Principles and Applications of Asymmetric Synthesis

170 ALDOL AND RELATED REACTIONS

Figure 3±6. Favored and unfavored transition states.

Scheme 3±41. Reaction with protected strained aldehyde (glyceraldehyde).

formationally constrained a- or b-alkoxyl±substituted aldehydes are excellent allyl-boration substrates. The diminished stereoselectivity is introduced not by the steric e¨ect but by the unfavorable lone pair/lone pair interaction between the tartrate carbonyl and the alkoxy substituents. This is true especially for conformationally unconstrained aldehyde substrates.73 In fact, Roush reagents (110, 111, and 112) exhibit a useful level of matched and mismatched diastereoselectivity in reactions with both chiral strained (Scheme 3±41) and unstrained aldehydes (Scheme 3±42).74

3.6 ASYMMETRIC ALLYLATION REACTIONS

171

Scheme 3±42. Example of allylation of unstrained aldehyde.

Garcia et al.75 have introduced another boron reagent 114 that can also be used in asymmetric allylation reactions.

With the aid of BF3 OEt2, methoxyborolane …R,R†-114 reacts with (E )- or (Z)-crotylpotassium to provide …E,R,R†-115 and …Z,R,R†-115, respectively. After adding the aldehyde to a solution of crotyl-borolane in THF at ÿ78 C for 4 hours, 2-aminoethanol is added. The solution is warmed to room temperature, and oxidative cleavage at this point gives the homoallylic alcohols with high stereoselectivity. The borolane moiety can be recovered by precipitating it as an amino alcohol complex and can be reused without any loss of enantiomeric purity. As shown in Scheme 3±43, the (E )- and (Z)-crotyl compounds lead to antiand syn-products 116, respectively. The diastereoselectivity is about 20:1, and the ee for most cases is over 95% (Table 3±11).

Kijanolide 117,76 tetronolide 118,76 and chlorothricolide 119,77 the aglycones of the structurally novel antitumor antibiotics kijimicin, tetrocaricin A, and chlorothrimicin, are highly valued targets for total synthesis. All three structures share a similar octahydronaphthalene fragment 121, which can be obtained by cyclization of 120. Compound 120, appropriately functionalized 2,8,10,12-tetradecatetraene acid, can be constructed via aldol reactions. Two

172 ALDOL AND RELATED REACTIONS

Scheme 3±43

TABLE 3±11. Reaction of Crotylboranes (E,R,R)-115 and (Z,R,R)-115 with Representative Achiral Aldehydes

					Major Product
Entry	Crotylborane	Aldehyde	Yield (%)	anti/syn Ratio	ee (%)
1	(E )-115	C2H5CHO	81	93/7	96
2	(E )-115	i-C3H7CHO	76	96/4	97
3	(E )-115	i-C4H9CHO	72	96/4	95
4	(Z)-115	C2H5CHO	73	7/93	86
5	(Z)-115	i-C3H7CHO	70	4/96	93
6	(Z)-115	i-C4H9CHO	75	5/95	97

ee ˆ Enantiomeric excess.

Reprinted with permission by Am. Chem. Soc., Ref. 75.

pairs of chiral centers, C-4/C-5 and C-6/C-7, can be regarded as aldol products, and the Roush reaction provides excellent access to these asymmetric centers.

Treatment of 122 with …R,R†-tartrate crotyl-boronate …E,R,R†-111 provides the alcohol corresponding to 123 with 96% stereoselectivity. Benzylation of this alcohol yields 123 with 64% overall yield. The crude aldehyde intermediate obtained by ozonolysis of 123 is again treated with …Z,R,R†-111 (the second Roush reaction), and a 94:5:1 mixture of three diastereoisomers is produced, from which 124 can be isolated with 73% yield. A routine procedure completes the synthesis of compound 120, as shown in Scheme 3±44. Heating a toluene solution of 120 in a sealed tube at 145 C under argon for 7 hours provides the cyclization product 127. Subsequent debromination, deacylation, and Barton deoxygenation accomplishes the stereoselective synthesis of 121 (Scheme 3±44).

With this method, that is, the reaction of tartaric acid ester±modi®ed crotylboronates with chiral 2-methyl aldehydes, the C-19 to C-29 fragment of rifamycin has been constructed similarly.76

Roush reported another tartrate boronate, (E )-g-[(menthofuryl)-dimethyl silyl]-allylboronate 130, for anti-a-hydroxyallyation of aldehydes. Reagent 130 can be obtained from commercially available menthofuran, which was selected

3.6 ASYMMETRIC ALLYLATION REACTIONS

173

Scheme 3±44. Asymmetric synthesis of octahydronaphthalene fragment 121.

174 ALDOL AND RELATED REACTIONS

Scheme 3±45. Application of the boronate.

Scheme 3±46. Synthesis of a,b-disubstituted tetrahydropyrans and tetrahydrofurans.

because of the signi®cantly easier protodesilylation of the resulting intermediate 2-furyl dimethylsilanes. On treatment with aldehyde, transformation of the allyl group accomplishes the synthesis of 131. The silyl group in 131 can be removed by the Fleming method, resulting in the free alcohol 132. This reagent provides an excellent method for anti-diol synthesis. Application of this compound is exempli®ed by the synthesis of (ÿ)-swainsonine (Scheme 3±45).78

Starting from substituted allyl bis-(2,4-dimethyl-3-pentyl)-l-tartrate boronic acid, synthesis of a,b-disubstituted tetrahydrofurans (134, n ˆ 1) or tetrahydropyrans (134, n ˆ 2) can be accomplished with high enantioselectivity (Scheme 3±46).79

3.6.2The Corey Reaction

As discussed in Section 3.3.2, Corey demonstrated the utility of compound 55, prepared from 1,2-diphenyl-1,2-diamino ethane 54, as a chiral auxiliary for asymmetric aldol reaction. In a similar manner, his group utilized this compound 55 in both …R,R†- and …S,S†-forms for allylation reactions. Treatment of 55 with allyltributyltin in dry CH2Cl2 at 0 C and then 23 C for 2 hours gives chiral allyl-borane 135. In this process, both the …R,R†- and …S,S†-forms can be obtained and applied in asymmetric allylation reactions. Thus, treatment of

3.6 ASYMMETRIC ALLYLATION REACTIONS

175

Scheme 3±47. Reaction of aldehydes with chiral allyl boranes 135. Reprinted with permission by Am. Chem. Soc., Ref. 41.

various aldehydes with …R,R†-135 in toluene or CH2Cl2 at ÿ78 C furnishes the homoallylic alcohol 136 with high optical purity (Scheme 3±47). The absolute con®guration of the product 136 can be predicted based on a chair-like transition state with optimized stereoelectronic and steric interaction between the substituents on the ®ve-membered ring.41

2-Haloallyl reagents 137 have been produced by treating enantiomers of 55 with the corresponding 2-haloallyl-n-butyltin; and 2-haloallyl carbinol 138 is obtained in high yield and predictable diastereoselectivity by reacting aldehydes with 137 (Scheme 3±48).41

Product 2-haloallyl carbinol 138 has wide synthetic utility in a number of transformations, as shown in Figure 3±7.41

3.6.3Other Catalytic Asymmetric Allylation Reactions

The most commonly used method for achieving asymmetric allylation is to use an organometallic reagent in which the metal is ligated by chiral modi®ers. Excellent results can be obtained for boron-containing80 and titaniumcontaining81 allyl moieties; but only low or modest results are obtained with silicon82 or tin83 compounds under similar conditions. The modest results with certain compounds suggest that the key issue is a di¨erence in the reaction mechanism: Allyl-boron or titanium reagents react through an associative cyclic transition structure,84 while allyl silanes or stannanes react through a less rigid, open chain transition structure. Good results have been achieved with asymmetric addition of allyl silane and/or allyl stannane (Sakurai reaction85 to carbonyl compouds in the presence of a Lewis acid).

176 ALDOL AND RELATED REACTIONS

Scheme 3±48. Reaction of aldehydes with chiral 2-haloallylboranes. Reprinted with permission by Am. Chem. Soc., Ref. 41.

Figure 3±7. Applications of compound 138 in organic synthesis. Reprinted with permission by Am. Chem. Soc., Ref. 41.

3.6 ASYMMETRIC ALLYLATION REACTIONS

177

Denmark and Almstead86 reported that Lewis acid promoted asymmetric allylation and crotylation of aldehydes with allyltrichlorosilanes. Kobayashi and Nishio87 demonstrated the allyl and crotyl trichlorosilane addition in which good yield (>85%) and diastereoselecvitity [anti/syn > 93:7 for (E)-crotyl and syn/anti > 96:4 for (Z)-crotyl] were obtained when DMF was used as the solvent. When one equivalent of DMF was used, the reaction proceeded very slowly, and a rather long reaction time was required for a reasonable conversion (e.g., 70 hours were required for 80% conversion). Better results were obtained by changing DMF to another Lewis base, phosphoramide. For example, with HMPA as a promotor, rapid reaction was observed (t1=2 ˆ 18 minutes). Using chiral phosphoramide as a promotor for asymmetric allylation, however, failed to enhance the stereoselectivity.

As an alternative approach, chiral Lewis base has been tested for catalytic allylation. Compound 139, reported by Iseki et al.,88 was the ®rst example of a chiral Lewis base that e¨ectively serves as a catalyst in asymmetric allylation in combination with HMPA. Allylation of aliphatic aldehydes with allyland crotyltrichlorosilanes in the presence of 139 provides up to 98% ee (Scheme 3±49).

Allylation of aromatic aldehydes with allyl trimethylsilane catalyzed by chiral acyloxyborane gives good results. In contrast, the results are normally poor for aliphatic aldehydes.89 Costa et al.90 introduced another enantioselective allylation procedure aiming to overcome this problem. In the following example, the enantioselective allylation of aldehyde octanal was carried out using

Scheme 3±49

178 ALDOL AND RELATED REACTIONS

Scheme 3±50

allyl-tributyltin as the allyl donor. The enantiomeric excess obtained normally can be over 90% when the reaction is carried out in the presence of a catalytic

Ê

amount of (20 mol%) BINOL-TiCl2 complex and activated 4 A MS (Scheme 3±50).90

Preparation of the catalyst can be accomplished under mild conditions without stirring, heating, or cooling, and allyl addition can also be conducted more conveniently using 10 mol% of a 2:1 BINOL/Ti catalyst system at room temperature.91

In the last few years, asymmetric catalysis by means of chiral Lewis acids has led to highly enantioselective protocols for a variety of synthetic transformations, including important C±C bond formation processes. The most successful chiral Lewis acids for catalytic enantioselective C±C bond formation contain B(III), Al(III), Ti(IV), Sn(II), and rare earth metals.

Ti-BINOL±catalyzed reactions have been well established. When the Ti is replaced by Zr,92 the resulting complex 140 can also catalyze the addition of allyl-tributyltin to aldehydes (aldehydes:allyl-tributyltin:140 ˆ 1:2:0.2 mol ratio)

Ê

in the presence of 4 A MS. Product 1-alken-4-ols are obtained in good yield and high ee. The Si-face of the aldehyde is attacked if (S)-BINOL is used, and Reface attack takes place when (R)-BINOL is used as the chiral ligand. For Zr complex±catalyzed reactions, the reaction proceeds much faster, although the

Scheme 3±51. Zirconate-catalyzed asymmetric allylation reactions.

	3.7 ASYMMETRIC ALLYLATION AND ALKYLATION OF IMINES			179
TABLE 3±12. Some Commonly Used Allylating Agents
Chiral Auxiliary	Reference	Chiral Auxiliary	Reference
	80a			93

41

70a

94					75

95

96

96

97

81

stereofacial selectivity is not improved. These two catalysts can complement each other in the way that the Ti catalyst is suitable for aliphatic aldehydes, while Zr catalyst can be used for aromatic ones.

For convenient reference, some commonly used allylating agents are listed in Table 3±12.

3.7ASYMMETRIC ALLYLATION AND ALKYLATION OF IMINES

Stereoselective addition of organometallics to CbN bond is not fully understood due to a number of di½culties. First, imines are not as electrophilic as