Direct organocatalytic de novo synthesis of carbohydrates

Article abstract of DOI:10.1002/anie.200462428

One small step for a catalyst: A biomimetic asymmetric synthesis of carbohydrates was accomplished by a proline-catalyzed aldol reaction of 2,2-dimethyl-1,3-dioxan-5-one as the methylene component with various aldehydes. This new organocatalytic C₃+C_n strategy leads directly to selectively protected simple sugars and amino sugars.

Full text of DOI:10.1002/anie.200462428

Communications
catalysts. While in part good diastereoselectivities were
[
10]
reached, the products turned out to be racemic in all cases.
We now report on the successful development of the first
diastereo- and enantioselective organocatalytic aldol reaction
[
11]
with 2,2-dimethyl-1,3-dioxan-5-one (1, dioxanone)
as a
DHA equivalent and methylene component. When suitable
aldehyde carbonyl components are employed, this biomi-
metic C +C strategy facilitates the direct assembly of
3
n
selectively protected ketoses in one step.
For our first example we chose 2-methylpropanal (2a) as a
model system for the aldol reaction with dioxanone and
optimized the reaction conditions in terms of chemical yield,
enantiomeric excess, and anti/syn ratio. The best reaction
conditions so far call for (S)-proline as the catalyst, DMF as
the solvent, and a temperature of 28C. The anti aldol product
Asymmetric Synthesis
Direct Organocatalytic De Novo Synthesis of
Carbohydrates**
3
a was obtained diastereoselectively with an excellent yield
of 97%, an anti/syn ratio of > 98:2, and a high enantiomeric
excess of 94% ee. Subsequently we were also able to show
that the aldol reaction of 1 with the a-branched aldehydes 2a,
b, d–g proceeds with good to very good yields, excellent anti/
syn ratios, and enantiomeric excesses in all cases (Scheme 1,
Dieter Enders* and Christoph Grondal
Dedicated to Professor Wilhelm Keim
on the occasion of his 70th birthday
Carbohydrates are a class of natural products of great
[
1]
importance in chemical, biological, and medicinal research.
Carbohydrates play a key role in many biological processes,
for example, as components of glycoproteins, nucleic acids,
[
2]
glycolipids, peptido- and proteoglycans, and liposaccharides.
They are both target molecules in modern organic synthesis
and sources of enantiopure building blocks (chiron
[
3]
[4]
approach) and chiral auxiliaries. An extensive arsenal of
methods for the de novo synthesis of carbohydrates is already
available, but typically several synthetic steps and extensive
[
5]
protecting group manipulations are necessary. Recently,
MacMillan et al. disclosed a “two-step” synthesis of aldo-
hexoses based on an asymmetric proline-catalyzed aldol
[
6]
reaction. Nature also employs a stereoselective aldol
reaction in the biosynthesis of carbohydrates; the carbohy-
drate skeleton is assembled by means of an enzyme-catalyzed
[
7]
aldol reaction of dihydroxyacetone phosphate (DHAP).
The application of DHAP in carbohydrate synthesis has
been investigated quite intensively with biological methods in
[
8]
particular, but also chemical methods could be employed
successfully with DHA and its derivatives as C building
3
[
9]
blocks in asymmetric synthesis. A new challenge concerning
syntheses with DHA as a C building block is the develop-
3
ment of organocatalytic methods. Barbas III et al. described a
direct aldol reaction of DHA with different aldehydes, in
which proline and various proline derivatives were used as
Scheme 1. (S)- and (R)-proline-catalyzed asymmetric aldol reaction of
dioxanone with various aldehydes.
Table 1). When the linear aldehyde 2c was employed, the
aldol product 3c was isolated in only moderate yield (40%),
but still excellent stereoselectivity (anti/syn = > 98:2,
[
*] Prof. Dr. D. Enders, Dipl.-Chem. C. Grondal
Institut fꢀr Organische Chemie
RWTH Aachen
Professor-Pirlet-Strasse 1, 52074 Aachen (Germany)
Fax: (+49)241-809-2127
9
7% ee). The lower yield may be explained by the fact that
linear aldehydes also undergo self-aldol condensation, which
is in direct competition with the crossed-aldol reaction. The
use of aromatic aldehydes as the carbonyl component
reduced the diastereoselectivity. For example, the (S)-pro-
line-catalyzed aldol reaction of 1 with ortho-chlorobenzalde-
hyde proceeded with a good yield of 73% but with an anti/syn
E-mail: enders@rwth-aachen.de
[
**] This work was supported by the Fonds der Chemischen Industrie
Kekulꢁ fellowship for C.G.). We thank the companies Degussa AG,
BASF AG, and Bayer AG for the donation of chemicals.
(
1
210
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200462428
Angew. Chem. Int. Ed. 2005, 44, 1210 –1212

Angewandte
Chemie
Table 1: (S)-proline-catalyzed asymmetric aldol reaction of dioxanone 1
[
a]
with aldehydes 2 to form the aldol products 3 (see Scheme 1).
[
b]
[c]
[d]
3
R
Yield [%]
anti/syn [%]
ee [%]
a
b
c
CH(CH )
97
86
40
69
>98:2
>98:2
>98:2
94:6
94
90
97
93
3
2
[i]
Cy
CH OBn
[i]
2
d
CH(OCH3)2
[
[
[
[
e,f]
g]
e
f
76
80
31
80
>98:2
>98:2
>98:2
>98:2
ꢀ98
ꢀ96
ꢀ96
ꢀ96
Scheme 2. Deprotection of 3e to give d-psicose (4) (mixture of the
four isomers a,b-d-psicofuranose and a,b-d-psicopyranose).
The formation of the anti aldol products 3 and the
e,g]
h]
f’
g
absolute configurations given are consistent with related
[
15]
proline-catalyzed aldol reactions. The
absolute configurations were also con-
firmed by polarimetric comparison with
independently synthesized aldol prod-
[
16]
ucts.
The observed relative topicity
[
a] General reaction conditions: 2.3 mmol dioxanone, 2.3 mmol alde-
hyde, 30 mol% (S)-proline, 1.2 mL DMF, 28C, 6 d. [b] Yields of 3 isolated
can be explained by the Houk–List
model for proline-catalyzed aldol reac-
tions with cyclic ketones, where an
enamine intermediate and an intermo-
lecular hydrogen bond play the decisive
1
after flash chromatography on silica gel. [c] Determined by H and
1
3
C NMR spectroscopy. [d] Determined by HPLC on chiral stationary
phases (Chiralpak AD, Chiralpak IA 5m, Daicel IA, Daicel OJ, Whelk 01).
Figure 1. Postulated
transition state
[e] (R)-proline was used as the catalyst. [f] Based on the ee value of 2e.
[g] Based on the ee value of 2 f. [h] Based on the ee value of 2g.
[i] Abbreviations: Bn=benzyl, Boc=tert-butyloxycarbonyl, Cbz=benzyl-
(Houk–List model)
for the (S)-proline-
catalyzed one-step
de novo synthesis of
simple sugars and
derivatives.
[
17]
role (Figure 1).
Further investigations revealed that
under proline catalysis compound 1
underwent self-aldol condensation to
give the adduct 5, which represents a
direct precursor of (S)-dendroketose
oxycarbonyl, Cy=cyclohexyl.
ratio of only 4:1 and enantiomeric excesses of 86% ee (anti)
and 70% ee (syn). The aldol products 3 accessible directly by
organocatalysis are selectively and partly orthogonal doubly
protected sugars and amino sugars, for example, l-ribulose
[
18]
(Scheme 3).
The aldol addition proceeded with high
enantioselectivity (94% ee) and a moderate yield of 57%.
This observation shows that in principle ketones can act as
carbonyl components under formation of quaternary stereo-
genic centers. It is unnecessary to point out that a simple
change of (S)- to (R)-proline as catalyst leads to the opposite
absolute configurations at the aldol C /C centers (here (R)-
(3c), d-erythro-pentos-4-ulose (3d), 5-amino-5-deoxy-l-psi-
cose (3 f, g), and 5-amino-5-deoxy-l-tagatose (3 f’). In the case
of 3d, the stereoselective ketose reduction followed by acetal
[
12]
hydrolysis should lead to an aldose (“inversion strategy”),
3
4
which will greatly expand the potential of this new protocol.
When we used the S-configured, enantiomerically pure
NBoc- (2 f) and NCbz-protected Garner aldehydes (2g), (S)-
proline proved to be the appropriate catalyst, since high
chemical yields (80%), excellent anti/syn ratios (> 98:2), and
high ee values (96% ee) were obtained for the corresponding
aldol products 3 f and 3g. As expected, (R)-proline was not
the appropriate catalyst for this aldol reaction because it led
to a significant decrease in yield (31%) although the
diastereoselectivity remained high (for 3 f’). Consequently,
dendroketose, see also 3e and 3 f’).
Scheme 3. (S)-proline-catalyzed asymmetric self-aldol condensation of
dioxanone 1 to give the double acetonide-protected (S)-dendroketose
(R)-proline was the appropriate catalyst for the reaction of a-
5.
branched R-configured aldehydes. This could be confirmed by
the aldol reaction of 1 with the R-configured 2,3-O-(isopro-
[
13]
pylidene)-d-glyceraldehyde (2e).
The double acetonide-
In conclusion, our asymmetric, (S)-proline-catalyzed aldol
[
14]
protected d-psicose 3e, which was obtained with 76% yield
in this way, was quantitatively deprotected with an acidic ion-
exchange resin (Dowex W50X2-200) to give the parent d-
psicose (4, Scheme 2). The identity of the ketohexose could be
proven unambiguously by spectroscopic comparison ( H and
C NMR, HPLC, and optical rotation data) with an authen-
reaction of the DHA equivalent 1 with various aldehydes
generates the same relative and absolute configuration as the
enzyme tagatose aldolase (TagA). Whereas the TagA cata-
[
19]
lyzed aldol reaction proceeds unselectively,
our organo-
1
catalytic approach offers a viable alternative. As shown with
the asymmetric synthesis of the rare ketosugar d-psicose (4)
and related simple sugars and amino sugars, this new protocol
1
3
tic, commercially available sample.
Angew. Chem. Int. Ed. 2005, 44, 1210 –1212
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1211

Communications
opens an impressively simple, biomimetic direct approach to
56; b) K. M. Koeller, C.-H. Wong, Chem. Rev. 2000, 100, 4465 –
493; c) A. Varki, Glycobiology 1993, 3, 97 – 130.
3] S. Hanessian, Total Synthesis of Natural Products: The “Chiron”
Approach, Pergamon, Oxford, 1983.
4] H. Kunz, K. Rꢁck, Angew. Chem. 1993, 105, 355 – 377; Angew.
Chem. Int. Ed. Engl. 1993, 32, 336 – 358.
4
selectively and differently protected simple carbohydrates
and related compounds in practically one step. At present, we
are optimizing and extending this procedure by varying the
methylene and carbonyl components as well as the organo-
catalyst.
[
[
[
5] a) T. Ogawa, Chem. Soc. Rev. 1994, 23, 397 – 407; b) S. J.
Danishefsky, M. T. Bilodeau, Angew. Chem. 1996, 108, 1482 –
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Hanessian, Preparative Carbohydrate Chemistry, Marcel
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lan, Angew. Chem. 2004, 116, 2004 – 2006; Angew. Chem. Int. Ed.
Experimental Section
Unless otherwise stated, all chemicals are commercially available and
were used without further purification. All new compounds were fully
characterized (IR, NMR, MS, elemental analysis, optical rotation).
[
3
e: Compound 1 (1.0 g, 7.69 mmol) was dissolved in dimethyl-
formamide (4 mL) in a 10-mL round-bottomed flask, and (R)-proline
266 mg, 2.31 mmol) was added with stirring. The suspension was
2004, 43, 2152 – 2154; b) A. B. Northrup, D. W. C. MacMillan,
Science 2004, 305, 1752 – 1755.
(
[
[
7] M. Calvin, Angew. Chem. 1962, 74, 165 – 175; Angew. Chem. Int.
Ed. Engl. 1962, 1, 65 – 75.
8] a) “Enolates, Organocatalysis, Biocatalysis and Natural Product
Synthesis”: W.-D. Fessner in Modern Aldol Reactions, Vol. 1
stirred for 30 min after which freshly prepared 2e (1.0 g, 7.69 mmol)
was added. The flask was evacuated, flushed with argon and stored at
2
8C for 6 d. The suspension was quenched with sat. aq. ammonium
chloride solution (2 mL) and extracted with ethyl acetate (3 ꢀ 5 mL).
The combined organic layers were concentrated and purified by flash
column chromatography using silica gel (diethyl ether/pentane, 2:1).
(Ed.: R. Mahrwald), Wiley-VCH, Weinheim, 2004, 201 – 272;
b) C.-H. Wong, T. D. Machajewski, Angew. Chem. 2000, 112,
1206 – 1230; Angew. Chem. Int. Ed. 2000, 39, 1352 – 1375; c) W.-
D. Fessner, C. Walter, Top. Curr. Chem. 1996, 184, 97 – 194; d) S.
Takayama, G. J. McGarvey, C.-H. Wong, Chem. Soc. Rev. 1997,
26, 407 – 415; e) M. Schꢁrmann, M. Schꢁrmann, G. A. Sprenger,
J. Mol. Catal. B 2002, 8, 19 – 20, 247 – 252.
2
4
Product 3e (1.52 g, 76%) was obtained as a colorless oil. [a] = 126.8
D
(
(
8
c = 1.02 in CHCl ); IR (CHCl ): v˜ = 3461 (s), 3133 (s), 2988 (m), 2939
3
3
m), 1747 (s), 1378 (s), 1224 (s), 1157 (m), 1069 (s), 990 (w), 948 (w),
ꢁ1
1
89 (m), 853 (s), 758 cm (s); H NMR (400 MHz, CDCl ): d = 1.33
3
(
s, 3H, CCH ), 1.37 (s, 3H, CCH ), 1.47 (s, 6H, C(CH ) ), 2.96 (s, 1H,
3
3
3
2
[
9] Review: D. Enders, M. Voith, A. Lenzen, Angew. Chem. 2005,
117; Angew. Chem. Int. Ed. 2005, 44, in press.
OH), 3.98–4.09 (m, 4H), 4.27–4.34 (m, 2H), 4.45 ppm (dd, J = 3.3 Hz,
1
3
J = 1.3 Hz, 1H, CH); C NMR (125 MHz, CDCl ): d = 23.2 (CH ),
3
3
[
10] a) A. Cꢂrdova, W. Notz, C. F. Barbas III, Chem. Commun. 2002,
024 – 3025; b) For an efficient proline-catalyzed aldol reaction
2
4.5 (CH ), 25.2 (CH ), 26.3 (CH ), 66.1 (CH ), 66.7 (CH ), 71.9 (CH),
3 3 3 2 2
3
7
4.9 (CH), 76.1 (CH), 100.5 (C(CH ) ), 109.2 (C(CH ) ), 206.9 ppm
3
2
3 2
+
of hydroxy acetone with aldehydes see: W. Notz, B. List, J. Am.
Chem. Soc. 2000, 122, 7386 – 7387.
(
CO); MS (CI, isobutane): m/z (%): 261 (1) [M + 1], 245 (82)
+
+
þ
5
[
[
M ꢁCH ], 202 (15) [M ꢁCO(CH ) ], 187 (41) [C H O ] , 131 (32)
3
3
2
8
11
þ þ þ +
[11] Dioxanone 1 can be synthesized easily by undergraduate
students on a 1-mol scale from simple precursors and is also
commercially available. a) D. Enders, M. Voith, S. J. Ince,
Synthesis 2002, 1775 – 1779; b) D. Enders, B. Bockstiegel, Syn-
thesis 1989, 493 – 496.
12] C. W. Borysenko, A. Spaltenstein, J. A. Straub, G. M. White-
sides, J. Am. Chem. Soc. 1989, 111, 9275 – 9276.
13] Freshly prepared 2e was used for the aldol reaction due to its
tendency for polymerization and racemization.
C H O ], 101 (100) [C H O ], 72 (14) [C H O ], 59 (50) [C H O ];
6
11
3
4
5
3
3
4
2
3
7
elemental analysis calcd for C H O (%): C 55.37, H 7.74; found: C
1
2
20
6
5
5.02, H 7.73.
: The aldol product 3e (520 mg, 2 mmol) was stirred with 10 mL
4
deionized water in a 10-mL round-bottomed flask, and Dowex
W50X2-200 ion-exchange resin (350 mg) was added. After complete
conversion (followed by TLC) the ion-exchange resin was removed
by filtration over glass wool, and the aqueous solution was lyophi-
lized, affording d-psicose (4) (360 mg, 100%). If necessary, d-psicose
[
[
2
D
4
[14] M. Majewski, P. Nowak, J. Org. Chem. 2000, 65, 5152 – 5160.
[15] a) B. List, Acc. Chem. Res. 2004, 37, 548 – 557; b) B. List, L.
Hoang, H. J. Martin, Proc. Natl. Acad. Sci. USA 2004, 101, 5839 –
was purified using silica gel (ethyl acetate/methanol, 6:1). [a]
=
2
0
[20]
+
3.02 (c = 1.16 in H O); Lit.: [a] = + 3.1 (c = 1.62 in H O);
2
D
2
1
H NMR (400 MHz, D O) mixture of a,b-d-psicofuranose and a,b-
2
5
842; c) “Enolates, Organocatalysis, Biocatalysis and Natural
Product Synthesis”: B. List in Modern Aldol Reactions, Vol. 1
Ed.: R. Mahrwald), Wiley-VCH, Weinheim, 2004, 161 – 200.
16] a) D. Enders, O. Prokopenko, G. Raabe, J. Runsink, Synthesis
d-psicopyranose: d = 3.31 (d, J = 11.8 Hz), 3.43–3.71 (m), 3.81–3.95
1
3
(m), 4.07 (m), 4.20 ppm (dd, J = 7.7 Hz, J = 4.7 Hz); C NMR
(
(
125 MHz, D O): d = 60.0 (CHOH), 61.4 (CHOH), 62.4 (CHOH),
2
[
6
6
2.9 (CH ), 63.1 (CHOH), 63.3 (CH ), 64.0 (CHOH), 64.2 (CHOH),
2
2
1996, 1095 – 1100; b) D. Enders, S. J. Ince, Synthesis 2002, 619 –
5.1 (CHOH), 65.5 (CH ), 65.9 (CHOH), 69.0 (CH ), 70.2 (CH ), 70.3
2
2
2
624.
(
CH ), 71.0 (CHOH), 71.7 (CHOH), 74.7 (CHOH), 82.7 (CHOH;
2
[
17] a) S. Bahmanyar, K. N. Houk, H. J. Martin, B. List, J. Am. Chem.
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Houk, B. List, J. Am. Chem. Soc. 2003, 125, 16 – 17; c) S.
Bahmanyar, K. N. Houk, J. Am. Chem. Soc. 2001, 123, 12911 –
CH ),
97.6
(C(OH)OCH ),
98.4
(C(OH)OCH ),
103.2
2
2
2
(
C(OH)OCH ), 105.6 ppm (C(OH)OCH ).
2
2
Received: October 26, 2004
Published online: January 14, 2005
12912.
[
[
18] H. C. Jarrell, W. A. Szarek, J. K. N. Jones, A. Dmytraczenko,
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Keywords: aldol reaction · amino sugars · asymmetric
.
synthesis · carbohydrates · organocatalysis
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[
1
212
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2005, 44, 1210 –1212