Biomimetic direct aldol reaction of pyruvate esters with chiral aldehydes

Article abstract of DOI:10.1002/adsc.201200914

Direct aldol reactions of pyruvate esters with sugar aldehydes is efficiently promoted by dinuclear metal complexes or chiral Cinchona alkaloid organocatalysts. Application of sterically hindered aryl esters enables the to-date problematic aldol reaction

Full text of DOI:10.1002/adsc.201200914

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DOI: 10.1002/adsc.201200914
Biomimetic Direct Aldol Reaction of Pyruvate Esters with Chiral
Aldehydes
Osama El-Sepelgya,* and Jacek Mlynarskia,b,*
a
Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland
E-mail: ozelsepelgy@yahoo.com or jacek.mlynarski@gmail.com
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, Warsaw, Poland
b
Received: October 19, 2012; Revised: November 16, 2012; Published online: January 16, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200914.
Abstract: Direct aldol reactions of pyruvate esters
with sugar aldehydes is efficiently promoted by di-
nuclear metal complexes or chiral Cinchona alka-
loid organocatalysts. Application of sterically hin-
dered aryl esters enables the to-date problematic
aldol reaction of pyruvate donors with syn- or anti-
selectivity en route to the short and efficient synthe-
sis of 3-deoxy-2-ulosonic acids.
Scheme 1. Homo (a) and cross (b) aldol reactions of pyru-
vate esters.
Keywords: aldol reaction; asymmetric synthesis;
carbohydrates; organocatalysis; pyruvates
Trying to solve the problem, Jørgensen developed
a chiral copper-based catalyst for asymmetric homo-
aldol reaction of ethyl pyruvate leading to diethyl 2-
hydroxy-2-methyl-4-oxoglutarate (2). This, in turn,
The aldol reaction, in addition to being an effective was isolated as the more stable isotetronic acid (3).[4]
method for the formation of carbon-carbon bonds, is A direct catalytic homoaldol reaction of ethyl pyru-
also an outstanding example of the inspiration trans- vate leading to 3 was also performed by Dondoni
ferred from a biochemical processes to chemical syn- under pyrrolidine-based organocatalytic control.[5] On
thesis. While initially the aldol reaction was used for the other hand, an organocatalytic cross aldol reaction
the synthesis of relatively simple organic com- of pyruvate ester was demonstrated only for highly
pounds,[1] now it constitutes an intensively explored active chloral hydrate.[6] In spite of many trials,
tool for the synthesis of complex natural products in- a direct activation of pyruvate donors towards reac-
cluding monosaccharides.[2] An important way to im- tion with aliphatic aldehydes was long thought to be
prove the efficiency of chemical methods for the aldol confined to the realm of enzymes.[7] Solving this prob-
reaction is the development of a catalytic system lem is not only important from the conceptual point
where both donor and acceptor substrates are activat- of view, but also because pyruvate- and phosphoenol
ed simultaneously to perform the direct aldol reaction pyruvate-dependent aldol reactions are vital in the
with high efficiency and stereoselectivity similar to al- formation of 3-deoxy-2-ulosonic acids and sialic acids,
dolase enzymes.[3]
which are essential sugar units for many biological
While such a methodology is known for many other processes and transformations.[8] As a C3 building
asymmetric aldol syntheses, the direct activation of block phosphoenol pyruvate participates also in the
pyruvate esters 1 still remains an elusive goal if not biosynthesis of the aromatic core of aryl amino acids
simply a white spot on the aldol reaction map. The in the shikimate pathway.
state-of-the-art of known methodologies is narrow
Now, we postulate that the stability of simple ali-
and strictly limited to the self-condensation of pyru- phatic pyruvate ester is sufficient for the reaction
vate donors with pyruvate-type acceptors (Scheme 1, with fast-reactive electrophiles, while addition to
path a) or the cross aldol reaction of active and non- other aldehydes needs the more stable enol form and
enolizable aldehydes (Scheme 1, path b).
a disciplined reaction course. In this article we show
that the better stability of the pyruvate ester enol
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281

Osama El-Sepelgy and Jacek Mlynarski
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Scheme 2. Direct aldol reaction of the pyruvic ester 6 with glyceraldehyde.
Table 1. Direct aldol reaction of the pyruvic ester 6 with
form may result from the bulky ester group attached
to the keto ester which allows one to perform the elu-
sive reaction with aliphatic aldehydes eventually fol-
lowing the biomimetic synthesis of ulosonic acids.
Previously Enders[9] and our group[10] had shown
that pyruvic derivatives such as those with dimethyl
acetal or thiazole ring moieties can be used as chemi-
cal equivalents of pyruvic esters in the catalytic reac-
tion with chiral glyceraldehyde. Unfortunately, de-
spite the enormous effort which we put in the activa-
tion of pyruvate methyl and ethyl esters by using
a broad range of metal catalysts and organic mole-
cules, we could not observe their reactions with ali-
phatic aldehydes.
Now, we began our thorough study by considering
the catalytic aldol reaction of various pyruvate esters
with (R)-glyceraldehyde (5) promoted by the asym-
metric dinuclear zinc catalyst with the ProPh ligand
(8)[11] and the lanthanium-lithium-BINOL complex
(9)[12] (Scheme 2). To test our presumption that steri-
cally hindered esters might support enol formation,
we tested tert-butyl, phenyl, and 4-methoxyphenyl
esters. Our initial attempts were, however, unsuccess-
ful and did not result in the formation of desired
aldols.
glyceraldehyde.[a]
Entry Catalyst
Solvent Yield[c] [%] anti/syn[d]
1
(S)-8 (5 mol%) THF
62
3/1
2
3
4
5
6
7
8
9
10
11
12
13
(R)-8 (5 mol%) THF
(R)-9 (5 mol%) THF
(S)-9 (5 mol%) THF
(S)-9 (5 mol%) THF
62
8/1
4/1
16/1
2/1[e]
5/1
2/1
7/1
1/1
1.5/1
6/1
81[b]
81[b]
81[b]
31
10a (20 mol%)
11a (20 mol%)
10b (20 mol%)
11b (20 mol%)
10c (20 mol%)
11c (20 mol%)
10d (20 mol%)
11d (20 mol%)
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
31
75
61
51
62
80
59
16/1
1/1.5
[a]
Reactions were performed with
5
(0.1 mmol),
6
(0.1 mmol), catalyst (see Table) in THF (12 h) or CHCl3
(48 h) at room temperature.
[b]
[c]
[d]
[e]
Reaction was performed at À208C.
Yield of isolated product.
1
Determined by H NMR analysis.
The (S)-aldehyde was used.
entry 2). The stereoselectivity of the reaction was fur-
Therefore, we investigated enolization of the more ther improved by using the La-Li-(S)-BINOL catalyst
bulky 2,6-di-tert-butyl-4-methoxyphenyl ester (6) by and performing the reaction at À208C (Table 1,
using (S)- and (R)-ProPh catalysts (Table 1).[13] To our entry 4). The anti-configured aldol ester was formed
delight the reaction of ester 6 with (R)-glyceraldehyde predominantly with high yield (81%) and an excellent
acetonide promoted by (R)-ProPh catalysts resulted anti/syn ratio of 16:1. The here elaborated efficient re-
in the clean and efficient formation of desired cross action conditions need only a (1:1) ratio of the two
aldol product 7 with a very good level of syn/anti dia- substrates. Application of either (R)-configured cata-
stereoselectivity favouring anti isomer (Table 1, lyst (entry 3) and (S)-glyceraldehyde with (S)-config-
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Biomimetic Direct Aldol Reaction of Pyruvate Esters with Chiral Aldehydes
Scheme 3. Efficient diastereoselective synthesis of KDG ester.
ured catalyst (entry 5) resulted in the loss of stereose- afforded high anti-diastereoselectivity (16:1) and high
lectivity as a consequence of the formation of mis- yield (80%) of aldol 7. It is interesting to mention
matched substrate-catalyst pairs.
that application of a quinidine-based catalyst fav-
Our results suggest that the remarkable stability of oured formation of the oposite syn-configured aldol
the pyruvate enol esters was attributed to the steric albeit with lower diastereoselectivity (entry 13).
hindrance present in the aryl moiety. This particular
This newly elaborated methodology could easily be
feature of the 2,6-di-tert-butyl-4-methoxyphenyl deriv- applied for the synthesis of sugar 3-deoxy-2-keto
ative was previously observed during the Grignard ad- acids (ulosonic acids), and to prove this concept we
dition to 1,2-esters.[14]
scaled up the synthesis and compared results obtained
To explore further this concept of stable hindered by using both enolization ways (Scheme 3). In recent
enol formation, we tested also the possibility of a par- years, several chemical and enzymatic methodologies
allel organocatalytic protocol for pyruvate ester de- have been reported for the synthesis of sialic and ulo-
protonation. This was an exciting challenge in the sonic acids[16] but our attempt seems to be the sim-
light of unknown protocol for such a substrate activa- plest and more closely related to enzymatic pathway.
tion. After many trials including various organocata- The anti-configured aldol product 7 possesses the con-
lyst structures and modes of activation, we selected figuration of natural 3-deoxy-d-gluco-hexulosonic
tertiary amines of Cinchona alkaloids as the most acid (KDG, Scheme 3) and can be easily transformed
promising candidates for further research.[15] The ter- into this biomolecule. By using the biomimetic con-
tiary amine-based catalysts could act through forma- cept and following the KDPG-aldolase function the
tion of a tight ion pair followed by aldehyde addition synthesis of 7 can be performed by using metal cata-
giving an additional evidence for the easy deprotona- lyst (9) or organocatalyst (10d) in high yield and high
tion and stable enol formation from 6.
stereoselectivity. Thus, the obtained anti-aldol 7 was
The results collected in Table 1, entries 6–13 highly easily deprotected with an acidic ion-exchange resin
support our concept. Initial application of cinchoni- (Amberlyst 15) in methanol to give the cyclic forms
dine (10a, CD) and cinchonine (11a, CN) to the ela- of the desired KDG ester 12 (Scheme 3).[17]
borated reaction showed promising results while yield
Next, we tested the flexibility of our methodology
and stereoselectivity remained poor (Table 1, entries 6 for the synthesis of a higher, eight-carbon ulosonic
and 7). The most efficient means turned out to be var- acid – KDO ester, starting from arabinose diacetonide
iation of the Cinchona alkaloid scaffold at the C-6’ 13 and the same pyruvate ester 6 (Scheme 4). Because
position of the quinoline core of quinine (10b, QN) of the different structure of the chiral aldehyde, appli-
and quinidine (11b, QD). Further alkylation of the cation of the metal-based catalyst resulted in a less se-
quinine by the bulky isopropyl group delivered an ef- lective formation of the desired aldol 14. The most
ficient and selective catalyst. To our delight the aldol promising catalyst was (R)-ProPh yet the unexpected
reaction from Scheme 2 promoted by 20 mol% of 10d formation of syn-configured aldol (anti/syn, 1:6, 70%
Adv. Synth. Catal. 2013, 355, 281 – 286
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Osama El-Sepelgy and Jacek Mlynarski
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Scheme 4. Synthesis of KDO and 4-epi-KDO esters.
yield) closed this entry to natural 3-deoxy-d-manno-
octulosonic acid (KDO).
However, the biomimetic synthesis of the desired
anti-configured aldol 14 was successfully performed
by using organocatalyst 11d (anti/syn, 85:15, 69%
yield). Interestingly, a parallel synthesis of the syn-
configured aldol by using organocatalyst 10d proved
to have additional practical advantages of the newly
described methodology (anti/syn, 11:89, 60% yield). It
is also a highly important observation as previously
published methodologies based on addition of lithium
enolates to chiral aldehydes led to anti-configured
products only.[18] Now, from both syn- and anti-config-
ured key intermediates, the syntheses of KDO ester
16 and pharmaceutically important 4-epi-KDO ester
15 were flexibly accomplished by simple deprotection
of isopropylidene residues (Scheme 4).
Scheme 5. Proposed approximate structure of the substrate-
catalyst 10d complex for the S-selective formation of aldols.
The diastereomeric excesses of the aldols 7 and 14
were determined by high resolution NMR of the reac- of pyruvate ester involves initial deprotonation by the
tion mixtures. For both aldol products separation of Cinchona catalyst 10d (CD, QN native configuration)
the diastereomers was easily possible by simple flash and subsequent attack to the aldehyde, the role of
chromatography making the elaborated methodology catalyst is also to provide an asymmetric environment
useful for a practical synthesis of natural keto acids to the reaction center through a network of hydrogen
and their isomers.
bonds. The large substituent in the aldehyde molecule
Although the number of possible conformations of is placed away from the bulky catalyst substituent.
Cinchona alkaloids in the solution makes it difficult The Re face of the aldehyde is covered so effectively
to analyse,[19] the transition state structure of the sub- by the quinolone ring that the pyruvate enol ap-
strate-catalyst complex can be rationalised by using proaches the Si face to produce the S-configured alco-
the model depicted at Scheme 5. While the reaction hol 7 or 14. By using catalyst 11d (CN, QD native
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Biomimetic Direct Aldol Reaction of Pyruvate Esters with Chiral Aldehydes
configuration) the diastereoisomeric (R)-alcohols are Acknowledgements
formed predominantly.
This project was operated within the Foundation for Polish
In conclusion, we showed that both metal-based
complexes and chiral tertiary amines can initiate
stable enol formation from hindered pyruvate esters
which can be further trapped by electrophilic alde-
hydes. This is the first example of an efficient catalytic
stereoselective aldol reaction of pyruvate esters with
aliphatic aldehydes closely resembling the biomimetic
synthesis of ulosonic acids. The elaborated methodol-
ogy allowed the first catalytic synthesis of 3-deoxy-2-
keto esters through a direct aldol reaction of sugar al-
dehydes with pyruvate esters. The presented protocol
provides an attractive and biomimetic approach to
ulosonic acids and constitutes another interesting
field of application for the powerful Trost and Shiba-
saki catalysts.
Moreover, we have presented new concept of direct
aldol reaction of keto esters promoted by chiral terti-
ary amines. The described methodology delivers
a flexible entry to both syn- and anti-configured
aldols while syn-selectivity was not achievable previ-
ously by using stoichiometrically generated lithium
enolates. Although obtaining better diastereoselectiv-
ity in the aldol reaction of hindered keto esters is
troublesome and constitutes a general problem,[20] our
further efforts will be direct to designing even more
efficient and stereoselective catalysts for the elaborat-
ed direct aldol reaction of pyruvate esters.
Science TEAM and MPD Programmes co-financed by the
EU European Regional Development Fund. The research
was carried out with the equipment purchased thanks to the
financial support of the European Regional Development
Fund in the framework of the Polish Innovation Economy
Operational Program (contract no. POIG.02.01.00-12-023/
08).
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Experimental Section
Direct Aldol Reaction of Aryl Pyruvate with
Glyceraldehyde
(1) Using catalyst 9:
(0.01 mmol, 10 mL, 1M) was added to a solution of potassi-
um bis(trimethylsilyl)amide (KHMDS) in toluene
A solution of water in THF
(0.0045 mmol, 9 mL, 0.5M) at 08C. After stirring for 15 min
a solution of LLB in THF (0.005 mmol, 0.1 mL, 0.05M) was
added and the stirring was continued at 08C for 30 min. The
catalyst solution was cooled to À208C and a mixture of al-
dehyde 5 (13 mg, 0.1 mmol) and aryl pyruvate 6 (31 mg,
0.1 mmol) in 0.5 mL THF was added to the solution. The re-
action mixture was stirred for 12 h at À208C, then quenched
with ammonium chloride, extracted with ethyl acetate, dried
with magnesium sulfate and purified on silica gel using 0–
2% methanolic dichloromethane as eluent to give aldol
adduct 7; yield: 35.5 mg (81%).
(2) Using Cinchona catalyst 10d: A mixture of aldehyde
5 (260 mg, 2 mmole), aryl pyruvate 6 (613 mg, 2 mmol) and
catalyst 10d[21] (141 mg, 0.4 mmol) in 10 mL of chloroform
was stirred for 48 h at room temperature. The reaction mix-
ture was purified on silica gel using 0–2% methanolic di-
chloromethane as eluent to give aldol adduct 7; yield:
698 mg (80%).
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Osama El-Sepelgy and Jacek Mlynarski
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