4.10 Enantioselective Aldol Reactions Catalyzed by Chiral Lewis Bases

4.10 Enantioselective Aldol Reactions Catalyzed by Chiral Lewis Bases

4.10 Enantioselective Aldol Reactions Catalyzed by Chiral Lewis Bases M Nakajima, Kumamoto University, Kumamoto, Japan r 2012 Elsevier Ltd. All rights...

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4.10 Enantioselective Aldol Reactions Catalyzed by Chiral Lewis Bases M Nakajima, Kumamoto University, Kumamoto, Japan r 2012 Elsevier Ltd. All rights reserved.

4.10.1 4.10.2 4.10.3 4.10.4 4.10.5 4.10.6 4.10.7 4.10.8 References

Introduction: Activation of Silyl Enol Ethers by Lewis Bases Enantioselective Aldol Reactions of Trichlorosilyl Enol Ethers Catalyzed by Lewis Bases Enantioselective Aldol Reactions Promoted by Lewis Base-activated Lewis Acids Enantioselective Reductive Aldol Reactions Enantioselective Direct Aldol-Type Reactions Via In Situ Generation of Silyl Enol Ethers Enantioselective Aldol Reaction of Trimethoxysilyl Enol Ethers Catalyzed by Chiral Phenoxides Aldol Reactions of Trimethylsilyl Enol Ethers Catalyzed by Phenoxides Conclusion

Glossary Hypervalent silicate The silicon atom expands its coordination sphere to give relatively stable penta- or hexacoordinated compounds due to its vacant threedimensional orbital. Hypervalent silicate formed from a tetracoordinate silicon with one or two basic molecules. Reductive aldol reaction Reductive aldol reaction is a tandem reaction consisting of the reductive formation of enol ether equivalent form a,b-unsaturated carbonyl compound and the following aldol reaction with another carbonyl compound. Tishchenko reaction The Tishchenko reaction is a disproportion reaction of aldehydes to produce esters. It is

4.10.1

198 198 202 204 204 206 208 209 209

often accompanied with aldol reaction (aldol-Tishchenko reaction), affording monoacyl protected 1,3-diol from two carbonyl compounds. Trichlorosilyl enol ether Trichlorosilyl enol ether is a silyl enol ether which possesses three chlorides on a silicon atom. It can be activated by Lewis bases such as phosphoramides, N-oxides or phosphine oxides to react with electrophiles. Trimethoxysilyl enol ether Trimethoxysilyl enol ether is a silyl enol ether which possesses three methoxy groups on a silicon atom. They are so stable that they survive aqueous work-up or silica gel column chromatography. They can be activated by lithium phenoxides to react with electrophiles.

Introduction: Activation of Silyl Enol Ethers by Lewis Bases

The aldol reaction is one of the most important carbon–carbon bond forming reactions. As it creates two contiguous stereogenic centers, a number of asymmetric aldol reactions have been reported in recent decades. Most of the recent significant developments in aldol reactions have been based on the conventional Mukaiyama-type catalysis (activation of an aldol acceptor) using a variety of chiral Lewis acids as catalysts. Although extremely high enantioselectivities have been obtained in some cases, Mukaiyama-type aldol reactions inevitably suffer from problems with syn/anti selectivity during the creation of the two contiguous asymmetric centers. As Lewis acid catalysts activate carbonyl groups, the reaction proceeds via an acyclic transition state, which prefers the syn isomer regardless of the E/Z isomeric states of the silyl enol ether (Figure 1). On the other hand, reactions that proceed via a sixmembered cyclic transition state may transmit the stereochemical information present in the enol ether (E/Z) to the stereochemical relationship (syn/anti) about the new CC bond of the product. If an appropriate chiral catalyst coordinates to the silicon atom of a silyl enol ether increasing the Lewis acidity of the silicon atom, the aldol reaction may proceed via a cyclic transition state that can control both the enantioselectivity and syn/anti selectivity (diastereoselectivity). In this chapter, we discuss the highly diastereo- and enantioselective aldol reactions of silyl enol ethers catalyzed by chiral Lewis bases.1

4.10.2

Enantioselective Aldol Reactions of Trichlorosilyl Enol Ethers Catalyzed by Lewis Bases

The above concept was first realized by Denmark et al., who used trichlorosilyl enol ethers as new types of aldol donors and optically active phosphoramides as chiral catalysts in enantioselective aldol reactions.2 In early reports, trichlorosilyl enol ethers were synthesized from a-chloroketones and trichlorosilane or enol acetates via stannyl enol ethers.3 Denmark developed a general protocol for the synthesis of trichlorosilyl enol ethers using trimethylsilyl enol ether and tetrachlorosilane (SiCl4), with mercury (II) acetate (Hg(OAc)2) as a catalyst. Later, they found a new synthetic route that did not require Hg(OAc)2.4 Geometrically defined enol ethers were prepared from the corresponding trimethylsilyl enol ethers via lithium enolates. These protocols enabled the preparation of a wide range of trichlorosilyl enol ethers (Figure 2).

198

Comprehensive Chirality, Volume 4

http://dx.doi.org/10.1016/B978-0-08-095167-6.00409-2

Enantioselective Aldol Reactions Catalyzed by Chiral Lewis Bases

199

Lewis acid-catalyzed aldol reaction OSi(CH3)3

R1CHO

OSi(CH3)3 R2

R3

H R2

LA

LA

(Z ) R3 R2

O

(E )

R3 OH

H

H R2

LA

LA

O

R1

O

R1

R3

R1CHO OSi(CH3)3

R1

R3 R2

preferentially syn-adduct

OSi(CH3)3 H

LA: Lewis acid

Lewis base-catalyzed aldol reaction

R2

R3 H

R1CHO

OSiX3

LB

R3

H

(Z )

R2

R3 R2

OSiX3 (E )

R2

LB LB: Lewis base

H

R1

SiXn

O

R1

R3 R2

O

R1 R3 H

R1CHO

OH O

LB

syn-adduct LB

OH O

SiXn

O

R1

O

R3 R2

anti-adduct

Figure 1 Lewis acid- and Lewis base-catalyzed aldol reactions.

OAc

OSnBu3 Bu3SnOMe

1

OSiCl3 SiCl4

2

OSiMe3

3 OSiMe3

OSiCl3 SiCl4

Et

OSiCl3

(i) MeLi (ii) SiCl4

Et

Hg(OAc)2 (1−5 mol%) 4

5

3

6

Figure 2 Synthesis of trichlorosilyl enol ethers.

Trichlorosilyl enol ethers react with aldehydes without a catalyst. However, the reaction rates increase significantly upon addition of a phosphoramide as a catalyst.4a The reaction of the trichlorosilyl enol ether derived from 2-hexanone (7) with benzaldehyde (8) proceeds at room temperature, whereas it proceeds at  78 1C in the presence of 10 as a catalyst. The corresponding aldol adduct was obtained in high enantioselectivity (Figure 3).

OSiCl3

catalyst

O

OH

+ PhCHO n-Bu Ph CH2Cl2 7 8 9 without catalyst: r.t., 95% yield with 10 as a catalyst (10 mol%): −78 °C , 92% yield, 85% ee

Ph

n-Bu

Ph

Me N O P N N Me 10

Figure 3 Aldol reaction of trichlorosilyl enol ether with phosphoramide 10.

The structures of enol ethers do not significantly influence the rate of reaction, although structure does greatly affect enantioselectivity. Enol ethers with small substituents, such as methyl or n-butyl, on the nonparticipating side of the molecule give high enantioselectivities, whereas large substituents, such as phenyl or tert-butyl, give a lower relative enantioselectivity (Figure 4).5 The aldehyde structure has a significant effect on both the reaction rate and the enantioselectivity (Figure 5). Aromatic and conjugate aldehydes give the aldol adducts in high chemical and optical yields, but the sterically less hindered aliphatic aldehydes

200

Enantioselective Aldol Reactions Catalyzed by Chiral Lewis Bases

OSiCl3 + PhCHO 8

R

O

10 (5 mol%)

OH

R

CH2Cl2, −78 °C

Ph

R

Yield, %

ee, %

Me n-Bu i-Pr tert-Bu Ph

98 98 97 95 93

87 85 81 52 49

Figure 4 Aldol reactions of various trichlorosilyl enol ether with benzaldehyde.

R OSiCl3 n-Bu

+ RCHO 7 Cl−

Ph

O H 11

O

Cl Si+ Cl

O

10 (10 mol%) CH2Cl2, −78 °C

OP(NR2)3

OH

n-Bu

Ph

Ph PhCH=CH tert-Bu PhCH2CH2

R

Cl

OP(NR2)3

O O

H

n-Bu

Cl Si Cl

Yield, % ee, % 98 94 81 n.r.

85 84 92 −

OP(NR2)3 OP(NR2)3

n-Bu

12

Figure 5 Aldol reactions of 7 with various aldehydes.

give no aldol adduct. The low reactivity of the aliphatic aldehyde may be explained by the formation of chlorohydrin 12, which is not a good electrophile toward enol ethers.6 Using the sterically less hindered phosphoramides or bisphosphoramides, the stereochemical information present in the trichlorosilyl enol ether is transmitted to an anti (from (E)-enol ether) or a syn (from (Z)-enol ether) relationship about the new CC bond of the product. For example, bisphosphoramide 15 catalyzes the reactions of E- and Z-13 with benzaldehyde to afford syn- and anti-14, respectively (Figure 6), because the reaction proceeded via a six-membered chair-like transition state.7 OSiCl3 (i) PhCHO 15 (10 mol%) (ii) MeOH, H+

Z-13 E/Z = 1/99

E-13 E/Z = 32/1

OSiCl3

Ph

Ph

OH

OMe

OH

OMe

syn-14 92% yield, OMe syn/anti = 99/1 90% ee C5H11 anti-14 91% yield OMe syn/anti = 1/32 82% ee C5H11

Me Me N N O O P P N (CH3)5 N N N Me Me Me Me 15 Figure 6 Aldol reactions of E- and Z-13 catalyzed by bisphosphoramide 15.

However, these stereochemical relationships are not present in all cases. For example, the relatively bulky phosphoramide 17 gives syn-16 from the E-enol ether 3, whereas the less hindered catalyst 10 gives anti-16 (Figure 7). Denmark et al. explained this stereochemistry in terms of the possibility of two reaction pathways. According to their report, the coordination state of the silicon atom of the silyl enol ether in the transition state strongly influences the diastereoselectivity. In the reaction of the trichlorosilyl enol ether of cyclohexanone, two phosphoramide ligands or the bisphosphoramide ligand 15 produces chair-like transition states with a hexacoordinated silicate to afford anti-16. In contrast, the bulky phosphoramide 17 forms a pentacoordinated silicate, which leads to a boat-like transition state, and affords syn-16 (Figure 8).8 Other types of catalyst have been considered. Nakajima et al. reported that the aldol reactions of trichlorosilyl enol ethers are promoted by N-oxides9 or phosphine oxides (Figure 9).10 Chiral phosphine oxides are easily prepared from a variety of commercially available chiral phosphine ligands. BINAPO (BINAP dioxide) (21), which is easily prepared from the commercially

Enantioselective Aldol Reactions Catalyzed by Chiral Lewis Bases

OSiCl3 + PhCHO 3

O

catalyst (10 mol%)

OH

O

Ph

CH2Cl2, −78 °C

8

OH

syn-16

O P

Ph

+

R N

Ph

201

anti-16

N

N R

Ph

R = Me: 10 R = Ph: 17

With 10 as a catalyst: 95% yield, syn/anti = 1/65, 93% ee (anti) With 17 as a catalyst: 94% yield, syn/anti = 97/1, 53% ee (syn) Figure 7 syn/anti-Selectivities depend on the structure of the catalyst used.

(R2N)3P

P(NR2)3 O Cl Si Cl O

O

P(NR2)3 O OP(NR2)3 O Si O Cl Cl H

PhCHO

2 (R2N)3P=O

(R2N)3P=O P(NR2)3 O Si Cl O Cl

(R2N)3P=O

OH Ph

anti-16

Chair-like transition state with hexacoorinated silicate

OSiCl3

3

O

H

Cl

O

OH

O Si OP(NR ) 2 3 O Cl

PhCHO

Ph syn-16

Boat-like transition state with pentacoordinated silicate Figure 8 Two plausible reaction pathways for the phosphoramide-catalyzed aldol reactions.

OSiCl3

+ PhCHO

Ph 18 E/Z = 1/10

20 (3 mol%) iPr NEt 2

O

CH2Cl2, −78 °C

OH Ph

Ph

8

N+ N+

Me 19 82% yield, syn/anti = 7/1 82% ee (syn)

O− O−

20

O Ph P Ph Ph P Ph O OSiCl3 + 3

RCHO

21 (10 mol%) iPr NEt 2 CH2Cl2, −78 °C

O

OH R

R

Time, h

Yield, % Syn/anti ee, % (anti)

Ph p-NO2C6H4 PhCH=CH PhCH2CH2

0.25 0.25 0.5 12

96 90 81 55

1/14 1/25 1/7 1/6

87 96 81 90

Figure 9 Aldol reaction of trichlorosilyl enol ether catalyzed by N-oxide and phosphine oxide.

available BINAP, catalyzes the aldol reaction of trichlorosilyl enol ether (3) derived from cyclohexanone and benzaldehyde derivatives, affording the corresponding adducts with high syn/anti- and enantioselectivities. The aliphatic aldehyde displays low reactivity, but the aromatic and conjugate aldehydes afford the corresponding adducts in high diastereo- and enantioselectivities (up to 96% enantiomeric excess (ee)). The stereochemical relationship between the E/Z configuration of the enol ether and the syn/anti configuration of the aldol adduct may be explained by the six-membered chair-like transition state.

202

Enantioselective Aldol Reactions Catalyzed by Chiral Lewis Bases

The nucleophilicity of trichlorosilyl ketene acetals derived from esters is expected to be enhanced compared with that of trichlorosilyl enol ethers derived from ketones or aldehydes, due to the additional oxygen substituent. However, poor enantioselectivities are observed for the reactions of ketene acetals with aldehydes due to rapid background reactions in the absence of a catalyst. Denmark et al. found that the N-oxides were good catalysts for the reactions of trichlorosilyl ketene acetals and ketones. They demonstrated high enantioselectivity using axially chiral N-oxide 25 as a catalyst in place of the phosphoramide. The corresponding aldol adduct 24 was obtained from the reaction of silylketene acetal 22 and acetophenone 23 in high yield and enantioselectivity (Figure 10).11

Me Me OSiCl3

O

+

OMe

25 (10 mol%)

Ph

22

Me

OH Ph

CH2Cl2, −20 °C

23

Me

O OMe

N+ N+ − O O−

tBu

24 94% yield, 84% ee

O

tBu

O

nBu

nBu

25

Figure 10 Aldol reaction of trichlorosilyl ketene acetal catalyzed by N-oxide 25.

Echavarren et al. applied the aldol reaction of trichlorosilyl enol ether to the synthesis of the sesquiterpenes, englerins A and B (Figure 11). The conjugate aldehyde 26 reacted smoothly with trichlorosilyl enol ether 27 in the presence of 10 to give the corresponding adduct 28 in 91% yield with a high diastereomeric ratio of more than 14:1. Using 28 as a precursor, they accomplished the total synthesis of englerins A and B.12

Ph Ph Ph OSiCl3

Me N

O H

O

P N N Me 10

O O

O

H O (−)-Englerin A

OH

Ph

27

OH

O

O H

CHO 10 (5 mol%) OTES 26

CH2Cl2, −78 °C

O O

OTES 28

H OH (−)-Englerin B

Figure 11 Total synthesis of the englerins A and B.

4.10.3

Enantioselective Aldol Reactions Promoted by Lewis Base-activated Lewis Acids

In certain cases, a Lewis base ligand can enhance the activity of a coordinated Lewis acid. Upon coordination to a Lewis base, the central atom in a Lewis acid becomes more electrophilic. Hence, the ligand is ionized and the generation of a cationic species results in a significant increase in the Lewis acidity (Figure 12). The Lewis acidity of SiCl4 is relatively weak compared with other typical Lewis acids, such as titanium tetrachloride (TiCl4) or boron tripluoride (BF3). However, complexation with phosphoramides results in cationic silicon species, which are highly Lewis acidic. As the Lewis acid is active only when coordinated to the Lewis base, a stoichiometric amount of SiCl4 and a catalytic amount of the chiral phosphoramide may be used for this type of enantioselective reaction. For example, Denmark and Wynn reported the enantioselective allylation of aldehydes promoted by Lewis base-activated Lewis acids (Figure 13).13 Denmark et al. accomplished the highly efficient asymmetric aldol reaction of silyl enol ethers catalyzed by Lewis baseactivated SiCl4 using this concept.6 Catalytic amounts of the bidentate phosphoramide 15 (1 mol%) and stoichiometric amounts of SiCl4 promote the aldol reactions of tert-butyldimethylsilyl (TBS) ketene acetals and aromatic aldehydes in high yields and enantioselectivities (Figure 14). It is important to note that the geometry of the ketene acetal does not affect the stereochemical outcome of the reaction. In the reaction of silyl ketene acetals derived from tert-butyl propionate (31), either the E- or the Z-enriched ketene acetal predominantly

Enantioselective Aldol Reactions Catalyzed by Chiral Lewis Bases

X

L D

δ+

X A

+

LL

δ−

L

δ− δ+

D

X

A

LL

X

X +

L

X

X−

A

D LL

X

203

X

Lewis base Lewis acid Increased Increased negative positive charge charge Cl Me2N Me2N P O + Si Cl Cl Me2N Cl

Me2N Me2N P O Me2N

Relatively weak Lewis acid

+

Cl Si Cl Cl

Cl−

Relatively strong Lewis acid

Figure 12 General concept of Lewis base activation of a Lewis acid.

SiCl4 (1.1 equivalent) PhCHO 8

OH

15 (5 mol%)

SnBu3

+

CH2Cl2, −78 °C

Ph

29

30

91% yield, 94% ee Figure 13 Enantioselective allylation catalyzed by a Lewis base-activated Lewis acid.

OTBDMS PhCHO

+

8

31

OH

15 (1 mol%)

OtBu CH3

SiCl4 (1.1 equivalent) CH2Cl2

O OtBu

Ph

CH3 32 E/Z = 95/5: 93% yield, syn/anti = 1/99, >99% ee (anti ) E/Z = 12/88: 73% yield, syn/anti = 1/99, >99% ee (anti) SiCl4 (1.1 equivalent)

OSiMe3 PhCHO +

nBuO

8

CH2 33

+ TBAOTf

15 (5 mol%) iPr NEt 2

O

OSiMe3

nBuO

CH2Cl2

Ph 34

99% yield, 99% ee OTBS PhCHO 8

+

OEt 35

SiCl4 (1.1 equivalent)

OH

15 (1 mol%) CH2Cl2

O

Ph

OEt 36

89% yield, / >99/1 98% ee Figure 14 Aldol reaction of silyl enol ethers catalyzed by a phosphoramide-activated Lewis acid.

gives the anti-aldol adduct 32 with high enantioselectivity. The anti-selectivity strongly suggests that the reaction proceeds through an open transition structure. Because most acid-catalyzed aldol reactions of silyl ketene acetals give the syn-adduct, these are rare examples of a stereoconvergent anti aldol process. Trimethylsilyl enol ethers are also used in aldol reactions, in which addition of a catalytic amount of an ammonium salt and an amine base improves the rate of reaction.14 This catalyst system is also applicable to vinylogous aldol reactions.15 Phosphine oxide BINAPO (21) was shown to function as an activator of SiCl4 in the reactions of tert-butyldimethylsilyl ketene acetal with aldehydes, but the selectivities were moderate (Figure 15).16 Denmark et al. applied their elaborated method to the synthesis of the macrolide RK-397 to demonstrate its utility in organic synthesis (Figure 16). The vinylogous aldol reaction of TBS silyl ketene acetal and a conjugate aldehyde using chiral phosphoramide 15 in the presence of SiCl4 gave the aldol adduct 41 in 96% ee. After several steps, the second aldol reaction of the trichlorosilyl enol ether derived from 42 and the conjugate aldehyde 43, using phosphoramide 10 as a catalyst, gave 44 in a 2:1

204

Enantioselective Aldol Reactions Catalyzed by Chiral Lewis Bases

1-Nap

SiCl4 (1.2 equivalent)

OTBDMS

O

+ H3C

H

OtBu

OtBu

1-Nap

CH2Cl2

CH3 38

37

OH O

BINAPO (21) (5 mol%)

H3C CH3 39

98% yield, 62% ee Figure 15 Aldol reaction of a silyl enol ether catalyzed by a phosphine oxide-activated Lewis acid.

TBSO EtO

O BnMe2Si

H 40

Ph OH

35

15 (1.5 mol%) SiCl4 (1.1 equivalent)

BnMe2Si

O

41 75% yield, 96% ee

O OEt BnMe Si 2

CHO

OPMB

43

OSiCl3

Me

42

OH O

O

O SiMe2Bn

10 O Me

OTMS

Ph

OPMB SiCl4 Hg(OAc)2

O

81% yield (27R)-44 / (27S)-44 = 2:1 OH

O

OH

Me OH

OH

OH OH OH

OH

RK-397 Figure 16 Total synthesis of RK-397.

diastereomeric ratio. Better selectivity (419:1) was obtained using the substrate-controlled aldol addition with the dibutylboron enolate derives from 42. From the desired isomer (27R-44), the total synthesis of RK-397 proceeded to completion.17

4.10.4

Enantioselective Reductive Aldol Reactions

Although high enantioselectivities were obtained with the aldol reactions of trichlorosilyl enol ethers, their application to the synthesis of natural products has been limited because the trichlorosilyl enol ethers must be prepared prior to the asymmetric reaction. Although the formation of trichlorosilyl enol ethers proceeds almost quantitatively, distillation of the products is sometimes troublesome. As trichlorosilyl enol ethers are easily hydrolyzed to produce polymeric gums and hydrogen chloride, special care is required during distillation, especially if labile substrates are employed. From a synthetic point of view, a one-pot process for the formation of trichlorosilyl enol ethers followed by the aldol reaction is required. One solution to this problem is the in situ generation of trichlorosilyl enol ethers from the enone and trichlorosilane, followed by the aldol reaction. This method referred to as a reductive aldol reaction. Sugiura and Nakajima found that the chiral phosphine oxide BINAPO activated trichlorosilane to react with an enone, providing the conjugate reduction product with high enantioselectivity (Figure 17).18 Fortunately, 1,2-reduction of the carbonyl compound did not proceed, which contributed to the success of this reductive aldol reaction. The reaction of b-ionone (49) and benzaldehyde (8) with trichlorosilane in the presence of BINAPO (21) as a chiral catalyst gave the corresponding syn-aldol adduct 50 with high enantioselectivity (Figure 18). The high syn-selectivity was explained by the formation of the Z-trichlorosilyl enol ether, as a consequence of the six-membered cyclic transition state with the s-cis conformation of enones. The Z-conformation of the silyl enol ether was confirmed by proton nuclear magnetic resonance (1H-NMR) spectroscopy.18a,19

4.10.5

Enantioselective Direct Aldol-Type Reactions Via In Situ Generation of Silyl Enol Ethers

Over the last decade, catalytic enantioselective direct aldol reactions, which do not require masked enol ethers to be prepared beforehand from ketones or esters (aldol donors), have attracted much attention due to their simple manipulation and high atom economy.20 Two types of direct aldol reactions have been reported: reactions catalyzed by chiral metal alkoxide complexes,21 which were initially reported by Shibasaki, and reactions involving the enamine process,22 pioneered by List and Barbas. Both strategies have been extensively investigated and are commonplace in the development of asymmetric reactions.

Enantioselective Aldol Reactions Catalyzed by Chiral Lewis Bases

O

BINAPO (21) (10 mol%) HSiCl3 (2.0 equivalent)

Me

Ph

Ph

O Ph

CH2Cl2, 0 °C, 20 h

45

SiCl3 Me H

H+

Ph

HN

Ar

Ph

Me 47 Ar = p-MeOC6H4

BINAPO (21) (10 mol%) HSiCl3 (3.0 equivalent)

O

Ph 46 97% yield, 97% ee Ar

SiCl3 NCOAr H+

Ph

CH2Cl2, r.t., 5 h

H

Me

Ph

O O

O

205

Me

O

N

Ph

Me 48 68% yield, 81% ee

Figure 17 Lewis base-catalyzed reduction of enones using trichlorosilane.

BINAPO O Me

R

+ PhCHO

49

8 Me Me

SiCl3

BINAPO (21) (10 mol%)

O Me

HSiCl3 (2.0 equivalent) CH2Cl2 –78 °C, 21 h

O

O

H R

H

Me

Ph

OH Ph

50

R 67% yield syn/anti = 99/1, 96% ee (syn)

R= Me O

Me Ph Ph +

Ph 51

BINAPO (21) (10 mol%)

O

CHO HSiCl (2.0 equivalent) 3 52 EtCN –78 °C, 24 h

Ph

OH Ph

Me Ph 98% yield syn/anti = 99/1, 98% ee (syn) 53

R R1

LBm O SiCl n H

LB: Lewis base

Figure 18 Enantioselective reductive aldol reaction catalyzed by BINAPO.

If trichlorosilyl enol ethers are prepared from the corresponding ketone and SiCl4 in the presence of phosphine oxides, and the resulting enol ethers are simultaneously activated by phosphine oxide to react with aldehydes, a new type of direct aldol-type reaction of two carbonyl compounds would be realized. Kotani and Nakajima found that trichlorosilyl enol ethers could be generated from a ketone, amine and SiCl4 using propionitrile as a solvent. The resulting trichlorosilyl enol ether reacted with the coexisting aldehyde at once in the presence of a Lewis base catalyst (Figure 19).23 In the reaction of ketone 54 with benzaldehyde (8), the corresponding anti-55 was produced in 73% ee with a syn/anti ratio of 1:31. Although the aromatic aldehydes gave results that were similar to those of benzaldehyde, the aliphatic aldehydes did not afford the corresponding adducts. The enantioselectivities were less than that in the reaction of the isolated trichlorosilyl enol ethers. Formation of the trichlorosilyl enol ethers did not proceed at  78 1C, resulting in higher enantioselectivities of the products. The reaction of the isolated trichlorosilyl enol ether 3 derived from cyclohexanone and benzaldehyde (8) gave an 87% ee at  78 1C, whereas the reaction of the in situ-generated enol ether gave only 54% ee at 0 1C. The use of trichlorosilyl triflate, which is easily prepared from phenyltrichlorosilane and trifluoromethanesulfonic acid, in place of SiCl4, however, improved the enantioselectivity to 83% ee by lowering the reaction temperature.24 Under these conditions, aliphatic aldehydes showed little reactivity as electrophiles. Therefore, it could be reasonably assumed that aliphatic aldehydes could act as good aldol donors via enolization by SiCl4 with an amine base. Direct cross-aldol reactions between two different aldehydes are classic CC bond forming reactions in organic synthesis. However, few examples of enantioselective direct aldol reactions have been reported between aldehydes due to several competing side reactions, including self-aldol reactions, dehydration and multiple aldol reactions. Direct cross-aldol reactions are conducted under conditions similar to those used for ketone reactions, and the aldol products are transformed to the corresponding diols by sodium borohydride (NaBH4) reduction to facilitate isolation. Although the stereoselectivity is modest, the reaction proceeds smoothly to afford the corresponding adduct without self-condensation product.23 The direct aldol-type reactions discussed above could be expanded to include enantioselective direct double aldol reactions of methyl ketones. Two successive aldol reactions at an a-carbon of a ketone constructs three contiguous chiral centers. However, few reports have described the successful control of the resulting stereocenters. If two molecules of an aldol acceptor react with one molecule of an aldol donor, both chiral and meso compounds are expected to form. Using SiCl4 as a silylating reagent and dicyclohexylmethylamine as a base, the reaction of acetylfuran (61) with furfural in the presence of BINAPO (21) afforded the diastereomixture of meso and chiral products (62) with a ratio of 8:92 (Figure 20). The enantioselectivity of the chiral product

206

Enantioselective Aldol Reactions Catalyzed by Chiral Lewis Bases BINAPO O

54

H

SiCl4 (1.5 equivalent) iPr NEt 2 EtCN, 0 °C

O 8

O

O

iPr NEt, 2

CH2Cl2, −40 °C

57

O

BINAPO (21) (10 mol%)

+

OCH3 58

O

O

O

OH

O

OH Ph

+

syn-16 anti-16 X = Cl: 0 °C, 81% yield, syn/anti =1/6, 54% ee (anti) X=OTf: −40 °C, 76% yield, syn/anti = 1/13, 83% ee (anti ) O

SiCl4 (1.5 equivalent) iPr NEt 2 EtCN, r.t.

OH Ph

+

Ph

BINAPO (21) (10 mol%)

CHO CHO

Ph

syn-16 anti-16 94% yield, syn/anti = 1/14, 87% ee (anti )

SiCl3X (2.0 equivalent) cHex NMe, EtCN 2

8

OH

+

O

OH Ph

O + PhCHO

O

syn-55 anti-55 R = Ph: 79% yield, syn/anti = 1/31, 73% ee (anti) R = 4-MeOC6H4: 69% yield, syn/anti = 1/38, 71% ee (anti ) R = PhCH2CH2: no reaction O

8

56

Ph

BINAPO (21) (10 mol%)

+ PhCHO

OH

Ph

O

OSiCl3

3

O

O

BINAPO (21) (10 mol%)

+ PhCHO

O

SiCl3

O

OH

OH

NaBH4

H

OH

MeOH 59

OCH3

60

OCH3

99% yield, 58% ee

Figure 19 Enantioselective direct aldol-type reactions catalyzed by BINAPO.

O R

CH3

+ RCHO

BINAPO (21) (10 mol%) SiCl4 (4.0 equivalent) cHex NMe 2 EtCN-CH2Cl2, −60 °C

R = 2-furyl

O

OH

80% yield R meso/chiral = 8/92 97% ee (chiral)

R HO

61

R 62

O CH3

+ PhCHO

BINAPO (21) (10 mol%) SiCl4 (4.0 equivalent) cHex NMe 2

O

OH 77% yield Ph meso/chiral = 2/98 93% ee (chiral)

CH2Cl2, −60 °C HO

63

8

Ph 64

Figure 20 Enantioselective double aldol reactions catalyzed by BINAPO.

was 97% ee. Mechanistic studies revealed that the stereochemistry of the first aldolization process was catalyst-controlled, and that of the second aldolization was substrate-controlled. The reaction of cyclopropylmethylketone 63 and benzaldehyde 8 gave the corresponding diol 64 in 93% ee (meso/chiral ¼ 2:98).25

4.10.6

Enantioselective Aldol Reaction of Trimethoxysilyl Enol Ethers Catalyzed by Chiral Phenoxides

A second solution to the problems associated with the use of labile trichlorosilyl enol ethers is the use of a more stable aldol donor. Trimethoxysilyl enol ethers, which are easily prepared from the corresponding lithium enolate and chlorotrimethoxysilane, or from the enone and trimethoxysilane (Figure 21),26 are so stable that they survive aqueous work-up or

Enantioselective Aldol Reactions Catalyzed by Chiral Lewis Bases O

OSi(OMe)3

207

O

(i) LDA

(MeO)3SiH

(ii) (MeO)3SiCl

Rh(PPh3)3Cl

56

57

58

Si(OMe)3 + TfOH O Me

(MeO)3SiOTf (1.5 equivalent) Et3N (2.0 equivaient)

59 without n-Bu4NI with n-Bu4NI

OSi(OMe)3 Me +

OSi(OMe)3 Me

60 1.5 >99

61 1 1

: :

Figure 21 Preparation of trimethoxysilyl enol ethers.

silica gel column chromatography. Regioselective formation of the a, a-disubstituted trimethoxysilyl enol ether of 2-methylcyclohexanone 59 was accomplished in the presence of tetrabutylammonium iodide as an additive and trimethoxysilyl triflate, prepared from allyltrimethoxysilane and triflic acid, as a silylating reagent.27 The only example of an aldol reaction of the trimethoxysilyl enol ether was reported by Yanagisawa et al. using the Tol-BINAP–AgF complex as a Lewis acid catalyst.28 Nakajima et al. found that trimethoxysilyl enol ether could be activated by lithium binaphtholate, and it subsequently acted as an aldol donor. In the presence of dilithium dichlorobinaphtholate 63 as a catalyst, high syn/anti- and enantioselectivities were obtained from the reaction of aldehyde 62 and trimethoxysilyl enol ether 60 derived from 2-methylcyclohexanone (Figure 22). The obtained syn/ anti ratio is far better than the ratios previously reported for the construction of quaternary carbon centers in enantioselective aldol reactions. Sterically congested aldol adducts with a hydroxy group at the b-position of the carbonyl function easily undergo a retro-aldol reaction, which reduces the chemical yields and stereoselectivities of the products. However, the reaction conditions in this system are so mild that the retro-aldol reaction does proceed. In each case, the anti-adducts predominantly form from the E-enol ether without exception, suggesting that these reactions proceed via a chair-like six-membered transition state.27,29 Cl OLi OLi OSi(OMe)3 Me

O

Cl 63 (10 mol%)

OH Me CH=CHPh

R1 R2 MeO –O X O Si O H OMeO X

PhCH=CHCHO + 62

60

THF, −45 °C, 3 h

64 98% yield, syn/anti = 1/20 90% ee (anti)

Figure 22 Aldol reaction of trimethoxysilyl enol ether catalyzed by lithium binaphtholate.

Surprisingly, the syn adduct predominantly forms from the same substrate, in the presence of water as an additive, with high enantioselectivity (Figure 23). The result suggests an acyclic transition state in the presence of water, although the details are not clear.30

PhCHO + 8

OSi(OMe)3 63 (10 mol%) Me THF, −45 °C 60

O

OH Ph Me

syn-65

O +

OH Ph Me

anti-65

Without H2O 94% yield, syn/anti = 1/49 42% ee (syn), 87% ee (anti ) With H2O 60% yield, syn/anti = 2.5/1 87% ee (syn), 4% ee (anti )

Figure 23 Aldol reaction of trimethoxysilyl enol ether in the presence of water.

Using the dilithium binaphtholate catalyst, the highly diastereo- and enantioselective direct aldol-Tishchenko reaction31 proceeds without using the trimethoxysilyl enol ether as an aldol donor (Figure 24).32 The enantioselective direct aldol-Tishchenko reaction has attracted much attention, since Shibasaki reported a successful example using a rare earth complex

208

Enantioselective Aldol Reactions Catalyzed by Chiral Lewis Bases

O O

Ph

O O

H

OH

Ph

H O

O

H

Ph

68 (10 mol%)

OH Ph

Ph

OLi OLi

Ph

H

67 81% yield, 93% ee Aldol-Tishchenko product

Acetalization and hydride shift

Direct aldol reaction

OH O

Ph

66

Ph

O

Ph

68

Figure 24 Aldol–Tishchenko reaction catalyzed by lithium binaphtholate.

as a catalyst.33 The direct aldol-Tishchenko reaction is a series of sequential reactions involving 1. formation of the lithium enolate, 2. aldolization, 3. acetalization and 4. hydride shift. Considering the similarities between the reaction mechanism of the first step of this reaction in the presence of the same catalyst, some of the aldol reactions of trimethoxysilyl enol ethers might proceed via a lithium enolate, rather than a hypervalent silicate complex derived from the trimethoxysilyl enol ether.

4.10.7

Aldol Reactions of Trimethylsilyl Enol Ethers Catalyzed by Phenoxides

Trimethylsilyl enol ethers, the most typical of silyl enol ethers have been tested for their utility as base-catalyzed aldol donors. Mukaiyama et al. investigated the aldol reaction of trimethylsilyl enol ethers and extensively screened various bases to activate the trimethylsilyl enol ethers. Among these bases, tributylammonium phenoxide was found to be an excellent catalyst, affording syn-71 from Z-enol ether 70 (Figure 25).34 They then developed chiral phenoxide catalysts and applied them to enantioselective tandem Michael additions.35 However, an enantioselective version of the phenoxide-catalyzed aldol reaction has not yet been reported.

O O

OSiMe3 +

Ph

69

70

O

OSiMe3

Ph

Ph

+

O

Ph

THF

75 (10 mol%)

Ph

−OPh

Ar2

71 82% yield, syn/anti = 96/4

OPh

72

OH O

PhONBu4 (10 mol%)

H O

Ar1

O N

THF

73

74 Ph 98% yield, 95% ee

N+

75

Ar1 = 9-anthracenyl Ar2 = 3,5-(CF3)2-C6H3

Figure 25 Aldol reaction of trimethylsilyl enol ether catalyzed by phenoxide.

Ishihara et al. developed a sodium phenoxide–phosphine oxide catalyst 79, which activates trimethylsilyl enol ethers (Figure 26). The reactivity is sufficiently high to produce a highly crowded aldol adduct without the competing retro-aldol reaction using 79 as a catalyst (0.5 mol%).36 An enantioselective version of this aldol reaction is expected.

−OPh Ph Ph P O + Na P O O P Ph Ph 79 Ph Ph Me3SiO (0.5 mol%) Ph Ph THF

Ph Ph P O

O Ph

OSiMe3 Ph

76

+

OMe 77

Figure 26 Aldol reaction of trimethylsilyl enol ether catalyzed by phenoxide–phosphine oxide.

O OMe

78 97% yield

Enantioselective Aldol Reactions Catalyzed by Chiral Lewis Bases

4.10.8

209

Conclusion

In this chapter we have described Lewis base catalyzed aldol reactions with particular focus on the reactions that proceed via a cyclic transition state involving a hypervalent silicon species. The most successful protocol was developed using trichlorosilyl enol ethers as aldol donors and chiral Lewis bases, such as phosphoramides, N-oxides and phosphine oxides, as catalysts. In most cases, the reactions proceed via a chair-like six-membered transition state, which leads to a good correlation between the E/Z stereochemistry of the starting enol ether and the syn/anti stereochemistry of the product. To generate trichlorosilyl enol ethers in situ, which are labile to water, the direct aldol-type reaction was developed. The direct aldol-type reaction evolved into the tandem double aldol reaction, which generates three contiguous chiral centers from two carbonyl compounds. This process will be applied to the synthesis of complex biologically active compounds. Trimethoxysilyl enol ethers are another set of aldol donors that could be activated by chiral phenoxides. Chiral binaphtholate catalyzes the aldol reaction of the enol ether derived from a, a-disubstituted ketone to afford the aldol adduct with quaternary carbon centers with high diastereo- and enantioselectivities. Recently, it was reported that trimethylsilyl enol ethers, the most accessible silyl enol ether, could be activated by bases. However, an enantioselective version of the reaction has not yet been reported. The development of Lewis base-catalyzed enantioselective aldol reactions of stable enol ethers are expected.

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