Principles and Applications of Asymmetric Synthesis

		8.3 NEW CONCEPTS IN ASYMMETRIC REACTION						493

Figure 8±7. Relationship between the enantiomeric excess of the chiral catalyst and that of the product.

was observed for Sharpless epoxidation reactions. Many other reactions have since been found that show the nonlinear e¨ect.105

Figure 8±1 depicts the relationship between the optical purity of the chiral catalyst and the ee of the product. In a simpli®ed case, when two enantiomeric chiral ligands (LR or LS) are attached to a metal center (M), complexes ML2 may be formed as the reactive species. Three complexes are possible: MLRLS, MLRLR, and MLSLS. Supposing that LR is in excess and the stability constant for the meso-complex MLRLS is greater than that of the chiral complexes, if meso-MLRLS is the more active catalyst, a lower than expected ee will be obtained [(ÿ)-NLEs, curve 3 in Fig. 8±7]. The ee will be higher than expected if the meso-catalyst is less reactive than MLRLR or MLSLS [(‡)-NLEs, curve 2 in Fig. 8±7].

Diethylzinc addition to aldehyde is one of the earliest reactions showing nonlinear e¨ects. The ®rst paper on this transformation was published in 1986.106 Diethylzinc is usually inert to aldehydes in hydrocarbon solvents. However, nucleophilic addition reactions proceed smoothly in the presence of b-dialkylamino alcohol, a¨ording the corresponding secondary alcohol with high yield. Particularly noteworthy is that no alkylation occurs when 100 mol% of amino alcohol is added to organozinc, while the reaction a¨ords the product with high yield in the presence of a catalytic amount (2±8 mol%) of amino alcohol. DAIB [(2S )-3-exo-(dimethylamino) isoborneol] is one of the best catalysts found thus far for catalyzing this reaction. Kagan and Oguni recognized this process as a chiral multiplication process, and a detailed study of its mechanism was provided by Kitamura et al.107

Reaction of diethylzinc and benzaldehyde in toluene containing a small

494 ENZYMATIC REACTIONS AND MISCELLANEOUS ASYMMETRIC SYNTHESES

amount of DAIB with 15% ee can a¨ord a product with 95% ee, which is close to the 98% ee achieved with enantiomerically pure (2S)-DAIB. The reaction rate depends largely on the enantiomeric purity of the DAIB. Enantiomerically pure DAIB leads to a much faster reaction than racemic DAIB. Kitamura et al. contend that this is the result of auto association of the chiral intermediates generated by the reaction between the catalyst …ÿ†-DAIB and the organozinc compound. When a mixture of …ÿ†- and …‡†-DAIB is used, two types of dimeric species are formed: homochiral […ÿ†-…ÿ†-134 and …‡†-…‡†-134] and heterochiral […ÿ†-…‡†-134]. The signs refer to the enantiomer of the chiral ligand DAIB included in the complex. The enantiomeric monomers DAIB±ZnEt 135 are the active catalysts in this reaction, and each one produces predominantly one enantiomer of the product alcohol (Scheme 8±51 and Fig. 8±8).

Scheme 8±51

There is an equilibrium between the dimer and monomer, and molecular orbital study suggests that the heterochiral dimer is more stable than the homochiral isomer. The existence and behavior of the dimeric species were well con®rmed by experiments such as cryoscopic molecular weight and NMR measurement. In the NMR study of a DAIB-catalyzed dialkylzinc addition reaction, noticeable changes were observed in the spectrum of the homochiral dimer on the addition of benzaldehyde, while the spectrum of the heterochiral complex remained the same. This may imply that the heterochiral complex is very stable and does not react, and the homochiral dimer leads to the reaction product.

For a review of nonlinear e¨ects in asymmetric synthesis, see Girard and Kagan.108

8.3.5Chiral Poisoning

Another interesting issue is the possibility of creating optically active compounds with racemic catalysts. The term chiral poisoning has been coined for the situation where a chiral substance deactivates one enantiomer of a racemic catalyst. Enantiomerically pure (R,R)-chiraphos rhodium complex a¨ords the (S)-methylsuccinate in more than 98% ee when applied in the asymmetric hydrogenation of a substrate itaconate.109 An economical and convenient method

8.3 NEW CONCEPTS IN ASYMMETRIC REACTION

495

Figure 8±8. Association of chiral intermediates.

has then been proposed using racemic [(chiraphos)Rh]2 2‡ in the presence of a chiral poison. This chiral poison is added to preferentially block the functioning of one enantiomer of this catalyst and let only the other one work. Using racemic [(chiraphos)Rh]2 2‡ plus (S)-methophos as the catalytic system, product dimethyl succinate can be obtained in 49% ee (Scheme 8±52).109 (S)- Methophos itself a¨ords the hydrogenation product only in less than 2% ee.

Similarly,110 (1R,2S)-ephedrine is an e¨ective poison in the kinetic resolution of allylic alcohols using racemic BINAP instead of the expensive (R)- BINAP. (R)-2-cyclohexenol can thus be obtained in >95% ee using a racemic

Scheme 8±52

496 ENZYMATIC REACTIONS AND MISCELLANEOUS ASYMMETRIC SYNTHESES

BINAP±Ru catalyst and (1R,2S)-ephedrine (Scheme 8±53). This result is similar to that obtained when catalyzed by pure (R)-BINAP. In pure (R)-BINAP complex±catalyzed hydrogenation, (S)-2-cyclohexenol can also be obtained with over 95% ee. This means that in the presence of (R)-BINAP±Ru catalyst, (R)-cyclohexenol is hydrogenated much faster than its (S)-enantiomer. When ephedrine is present, (R)-BINAP±Ru will be selectively deactivated, and the action of (S)-BINAP±Ru leads to the selective hydrogenation of (S)-2- cyclohexenol, leaving the intact (R)-2-cyclohexenol in high ee.

Scheme 8±53

8.3.6Enantioselective Activation and Induced Chirality

In contrast to chiral poisoning, the concept of chiral activation has also emerged recently. An additional activator selectively or preferentially activates one enantiomer of the racemic catalyst, resulting in much faster reaction, and gives products with high ee.

The idea of enantioselective activation was ®rst reported by Mikami and Matsukawa111 for carbonyl-ene reactions. Using an additional catalytic amount of (R)-BINOL or (R)-5,50-dichloro-4,40,6,60-tetramethylbiphenyl as the chiral activator, (R)-ene products were obtained in high ee when a catalyst system consisting of rac-BINOL and Ti(OPri)4 was employed for the enantioselective carbonyl ene reaction of glyoxylate (Scheme 8±54). Amazingly, racemic BINOL can also be used in this system as an activator for the (R)-BINOL± Ti catalyst, a¨ording an enhanced level of enantioselectivity (96% ee).

RuCl2(TolBINAP)(DMF)n in either racemic or enantiomerically pure form is a feeble catalyst for the hydrogenation of simple ketones. However, when (S,S)-1,2-diphenyl ethylenediamine [(S,S )-DPEN] is present in the reaction mixture, the asymmetric hydrogenation of the carbonyl group in 2,4,4-trimethyl- 2-cyclohexenone takes place, providing the corresponding (S)-alcohol in 95% ee and with 100% yield. As shown in Scheme 8±55, in the presence of racemic RuCl2[…G†-Tolbinap)(DMF)n], (S,S)-DPEN, and KOH in a 7:1 mixture of isopropanol and toluene, the allylic alcohol is produced with high ee and high yield.

The complex TolBINAP±Ru dichloride existing in aggregate form is incapable of catalyzing the hydrogenation reaction. In the presence of (S,S)-DPEN, however, a monomeric diphosphine/diamine complex is readily formed to facilitate catalytic hydrogenation. In other words, under the hydrogenation conditions, one of the precatalysts, RuCl2[(R)-Tolbinap)(DMF)n], is selectively

8.3 NEW CONCEPTS IN ASYMMETRIC REACTION				497

Scheme 8±54

Scheme 8±55

activated in the course of the reaction, providing the product with enantioselectivity very close to the 96% that is obtained with a combination of enantiomerically pure (R)-Tolbinap and (S,S)-DPEN.

Another new strategy for catalytic asymmetric hydrogenation of prochiral ketones using achiral diphosphine ligand has also been demostrated.112 In this design, a conformationally ¯exible bis(phosphanyl)biphenyl ligand (BIPHEP) was used for preparing the Ru catalyst. Following the activation by a chiral diamine, high enantioselectivity is obtained in the asymmetric hydrogenation of aromatic ketones.

The ability to rotate freely about the C±C0 bond linking the two benzene rings makes possible a low energy barrier interconversion of the (R)- and (S)- con®gurations of biphenyl bidentate ligands 136 and 137. This free rotation makes it possible for the complex to adopt a more favored con®guration. Studies show that 136 and 137 are interconvertible, and equilibrium is established in the complex solution (CDCL3/(CD3)2CDODb1/2) after it stands for 3 hours at room temperature or 30 minutes at 80 C. An NMR study of a dilute solution of DM-BIPHEP/RuCl2/(S,S)-DPEN shows that a 3:1 mixture of 136 and 137 is formed. The equilibrium is established through the cleavage of an Ru±P bond, rotation along the C±C0 bond to invert the diphosphine con®gu-

498 ENZYMATIC REACTIONS AND MISCELLANEOUS ASYMMETRIC SYNTHESES

ration, and re-coordination of the P and Ru atom. When catalytic asymmetric hydrogenation of ketone is performed in the presence of this catalyst and a base, very good results are obtained.

A similar reaction was reported by Reetz and Neugebauer113 for the asymmetric hydrogenation of dimethyl itaconate (see Section 6.1.2.6). They used C2- symmetric 1,4:3,6-dianhydro-d-mannite as the backbone (R1 in 138), together with 2,20-dihydroxy-3,30-dimethyl-1,10-biphenyl (R2 in 138) to construct the diphosphite ligand 138. Asymmetric hydrogenation using the 138-coordinated Rh complex 139 leads to excellent enantioselectivity.113 Studies by Reetz's group have shown that under the hydrogenation conditions, chirality of the biphenyl ligand is formed by the induction of chiral backbone HO-R1-OH, and it is this dynamically formed chiral ligand that gives the high stereo induction in the catalytic hydrogenation. The results presented in Scheme 8±56 show that

Scheme 8±56. Reprinted with permission by Wiley-VCH Verlag GmbH, Ref. 113.

8.4 CHIRAL AMPLIFICATION, CHIRAL AUTOCATALYSIS

499

catalytic hydrogenation using achiral biphenyl ligand (Entry 6) can result in a product that shows comparable enantioselectivity to that obtained when using chiral BINAP ligand.

8.4 CHIRAL AMPLIFICATION, CHIRAL AUTOCATALYSIS, AND THE ORIGIN OF NATURAL CHIRALITY

Another achievement in recent asymmetric reaction study is the so-called chiral autocatalysisÐwhere the product itself catalyzes its own asymmetric synthesis. In this process, the chiral catalyst and the products are the same in an asymmetric autocatalytic reaction. The separation of chiral catalyst from the product is not required, because the product itself is the catalyst. Starting from an optically active product with very low ee, this process allows the formation of a product with high ee values.106,114

Soai et al.115 found that (S)-pyrimidyl alcohol 141 (20% mol, 94.8% ee) catalyzed its own synthesis in a reaction between the corresponding aldehyde 140 and diisopropyl zinc. The product eventually reached 48% yield and 95.7% ee (Scheme 8±57). In a similar manner, when the reaction was carried out starting from 20% of the (S)-141 with only 2% ee, the ®rst cycle gave the alcohol in 10% ee. Subsequent reaction cycles increased the ee up to 88%.

Scheme 8±57

A one pot asymmetric autocatalytic e¨ect for the above reaction has also been shown, with remarkable ampli®cation of enantiomeric excess (Scheme 8±58).115c Thus, a trace (about 3 mg) of 2-methylpyrimidyl alcohol 141 with only a slight enantiomeric excess (0.2±0.3% ee) can be automultiplied with

Scheme 8±58

500 ENZYMATIC REACTIONS AND MISCELLANEOUS ASYMMETRIC SYNTHESES

dramatic ampli®cation of enantiomeric excess (up to about 90% ee) in a one pot asymmetric autocatalytic reaction using diisopropylzinc and 2-methylpyr- imidine-5-aldehyde.

Another practically perfect asymmetric catalysis has been observed in reactions using (2-alkynyl-5-pyrimidyl)alkanols as the catalyst. The asymmetric autocatalysis shown in Scheme 8±59 gives the corresponding product in high yield with over 99% ee.116

Scheme 8±59

The origin of chirality is an interesting issue that has attracted considerable attention. What is the origin of the chiral homogeneity in natural compounds such as l-a-amino acids? Several physical factors have been suggested as leading to the creation of this chirality. Moradpour et al.,117 Bernstein et al.,118 and Flores and Bonner119 suggested that chirality could be induced in organic molecules by photosynthesis or photolysis using left or right circularly polarized light (CPL). However, the degree of enantiomeric imbalance caused by these physical factors is too small to be associated with the large enantiomeric imbalance in molecules found in nature. Shibata et al.120 introduced a reaction system showing the possibility of ampli®cation of enantiomeric imbalance starting from a trace amount of chiral initiator with low ee. This system suggests that slight symmetry breaking induced by the presence of a chiral initiator of very low ee can be dramatically ampli®ed by asymmetric autocatalysis.

In Shibata's study, an amino acid such as leucine or valine with a very low ee is chosen as the initiator. The reason for using leucine or valine is that they are biologically important amino acids. Furthermore, some naturally occurring physical factor such as CPL can cause a slight imbalance of the enantiomers. This is important because a probiotic system might contain such amino acids, and CPL radiation over hundreds of thousands of years might then cause the enrichment of one isomer of the amino acid. Shibata's study shows that the ®rst cycle of addition of diisopropylzinc to 2-methylpyrimidine-5-aldehyde 140 in the presence of an amino acid with slight enantiomeric imbalance can produce additional product 141 with small enantiomeric excess. Subsequent asymmetric autocatalysis then provides product 141 showing high enantiomeric excess.

Thus, it is possible that amino acids were ®rst produced in a probiotic system. A slight enantiomeric imbalance in these amino acids might have been created by the action of some naturally occurring physical factors such as CPL. Alternatively, the imbalance might have been created in the presence of some physical factors at the time when these amino acids were formed. This imbalance might then have been ampli®ed in other asymmetric reactions catalyzed by

8.6 REFERENCES 501

the amino acids, generating products with much higher enantiomeric excess and thus creating the natural chirality.

8.5SUMMARY

This ®nal chapter summarizes the enzyme-catalyzed asymmetric reactions and introduces some new developments in the area of asymmetric synthesis. Among the new developments, cooperative asymmetric catalysis is an important theme because it is commonly observed in enzymatic reactions. Understanding cooperative asymmetric catalysis not only makes it possible to design more enantioselective asymmetric synthesis reactions but also helps us to understand how mother nature contributes to the world.

Another question that has challenged the minds of scientists is the origin of chirality. Some scientists have argued that the breaking of the enantiomer balance was caused by some physical factors such as circularly polarized light, magnetic ®elds, or electric ®elds after the organic compounds were formed. Others thought that the imbalance was created during the formation of chiral organic compounds in the presence of the above-mentioned physical factors. Shibata's asymmetric autocatalysis and chiral ampli®cation provided some interesting information about the possible origin of chirality in nature.

8.6REFERENCES

1.(a) Whitesides, G. M.; Wong, C. H. Angew. Chem. Int. Ed. Engl. 1985, 24, 617. (b) Jones, J. B. Tetrahedron 1986, 42, 3351. (c) Chen, C. S.; Sih, C. J. Angew. Chem. Int. Ed. Engl. 1989, 28, 695. (d) Boland, W.; Frossl, C.; Lorenz, M. Synthesis 1991, 1049. (e) Santaniello, E.; Ferraboschi, P.; Grisenti, P.; Manzocchi, A. Chem. Rev. 1992, 92, 1071. (f ) Look, G. C.; Fotsch, C. H.; Wong, C. H. Acc. Chem. Res. 1993, 26, 182. (g) Mori, K. Synlett 1995, 1097. (h) Scho¨ers, E.; Golebiowski, A.; Johnson, C. R. Tetrahedron 1996, 52, 3769. (i) Johnson, C. R. Acc. Chem. Res. 1998, 31, 333.

2.Hudlicky, T.; Olivo, H, F.; McKibben, B. J. Am. Chem. Soc. 1994, 116, 5108.

3.Kirchner, G.; Scollar, M. P.; Klibanov, A. M. J. Am. Chem. Soc. 1985, 107, 7072.

4.Weidner, J.; Theil, F.; Schick, H. Tetrahedron Asymmetry 1994, 5, 751.

5.Johnson, C. R.; Bis, S. J. Tetrahedron Lett. 1992, 33, 7287.

6.Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014.

7.(a) Johnson, C. R.; Penning, T. D. J. Am. Chem. Soc. 1988, 110, 4726. (b) Parry, R. J.; Haridas, K.; De Jong, R.; Johnson, C. R. Tetrahedron Lett. 1990, 31, 7549.

(c) Parry, R. J.; Haridas, K.; De Jong, R.; Johnson, C. R. J. Chem. Soc. Chem. Commun. 1991, 740. (d) Johnson, C. R.; Nerurker, B. M.; Golebiowski, A.; Sundram, H.; Esker, J. L. J. Chem. Soc. Chem. Commun. 1995, 1139.

8.Prelog, V. Pure Appl. Chem. 1964, 9, 119.

9.(a) Gu, J.; Li, Z.; Lin, G. Tetrahedron 1993, 49, 5805. (b) Wei, Z.; Li, Z.; Lin, G.

Tetrahedron 1998, 54, 13059.

502ENZYMATIC REACTIONS AND MISCELLANEOUS ASYMMETRIC SYNTHESES

10.(a) Leuenberger, H. G. W.; Boguch, W.; Barner, R.; Schmidt, M.; Zell, R. Helv. Chim. Acta 1976, 59, 1832. (b) Kawai, Y.; Hayashi, M.; Inaba, Y.; Saitou, K.; Ohno, A. Tetrahedron Lett. 1998, 39, 5225.

11.Nugent, T. C.; Hudlicky, T. J. Org. Chem. 1998, 63, 510.

12.Johnson, C. R.; Golebiowski, A.; Sundram, H.; Miller, M. W.; Dwaihy, R. L.

Tetrahedron Lett. 1995, 36, 653.

13.(a) Stewart, J. D.; Reed, K. W.; Kayser, M. M. J. Chem. Soc. Perkin Trans. 1 1996, 755. (b) Stewart, J. D.; Reed, K. W.; Zhu, J.; Chen, G.; Kayser, M. M.

J.Org. Chem. 1996, 61, 7652. (c) Stewart, J. D.; Reed, K. W.; Martinez, C. A.; Zhu, J.; Chen, G.; Kayser, M. M. J. Am. Chem. Soc. 1998, 120, 3541.

14.(a) Robert, S. M.; Willetts, A. J. Chirality 1993, 5, 334. (b) Levitt, M. S.; Newton,

R.F.; Robert, S. M.; Willetts, A. J. J. Chem. Soc. Chem. Commun. 1990, 619.

15.(a) Oku, J.; Inoue, S. J. Chem. Soc. Chem. Commun. 1981, 229. (b) Mattews, B. R.; Jackson, W. R.; Jayatilake, G. S.; Wilshire, C.; Jacobs, H. A. Aust. J. Chem. 1988, 41, 1697.

16.(a) Minamikawa, H.; Hayakawa, S.; Yamada, T.; Iwasawa, N.; Nazasaka, K. Bull. Chem. Soc. Jpn. 1988, 61, 4379. (b) Narasaka, K.; Yamada, T.; Minamikawa

H.Chem. Lett. 1987, 2073.

17.Mori, A.; Ohno, H.; Nitta, H.; Tanaka, K.; Inoue, S. SynLett 1991, 563.

18.Reetz, M. T.; Kunisch, F.; Heitmann, P. Tetrahedron Lett. 1986, 27, 4721.

19.(a) E¨enberger, F.; Ziegler, T.; FoÈrster, S. Angew. Chem. Int. Ed. Engl. 1987, 26, 458. (b) E¨enberger, F.; HoÈrsch, B.; FoÈrster, S.; Ziegler, T. Tetrahedron Lett. 1990, 31, 1249. (c) E¨enberger, F.; HoÈrsch, B.; Weingart, F.; Ziegler, T.; KuÈhner, S. Tetrahedron Lett. 1991, 32, 2605. (d) Brussee, J.; Loos, W. T.; Kruse, C. G.; Van der Gen, A. Tetrahedron 1990, 46, 979. (e) Niedermeyer, U.; Kula, M. Angew. Chem. Int. Ed. Engl. 1990, 29, 386. (f ) Klempier, N.; Griengl, H.; Hayn, M. Tetrahedron Lett. 1993, 34, 4769. (g) Klempier, N.; Pichler, U.; Griengl, H. Tetrahedron Asymmetry 1995, 6, 845. (h) Schmidt, M.; HerveÂ, S.; Klempier, N.; Griengl, H. Tetrahedron 1996, 52, 7833.

20.E¨enberger, F.; Ziegler, T.; FoÈrster, S. Angew. Chem. Int. Ed. Engl. 1987, 26, 458.

21.Klempier, N.; Griengl, H.; Hayn, M. Tetrahedron Lett. 1993, 34, 4769.

22.(a) Han, S.; Lin, G.; Li, Z. Tetradedron Asymmetry 1998, 9, 1835. (b) Lin, G.; Han, S.; Li, Z. Tetrahedron 1999, 55, 3531.

23.(a) Nakamura, K.; Miyai, T.; Kawai, Y.; Nakajima, N.; Ohno, A. Tetrahedron Lett. 1990, 31, 1159. (b) Ozegowski, R.; Kunath, A.; Schick, H. Tetrahedron Asymmetry 1993, 4, 695. (c) Ferraboschi, P.; Casati, S.; Grisenti, P.; Santaniello, E. Tetrahedron Asymmetry 1993, 4, 9. (d) Howell, J. A. S.; Palin, M. G.; El Hafa, H.; Top, S.; Jaouen, G. Tetrahedron Asymmetry 1992, 3, 1355. (e) Kamal, A.; Damayanthi, Y.; Rao, M. V. Tetrahedron Asymmetry 1992, 3, 1361. (f ) Kawai, Y.; Takanobe, K.; Tsujimoto, M.; Ohno, A. Tetrahedron Lett. 1994, 15, 147. (g) Tsuji, K.; Terao, Y.; Achiwa, K. Tetrahedron Lett. 1989, 30, 6189. (h) Bevinakatti, H. S.; Newadkar, R. V. Tetrahedron Asymmetry 1993, 4, 773. (i) Chenevert, R.; Courchesne, G. Tetrahedron Asymmetry 1995, 6, 2093. ( j) Barnier, J.; Blanco, L.; Rousseau, G.; GrubeÂ-Jampel, E.; Fresse, I. J. Org. Chem. 1993, 58, 1570. (k) FoÈrster, S.; Roos, J.; E¨enberger, F.; Wajant, H.; Sprauer, A. Angew. Chem. Int. Ed. Engl. 1996, 35, 437. (l) Roberts, S. M.; Willetts, A. J. Chirality 1993, 5, 334. (m) Levitt,