Principles and Applications of Asymmetric Synthesis

342 ASYMMETRIC CATALYTIC HYDROGENATION AND OTHER REDUCTION REACTIONS

Scheme 6±8

6.1.2.3 Sodium Borohydride Reduction of a,b-Unsaturated Esters. In 1989, Leutenegger et al.29 reported a semicorrin-type chiral C2-symmetric ligand bearing the structural features of 11a±c. Such chiral ligands are readily accessible in enantiomerically pure form from pyroglutamic acid.30 By varying substituent R at the two chiral centers in the compound, a series of chiral ligands can be obtained.

A cobalt complex containing this type of ligand is e¨ective in the sodium borohydride±mediated enantioselective reduction of a variety of a,b-unsaturated carboxylates. As can be seen from Scheme 6±8, in the presence of a catalytic amount of a complex formed in situ from CoCl2 and chiral ligand 11, reduction proceeds smoothly, giving product with up to 96% ee. The chiral ligand can easily be recovered by treating the reaction mixture with acetic acid.

The reaction can be used on a laboratory scale in vitamin synthesis. The enantioselectivity of this method lies in the same range as that observed in the catalytic hydrogenation of structurally related substrates. In contrast with chiral Rh or Ru complex±mediated catalytic hydrogenation, reduction of a,b-

6.1 INTRODUCTION 343

unsaturated carboxylate can proceed with excellent ee even in the absence of the a-acylamido group in the substrate (Scheme 6±9).

Scheme 6±9. Reprinted with permission by VCH, Ref. 29.

6.1.2.4 Asymmetric Hydrogenation of Enol Esters. Prochiral ketones represent an important class of substrates. A broadly e¨ective and highly enantioselective method for the asymmetric hydrogenation of ketones can produce many useful chiral alcohols. Alternatively, the asymmetric hydrogenation of enol esters to yield a-hydroxyl compounds provides another route to these important compounds.

The asymmetric hydrogenation of enol esters generally proceeds with moderate to high enantioselectivities. In the presence of Rh-DuPhos catalyst,31 highly enantioselective hydrogenation of enol esters bearing various substituents can be achieved, giving chiral alcohol derivatives at high optical purity. As shown in Scheme 6±10, a series of a-enol esters is hydrogenated in the presence

344 ASYMMETRIC CATALYTIC HYDROGENATION AND OTHER REDUCTION REACTIONS

Scheme 6±10. Reprinted with permission by Am. Chem. Soc., Ref. 32.

of […S;S†-(Et-DuPhos)Rh]‡, providing the corresponding product with high enantioselectivity irrespective of the (Z)/(E ) ratio of the starting material.32

Allylic alcohol derivatives are quite useful in organic synthesis, so the asymmetric synthesis of such compounds via asymmetric hydrogenation of dienyl (especially enynyl) esters is desirable. The ole®n functionality preserves diverse synthetic potential by either direct or remote functionalization. Boaz33 reported that enynyl ester and dienyl ester were preferred substrates for asymmetric hydrogenation using Rh-(Me-DuPhos) catalyst [Rh(I)-…R;R†-14], and products with extremely high enantioselectivity (>97%) were obtained (Schemes 6±11 and 6±12).

While Rh-DuPhos±mediated asymmetric hydrogenation of acyclic enol esters shows high levels of enantioselectivity, it does not provide the same high

Scheme 6±11. Asymmetric hydrogenation of dienyl esters.

6.1 INTRODUCTION 345

Scheme 6±12. Asymmetric hydrogenation of enynyl esters.

selectivity with cyclic enol ester substrates. Changes in the steric and electronic properties of the substrates sometimes lead to unexpected results. Jiang et al.34 achieved excellent enantioselectivity in the asymmetric hydrogenation of cyclic enol ethers using a PennPhos series developed by their group as the chiral ligand. In the model reaction shown in Scheme 6±13, asymmetric hydrogenation of 3,4-dihydronaphth-1-yl acetate catalyzed by Me-PennPhos (19, R ˆ Me) gives the corresponding acetate with 100% conversion and over 99% ee. Other chiral ligands such as BINAP and DuPhos give only poor results.

The asymmetric hydrogenation of enol esters can also be catalyzed by chiral amidophosphine phosphinite catalysts derived from chiral amino acids, but the enantioselectivity of these reactions has thus far been only moderate.35

Scheme 6±13. Reprinted with permission by Wiley-VCH Verlag GmbH, Ref. 34.

346 ASYMMETRIC CATALYTIC HYDROGENATION AND OTHER REDUCTION REACTIONS

6.1.2.5 Asymmetric Hydrogenation of Unfunctionalized Ole®ns. Enantioselective hydrogenation with catalysts bearing rhodium or ruthenium as the metal and chiral diphosphane as the ligand is one of the most powerful methods in asymmetric catalysis. However, the range of substrates is still limited to certain classes of ole®ns bearing polar groups that can coordinate with the catalyst. As has been discussed thus far, most of the substrates have polar functional groups. Examples of the asymmetric hydrogenation of unfunctionalized ole®ns with high enantioselectivity are rare.

Lightfoot et al.36 have reported a series iridium complexes 21 containing phosphanodihydroxazole ligands 20. These complexes give high enantioselectivity in the asymmetric hydrogenation of unfunctionalized ole®ns. Selected results are given in Table 6±2.

Broene and Buchwald37 synthesized chiral titanocene compound 22 for the asymmetric hydrogenation of trisubstituted ole®ns.

The reaction was carried out by addition of 1.95 equivalents of n-BuLi to a THF solution of 22 at 0 C to generate the active catalyst, which was then combined with substrate (S/C about 20:1) under an inert atmosphere using phenylsilane as the stabilizing agent. Trisubstituted unfunctionalized ole®ns can be hydrogenated in good yield with high ee. Representative results are listed in Table 6±3.

6.1.2.6 New Developments in the Asymmetric Hydrogenation of Enamides. Besides the chiral phosphine ligands mentioned above, chiral phosphinites and chiral phosphinamidites also have emerged as powerful ligands for catalytic asymmetric hydrogenation of a variety of substrates. Selke et al.38a and RajanBabu et al.38c developed a series of phosphinites derived from d-(‡)- glucose and found them to be e¨ective ligands for the rhodium-catalyzed

			6.1	INTRODUCTION	347
TABLE 6±2. Asymmetric Hydrogenation of Unfunctionalized Ole®ns
Entry	Substrate	Catalyst (mol%)		Yield (%)	ee (%)
1		21d (4)		96	84
2		21d (1)		95	96
3		21f	(0.1)	>99	97
4		21f	(0.5)	98	95
5		21f	(0.3)	97	95
6		21f	(0.3)	>99	61
7		21f	(1)	97	42
8		21f	(0.5)	>99	91
9		21g (2)		>99	81

ee ˆ Enantiomeric excess.

asymmetric hydrogenation of dehydroamino acid derivatives. The most important advantage of chiral phosphinite ligands over their corresponding phosphine counterparts is their ease of preparation, which can be achieved by reacting the corresponding chiral alcohol with chlorophosphines. Chan et al.39 have developed spiro ligand 23 (SpirOP), which has shown great e½ciency in catalytic hydrogenation reactions. Chiral ligand 24 is also a chiral phosphinite ligand that has shown catalytic results as good as chiral phosphine ligands.40

348	ASYMMETRIC CATALYTIC HYDROGENATION AND OTHER REDUCTION REACTIONS
TABLE 6±3. Chiral Titanocene-Catalyzed Asymmetric Hydrogenation of
Unfunctionalized Trisubstituted Ole®ns
Entry	Substrate	Time (h)	Yield (%)	ee (%)
1		48	91	>99
2		48	79	95
3		44	77	92
4		132	70	93
5		184	70	83
6		169	87	83

Reprinted with permission by Am. Chem. Soc., Ref. 37.

The most di½cult aspect of research in asymmetric catalysis is ®nding e¨ective ligands. As suggested by Noyori, the highly skewed naphthyl rings in BINAP are the determining features that made the ligand so e¨ective in asymmetric catalytic reactions. A rigid ligand±metal complex structure is thus essential for obtaining e¨ective chiral recognition. In designing novel ligands for catalytic asymmetric hydrogenation, one should always keep this in mind. In the above phosphinite ligand 23, the spiro backbone, which mimics the skewed positions of the binaphthyl rings in BINAP, possesses a highly rigid structure, and this makes it possible to compensate for the conformational ¯exibility caused by the introduction of the C±O±P bond. The asymmetric hydrogenation of prochiral enamides shows that the spiro phosphinite ligand 23 is superior to the less rigid chiral phosphinite and phosphines. Representative results are shown in Scheme 6±14.

The Rh-23±catalyzed asymmetric hydrogenation of (Z)-2-acetamidoacrylic

6.1 INTRODUCTION 349

Scheme 6±14. Spiro phosphinite±catalyzed reactions. Reprinted with permission by Am. Chem. Soc., Ref. 39b.

acid gives very high enantioselectivity (>99.9% ee) in the product. When …1R;5R;6R†-23 is used as the ligand, the (R)-con®guration is obtained in all products. It is not only the unsaturated acid that can be reduced with high enantioselectivity; excellent results can also be obtained for the corresponding esters as well.

In chiral ligand 24, the two cyclopentane rings restrict the conformational ¯exibility of the nine-membered ring, and the four stereogenic centers in the backbone dictate the orientation of the four P-phenyl groups. Scheme 6±15 shows the application of Rh-24 in the asymmetric hydrogenation of dehydroacylamino acids.

The somewhat higher enantioselectivity of Rh-23 as compared with Rh-24 may be due to the di¨erent rigidities of these two chiral ligands: The carbon backbone of chiral compound 23 is an absolutely rigid structure, while that of compound 24 is slightly more ¯exible because of the possibility of free rotation along the C±C bond linking the two ®ve-membered rings.

In contrast to the success in the synthesis of optically active amino acids and related compounds, only limited success has been achieved in the asymmetric synthesis of chiral amines or related compounds. One breakthrough is the asymmetric hydrogenation of arylenamides with Rh catalysts containing

Scheme 6±15. Reprinted with permission by Am. Chem. Soc., Ref. 40.

350 ASYMMETRIC CATALYTIC HYDROGENATION AND OTHER REDUCTION REACTIONS

DuPhos and BPE ligands.41 In addition to the phosphinite ligands, the easily prepared bis-aminophosphines42 have also been found to be e¨ective ligands in catalytic hydrogenation reactions. From a practical point of view, it is always desirable to develop e¨ective ligands that can be easily prepared and manipulated. Zhang et al.43 have used chiral bis-aminophosphine ligands 25 and 26 for asymmetric synthesis of chiral amine derivatives.

With these ligands, the catalytic hydrogenation of a-arylenamides gives a fast rate of reaction and up to 99% product ee when the reaction is carried out at 5 C under 1 atm of H2 (Scheme 6±16).

Scheme 6±16. Asymmetric hydrogenation of enamide using 25 or 26 as the chiral ligand.

Chirality transfer in catalytic asymmetric hydrogenation can be achieved not only by using powerful chiral ligands such as BINAP or DuPhos but also by the formation of a dynamic conformational isomer. The availability of many enantiomerically pure diols allows the production of electron-de®cient, bidentate phosphate in the form of 27. The backbone O±R1 ±O can de®ne the chirality of the O±R2 ±O in complex 28, hence realizing the chirality transfer.44

When a commercially available C2-symmetric 1,4:3,6-dianhydro-d-mannite 29 is chosen as the backbone, reaction of this diol compound with chlorophosphoric acid diaryl ester gives a series of phosphorate ligands 30. These were tested using the asymmetric hydrogenation of dimethyl itaconate as a model

6.1 INTRODUCTION 351

reaction. When 30 bearing two achiral b-naphthoxy residues at each phosphorus center was used, the stereoselectivity of the reaction was only 21%. This means that the backbone diol is only a poor ligand for chirality transfer. When 30 containing (S)- or (R)-binaphthol was used as the chiral ligand, ee values of 88% and 95% were obtained, consistent with the mismatched and matched pairs, respectively.

When atropisomeric biphenol units are present in the P/O hetereocycle, the enantioselectivity of the reaction is not expected to be very high because these biphenol moieties themselves are not chiral. However, enhancement of enantioselectivity has been observed, especially when 2,20-dihydroxy-3,30-dimethyl- 1,10-biphenyl is used as an achiral diol. A very high enantioselectivity of 98.2% has been found, even though 2,20-dihydroxy-3,30-dimethyl-1,10-biphenyl itself is achiral. The explanation for this high enantioselectivity is that a dynamic chirality is induced into 2,20-dihydroxy-3,30-dimethyl-1,10-biphenyl by the mannite backbone, and this dynamic chirality is the cause of the high enantioselectivity of the hydrogenation reaction. There are three de®ned diastereomeric metal complexes possible (R=R, S=S, and R=S combinations in the biphenol moieties), and these three atropisomers are interconvertable due to the low energy barrier for free rotation along the biaryl axis. One of the atropisomers is more stable than the others under the preexisting chirality in the mannite, and it is this atropisomer that induces the high enantioselectivity in asymmetric hydrogenation. The results are shown in Scheme 6±17.

Scheme 6±17. Reprinted with permission by Wiley-VCH Verlag GmbH, Ref. 44.