Principles and Applications of Asymmetric Synthesis

Scheme 3±17

Scheme 3±18

Starting from ketone(R)-/(S)-49, the asymmetric aldol reaction with aldehyde in the presence of 45a or 45b a¨ords all four isomers of b-hydroxyl ketone 47, 48, 50, and 51 with high yields and stereoselectivities (Scheme 3±17).

Treating boron reagent 45a with an oxazoline compound gives the azaenolate 52. Subsequent aldol reaction of 52 with aldehyde yields mainly threoproduct (anti-53) with good selectivities (Scheme 3±18).38

When a chiral auxiliary is present in the oxazoline ring and the boron part is replaced with an achiral bicyclic system (46 bearing 9-BBN), erythro-b-hydroxy esters (syn-53) can be obtained as the major product upon reaction of the enolate with several aldehydes.37

3.3.2Aldol Reactions Controlled by Corey's Reagents

Corey et al.39 introduced a chiral controller system, chiral auxiliary 55, which has shown excellent practical potential because of its availability, recoverability, and high enantioselectivity. Furthermore, using conformation analysis,

152 ALDOL AND RELATED REACTIONS

Scheme 3±19. Synthesis and resolution of chiral compound 54.

the absolute con®guration of the product can be predicted when 55 is involved in the reaction (see Scheme 3±20 and Table 3±5, later, for some examples). Starting from benzil, compound 1,2-diamino-1,2-diphenylethane (stilbenediamine) is synthesized. Using tartaric acid as the resolving agent, stilbenediamine in both …R,R†- and …S,S†-forms can be obtained.40 Scheme 3±19 depicts the synthesis of both isomers of 54. Compound 54 is a key compound for synthesizing 55 and related compounds.

Conversion of diamine 54 to bis-sulfonaminde, followed by treatment with BBr3, yields the corresponding catalyst 55. Application of this controller in enantioselective aldol reactions has led to striking success. The reaction can be used not only in aldol reactions but also in allylation reactions. Treating a solution of 55a with allyl tributyltin results in chiral allyl borane, and reaction of this allyl borane with a variety of aldehydes gives the corresponding homoallyl alcohols with high enantiomeric excess (>90%).41 The allylation reaction is discussed in detail in a later section.

As illustrated in Scheme 3±20 and Table 3±5, using 55a or 55b as the chiral auxiliary, syn-aldol adduct 56 can be obtained with high stereoselectivity via aldol reaction of diethyl ketone with various aldehydes.39

Scheme 3±20

TABLE 3±5. Reaction of Aldehydes with the Enolate from Diethyl Ketone and Bromoborane (R,R)-55b

ee ˆ Enantiomeric excess.

Reprinted with permission by Am. Chem. Soc., Ref. 39.

With 55 as the chiral auxiliary, good enantioselectivity can be obtained in reactions between aldehydes and esters. In the case of phenyl thioacetate, as depicted in Scheme 3±21, an aldol reaction induced by 55a or 55b can also give acceptable stereoselectivity.

It is proposed that stereochemistry of the controlled aldol addition originates when the phenyl groups of the stien ligand force the vicinal N-sulfonyl substituents to occupy the face of the ®ve-membered ring opposite the face where they are linked. The optimized stereoelectronic and steric arrangements of the favored transition state for the formation of the major product are depicted in Figure 3±4.

Scheme 3±21

154 ALDOL AND RELATED REACTIONS

Figure 3±4. Transition state.

3.3.3Aldol Condensations Controlled by Miscellaneous Reagents

Both antiand syn-3-hydroxy-2-methylcarbonyl units (e.g., 61 and 62) are frequently embedded in natural products of propionate origin, such as macrolide antibiotics.

Double asymmetric aldol reaction has been widely used for the e½cient construction of the syn-unit.10b,42 With above-described organoboron compounds (Section 3.3.1), anti-selectivity can be obtained.

Because anti/syn ratios in the product can be correlated to the E…O†=Z…O† ratio of the involved boron enolate mixture,10b initial experiments were aimed at the preparation of highly E…O†-enriched boron enolate. The E…O†=Z…O† ratio increases with the bulk of the alkanethiol moiety, whereas the formation of Z…O† enolates prevails with (S)-aryl thioates. (E=Z ˆ 7:93 for benzenethiol and 5:95 for 2-naphthalenethiol esters). E…O† reagent can be formed almost exclusively by reaction of (S)-3,3-diethyl-3-pentyl propanethioate 64 with the chiral boron tri¯ate. High reactivity toward aldehydes can be retained in spite of the apparent steric demand (Scheme 3±22).43

Scheme 3±22

156 ALDOL AND RELATED REACTIONS

Scheme 3±24

enolates or chiral aldehydes. In addition to their discovery of the usefulness of enol equivalents in aldol reactions, Mukaiyama et al.45 also demonstrated that tributyltin ¯uoride, stannous tri¯ate, or trityl tri¯ates are even more e¨ective reagents for aldol reactions. Based on the concept of ``enol species'', they developed various highly selective and practical asymmetric reactions, particularly stannous tri¯ate-mediated aldol reactions. Divalent tin has vacant d orbitals that enable it to form complexes with amines. The tin(II) metal is bonded with two nitrogen atoms, leaving one vacant orbital coordinatable to an aldehyde without losing the favorable chiral environment. Almost complete stereochemical control is therefore achieved starting from achiral aldehyde and silyl enol ethers with a catalytic amount of diamine.46 Thus, compound 68 is ®rst treated with Sn(OTf )2 and a chiral amine 69, followed by an aldehyde, yielding b-cyclohexyl (S)-imide 70 in about 90% ee (Scheme 3±24).47

In the presence of a chiral promoter, the asymmetric aldol reaction of prochiral silyl enol ethers 71 with prochiral aldehydes will also be possible (Table 3±6). In this section, a chiral promoter, a combination of chiral diaminecoordinated tin(II) tri¯ate and tributyl ¯uoride, is introduced. In fact, this is the ®rst successful example of the asymmetric reactions between prochiral silyl enol ethers and prochiral aldehyde using a chiral ligand as promoter.

As depicted in Scheme 3±25, the aldol reaction carried out at ÿ78 C can give the corresponding aldol adduct 72 in 78% yield with 82% ee. The combination of chiral diamine-coordinated tin(II) tri¯ate and tributyltin ¯uoride is so essential that the enantioselectivity cannot be obtained without tributyltin ¯u-

TABLE 3±6. The Reaction of Silyl Enol Ether of S-Ethyl Ethanethiate with Benzaldehyde

ee ˆ Enantiomeric excess.

Scheme 3±25

oride in the reaction system. When Bu3SnF was present, diamine A induced good yield for the product. The reaction induced by diamine B gives a higher ee but a moderate yield (Table 3±6).

It has been proposed that the reaction is promoted by the formation of the active species 73, in which, the cationic center of the tin(II) tri¯ate activates an aldehyde, and, at the same time, the electronegative ¯uoride is able to interact with a silicon atom of the silyl enol ether to make the enol ether more reactive. This dual process results in the formation of the entropically favored intermediate (Scheme 3±25).46

Perfect stereochemical control in the synthesis of syn-a-methyl-b-hydroxy thioesters has been achieved by asymmetric aldol reaction between the silyl enol ether of S-ethyl propanethioate (1-trimethylsiloxy-1-ethylthiopropene) and aldehydes using a stoichiometric amount of chiral diamine-coordinated tin(II)

Scheme 3±26