Mimicking dihydroxy acetone phosphate-utilizing aldolases through organocatalysis: A facile route to carbohydrates and aminosugars

Article abstract of DOI:10.1021/ol0502533

(Chemical Equation Presented) A practical and environmentally friendly organocatalytic strategy designed to mimic the DHAP aldolases has been developed and shown to be effective in the preparation of carbohydrates and aminosugars. (S)-Proline and (S)-2-py

Full text of DOI:10.1021/ol0502533

ORGANIC
LETTERS
2
005
Vol. 7, No. 7
383-1385
Mimicking Dihydroxy Acetone
Phosphate-Utilizing Aldolases through
Organocatalysis: A Facile Route to
1
†
Carbohydrates and Aminosugars
Jeff T. Suri, Dhevalapally B. Ramachary, and Carlos F. Barbas, III*
The Skaggs Institute for Chemical Biology and the Departments of Chemistry and
Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
carlos@scripps.edu
Received February 6, 2005
ABSTRACT
A practical and environmentally friendly organocatalytic strategy designed to mimic the DHAP aldolases has been developed and shown to
be effective in the preparation of carbohydrates and aminosugars. (S)-Proline and (S)-2-pyrrolidine-tetrazole catalyzed the aldol reaction between
dihydroxy acetone variants such as 1,3-dioxan-5-one and 2,2-dimethyl-1,3-dioxan-5-one with aldehydes to give the corresponding polyols in
good yields with very high ees.
2
Dihydroxy acetone phosphate-utilizing aldolases such as FDP
aldolase have been developed into exceptionally powerful
tools for the asymmetric synthesis of carbohydrates and their
control. DHAP aldolases have been used to prepare a diverse
range of stereochemically complex carbohydrates and aza-
3
sugars, molecules of great significance in medicinal chem-
1
4
derivatives. Enzymes of this family catalyze the aldol
istry and glycobiology.
addition of dihydroxy acetone phosphate (DHAP) with a
range of aldehyde acceptors to form a new C-C bond while
creating two hydroxy-substituted stereogenic centers. Typi-
cally, these reactions take place with complete stereospeci-
ficity, and with the appropriate aldolase enzyme, all four
stereoisomers can be generated with high levels of stereo-
Although many attempts have been made to effect these
same transformations using lithium- and boron-enolate
chemistries, highly stereoselective catalytic reactions have
5
(
2) (a) Takayama, S.; McGarvey, G. J.; Wong, C.-H. Annu. ReV.
Microbiol. 1997, 51, 285-310. (b) Fessner, W.-D.; Walter, C. Top. Curr.
Chem. 1996, 184, 97-194. (c) Fessner, W.-D. In Microbial Reagents in
Organic Synthesis; Servi, S., Ed.; Kluwer Academic Publishers, Dordrecht,
1992; Vol. 381, pp 43-55.
†
This report is cordially dedicated to Professor C.-H. Wong for his many
contributions in enzymatic carbohydrate synthesis.
(3) (a) Koeller, K. M.; Wong, C.-H. Chem. ReV. 2000, 100, 4465-4493.
(b) Takayama, S.; Martin, R.; Wu, J.; Laslo, K.; Siuzdak, G.; Wong, C.-H.
J. Am. Chem. Soc. 1997, 119, 8146-8151. (c) Pederson, R. L.; Kim, M. J.;
Wong, C.-H. Tetrahedron Lett. 1988, 29, 4645-4648. (d) Ziegler, T.; Straub,
A.; Effenberger, F. Angew. Chem. 1988, 100, 737-738.
(4) (a) Hang, H. C.; Bertozzi, C. R. Acc. Chem. Res. 2001, 34, 727-
736. (b) Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357-2364.
(1) (a) Wong, C.-H.; Whitesides, G. M. Enzymes in Synthetic Organic
Chemistry; Pergamon, Oxford, 1994. (b) Machajewski, T. D.; Wong, C.-
H.; Lerner, R. A. Angew. Chem., Int. Ed. 2000, 39, 1352-1374. (c)
Takayama, S.; McGarvey, G. J.; Wong, C.-H. Chem. Soc. ReV. 1997, 26,
4
1
07-415. (d) Wymer, N.; Toone, E. J. Curr. Opin. Chem. Biol. 2000, 4,
10-119.
1
0.1021/ol0502533 CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/01/2005

6
remained elusive. Organocatalysis has emerged as a simple
and yet powerful methodology in asymmetric enamine-based
chemistries. In analogy to enzymes, organocatalysis allows
for the direct coupling of aldehydes and ketones with a
variety of electrophiles without the use of preformed enolates.
Many reactions have been reported, and in some cases,
Table 1. Dihydroxy Acetone Derivatives in Direct Aldol
Reaction
7
remarkably high levels of stereoselectivity have been achieved.
In studies aimed at recapitulating the chemistry of aldolase
8
enzymes with organocatalysis, we report here the efficacy
of this approach in aldol reactions between dihydroxy acetone
derivatives and aldehyde acceptors, with the ultimate goal
being to mimic the aldolase enzymes and achieve complete
stereocontrol (eq 1) without the substrate restrictions endemic
to natural enzymes.
In earlier studies, we reported that under aqueous buffered
conditions, (S)-proline can catalyze the aldol reaction
between unprotected dihydroxy acetone and various alde-
8
b
hydes. Although moderate ees were obtained (up to 63%
9
ee), the diastereoselectivity was low for almost all cases,
hampering the general utility of this reaction in asymmetric
synthesis. To overcome this shortcoming we have now
investigated the aldol reaction between various protected
versions of dihydroxy acetone10 and nitrobenzaldehyde in
a
b
Isolated yield after column chromatography. Determined by chiral-
phase HPLC analysis. c Performed at 4 °C. d Performed with 20 mol %
S)-2-pyrrolidine-tetrazole8f as a catalyst.
8f
the presence of proline or (S)-2-pyrrolidine-tetrazole (Table
).
In DMF at ambient temperature, the reaction with dihy-
(
1
droxy acetone was very sluggish, providing minimal product
after 48 h (entry 1), a reaction hampered by dimerization of
this ketone in organic solvent. The benzyl-protected ketone
as well as the silyl-protected version (entries 2 and 3) also
gave small amounts of product. However, the cyclic deriva-
tives (entries 4-9) were found to be suitable substrates for
this aldol reaction, giving polyol products in excellent yield
after 48 h. The degree of stereoselectivity was dependent
on the protecting group. For example, 1,3-dioxan-5-one
underwent aldolization, giving product with high ee and dr
(entries 4 and 5, up to 94% ee and 15:1 dr), while
1
1
(
5) (a) Kim, K. S.; Hong, S. D. Tetrahedron Lett. 2000, 41, 5909-5913.
(
b) Majewski, M.; Nowak, P. Synlett 1999, 1447-1449. (c) Majewski, M.;
Nowak, P. J. Org. Chem. 2000, 65, 5152-5160. (d) Murga, J.; Falomir,
E.; Carda, M.; Gonzalez, F.; Marco, J. A. Org. Lett. 2001, 3, 901-904. (e)
Marco, J. A.; Carda, M.; Falomir, E.; Palomo, C.; Oiarbide, M.; Ortiz, J.
A.; Linden, A. Tetrahedron Lett. 1999, 40, 1065-1068.
1
,5-dioxaspiro[5.5]undecan-3-one gave the corresponding
adduct with much less stereoselectivity (entries 9 and 10,
up to 67% ee and 5:1 dr). At subambient temperatures, 2,2-
dimethyl-1,3-dioxan-5-one gave good ees and diastereo-
selectivity (entries 6-8). X-ray crystallographic analysis of
this adduct revealed the major product to be anti with respect
to the newly formed hydroxyl group, and the absolute
configuration was 3S,4S (see Supporting Information). This
stereochemical outcome is in accordance with other (S)-
(6) Excellent stereoselectivities have been obtained using chiral auxil-
iaries; see: (a) Enders, D.; Ince, S. J.; Bonnekessel, M.; Runsink, J.; Raabe,
G. Synlett 2002, 962-966. (b) Enders, D.; Ince, S. J. Synthesis 2002, 619-
6
4
24. (c) Enders, D.; Hundertmark, T. Tetrahedron Lett. 1999, 40, 4169-
172.
(7) For reviews see: (a) Dalko, P. I.; Moisan, L. Angew Chem. Int. Ed.
2
004, 43, 5138-5175. (b) Dalko, P. I.; Moisan, L. Angew Chem. Int. Ed.
2
001, 40, 3726-3748. (c) Acc. Chem. Res. 2004, 37, special issue on
organocatalysis.
(
8) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
7
1
22, 2395-2396. (b) Cordova, A.; Notz, W.; Barbas, C. F. III. Chem.
proline-catalyzed aldol reactions.
Commun. 2002, 3024-3025. (c) Chowdari, N. S.; Ramachary, D. B.;
Cordova, A.; Barbas, C. F. Tetrahedron Lett. 2002, 43, 9591-9595. (d)
Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798-
The scope of this reaction was then demonstrated using
the commercially available 2,2-dimethyl-1,3-dioxan-5-one
and various aliphatic, aromatic, and oxy- and amine-
substituted acceptors (Table 2). In contrast to the aromatic
substrates, greater stereoselectivity was provided with ali-
phatic substrates. For example, when isovaleraldehyde was
6
799. (e) Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W.
C. Angew. Chem., Int. Ed. 2004, 43, 2152-2154. (f) Torii, H.; Nakakai,
M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed. 2004,
4
3, 1983-1986.
(
9) Two substrates gave drs of >20:1 but without any ee.
(10) Following our initial submission, Enders et al. published an extensive
review related to the use of 2,2-dimethyl 2,2-dimethyl-1,3-dioxan-5-one in
synthetic chemistry and a complementary study of its use under proline
catalysis. See: (a) Enders, D.; Voith, M.; Lenzen, A. Angew. Chem., Int.
Ed. 2005, 44, ASAP. (b) Enders, D.; Grondal, C. Angew. Chem., Int. Ed.
(11) Significantly, 4-thianone has been used as a masked cyclic ketone
surrogate of the unreactive 3-pentanone for proline catalysis. See: (a) Ward,
D. E.; Jheengut, V. Tetrahedron Lett. 2004, 45, 8347-8350. (b) Nyberg,
A. I.; Usano, A.; Pihko, P. M. Synlett 2004, 11, 1891-1896.
2
005, 44, 1210-1212.
1384
Org. Lett., Vol. 7, No. 7, 2005

that reactions with imines and alkenes, Mannich and Michael-
type reactions, were also facile, suggesting the synthetic
scope of this methodology will reach beyond that observed
with enzymes with respect to electrophile range.13
Table 2. Stereoselective Direct Coupling of
,2-Dimethyl-1,3-dioxan-5-one with Aldehyde Acceptors
2
Reactions were readily performed on a gram scale, and
deprotection and further elaboration of the aldol products
allowed for the rapid construction of carbohydrate architec-
tures. For example, treatment of the aldol adducts with
Dowex resin in H O/THF gave the corresponding dihydroxy
2
products in quantitative yield (see Supporting Information).
The phthalimido-protected aldol product was reduced with
(
(
L)-Selectride to give the stereochemically rich polyol 1
Scheme 1). Deprotection with TFA and methylamine-
1
4
Scheme 1. Synthesis of 1-Amino-1-deoxy-D-lyxitol
induced cleavage of the phthalimide group afforded 1-amino-
1
5
1
-deoxy-D-lyxitol 2, a carbohydrate construct traditionally
prepared from the chiral pool of naturally occurring sugars.
In summary, we have demonstrated the effectiveness of
organocatalysis in the preparation of carbohydrates and
aminosugars in a strategy designed to mimic the DHAP
aldolases. This efficient strategy promises simplified routes
to complex carbohydrates and their derivatives.
Acknowledgment. This study was supported in part by
the NIH (CA27489) and the Skaggs Institute for Chemical
Biology. We thank Dr. Raj K. Chadha for X-ray structural
analysis and Rajeswari Thayumanavan for technical as-
sistance.
a
Isolated yield. b Determined by HPLC and NMR analysis. c Determined
d
by chiral-phase HPLC analysis. Reaction time ) 48 h.
the donor, the corresponding adduct was obtained in 98%
ee and with 10:1 dr (entry 2). The product of the reaction
with cyclopentane carboxaldehyde (entry 3) was obtained
in 97% ee with no other diastereomer observed. When oxy-
and amino-substituted aldehydes were reacted with proline
and 2,2-dimethyl-1,3-dioxan-5-one (entries 4-6), the reac-
tions proceeded with high levels of stereocontrol (>94% ee,
Supporting Information Available: Experimental pro-
cedures, characterization data, and X-ray files. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0502533
>
15:1 dr), giving the corresponding polyols and aminols
(12) Ekeberg, D.; Morgenlie, S.; Stenstrom, Y. Carbohydr. Res. 2002,
3
37, 779-786.
(entries 4-7). Significantly, these aldol products are pro-
(
13) Results concerning Mannich-type and Michael reactions will be
tected azasugars (entry 4) and carbohydrates (L-ribulose and
D-tagatose, entries 5 and 6), compounds that are otherwise
most efficiently prepared via enzymatic reactions or from
reported in due course.
(14) Enders, D.; Muller-Huwen, A. Eur. J. Org. Chem. 2004, 1732-
1
739.
1b
(15) Blanc-Muesser, M.; Defaye, J.; Horton, D. Carbohydr. Res. 1979,
12
the chiral pool. Unlike natural aldolase enzymes, we found
68, 175-187.
Org. Lett., Vol. 7, No. 7, 2005
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