ASYMMETRIC AUTOCATALYSIS AND HOMOCHIRALITY OF BIOMOLECULES

Kenso Soai* and Itaru Sato
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science,
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Fax: +81-3-3235-2214
E-mail: soai@rs.kagu.tus.ac.jp(Received 17 July 2002 Accepted 20 August 2002)

Abstract
Asymmetric automultiplication of chiral compounds by asymmetric autocatalysis is realized for the first time wherea chiral product acts as a chiral catalyst for its own production. We disclosed chiral 3-pyridyl alkanol, 3-quinolyl alkanol,and 5-pyrimidyl alkanols operate as asymmetric autocatalysts in the enantioselective additions of i-Pr2Zn to pyridine-3carbaldehyde, quinoline-3-carbaldehyde and, pyrimidine-5-carbaldehyde, respectively. Especially, practically perfectasymmetric autocatalysis (>99%, >99.5% ee) is attained using 2-alkynyl-5-pyrimidyl alkanol as an asymmetricautocatalyst in the enantioselective addition of diisopropylzinc to corresponding pyrimidine-5-carbaldehyde. In addition,
asymmetric autocatalysis with amplification of ee is realized. Asymmetric autocatalyst with very low ee enhances its ee
significantly up to >99.5% ee during the asymmetric autocatalysis without the assistance of any other chiral auxiliaries.
Moreover, various chiral compounds with very low ee act as chiral initiators in the reaction of pyrimidine-5carbaldehyde and diisopropylzinc to give 5-pyrimidyl alkanol with high ee in combination of asymmetric autocatalysis.
Amino acids and [6]helicene with very low ee which are produced by asymmtric photolysis and photosynthesis using
circularly polarized light (CPL) serve as chiral initiators of asymmetric autocatalysis, and 5-pyrimidyl alkanol with highee is obtained. Inorganic chiral crystals such as quartz and sodium chlorate also work as chiral initiators. These resultscorrelate for the first time the proposed origins of chirality of organic compounds such as CPL and quartz with thechirality of organic compounds with very high ee.
Key words: chirality, asymmetric autocatalysis, amplification, enantioselective addition, 5-pyrimidyl alkanols, chiralinitiator, circularly polarized light, amino acids, quartz, sodium chlorate

Viva Origino 30 (2002) 186-198© 2002 by SSOEL Japan186

Viva Origino 30 (2002) 186-198

不斉自己触媒反応と生体関連化合物のホモキラリティ-

硤合憲三*、佐藤格

東京理科大 理学部応用化学科〒162-8601 東京都新宿区神楽坂 1-3
FAX 03-3235-2214
E-mail: soai@rs.kagu.tus.ac.jp

最近、われわれは、極微小鏡像体過剰率の化合物

はじめに生命の起源の探求に際し、生体関連化合物におけが自己を合成する不斉自己触媒として作用し、そのる不斉の起源の解明は不可避の問題であると考えら

自己増殖過程で鏡像体過剰率を著しく向上させ、最れている。生命を形づくり、細密な機構をもって生終的にほぼ一方のみの鏡像異性体になる不斉自己触命活動を維持している生体関連化合物の多くは、可媒反応を見出した [1-15]。さらに、不斉の起源とさ能な２つの鏡像異性体のうち一方のみが存在するこれる諸力により誘起される程度の極微小な鏡像体過とが知られている。例えば DNA を構成するデオキ

剰率の化合物をもとに、不斉自己増殖反応によりき

シリボヌクレオシドの糖部分は、D-2-デオキシリボ

わめて高い鏡像体過剰率の有機化合物に至る化学プースであり、タンパク質は基本的に L-α-アミノ酸にロセスを具現することができた。以下にその内容をよって構成されている。もしＤ型と L 型両方の糖か紹介する。

らなるヌクレオシドが混在した DNA では、3 次元構
1. 不斉自己触媒反応

造が変化し、二重らせんの形成や正常な遺伝情報の伝達を行うことはできなくなるだろう。一方、L 型

不斉触媒反応 (asymmetric catalysis) は少量のキとＤ型アミノ酸が混在したタンパク質では、酵素作

ラルな触媒（Ｃ＊）の存在下に反応を行ない、キラ用等が正常に発現しなくなり、生命活動を維持する

ルな生成物（P＊）を得ようとする反応であり、少量ことはできないであろう。

の不斉源から多量のキラル化合物が得られる（図１）。

これまでに地球上の生体関連有機化合物がこのよ

しかし、一般に得られた生成物がさらに反応を促進

うな単一の不斉（ホモキラリティー）という形質をすることはない。もし生成物自身が不斉触媒として獲得した要因として、右および左円偏光や水晶など作用し、自己と同一構造かつ同一絶対配置を持つ化の不斉な無機結晶が提唱されてきた。しかし、これ合物を合成する反応が実現できれば、きわめて効率

らの要因が有機化合物に誘起する不斉の偏りは一般的かつ直接的な合成反応になる。これはキラルな生に極微小に過ぎないとされている。したがって、こ

成物自身の自己増殖反応であり、例えば生命系の自れらの要因により得られた化合物の極微小の鏡像体

己再生産過程などと比較しても極めて興味深い。こ

過剰率と、生体関連有機化合物のきわめて高い鏡像の不斉自己触媒反応 (asymmetric autocatalysis) の概体過剰率には大きな隔たりがあるといえる。つまり、念については 1953 年に Frank が数式により提唱してわずかな不斉の偏りからほぼ完全な鏡像体過剰率へいるが、実験的にこれを実現するものではなかったと導く化学プロセスの実現なくして両者を関連付け、[16]。

これらを同義のものとして扱うことは困難であろう。

187

Viva Origino 30 (2002) 186-198`

r 3-ûû!}û (S)-2 Mµ=njí.²þ 2³LnIj/2JÛpDE= [21]LFigure 3. Highly enantioselective asymmetric autocatalysis of
3-quinoly and 5-pyrimidyl alkanols.

H33-ûû!}û5-ûû!}ûM
=ûsz:J'Kmûû%&M¢eÑI0WÇ2JÏ#1$t23¢m=nFigure 1. Principle of asymmetric catalysis and asymmetricautocatalysis.

K

3j

j?H3TX²þ4³
LmTÎf94%ee (S)-3-ûû!}û 4 M
:J'KJ+,ØÙû%&-3-!

û"ûsz 3 ÖÝ5M¢e(S)-3-ûû!}û 4 j
I [22]L¬5-r

94% ee :JµHûû!}û 6a M

'K093% ee  (S)-6a H0
90% ee (S)-6a j2 67j8$ûDE=
Figure 2. The first example of asymmetric autocatalysis.

>99.59 ee (S)-6b H0 98% ee0ûszûû [1719]3;KJ

(S)-6b jåI:I

-3-!û"ûszM)*:nIM^3=WD0TK3 3-J3-

FG [20]LånD 1990

-3-!û"ûsz 1%&M-iû>ûM×?: 5-r

ûû!}û (S)-2 Mûû!}û (S)-2

3 3,3-:

ûû!}û

:J@A^ï0ê¯:B

8$û-1-C$>ûM×?: 5-ûû!}û 6c 3;KJDÛ¯ÔÕT@+,ØÙû

n¥

:JµHI [23]LH373`KJ;<:Â=_63#$û%&3=#$ûjÇ2J'(
3¢m=nr

A^ïM\X

:J'K

m=n

jí.

²E³[24]LmTÎf 99.5% ee ó¯(S)-6c MÞ1MW



188

:J'Km=

-5-!

Viva Origino 30 (2002) 186-198
Table 1. Practically perfect asymmetric autocatalysis of 2-alkynyl-5-pyrimidyl alkanol.
asymmetric autocatalyst
N

OH
N

CHO

N

(S )-6c (>99.5% ee)+

NN

i-Pr2 ZnOHN5c( S )-6c (>99%, >99.5% e e)asymmetric autocatalyst
productee (%)
Entry
yield (%)
>99.5
1
>99
2
>99
>99.5
3
>99
>99.5
4
>99
>99.5
5
>99
>99.5
6
>99
>99.5
7
>99
>99.5
8
>99
>99.5
9
>99
>99.5
10
>99
>99.5
Molar ratio. Aldehyde 5c : diisopropylzinc : asymmetric autocatalyst 6c = 1.0 : 1.7 : 0.2.

û"ûsz 5c Ö

ca. 6 x 107

2. æYMZe

+,ØÙû%&Ý53=M¢eamplification
factoree (%)
>99.5
>99.5
>99.5
>99.5
>99.5
>99.5
>99.5
>99.5
>99.5
>99.5

gÆD[abFÍ 99% ó¯abÊÌÍ 99.5 % ó¯D(S)-6c jµHIL

K0

µHI

rj

¥eL|\QW]¨'MF^:0|Þ1VM\f\abrWYdMªGm=H"HµHIrM'KJM¢enjí.=LJKDµH

IabÊÌÍ 99.5 % ee ó¯
b

I

b

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 a

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ÊÌÍhjÏK

FGHI=LÛ9a
ÊÌÍjåIM¯JæYMcmpj Kagan H3Q

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99.5% ee ó¯ 5- ûû!}û(S)-6c jrVjcT=aD0µFÍ 999ó¯DµHILmTÎf

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Pm=LnQ30123'K 5-ûH3ê¯=nû!}û (S)-6c æ$ú0RSTUV3WXrjµHI:JhPn:JWåab
0H"

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ÊÌÍM

3í.TKLgh3;KJ0åH"

m=L

HrMH3

K=n

189

j@^DE=LW:ab:J'ÊÌÍjê¯mViva Origino 30 (2002) 186-198

Figure 4. Consecutive asymmetric autocatalysis of pyrimidyl alkanol (S)-6a with amplification of ee.

Figure 5. Change of the amount of S- and R-isomers of 6a in consecutive asymmetric autocatalysis.

=MÛ«D£Iq

H3åab:J'K=nÊÌÍMÏ2=njD£Ç2J[ab

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:J

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jí.=

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i

GHI=LÎIÎI05-

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ûû



ûû!}ûn¥(þ 4)µHIÊÌÍ!}ûM

F+,Øûû!}û (S)-6a ab5-ÊÌÍHÏab

ÊÌÍM\X|\Mµ=n-5-!û"ûsz 5a:JM¢eûû!}ûabÊÌÍ0H3ê¯

M'KÛ3Q¬3nIj@^DE=n:579 ee  (S)-6a jµHILH3 I

Mcmn

MLQMmnjí.[34]LmTÎfÎÑ 2% ee

(S)-5-û 6a abûû!}û 6a M

190

5-

D (S)-5-Tûû!}

ÊÌÍ0 81%H30 889ee 3êViva Origino 30 (2002) 186-198¯:Lû!}û(S)-6c 3q¬IJKrabcd

kM'Klm3Q
5-

= S

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¢}û [35]3-ûû!}û [36] 5-!û"+û-3-æçÍjR 2,500 VDE=3:R

abcd

ûû!

ûû!}û [37]M'K0DE

W3

sDWabÊÌÍjê¯m=DE=n

jÇ2J

téTê¯3uv:JK=W

FGHI=L3Wê¯MZej¢mnI3:a3;KJne=n3Ç2JÈÉTabj?H3TXL

2-û>û-5-
KÇÈÉabM-iûû!}û 6c M'

KJ 99.5% ee ó¯ûTÊÌÍ
n¥0Ç2J$Y3æ$m=nrabrMµp0ÎIÎIo=wQD0TKLÊÌÍó¯e3abMìí:LÎÑ

0.69 ee (S)-6c M

ÊÌÍM\XM':J'KJÊÌÍê¯MZeæç0£Î2J[KabÊÌÍHíª:

JWn6ïMxQ=nTPæç:`DµHI(S)-6c M

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hiabcd¢X¤<D5-ûû!}û(S)-6c 

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ab

:J'K=

I3;KJã/3'K 5-

3T=WDEQÇÈÉû

Figure 6. Change of the amount of S- and R-isomers of 6c in consecutive asymmetric autocatalysis.

191

Viva Origino 30 (2002) 186-198

3. [ab

9 W

ÊÌÍ°Uklô

3¨':åI:I

m=M\`û!}ûjÏKab

z{D0[abÊÌÍ 5-}ûM
[ab

:J°

ÍDµHI(entries 5, 6 ¹ 7, 8)LH3Ç2

ûû!

JÉTKmTÎf8$û:0/23|5:

ÊÌÍsabcd

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1 (þ 7)

nIM

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j@^DEQ 5-ûû!}û 6b j 73% ee DµHI 2-C}û 10 M'K030DE= R

 5-ûû!}û 6b j 769 ee DµHILk

rm= 5-

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j23

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

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Û9Ú

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FGHIJK=¶·:J3»¼½Mm=å½|>0ÎÑTjHWgh#1$t}

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DµHI=ab"ûsz 5bûû!}û (R)-6bÊÌÍ0ÈÉ²R 2%

j3(R)-7 klôD0(S)-6b jåI:IÏK

ee³DEQ]P°Uj\`Ç2J

ab

ÏKab

ÊÌÍD

r:(entries 1, 2)LnIHÂÊÌÍ

0?TÐQjE=LÎIÎ=0i:Qsû#~ûÎÑT

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abcd

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rm= 5-

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Bonner HjÊDWÞ1

ÌÍ (R 29ee) L-Ù+u 11 MWDE=

FGHI=LH3[KabWÊÌÍdDj¢: (entries 3,

g:JK= [48]LånD[ab4)Lne3:JµHI 5-

ûû!

J

}û0MLQMmn

3Q

û%&M¢XLåÂ= 23% ee (R)-5-

H3åabjí.=nÊÌÍMê¯=n

-5-!û"ûsz 5b:ûû!}û 6b jµHI=n

+ØÙ

j?H

3TX [39]Lne30123'K L-Ù

0?HDE=LûT!ûv 8

192

Viva Origino 30 (2002) 186-198

Figure 7. Schematic representation of asymmetric autocatalysis initiated by various chiral initiators with low ee.
Table 2. Asymmetric autocatalysis of pyrimidy alkanol in the presence of various chiral initiators with low ee.
entry a)
1
2

OH
Ph

5
6

config.
SR

ca. 0.05
ca. 0.05

S
R

54 b)
38 c)

R
S

ca. 0.1
ca. 0.1

S
R

76
73

R
S

ca. 0.1
ca. 0.1

S
R

79
85

R
S

ca. 0.1
ca. 0.1

S
R

73
76

S
R

CO2 Me7

34pyrimidyl alkanol 6bconfig.
ee (%)
68
R
70
S

chiral initiatoree (%)
ca. 0.1
ca. 0.1

CO 2H
Ph

Me

8
7
8

NH 2
Ph

9

Me

OH

9
10

10
a) Molar ratio of chiral initiator : aldehyde 5b: diisopropylzinc is 0.01-0.02 : 1.0 : 2.4.
Aldehyde 5b and diisopropylzinc were added in three portions.
b) An average value of three experiments under the same reaction conditions (56, 53, 53% ee).
c) An average value of three experiments under the same reaction conditions (40, 37, 38% ee).

Figure 8. Asymmetric autocatalysis of pyrimidyl alkanol 5b in the presence of L-leucine with low enantiomeric excess: the firstcorrelation between the chirality of circularly polarized light (CPL) and an organic compound with high enantiomeric excess.

193

Viva Origino 30 (2002) 186-198+uabÊÌÍjÇ2JÉK3WµHI= 5-ÎHÑûû!}û(R)-6b ab

6:J'K=rªHWj\I=LÊÌÍ0i:Q3é:Pê¯:LnIM

J'K

H33Qê¯=n0Ç2ØÙû%&M

JöDEQ:jXJÂ=0"

T



(Chirality)DE=»¼½
ûM/2J
iM6

rm=%

ûû!}û 6c jFÍ 95%D

r:(>95% ee)klôD0(R)-6c j 93% ee DµHILÊÌÍånD½r [50]DÊèMÛ«:nbÍ (<2% ee)TjHrD£=n

rm=QW[KaÊÌÍDE=ÎÑ 0.13% ee (P)-(+)-12 M'

K

H3»¼½3=½r3Q[abn¥95% ee (S)-5-

3TQ»¼½

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Figure 9. Asymmetric autocatalysis of pyrimidyl alkanol 6c using [6]helicene as a chiral initiator.

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ó¯Â=0¸;¹º¾¿¸§1¹º195Viva Origino 30 (2002) 186-198;ÎQ3
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R 0.00005% ee KeËÇÈÉ 5-ûû!}û 6c Híªm=4J I Dab ÊÌÍ0 99.5% ee ó¯3¡
m=L
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Angew. Chem. Int. Ed., in press.
¬6M5GÑ3 !û"ûsz 5+,ØÙû%&M= líwÌó¯ab ÊÌÍM\`R ¬0S 5- ûû!}û 6 j rm=L
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substances by the addition of diisopropylzinc topyrimidine-5-carbaldehyde

inconjunction

withasymmetric autocatalysis. Tetrahedron Asymmetry.,in press.

198