Asymmetric autocatalysis induced by meteoritic amino acids with hydrogen isotope chirality

Article abstract of DOI:10.1039/b908754k

Achiral meteoritic amino acids, glycine and α-methylalanine, with hydrogen isotope (D/H) chirality, acted as the source of chirality in asymmetric autocatalysis with amplification of ee to afford highly enantioenriched 5-pyrimidyl alkanols. The Royal Soci

Full text of DOI:10.1039/b908754k

View Article Online / Journal Homepage / Table of Contents for this issue
This article was published as part of the
2009 ‘Catalysis in Organic
Synthesis’ web theme issue
Showcasing high quality research in organic chemistry
Please see our website
(http://www.rsc.org/chemcomm/organicwebtheme2009)
to access the other papers in this issue.

COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Asymmetric autocatalysis induced by meteoritic amino acids
with hydrogen isotope chiralitywz
Tsuneomi Kawasaki,ab Masako Shimizu,a Daisuke Nishiyama,a Masateru Ito,a
Hitomi Ozawaa and Kenso Soai*ab
Received (in Cambridge, UK) 5th May 2009, Accepted 8th June 2009
First published as an Advance Article on the web 24th June 2009
DOI: 10.1039/b908754k
Achiral meteoritic amino acids, glycine and a-methylalanine,
with hydrogen isotope (D/H) chirality, acted as the source of
chirality in asymmetric autocatalysis with amplification of ee to
afford highly enantioenriched 5-pyrimidyl alkanols.
One of the most fascinating subjects about the prebiotic world is
the origin of homochirality, as in L-amino acids and D-sugars.1
According to the theory of the extraterrestrial origin of biological
homochirality, the amino acids in meteorites have been considered
to play an important role in molecular evolution2 because a
variety of prebiotic organic molecules, especially L-enriched
amino acids with only slight enantiomeric excess (ee), have been
identified.3 Their stable-isotope enrichment (2H, 13C and 15N)
supports an extraterrestrial origin for these chiral amino acids.4
On the other hand, meteorites also include achiral amino acids
such as glycine and a-methylalanine that have also been identified
as isotopically enriched relative to terrestrial compounds.4c The
dD value of Vienna standard mean ocean water of meteoritic
glycine and a-methylalanine appeared to be 399% and 3097%, in
contrast to the terrestrial biogenic compounds, which range from
350% to 50%. Although glycine and a-methylalanine composed
Fig. 1 Generation of chirality by the deuterium substitution of
enantiotopic hydrogen in glycine and a-methylalanine.
Although there are few reports on asymmetric
a
reactions,1g,5 and separation6 induced by hydrogen isotope
chirality, unlike usual chiral compounds the recognition of the
enantiomers solely as a result of isotope labeling still remains
difficult. Thus, the development of a highly sensitive method
for the detection of isotopic chirality in meteoritic organic
compounds, especially amino acids, which are identified in
carbonaceous chondrites4c with an achiral framework and
isotopic enrichment, is a challenging subject.
We and others have extensively studied asymmetric auto-
catalysis with amplification of ee.7–11 We have also reported
that the external chiral initiator,12 such as chiral natural amino
acids,12e in the reaction of pyrimidine-5-carbaldehyde and
diisopropylzinc (i-Pr2Zn) controls the absolute configuration
of the produced 5-pyrimidyl alkanols and that the ee of the
produced pyrimidyl alkanols is high, in conjunction with
asymmetric autocatalysis. Chiral deuterated primary alcohols
and carbon isotopically chiral compounds can work as chiral
triggers of this autocatalytic amplification of ee.13
We report here that the isotopically chiral glycine-a-d (1)14
and a-methyl-d3-alanine (2)15 induce the enantioselective
addition of i-Pr2Zn to pyrimidine-5-carbaldehyde 3 to afford,
in combination with asymmetric autocatalysis, pyrimidyl
alkanol 4 with significantly high ee. The absolute configuration
of the corresponding alkanol 4 was controlled efficiently by the
chirality resulting from hydrogen isotope substitution of 1 and 2
(Scheme 1). Hydrogen isotope enantiomers of compounds 1 and
2 were synthesized by a previously reported method14,15 and the
ee was determined from the 1H NMR spectrum of the camphanyl
amide of 1 and the a-methoxy-a-(trifluoromethyl)phenyl-
acetamide (MTPA amide) of 2 by the diastereomer method.
The results of asymmetric autocatalysis triggered by
isotopically chiral amino acids are summarized in Table 1.
When the i-Pr2Zn addition was performed in the presence of
the (S)-glycine-a-d (1) with an ee of 93%, the (S)-5-pyrimidyl
alkanol 4 was obtained in a 94% yield with an ee of 96%
1
of H are achiral, this is not the case of meteoritic compounds
because their hydrogen isotope ratio is high and should include
the isotopically chiral components. Deuteration of the methylene
group of glycine and one methyl group of a-methylalanine
produces the hydrogen isotopically chiral compounds glycine-a-d
1 and a-methyl-d3-alanine 2 (Fig. 1).
To the best of our knowledge, there are no reports on the
analysis of isotopic chirality of achiral meteoritic amino acids.
Analysis of the isotopic chirality in meteoritic achiral molecules
is an important subject to help understand the possible role of
these compounds as the origin of chirality. In addition, it may
expand research on the pathway by which chirality and
isotope enrichment are produced in the meteoritic compounds
in the universe.
a Department of Applied Chemistry, Tokyo University of Science,
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan.
E-mail: soai@rs.kagu.tus.ac.jp; Fax: +81 3 5261 4631;
Tel: +81 3 5228 8261
b Research Institute of Science and Technology, Tokyo University of
Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Procedures
for the asymmetric autocatalysis in the presence of 1 and 2, the
preparation of enantiomers of 1 and 2, and the determination of the
enantiomeric purity of 1 and 2. See DOI: 10.1039/b908754k
ꢀc
This journal is The Royal Society of Chemistry 2009
4396 | Chem. Commun., 2009, 4396–4398

Scheme 1 Isotopically chiral amino acid induced asymmetric autocatalysis of 5-pyrimidyl alkanol 4 in the addition of i-Pr2Zn to aldehyde 3.
Table 1 The enantioselectivity and stereochemical correlation between the hydrogen isotope chirality of achiral amino acids, i.e., glycine 1 and
a-methylalanine 2, and absolute configuration of the subsequent pyrimidyl alkanol 4
Pyrimidyl alkanol 4
Entry
Amino acida (% ee)
Yieldb (%)
eec (%)
Config.
Series I (glycine-a-d 1)d
1
2
3
4
5
6
7
8
(S)-1 (93)
(S)-1 (93)
(S)-1 (94)
(S)-1 (94)
(R)-1 (96)
(R)-1 (96)
(R)-1 (92)
(R)-1 (92)
94
98
94
95
94
94
90
93
96
95
94
93
93
91
91
92
S
S
S
S
R
R
R
R
Series II (a-methyl-d3-alanine 2)e
9f
(R)-2 (81)
95
97
94
92
99
93
84
93
99
98
96
97
98
99
97
96
S
S
S
S
R
R
R
R
10f
11
12
13f
14f
15
16
(R)-2 (81)
(R)-2 (81)
(R)-2 (81)
(S)-2 (69)
(S)-2 (69)
(S)-2 (69)
(S)-2 (69)
a
b
c
The ee of 1 and 2 were determined from the 1H NMR spectrum of the camphanyl amide of 1 and the MTPA amide of 2. Isolated yield. The ee was
d
determined using HPLC employing a chiral stationary phase. The molar ratio was 1/3/i-Pr2Zn = 0.05/1.05/2.2. The aldehyde 3 and i-Pr2Zn were
added in three separate portions. Experimental details are as follows (entry 1): i-Pr2Zn (0.15 mL of 1 M methylcyclohexane (MCH) solution, 0.15 mmol)
was added to (S)-1 (3.8 mg, 0.05 mmol) and the mixture was stirred for 12 h at room temperature. After the addition of i-Pr2Zn (0.5 mL of 1 M MCH
solution, 0.5 mmol,) at 0 1C, a MCH (2.0 mL) solution of 3 (9.4 mg, 0.05 mmol) was added over a period of 1 h and the mixture was stirred for 6 h
at 0 1C. After toluene (3.2 mL) and i-Pr2Zn (0.4 mL of 1 M toluene solution, 0.4 mmol) were added, the reaction mixture was stirred for 10 min. Then, a
toluene (1.5 mL) solution of 3 (37.6 mg, 0.2 mmol) was added over a period of 1 h at 0 1C, and the mixture was stirred for 2 h. Moreover, after toluene
(14.4 mL) and i-Pr2Zn (1.6 mL of 1 M toluene solution) were added and the mixture was stirred for 10 min, a toluene (4.0 mL) solution of 3 (150.6 mg,
0.8 mmol) was added over a period of 1 h. After stirring for 1 h, the reaction was quenched with 1 M aqueous hydrochloric acid (5 mL) at 0 1C. After
neutralization with saturated aqueous sodium hydrogen carbonate (15 mL), the mixture was filtered through Celite, and the filtrate was extracted with
ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate and evaporated in vacuo. Purification of the residue using silica
e
gel thin layer chromatography (hexane–ethyl acetate = 2/1, v/v) gave (S)-4 (229 mg, 0.9849 mmol, 96% ee) in 94% yield. The molar ratio was
f
2/3/i-Pr2Zn = 0.075/0.625/1.35. The aldehyde 3 and i-Pr2Zn were added in four separate portions. Each pair of reactions (9/13 and 10/14) was
performed using the same apparatus to exclude any effect other than that of isotopically chiral amino acid 2.
(Table 1, series I, entry 1). The results were reproducible.
Thus, (S)-4 with an ee of 95% was obtained in the presence of
(S)-1 (entry 2). The asymmetric autocatalysis using (S)-1 with
94% ee prepared in a different batch supported the reprodu-
cibility; that is, (S)-1 induces the formation of (S)-4 with high
ee (entries 3, 4). On the other hand, in the presence of the (R)-1
instead of the (S)-1 enantiomer, the reaction between aldehyde
3 and i-Pr2Zn always gave (R)-4 with an ee of 91–93% in a
yield of 90–94% (entries 5–8). These results clearly exhibit the
correlation between the chirality of the glycine-a-d (1) and the
absolute configuration of the resulting alkanol 4.
Next, we examined the highly enantioselective addition
of i-Pr2Zn to pyrimidine-5-carbaldehyde 3 using the (R)- and
(S)-a-methyl-d3-alanine (2). In the presence of (R)-a-methyl-
d3-alanine (2), (S)-5-pyrimidyl alkanol 4 was induced, and was
obtained with an ee of 96–99% (series II, entries 9–12). On the
other hand, in the presence of (S)-2, the reaction between
aldehyde 3 and i-Pr2Zn always gave (R)-alkanol 4 with an ee of
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 4396–4398 | 4397

96–99% in a yield of 84–99% (entries 13–16). To exclude any
effect other than that of the a-methyl-d3-alanine (2), both
reactions (entries 9, 13 and 10, 14) induced by (R)- and (S)-2
were performed using the same apparatus to give the (S)- and
(R)-alkanols 4, respectively.
8, 811–814; (c) R. N. Harris III, P. Sundararaman and C. Djerassi,
J. Am. Chem. Soc., 1983, 105, 2408–2413.
7 K. Soai, T. Shibata, H. Morioka and K. Choji, Nature, 1995, 378,
767–768.
8 (a) I. Sato, H. Urabe, S. Ishiguro, T. Shibata and K. Soai, Angew.
Chem., Int. Ed., 2003, 42, 315–317; (b) T. Shibata, S. Yonekubo
and K. Soai, Angew. Chem., Int. Ed., 1999, 38, 659–661;
(c) T. Shibata, H. Morioka, T. Hayase, K. Choji and K. Soai,
J. Am. Chem. Soc., 1996, 118, 471–472; (d) F. Lutz, T. Kawasaki
and K. Soai, Tetrahedron: Asymmetry, 2006, 17, 486–490.
9 (a) J. Podlech and T. Gehring, Angew. Chem., Int. Ed., 2005, 44,
5776–5777; (b) C. Bolm, F. Bienewald and A. Seger, Angew.
Chem., Int. Ed. Engl., 1996, 35, 1657–1659; (c) M. H. Todd, Chem.
Soc. Rev., 2002, 31, 211–222; (d) M. Avalos, R. Babiano, P. Cintas,
The chirality of these enantiomers is mainly due to the very
small difference between the lengths of the C–D and C–H
bonds.16 The high ee observed in the above asymmetric reactions
may be explained as follows. In the initial step of the reaction,
the isotopically chiral amino acid (or its zinc salt) induces a slight
enantiomeric imbalance in the addition of i-Pr2Zn to 3. The
resulting isopropylzinc alkoxide of 4 has a small ee, which
possesses the absolute configuration corresponding to that of
the isotopically chiral amino acid. Then, the ee is enhanced
during the subsequent asymmetric autocatalysis followed by
hydrolysis, which affords alkanol 4 with high ee.13
J. L. Jimenez and J. C. Palacios, Chem. Commun., 2000, 887–892;
´
(e) H. Buschmann, R. Thede and D. Heller, Angew. Chem., Int.
Ed., 2000, 39, 4033–4036; (f) K. Mikami and M. Yamanaka, Chem.
Rev., 2003, 103, 3369–3400; (g) I. D. Gridnev, Chem. Lett., 2006,
´
35, 148–153; (h) L. Caglioti, C. Zucchi and G. Palyi, Chim. Oggi,
2005, 23, 38–43.
10 (a) K. Soai, T. Shibata and I. Sato, Bull. Chem. Soc. Jpn., 2004, 77,
1063–1073; (b) K. Soai, T. Shibata and I. Sato, Acc. Chem. Res.,
2000, 33, 382–390; (c) K. Soai and T. Kawasaki, Chirality, 2006,
18, 469–478; (d) K. Soai and T. Kawasaki, Top. Curr. Chem., 2008,
284, 1–33; (e) K. Soai and T. Kawasaki, in Organometallic
Chirality, ed. G. Palyi, C. Zucchi and L. Caglioti, Mucchi Editore,
Modena, 2008, ch. 6, pp. 107–125.
In conclusion, the enantioselective addition of i-Pr2Zn to
pyrimidine-5-carbaldehyde 3 was achieved by utilizing the
hydrogen isotopic chirality of achiral amino acids, that is,
glycine-a-d (1) and a-methyl-d3-alanine (2). The observed ee of
the produced pyrimidyl alkanol 4 was amplified up to 99% ee
in conjunction with asymmetric autocatalysis. This is the
first example of a highly enantioselective reaction induced by
the chirality resulting from deuterium substitution of amino
acids, which are detected in meteorites as achiral isotopically
enriched molecules. We believe that the asymmetric autocatalysis
significantly increases the value of the implications of isotope
substitution in achiral meteoritic amino acids in the study of the
origin and prebiotic evolution of biological homochirality.
11 (a) I. Sato, D. Omiya, H. Igarashi, K. Kato, Y. Ogi, K. Tsukiyama
and K. Soai, Tetrahedron: Asymmetry, 2003, 14, 975–979;
(b) I. D. Gridnev, J. M. Serafimov and J. M. Brown, Angew.
Chem., Int. Ed., 2004, 43, 4884–4887; (c) D. G. Blackmond, Proc.
Natl. Acad. Sci. U. S. A., 2004, 101, 5732–5736; (d) J. R. Islas,
D. Lavabre, J.-M. Grevy, R. H. Lamoneda, H. R. Cabrera,
J.-C. Micheau and T. Buhse, Proc. Natl. Acad. Sci. U. S. A.,
2005, 102, 13743–13748; (e) Y. Saito and H. Hyuga, J. Phys. Soc.
Jpn., 2004, 73, 33–35; (f) G. Lente, J. Phys. Chem. A, 2005, 109,
11058–11063; (g) K. Micskei, G. Pota, L. Caglioti and G. Palyi,
J. Phys. Chem. A, 2006, 110, 5982–5984; (h) J. Klankermayer,
I. D. Gridnev and J. M. Brown, Chem. Commun., 2007, 3151;
(i) F. Lutz, T. Igarashi, T. Kawasaki and K. Soai, J. Am. Chem.
Soc., 2005, 127, 12206–12207; (j) F. Lutz, T. Igarashi,
T. Kinoshita, M. Asahina, K. Tsukiyama, T. Kawasaki and
K. Soai, J. Am. Chem. Soc., 2008, 130, 2956–2958;
(k) J. M. Brown, I. Gridnev and J. Klankermayer, Top. Curr.
Chem., 2008, 284, 35–65; (l) D. Lavabre, J.-C. Micheau, J. R. Islas
and T. Buhse, Top. Curr. Chem., 2008, 284, 67–96; (m) Y. Saito and
H. Hyuga, Top. Curr. Chem., 2008, 284, 97–118; (n) L. Schiaffino
and G. Ercolani, Angew. Chem., Int. Ed., 2008, 47, 6832–6835.
12 (a) T. Shibata, J. Yamamoto, N. Matsumoto, S. Yonekubo,
S. Osanai and K. Soai, J. Am. Chem. Soc., 1998, 120,
12157–12158; (b) K. Soai, S. Osanai, K. Kadowaki,
S. Yonekubo, T. Shibata and I. Sato, J. Am. Chem. Soc., 1999,
121, 11235–11236; (c) T. Kawasaki, M. Sato, S. Ishiguro, T. Saito,
Y. Morishita, I. Sato, H. Nishino, Y. Inoue and K. Soai, J. Am.
Chem. Soc., 2005, 127, 3274–3235; (d) T. Kawasaki, H. Tanaka,
T. Tsutsumi, T. Kasahara, I. Sato and K. Soai, J. Am. Chem. Soc.,
2006, 128, 6032–6033; (e) I. Sato, Y. Ohgo, H. Igarashi,
D. Nishiyama, T. Kawasaki and K. Soai, J. Organomet. Chem.,
2007, 692, 1783–1787; (f) T. Kawasaki, K. Suzuki, Y. Hakoda and
K. Soai, Angew. Chem., Int. Ed., 2008, 47, 496–499;
(g) T. Kawasaki, T. Omine, K. Suzuki, H. Sato, A. Yamagishi
and K. Soai, Org. Biomol. Chem., 2009, 7, 1073–1075.
Notes and references
1 (a) K. Mislow, Collect. Czech. Chem. Commun., 2003, 68, 849–864;
(b) B. L. Feringa and R. A. van Delden, Angew. Chem., Int. Ed.,
1999, 38, 3418–3438; (c) M. Bolli, R. Micula and A. Eschenmoser,
Chem. Biol., 1997, 4, 309–320; (d) W. A. Bonner, Origins Life
Evol. Biosphere, 1995, 25, 175–190; (e) C. Girard and H. B. Kagan,
Angew. Chem., Int. Ed., 1998, 37, 2923–2959; (f) H. Zepik,
E. Shavit, M. Tang, T. R. Jensen, K. Kjaer, G. Bolbach,
L. Leiserowitz, I. Weissbuch and M. Lahav, Science, 2002, 295,
1266–1269; (g) M. M. Green, J.-W. Park, T. Sato, A. Teramoto,
S. Lifson, R. L. B. Selinger and J. V. Selinger, Angew. Chem., Int.
Ed., 1999, 38, 3139–3154; (h) J. M. Ribo
J. M. Claret and R. Rubires, Science, 2001, 292, 2063–2066;
(i) B. Barabas, L. Caglioti, K. Micskei, C. Zucchi and G. Palyi,
´
, J. Crusats, F. Sagues,
´
´
Origins Life Evol. Biosphere, 2008, 38, 317–327; (j) A. Guijarro and
M. Yus, The Origin of Chirality in the Molecules of Life, The Royal
Society of Chemistry, Cambridge, 2009.
2 (a) W. Notz and B. List, J. Am. Chem. Soc., 2000, 122, 7386–7387;
(b) S. Pizarello and A. L. Weber, Science, 2004, 303, 1151–1151;
(c) A. Cordova, M. Engqvist, I. Ibrahem, J. Casas and H. Sunden,
´ ´
Chem. Commun., 2005, 2047–2049.
3 (a) K. Kvenvolden, Nature, 1970, 228, 923–926; (b) J. R. Cronin
and S. Pizzarello, Science, 1997, 275, 951–955; (c) M. H. Engel and
B. Nagy, Nature, 1982, 296, 837–840; (d) D. O. Glavin and
J. P. Dworkin, Proc. Natl. Acad. Sci. U. S. A., 2009, 106,
5487–5492.
4 (a) S. Epstein, R. V. Krishnamurthy, J. R. Cronin, S. Pizzarello
and G. U. Yuen, Nature, 1987, 326, 477–479; (b) M. H. Engel and
S. A. Macko, Nature, 1997, 389, 265–268; (c) S. Pizzarello and
Y. Huang, Geochim. Cosmochim. Acta, 2005, 69, 599–605.
5 (a) H. Pracejus, Tetrahedron Lett., 1966, 7, 3809–3813;
(b) A. Horeau, A. Nouaille and K. Mislow, J. Am. Chem. Soc.,
1965, 87, 4957–4958.
13 (a) I. Sato, D. Omiya, T. Saito and K. Soai, J. Am. Chem. Soc.,
2000, 122, 11739–11740; (b) T. Kawasaki, Y. Matsumura,
T. Tsutsumi, K. Suzuki, M. Ito and K. Soai, Science, 2009, 324,
492–495.
14 (a) J. R. Walker and W. Curley, Jr., Tetrahedron, 2001, 57,
6695–6701; (b) R. M. Williams, D. Zhai and Peter J. Sinclair,
J. Org. Chem., 1986, 51, 5021–5022.
15 cf. D. Seebach and A. Fadel, Helv. Chim. Acta, 1985, 68,
1243–1250.
16 (a) L. S. Bartell, E. A. Roth, C. D. Hollowell, K. Kuchitsu and
J. E. Young, Jr., J. Chem. Phys., 1965, 42, 2683–2686;
(b) L. S. Bartell and R. R. Roskos, J. Chem. Phys., 1966, 44,
457–463.
6 (a) K. Kimata, M. Kobayashi, K. Hosoya, T. Araki and
N. Tanaka, J. Am. Chem. Soc., 1996, 118, 759–762;
(b) W. H. Pirkle and K. Z. Gan, Tetrahedron: Asymmetry, 1997,
ꢀc
This journal is The Royal Society of Chemistry 2009
4398 | Chem. Commun., 2009, 4396–4398