Principles and Applications of Asymmetric Synthesis

8.2 MISCELLANEOUS METHODS									473

Figure 8±5. Proposed mechanism for the catalytic arylation of 2,3-dihydrofuran with phenyl tri¯ate in the presence of Pd(OAc)2-(R)-BINAP catalyst.

The proposed mechanism is illustrated in Figure 8±5.60a Oxidative addition of the phenyl tri¯ate to the palladium(0)±BINAP species A gives phenylpalladium tri¯ate B. Cleavage of the tri¯ate and coordination of 2,3-dihydrofuran on B yields cationic phenyl palladium ole®n species C. This species C bears a 16-electron square±planar structure that is ready for the subsequent enantioselective ole®n insertion to complete the catalytic cycle (via D, E, F, and G). The base and catalyst precursor have profound e¨ects on the regioselectivity and enantioselectivity.

474 ENZYMATIC REACTIONS AND MISCELLANEOUS ASYMMETRIC SYNTHESES

8.2.10Intramolecular Enyne Cyclization

Intramolecular enyne coupling of allylic enolates can be catalyzed by PdX2, and this reaction can be used in the synthesis of various substituted g- butyrolactones.64 The strategy is outlined in Scheme 8±27.

Scheme 8±27

The allylic 2-alkynoates 77 are a group of special enynes with an ester linkage between their double bond and triple bond. When halopalladation of the triple bond is followed by C±C double bond insertion and the cleavage of the carbon±palladium bond, a series of g-lactones (78±81) can be obtained.

There are many advantages of this divalent palladium-catalyzed cyclization. First, oxygen-free conditions are no longer required. Second, the organic ligandfree catalyst can be more easily recovered under certain conditions. This reaction normally proceeds with high stereoselectivity, providing greater potential for the synthesis of biologically active compounds. Scheme 8±28 illustrates the synthesis of …ÿ†-methylenolactocin.65 The key step is the intramolecular cyclization of 82 [LiBr, Pd(OAc)2, HOAc, room temperature], giving lactone 83 in

8.2 MISCELLANEOUS METHODS

475

65% yield and extremely high diastereoselectivity (the other diastereomer cannot be detected) (Scheme 8±28).

Scheme 8±28

8.2.11Asymmetric Darzens Reaction

Compared with many other reactions for enantioselective formation of C±C bonds, the asymmetric Darzens condensation66 has received less attention. Therefore, there is ample opportunity for chemists to improve the enantioselectivity of the reaction, as well as to develop the reaction itself.

Darzens reaction, the reaction between a carbonyl compound and an a-halo ester in the presence of a base, consists of an initial aldol-type addition and a subsequent intramolecular SN2 reaction, forming an epoxide as its ®nal product. Its high stereoselectivity thus relies on the stereoselectivity of the nucleophilic addition of an a-halo ester onto the carbonyl substrate, which can be either an aldehyde or a ketone.

Early work on the asymmetric Darzens reaction involved the condensation of aromatic aldehydes with phenacyl halides in the presence of a catalytic amount of bovine serum albumin. The reaction gave the corresponding epoxyketone with up to 62% ee.67 Ohkata et al.68 reported the asymmetric Darzens reaction of symmetric and dissymmetric ketones with …ÿ†-8-phenylmenthyl a- chloroacetate as examples of a reagent-controlled asymmetric reaction (Scheme 8±29). When this …ÿ†-8-phenyl menthol derivative was employed as a chiral auxiliary, Darzens reactions of acetone, pentan-3-one, cyclopentanone, cyclohexanone, or benzophenone with 86 in the presence of t-BuOK provided diastereomers of (2R,3R)-glycidic ester 87 with diastereoselectivity ranging from 77% to 96%.

Scheme 8±29. …ÿ†-Menthol derivative±mediated asymmetric Darzens reaction.

476 ENZYMATIC REACTIONS AND MISCELLANEOUS ASYMMETRIC SYNTHESES

The Darzens reaction can also proceed in the presence of a chiral catalyst. When chloroacetophenone and benzaldehyde are subjected to asymmetric Darzens reaction, product 89 with 64% ee is obtained if chiral crown ether 88 is used as a phase transfer catalyst (Scheme 8±30).69

Scheme 8±30

8.2.12Asymmetric Conjugate Addition

The conjugate addition of a nucleophile to a,b-unsaturated organic substrates is an important method for assembling structurally complex molecules. b- Substituted carbonyl compounds produced through 1,4-conjugate addition with organometallic reagents can also be versatile synthons for further organic transformations.

Enantioselective conjugate addition of an organometallic reagent to a prochiral substrate may be an attractive method for creating chiral centers in organic molecules. This can be achieved either by addition of a chiral organometallic reagent to a,b-unsaturated compounds or by addition of an achiral reagent in the presence of chiral catalysts. Organocopper compounds have played an important role in asymmetric conjugate additions.

In chiral ligand-modi®ed organocopper compounds of the type RCu(L*)Li, the chiral ligand L* governs the stereoselectivity of the reaction. Good results can be obtained using these chiral cuprates in a stoichiometric manner, and naturally occurring alcohols and amines such as ephedrine and proline derivatives can be used as chiral ligands. However, these chiral cuprate-mediated reactions do entail two problems.

1.In solution, organocopper compounds may exist as an equilibrium of several species, and a loss of enantioselectivity may be inevitable if this equilibrium process produces some achiral but more reactive cuprate species. The way to overcome this problem is to develop a highly reactive chiral reagent to suppress the undesired, nonchiral species-mediated reactions.

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2.Another problem is that most of the chiral organocopper reagents exhibit high substrate speci®city. Good results with a speci®c chiral copper reagent may be observed for only one or a few substrates.

Both problems can be overcome via ligand-accelerated catalysis.70 In this process, the presence of a suitable chiral ligand can lead to the formation of a highly reactive catalyst, and thus a stereoselective reaction may be favored over a nonselective one. In the presence of chiral copper, nickel, or rhodium complex, additions of organolithium, Grignard, or an organozinc reagent have all shown good to excellent enantioselectivity in asymmetric conjugate additions.

This work was initiated in 1988 when Villacorta et al.71a reported the asymmetric conjugate addition of a Grignard reagent to 2-cyclohexenone. This study showed that 1,4-adducts with 4±14% ee were obtained in the presence of aminotroponeimine copper complex.71a Enhanced results (74% ee) were obtained by adding HMPA or silyl halides.71b Several other copper complexes were also used for inducing asymmetric conjugate addition reactions. Moderate results were obtained in most cases when THF was used as the solvent and HMPA as the additive.

Based on the fact that hexamethylphosphoric triamide can greatly enhance the stereoselectivity of the reaction, chiral phosphorous amidites of type 90 have been synthesized and tested for inducing asymmetric conjugate additions, and indeed good results have been obtained. For example, Scheme 8±31 shows that product was obtained with 87% ee.72

Scheme 8±31

In the conjugate addition of diethylzinc to enones catalyzed by copper reagent CuOTf or Cu(OTf )2 in the presence of 90, an ee of over 60% has been obtained. Study also shows that the actual catalyst in the reaction may be a Cu(I) species formed via in situ reduction of Cu(II) complexes.

The chiral phosphorous amidite was tested for asymmetric conjugate addition with other acyclic substrates, and again good results were obtained. The examples show that binaphthol-containing phosphorous amidites are good ligands for asymmetric conjugate additions. Further modi®cations have been

478 ENZYMATIC REACTIONS AND MISCELLANEOUS ASYMMETRIC SYNTHESES

carried out to enhance the stereoselectivity of the reaction. The bridging of binaphthol and a chiral amine through a phosphorous center may be a general feature of catalysts potentially suitable for highly enantioselective conjugate additions.

Chiral ligand 91, which bears C2-symmetric chiral ligand binaphthol and another C2-symmetric chiral ligand bis(1-phenylethyl)amine, was synthesized.73 This chiral ligand can be used in copper-catalyzed conjugate addition of dialkylzinc reagents to numerous cyclic enones. Products with good yield and excellent enantioselectivity can be obtained through this process. For the reaction shown in Scheme 8±32, an ee of over 90% can generally be observed.

Scheme 8±32

Phosphite compounds, which have been discussed in the context of their application in asymmetric hydrogenation reactions (see Section 6.1.2.6), can also be used to e¨ect the copper salt±mediated asymmetric conjugate addition of diethylzinc to enones.74 As shown in Scheme 8±33, in the presence of diphosphite 92 and copper salt [Cu(OTf )2], the asymmetric conjugate addition proceeds smoothly, giving the corresponding addition product with high conversion and ee. In contrast, the monophosphite 93 gave substantially lower ee.

Silylketene acetals and enolsilanes can also undergo conjugate addition to a,b-unsaturated carbonyl derivatives. This reaction is referred to as the Mukaiyama-Michael addition and can also be used as a mild and versatile method for C±C bond formation. As shown in Scheme 8±34, in the presence of C2-symmetric Cu(II) Lewis acid 94, asymmetric conjugate addition proceeds readily, giving product with high yield and enantioselectivity.75

Shibasaki's lanthanide±alkaline metal±BINOL system, discussed in Chapters 2 and 3, can also e¨ect the asymmetric conjugate addition reaction. As shown in Scheme 8±35, enantioselective conjugate addition of thiols to a,b- unsaturated carbonyl compounds proceeds smoothly, leading to the corresponding products with high yield and high ee.76

It is worth noting that conjugate addition can also be e¨ected by the addition of aryland alkenylboronic acid reagents to enones in the presence of rhodium catalysts. This new catalyst system has the following advantages:

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Scheme 8±33. Reprinted with permission by Pergamon Press Ltd., Ref. 74(b).

1.Organoboronic acids are stable in the presence of oxygen and moisture, permitting a protic or even aqueous reaction medium.

2.In the absence of rhodium catalyst, organoboronic acids are much less reactive toward enone substrates than the corresponding organometallic reagents used previously (such as organolithium reagents or Grignard reagents), and no 1,2-addition to enones takes place in the absence of the catalyst.

Thus, conjugate addition of PhB(OH)2 to cyclohexenone proceeds smoothly in the presence of 3 mol% of Rh(acac)(C2H4)2 and (S)-BINAP (1:1), providing the product in 97% ee with (S)-con®guration predominant (Scheme 8±36).77

In addition to the asymmetric conjugate addition involving an enone substrate and a relatively inactive nucleophile, there exists another kind of reaction in which a deactivated substrate and a normal nucleophile are involved. For example, under proper conditions, ordinary organometallic compounds such as

480 ENZYMATIC REACTIONS AND MISCELLANEOUS ASYMMETRIC SYNTHESES

Scheme 8±34. Reprinted with permission by Am. Chem. Soc., Ref. 75.

Scheme 8±35. LSB-promoted catalytic asymmetric conjugate addition of thiols to enones. Reprinted with permission by Am. Chem. Soc., Ref. 76.

organolithium or Grignard reagent can also be used to achieve a similar result. As shown in Scheme 8±37, when activated by chiral Ni catalyst, ketal substrate can undergo a similar Michael-type addition, providing the substituted ketal with moderate to excellent ee. The resulting compound can be converted to the corresponding ketone or enol ether upon acid or base treatment. Chiral phosphine ligand can generally be utilized for this purpose.78

More information on asymmetric conjugate additions is provided elsewhere.79,80

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481

Scheme 8±36

Scheme 8±37

8.2.13Asymmetric Synthesis of Fluorinated Compounds

This section focuses on the preparation of ¯uorinated compounds through asymmetric hydrogenation/reduction reactions and nucleophilic additions by listing some examples. The ®rst successful example of catalytic asymmetric hydrogenation of a ¯uoro-compound was reported by KoÈnig et al.81

Scheme 8±38 presents some examples of asymmetric hydrogenations of ¯uorine-containing substrates catalyzed by Rh(I) complex. DIPAMP±Rh(I) complex [97-Rh(I)] catalyzes the enantioselective hydrogenation of ¯uorinecontaining substrates with up to 77% ee.82 C2-symmetric chiral bidentate ligands such as bis(phospholanes), which were developed by Burk et al.,83 have also proved suitable for the hydrogenation of ¯uorine-containing substrates. Thus, when 98 or 99 is applied in the hydrogenation of 95, the corresponding hydrogenation product 96 is obtained with 94% ee and >95% ee, respectively.

Scheme 8±38. Enantioselective hydrogenation of 1,1,1-tri¯uoro-2-(acetoxy)-2-propene.

482 ENZYMATIC REACTIONS AND MISCELLANEOUS ASYMMETRIC SYNTHESES

Saburi et al.84 found that ruthenium complexes containing chiral ligand can be used to catalyze the asymmetric hydrogenation of 2-¯uoro-2-alkenoic acid (Z)- or (E )-100, providing the corresponding product 101 with good enantioselectivity (Scheme 8±39 and Table 8±2).

Scheme 8±39. Enantioselective hydrogenation of 2-¯uoro-2-alkenoic acid.

TABLE 8±2. Catalytic Hydrogenation of Fluorine-Containing a,b-Unsaturated

Carboxylic Acids

Entry	Catalyst	Substrate	R	Reaction Condition	ee (%)
1	A	(Z)-100a	C3H7	35 ±80 C, 24 h	91
2	A	(Z)-100b	C5H11	35 ±80 C, 24 h	89
3	B	(Z)-100a	C3H7	35 ±80 C, 24 h	89
4	B	(Z)-100b	C5H11	35 ±80 C, 24 h	89
5	A	(E )-100a	C3H7	50 C, 24 h	83

ee ˆ Enantiomeric excess.

Reprinted with permission by Pergamon Press Ltd., Ref. 84.

Besides the above-mentioned catalytic asymmetric hydrogenation method for preparing ¯uorine-containing compounds, other reactions such as asymmetric reduction of achiral ¯uorine-containing ketones are also feasible methods for preparing chiral ¯uorinated compounds. For example, the oxazaborolidine system, which has been discussed in Chapter 6, can also be employed in the catalytic reduction of tri¯uoromethyl ketones. Scheme 8±40 depicts some examples.85

In Scheme 8±40, the reaction of 9-anthryl tri¯uoromethyl ketone 103 and mesityl tri¯uoromethyl ketone 104 with catecholborane 106 in the presence of 10 mol% of chiral catalyst 107 (CBS) provides (R)-carbinol 108 and 109 with 94% and 100% ee, respectively. When methyl ketone instead of tri¯uoromethyl ketone is used in the reaction, product 110 is obtained with (S)-con®guration in 99.7% ee with over 95% yield.