majority of metal (M)/ligand (L) chiral amplification systems are
ML2 although recently an efficient ML3 system has been
reported.11 In terms of this nomenclature, poly-leucine is acting
as an L5 catalyst and is thus the first metal-free chiral amplification
system and the most complex based on number of components.
The application of Bernoullian analysis to the formation of
scalemic peptides has been criticised for creating a ‘‘hopeless
quagmire of undesired and inconsequential diastereoisomers’’.12
Judged from the viewpoint of unique peptides acting as catalysts
this statement is true. However based on a single catalytic site, the
proportion of catalytically active material is independent of the
degree of polymerisation because the probability of appending
additional residues to a putative catalytic site is always 1. Therefore
the enantiomeric excess only depends on the number of residues in
the catalytic site for monomer of a given enantiomeric purity.
The formation of a homochiral catalytic site is a prerequisite for
the efficient development of this form of enantioselective catalysis.
Consider a putative catalytic site sequence LDLD and its enantiomer
DLDL. Since both of these contain an identical number of each
enantiomer of the residues, no matter what the relative proportion
of the monomers, there will always be equal amounts of the two
catalytic sites.
Table 2 Predicted percentage enantiomeric excess and percentage
active catalyst for unique catalytic sites containing n homochiral
residues prepared from monomers of four enantiomeric purities
Ratio, % ee of monomers
1.1:1, 4.76
eea Cat.b
1.2:1, 9.1
ee Cat.
9.1 100
1.5:1, 20
2.5:1, 42.9
n
ee
Cat.
ee
Cat.
1
2
3
4
5
6
7
8
4.76 100
20
100
52
28
15.5
42.9
72.4
87.9
95
97.97
99.18
100
59.2
9.5
14.2
18.8
23.4
27.8
32.2
36.4
50.1
25.2
12.7
6.39 42.7
3.23 49.8
1.64 56.4
0.83 62.3
18.0
26.7
34.9
50.4
25.6
13.1
38.5
54.3
67.0
76.7
83.9
88.9
38.8
26.7
18.8
13.3
9.5
6.77
3.53
1.84
8.8
5.1
2.96 99.67
1.75 99.86
0.966 92.5
6.78
a ee is the percentage enantiomeric excess of catalytic sites. b Cat. is
the percentage of catalyst in the mixture of oligomers.
Any proposal about the origin of life must necessarily be
speculative, however the results presented here provide an example
whereby a modest enantiomeric excess of a monomeric unit is
translated into oligomers expressing appreciable highly enantio-
selective catalytic activity.
Notes and references
1 B. L. Feringa and R. A. van Delden, Angew. Chem., Int. Ed., 1999, 38,
3418.
2 J. Jacques, A. Collet and S. H. Wilen, Enantiomers, Racemates and
Resolutions, Wiley Interscience, New York, 1981, pp. 53–88.
3 P. A. Bentley, R. W. Flood, S. M. Roberts, J. Skidmore, C. B. Smith and
J. A. Smith, Chem. Commun., 2001, 1616.
4 1,3-Diaminopropane (8.1 ml, 0.2 mmol) was added dropwise to L-Leu-
NCA (0.8 g, 5.1 mmol) and D-Leu-NCA (1.2 g, 7.6 mmol) in THF
(30 ml) which was stirred under a nitrogen atmosphere for 4 days. The
white solid was filtered off, extracted with the following solvents (50 ml)
for 30 min each: water, acetone–water (1:1), acetone–water (4:1), acetone
(62), ethyl acetate (62) and diethyl ether (62), and dried under high
vacuum overnight (1.25 g, 87%).
5 If a peptide chain has an N-terminal L-residue, will it preferentially react
with a L-NCA monomer or a D-NCA monomer? Most studies indicate
that there is a weak preference for homocoupling: T. Hitz and P. L. Luisi,
Helv. Chim. Acta, 2002, 85, 3975; H. R. Kricheldorf and T. Mang,
Makromol. Chem., 1981, 182, 3077.
6 A similar analysis of two-step reactions was made by K. Soai, H. Hori
and M. Kawahara, J. Chem. Soc., Chem Commun., 1992, 106, and
(added after submission) for polymerisations: T. H. Hitz and P. L. Luisi,
Origins Life Evol. Biosphere, 2004, 34, 93.
7 This analysis is fundamentally the same as that proposed by Kagan:
D. Guillaneux, S.-H. Zhao, O. Samuel, D. Rainford and H. B. Kagan,
J. Am. Chem. Soc., 1994, 116, 9430, but we are proposing a new way to
calculate the proportions of the homo- and hetero-chiral constituents
(Kagan’s a and b variables).
8 The permutation was implemented by converting decenary numbers to
binary numbers in the range 0 to 231 2 1. The standard binary numbers
were padded with zeros on the left and converted to 31 character strings,
in which 0 represents the L-enantiomer and 1 the D-enantiomer. The
individual examples were extracted (Right$) and analysed using standard
string commands. A Microsoft1 Visual Basic 3.0 program, in which
chain length, catalytic site length and enantiomeric excess are definable
variables is available from D. R. K. All other calculations were
performed in Microsoft1 Excel.
9 A. Berkessel, N. Gasch, K. Glaubitz and C. Koch, Org. Lett., 2001, 3,
3839.
10 Described in the previous paper in this issue.
11 H. Furano, T. Hanamoto, Y. Sugimoto and J. Inanaga, Org. Lett., 2000,
2, 49.
12 W. A. Bonner, Origins Life Evol. Biosphere, 1999, 29, 615.
Fig. 1 Percentage catalyst and percentage enantiomeric excess of unique
catalytic sites as a function of the number of monomer units prepared from
monomers of four enantiomeric purities (cf. Table 2).8
the amount of catalyst decreases more slowly because it is a sum of
powers.7 Application of this analysis to longer oligomers and
various enantiomeric ratios (those in Table 1) are shown in Table 2
and Fig. 1.
Comparison of the data in the tables and Fig. 1 shows that the
observed enantiomeric excesses for the epoxidation of chalcone and
those predicted for a catalytic site composed of five residues are
identical within experimental error. A catalytic site composed of
five homochiral units is in perfect agreement with studies of short
oligomers bound to PEG9 and our molecular model for the active
site,10 which requires five terminal homochiral residues. The vast
2 0 2 2
C h e m . C o m m u n . , 2 0 0 4 , 2 0 2 1 – 2 0 2 2