Methodologies in Asymmetric Catalysis - American Chemical Society

Chapter 6

Downloaded by PENNSYLVANIA STATE UNIV on July 21, 2013 | http://pubs.acs.org Publication Date: July 4, 2004 | doi: 10.1021/bk-2004-0880.ch006

Asymmetric Autocatalysis and the Origin ofHomochiralityofBiomolecules Kenso Soai,ItaruSato, and Takanori Shibata Department of Applied Chemistry, Faculty ofScience,Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan

When a chiral compound operates as a chiral catalyst for its own production, the process is defined as asymmetric autocatalysis. In the enantioselective addition of diisopropylzinc to nitrogen-containing aryl aldehydes, asymmetric autocatalysis has been realized. 3-Pyridyl-, 5pyrimidyl-, and 3-quinolylalkanols are efficient chiral catalysts for the enantioselective isopropylation of the corresponding aldehydes, and the alkanols themselves are obtained in high yields and in high enantiomeric excess (ee). Asymmetric autocatalyst with extremely low ee value automultiplies with significant amplification of the ee to afford the (same) products with extremely high ee values. In the presence of chiral molecules with only a slight enantiomeric imbalance, which can be induced by chiral physical factors, organic molecules with extremely high ee are obtained using an asymmetric autocatalytic system. Moreover, absolute asymmetric synthesis, i.e., thereactionof pyrimidine carbaldehyde and diisopropylzinc in the absence of chiral molecules, yields enantioenriched (S)-or (R)-alkanols with a stochastic distribution.

© 2004 American Chemical Society In Methodologies in Asymmetric Catalysis; Malhotra, S.; ACS Symposium Series; American Chemical Society: Washington, DC, 2004.

85

86 Catalytic asymmetric synthesis is a very efficient protocol for the synthesis of chiral compounds, because a high yield of enantiomerically enriched molecules can be obtained using a small amount of enantiomerically enriched molecules (chiral catalysts). In fact, many types of selective chiral catalyst have been reported for various asymmetric reactions, including reduction, oxidation, and carbon-€arbon forming reactions. The structures of the initial asymmetric catalysts and the chiral products in these reactions are usually very different. In contrast, in asymmetric autocatalysis, the structures of an asymmetric catalyst and the chiral product are the same, which means that the chiral product acts as a chiral catalyst for its own production, and that enantioselective automultiplication proceeds without the aid of other chiral compounds (auxiliaries) (see Scheme 1). Mathematical mechanism of asymmetric autocatalysis was proposed, but no concrete examples of asymmetric autocatalytic reactions have been disclosed. Therefore, the discovery of chiral molecules that have asymmetric autocatalytic abilities is a challenging and fascinating topic in organic chemistry. 1


2,3

4

Asymmetric autocatalysis |

Q

The same structure and configuration

Product

Scheme 1. The principle of asymmetric autocatalysis. 58

Alberts and Wynberg reported on asymmetric autoinduction. However, this type of reaction needs to be distinguishedfromasymmetric autocatalysis. In asymmetric autoinduction, a chiral product forms a chiral complex with a catalyst, and therefore, toe process is related to asymmetric induction, but the compound itself cannot operate as a chiral catalyst. 5

Discovery and Development of Asymmetric Autocatalysis In 1990, we discovered the first asymmetric autocatalysis reaction in the enantioselective isopropylation of aldehydes. When the addition of diisopropylzinc (/-Pr Zn) topyridine-3-carbaldehyde using a catalytic amount of (S>2-methyl-l-(3-pyridyl>l-propanol 1 with 86% ee was examined, it was found that (S)-pyridyl alkanol 1 was newly formed in a 67% yield, which possessed the same configuration (S enantiomer, 35% ee) as the catalyst Chiral 6

2

In Methodologies in Asymmetric Catalysis; Malhotra, S.; ACS Symposium Series; American Chemical Society: Washington, DC, 2004.

87 isopropylzinc alkoxide formed in situ from alkanol 1 and i-Pr Zn operated as a true catalyst. Other than nitrogen-containing alcohols, ferrocenyl alkanol 3 and diol 4 have also been found to be asymmetric autocatalysts. 2

7.

1:R=H 2: R=CON(*Pr)

3

4


2

5: R=H 6: R=Me

Highly Enantioselective Asymmetric Autocatalysis

The above-mentioned alcohols operate as asymmetric autocatalysts. However, their enantioselectivity is not very high. The ee of the alcohols formed is lower than that of the catalysts. Chiral pyrimidyl alkanols were found to exhibit the first highly enantioselective asymmetric autocatalysis. When chiral (iS)-pyrimidyl alkanol 5 with a 93% ee was used as an asymmetric autocatalyst in the enantioselective addition of ?-Pr Zn to pyrimidine-5-carbaldehyde, the (5)pyrimidyl alkanol 5 formed had an ee of 90%. When a chiral (S>pyrimidyl alkanol with a 2-methyl substituent 6 having >99.5% ee was used, then the ee of the newly formed (S)-alkanol 6 reached a value of 98%. This asymmetric autocatalysis is superior to conventional (nonautocatalytic) asymmetric synthesis for the following reasons: (1) It is not necessaiy to have an asymmetric catalyst with a structure different fiom that of the chiral product. (2) TTie chiral product serves as an asymmetric catalyst for its own production, and therefore, the chiral product automultiplied itself exponentially. (3) The catalyst does not deteriorate, because the catalyst formed continuously as the reaction proceeded, and (4) separation of the chiral product from the (auto)catalyst is not necessary. Chiral 3-quinolyl alkanol 7 and chiral 5-carbamoyl-3-pyridyl alkanols have also been shown to be highly enantioselective asymmetric autocatalysts. (5)-3-quinolyl alkanol 7 with a 94% ee catalyzes the enantioselective addition of i-Pr Zn to quinoline-3-carbaldehyde to yield (S)-alkanol 7 with a 94% ee, having the same configuration as the catalyst. Introduction of a carbamoyl group at the 5-position of the pyridine ring drastically increases tie enantioselectivity of 3-pyridyl alkanol acting as an asymmetric autocatalyst. Chiral (*S)-5-caibamoyl-3-pyridyl alkanol 2 (94% ee) 9

2

10

11

2

10

11


88 catalyzes the enantioselective addition of *-Pr Zn to 5-caibamoylpyridine-3carbaldehyde to yield (S)-alkanol 2 with an ee up to 86%. Substiiuents on fee nitrogen atom of the carbamoyl group play a pivotal role in the asymmetric induction, and a pyridyl alkanol possessing isopropyl groups on the nitrogen atom is the most highly enantioselective asymmetric autocatalyst. 2


A Near Perfect Asymmetric Autocatalyst: 2-Alkynyl-5-pyrimidyl Alkanol As a result of studying the effect of substituents on the pyrimidine ring, the 2-position was found to be the most important position for asymmetric induction. Among the various substituents examined, ethynyl and alkenyl groups were found to be the best (see Scheme 2): When (5)-l-(2-ier/-butylethynyl-5pyrimidyO-2-mefliylpropanol 9 with >99.5% ee was used as an asymmetric autocatalyst in the addition of i-Pr Zn to 2-(^-butylethynyl)pyrimidine-5caibaldehyde 8 in cumene at 0 °C, then (S>pyrimidyl alkanol 9 was obtained quantitatively in near perfect enantioselectivity (>99% isolated yield, and >99.5% ee). Next, we examined a consecutive reaction, where the (S)-alkanol 9 that was obtained was further used as a catalyst for anew reaction. As a result, even the tenth such reaction proceeded in a quantitative manner in near-perfect enantioselectivity. A sixfold increase in (5)-pyrimidyl alkanol 9 was afforded by each reaction, and thus, the amplification factor of ten successive asymmetric autocatalytic reactions reached a value of 6 (ca. 60,000,000). In contrast, if the (J?)-pyrimidyl alkanol 9 with >99.5% ee was used as an asymmetric autocatalyst instead of the (S>9, then the resulting compound (R)-9 wift >99.5% ee was obtained in >99% isolated yield. 12

13

2

2

10

consecutive runs 1st run 2nd run 10th run

yield, ee >99%, >99.5% ee >99%, >99.5% ee >99%, >99.5% ee

Scheme 2. Near perfect asymmetric autocatalysis, in which the product is used as the asymmetric autocatalystfor the next run.


89

Asymmetric Autocatalysis with Amplification of the Enantiomeric Excess When an asymmetric autocatalyst with a low ee is used, then a product with a higher ee value can be obtained. Using the (5>pyrimidyl alkanol 5 with only a 2% ee value as a catalyst in the reaction between /-Pr Zn and tie aldehyde 10, compound (*S)-5, which includes the catalyst and a newly formed alkanol 5 was obtained with an amplified ee of 10% (see Figure l). In this case, the asymmetric autocatalytic reactions we examined were reactions where the product obtained from one reaction served as the asymmetric autocatalyst for the next. Successive reactions providing an amplification of the ee value are one of the advantages of asymmetric autocatalysis, and this can never be realized in TOH-autocatalytic asymmetric amplification. The ee of the obtained product 5 increased to 57% ee, 81% ee, and 88% ee, over consecutive reactions. This is an unprecedented and unique asymmetric reaction pathway, which includes asymmetric autocatalysis and asymmetric amplification. As shown in Figure 1, during the first four consecutive asymmetric autocatalytic reactions, the initial catalyst (S)-S increases 239-fold. On the other hand, (Λ)-5 increases by only 16fold. It should be noted that, even i f an asymmetric autocatalyst with an extremely low ee was used as the initial catalyst, an almost enantiomerically pure product (asymmetric autocatalyst) can be obtained by consecutive asymmetric reactions. In practice, only a slightly (£)-enriched 9 with a 0.00005% ee value (S isomer:/? isomer = 50.000025:49.999975) was used as the initial catalyst, and an almost enantiomerically pure 9 resulted after only three consecutive enantioselective isopropylations of aldehyde 8 (see Scheme 3). During these asymmetric autocatalysis reactions, the sight excess of (S)-9 in the initial catalyst was automultiplied by a factor of ca. 630,000, while the (R)-9 was automultiplied by a factor of less than 1,000. Chiral isopropylzinc alkoxides formed in situ from the (Sy and (i?)pyrimidyl alkanols 9 and i-Pr Zn probably also work as asymmetric autocatalysts. A sigmoid curve in the relationship between the yield of the product 9 and the reaction time suggests that the reaction is autocatalytic and that reaction proceeds via second order with isopropylzinc alkoxide of pyrimidyl alkanol 9. In the amplification oftheee, an inhibition mechanism can suppress the activity of the minor enantiomer of the catalyst. Kagan discussed this aspect in non-autocatalytic reactions as arising from aggregations of chiral ligands. We also postulate that aggregation of tie catalyst occurs. However, clarification of the inhibition mechanism in the present asymmetric autocatalysis requires further investigation. Not only pyrimidyl alkanols, but 3-quinolyl alkanols and 5-carbamoyl-3pyridyl alkanols are also asymmetric autocatalysts providing an amplification of the ee value. 2


14

14

15

2

16

18



Figure 7. Thefirstasymmetric autocatalysis with amplification ofee



Scheme 3. Amplification of extremely low ee values in the asymmetric autocatalysis of 9.


92

Asymmetric Autocatalysis Initiated by Various Chiral Organic Molecules If the alkylation of pyrimidine-5-caibaldehyde with diisopropylzinc is conducted in the presence of a chiral compound with a low ee value (denoted here as a, "chiral initiator"), and the chiral initiator is not a pyrimidyl alkanol, then a slight enantiomeric imbalance is expected to be induced in the initially formed zinc alkoxide of the pyrimidyl alkanol. This small imbalance is drastically amplified by the ensuing asymmetric autocatalysis of the pyrimidyl alkanol, even if it was initially extremely small. The asymmetric alkylation of pyrimidine-5-caibaldehyde 11 by i-FitZn was studied when methyl mandelate 12 with a low ee of ca. 0.1% was used as the chiral initiator (Scheme 4). In the presence of (Λ)-12, (5)-pyrimidyl alkanol 6 was obtained with a much higher ee than that of the chiral initiator. On the other hand, in the presence of (S)-12, (R)-6 with much higher ee was formed. These results show that small enantiomeric imbalances in the methyl mandelate 12 were recognized and amplified in the resulting pyrimidyl alkanol 6. Chiral carboxylic acid 13, amines 14, and alcohols also work as chiral initiators. It should be noted that this effect is observed even with 2-butanol 15 having ca. 0.1% ee, because a slight difference between the methyl and ethyl substituents on the asymmetric carbon of 2-butanol can be recognized by the reaction between pyrimidine-5-carbaldehyde 11 andi-PraZn.


19

198

Can the Mystery of Homochirality be Solved by Asymmetric Autocatalysis? The enantiomeric ratios of naturally occurring organic molecules are biased towards one enantiomer, such as that seen in L-amino acids or D-ribose. The origin of this homochirality has been a topic of discussion for many years. Not only the chiral substances, but also chiral physical forces have been proposed as being the origin of chiral bias. However, the enantiomeric imbalance induced by these chiral factors is very small, and therefore, without any chiral amplification mechanism, it has not been possible to correlate tiny imbalances in the homochirality of biologically important molecules On the other hand, this tendency can be explained by enantiomeric amplification of the small fluctuations in a random chance mechanism. It is noteworthy that the asymmetric amplification mechanism is indispensable for making a significant connection between the small fluctuations and a large enantiomeric imbalance. In the latter case, if we examine the random chance mechanism with a suitable enantiomeric amplification method, then the stochastic formation of two enantiomers should be observed. 20



15

X OH

(S)-6

Ν

X

Me

(fl)-6

S "OH

Asymmetric autocatalysis

very Υύφ

'OH

Is

very nigh

(S)-6

Scheme 4. Asymmetric Autocatalysis Initiated by Various Chiral Molecules

14

13

12

3

rCH L.

3

C CHH ,

OH

Phs^OCOaMe Prv-jCOaH P h ^ H C H a v ^ ^ v ^

Chiral initiators with very low (0.05-0.1%) ee's

11

Chiral initiator with very low ee

Asymmetric autocatalysis


94 Circularly Polarized Light as an Origin of Chirahty Several physical factors have been proposed as being the origin of chiral oiganic compounds, and circularly polarized light (CPL) is a potent candidate among these. However, the degree of enantiomeric imbalance induced by CPL is too small to be correlated with the large enantiomeric imbalance observed in molecules found in nature. For example, the asymmetric photolysis of racemic leucine 16 with right-CPL affords L-leucine 16, but with only a 2% ee (L:D = 51:49). Similarly, in asymmetric photosynthesis using CPL, chiral [6]helicene 17 can be obtained, but wifli a very low ee (

Methodologies in Asymmetric Catalysis - American Chemical Society

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