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Principles and Applications of Asymmetric Synthesis

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120 a-ALKYLATION AND CATALYTIC ALKYLATION OF CARBONYL COMPOUNDS

Scheme 2±53

TABLE 2±16. Enantioselective Alkylation of Ketones

 

 

 

Yield

 

 

 

Yield

Entry

Substrate

ee (%)

(%)

Entry

Substrate

ee (%)

(%)

 

 

72

 

 

 

90

83

1

 

…‡†-(R)-

58

5

 

…ÿ†-

 

2

 

80

53

6

 

60

63

 

 

 

 

 

…ÿ†-

 

 

 

…‡†-

 

3

 

91

91

7

 

75

76

 

 

…ÿ†-

 

 

 

…‡†-

 

4

 

86

79

 

 

 

 

 

 

…ÿ†-(R)-

 

 

 

 

 

ee ˆ Enantiomeric excess.

Reprinted with permission by Am. Chem. Soc., Ref. 139.

using highly substituted chiral 1,4-diol as ligand, both aromatic and aliphatic aldehyde could be converted to the corresponding cyanohydrin with more than 85% yield and over 90% ee. While the Narasaka method was e¨ective in preparing optically active cyanohydrins, it required a stoichiometric amount of titanium and tartaric acid derivatives. Hayashi et al.144 reported that a similar catalytic system based on the modi®ed Sharpless catalyst was also e¨ective as an asymmetric catalyst for the addition of TMSCN to aromatic aldehydes. The

2.8 ASYMMETRIC CYANOHYDRINATION

121

Scheme 2±54

Scheme 2±55

use of cyclic dipeptides, described by Mori et al.,145 worked satisfactorily as well.

The best results for the asymmetric cyanohydrination reactions are obtained through biocatalysis, using the readily available enzyme oxynitrilase. This provides cyanohydrins from a number of substances with over 98% ee.146

Hayashi et al.147 reported another highly enantioselective cyanohydrination catalyzed by compound 138. In this reaction, a Schi¨ base derived from b- amino alcohol and a substituted salicylic aldehyde were used as the chiral ligand, and the asymmetric addition of trimethylsilylcyanide to aldehyde gave the corresponding cyanohydrin with up to 91% ee (Scheme 2±56).

Bolm and MuÈller148 reported that a chiral titanium reagent generated from optically active sulfoximine (R)-139 and Ti(OPri)4 promotes the asymmetric addition of trimethylsilyl cyanide to aldehydes, a¨ording cyanohydrins in high yields with good enantioselectivities (up to 91% ee) (Scheme 2±57). The aldehydes can be either aromatic or aliphatic. For example, in the presence of a stoichiometric amount of Ti(OPri)4 and 1.1 eq. of (R)-139, trimethylsilylcyanation of benzaldehyde at ÿ50 C, followed by acidic cleavage of the trimethylsilyl group gave (S)-mandelonitrile with 72% yield and 91% ee. Lowering the reaction temperature did not signi®cantly improve the ee values.

The proposed reaction mechanism is shown in Figure 2±8. First, a chiral titanium complex (R)-140 is formed by the exchange of two titanium alkoxides.

122 a-ALKYLATION AND CATALYTIC ALKYLATION OF CARBONYL COMPOUNDS

Scheme 2±56

Scheme 2±57

Figure 2±8. Proposed reaction mechanism for Ti(OPri)4-mediated asymmetric silylcyanation.

Complex (R)-140 serves as a chiral Lewis acid and coordinates to the aldehyde at the less hindered b-face of 141. Re-side cyanation of (R)-141 and the subsequent cleavage of the alkoxide group give the product 142. Because at this stage the catalyst turnover is blocked, the reaction cannot be carried out in a catalytic manner.

2.8 ASYMMETRIC CYANOHYDRINATION

123

 

 

 

 

 

 

 

 

 

 

 

 

Scheme 2±58. Reprinted with permission by Elsevier Science Ltd., Ref. 149.

Mori et al.149 also reported the asymmetric cyanosilylation of aldehyde with TMSCN using 132 (X ˆ CN) as the precatalyst. The chiral dicyano complex was generated in situ, and the asymmetric cyanosilylation gave ee values of up to 75%. Scheme 2±58 depicts the proposed reaction process.

The addition of cyanide to imines, the Strecker reaction, constitutes an interesting strategy for the asymmetric synthesis of a-amino acid derivatives. Sigman and Jacobsen150 reported the ®rst example of a metal-catalyzed enantioselective Strecker reaction using chiral salen Al(III) complexes 143 as the catalyst (see Scheme 2±59).

Among the complexes of Ti, Cr, Mn, Co, Ru, and Al, which catalyzed the reaction with varying degrees of conversion and enantioselectivity, complex 143 was found to give the best result, and it was found that the uncatalyzed reaction between HCN and 144 could be completely suppressed at ÿ70 C. For example, in Scheme 2±59, the reaction for an aromatic substrate 144, such as R ˆ Ph, can be completed within 15 hours, providing product 145 (R ˆ Ph, without a tri¯uoroacetyl group) with 91% isolated yield and 95% ee. Because the cyano addition product has been observed to undergo racemization upon exposure to silica gel during the isolation procedure, the product is transformed to the corresponding stable tri¯uoroacetamide derivative. This is the ®rst example in which a main group metal±salen complex has been identi®ed as a highly e¨ective asymmetric catalyst.

In contrast, testing substrates in Scheme 2±59 demonstrates that alkylsubstituted imines undergo the addition of HCN with considerably lower ee. (For R ˆ cyclohexyl, 57% ee; and 37% ee for R ˆ t-butyl.) The N-substituent does not exert a signi®cant in¯uence on the enantioselectivity of the reaction.

For more information about the asymmetric addition of trimethylsilyl cyanide to aldehydes, see Belokon et al.151

124 a-ALKYLATION AND CATALYTIC ALKYLATION OF CARBONYL COMPOUNDS

Scheme 2±59. Chiral Al-salen±catalyzed Strecker reaction.

2.9ASYMMETRIC a-HYDROXYPHOSPHONYLATION

a-Hydroxyphosphonyl compounds (phosphonates and phosphonic acids) are biologically active and can be used for enzyme inhibitors (e.g., renin synthase inhibitor152 and HIV protease inhibitor153). Although the biological activities of a-substituted phosphonyl compounds depend on their absolute con®guration,154 it is only recently that detailed studies on the synthesis of optically active phosphonyl compounds have begun to emerge. The most e½cient and economic route to chiral hydroxylphosphonate involves asymmetric a-hydroxy- phosphonylation.

One common approach incorporates an oxazaborolidine-mediated catecholborane reduction starting from a-ketophosphonates (146).155 The reaction proceeds with good yield and gives excellent ee (up to 99%).

Enantioselective synthesis of a-hydroxy phosphonates can also be achieved by asymmetric oxidation with camphorsulfonyl oxaziridines (Scheme 2±60).156 Reasonable yields can usually be obtained. …‡†-147a or …‡†-147b favors formation of the (S)-product, as would be expected, because these oxidations proceed via a transition state that parallels that previously discussed for the stereoselectivity observed with ketones.157

Attempts have also been made to explore chiral catalysis in the Pudovik reaction (the addition of dialkylphosphites to aldehydes). Rath and Spilling158

2.9 ASYMMETRIC a-HYDROXYPHOSPHONYLATION

125

 

 

 

 

Scheme 2±60

and Yokomatsu et al.159 independently published the lanthanum binaphthoxide complex catalyzed addition of diethylphosphite to aromatic aldehydes. Lanthanum (R)-binaphthoxide complex gives (S)-hydroxyphosphonates in good yield with modest enantioselectivity. The catalyst LaLi3(BINOL)3 (LLB) was prepared from lanthanum trichloride by the method reported by Sasai et al.160 for catalytic enantioselective nitroaldol reaction.

Sasai et al.161 revealed an improved condition for the preparation of LLB, which involves the reaction of a mixture of LaCl3 7H2O (1 eq.), (R)- or (S)- BINOL dilithium salt (2.7 eq.), and t-BuONa (0.3 eq.) in THF at 50 C. The LLB obtained is e¨ective for the hydrophosphonylation of various aldehydes, and the desired a-hydroxyphosphonates can be obtained in up to 95% ee (89% yield). With slow addition of the aldehyde, the ee of the product can be further increased (Scheme 2±61).

LLB, a so-called heterobimetallic catalyst, is believed to activate both nucleophiles and electrophiles.162 For the hydrophosphonylation of comparatively unreactive aldehydes, the activated phosphite can react with only the molecules precoordinated to lanthanum (route A). The less favored route (B) is a competing reaction between Li-activated phosphite and unactivated aldehyde, and this unfavored reaction can be minimized if aldehydes are introduced slowly to the reaction mixture, thus maximizing the ratio of activated to inactivated aldehyde present in solution. Route A regenerates the catalyst and completes the catalysis cycle (Fig. 2±9).

Scheme 2±61

126 a-ALKYLATION AND CATALYTIC ALKYLATION OF CARBONYL COMPOUNDS

Figure 2±9. Proposed mechanism for the asymmetric hydroxyphosphonylation catalyzed by LLB.

Scheme 2±62

Other homochiral cyclic diol ligands such as (S,S)-148 for titanium alkoxide have also been tested for catalyzing phosphonylation of aldehydes, but it has been found that these diols are a poor choice of ligand for asymmetric phosphonylation.163 For most of the aldehydes studied (substituted benzaldehydes, a,b-unsaturated aldehydes, and cyclohexanecarboxaldehyde), only moderate enantioselectivity was obtained (Scheme 2±62).

To complement the above information, a highly enantioselective synthesis of a-amino phosphonate diesters should be mentioned.164 Addition of lithium diethyl phosphite to a variety of chiral imines gives a-amino phosphonate with good to excellent diastereoselectivity (de ranges from 76% to over 98%). The stereoselective addition of the nucleophile can be governed by the preexisting chirality of the chiral auxiliaries (Scheme 2±63).

Scheme 2±63

2.11 REFERENCES 127

The diastereofacial selectivity is explained by the proposed chelated intermediate 151. Internal delivery of the nucleophile takes place from the less hindered side. Removal of the chiral directing moiety with a catalytic amount of palladium hydroxide on carbon in absolute ethanol then furnishes the ®nal product. This process yields the amino ester in 83±100% yield without observable racemization.

2.10SUMMARY

This chapter has given a general introduction to the a-alkylation of carbonyl compounds, as well as the enantioselective nucleophilic addition to carbonyl compounds. Chiral auxiliary aided a-alkylation of a carbonyl group can provide high enantioselectivity for most substrates, and the hydrazone method can provide routes to a large variety of a-substituted carbonyl compounds. Chiral sultam and chiral oxazoline are also useful chiral auxiliaries for the asymmetric synthesis of such carbonyl compounds. The SRS method (self-regeneration of stereocenters), starting from inexpensive chiral compounds, provides a convenient synthesis for chiral compounds with quaternary chiral centers. Perhaps the most important method developed in this area is the enantioselective addition of dialkylzinc to carbonyl groups. The reaction is normally carried out under very mild conditions, giving excellent results in both conversion and enantioselectivity.

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128a-ALKYLATION AND CATALYTIC ALKYLATION OF CARBONYL COMPOUNDS

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