Asymmetric organocatalytic formation of protected and unprotected tetroses under potentially prebiotic conditions

Article abstract of DOI:10.1039/c1ob06798b

Esters of proteinogenic amino acids efficiently catalyse the formation of erythrose and threose under potentially prebiotic conditions in the highest yields and enantioselectivities yet reported. Remarkably while esters of (l)-proline yield (l)-tetroses, esters of (l)-leucine, (l)-alanine and (l)-valine generate (d)-tetroses, offering the potential to account for the link between natural (l)-amino acids and natural (d)-sugars. The effect of pH and NaCl on the yields and enantioselectivities was also investigated and was shown to be significant, with the optimal enantioselectivities occurring at pH 7.

Full text of DOI:10.1039/c1ob06798b

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PAPER
Asymmetric organocatalytic formation of protected and unprotected tetroses
under potentially prebiotic conditions†‡
Laurence Burroughs,a Paul A. Clarke,*a Henrietta Forintos,b James A. R. Gilks,b Christopher J. Hayes,*b
Matthew E. Vale,a,b William Wadea and Myriam Zbytniewskia
Received 26th October 2011, Accepted 10th November 2011
DOI: 10.1039/c1ob06798b
Esters of proteinogenic amino acids efficiently catalyse the formation of erythrose and threose under
potentially prebiotic conditions in the highest yields and enantioselectivities yet reported. Remarkably
while esters of (L)-proline yield (L)-tetroses, esters of (L)-leucine, (L)-alanine and (L)-valine generate
(D)-tetroses, offering the potential to account for the link between natural (L)-amino acids and natural
(D)-sugars. The effect of pH and NaCl on the yields and enantioselectivities was also investigated and was
shown to be significant, with the optimal enantioselectivities occurring at pH 7.
in terms of both the yield and enantioselectivity of the carbo-
hydrates formed. In a report by Pizzarello and Weber they
Introduction
One of the fundamental questions in the chemical and biological
sciences is how did the reasonably complex building blocks of
life, such as carbohydrates, form in the absence of any biological
processes; and how did one enantiomer of these molecules come
to dominate? In an important recent study, Sutherland has shown
that RNA nucleotides can be prepared under plausible prebiotic
conditions,1 but this work requires glyceraldehyde to be present
as a potential starting material. It has been suggested that the
autocatalytic formation of glyceraldehyde from glycolaldehyde
and formaldehyde in the presence of Ca(OH)2 or other group II
hydroxides (the formose reaction)2 could be a possible route, as
higher carbohydrates such as the tetroses and the pentoses have
been detected in the reaction.3,4 However, the formose reaction
is inefficient in the formation of these higher carbohydrates as
the basic reaction conditions lead to decomposition. Further-
more, it does not explain the emergence of homochirality in
higher carbohydrates, although the recent work of Blackmond
and Breslow provides insight into this problem.5
demonstrated that the non-proteinogenic amino acid isovaline
(100% ee) was able to catalyze the dimerization of glycolalde-
hyde in water, generating threose and erythrose products with
enantiomeric excesses between 5–12%, although no yields were
given.6a They also reported that dipeptides were also capable of
catalyzing this reaction over extended reaction times at pH = 5.4
in higher enantioselectivities and yields.6b Zinc-proline com-
plexes have also been reported to catalyze this dimerization and
trimerization reaction in water, although the yields were low and
no enantioselectivities were reported.7
Recently the pioneering studies of Barbas, List, MacMillan
and Cordova have all independently shown that high enantios-
electivities can be achieved in the aldol dimerization of alde-
hydes, including protected glycolaldehyde, in organic solvents
using proline (100% ee) as a catalyst.8–14 However, these reac-
tions are nowhere near as successful in water, which must be
viewed as the solvent for any prebiotic formation of carbo-
hydrates.12,13 In addition to this work, several groups have
reported studies in which water was added to an organocatalytic
aldol reaction in organic solvents.15–26 In most cases that we are
aware of the amount of water introduced is a relatively small
quantity when compared to either the organic solvent or one of
the aldol partners. Nonetheless, these studies have sparked some
interesting debates on the nature of ‘aqueous reactions’.22,23 In a
departure from the use of amino acids, Janda has shown that nic-
otine24 and C2-aromatic substituted pyrrolidines are effective
aldol-catalysts in water. Interestingly they showed that the best
catalysts have electron-withdrawing substituents on the aromatic
portion, although so far only racemic studies have been
reported.25
An alternative mechanism for the formation of carbohydrates,
and one which can in theory generate enantiomeric enriched pro-
ducts, is the organocatalytic dimerization and trimerization of
glycolaldehyde in water. However, this process is very inefficient
aDepartment of Chemistry, University of York, Heslington, York, North
Yorks, UK, YO10 5DD. E-mail: paul.clarke@york.ac.uk
bSchool of Chemistry, University of Nottingham, University Park,
Nottingham, Notts, UK, NG7 2RD. E-mail: chris.hayes@nottingham.ac.
uk
†Electronic supplementary information (ESI) available: Experimental
procedures for the preparation of compounds not detailed in the exper-
imental section. Spectroscopic characterization of compounds not
detailed in the experimental section. See DOI: 10.1039/c1ob06798b
‡This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
We were intrigued by these reports and the lack of any
efficient asymmetric organocatalytic process for the formation of
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1565–1570 | 1565

Table 1 (L)-proline ester catalyzed formation of TIPS-protected
tetroses in water
carbohydrates in water, and so we set out to develop a simple,
organocatalytic, high yielding, enantioselective and potentially
prebiotic formation of tetroses in water. In light of the fact that
proline is an excellent catalyst for the desired aldol dimerization
in organic solvents, we wondered if simple modifications could
be made to proline to enable it to efficiently catalyze the reaction
in water. It is known that the carboxylic acid group of proline
plays a key hydrogen-bonding role during the catalytic aldol
reaction in organic solvents,8 and this interaction will almost cer-
tainly be lost in aqueous conditions, which no doubt accounts
for its lack of catalytic activity in water. We wondered whether
simple esters of proline could act as aldol catalysts in water, as
the resulting pyrrolidine would bear an electron-withdrawing
substituent at C2, similar to the aromatic substituted catalysts of
Janda.
Major
Combined
yield (%)
Ratio
% ee
Entry Catalyst productc
(anti : syn)d
(anti)e
1a
2a
3a
4b
5b
6b
3
4
5
5
6
7
(L)-2-anti
(L)-2-anti
(L)-2-anti
(L)-2-anti
(L)-2-anti
8
68
57
80
77
49
40f
4.5 : 1
4 : 1
15
22
15
1.5 : 1
1.5 : 1
2 : 1
18
10
N/Ag
17h
a Reaction time 48 h. b Reaction time
5
h. c Major enantiomer
determined by correlation to the work of Northrup and MacMillan (ref.
13). d Determined by integration of the aldehyde resonances in the 1H
NMR. e See supporting information.† f Isolated yield of acetal 8. g 10%
of 2-anti was also formed. h % ee of acetal 8.
Initially the reactions were run for 48 h (entries 1–3), but that
could be shortened to 5 h (entries 4, 5) without detriment to the
yield or stereoselectivity of the reaction. It is worth noting that
this level of enantioselectivity is slightly better than that reported
by Pizzarello and Webber in their earlier work.6a Interestingly
when catalyst 7 was employed (entry 6) the major product was
not the tetrose product (the anti-aldol dimer accounted for only
10% of the product), but acetal 8. Acetal 8 is effectively a trimer
of TIPS-glycolaldehyde 1, and its formation was unexpected. It
is obviously produced by the reaction of the initially formed
anti-aldol dimer 2-anti and another equivalent of 1 by an acetali-
zation process. While these acetals have been isolated before in
organocatalytic aldol reaction in organic solvents, notably by
MacMillan,28 it is surprising that they form so readily and in
such high yields in an aqueous media. As we do not see for-
mation of acetal 8 with any of the other catalysts, we believe that
8 is formed from 2-anti by reaction with the catalyst-derived
iminium ion 9, rather than by reaction with 1 directly
(Scheme 1).
Results and discussion
Our initial studies27 focused on the dimerization of TIPS-
protected glycolaldehyde. We chose this as our initial substrate
for several reasons. Firstly, this aldehyde had been used by Mac-
Millan in his work on the organocatalytic formation of sugars in
organic solvents, and as such the products had been fully charac-
terized, including the analysis of the enantioselectivities.13 Sec-
ondarily, the reactions of protected versions of glycolaldehyde
would be easier to monitor and their products easier to isolate.
Thirdly, the experience gained in studying the TIPS-protected
glycolaldehyde 1 reaction would be invaluable for when we
started to investigate the aldol reaction of unprotected glycolal-
dehyde. The initial catalysts we alighted upon were the commer-
cially available methyl 3, ethyl 4 and benzyl 5 esters of (L)-
proline. Additionally, we also synthesized the heneicosyl 6 and
icosyl 7 esters of (L)-proline as Barbas had demonstrated that
increasing the local hydrophobic environment of the catalyst led
to enhanced enantioselectivities in some of the aldol reactions he
had carried out in mixed organic/aqueous systems.16 The henei-
cosyl 6 and icosyl 7 esters were prepared by the EDCI mediated
coupling of Boc-(L)-proline with the appropriate alcohol. With
all five catalysts in hand we examined their efficiency at catalyz-
ing the aqueous aldol dimerization of TIPS-glycolaldehyde 1
in water. We were pleased to find that these (L)-proline esters
catalyzed the reaction efficiently, giving tetrose products in good
isolated yields with moderate diastereoselectivity and enantios-
electivity (Fig. 1, Table 1).
Scheme 1 (L)-Proline icosyl ester catalyzed formation of cyclic
acetal 8.
Having demonstrated that esters of (L)-proline were able to cat-
alyze the aldol dimerization of 1, we wondered if esters of other
proteinogenic amino acids could also catalyze this reaction. As
the key intermediate in the aldol dimerization reaction is the for-
mation of a reactive enamine intermediate, we were concerned
that other amino acid esters may not be as efficient as proline in
this reaction as they contain primary amine groups which may
stall the reaction due to the catalyst being trapped as an imine or
hemiaminal. In order to obviate this possibility we decided
to synthesize N-methyl derivatives of amino acid esters of
(L)-alanine 10, (L)-leucine 11 and (L)-valine 12 (Scheme 2).
Fig. 1 (L)-proline ester catalyzed dimerization and trimerization of
TIPS-glycolaldehyde in water.
1566 | Org. Biomol. Chem., 2012, 10, 1565–1570
This journal is © The Royal Society of Chemistry 2012

Table 2 (L)-N-Methyl-amino acid ester catalyzed formation of TIPS-
protected tetroses in water
Table 3 (L)-Amino acid ester catalyzed formation of TIPS-protected
tetroses in water and pH = 7 buffer
Major
Combined
yield (%)
Ratio
% ee
Major
Combined
yield (%)
Ratio
% ee
Entry Catalyst producta
(anti : syn)b
(anti)c
Entry Catalyst productb
(anti : syn)c
(anti)d
1
2
3
10
11
12
(D)-2-anti 70
(D)-2-anti 80
(D)-2-anti 33
3 : 1
1.5 : 1
1 : 1
7
17
31
1a
2a
3a
4a
5a
5
6
7
11
12
(L)-2-anti
(L)-2-anti
8
(D)-2-anti 79
(D)-2-anti 40
70
1.5 : 1
5.5 : 1
N/A
1.5 : 1
1.5 : 1
47
46
23f
57
79
52
32e
a Major enantiomer determined by correlation to the work of Northrup
and MacMillan (ref. 13). b Determined by integration of the aldehyde
resonances in the 1H NMR. c See supporting information.†
a Reaction time 5 h. b Major enantiomer determined by correlation to the
work of Northrup and MacMillan (ref. 13). c Determined by integration
of the aldehyde resonances in the 1H NMR. d See supporting
information.† e Isolated yield for acetal 8. f % ee of acetal 8.
Scheme 2 Synthesis of catalysts 10, 11 and 12.
Catalysts 10, 11 and 12 were prepared by Boc-protection of
the ethyl ester of the appropriate amino acid with Boc2O fol-
lowed by deprotonation of the carbamate nitrogen and trapping
the anion with methyl iodide. The catalyst was then revealed
by TFA-mediate deprotection which provided 10, 11 and 12 in
42%, 53% and 49% overall yields respectively. These catalysts
were then tested in the dimerization reaction of 1 in water over
5 h (Table 2).
Fig. 2 pH of aldol reaction of TIPS-glycolaldehyde 1 catalyzed by (L)-
proline benzyl ester.
Catalysts 10 and 11 catalyzed the reaction in moderate to good
yields and diastereoselectivities, with enantioselectivities of the
same numerical magnitude as the (L)-proline ester catalysts 3–6
(entries 1 and 2). The (L)-valine derived catalyst 12 catalyzed the
reaction in lower yield and diastereoselectivity, but with an enan-
tioselectivity nearly double that of the (L)-leucine derived cata-
lyst 11 (entry 3) or over four times that of the (L)-proline derived
catalysts (Table 1). This is the largest % ee to date reported for
the dimerization of 1 in water with an amino acid derivative as
catalyst. Surprisingly however, it was the (D)-enantiomer of ery-
throse (D)-2-anti which was generated as the major enantiomer in
these reactions. This is in contrast to the reaction run with cata-
lysts derived from (L)-proline which generated (L)-erythrose (L)-
2-anti as the major product. This switch from (L)-erythrose with
(L)-proline catalysts to (D)-erythrose with (L)-alanine, (L)-leucine
and (L)-valine marks an unexpected and significant switch in the
enantiomer of the product generated.
Janda has pointed out that general base catalysis of the aldol
dimerization may operate when amine-based catalysts are used in
aqueous media,22 and this could well lead to a reduction in the
enantioselectivity seen. We wished to explore the influence of
pH on the reaction and decided to monitor the pH of the aldol
dimerization reaction and to run the reaction at both pH = 6,
which should be optimal for enamine formation, and pH = 7. At
pH = 6 there should be no general base catalysis, however, some
acid catalysis may operate. At pH = 7 there should be no general
base or acid catalysis and so the yields and enantioselectivities
should result from an enamine catalyzed process. The benzyl
ester of (L)-proline 5 was chosen as the catalyst for these studies.
The first reaction repeated the conditions reported in Table 1,
entry 5 and the pH was monitored over the 48 h period. From
the pH profile (Fig. 2) it can be clearly seen that the pH at the
start of the reaction is basic (pH = 8.5) and that it increases to a
maximum (pH = 8.8) after approximately 5 h. After this time the
pH drops steadily to a final pH = 7.8 after 48 h. These obser-
vations clearly demonstrated that a general base mediated aldol
reaction could be in operation under these conditions. We next
decided to run the dimerization of 1 in the presence of KH2PO4/
NaOH buffered to pH = 7 and use each of the available catalysts
3–7 and 10–12 (Table 3).
We were please to find that under these buffered conditions
we still obtained good yields of tetrose products 2-syn and 2-
anti. More importantly, however, was the increase in enantios-
electivity of the reactions, with the % ee of each of the buffered
reactions being substantially higher than the comparative unbuf-
fered reactions. In the case of catalysts 5 and 6 the % ee
increased from 18% to 47% to 10% to 46% respectively (entries
1 and 2). The biggest increase in enantioselectivity was seen
with catalyst 11 which in the unbuffered reaction gave the
product with a 17% ee and in the pH = 7 buffered reaction gen-
erated product with a 57% ee (entry 4). The reaction with the
highest enantioselectivity used (L)-valine derived catalyst 12
which in the pH = 7 buffered reaction returned a product with an
impressive 79% ee (entry 5), compared to 31% ee from the
unbuffered reaction. Significantly, (L)-proline catalysts 5 and 6
still produced (L)-erythrose as the major enantiomer, while (L)-
leucine and (L)-valine catalysts still produced (D)-erythrose as the
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1565–1570 | 1567

Table 4 (L)-Amino acid ester catalyzed formation of TIPS-protected
tetroses in water and pH = 6 buffer
2-anti produced. The enantioselectivities were lower than those
that had been seen for the pH = 7 buffered reaction, but were in
general higher than for the unbuffered reaction. No acetal 8 for-
mation was seen at pH = 6 when catalyst 7 was used, with the
reaction returning tetrose products in yields and enantioselectiv-
ities comparable to the other catalysts in this set of reactions.
The final set of reaction conditions we examined was running
the aldol dimerization of 1 in unbuffered brine in an attempt to
mimic sea water29 as the reaction medium (Table 5). In the case
of catalyst 5 (entry 1) the yield was too low to enable us to deter-
mine the enantioselectivity of the reaction, however, the ratio of
erythrose 2-anti/threose 2-syn was 1 : 1. The trend of (L)-proline
derived catalysts giving (L)-erythrose and the major product and
(L)-alanine and (L)-leucine catalysts giving (D)-erythrose as the
major enantiomer continued (entries 4 and 5). Thus demonstrat-
ing that for all the conditions investigated there is a link between
acyclic (L)-amino acids and (D)-tetroses. This is significant and
consistent with the work on the organocatalytic formose reaction
recently reported by Breslow.5c Interestingly under these con-
ditions it is catalyst 6, not 7, which generates acetal 8 as the
major product in 41% yield and 15% ee. A 1 : 1 mixture ery-
throse 2-anti and threose 2-syn was also isolated from this reac-
tion, although the erythrose 2-anti was racemic. Considering that
the acetal 8 had an ee of 15% this provides further evidence of
the intermediacy of an iminium (such as 9), as a kinetic resol-
ution of the erythrose 2-anti seems to be occurring.
With studies on the dimerization of 1 and hence the synthesis
of TIPS-protected erythrose 2-anti and threose 2-syn complete
we decided to investigate whether our catalysts could promote
the dimerization of unprotected glycolaldehyde 14, and hence
lead directly to the formation of erythrose 14-anti and threose
14-syn (Scheme 3). We chose to use catalysts 11 and 12 as they
had consistently provided the highest enantioselectivities and
should generate the (D)-enantiomers of the product tetroses. We
also decided to investigate the tetrose-forming reaction under
each of the conditions we had studied for the formation of the
TIPS-protect tetroses. Hence the reactions were run with cata-
lysts 11 and 12 for 5 h in unbuffered aqueous media, water
Major
Combined
yield (%)
Ratio
% ee
Entry Catalyst productb
( : syn)c
(anti)d
1a
2a
3a
4a
5
6
7
11
(L)-2-anti
(L)-2-anti
(L)-2-anti
(D)-2-anti
33
30
24
33
5 : 1
8 : 1
1 : 1
1 : 1
22
20
30
16
a Reaction time 5 h. b Major enantiomer determined by correlation to the
work of Northrup and MacMillan (ref. 13). c Determined by integration
of the aldehyde resonances in the 1H NMR. d See supporting
information.†
major enantiomer, thus showing that while the level of the asym-
metric induction was influenced by pH, the absolute sense of the
reaction was not. It is worth noting that the use of catalyst 7
under pH = 7 buffered conditions still generated acetal 8 as the
major product (entry 3) in a similar yield and slightly higher %
ee to that seen in the unbuffered reaction. These results indicate
that a general base-mediated condensation may well be occurring
in the unbuffered reaction and could account for the reduced
enantioselectivities. They also suggest that the enamine-mediated
reaction is at least as efficient (in terms of yield) as the general
base-mediated reaction. It is worth noting too, that these results
represent the highest enantioselectivity (79% ee) seen in the
single amino acid residue catalyzed dimerization of a protected
glycolaldehyde derivative in an aqueous environment.
We next decided to see what effect running the reactions at pH
= 6 would have on the yield, diastereoselectivity and enantios-
electivity of tetrose 2-syn/2-anti formation. The reactions were
buffered to pH = 6 with KH2PO4/NaOH and run for 5 h
(Table 4) as in the previous trials in unbuffered solution and
when buffered at pH = 7. As can be seen from Table 4, the
yields of all of the reactions were substantially lower at pH = 6
than at the other pHs investigated. This came as a surprise as we
envisaged a yield increase due to pH = 6 being the accepted
optimal pH for enamine formation. However it was noted that
there was a significant amount of unidentified silyl residue in the
1H NMR of the crude reactions, so we assume that degradation
of either the starting material 1 or products 2-syn/2-anti was
occurring over the reaction time. In the cases of catalysts 5 and 6
(entries 1 and 2) there was a significant increase in the diaster-
eoselectivity of the reaction with more of the erythrose product
Table 5 (L)-Amino acid ester catalyzed formation of TIPS-protected
tetroses in unbuffered brine
Major
Combined
yield (%)
Ratio
% ee
Entry Catalyst productb
(anti : syn)c
(anti)d
e
1a
2a
3a
4a
5a
5
6
7
10
11
(L)-2-anti
8f
(L)-2-anti
(D)-2-anti 31
(D)-2-anti 26
8
1 : 1
N/Af
1 : 1
1 : 1
1 : 1
—
41g
57
15h
23
23
16
a Reaction time 5 h. b Major enantiomer determined by correlation to the
work of Northrup and MacMillan (ref. 13). c Determined by integration
of the aldehyde resonances in the 1H NMR. d See supporting
information.† e Not determined. f The reaction also produced 2-anti/2-
syn in a 1.0 : 1.0 anti : syn ratio where 2-anti could be isolated in 18%
yield, 0% ee (anti). g Isolated yield for acetal 8. h % ee of acetal 8.
Scheme 3 Organocatalytic synthesis of erythrose and threose under
aqueous conditions.
1568 | Org. Biomol. Chem., 2012, 10, 1565–1570
This journal is © The Royal Society of Chemistry 2012

Table 6 (L)-amino acid ester catalyzed formation of unprotected
(D)-tetroses
pH on the reaction indicate that the tetroses are most likely
formed via an enamine-mediated process but that in systems
where the pH <7 or pH >7 the enantioselectivity of the dimeriza-
tion could be eroded by general acid or general base catalysis
respectively. Fascinatingly and significantly while esters of (L)-
proline generated tetrose products in the unnatural (L)-enantio-
meric series, esters of acyclic (L)-amino acids (valine, alanine
and leucine) all generated tetrose products in the natural (D)-
enantiomeric series. This offers one potential explanation to
account for the relationship between (L)-amino acids and (D)-
sugars in nature. We have also noted that while hexoses, the pro-
ducts of aldol trimerization, are not formed in these reactions,
‘hexose-like’ acetal trimers are formed efficiently with some (L)-
proline derived catalysts.
Yield of Yield of Product
% ee
Entry Medium
Catalyst 17 (%)b 18 (%)b enantiomerc 18d
1a
2a
3a
4a
5a
6a
7a
8a
unbuffered 11
2.4
7.1
2.5
2.0
0.0
3.0
3.0
9.8
1.6
0.9
0.5
2.0
0.0
2.0
3.0
2.2
(D)-18
(D)-18
(D)-18
(D)-18
N/A
(D)-18
(D)-18
(D)-18
25
66
43
20
N/A
40
pH 7
pH 6
brine
11
11
11
unbuffered 12
pH 7
pH 6
brine
12
12
12
14
30
a Reaction time 5 h. b After reduction and acylation. c Major enantiomer
determined by correlation to the work of Cordova (ref. 17).
d Determined by GC.
buffered to pH = 7, water buffered to pH = 6 and unbuffered
brine (Table 6). However, due to the difficulty inherent in
directly assaying the yield, diastereo- and enantioselectivity of
the tetrose products we adopted the analysis protocol reported by
Cordova.17 This involved reduction of the tetrose products with
NaBH4 in MeOH followed by acylation with acetic anhydride in
pyridine/CH2Cl2 with DMAP and analysis by chiral GC. The
unfortunate consequence of this procedure is that upon reduction
the erythrose 14-anti is converted to erythritol 15 which is a
meso-compound, and so only the enantiomeric excess of the
threitol-derived tetraacetate 18, and hence of threose 14-syn
could be determined.30
As can be seen from Table 6, in all cases the major enantiomer
of the product formed was the (D)-enantiomer, continuing the
trend seen in our earlier work on the protected glycolaldehyde.
The (L)-leucine derived catalyst 11 generally gave products with
higher % ee than the (L)-valine derived catalyst 12 (entries 1–4 to
entries 5–8). Dimerization reactions run at pH = 7 gave the
highest % ee out of all the conditions investigated (entries 2 and
6), with the highest overall % ee of 66% arising from the (L)-
leucine derived catalyst 11 at pH = 7 (entry 2). To date this is the
highest % ee for the dimerization of glycolaldehyde by a catalyst
containing a single amino acid under aqueous conditions. As in
the case of the dimerization of the protected glycolaldehyde 1,
those reactions run at pH = 6 and in brine had lower % ee values
(entries 3, 4, 7 and 8). It is possible that this is due to competing
general base or acid catalysis. Surprisingly, when the dimerization
reaction was run unbuffered with catalyst 12, no product could be
isolated (entry 5). We attribute the lower yields of these unpro-
tected reactions to the difficulty in product manipulation and iso-
lation. It is probable that not all of the tetrose products were
reduced and converted to the tetraacetates thus resulting in loss of
material to the aqueous phase. Although it is worth noting that
the (L)-valine derived catalyst 12 often gives lower isolated yields
of products than the (L)-leucine derived catalyst 11.
Experimental section
General procedure for the amino acid ester catalyzed
dimerization of 1
Amino acid ester (0.129 mmol) was added to 2-(triisopropylsily-
loxy)acetaldehyde 1 (280 mg, 1.29 mmol) in either water, or pH
7 phosphate buffer or pH 6 phosphate buffer or brine (5 mL).
After 5 h the reaction mixture was extracted with chloroform
(3 × 10 mL). The organic extracts were combined, dried with
magnesium sulfate, filtered and concentrated in vacuo to provide
the crude reaction mixture. This was then purified by flash
column chromatography using Merck TLC grade silica gel with
silica/alumina binder supplied by Aldrich (15 : 1 pentane :
diethyl ether) to provide clean 2-anti (in quantities suitable for
the analysis of enantioselectivity) and a mixture of 2-syn/2-anti
as a clear, colourless oil (See Tables 1–5 for combined yields of
2-anti and 2-syn/2-anti product mix and diastereomeric ratios of
the crude reaction mixture). The data was found to be in accord-
ance with the literature.12 1H NMR (400 MHz, CDCl3): δ (anti):
1.03–1.08 (m, 42H, SiCH(CH3)2); 2.39 (d, 5.5 Hz, 1H, OH);
3.75–3.85 (m, 2H, CH2); 3.95–3.99 (m, 1H, CHOHCH2); 4.24
(dd, 4.0 Hz, 2.0 Hz, 1H, CHOHCHO); 9.68 (d, 2.0 Hz, 1H,
CHO); (syn): 1.03–1.08 (m, 42H, SiCH(CH3)2); 2.74 (d, 10.0
Hz, 1H, OH); 3.76–3.92 (m, 2H, CH2); 3.95–3.98 (m, 1H,
CHOHCH2); 4.28 (dd, 5.0 Hz, 2.0 Hz, 1H, CHOHCHO); 9.74
(d, 1.5 Hz, 1H, CHO);13C NMR (100 MHz, CDCl3): δ (anti):
11.9, 12.4, 18.0, 62.8, 74.4, 79.0, 202.4; (syn): 11.9, 12.4, 18.0,
62.2, 74.4, 78.1, 203.8.
General procedure for conversion of 2-syn/2-anti to the para-
nitrobenzoate and the determination of its enantiomeric excess
A
sample of (anti)-3-hydroxy-2,4-bis(triisopropylsilyloxy)
butanal 2-anti (10.7 mg, 0.0247 mmol) was added to a solution
of 4-nitrobenzoyl chloride (11.3 mg, 0.0609 mmol) and
4-(dimethylamino)pyridine (0.664 mg, 0.00543 mmol) in
dichloromethane (0.5 mL) at 0 °C under argon. Triethylamine
(0.0172 mL, 0.124 mmol) was then added to the reaction
mixture. After 3 h methanol (0.5 mL) was added to the solution,
followed by sodium borohydride (9.34 mg, 0.247 mmol). After
1 h the reaction mixture was allowed to warm to room tempera-
ture. After a further 2 h the solution was diluted with dichloro-
methane (5 mL) and washed with saturated sodium bicarbonate
Conclusions
We have developed a simple system for the formation of threose
and erythrose, catalyzed by esters of proteinogenic amino acids,
under aqueous and potentially prebiotic conditions. This has
resulted in the highest enantioselectivities reported to date for
the formation of these simple tetroses. Studies on the effect of
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1565–1570 | 1569

solution (5 mL). The aqueous layer was extracted with dichloro-
methane (3 × 2 mL). The organic extracts were then combined,
dried with magnesium sulfate, filtered and concentrated in vacuo
to give the crude acylated and reduced product. Purification
by preparative thin-layer chromatography (4 : 1 pentane : diethyl
ether) provided the 1-hydroxy-3-p-nitrobenzoate derivative
(2.8 mg, 0.0048 mmol, 19%) as a colourless oil. The enantio-
meric excess was then determined by chiral shift NMR analysis
exchange scheme (MZ) for funding, Prof. Ian Fairlamb for use
of the GC.
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using
europium
tris[3-(trifluoromethylhydroxymethylene)-
(+)-camphorate] (0.9 mg, 0.0010 mmol) in deuterated chloro-
form (0.7 mL). Only HPLC data provided in the literature,12 full
data provided below; IR (film) 2945, 2891, 2867, 1724, 1607,
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Glycolaldehyde dimer 13 (240 mg, 2.00 mmol) was added to a
stirred mixture of amino acid ester (0.10 mmol) in either water
or pH 7 phosphate buffer, or pH 6 phosphate buffer or brine
(3 mL). After 5 h the reaction mixture was concentrated
in vacuo, and re-dissolved in methanol (3 mL) at 0 °C. Sodium
borohydride (152 mg, 4.00 mmol) was then added carefully and
the reaction kept at 0 °C for 3 h, after which it was allowed to
warm to room temperature. After a further 15 h, the reaction was
cooled to 0 °C and quenched with 2 M hydrochloric acid
(3 mL). It was then concentrated in vacuo and re-dissolved in
dichloromethane (5 mL). Pyridine (1 mL) was then added, fol-
lowed by 4-dimethylaminopyridine (1.3 mg, 0.01 mmol) then
acetic anhydride (3 mL). The reaction mixture was stirred for
7 h, then washed with water (10 mL) and extracted with dichlor-
omethane (3 × 5 mL). The separated and combined organics
were then washed with 1 mol dm−3 hydrochloric acid (10 mL),
brine (10 mL) and finally water (10 mL). The organic layer was
then dried with magnesium sulfate and concentrated in vacuo to
give the crude reduced and acylated derivative tetroses (see
Table 6). These were purified by flash column chromatography
using silica gel 60 (220–240 mesh) (8 : 2 hexane : ethyl acetate)
to give the separated acylated tetrols 17 and 18 as a colourless
oils (individual yields provided in Table 6). The chiral product
18 was then dissolved in ethyl acetate and analysed by chiral-
phase GC analysis using the conditions provided in the litera-
ture.17,31 GC tetra-acetylated threitol: (CP-Chirasil-Dex CB); Tinj
= 250 °C, Tdet = 275 °C, flow = 1.5 mL min−1, ti = 100 °C
(10 min), (100 °C min−1) tf = 200 °C (40 min): (L)-isomer: tR =
36.33 min; (D)-isomer: tR = 36.79 min.
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29 The precise composition of sea water on the prebiotic (Hadean) Earth
(4.3–3.8 Ga) is a matter of some debate as there is no geological record
of rocks of that age. There is, however, a consensus view that the oceans
did contain sodium chloride, much the same as modern oceans. See:
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30 The reduction–acetylation protocol was performed independently on
samples of enantiomerically pure erythrose and threose to provide refer-
ence samples for chiral-GC analysis. In addition, these studies confirmed
that threose and erythrose do not interconvert under the reaction
conditions.
Acknowledgements
We thank the University of York/EPSRC DTA (LB), the Uni-
versity of Nottingham (MEV) and the ERASMUS
31 Spectroscopic data for the tetraacetate standards are presented in the sup-
porting information†.
1570 | Org. Biomol. Chem., 2012, 10, 1565–1570
This journal is © The Royal Society of Chemistry 2012