The Nobel Prize in Chemistry for 2001

Chemistry for Everyone

The Nobel Prize in Chemistry for 2001 Addison Ault Cornell College, Mount Vernon, IA 52314; [email protected]

The Royal Swedish Academy of Sciences awarded shares of the Nobel Prize in Chemistry for the year 2001 to three scientists for their development of methods for the efficient catalytic production of just one member of a pair of enantiomers. One half of the prize was divided equally between William S. Knowles, retired since 1986 from the Monsanto Company, St. Louis, MO, and Ryoji Noyori, since 1972 Professor of Chemistry at Nagoya University and since 2000 Director of the Research Center for Materials Science at Nagoya University, Nagoya, Japan. The other half of the prize was awarded to K. Barry Sharpless, since 1990 W. M. Keck Professor of Chemistry at the Scripps Institute, La Jolla, CA. Introduction Since the time of Pasteur the production of pure enantiomers has been of interest to chemists. Our interest continues because as living organisms, we depend upon a chemistry that distinguishes enantiomers. For example, one enantiomeric form of carvone smells like spearmint, whereas the other smells like caraway; only one enantiomer of monosodium glutamate has the “meaty” or umami taste, and the other is tasteless; and we perceive as sweet only one of the four stereoisomeric forms of aspartame. It is also generally true that only one stereoisomeric form of a drug will have the desired effect; other isomers are at best harmless and at worst have undesired side effects. Possibly the most (in)famous example of this is thalidomide, one of whose enantiomers has a sedative effect, and the other is teratogenic. Preparation of Pure Enantiomers Pure enantiomers can be obtained (i) by resolution of racemates, (ii) by kinetic resolution, (iii) from pure enantiomers of natural occurrence, (iv) by the use of chiral auxiliaries, and (v) by reactions that employ chiral catalysts.

By Resolution of Racemates An early approach to the preparation of a pure enantiomer was the separation (resolution) of the components of a racemic mixture (equimolar mixture) of the enantiomers, which is typically produced in a chemical reaction. This approach usually requires a full molar equivalent of the chiral agent (resolving agent), though the resolving agent can be recovered and reused. An especially efficient method of separating enantiomers is chromatography on a chiral adsorbent. In favorable cases both enantiomers can be obtained in pure form, and a small amount of the chiral agent can resolve a large amount of the racemate. By Kinetic Resolution Kinetic resolution uses a chiral catalyst to obtain a pure enantiomer from a racemic mixture. In the presence of the chiral catalyst the enantiomers react through diastereomeric transition states at different rates. Usually the desired product 572

is R′, the product of the enantiomer that reacts, but sometimes the desired product is the unchanged enantiomer, S. R

+

R

S

+

R

SR

enzyme

diastereomeric transition states

enantiomers

RR

R'

+

R

From Pure Enantiomers of Natural Occurrence A pure enantiomer can sometimes be prepared from another pure enantiomer that occurs in nature. R-(᎑)-carvone, for example, the enantiomer that smells like spearmint, is prepared on a large scale for use as a flavoring from R-(᎑)limonene, a by-product of the citrus industry. By the Use of Chiral Auxiliaries In this approach, a molecule that would otherwise produce equimolar amounts of a pair of enantiomers from its enantiotopic atoms, groups, or faces, is first connected to a chiral molecule, called in this situation a “chiral auxiliary”. The result is a molecule in which all of the prior enantiotopic relationships have been converted to diastereotopic relationships, and one can hope that nonchiral reagents will make the desired distinctions and create the new centers of chirality with the desired configuration. After this has happened, the chiral auxiliary is removed, recovered, and reused. By Reactions That Employ Chiral Catalysts Many pure enantiomers are prepared on an industrial scale by reactions catalyzed by enzymes. Sometimes a single enzyme, the chiral agent, is used, as in the enzyme-catalyzed addition of ammonia to fumaric acid to form S-aspartic acid, one of the two amino acid components of aspartame. Alternatively, the metabolic machinery of an entire organism is adapted to the synthesis of a single enantiomer, as in the industrial synthesis of S-monosodium glutamate from starch hydrolysate, urea, and air by Corynebacterium glutamicum on the scale of thousands of tons per year. The Nobel Prize in Chemistry for 2001 The goal, however, was to use small chiral molecules, not necessarily of natural origin, to prepare selective yet versatile catalysts for the synthesis of a great variety of pure enantiomers. It is the bringing of this dream to practice that was recognized by awarding the Nobel Prize in Chemistry for the year 2001 to Knowles, Noyori, and Sharpless.

The Work of William Knowles In 1968, Knowles and Sabacky reported one of the first indications that chiral, nonenzymatic, hydrogenation catalysts are capable of producing enantiomerically enriched products (1). In this paper they described a reduction of α-phenylacrylic acid in the presence of 0.15 mol % of a soluble rhodium-

Journal of Chemical Education • Vol. 79 No. 5 May 2002 • JChemEd.chem.wisc.edu


based catalyst that gave S-(+)-2-phenylpropionic acid in an optical purity of 15% (the product contained 57.5% of the S enantiomer and 42.5% of the R enantiomer; 15% enantiomeric excess of the S enantiomer): H2 gas soluble chiral

H2C

C

rhodium catalyst

OH

H H3C

O α-phenylacrylic acid

C

OH O

S-(+)-2-phenylpropionic acid 15% ee

Within just a few years Knowles was able to report the extension of this approach to the synthesis of L-DOPA, a substance effective in the treatment of Parkinson’s disease (2, 3): OH HO

CH2 H H 2N

termine the enantiospecificity of the addition of hydrogen to a carbon–carbon bond during catalytic hydrogenation. C2-Symmetric Ligands One of the most fruitful insights was provided by Henri B. Kagan and Tuan-Phat Dang (ref 13 cited by Sharpless [4 ]), who pointed out that the use of C2 symmetric bidentate chiral ligands would reduce by half the number of ways the chiral ligand can bind to the central metal. Many car keys have C2 symmetry, and thus, like the catalysts, they have two right ways up and no wrong way up. Figure 1 shows the structures of some of the better chiral ligands that have been used in the preparation of chiral catalysts.

The Work of Ryoji Noyori Other effective ligands were developed under the leadership of Ryoji Noyori. Intermediates and products of interest to both chemists and consumers have been synthesized in high yield and high enantiomeric excess. For example, S-naproxen, an antiinflammatory drug, is obtained in quantitative yield with an enantiomeric excess of 97% by the addition of hydrogen to 1 in the presence of a soluble ruthenium-based catalyst (5).

C

CH2

COOH

OH

H2 gas soluble chiral

L-DOPA

S-(᎑)-3-(3,4-dihydroxyphenyl)-L-alanine

H3 C

With the most highly enantiospecific catalysts, quantitative yields of an L-DOPA precursor were obtained that had an enantiomeric excess of 95%. O H3C

ruthenium catalyst

O O 1

H CH3 OH

CH3

H3 C

O O

O

C H

O

Dextromethorphan, 4, could be prepared from 3, formed by catalytic hydrogenation of 2 in the presence of a soluble ruthenium-based catalyst (5).

rhodium catalyst

C N

S-naproxen: 100%, 97% ee


H

O

COOH CH3


N

O H 3C

CHO

CH3

N CHO H

ruthenium catalyst

O O

O

CH3

CH3

O CH2 H HN O

3 100%; 97% ee

2

C COOH O

CH3

CH3

100%; 95% ee

This immediate product of the reduction is hydrolyzed to DOPA by HBr. Since the solubility of the excess S enantiomer and the solubility of the S enantiomer in the racemate are not independent, the pure S enantiomer can be crystallized from the mixture with no losses (2, p 108). This success quickly inspired others to investigate other ligands and metals, and their combinations, that would de-

H3C

N H

4 S-dextromethorphan

Furthermore, S-phenylalanine, one of the two amino acid components of the sweetener aspartame can, like L-DOPA,

JChemEd.chem.wisc.edu • Vol. 79 No. 5 May 2002 • Journal of Chemical Education

573


be prepared by a rhodium-catalyzed enantiospecific hydrogenation (6 ):

O

H OH O H

O H2 gas

O-Et

O-Et

R-BINAP ruthenium catalyst

SS isomer 99% 92% ee

racemic O H2N

O

O

CH3

N

OH

H H2 N

H

H

H

O

HOOC S,S-aspartame the sweet isomer

S-phenylalanine

Noyori also directed the development of catalysts that permit the highly enantiospecific reduction of simple aliphatic and aromatic ketones, even in the presence of a carbon–carbon double bond (ref 31 cited by Noyori [5]). An example is: O

OH

H2 gas

RR

R'

+

R

Racemization

S

+

enantiomers

R

SR

enzyme

diastereomeric transition states

Enzymatic versions of this “trick” have been known for some time, but Noyori demonstrated its application to enantiospecific reductions of chiral β-keto esters to give high yields of the desired one of four possible stereoisomeric β-hydroxyesters. The following equation represents a good example (7 ). Racemization is fast in the presence of the catalyst. 574

O

H-O

chiral titanium catalyst

R-(+)-glycidol 98% ee O atom delivered to si face only

allyl alcohol si face toward us

Dynamic Kinetic Resolution A final accomplishment that will be mentioned is the demonstration of a more efficient version of kinetic resolution. In a normal kinetic resolution, one member of a pair of enantiomers is transformed and the other is unchanged. Thus the best possible outcome is that the half of the racemic starting material that reacts is converted to the desired pure enantiomer R′ as indicated above, or the half of the starting material that does not react is what you want, S as indicated above. You then isolate the desired material, and the other half goes to some other purpose. In contrast, the “perfect” kinetic resolution would convert all of the racemic starting material to the desired enantiomer. Thus if one could add a means of racemization to a “normal” kinetic resolution, the unconsumed enantiomer, say S, would be racemized, forming more R that could be converted to the desired R′. The higher the rate of racemization, the higher the degree of enantiospecificity of the chiral agent, normally an enzyme; and the lower the degree of reactivity of the “unconsumed” enantiomer, S, the greater the yield and enantiomeric purity of the desired material, R′. This process is summarized below. R

TBHP

H-O

99%; 90% ee

+

H

H

BINAP ruthenium catalyst system

R

The Work of Barry Sharpless The work of Knowles and Noyori was entirely concerned with the catalytic enantiospecific addition of a hydrogen molecule to a double bond and was based on chiral modifications of the soluble Wilkinson hydrogenation catalysts. In contrast, K. Barry Sharpless took a completely independent approach that had as its goal the catalytic enantiospecific addition of an oxygen atom to a carbon–carbon bond to form a chiral epoxide. A minimalist example would be the asymmetric epoxidation of allyl alcohol with tert-butylhydroperoxide to give R-(+)glycidol, now an industrial process:

In the Aldrich catalog, the 97% pure, 98% ee, R and S forms are less than four times more expensive than the racemate. The great value of the asymmetric “Sharpless epoxidation” lies in both the variety of applications for the products of the reaction and the variety of allylic alcohols that will give a product in good yield with a high enantiomeric excess. This second success was not expected; as Sharpless said, “For years, right up until January 1980, when the asymmetric epoxidation was discovered, every expert in asymmetric synthesis and catalysis advised me that what we sought—a catalyst that was both selective and versatile—was simply impossible” (4). There was good reason to believe this. Experience with enzymes, the masters of specificity, provided examples of high enantiospecificity but were typically active toward only one substrate. It is interesting that most of the enzymes useful to organic chemists are digestive enzymes, or liver or kidney enzymes, whose job is to deal with substrates that do not participate in the normal chemistry of the organism; one might expect them to be more versatile, or, in the words of Sharpless, to exhibit greater “substrate promiscuity” (4). Two examples illustrate the range of possible applications of the “Sharpless epoxidation”. Consider first the synthesis of disparlure, a synthetic form of the sex pheromone of the gypsy moth, used in the control of this pest. H

O

H

7R,8S-(+)-7,8-epoxy-2methyloctadecane disparlure

Asymmetric oxidation of the allylic alcohol 5 gave 6, which was



converted to disparlure by oxidation to the aldehyde, treatment of the aldehyde with the Wittig reagent derived from 1-bromo4-methylpentane, and reduction of the resulting alkenes. H TBHP chiral titanium catalyst

OH H 5 H O OH H 6

Sharpless tells us “The synthesis of the gypsy moth sex attractant, (+)-disparlure, used by the US government for insect control, was the first application and, in fact, federal revenues saved in just two years exceeded that expended on grants funding the 10-year search for the method” (4 ). At the other end of the spectrum of sophistication was the total synthesis of the L member of each of the eight pairs of stereoisomeric hexoses, work done in collaboration with Satoru Masamune of MIT. This “sugar project” was undertaken to demonstrate Masamune’s strategy for asymmetric synthesis and Sharpless’s method for asymmetric synthesis. Since the stereochemical outcome of each stereospecific reaction in this project could be reversed by using the chiral catalyst of opposite handedness, a virtual synthesis of the D member of each pair of enantiomers was also accomplished (8). CHO H

OH

H

OH

H

OH

H

OH CH2OH

16 sterioisomeric forms as 8 pairs of enantiomers

excess TBHP

H HO S isomer consumed

L-diethyl

tartrate Ti(OiPr)4

HO H R isomer nonreactive

+ H HO

O

97% this diastereomer

φ

φ

As a last example we look at the one of five experiments run on January 18, 1980, which Sharpless says provided the vital clue that pointed to the successful development of the titanium-catalyzed asymmetric epoxidation reaction. The experiment is summarized below (4 ). +

The point of the experiments was to determine the diastereomeric ratio of products of the epoxidation of racemic isopropyl vinyl carbinol under different conditions, and the reaction illustrated by the equation was the only one of the five that involved a chiral agent. L-(+)-Diethyl tartrate was included in one experiment because its C2 symmetry appealed to Tsutomu Katsuki, who was actually doing the experiments. Although the experiments were intended to determine diastereospecificity, the especially high degree of diastereospecificity obtained in this reaction suggested that the titanium–tartrate system might also be highly enantiospecific when applied to prochiral allylic alcohols—which we now know was to be the case. After Katsuki noticed that the reaction stopped when only half of the starting material had been consumed, it was surmised (but not verified until later) that only one enantiomer underwent reaction. As the equation indicates, the reaction was also very highly enantiospecific. It thus also qualifies as the first application of catalytic asymmetric epoxidation to a kinetic resolution. Later work revealed how fortunate it was that Sharpless and Katsuki chose isopropyl vinyl carbinol to screen for diastereospecificity: the slower-reacting R enantiomer reacted so slowly that it appeared not to have reacted at all, even with the excess TBPH that was present. Had it reacted, it would have shown the opposite diastereospecific bias from that of the faster-reacting enantiomer, and the overall diastereospecificity would have appeared much smaller. Would it have been so small that the titanium–tartrate combination would not have been applied in a screen for enantiospecificity? Fortunately, we do not know the answer to that question. Sharpless and his group also developed several other asymmetric additions to the carbon–carbon double bond. Perhaps the best developed of these is “asymmetric dihydroxylation”, which leads to 1,2-diols in good yields and high enantiomeric excess. The oxidant is osmium tetroxide, a reagent highly specific for the carbon–carbon double bond, which adds by a syn mechanism. When the asymmetric hydroxylation (AD-mix) is applied to trans-stilbene in the presence of the chiral catalyst (DHQD)2PHAL (Fig. 1), the S,S enantiomer of the chiral diol is produced in almost quantitative yield (9).

HO H R isomer remains

C H

H

AD-mix (DHQD)2PHAL

C

φ E isomer

H H

C

C

OH OH

φ 99.5% S,S isomer

Use of the ligand (DHQ)2PHAL (Fig. 1) gives a 99.8% yield of the R,R isomer. The asymmetric dihydroxylation is catalytic not only with respect to the chiral ligand, as we expect, but also with respect to osmium, which is much too expensive to use in a stoichiometric amount. Possible co-oxidants used to reoxidize osmium include potassium ferricyanide, tert-butylhydrogen peroxide, and N-methylmorpholine-N-oxide. Although the goal of the research of Knowles, Noyori, Sharpless, and others was to make small chiral molecules, not of natural origin, that could be used to prepare chiral catalysts for the synthesis of pure enantiomers, the achievement was much more than emulation of the specificity and efficiency of enzymes. The catalytic systems of Knowles, Noyori, and


575


φ P O

CH3

O CH3 O P

P

O

P

C

C

φ

φ

P

H3 C C H H3C C H

H

H

φ

φ

P

H3C O

φ

P

φ

φ CAMP Knowles, 1970 6th phosphine prepared 80–88% ee in production of L-DOPA chirality at P

DiPamp Knowles, 1974 15th phosphine prepared 95% ee in production of L-DOPA chirality at P C2 symmetry

O

R,R-DIOP Kagan, 1971 83% ee in production of L-DOPA chirality at C C2 symmetry

Chiraphos Bosnich; ref in 2 95%+ ee in production of L-DOPA chirality at C C2 symmetry

O-Et

Et-O

C Pφ2

HO C H HO C H

Pφ2

O C

H

C H

C O

N O

H 3C

C

O-Et

Et-O

N

N O

O O

O

N

N

(DHQ)2PHAL * Sharpless, 1994 C2 symmetry

CH3

H3C

O

S,S-diethyl tartrate “unnatural” Sharpless, 1980 C2 symmetry

R,R-diethyl tartrate “natural” Sharpless, 1980 C2 symmetry

R-BINAP Noyori; ref in Noyori and Hidemasa, 1985 97% ee in production of S-naproxen with S isomer axial chirality

OH C OH

N O O CH3

O

N

N

(DHQD)2PHAL * Sharpless, 1994 C2 symmetry

Figure 1. Chiral ligands. Asterisks denote diastereomeric ligands. Without the ethyl groups on the quinuclidine ring they would be enantiomeric.

576



Sharpless produce not only molecules that occur naturally but also a great variety of molecules that do not occur in nature. Furthermore, in most cases the nonnatural catalytic systems can produce both enantiomers in high enantiomeric purity. This can be done because the nonnatural chiral molecules from which the catalysts are prepared are available in both enantiomeric forms. Enzymatic systems cannot produce both enantiomers because enzymes do not occur in both enantiomeric forms. Literature Cited 1. 2. 3. 4. 5. 6. 7. 8.

Knowles, W. S.; Sabacky, M. J. Chem. Commun. 1968, 1445–1446. Knowles, W. S. Acc. Chem. Res. 1983, 16, 106–112. Knowles, W. S. J. Chem. Educ. 1986, 63, 222–225. Sharpless, K. B. Chem. Br. 1986, 38–44. Noyori, R. Acta Chem. Scand. 1996, 50, 380–390. Noyori, R. Chemtech 1992, 22 (Jun), 360–367. Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345–350. Ko, S. Y.; Lee, Albert W. M.; Masamune, S.; Reed, L. A. III; Sharpless, K. B.; Walker, F. J. Science 1983, 220, 949–951. 9. Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547.

Bibliography

William S. Knowles and Others 1. Knowles, W. S.; Sabacky, M. J. Catalytic Asymmetric Hydrogenation Employing a Soluble, Optically Active, Rhodium Complex; Chem. Commun. 1968, 1445–1446. The authors report the reduction of α-phenylacrylic acid in the presence of 0.15 mol % of a chiral, soluble, rhodium complex to give optically active hydratropic acid containing an enantiomeric excess of 15%. 2. Knowles, William S. Asymmetric Hydrogenation; Acc. Chem. Res. 1983, 16, 106–112. The author reviews the progress and prospects of this growing field. 3. Knowles, W. S. Application of Organometallic Catalysis to the Commercial Production of L-DOPA; J. Chem. Educ. 1986, 63, 222–225. The author describes the development at the Research Division of the Monsanto Agricultural Products Company of a practical commercial method for the production of L-DOPA, the enantiomer of 3,4-dihydroxyphenylalanine that is effective in the control of Parkinson’s disease.

Ryoji Noyori and Others 4. Noyori, Ryoji; Takaya, Hidemasa. Binaphthyls: the Beauty and Chiral Uses; Chem. Scripta 1985, 25 (5), 83–89. The authors describe the virtues of the C2-symmetric binaphthyldiphosphines as chiral ligands for asymmetric catalytic hydrogenation. 5. Noyori, Ryoji. Chemical Multiplication of Chirality: Science and Applications; Chem. Soc. Rev. 1989, 18, 187–208. A detailed review of examples of the synthesis of pure enantiomers with an emphasis on systems using BINAP, emphasizing systems using BINAP and presenting some mechanisms and ORTEP drawings of several metal–ligand complexes. 6. Noyori, Ryoji; Takaya, Hidemasa. BINAP: An Efficient Chiral Element for Asymmetric Catalysis; Acc. Chem. Res. 1990, 23, 345–350. A review of the development and application of chiral, soluble, rhodium and ruthenium catalysts for the enantiospecific synthesis of single enantiomers.

7. Noyori, Ryoji. Chiral Metal Complexes as Discriminating Molecular Catalysts; Science 1990, 248, 1194–1199. Another detailed review of the synthesis of pure enantiomers, emphasizing systems using BINAP and presenting some mechanisms and ORTEP drawings of several metal–ligand complexes. 8. Noyori, Ryoji. Asymmetric Catalysis by Chiral Metal Complexes; Chemtech 1992, 22 (Jun), 360–367. A somewhat less detailed review of the material presented in bibliography ref 6. 9. Noyori, Ryoji. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994. A comprehensive and authoritative review of this rapidly expanding field of research. 10. Noyori, Ryoji. Asymmetric Hydrogenation; Acta Chem. Scand. 1996, 50, 380–390. Another authoritative review, including references to important industrial applications.

K. Barry Sharpless and Others 11. Ko, Soo Y.; Lee, Albert W. M.; Masamune, Satoru; Reed, Lawrence A. III; Sharpless, K. Barry; Walker, Frederick J. Total Synthesis of the L-Hexoses; Science 1983, 220, 949–951. 12. Sharpless, K. Barry. A New Strategy for Full Control of Relative Stereochemistry Expands the Role of Asymmetric Synthesis; Chem. Scripta 1985, 25 (5), 71–77. The author considers the interactions of chiral substrates with chiral reagents and points out that a highly enantiospecific reagent can overwhelm a mildly diastereofacial tendency in a substrate. 13. Sharpless, K. Barry. The Discovery of Titanium-Catalyzed Asymmetric Epoxidation; Chemtech 1985, 15, 692–700. An account of the author’s discovery, with stories of some of the wrong turns, bad guesses, and crucial observations that characterize how scientific progress actually takes place. 14. Sharpless, K. Barry. The Discovery of the Asymmetric Epoxidation; Chem. Br. 1986, 38–44. An account similar to that in bibliography ref 13. 15. Kolb, Hartmuth C.; Van Nieuwenhze, Michael S.; Sharpless, K. Barry. Catalytic Asymmetric Dihydroxylation; Chem. Rev. 1994, 94, 2483–2547. A review with references to all Sharpless’s papers on the subject.

Kinetic Resolution 16. Martin, Victor S.; Woodard, Scott S.; Katsuki, Tsutomu; Yamada, Yasuhiro; Ikeda, Masanori; Sharpless, K. Barry. Kinetic Resolution of Racemic Allylic Alcohols by Enantioselective Epoxidation. A Route to Substances of Absolute Enantiomeric Purity; J. Am. Chem. Soc. 1981, 103, 6237–6240. Examples of the kinetic resolution of racemic allylic alcohols. 17. Chen, Ching-Shih; Fujimoto, Yoshinori; Girdaukas, Gary; Sih, Charles J. Quantitative Analyses of Biochemical Kinetic Resolutions of Enantiomers; J. Am. Chem. Soc. 1982, 104, 7294– 7299. An analysis of kinetic resolution in terms of the rate ratios of competing processes. 18. Kitamura, M.; Ohkuma, T.; Tokunaga, M.; Noyori, R. Dynamic Kinetic Resolution in BINAP–Ruthenium(II) Catalyzed Hydrogenation of 2-Substituted 3-Oxo Carboxylic Esters; Tetrahedron: Asymmetry 1990, 1, 1–4. An analysis of kinetic resolution that includes the possibility of the racemization of the remaining, enantiomerically depleted, racemic substrate (dynamic kinetic resolution). 19. Kitamura, M.; Tokunaga, M.; Noyori, R. Mathematical Treatment of Kinetic Resolution of Chirally Labile Substrates; Tetrahedron 1993, 49, 1853–1860. The authors generalize the subject treated in bibliography ref 18.


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The Nobel Prize in Chemistry for 2001

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