Biomimetic syn-aldol reaction of dihydroxyacetone promoted by water-compatible catalysts

Article abstract of DOI:10.1002/ejoc.201301436

The syn-selective direct aldol reaction of unprotected dihydroxyacetone with glyceraldehyde has been catalyzed by serine-based organocatalysts. The application of the catalysts mimics the biosynthesis of ketohexoses in aqueous solvents and leads to fructose and sorbose with excellent diastereoselectivity (up to 95:5 dr). The organocatalytic C₃ + C₃ methodology presented herein is a versatile direct entry to protected syn-configured sugars of both the D and L series. The syn-selective direct aldol reaction of unprotected dihydroxyacetone with D- or L-glyceraldehyde catalyzed by serine-based organocatalysts leads to D- or L-configured fructose and sorbose with excellent diastereoselectivities (up to 95:5 dr).

Full text of DOI:10.1002/ejoc.201301436

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301436
Biomimetic syn-Aldol Reaction of Dihydroxyacetone Promoted by
Water-Compatible Catalysts
Oskar Popik,[a] Bartosz Zambron´,[b] and Jacek Mlynarski*[a,b]
Keywords: Aldol reactions / Organocatalysis / Carbohydrates / Ketoses / Asymmetric synthesis
The syn-selective direct aldol reaction of unprotected di-
hydroxyacetone with glyceraldehyde has been catalyzed by
serine-based organocatalysts. The application of the catalysts
mimics the biosynthesis of ketohexoses in aqueous solvents
and leads to fructose and sorbose with excellent diastereo-
selectivity (up to 95:5 dr). The organocatalytic C3 +C3 meth-
odology presented herein is a versatile direct entry to pro-
tected syn-configured sugars of both the
D and L series.
Introduction
The aldol reaction is one of the most important trans-
formations for the construction of C–C bonds in both the
laboratory and in nature.[1] This particular reaction is cru-
cial in the context of living organisms, being the most im-
portant biochemical process for the synthesis of naturally
occurring carbohydrates. For example, dihydroxyacetone
phosphate (DHAP) participates in an enzyme-catalyzed
aldol reaction with (R)-glyceraldehyde-3-phosphate to form
d-fructose-1,6-diphosphate (Scheme 1).[2] In general, the
construction of four differently configured sugars is con-
trolled by four different aldolases. In addition to one (R)-
configured stereogenic center delivered from the glyceralde-
hyde substrate, these reactions create two new stereogenic
centers in the form of syn- (fructose and sorbose) or anti-
ketohexoses (psicose and tagatose; Scheme 1).[3]
Scheme 1. Biomimetic synthesis of all four d-ketohexoses.
This versatile and simple C3 +C3 strategy involving the
DHA synthon, although most favored by nature, is still be-
yond the reach of organic chemists, especially the synthesis
of syn-configured ketohexoses.[4] Chemists have long been
pursuing simple catalysts to mimic nature’s aldolase en-
zymes, but the asymmetric synthesis of carbohydrates with
DHA derivatives as donors[5] has only been achieved re-
cently with enamine-based organocatalysis.[6] The best re-
sults in the direct synthesis of ketohexoses were achieved
when (S)-proline was used as a catalyst, and the reactions
were largely limited to cyclic-protected DHA derivatives
such as 2,2-dimethyl-1,3-dioxan-5-one.[4] Because (S)- and
(R)-proline catalysts have provided access to anti-1,2-
diols,[7] they mimic tagatose and fuculose aldolases for diox-
anone substrate.[6] More recently, Luo et al. showed that
anti-selective reactions of dioxanone with aromatic alde-
hydes can be promoted by chiral primary amines, thus con-
firming that the stereoselectivity of the reaction depends on
E-configured enamines formed exclusively from cyclic
ketones.[8]
Recently, Barbas and co-workers reported that primary
amino acids can catalyze the syn-aldol reaction of protected
DHA with glyceraldehyde. In addition, O-tert-butyl-l-
threonine (20 mol-%) promoted the aldol reaction of tert-
butyldiphenylsilyl (TBDPS) protected dihydroxyacetone
with (R)-glyceraldehyde to form protected d-fructose with
a high diastereoisomeric ratio (98:2).[9] Similarly, an O-tert-
butyl-l-threonine-based amide acted as an efficient catalyst
for the reaction of TBDPS-protected DHA with the aceton-
ide of (R)-glyceraldehyde providing the protected d-sorbose
derivative in 86% yield and with a 3:1 syn/anti ratio.[10] The
catalysts used were also water-tolerant making the pre-
sented reactions biomimetically even more relevant. This
methodology provides a direct route to aldol products of
[a] Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, Warsaw, Poland
[b] Faculty of Chemistry, Jagiellonian University,
Ingardena 3, 30-060 Krakow, Poland
E-mail: jacek.mlynarski@gmail.com
www.jacekmlynarski.pl
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301436.
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Eur. J. Org. Chem. 2013, 7484–7487

syn-Aldol Reaction of Dihydroxyacetone
the type synthesized with DHAP aldolase enzymes, but still fording preferential and exclusive formation of syn-aldols.
requires a protected ketone donor. Reactions of unprotec- The first experiments showed that the reaction controlled
ted DHA have so far been unselective[11] or limited to non- by catalyst 7a, composed of (S,S)-diphenylethylenediamine
chiral aldehydes.[10,12]
and l-serine, resulted in the formation of protected d-
Because biomimetic access to syn-1,2-diols by enamine sorbose (4) in good yield and with a 7:3 syn/anti dr when
organocatalysis and a C3-dihydroxyacetone-based strategy 20 mol-% of the organocatalyst was used (Table 1, Entry 2).
with an unprotected donor are still not possible, we present Interestingly, enantiomeric catalyst 7b delivered protected
herein our attempt towards resolving this fundamental d-fructose (3) in very good yield and with high stereoselec-
problem. This communication presents a versatile and tivity (9:1, Table 1, Entry 3). It is important to mention that
stereoselective access to syn-configured d- and l-ketohex- we did not observe racemization of the glyceraldehyde or
oses from DHA and (R)- and (S)-glyceraldehyde, respec- the hexoses during the reaction, and high enantiomeric ex-
tively. To meet the biomimetic criteria, we focused on water- cesses were confirmed for all the products by NMR experi-
tolerant organocatalysts that form enamine intermediates in ments and chiral HPLC analysis.
homogeneous aqueous solvents. The presented aldol reac-
tion is also a rare example of the practical synthesis of natu-
ral products in an aqueous environment.[13]
Table 1. Direct aldol reaction of dihydroxyacetone (2) with (R)-
glyceraldehyde 1.[a]
Entry Catalyst (mol-%) Yield[b] [%] Fructose(3)/sorbose(4)[c]
1
2
3
4
5
6
7
8
9
7a (10)
7a (20)
7b (20)
7c (20)
7d (20)
8a (20)
8a (40)
8b (20)
8b (40)
8c (20)
9 (20)
29
67
75
52
53
25:75
30:70
90:10
90:10
50:50
55:45
55:45
60:40
65:35
70:30
–
Results and Discussion
Based on our earlier development of syn-aldol reactions
of hydroxyacetone catalyzed by amino acids,[14,15] we ini-
tially screened various bis(amides) containing primary
amines. The four isomeric bis(serinamides) 7a–7d demon-
strated activity and stereoselectivity superior to that ob-
tained previously by other authors. We decided to use O-
tert-butyldiphenylsilyl-protected bis(serinamides) as these
catalysts are very hydrophobic, mimicking the nature and
mode of action of enzymes. The idea behind this was that
more bulky substituents can effectively protect reactive sites
from water molecules and also shield one of the sites from
nucleophilic attack resulting in higher enantioselectivity
(Scheme 2).
27[d]
35[d]
27[d]
35[d]
32[d]
traces
traces
10
11
12
10 (20)
–
[a] Reactions were performed with (R)-1 (1 mmol), DHA (2;
2 mmol as a dimer) and catalyst (20 or 40 mol-%) in DMF/H2O
(9:1, 1 mL) at room temp. for 24 h. [b] Yield of the isolated product.
1
[c] Determined by H NMR analysis. [d] Reaction time of 72 h.
The diastereoisomeric catalysts 7c and 7d were less ef-
ficient, revealing that the stereochemistry of the amino acid
motif has a significant effect on the stereoselectivity of the
reaction. Thus, the application of (R)-configured serine in
bis(amide) 7c supports the formation of d-fructose (Table 1,
Entry 4). Interestingly, the stereochemistry of the whole cat-
alyst molecule seems to be essential for the formation of a
monosaccharide. The unselective formation of fructose and
sorbose (1:1, Entry 5) by catalyst 7d, as well as the lower
yields observed for mismatched catalysts 7c and 7d strongly
support the hypothesis that a chiral catalyst and chiral alde-
hyde molecule should work together and match each other.
Interestingly, mono(serinamides) 8a–8c induced poorer
stereoselectivity and yields even when used in two-fold ex-
cess, further demonstrating the need for a C2-symmetrical
bis(amide) catalyst (Entries 6–10). The use of O-tert-butyl-
diphenylsilyl-protected l-serine 9 and O-tert-butyl-l-threo-
nine 10[12] were unsuccessful in the tested aldol reaction.
Having in hand the efficient enantiomeric catalysts 7a
Scheme 2. Organocatalysts used in this study for the syn-selective
direct aldol reaction of DHA.
The four catalysts 7a–7d, which are readily available from
(S,S)- and (R,R)-diphenylethylenediamine and the two ser-
ine enantiomers,[14,16] were initially screened in the aldol re-
action of (R)-glyceraldehyde (1, 1 mmol) and unprotected
dihydroxyacetone (2, 4 mmol). In an effort to improve the and 7b, we tested the ability of the reactions of both enan-
reaction rates and stereoselectivities, we evaluated different tiomeric glyceraldehyde acetonides (R)-1 and (S)-1 to give
solvents and various conditions. The best results observed rapid and direct access to d- and l-hexoses, respectively.
in DMF/water are collected in Table 1. All the bis(amides) Under the optimized conditions, the reactions were com-
were observed to catalyze the reaction very smoothly, af- plete in 24 h at room temperature (Scheme 3).
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O. Popik, B. Zambron´, J. Mlynarski
SHORT COMMUNICATION
Table 2. Enantioselective direct aldol reaction of dihydroxyacetone
(2).[a]
Entry
Aldol (R)
Yield[b] [%]
syn/anti[c]
ee[d] [%]
1
2
3
4
5
6
7
11a (4-O2NC6H4)
11b (4-NCC6H4)
11c (4-F3CC6H4)
11d (4-ClC6H4)
11e (2-ClC6H4)
11f (C6H5)
78[e]
71
9:1
6:1
8:1
9:1
10:1
8:1
9:1
91
92
89
92
91
86
85
61
51[f]
49
15
11g (CH2OBn)
22[f]
[a] Reactions were performed with aldehyde (0.5 mmol), DHA (2;
1 mmol as a dimer) and catalyst 7a (20 mol-%) in THF/H2O (9:1,
1 mL) at room temp. for 48 h. [b] Yield of the isolated product. [c]
Determined by 1H NMR spectroscopy and HPLC analysis. [d] The
enantiomeric excess of the syn isomer was determined by HPLC
analysis on a chiral phase column (Chiralpak OD-H and AS-H).
[e] Reaction time of 24 h. [f] Reaction time of 72 h.
Scheme 3. Stereoselective synthesis of d- and l-fructose and -sor-
bose.
formation of the enamine in the aqueous media and its
highly stereoselective nucleophilic addition to the aldehyde.
The organocatalytic enantioselective reaction of di-
hydroxyacetone presented above took place in a homogen-
eous organic aqueous solution. To gain a deeper insight
into the enamine mechanism of hydroxyacetone activation
by primary amine catalyst 7a we used ESI-MS. The results
of the analysis of a mixture of unprotected DHA and cata-
lyst 7a (1:1) in an aqueous DMF solution are presented in
Scheme 4. The high-resolution mass spectrum confirms the
formation of an enamine in the aqueous medium: The sig-
nal at m/z = 935 is in accord with the expected molecular
weight. The isotopic pattern of this signal corresponds to
the calculated pattern of the expected enamine structure.[16]
A plausible enamine-based transition state for the syn-aldol
reaction of dihydroxyacetone catalyzed by 7a is presented
in Scheme 4. The (3R,4S) absolute configuration of the
aldols 11 was assigned by analogy to previously published
When used with chiral (R)- and (S)-aldehydes in the pres-
ence of d- and l-serine-based catalysts, a matched/mis-
matched situation becomes apparent. In the case of (R)-
glyceraldehyde, application of catalyst 7b resulted in the for-
mation of d-fructose in high yield and dr, whereas the use
of catalyst 7a led to the stereoselective formation of d-sor-
bose with a good diastereoisomeric ratio. Again, we con-
firmed the exclusive formation of two syn-aldols. In con-
trast, l-fructose was formed with 7a and (S)-1, whereas l-
sorbose resulted from the 7b/(S)-glyceraldehyde matched
chiral pair.
These results are interesting not only in terms of a biomi-
metic synthesis of natural carbohydrates, but, significantly,
protected unnatural l-carbohydrates are also formed, which
otherwise are most efficiently prepared by difficult unnatu-
ral enzymatic reactions or from the chiral pool.[17]
To understand better the reaction mechanism and dis-
cuss the competition between enamine formation and the
general base mechanism, we also studied the enantioselec-
tive direct organocatalytic syn-aldol reaction of unprotected
dihydroxyacetone with achiral aldehydes. Under the opti-
mized conditions, the reactions were performed in aqueous
THF solution in the presence of catalyst 7a. For practical
reasons, the triol products were peracetylated and the re-
sulting esters 11 analyzed by HPLC on a chiral stationary
phase. The results of these experiments are collected in
Table 2.
The reaction of unprotected dihydroxyacetone with a
variety of aromatic aldehydes provided the desired syn-aldol
products in moderate to good yields and with excellent dia-
stereo- and enantioselectivity. As expected, the activated
aromatic aldehydes were the more reactive substrates
(Table 1, Entries 1–3), and benzaldehyde was a much less
reactive acceptor (Entry 6). In all cases, however, high
Scheme 4. HRMS (ESI) spectrum of the enamine formed in situ
from dihydroxyacetone (2) and catalyst 7a in aqueous solution and
the plausible structure of transition state based on enamine forma-
stereoselectivity was observed, which confirms the efficient tion.
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Eur. J. Org. Chem. 2013, 7484–7487

syn-Aldol Reaction of Dihydroxyacetone
results.[12] Organocatalyst 7a can form a hydrogen-bond-
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Re face resulting in the formation of syn-(3R,4S)-aldols.
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Conclusions
We have presented a highly enantioselective syn-aldol re-
action of unprotected dihydroxyacetone (2) with aldehydes
including achiral and optically pure acceptors. The pre-
sented serine-based organocatalysts 7a and 7b are active not
only with aromatic aldehydes, but can also efficiently pro-
mote the stereoselective synthesis of d- and l-configured
syn-hexoses. In all cases, syn-aldols were formed exclusively
without substrate racemization. The reactions of chiral
glyceraldehydes promoted by enantiomeric bis(serinamides)
mimic the reactions catalyzed by fructose and rhamnulose
aldolases, but also give direct access to unnatural l-carbo-
hydrates from the (S)-glyceraldehyde precursor. Such a
stereoselective methodology closely related to the biosyn-
thesis of sugars from unprotected dihydroxyacetone in an
aqueous environment and at ambient temperature has never
been published previously. This study not only describes
biomimetic aldol reactions but also provides one of the
most efficient de novo syntheses of sugars by enamine-
based organocatalysis.[18]
[13] a) J. Mlynarski, J. Paradowska, Chem. Soc. Rev. 2008, 37,
1502–1511; b) N. Mase, C. F. Barbas III, Org. Biomol. Chem.
2010, 8, 4043–4050.
[14] J. Paradowska, M. Pasternak, B. Gut, B. Gryzło, J. Mlynarski,
J. Org. Chem. 2012, 77, 173–187.
[15] C. Nicolas, R. Pluta, M. Pasternak-Suder, O. R. Martin, J.
Mlynarski, Eur. J. Org. Chem. 2013, 1296–1305.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and HPLC analysis as well
1
as H and 13C NMR spectra of all catalysts and aldol products.
[16] See the Supporting Information for detailed reaction condi-
tions and compound characterisation data.
[17] M. M. L. Zulueta, Y.-Q. Zhong, S.-C. Hung, Chem. Commun.
2013, 49, 3275–3287.
Acknowledgments
This project operated within the Foundation for Polish Science
TEAM Programmes co-financed by the EU European Regional
Development Fund. Financial support from the Polish National
Science Centre (grant number NCN 2011/03/B/ST5/03126) is grate-
fully acknowledged.
[18] Previously, the non-enamine, syn-selective reactions of hy-
droxy- and dihydroxyacetone under a general base mechanism
have been communicated: M. Market, M. Mulzer, B. Schetter,
R. Mahrwald, J. Am. Chem. Soc. 2007, 129, 7258–7259. How-
ever, the presented diastereoselective substrate-based method-
ology is not applicable to the flexible synthesis of all syn-con-
figured ketohexoses.
[1] R. Mahrwald (Ed.), Modern Aldol Reactions, Wiley-VCH,
Weinheim, 2004.
Received: September 19, 2013
Published Online: October 16, 2013
Eur. J. Org. Chem. 2013, 7484–7487
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7487