Direct amino acid catalyzed asymmetric synthesis of polyketide sugars

Article abstract of DOI:10.1002/anie.200461400

Back to the future: In a biomimetic asymmetric synthesis of sugars (see scheme) sequential cross-aldol reactions of simple aldehydes were catalyzed by amino acids. Deoxysugars were obtained with excellent chemoselectivity and up to > 99% ee. This transfor

Full text of DOI:10.1002/anie.200461400

Angewandte
Chemie
Carbohydrate Synthesis
cross-aldol reaction with high stereoselectivity.[10] However,
achieving the next amino acid catalyzed aldol step to obtain
hexoses with high enantioselectivity has not yet been
reported. Initial attempts at conducting one-pot direct
catalytic sequential aldol reactions furnished nearly racemic
triketide sugars.[10f,g]
Based on retrosynthetic analysis and our interest in
developing biomimetic stereoselective transformations cata-
lyzed by amino acids,[11] we envisioned a potential two-step
sugar synthesis based on direct amino acid catalyzed selective
iterative aldol reactions with aldehydes. Herein, we report the
enantioselective de novo synthesis of either enantiomer of
natural and unnatural hexoses with up to > 99% ee. The
simplicity and the high stereoselectivity of the hexose
formation may support a prebiotic pathway in which amino
acids transferred their chiral information to sugars.
Direct Amino Acid Catalyzed Asymmetric
Synthesis of Polyketide Sugars**
Jesffls Casas, Magnus Engqvist, Ismail Ibrahem,
Betul Kaynak, and Armando Córdova*
The directed asymmetric assembly of simple achiral building
blocks into stereochemically complex molecules like carbo-
hydrates and polyketides has long been accomplished by
enzymes in nature.[1,2] The growing interest in glycobiology[3]
and the search for novel antibiotics has led to increased
activity in developing reaction designs and methods for the
synthesis of sugars and polyketides.[1,2,4,5] Among the plethora
of methods, the aldol reaction is well established in carbohy-
drate and triketide synthesis.[6,7] However, it usually requires
protective group strategies and subsequent reduction–oxida-
tion steps. One efficient synthetic strategy based on retro-
synthetic analysis would be a two-step sugar synthesis
involving two iterative aldol reactions with three carbonyl
compounds [Eq. (1)]. This potential iterative double-aldol
route seems simple and attractive. However, it is challenging
to carry out due to the intrinsic chemoselectivity problems
with enolizable aldehydes. For example, it is difficult to
control whether they would act as donors or acceptors in the
sequential aldol reactions.
In initial experiments we investigated the one-pot direct
amino acid catalyzed sequential trimerization of propional-
dehyde (Scheme 1). To our delight we were able to signifi-
Scheme 1. Direct catalytic one-pot enantioselective synthesis of 1.
cantly increase the ee value of the previously reported
triketide hexose ent-1 from 49% to 85% ee by altering the
reaction conditions. However, the new one-pot procedure
only provided trace amounts of hexose 2.
To improve the efficiency and selectivity of the tandem
aldol process we decided to isolate the b-hydroxy aldol
intermediate from the first aldol transformation prior to the
second aldol reaction.[12] The two-step synthetic protocol
made it possible to investigate other amino acids as catalysts
as well as change the stereochemistry of the amino acid
catalyst prior to the second aldol addition. This approach
would potentially improve the efficiency and selectivity of the
second direct cross-aldol addition. Hence, propionaldehyde
was dimerized utilizing l-proline catalysis, and the corre-
sponding isolated b-hydroxy aldehyde was treated with
propionaldehyde in the presence of a catalytic amount of d-
proline (Table 1, entry 1). To our delight we were able to
isolate hexose 1 as a single diastereomer in 29% yield with
99% ee.
To date, only enzymes have been able to catalyze
sequential one-pot direct aldol reactions with high stereo-
selectivity.[8] Recently, organocatalysis has been revitalized in
the area of asymmetric synthesis.[9] The use of enamine
catalysis has enabled the first step of the sequential direct
[*] Dr. J. Casas, M. Engqvist, I. Ibrahem, Prof. Dr. A. Cꢀrdova
Department of Organic Chemistry
Stockholm University
10691 Stockholm (Sweden)
Fax: (+46)8-154-908
E-mail: acordova@organ.su.se
acordova1a@netscape.net
Encouraged by this result we performed the iterative aldol
reactions vide infra with a variety of aldehyde substrates
(Table 1). The short synthesis of hexoses proceeded with
excellent chemo-, diastereo-, and enantioselectivy. In all cases
except one, the corresponding hexoses were isolated as single
diastereomers in good overall yield with > 99% ee. Thus, out
of 16 possible stereoisomers amino acid catalysis directs in
some cases the creation of a single enantiomer. The yields of
the hexoses 1–5 were comparable or higher than most
conventional multistep sugar syntheses.[6] In addition, this
two-step synthesis of sugars is inexpensive and easy to
Dr. B. Kaynak
Department of Structural Chemistry
The Arrhenius Laboratory
Stockholm University
10691 Stockholm (Sweden)
[**] We gratefully acknowledge the Swedish National Research council
and Wenner-Gren Foundation for financial support. We thank Prof.
Jan-E. Bꢁckvall and Prof. Stefan Oscarsson for valuable discussions.
We also thank the referees for suggesting the crystal structure
analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 1343 –1345
DOI: 10.1002/anie.200461400
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
Table 1: Two-step direct amino acid catalyzed enantioselective synthesis of hexoses.
two-step aldol strategy opens up a novel
route to enantiomerically pure d-lactones
from simple aldehydes. This type of com-
pounds were previously synthesized in
11 steps by Staunton and co-workers using
Evans-type aldol reactions.[6d]
The absolute configurations of sugars 1–
5 have been assigned based on the crystal
Entry
R
R1
Cat. I
Cat. II
Sugar
Yield [%][a]
ee [%][b]
structure of the a-anomer of sugar
2
(Figure 1) and synthesis.[13] The crystal
structure reveals that the previously sug-
gested relative configuration of triketide
1
2
3
4
5
6
7
8
Et
iPr
iPr
iBu
c-Hexyl
Et
iPr
Me
Me
Me
Me
Me
Me
Me
OBn
l-proline
l-proline
d-proline
l-proline
l-proline
d-proline
d-proline
l-proline
d-proline
d-proline
l-proline
d-proline
1
2
29
42
40
24
41
30
15
39[d]
99
>99
>99
>99
>99
>99
>99
>99
ent-2
3
4
ent-1
ent-2
5
sugar
2 2
is incorrect.[10f] The hexose
d-proline
obtained by proline catalysis has a manno-
pyranoside configuration and not the pre-
viously believed gulopyranoside configura-
tion. Furthermore, sequential l-proline and
d-proline catalysis furnished l-hexoses.
Accordingly, the observed stereochemistry
of the hexoses can be readily explained
(Scheme 3). The initial formation of the b-
hydroxyaldehyde proceeds by means of a
l-4-hydroxyproline[c]
l-4-hydroxyproline[c]
d-proline
BnOCH2
[a] Overall yield of the isolated hexoses based on the two steps. [b] Determined by chiral-phase GC
analyses of the peracetylated products and compared to racemic standards generated by d,l-proline
catalysis. [c] 30 mol% hydroxyproline was used. [d] The overall combined yield of a 10:1 mixture of
diastereomers (anti:syn).
conduct, and it generates minimal waste products. The
sequential direct catalytic aldol reactions were also readily
scaled up and performed on a gram scale. For example, we
performed the two-step catalytic asymmetric synthesis of
hexose 2 on a 2-g scale, and triketide sugar 2 was obtained in
crystalline form in 42% yield with > 99% ee. Starting the
iterative aldol reactions with d-proline as the catalyst
furnished the opposite enantiomer of the hexoses without
affecting the stereoselectivity of the reaction. Furthermore,
performing the two-step synthesis employing sequential d-
proline and l-4-hydroxyproline catalysis improved the ee of
the triketide sugar ent-1 from 99 to > 99% ee. Moreover, the
amino acids are able to catalyze the total synthesis of natural
hexoses in one step. For example, l-4-hydroxyproline cata-
lyzed the trimerization of a-benzyloxyacetaldehyde to yield
2,4,6-tri-O-benzylallose in 28% yield as a single diastereomer
with > 99% ee. The hexoses obtained from the tandem direct
catalytic asymmetric aldol reactions have free hydroxy groups
at C1 and C3, allowing for introduction of orthogonal
protective groups and selective di- or polysaccharide cou-
plings. Furthermore, the aldehyde substrates and the amino
acid catalysts can be freely varied, potentially providing
access to a wide range of deoxyhexoses.
re-facial attack on the acceptor aldehyde by the l-proline-
derived enamine, which is in accordance with previous
reported proline-catalyzed aldol reactions with aldehydes.[8]
Next, the d-proline-catalyzed aldol addition proceeds in a
highly anti-selective fashion with the anti-b-hydroxyaldehyde
isomer to form the L-mannose structural motif.
Figure 1. The crystal structure of the a-anomer of hexose 2.
The hexoses were quantitatively converted into d-lactones
by oxidation with MnO2. For example, lactones 6 and 7 were
prepared in three steps with > 99% ee (Scheme 2). Thus, the
Scheme 2. Direct catalytic enantioselective synthesis of d-lactones 6
and 7.
Scheme 3. The reaction pathway for the amino acid catalyzed triketide
hexose synthesis.
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Angewandte
Chemie
Angew. Chem. 1997, 109, 1942; Angew. Chem. Int. Ed. Engl.
The ability of amino acids to catalyze the asymmetric
formation of sugars may have prebiotic significance. In fact, it
has been reported that terrestrial and extraterrestrial amino
acids catalyze the formation of tetroses under prebiotic
conditions.[14] Perhaps amino acids catalyzed asymmetric
aldol reactions according to the routes presented and trans-
ferred their chiral information to hexoses,[15] which are the
building blocks of prebiotic RNA and most common poly-
saccarides.
In summary, we disclose the direct amino acid catalyzed
asymmetric de novo synthesis of hexoses with excellent
chemo-, diastereo-, and enantioselectivity. The employment
of a two-step direct catalytic synthetic protocol furnished
either l- or d-sugars in most cases with > 99% ee. Thus, the
novel synthetic approach allows for the creation of four
contiguous stereocenters with excellent stereocontrol. Our
hexose synthesis is inexpensive and easy to conduct, and it
generates minimal waste products. The iterative aldol reac-
tion methodology allows for variation of both the catalyst and
the three carbonyl components, hence facilitating a modular
enantioselective synthesis of functional sugars and isotope-
labeled sugars. The ability of amino acids to mediate
asymmetric formation of natural sugars may support a
catalytic prebiotic homochirality pathway in which chiral
amino acids transferred their stereochemical information to
carbohydrates.
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Received: July 22, 2004
Published online: December 28, 2004
[11] a) A. Cꢁrdova, H. Sundꢂn, M. Engqvist, I. Ibrahem, J. Casas, J.
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[12] After the submission of this manuscript MacMillan and co-
workers reported an excellent short synthesis of hexoses based
on a proline-catalyzed dimerization of protected glycoaldehydes
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[13] CCDC-251202 contains the crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.cam.
ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambridge CB21EZ,
UK; fax: (+ 44) 1223-336-033; or deposit@ccdc.cam.ac.uk).
[14] S. Pizarello, A. L. Weber, Science 2004, 303, 1151. For a Zn/
amino acid mediated sugar synthesis under prebiotic conditions
see: J. Kofoed, M. Machuqueiro, J.-L. Reymond, T. Darbre,
Chem. Commun. 2004, 26, 1540.
Keywords: aldehydes · aldol reaction · asymmetric catalysis ·
carbohydrates · hexoses
.
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