Amino acid-catalyzed asymmetric carbohydrate formation: Organocatalytic one-step de novo synthesis of keto and amino sugars

Article abstract of DOI:10.1002/adsc.200505323

A direct de novo synthesis of ketoses and amino sugars by amino acid-catalyzed asymmetric aldol, Mannich and Michael reactions with dihydroxy-acetone phosphate mimics as donors is presented. Proline, proline derivatives and thiazolidine-4-carboxylic acids

Full text of DOI:10.1002/adsc.200505323

FULL PAPERS
DOI: 10.1002/adsc.200505323
Amino Acid-Catalyzed Asymmetric Carbohydrate Formation:
Organocatalytic One-Step De Novo Synthesis of Keto and
Amino Sugars
Ismail Ibrahem, Weibiao Zou, Yongmei Xu, Armando C o´ rdova*
Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
Fax: (þ46)-8-154-908, e-mail: acordova@organ.su.se, acordova1a@netscape.net
Received: August 17, 2005; Accepted: October 20, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A direct de novo synthesis of ketoses and ses, carbohydrate derivatives, amino and aza sugars
amino sugars byamino acid-catal yz ed as ym metric al-
and the total synthesis of polyoxamic acids. The addi-
dol, Mannich and Michael reactions with dihydroxy- tion of water significantlyaccelerated and improved
acetone phosphate mimics as donors is presented. the enantioselectivityof the proline-mediated biomi-
Proline, proline derivatives and thiazolidine-4-carbox- metic asymmetric CÀC bond-forming reactions.
ylic acids catalyzed the asymmetric assembly of keto
sugars and amino sugars in high yield with up to
>
99% ee. The organocatalytic C þC methodology Keywords: amino acids; asymmetric catalysis; carbo-
3
n
presented herein is a direct entryto the de novo syn- hydrate synthesis; dihydroxyacetone; ketoses; proline
thesis of orthogonallyprotected C , C , and C keto- derivatives
4
5
6
[
7]
Introduction
steps. The reduction of protective group strategies
can be accomplished bythe utilization of aldolase en-
Carbohydrates are involved in life-essential metabolic zymes as catalyst for the highly selective de novo syn-
[
3,8]
processes, signal transduction and the immune re- thesis of carbohydrates.
sponse. Theyare also the building blocks of several
[1]
Organocatalysis has experienced a renaissance in
fundamental oligo- and polysaccharides. The amino asymmetric catalysis and recently amino acid catalysis
acid-mediated asymmetric neogenesis of sugars is an an- was added to the repertoire of carbohydrate syn-
[
2]
[9–11]
cient process,[ which enzymes have catalyzed for bil- thesis.
For example, amino acids have been used as
3]
lions of years. The biosynthesis of sugars is accomplish- catalysts for the de novo synthesis of C aldoses with ex-
6
[
12]
ed via enzyme-catalyzed pathways from simple achiral cellent enantioselectivity. In this context and inspired
precursors with absolute stereocontrol. For example, bythe high selectivityof the DHAP-dependent aldolase
[
1a]
one of the keytransformations in the gluconeogenesis
is the aldolase enzyme-catalyzed aldol reaction between step de novo synthesis of C ketoses [Eq. (1)].
enzymes, we recently reported an organocatalytic one-
[
11f]
6
dihydroxyacetone phosphate (DHAP) and glyceralde-
hydes 3-phosphate that furnish fructose 1,6-diphos-
[1a,3a, b]
phate.
The rapidlygrowing development of glycobiologyand
carbohydrate-based pharmaceuticals sets demands for
the increased development of reaction design and meth-
odological advancement for the selective construction
[
4]
of natural and unnatural carbohydrates. In this con-
text, the de novo synthesis of carbohydrates is of im-
ð1Þ
[
5,6]
mense importance.
monosaccharide syntheses start from the chiral pool However, the chiral amine-catalyzed reaction between
and involve multiple steps and theyrequire protective 1,3-dihydroxyacetone and other acceptor aldehydes
group strategies and subsequent reduction-oxidation than protected (R)-glyceraldehyde gave the desired
However, most conventional
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Ismail Ibrahem et al.
products with low enantiomeric excesses. Moreover, Results and Discussion
onlytrace amounts of products were observed in orga-
nocatalytic Mannich reactions with dihydroxyacetone
as the donor.
Aldol Reactions
Protected dihydroxyacetone derivatives have been
employed as synthetic equivalents of 1,3-dihydroxyace- To begin with, we investigated the direct (S)-proline-cat-
tone for the synthesis of carbohydrate derivatives and alyzed asymmetric aldol reaction between dimethyl-1,3-
[
5]
polyhydroxylated compounds. In addition, protected dioxan-5-one (1) and p-nitrobenzaldehyde in DMSO
1,3-dihydroxyacetone derivatives have the advantages [Eq. (4)]. The reaction was slow and the desired aldol
of circumventing dimerization unlike 1,3-dihydroxyace- product 2a was isolated in 58% yield with 12:1 dr and
tone, and are soluble in organic solvents. Thus, our focus 73% ee after 7 days reaction time [Eq. (9)]. Water is
turned towards employing protected dihydroxyacetone known to have a beneficial effect in proline-catalyzed al-
[
16]
derivatives as DHAP mimics in direct organocatalytic dol reactions. Hence, we performed the above reac-
aldol reactions [Eq. (2)]. tion in wet DMSO. Thus, vigorouslystirring ketone 1
(
(
1.5 mmol), p-nitrobenzaldehyde (0.5 mmol) and water
2.5 mmol, 45 mL) in the presence of a catalytic amount
of (S)-proline (0.15 mmol) for 24 h furnished the desired
aldol product 2a in 72% yield with 18:1 dr (anti:syn) and
ð2Þ
93% ee [Eq. (5)].
Furthermore, amino acid-mediated enantioselective re-
actions have the advantage as compared to aldolase en-
zyme-catalyzed reactions of not being limited to alde-
hydes as electrophiles. Thus, the use of DHAP mimics
could plausibly be extended to organocatalytic asym-
[
13,14]
metric Mannich and Michael reactions [Eq (3)].
ð4Þ
ð5Þ
ð3Þ
We most recentlyreported a highlyenantioselective
The preliminaryaldol experiments with ketone 1 dem-
one-step de novo synthesis of carbohydrates using di- onstrated the importance of water to accomplish high
methyl-1,3-dioxan-5-one (1) as a DHAP mimetic in pro- stereoselectivityand enantioselectivityin the amino
[
15]
line-catalyzed aldol and Mannich reactions.
acid-catalyzed asymmetric aldol reactions.
In this paper, we present (i) the development of the di-
rect organocatalytic asymmetric aldol reactions be-
tween protected dihydroxyacetone 1 and different ac- Solvent Screen
ceptor aldehydes and its application in a one-step de
novo synthesis of C , C and C ketoses; (ii) the organo- We next performed a solvent screen for the proline-cat-
4
5
6
catalytic three-component asymmetric Mannich reac- alyzed aldol reaction between 1 and p-nitrobenzalde-
tion with 1 as the donor and its application in a de hyde (Table 1).
novo synthesis of orthogonally protected amino sugars;
The reaction worked in several of the solvents tested.
(
iii) the expeditious formal total synthesis of polyoxamic However, the reactions in NMP (N-methylmorphilidi-
acids; (iv) the proline-catalyzed asymmetric Michael re- none) and dioxane onlyfurnished trace amounts of 2a.
action with DHAP mimetic 1 as the donor and its appli- The fasted reaction rates were obtained in DMSO and
cation to the synthesis of aza-sugars; and (v) the kinetics the highest enantioselectivityin DMF. Importantl y, wa-
and mechanisms of the water-accelerated amino acid- ter (1–10 equivalents) accelerated and increased the
catalyzed CÀC bond-forming reactions.
enantioselectivity of the proline-catalyzed asymmetric
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One-Step De Novo Synthesis of Keto and Amino Sugars
Table 1. Solvent screen for the biomimetic aldol reaction.
FULL PAPERS
actions between 1 and aromatic acceptor aldehydes
were increased by20%.
The beneficial effect of a small amount of water can be
explained bya faster h yd rol ys is of intermediates of the
[
16]
catalytic cycle,
which increases turnover and sup-
presses catalyst inhibition.
Catalyst
We next screened a series of cyclic five-membered ami-
no acid derivatives and proline-derived dipeptides for
their abilityto mediate the direct organocatal yt ic one-
step de novo synthesis of carbohydrate derivatives
(
Table 2).
Table 2. Catalyst screen for the biomimetic aldol reaction.
[
a]
Isolated yield of the pure products after silica gel chroma-
tography.
dr¼anti/syn ratio of the products as determined byNMR.
Determined bychiral-phase HPLC anal ys is.
Reaction performed without 5 equivs. of water.
[
[
[
b]
c]
d]
n.d.¼not determined.
CÀC bond-forming reactions with DHAP mimetics. For
example, the aldol reactions without addition of water
were sluggish and progressed at a significantlylower
rate as compared to the reaction with 5 equivalents of
water (Figure 1). Furthermore, the enantiomeric excess
of the desired aldol products from proline-catalyzed re-
[
a]
Isolated yield of the pure products after silica gel chroma-
tography.
dr¼anti/syn ratio of the products as determined byNMR.
Determined bychiral-phase HPLC anal ys is.
10 mol% proline was used.
[
[
[
[
b]
c]
d]
e]
Figure 1. Product 2a formation as a function of time for the
proline-catalyzed enantioselective aldol reaction between ke-
tone 1 and p-nitrobenzaldehyde with no water added (~) and
Reaction performed in DMF without 5 equivs. of water.
5
equivalents of water present (
&
).
n.d.¼not determined.
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Ismail Ibrahem et al.
We found that several of the cyclic amino acids cata- Table 3. Direct proline-catalyzed de novo synthesis of keto-
[
17]
ses and polyhydroxylated compounds 2.
lyzed the reaction with excellent enantioselectivity.
For example, hydroxyproline was able to catalyze the
formation of 2a in 45% yield with 4:1 dr and>99% ee
after 24 h. In addition, proline-derived dipeptides were
able to catalyze the formation of 2a. However, the reac-
tion conditions are veryimportant to achieve a high
asymmetric induction. For example, (S)-pro-(S)-pro
mediated the formation of 2a in 88% yield with 2:1 dr
and 60% ee when the reaction was performed in DMF
and no water was added. Proline was the most efficient
organocatalyst tested in Table 2. In addition, lowering
the catalyst amount to 10% significantly increased the
reaction time as well as decreased the ee of 2a from 93
to 83%.
Substrate Scope
Based on the solvent and catalyst screen, we chose to
perform the organocatalytic asymmetric aldol reactions
between DHAP mimetic 1 and different acceptor alde-
hydes with proline as the catalyst and in wet DMSO (Ta-
ble 3).
The reactions proceeded smoothlyand aldol products
2
9
a–2i were isolated in high yield and up to>19:1 dr and
3–¼98% ee. In particular, the reactions with aliphatic
acceptor aldehydes were highly diastereoselective and
enantioselective. For example, protected ribulose 2c
was synthesized in 85% yield with>19:1 dr and¼
9
8% ee (entry4). Furthermore, the ( S)-proline-cata-
lyzed diastereoselective aldol reaction between 1 and
protected (R)-glyceraldehyde furnished the corre-
sponding d-tagatose in 74% yield with>19:1 dr and¼
[
a]
Isolated yield of the pure products after silica gel chroma-
tography.
dr¼anti/syn ratio of the products as determined byNMR.
Determined bychiral-phase HPLC anal ys is. Bn ¼benzyl.
No water was added.
[
[
b]
c]
9
8% ee (entry5). In addition, ( R)-proline catalysis fur-
nished d-psicose in 68% yield with>19:1 dr and¼
[d]
[e]
98% ee (entry6). Hence, amino acid catal ys is provides
Based on the ee value of the starting protected (R)-glycer-
aldehyde and chiral shift reagents.
a new entryfor a one-step s yn thesis of C þC sugars
3
n
with excellent stereoselectivity. The unique feature of
these results is that a single reaction sequence can con-
vert a protected dihydroxyacetone into a carbohydrate
in one step with enzyme-like stereoselectivity when an cyclic 5-membered amino acid derivatives catalyzed
amino acid is employed as the catalyst. In the cases of ar- the asymmetric assembly of protected d-tagatose 2d
omatic acceptor aldehydes, the reactions proceeded and (R)-proline mediated the formation of d-piscose
[
5]
with moderate diastereoselectivityand excellent enan-
2e, respectively. Thus, the stereoselectivityof ( S)-pro-
tioselectivity. For example, aldol product2f was isolated line and (R)-proline are complimentaryto tagatose al-
[
3b]
in 77% yield with 2:1 dr and 96% ee (Entry 7). More- dolase and fuculose aldolase, respectively. Moreover,
over, the (S)-proline-catalyzed self-aldol reaction of ke- the acetonide protective groups were readilyremoved
tone 1 furnished the protected dendroketose in 61% bystandard acidic conditions to give the corresponding
yield and 95% ee. The reactions were operationally sim- natural d-ketoses (Scheme 1).
ple and can be performed on a gram-scale.
Furthermore, the optical rotation and spectral data of
the anti-aldol product 2e demonstrated that the absolute
and relative stereochemistryof the aldol products de-
rived by( S)-proline and its derivatives catalysis is in ac-
cordance with previous reported (S)-proline-catalyzed
Determination of the Absolute Stereochemistry
[
5]
The absolute and relative configurations of the known reactions.
ketoses 2d and 2e confirmed that (S)-proline and other
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One-Step De Novo Synthesis of Keto and Amino Sugars
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Table 4. Solvent screen for the biomimetic Mannich reaction.
Scheme 1. Deprotection of d-tagatose.
[
a]
Isolated yield of the pure products after silica gel chroma-
tography.
[
[
b]
c]
Dr¼anti/syn ratio of the products as determined byNMR.
Asymmetric Mannich Reactions
Determined bychiral-phase HPLC anal ys is.
n.d.¼not determined.
Amino and aza sugars are of immense importance as en-
zyme inhibitors and aminoglycosidase mimics. They
are usuallyprepared in multi-step s yn thetic sequences.
[18]
p-anisidine and a-ethyl glyoxylate in different solvents
Retro-synthetic analysis suggested that amino acid-cat- (Table 4).
alyzed asymmetric three-component Mannich reactions
We found that proline was able to catalyze the forma-
with DHAP mimetic 1 would be a potential one-step en- tion of 3b in all solvents tested. The order of reactivityof
tryto orthogonallyprotected amino sugars [Eq. (3)]. In
the solvents was in the following order: DMSO, TFE,
an initial experiment, ketone 1 (1.5 mmol), formalde- NMP and DMF. The highest enantioselectiviywas ob-
hyde (1 mmol, 36% aqueous solution) and p-anisidine tained in DMSO and DMF. The proline-catalyzed Man-
(
1.1 mmol) were vigorouslystirred in the presence of a
nich reaction in chloroform furnished nearlyracemic
catalytic amount of (S)-proline (0.15 mmol) [Eq. (6)]. amino acid derivative 3b.
After 24 h the desired protected amino sugar 3a was iso-
[
15a]
lated in 84% yield and>99% ee.
Substrate Scope and Formal Total Synthesis
Encouraged bythis result we decided to investigate the
proline-catalyzed three-component Mannich reactions
between donor 1, p-anisidine and different acceptor al-
dehydes in wet DMSO (Table 5).
The proline-catalyzed asymmetric Mannich reactions
proceeded with excellent chemoselectivityand the cor-
responding products 3a–3 g were isolated in good yield
and in several cases with >92% ee. The addition of wa-
ter (5 equivalents) was of significant importance. For ex-
ample, the (S)-proline-catalyzed Mannich reaction be-
tween 1, p-anisidine and a-benzyloxyacetaldehyde
without addition of water furnished trace amounts of
the corresponding p-methoxyphenyl (PMP) protected
amino sugar 3c (Entry3). In contrast, addition of 5
equivalents of water to the reaction mixture significant-
lyaccelerated the reaction and protected 4-amino-4-de-
ð6Þ
Solvent Screen
We next investigated the one-pot direct proline-cata- oxy-threo-pentulose 3c was isolated in 70% yield in a 6:1
lyzed three-component Mannich reaction between 1, dr (syn:anti) and 98% ee (Entry4). Moreover, the ( R)-
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Ismail Ibrahem et al.
Table 5. Direct proline-catalyzed three-component asymmet-
ric Mannich reactions with DHAP mimetic 1.
Scheme 2. The highlychemo- and enantioselective one-step
synthesis of protected polyoxamic acid 4.
[
20]
acids involve around six to eight steps. However, ret-
ro-synthetic analysis suggests that amino acid-catalyzed
asymmetric Mannich reactions between 1 and a-ethyl
glyoxylate would be a novel short entry for the synthesis
of polyoxamic acids. Thus, in situ chemoselective reduc-
tion of the keto functionalityof the amino acid deriva-
tive 3b derived by( S)-proline catalysis furnished the de-
sired polyoxamic acid 4 in 30% yield as a predominant
diastereomer and >99% ee (Scheme 2). Our reaction
constitutes a novel one-step total synthesis of orthogo-
nallyprotected polyoxamic acids such as 4. Importantly,
either enantiomer of the polyoxamic acid 4 can be
formed bysimplyutilizing ( S)- or (R)-proline as the cat-
alyst.
The direct catalytic three-component asymmetric
Mannich reaction was also catalyzed by praline-tetra-
[
a]
Isolated yield of the pure products after silica gel chroma-
tography.
dr¼syn/anti ratio of the products as determined byNMR.
Determined bychiral-phase HPLC anal ys is.
Not determined.
zole with excellent chemo- and enantioselectivity
[
[
[
[
b]
c]
d]
e]
[21]
[
Eq. (7)].
Based on the ee value of the starting protected (R)-glycer-
aldehyde.
Bn¼benzyl.
proline-catalyzed three-component Mannich reaction
between DHAP mimetic 1, p-anisidine and R-isopropy-
lideneglyceraldehyde proceeded with high chemo- and
diastereoselectivityand furnished the corresponding
protected d-4-amino-4-deoxysorbose 3e in 55% yield
with >19:1 dr and¼98% ee. In this case, (R)-proline
was more efficient than (S)-proline. However, the pro-
line-catalyzed Mannich reactions with benzaldehyde
and i-butyraldehyde furnished the corresponding prod-
uct 3f and 3 g with 75% ee and 48% ee, respectively.
Thus, onlymoderate ees were obtained in these cases.
The proline-catalyzed one-pot three-component Man-
nich reactions between a-glyoxylate, ketone 1, and p-
anisidine furnished the desired amino acid derivative
ð7Þ
Determination of the Absolute Stereochemistry
3
b in 77% yield with 16:1 dr and>99% ee (Entry2).
The reaction is readilyscaled up and the amino acid-cat-
alyzed asymmetric assembly of 3b was performed on a 3 were assigned byNMR analysis and the absolute con-
gram scale. figuration based on correlation to the established previ-
Polyxamic acids are naturally occurring and parts of ous (S)-proline-catalyzed Mannich reactions. For ex-
The relative stereochemistries of the Mannich products
[
13]
[19]
polyoxindes. Previous total syntheses of polyoxamic ample, (S)-proline asymmetrically assembled the corre-
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One-Step De Novo Synthesis of Keto and Amino Sugars
sponding the l-amino sugar 3a as determined bysynthe-
FULL PAPERS
reacts with the chiral enamine and CÀC bond formation
[
13 g]
sis.
The relative configuration of the products was occurs resulting in an iminium intermediate, which also
syn and (S)-proline mediated the asymmetric assembly potentially undergoes oxazolinone formation. Hydroly-
of (S)-amino acid derivative 3b.
sis of the product iminium intermediate bywater gives
the enantiomericallyenriched aldol product and the cat-
alytic cycle can be repeated.
Michael Reactions
The same reaction mechanism is true for the proline-
catalyzed direct asymmetric Mannich reactions (Sche-
We next turned our attention towards a plausible syn- me 3b). However, in this case, the chiral enamine inter-
thesis of polyhydroxylated pyrrolidines, which are mediate reacts with the in situ generated imine to give an
used as enzyme inhibitors, via amino acid-catalyzed Mi- enantiomericallyenriched Mannich product (after hy-
chael reactions between DHA mimetic 1 and nitrostyr- drolysis).
enes [Eq. (3)]. In an initial experiment, ketone 1
The stereochemistryof the ( S)-proline-catalyzed al-
(
1.5 mmol), H O (5 mmol) and phenylnitrostyrene dol reactions with 1 was explained in terms of a Re-facial
2
(
0.5 mmol) in DMSO (2.0 mL) were reacted in the pres- attack on the aldehyde by the Si-face of the enamine
ence of a catalytic amount of (S)-proline. After 8 days (Figure 2, I). The stereochemistryof the ( S)-proline-cat-
of vigorous stirring the desired Michael product 5 alyzed Mannich reactions with 1 was explained in terms
was isolated in 40% yield with 6:1 dr and 11% ee of an Si-facial attack on the imine with a trans-configu-
[22]
[
Eq. (8)].
ration bythe Si-face of the enamine (Figure 2, II). The
six-membered transition states I and II are stabilized
byh yd rogen bonding between the ox yg en atom of the
aldehyde and the nitrogen atom of the imine and the car-
boxylic group of proline, respectively. The switch of fa-
cial selectivitybetween the aldeh yd e and imine is ex-
plained bythe fact that a Re-facial attack on the imine
would lead to steric repulsion with the pyrrolidine moi-
etyof the enamine. Hence, proline affords b-hydroxy
ketones 2 with anti-configuration and b-amino ketones
[
13b, q,24]
3
with a syn-stereochemistry.
The small excess of water will potentiallyfacilitate
proton-transfer in the transition state, which both lowers
the LUMO of the incoming electrophile as well as di-
rects the enantioselectivityof the newlyformed stereo-
centers. Thus, the higher Brønsted acidityof the amino
acid when water is added to the polar aprotic organicsol-
vent plausiblyaccounts for the observed higher stereo-
selectivity of the water accelerated carbohydrate syn-
thesis and Mannich reactions. Moreover, a small amount
of water stabilizes the carbanion that is formed in the
transition states I and II.
ð8Þ
The Michael adduct was readilytransformed to the cor-
responding pyrrolidine 6 byh yd rogenation. Thus, the
amino acid-catalyzed Michael reactions with 1 as the do-
nor constitutes a novel entryto important hydroxy-sub-
stituted pyrrolidines or aza sugars.
Conclusion
In summary, we disclose thede novo synthesis of ketoses
byamino acid-catal yz ed C ÀC bond-forming reactions
with dihydroxyacetone mimetic 1 as the donor. The cy-
clic five-membered amino acids catalyzed the asymmet-
ric assemblyof keto sugars and amino sugars with en-
zyme-like selectivity to yield the desired carbohydrates
Mechanism
The mechanism of the proline-catalyzed aldol reactions in high yield with up to >99% ee. The organocatalytic
with DHAP mimetic 1 is depicted in Scheme 3a. The do- C þC methodologypresented herein is a direct entry
3
n
nor 1reacts with proline, resulting in iminium formation. to a one-step de novo synthesis of orthogonally protect-
The iminium intermediate can either form an enamine ed C , C and C ketoses. In comparison to aldolase en-
4
5
6
[
23]
or an oxazolidinone intermediate. The oxazolidinone zymes, organocatalysis has a broader scope with respect
formation leads to catalyst inhibition and consequently to the electrophile. Thus, orthogonallyprotected amino
decrease of the turnover. Next, the acceptor aldehyde sugars and nitro sugars are synthesized by proline-medi-
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Ismail Ibrahem et al.
Scheme 3. a) The reaction mechanism of the proline-catalyzed direct asymmetric aldol reactions with 1 as the donor. b) The
reaction mechanism of the proline-catalyzed direct asymmetric Mannich reactions with 1 as the donor.
ated asymmetric Mannich and Michael reactions. A tion of water (1–10 equivs.) significantlyaccelerates
novel one-step formal total synthesis of polyoxamic and improves the enantioselectivityof the proline-medi-
acids was also accomplished. We found that an impor- ated asymmetric reactions with protected dihydroxya-
tant water effect existed in the proline-catalyzed biomi- cetones as donors, which is due to suppression of catalyst
metic aldol, Mannich and Michael reactions. The addi- inhibition during the catalytic cycle and more efficient
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One-Step De Novo Synthesis of Keto and Amino Sugars
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ed on an IonSpec FTMS mass spectrometer with a DHB-ma-
trix.
Typical Experimental Procedure for the Proline-
Catalyzed Asymmetric Biomimetic Aldol Reactions
with 1 as the Donor
The aldehyde (0.5 mmol) was added to a round-bottomed flask
charged with proline (30 mol %) and 2 mL DMSO. Next, the
ketone 1 (1.5 mmol) and water (2.5 mmol, 45 mL) were added
to the flask and the mixture was vigorouslystirred for 24 h at
room temperature. The reaction was quenched byaddition of
brine followed byextraction with EtOAc. The aqueous-phase
was back-extracted with EtOAc (3Â15 mL). The combined
organic layers were dried over anhydrous NaSO , filtered
4
and concentrated. The pure protected sugars 2 were obtained
bysilica gel column chromatography(toluene: EtOAc mix-
tures).
Figure 2. Proposed transition states I and II for the proline-
catalyzed asymmetric aldol and Mannich reactions, respec-
tively.
Typical Experimental Procedure for the Proline-
Catalyzed Asymmetric Biomimetic Three-Component
Mannich Reactions with 1 as the Donor
stabilization of the carbanion in the transition state, re-
The aldehyde (0.5 mmol) was added to a round-bottomed flask
spectively. In addition, the high stereoselectivity of the charged with proline (30 mol %), p-anisidine (0.55 mmol) and
amino acid-catalyzed carbohydrate synthesis makes it 2 mL DMSO. Next, the ketone 1 (1.5 mmol) and water
(
2.5 mmol, 45 mL) were added to the flask and the mixture
an attractive alternative to biocatalytic carbohydrate
synthesis. The reaction constitutes an environmentally
benign route for the expeditious synthesis of valuable
carbohydrates.
was vigorouslystirred for 24 h at room temperature. The reac-
tion was quenched byaddition of brine followed byextraction
with EtOAc. The aqueous-phase was back-extracted with
EtOAc (3Â15 mL). The combined organic layers were dried
over anhydrous NaSO , filtered and concentrated. The pure
4
protected amino sugars 3 were obtained bysilica gel column
chromatography(toluene:EtOAc mixtures). In the case of
Mannich product 3a, neutral aluminum oxide was used for
the column chromatography.
Experimental Section
General Methods
Chemicals and solvents were either purchased puriss p.A. from
commercial suppliers or purified bystandard techniques. For
thin-layer chromatography (TLC), silica gel plates Merck 60
F254 were used and compounds were visualized byirradiation
with UV light and/or bytreatment with a solution of phospho-
molybdic acid (25 g), Ce(SO ) .H O (10 g), concentrated H
2
One-Pot Three-Component Asymmetric Synthesis of
Protected Polyoxamic Acid 4
The a-ethyl glyoxylate (0.5 mmol) was added to a round-bot-
tomed flask charged with proline (30 mol %), p-anisidine
(0.55 mmol) and 2 mL DMSO and the reaction mixture was
stirred for 20 minutes. Next, the ketone 1 (1.5 mmol) and water
(2.5 mmol, 45 mL) were added to the flask and the mixture was
vigorouslystirred for 24 h at room temperature. The reaction
temperature was decreased to 08C and the mixture diluted
4
2
2
SO (60 mL), and H O (940 mL) followed byheating or by
4
2
treatment with a solution of p-anisaldehyde (23 mL), concen-
trated H SO4 (35 mL), acetic acid (10 mL), and ethanol
2
(
900 mL) followed byheating. Flash chromatographywas per-
formed using silica gel Merck 60 (particle size 0.040–
1
13
0
.063 mm), H NMR and C NMR spectra were recorded on
with MeOH (2.0 mL). Next, NaBH was slowlyadded to the re-
4
Varian AS 400 and 300. Chemical shifts are given in d relative
to tetramethylsilane (TMS), the coupling constants Jare given
action mixture which was stirred at 08C. After 15 minutes the
reaction mixture was slowlyadded to a mixture of EtOAc
(15.0 mL) and 2 N HCl (2.0 mL), the whole was cooled to
08C, and stirred for 20 minutes. Then the reaction mixture
in Hz. The spectra were recorded in CDCl as solvent at room
3
temperature, TMS served as internal standard (d¼0 ppm) for
1
H NMR, and CDCl was used as internal standard (d¼
was dried with MgSO and filtered. The organic phase was con-
3
4
13
7
3
7.0 ppm) for C NMR. GC was carried out using a Varian
800 GC Instrument. Chiral GC-column used: CP-Chirasil-
centrated and purified bysilica gel column chromatography
(toluene:EtOAc, 1:1) to give polyoxamic acid 4 as a clear oil;
1
Dex CB 25 mÂ0.32 mm. HPLC was carried out using a Waters
690 Millennium with photodiode arraydetector. Optical rota-
tions were recorded on a Perkin Elmer 241 Polarimeter (d¼
89 nm, 1 dm cell). High-resolution mass spectra were record-
yield: 52 mg (30%). H NMR (400 MHz, CDCl ): d¼1.22 (t,
3
2
J¼7.2 Hz, 3H), 1.43 (s, 3H), 1.47 (s, 3H), 3.74 (s, 3H), 3.79
(m, 1H), 3.86 (dd, J¼12.1, 2.1 Hz, 1H), 4.01 (d, J¼1.8 Hz,
1H), 4.07 (m, 1H), 4.12–4.24 (m, 2H), 4.33 (m, 1H), 6.78 (s,
5
Adv. Synth. Catal. 2006, 348, 211 – 222
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
219

FULL PAPERS
Ismail Ibrahem et al.
1
3
4
6
1
H); C NMR (100 MHz, CDCl ): d¼14.5, 18.9, 29.4, 55.8,
benzaldehyde (0.5 mmol) was added to a round-bottomed
flask charged with proline (30 mol %) and 2 mL DMSO.
Next, the ketone 1 (1 mmol) and water (2.5 mmol, 45 mL)
were added to the flask and the reaction mixture was vigorous-
lystirred at room temperature. After one of the times shown in
3
1.7, 62.6, 65.5, 65.9, 66.6, 99.6, 114.9, 118.4, 139.9, 154.7,
2
6
71.2; [a] : À16.4 (c¼1.0, CHCl ); MALDI-TOF MS:
D
3
þ
m/z¼362.1582; calcd. for C H O N (MþNa ): 362.1580.
1
7
25
6
Figure 1 ( ) an aliquot of the reaction mixture (10 mL) was dis-
&
solved in CDCl and the conversion of p-nitrobenzaldehyde
3
Proline-Catalyzed Asymmetric Biomimetic Michael
Reactions with 1 as the Donor and Asymmetric
Synthesis of Aza Sugar 6
and formation of 2a were determined byNMR analysis.
A series of parallel reactions were also started in parallel and
run for different reaction times, which are shown in Figure 1
(
~). The p-nitrobenzaldehyde (0.5 mmol) was added to a
round-bottomed flask charged with proline (30 mol %) and
mL DMSO. Next, the ketone 1 (1 mmol) was added to the
flask and the reaction mixture was vigorouslystirred at room
temperature. After one of the times shown in Figure 1 (~) an
aliquot of the reaction mixture (10 mL) was dissolved in
To a suspension of l-proline (30 mol %) in DMSO (1 mL) and
H O (10 equivs.) was added the dioxanone (0.75 mmol) and ni-
2
2
troolefin (0.25 mmol). The resulting mixture was allowed to
stir until TLC indicated complete conversion. The reaction
was quenched with brine and extracted with ethyl acetate
(
3Â10 mL), the combined organic phase was dried over anhy-
CDCl and the conversion of p-nitrobenzaldehyde and forma-
dride Na SO , filtered and concentrated under vacuum. The
3
2
4
tion of 2a were determined byNMR analysis.
residue was purified bysilica gel column chromatography
(
pentane:EtOAc,15:1 ! 4:1) to give the Michael product 5;
1
yield: 28 mg (40%). H NMR (CDCl , 400 MHz): d¼7.38–
3
7
.21 (m, 5H, Ar), 4.92 (dd, 1H, J¼12.8, 9.2 Hz), 4.67 (dd, 1H,
Acknowledgements
J¼12.8, 6.8 Hz), 4.58 (dd, 1H, J¼3.6, 1.2 Hz), 4.12 (ddd, 1H,
J¼9.2. 6.8, 4.0 Hz), 3.90–3.86 (m, 2H), 1.46 (s, 3H), 1.45 (s,
Support by Prof. J.-E. Bäckvall and Stockholm University is
gratefully acknowledged. We thank the Swedish National Re-
search Council, Lars Hierta Foundation, Carl-Trygger Founda-
tion and Wenner-Gren Foundation for financial support.
1
3
3
1
H); C NMR (CDCl , 100 MHz): d¼206.72, 134.82, 129.39,
3
28.49, 128.07, 101.13, 76.34, 74.54, 66.99, 43.22, 24.01, 23.22;
HPLC (Daicel Chiralpak AS, iso-hexanes/i-PrOH¼90:10,
flow rate 0.5 mL/min, l¼230 nm): major isomer: t ¼
R
2
5
1
7.71 min; minor isomer: t ¼21.69 min; [a] : À33.4 (c 1.0,
R
D
References and Notes
CHCl ).
3
A mixture of nitroketone 5 (28 mg, 0.1 mmol ) and 20%
Pd(OH) on carbon (4 mg) in 5 mL of methanol was hydrogen-
ated at 90 psi for 2 days. The solution was filtered through celite
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and concentrated to give aza sugar 6 as a liquid; yield: 20 mg
1
(
86%). H NMR (CDCl , 300 MHz): d¼7.41–7.18 (m, 5H,
3
Ar), 4.29 (dd, 1H, J¼5.1, 2.1 Hz), 4.21–4.10 (m, 2H), 3.86
(
9
dd, 1H, J¼9.3, 8.4 Hz), 3.31–3.23 (m, 1H), 2.91 (1H, J¼
1
3
.9 Hz), 2.83–2.75 (m, 1H), 1.40 (s, 3H), 1.39 (s, 3H);
C
NMR (CDCl , 75.44 MHz): d¼141.69, 128.66, 127.47, 126.82,
3
98.06, 75.36, 64.37, 63.24, 59.05, 48.56, 28.66, 19.73.
2
004, 26, 1540.
Typical Experimental Procedure for the Catalyst
Screen
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2
94, 369.
45 mL) were added to the flask and the reaction mixture was
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back-extracted with EtOAc (3Â15 mL). The combined organ-
2
001.
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1
19; d) D. Enders, M. Voith, S. J. Ince, Synthesis 1996,
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Experimental Procedure for the Measurements of the
Formation of 2a as a Function of Time
Several reactions were started in parallel and run for different
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&
). The p-nitro-
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 211 – 222