef- across the double bond of the glucal to give a 2-deoxyglucoside. precursors to such structures are hard to frey DePinto. Transesterification of that sugarreduce. Burk's team finds success with The Cambridge team focuses on early the dimethylphospholane versions of the transition metals, especially titanium, for bound lactate with pyrithione [1-hyethylene and phenylene catalysts. These catalysts. "Titanium is three to four droxy-2(lJFi)-pyridinethione] leads to a C
C
H
H
Glucose chiral auxiliary mediates asymmetric radical reactions CH 2 OBn
CH 2 OBn
•Q OBn/)
Ç°2CH3 +
H
° +
BnO Tri-O-benzyl-D-glucal
H
J— Ο —*_j(0Bn)_ BnON /(XSXOoCU
ChL
CH,
Methyl (S)-lactate /N02 H9C = CV ^CH3
CH2OBn TiCI3 "^
Bn = benzyl
42
SEPTEMBER 4,1995 C&EN
\OBn / RnONl / O n CH,
N0 2
Ν 7
7
-4—s-/ CH,
H
~Λ
)
\ = /
2°
\OBn , BnO\| / O ^ R . ^ C H , CH 3
Ο
Cascade reactions telescope several reactions into one 1)CH2=C(CH3)2, H + 2 AD mix
XHpOH
n
'^e^i3^
1)TDI
Ο
2) RuCI3, NalO,
S0 2
Ο
)
S0 2
'
Ο
P
- • n-C6H1
CH2OC(CH3)3
S0 2
Note: AD-mix β is Sharpless asymmetric dihydroxylation reagent, marketed by Aldrich Chemical under license from Sepracor;TDI = thionyldiimidazole.
hydroxamate ester. The hydroxamate is susceptible to photolytic cleavage at -78 to -79 °C to form a free radical. Addition of an unsaturated compound like 2-nitropropene at that moment results in a new carbon-carbon bond with an (R)configuration at the former α-carbon of the lactate. The end product after separation from the deoxyglucose chiral auxiliary is 4-oxo-(2K)-pentanol in 80% enantio meric excess. Thus the overall process is a free-radical analog of an aldol reac
tion. Garner points out that L-rhamnose is equally available commercially as a chiral auxiliary that is opposite in ste reochemical sense from glucose. Thus chemists can use either glycal (unsatur ated sugar) to dictate one or the other configuration during carbon-carbon bond formation. Yet another strategy to work with chirality is the cascade reaction. True, setting up the functional groups in the substrate is a challenge. But when suc cessful, the substrate undergoes a se-
Phospholane catalysts tackle tough substrates . . . H 3 C 98% ee S-isomer with (/?,fl)-diisopropyl-BPE
quence of reactions that assembles a complex molecule. Graduate student Thomas J. Beauchamp of the University of Minnesota, Minneapolis, reported application of a cascade to make structures containing repeating tetrahydrofuran (THF) units. Such structures exist in certain naturally occurring macrolide ionophore antiinfective agents. One past approach has been a cascade of openings of epoxide rings, which snake around to close five-membered ether rings. But as Beauchamp explains, it is hard to set up the right sequence of enantiomeric epoxide rings. Working with organic chemistry professor Scott D. Rychnovsky, Beauchamp uses a se quence of asymmetric cyclic sulfates that he makes from corresponding polyols, which in turn come from asymmetric di hydroxylation reactions on olefins. The Minnesota workers demonstrated the principle with the tert-butyl ether of nonadeca-4,8,12-trien-l-ol. Simultaneous asymmetric dihydroxylation of all three olefinic bonds gives an enantiomeric tris(diol). Reaction of that with thionyldi imidazole converts the three diol ar rangements to three cyclic sulfite esters. Oxidation yields cyclic sulfates. Heating in aqueous acetonitrile hydrolyzes the tert-butyl ether, and the lib erated hydroxyl group arcs back to open the adjacent cyclic sulfate and close a THF ring. The resulting hydrogen sul fate half-ester unravels easily, and the newly freed hydroxyl group attacks the adjacent cyclic sulfate, closing yet a sec ond THF ring. Rychnovsky and Beau champ have also made the intermediate corresponding to the C17 to C32 section of the ionomycin molecule, which con tains two chiral THF rings. Other work ers have used this segment in the total synthesis of ionomycin. • SEPTEMBER 4,1995 C&EN
43
