Scheme 3 Amino ester catalysed formation of a cyclic acetal.
Scheme 4 Amino ester catalysed formation of (D)-threose.
pH = 7 buffered conditions, the % enantiomeric excess of
the (L)-erythrose product 2-anti was dramatically increased
(46% ee) and the anti : syn ratio was improved to 5.5 : 1.
Although the isolated yield was still moderate (52%) the mass
balance of the reaction was unreacted starting aldehyde.
In contrast to the results observed previously, only a small
amount of the anti-aldol dimer was produced (10–11%) when
using the straight chain (icosyl) ester catalyst 10 under either
the buffered or unbuffered conditions. The major product
produced in both cases (entries 5 and 6, Table 2) was the
unusual acetal product 8 which is effectively a trimer of the
aldehyde starting material. Although the formation of this
product was unexpected, especially at pH = 7, its production
from the initially formed anti-aldol dimer 2-anti can obviously
be explained by invoking a simple acetalisation process
(Scheme 3).
predominating. This is the highest asymmetric induction reported
for the direct aldol dimerisation of unprotected glycolaldehyde
13, in either aqueous or organic solvents, and represents a
dramatic improvement over the 10% ee originally reported in
the work of Pizzarello and Weber, while additionally offering
the potential to account for the link between (L)-amino acids
and (D)-carbohydrates.
Notes and references
1 A. Jorissen and C. Cerf, Origins Life Evol. Biosphere, 2002, 32,
129–142.
2 R. Root-Bernstein, BioEssays, 2007, 29, 689–698.
3 Z. Martins, O. Botta, M. L. Fogel, M. A. Sephton, D. P. Glavin,
J. S. Watson, J. P. Dworkin, A. W. Schwartz and P. Ehrenfreund,
Earth Planet. Sci. Lett., 2008, 270, 130–136.
4 S. L. Miller and H. C. Urey, Science, 1959, 130, 245–251.
5 S. Pizzarello and A. L. Weber, Science, 2004, 303, 1151.
6 J. Kofoed, J.-L. Reymond and T. Darbre, Org. Biomol. Chem.,
2005, 3, 1850.
7 B. List, R. A. Lerner and C. F. Barbas III, J. Am. Chem. Soc.,
2000, 122, 2395–2396.
8 K. Sakthivel, W. Notz, T. Bui and C. F. Barbas III, J. Am. Chem.
Soc., 2001, 123, 5260–5267.
9 B. List, L. Hoang and H. J. Martin, Proc. Natl. Acad. Sci. U. S. A.,
2004, 101, 5839–5842.
10 B. List, Tetrahedron, 2002, 58, 5573–5590.
11 A. B. Northrup, I. K. Mangion, F. Hettche and D. W. C.
MacMillan, Angew. Chem., Int. Ed., 2004, 43, 2152–2154.
12 A. B. Northrup and D. W. C. MacMillan, Science, 2004, 305,
1752–1755.
As we do not see the acetal product 8 in any of the other
aldol dimerisations described above, we believe that the acetal
8 is formed from the anti-aldol dimer 2-anti by reaction with
the catalyst-derived iminium ion 11 rather than by reaction
directly with TIPS-glycolaldehyde 1 present in the reaction
mixture. The reason for why the long-chain isocosyl ester
catalyst 10 prefers this reaction manifold rather than stopping
at the aldol dimer 2-syn/2-anti is not yet clear, but this result is
reproducible and is not pH dependent.
Having demonstrated that amino acid-derived ester catalysts
are capable of performing aldol dimerisations of TIPS-glycol-
aldehyde 1 in water, we next examined the aldol dimerisation
of glycolaldehyde 13 itself under our optimised conditions.
The N-methyl leucine ethyl ester catalyst 7 was chosen for this
purpose as it provided the best compromise between yield and
% enantiomeric excess of the tetrose products under neutral
reaction conditions. Thus, an aqueous solution of glycolaldehyde
dimer 12 was buffered to pH = 7 as previously described, and
N-methyl leucine ethyl ester 7 (10 mol%) was added and the
mixture was stirred vigorously for 5 hours (Scheme 4).
Due to the high polarity and water solubility of the unprotected
tetrose products (erythrose 14 and threose 15), we decided to
reduce the crude reaction mixture (NaBH4, MeOH) to afford
erythritol 16 and threitol 17, which were then acetylated with
excess acetic anhydride to afford the corresponding tetra-
acetylated products 18 and 19 in a 8 : 1 ratio.16 The meso com-
pound 18 corresponds to the anti-aldol product (erythrose 14)
and the C2-symmetric compound 19 corresponds to the
syn-aldol product (threose 15), and pleasingly the threose derived
tetra-acetate 19 was produced in 68% ee with (D)-threitol
13 A. Co
Chem. Commun., 2005, 2047–2049.
14 A. Cordova, W. Notz and C. F. Barbas III, Chem. Commun., 2002,
rdova, M. Engqvist, I. Ibrahem, J. Casas and H. Sunden,
´ ´
´
3024–3025.
15 N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka
and C. F. Barbas III, J. Am. Chem. Soc., 2006, 128, 734–735.
16 A. Cordova, I. Ibrahem, J. Casas, H. Sunden, M. Engqvist and
´ ´
E. Reyes, Chem.–Eur. J., 2005, 11, 4772–4784.
17 J. Mlynarski and J. Paradowska, Chem. Soc. Rev., 2008, 37,
1502–1511.
18 F. Rodrıguez-Llansola, J. F. Miravet and B. Escuder, Chem.
´
Commun., 2009, 7303–7305.
19 M. De Nisco, S. Pedatella, H. Ullah, J. H. Zaidi, D. Naviglio,
¨
¨
O. Ozdamar and R. Caputo, J. Org. Chem., 2009, 74, 9562–9565.
20 N. Mase, N. Noshiro, A. Mokuya and K. Takabe, Adv. Synth.
Catal., 2009, 351, 2791–2796.
21 A. P. Brogan, T. J. Dickerson and K. D. Janda, Angew. Chem.,
Int. Ed., 2006, 45, 8100–8102.
22 Y. Hayashi, Angew. Chem., Int. Ed., 2006, 45, 8103–8104.
23 T. J. Dickerson and K. D. Janda, J. Am. Chem. Soc., 2002, 124,
3220–3221.
24 C. J. Rogers, T. J. Dickerson, A. P. Brogan and K. D. Janda,
J. Org. Chem., 2005, 70, 3705–3708.
25 S. Aratake, T. Itoh, T. Okano, T. Usui, M. Shoji and Y. Hayashi,
Chem. Commun., 2007, 2524.
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This journal is The Royal Society of Chemistry 2010
4778 | Chem. Commun., 2010, 46, 4776–4778