Dihydroxyacetone variants in the organocatalytic construction of carbohydrates: Mimicking tagatose and fuculose aldolases

Article abstract of DOI:10.1021/jo0602017

Dihydroxyacetone variants have been explored as donors in organocatalytic aldol reactions with various aldehyde and ketone acceptors. The protected form of dihydroxyacetone that was chosen for in-depth study was 2,2-dimethyl-1,3- dioxan-5-one, 1. Among the catalysts surveyed here, proline proved to be superior in terms of yield and stereoselectivities in the construction of various carbohydrate scaffolds. In a fashion analogous to aldolase enzymes, the de novo preparation of L-ribulose, L-lyxose, D-ribose, D-tagatose, 1-amino-1-deoxy-D-lyxitol, and other carbohydrates was accomplished via the use of 1 and proline. In reactions using 2,2-dimethyl-1,3-dioxan-5-one 1 as a donor, (S)-proline can be used as a functional mimic of tagatose aldolase, whereas (R)-proline can be regarded as an organocatalytic mimic of fuculose aldolase.

Full text of DOI:10.1021/jo0602017

Dihydroxyacetone Variants in the Organocatalytic Construction of
Carbohydrates: Mimicking Tagatose and Fuculose Aldolases
Jeff T. Suri, Susumu Mitsumori, Klaus Albertshofer, Fujie Tanaka, 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 January 30, 2006
Dihydroxyacetone variants have been explored as donors in organocatalytic aldol reactions with various
aldehyde and ketone acceptors. The protected form of dihydroxyacetone that was chosen for in-depth
study was 2,2-dimethyl-1,3-dioxan-5-one, 1. Among the catalysts surveyed here, proline proved to be
superior in terms of yield and stereoselectivities in the construction of various carbohydrate scaffolds. In
a fashion analogous to aldolase enzymes, the de novo preparation of L-ribulose, L-lyxose, D-ribose,
D-tagatose, 1-amino-1-deoxy-D-lyxitol, and other carbohydrates was accomplished via the use of 1 and
proline. In reactions using 2,2-dimethyl-1,3-dioxan-5-one 1 as a donor, (S)-proline can be used as a
functional mimic of tagatose aldolase, whereas (R)-proline can be regarded as an organocatalytic mimic
of fuculose aldolase.
Introduction
that enable efficient coupling of carbonyl compounds, wherein
any given aldolase typically operates on a select set of carbonyl
compounds.
Carbohydrates constitute an important class of biomolecules.
Like nucleic acids and proteins, carbohydrates play a key role
in many physiological processes such as cell recognition and
metabolic function. They are also important in medicinal
chemistry where, for example, they are used in antibiotic agents
and have potential as anticancer therapeutics and vaccines.
In an attempt to mimic the activity of enzymes in catalytic
asymmetric synthesis, we have actively developed the utility
4
of organocatalysts such as proline and other chiral amines. Like
1
enzymes, organocatalysts can effectively catalyze aldol addition
reactions providing for the direct coupling of aldehyde and
ketone donors to various aliphatic and aromatic acceptors with
2
The stereochemical complexity of carbohydrates has made
their de novo synthesis a formidable challenge, one that has
thus far been very successfully tackled via the use of enzymes.
Among enzymes used in carbohydrate synthesis, the C-C bond-
forming aldolases have received significant attention. A wide
variety of naturally occurring aldolase enzymes are available
5
excellent stereoselectivities. These studies have allowed us to
3
effectively recapitulate the activity of two of nature’s aldolases,
DERA aldolase, with its unique ability to use both aldehydes
and ketones as donors in aldol reactions, and threonine aldolase,
(4) For reviews see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2001, 40, 3726. (b) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58,
2481. (c) Allemann, C.; Gordillo, R.; Clemente, F.; Cheong, P. H.-Y.; Houk,
K. N. Acc. Chem. Res. 2004, 37, 558. (d) Dalko, P. I.; Moisan, L. Angew
Chem., Int. Ed. 2004, 43, 5138-5175. (e) Notz, W.; Tanaka, F.; Barbas,
C. F., III Acc. Chem. Res. 2004, 37, 580. For recent work see: (f) Suri, J.
T.; Steiner, D. D.; Barbas, C. F., III Org. Lett. 2005, 7, 3885-3888. (g)
Steiner, D. D.; Mase, N.; Barbas, C. F., III Angew. Chem., Int. Ed. 2005,
44, 3706-3710. (h) Chowdari, N. S.; Suri, J. T.; Barbas, C. F., III Org.
Lett. 2004, 6, 2507. (i) Ramachary, D. B.; Barbas, C. F., III Org. Lett.
2005, 7, 1577-1580. (j) Chowdari, N. S.; Barbas, C. F., III Org. Lett. 2005,
7, 867-870. (k) Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III Org.
Lett. 2004, 6, 3541-3544.
(
1) (a) Ritter R. T.; Wong, C.-H. Angew. Chem., Int. Ed. 2001, 40, 3508-
3
533. (b) Wong, C.-H.; Bryan, M. C.; Nyffeler, P. T.; Liu, H.; Chapman,
E. Pure Appl. Chem. 2003, 75, 179-186. (c) Wrodnigg, T. M.; Sprenger,
F. K. Mini-ReV. Med. Chem. 2004, 4, 437-459.
(
2) Barchi, J. J., Jr. Curr. Pharm. Des. 2000, 6, 485-501.
(3) (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,
07-415. (d) Wymer, N.; Toone, E. J. Curr. Opin. Chem. Biol. 2000, 4,
10-119. (e) Koeller, K. M.; Wong, C.-H. Nature 2001, 409, 232-240.
4
1
10.1021/jo0602017 CCC: $33.50 © 2006 American Chemical Society
3
822
J. Org. Chem. 2006, 71, 3822-3828
Published on Web 04/06/2006

Dihydroxyacetone Variants
SCHEME 1. Aldolase-Catalyzed Assembly of Sugars
which provides expedient access to â-hydroxyamino acids.4k
Dihydroxyacetone phosphate dependent aldolases are a particu-
larly intriguing class of aldolases that catalyze the aldol addition
of dihydroxyacetone phosphate (DHAP) to a range of aldehyde
acceptors, forming a new C-C bond while creating two
hydroxy-substituted stereogenic centers. Typically, these reac-
tions take place with complete stereocontrol, and with the
appropriate aldolase enzyme, all four stereoisomeric products
SCHEME 2
investigate the use of protected forms of DHA in carbohydrate
synthesis, with the ultimate goal of mimicking the DHAP
aldolase enzymes and achieving complete stereocontrol without
the substrate restrictions endemic of natural enzymes (Scheme
6
can be generated with high levels of stereocontrol (Scheme 1).
To approach the powerful chemistry available through the
DHAP aldolases, we studied the aldolization of dihydroxyac-
etone (DHA). In aqueous media, DHA serves as a donor in the
proline-catalyzed aldol reaction; however, enantioselectivities
2
). Herein we describe a full account of our investigation.
Results and Discussion
5
k
7
8
Dihydroxyacetone Analogues as Donors. We initially
studied various protected forms of DHA to determine the most
general and synthetically useful derivative for further reactions.
In DMF, unprotected DHA gave no reaction with nitrobenzal-
dehyde when stirred at room temperature in the presence of 20
mol % (S)-proline (Table 1, entry 1). Symmetric protection of
DHA with benzyl or silyl groups (entries 2-4) or monosub-
are poor. These studies prompted us and others to further
(5) For references on organocatalyzed aldol reactions see: (a) Mase, N.;
Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III
J. Am. Chem. Soc. 2006, 128, 734-735. (b) Mitsumori, S.; Zhang, H.;
Cheong, P. H.-Y.; Houk, K. N.; Tanaka, F.; Barbas, C. F., III J. Am. Chem.
Soc. 2006, 128, 1040-1041. (c) Mase, N.; Tanaka, F.; Barbas, C. F., III
Angew. Chem., Int. Ed. 2004, 43, 2420. (d) Mase, N.; Tanaka, F.; Barbas,
C. F., III Org. Lett. 2003, 5, 4369. (e) Cordova, A.; Notz, W.; Barbas, C.
F., III J. Org. Chem. 2002, 67, 301. (f) Chowdari, N. S.; Ramachary, D.
B.; Cordova, A.; Barbas, C. F., III Tetrahedron Lett. 2002, 43, 9591. (g)
Sakthivel, K.; Notz, N.; Bui, T.; C. F. Barbas, C. F., III J. Am. Chem. Soc.
stitution of one of the hydroxy groups with a silyl, phthalimido,
or benzyl group (entries 5 and 6) gave no product.9
When the hydroxy groups in the substrate were constrained
through an alkyl linker (entries 7-13), the aldol reaction with
nitrobenzaldehyde ensued at room temperature. The cyclohex-
anone-like structure (entries 7 and 8) gave slightly superior
results in terms of stereoselectivity; however, 2,2-dimethyl-1,3-
dioxan-5-one 1 (entries 9-11) was chosen because it was more
accessible via synthesis or commercial sources. Interestingly,
an increase in steric bulk on the donor resulted in a decrease in
stereocontrol (entries 12 and 13). Attempts to reproduce
published studies concerning the use of L-alanine as a catalyst
2
001, 123, 5260. (h) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem.
Soc. 2000, 122, 2395-2396. (i) Notz, W.; List, B. J. Am. Chem. Soc. 2000,
22, 7386. (j) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573.
k) Cordova, A.; Notz, W.; Barbas, C. F. III Chem. Commun. 2002, 67,
034. (l) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.;
1
(
3
Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 5262. (m) Northrup,
A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798-6799. (n)
Bøgevig, A.; Kumaragurubaran, N.; Jørgensen, K. A. Chem. Commun. 2002,
10
6
20. (o) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem., Int.
1
1
Ed. 2003, 42, 2785. (p) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.;
Cordova, A. Angew. Chem., Int. Ed. 2005, 44, 1343. (q) Hartikaa, A.;
Arvidsson, P. I. Tetrahedron: Asymmetry 2004, 15, 1831. (r) Torii, H.;
Nakakai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int.
Ed. 2004, 43, 1983-1986. (s) Martin, H. J.; List, B. Synlett 2003, 1901. (t)
Kofoed, J.; Nielsen, J.; Reymond, J.-L. Bioorg. Med. Chem. Lett. 2003,
(8) (a) Enders, D.; Grondal, C. Angew Chem., Int. Ed. 2005, 44, 1210-
1212. (b) Ibrahem, I.; Cordova, A. Tetrahedron Lett. 2005, 46, 3363-3367.
(c) Attempts to reproduce published studies concerning the use of L-alanine
as a catalyst for the synthesis of 2h under the conditions described by
C o´ rdova failed. Under these conditions, 2h was obtained in only 24% yield
and 78% ee; see: C o´ rdova, A.; Zou, W.; Ibrahem, I.; Reyes, E.; Engqvist,
M.; Liao, W.-W. Chem. Commun. 2005, 3586-3588. (d) Westermann, B.;
Neuhaus, C. Angew Chem., Int. Ed. 2005, 44, 4077-4079. (e) Enders, D.;
Palecek, J.; Grondal, C. Chem. Commun. 2006, 655-657. (f) Grondal, C.;
Enders, D. Tetrahedron 2006, 62, 329-337.
(9) Westermann and Neuhaus tested dihydroxyacetone phosphate as a
substrate for the Mannich reaction and observed no reaction; see ref 8d.
(10) (a) Hoppe, D.; Schmincke, H.;. Kleemann, H.-W. Tetrahedron 1989,
45, 687-694. (b) Forbes, D. C.; Ene, D. G.; Doyle, M. P. Synthesis 1998,
879-882. (c) Carman, R. M.; Handley, P. N. Aust. J. Chem. 2001, 54,
769-776. (d) Enders, D.; Voith, M.; Ince, S. J. Synthesis 2002, 1775-
1779.
1
3, 2445. (u) Tang, Z.; Jiang, F.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang,
Y.-Z.; Wu, Y.-D. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5755. (v)
Berkessel, A.; Koch, B.; Lex, J. Adv. Synth. Catal. 2004, 346, 1141. (w)
Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V.
Org. Biomol. Chem. 2005, 3, 84. (x) Hayashi, Y.; Sumiya, T.; Takahashi,
J.; Gotoh, H.; Urushima, T.; Shoji; M. Angew. Chem., Int. Ed. 2006, 45,
9
58-961. (y) Tang, Z.; Yang, Z.-H.; Chen, X.-H.; Cun, L.-F.; Mi, A.-Q.
Jiang, Y.-Z.; Gong, L.-Z. J. Am. Chem. Soc. 2005, 127, 9285-9289.
(
6) (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,
1
992; Vol. 381, pp 43-55. (d) Henderson, I.; Sharpless, K. B.; Wong C.-
H. J. Am. Chem. Soc. 1994, 116, 558-561.
7) Suri, J. T.; Ramachary, D. B.; Barbas, C. F., III Org. Lett. 2005, 7,
383-1385.
(
1
(11) Kim, K. S.; Hong, S. D. Tetrahedron Lett. 2000, 41, 5909-5913.
J. Org. Chem, Vol. 71, No. 10, 2006 3823

Suri et al.
TABLE 1. Aldol Reaction of Dihydroxyacetone Analogs with
Nitrobenzaldehyde
TABLE 2. Aldol Reaction of 1 with Aromatic Acceptors
a
b
Isolated yield after column chromatography. Determined by chiral-
c
d
phase HPLC analysis. Performed at 4 °C. 20 mol % of (S)-2-pyrrolidine-
tetrazole used as catalyst.
6
k
for the synthesis of 2h under the conditions described by
C o´ rdova failed.8
c
Aldehyde Acceptors. The scope of the proline-catalyzed
reaction was then explored using 1 and various aromatic and
aliphatic substrates. As indicated in Table 2, activated benzal-
dehydes as well as heterocyclics were suitable acceptors when
the reaction was conducted in DMF at subambient temperature.
Reactions gave good yields (60-89%), high enantioselectivities
(
2
84-95% ee), and diastereoselectivities (drs) that ranged from
a
Isolated yield after column chromatography. b Determined by H NMR
1
:1 to 6:1.
and HPLC analysis. c Determined by chiral-phase HPLC analysis.
The aliphatic acceptors were better substrates than the others
tested in terms of stereocontrol. The aldol products were
obtained in moderate yields with excellent diastereo- and
enantioselectivities (Table 3). For example, the nonbranched
aldehydes (entries 1-3) gave dr’s that ranged from 10:1 to 55:1
and ee’s of 98%. Adducts were obtained from branched
aldehydes (entries 4-6) with excellent ee’s and dr’s of up to
1
,3-diols (Table 4). The anti-selective reduction of adduct 3f
could be achieved using L-selectride (entry 1), NaBH(OAc)3
entry 11), LiBH4 (entry 12), or NaCNBH3 (entry 13). None of
(
the reducing agents provided the syn-1,3-diol products in
significant amounts, although some stereocontrol resulted when
Me4NBH(OAc)3 and Bu4NBH4 (entries 6 and 10) were used.
9
9:1. Significantly, the polyols and aminols that were formed
are protected carbohydrates (entry 1, L-ribulose) and azasugars
entry 3), compounds that are otherwise most efficiently
If the hydroxy group in the aldol adduct was protected with
tert-butyldimethylsilyl (TBS), the diastereoselectivity was re-
versed providing the syn-1,3-diol products in good yield
(
3b
prepared via enzymatic reactions or via purification from the
chiral pool.
1
2
(Scheme 3). Deprotection of the reduced products was carried
The synthesis of various carbohydrates was completed using
a two-step reduction-deprotection sequence. A gamut of reduc-
ing agents were tested with aldol adduct 3f to determine reagents
with the potential to provide selective access to anti- and syn-
out using Dowex resin to provide the carbohydrates L-lyxose
and D-ribose. Conversion of the aldehydes into the oximes 6
and comparison to authentic samples provided further structural
proof of the prepared sugars (Scheme 4).
From 3c, the phthalimide protected aminosugar 7 was
prepared (Scheme 5). Reduction of 3c allowed for the prepara-
(
12) Ekeberg, D.; Morgenlie, S.; Stenstrom, Y. Carbohydr. Res. 2002,
3
37, 779-786.
3824 J. Org. Chem., Vol. 71, No. 10, 2006

Dihydroxyacetone Variants
TABLE 3. Aldol Reaction of 1 with Aliphatic Acceptors
TABLE 4. Stereoselective Reduction of Aldol Adduct 3f
ratio 4a:4ba
entry
reagent
condition
(% yield)
1
2
3
4
5
6
L-selectride
DIBAL-H
DIBAL-H
NaBH4
-78 °C, THF
>20:<1 (62%)
ca. 1:1
ca. 1:1
6.3:1
4.2:1
1:1.4
-78 °C, THF
-78 °C, toluene
-20 °C, MeOH
-78 f -20 °C, toluene
Red-Al
Me4NBH(OAc)3 -40 f -20 °C,
MeCN, AcOH
7
8
9
0
1
2
3
Cl3SiH
NaBH4, CeCl3
LiAlH4
Bu4NBH4
NaBH(OAc)3
LiBH4
Et3N, CH2Cl2
0 °C, MeOH
-78 °C, THF
-20 °C, CH2Cl2
complex mixture
1.5:1
1.6:1
1
1
1
1
1:2.7
-20 °C, CH2Cl2, AcOH >20:<1 (69%)
-78 °C, THF
>20:<1
>20:<1
NaCNBH3
-20 °C, CH2Cl2, AcOH
a
1
Determined by H NMR.
substrate, allowing for the synthesis of acetonide-protected
6
D-tagatose (Scheme 6) that readily crystallized to afford X-ray
quality crystals (see Supporting Information). In a similar
fashion, D-psicose can be prepared from (R)-glyceraldehyde, as
8
a
has recently been reported.
The galactose-derived 12 was prepared and utilized as an
acceptor. The reaction of 1 with 12 in the presence of (R)-proline
afforded 13 as a single diastereomer in 60% yield along with
1
4
the self-aldol product of 1 (Scheme 7).
Product 13 with its nine-carbon backbone is classified as a
“
higher carbon sugar”, which have gained attention because of
their potential as antibiotics. 3-Deoxy-D-manno-2-octulosonic
acid is an essential component necessary for the growth of
Gram-negative bacteria and inhibitors of its synthesis are
1
5
antibiotics. Typical synthetic routes for higher carbon sugars
involve homologation of lower carbon sugars and require the
introduction of new stereogenic centers in a controlled manner.
Protocols involving Wittig olefination of C6 sugars and
(14) The self-condensation of 1 is a competing side reaction giving
acetonide protected dendroketose 12b.
a
b
1
Isolated yield after column chromatography. Determined by H NMR
and HPLC analysis. Determined by chiral-phase HPLC analysis. d Aldol
products were converted to 3,5-dinitrobenzoate esters for ee determination
by HPLC.
c
tion of aminosugar 1-amino-1-deoxy-D-lyxitol 9, a carbohydrate
traditionally isolated from the chiral pool of naturally occurring
sugars.13
In contrast to the anti-selective reduction of 3f using
L-selectride, the phthalimido protected adduct 3c was diaste-
reoselectively reduced to the syn-1,3-diol product 8. Subsequent
deprotection with trifluoroacetic acid (TFA) and methylamine-
induced cleavage of the phthalimido group afforded 9 in 60%
yield.
(
15) (a) Ungm, F. M. AdV. Carbohydr. Chem. Biochem. 1981, 38, 323.
(b) Iwasa, T.; Kusuka, T.; Suetomi, K. J. Antibiot. 1978, 31, 511-518. (c)
Harada, S.; Kishi, T. J. Antibiot. 1978, 31, 519-524. (d) Harada, S.; Mizuta,
E.; Kishi, T. Tetrahedron 1981, 37, 1317-1327. (e) Takatsuki, A.; Arima,
K.; Tamura, G. J. Antibiot. 1971, 24, 215-223. (f) Takatsuki, A.; Tamura,
G. J. Antibiot. 1971, 24, 224-231. (g) Takatsuki, A.; Tamura, G. J. Antibiot.
1971, 24, 232-238. (h) Takatsuki, A.; Kawamura, K.; Okina, M.; Kodama,
Y.; Ito, T.; Tamura, G. Agric. Biol. Chem. 1977, 41, 2307-2309. For
references on analogues of 3-deoxy-D-manno-2-octulosonic acid, see: (i)
Claesson, A.; Luthman, K.; Gustafsson, K.; Bondesson, G. Biochem.
Biophys. Res. Commun. 1987, 143, 1063. (j) Molin, H.; Ring, B. G.
Tetrahedron Lett. 1985, 26, 617. (k) Norbeck, D. W.; Kramer, J. B.
Tetrahedron Lett. 1987, 28, 773. (l) Norbeck, D. W.; Kramer, J. B.; Lartey,
P. A. J. Org. Chem. 1987, 52, 2174. (m) Tadanier, J.; Lee, C. M.; Wittern,
D.; Wideburg, N. Carbohydr. Res. 1990, 201, 185. (n) Tadanier, J.; Lee,
C. M.; Hengeveld, J.; Rosenbrook, W., Jr.; Whittern, D.; Wideburg, N.
Carbohydr. Res. 1990, 201, 209.
In addition to simple achiral aldehyde acceptors, we also
explored the use of chiral acceptors. The readily available
acetonide protected (S)-glyceraldehyde 10 proved to be a good
(
13) Blanc-Muesser, M.; Defaye, J.; Horton, D. Carbohydr. Res. 1979,
6
8, 175-187.
J. Org. Chem, Vol. 71, No. 10, 2006 3825

Suri et al.
SCHEME 3. Protection/Reduction Sequence To Selectively Afford syn-1,3-Diols
a
b
1
Isolated yield. Determined by H NMR.
SCHEME 4. Preparation of d-Ribose and L-Lyxose and Conversion into the Corresponding Oximes 6
SCHEME 5. Preparation of Amino Sugars 7 and 9
SCHEME 6. Preparation of Acetonide-Protected D-Tagatose
sugars. With the appropriate aldehyde acceptor the preparation
of various higher carbon sugars may become more facile via
organocatalysis. Current studies are underway to investigate this
possibility.
Ketone Acceptors. In our initial studies concerning the cross-
aldol of 1 with a variety of aldehydes, in some reactions we
noted a side product formed by the self-aldolization of 1.14 This
finding encouraged studies of crossed-ketone aldol reactions.
We examined the reaction of 1 with various ketone acceptors.
An initial solvent screen was performed with diethyl ketoma-
lonate 14 as the acceptor (Table 5). Dichloromethane gave the
highest yield, albeit with almost no enantioselectivity. Among
the other nonsymmetric ketones that were tested, only ethyl
trifluoropyruvate 16 (Table 6) proved to be a useful substrate.20
A solvent screen of 1 with 16 revealed CH2Cl2 to be the
optimum solvent, giving an anti:syn ratio of 85:15 and >99%
ee for the anti product (entry 1).
SCHEME 7. Preparation of Higher Carbon Sugar 13
subsequent osmylation,16 intramolecular C-glycosidations,
17
18
enzyme-mediated aldolizations, and 1,3-dipolar cycloaddi-
A catalyst screening that utilized various additives as well
1
9
tions have been employed for synthesis of higher carbon
5r
5c
as the tetrazole-based catalyst and a diamine-based catalyst
entries 8 and 9, Table 7) indicated that proline was superior in
(
(16) (a) Brimacombe, J. S.; Hanna, R.; Kabir, A. K. M. S. Bennett, F.;
terms of yield and stereoselectivities and that, at a cost to yield,
Taylor, I. D. Org. Biomol. Chem. 1986, 815-821. (b) Brimacombe, J. S.;
Hanna, R.; Kabir, A. K. M. S. Org. Biomol. Chem. 1986, 823-828. (c)
Brimacombe, J. S.; Kabir, A. K. M. S. Carbohydr. Res. 1986, 150, 35-51.
(20) (a) Torok, B.; Abid, M.; London, G.; Esquibel, J.; Torok, M.;
Mhadgut, S. C.; Yan, P.; Prakash, G. K. S. Angew Chem., Int. Ed. 2005,
44, 3086-3089. (b) Lyle, M. P. A.; Draper, N. D.; Wilson, P. D. Org.
Lett. 2005, 7, 901-904. (c) Gathergood, N.; Juhl, K.; Poulsen, T. B.;
Thordrup, K.; Jorgensen, K. A. Org. Biomol. Chem. 2004, 2, 1077-1085.
(d) Bogevig, A.; Gothelf, K. V.; Jorgensen, K. A. Chem.-Eur. J. 2002, 8,
5652-5661. (e) Prakash, G. K. S.; Yan, P.; Torok., B.; Olah, G. A. Synlett
2003, 4, 527-531.
(
8
d) Brimacombe, J. S.; Kabir, A. K. M. S. Carbohydr. Res. 1986, 158,
1-89.
(17) Craig, D.; Pennington, M. W.; Warner, P. Tetrahedron 1999, 55,
1
3495-13512.
(
18) Bedarski, M. D.; Waldmann, H. J.; Whitesides, G. M. Tetrahedron
Lett. 1986, 27, 5807.
19) Paton, R. M.; Young, A. A. Org. Biomol. Chem. 1997, 629-635.
(
3826 J. Org. Chem., Vol. 71, No. 10, 2006

Dihydroxyacetone Variants
TABLE 5. Solvent Effects on the Aldol Reaction of 1 with Diethyl
Ketomalonate 14
TABLE 7. Catalyst Screen for the Aldol Reaction of 1 with Ethyl
Trifluoropyruvate 15
%
time yielda anti:synb % eec
entry
solvent
% yieldb
% eec
entry
catalyst
additive
1
2
3
4
5
6
DMF
26
54
40
12
39
38
3
1
3
2
1
4
1
2
3
4
5
6
7
8
9
(()-proline
(S)-proline
(S)-proline
(S)-proline
(S)-prolined
24 h
3 h
48 h
264 h
72 h
31
4
41
83
78
3
28
39
11
86:14
CH2Cl2
CH2Cl2
MeCN
toluene
THF
90:10 >99/33
85:15 >99/38
87:13 >99/54
75:25
>95:1
92:8
a
40/62
>99/-
86/20
(S)-proline H2O (5 equiv) 48 h
(S)-proline H2O (2 equiv)
72 h
48 h
48 h
a
hreaction time. b Isolated yield after column chromatography. c De-
3
e
cat1
79:21
87:13 >99/37
58/75
termined by chiral-phase HPLC analysis.
f
cat2
TFA (1 equiv)
a
Isolated yield after column chromatography. b Determined by H NMR
1
TABLE 6. Solvent Effects on the Aldol Reaction of 1 with Ethyl
Trifluoropyruvate 16
c
d
and HPLC analysis. Determined by chiral-phase HPLC analysis. 30 mol
f
%
catalyst used. e (S)-2-Pyrrolidine-tetrazole. (S)-(+)-1-(2-Pyrrolidinyl-
methyl)-pyrrolidine.
to be superior in terms of yield and stereoselectivities in the
construction of various carbohydrate scaffolds. Our studies
reveal that (S)-proline can be used as a functional mimic of
tagatose aldolase, whereas (R)-proline can be regarded as an
organocatalytic mimic of fuculose aldolase in reactions using
2
,2-dimethyl-1,3-dioxan-5-one 1 as a donor. In a fashion
analogous to aldolase enzymes, the de novo preparation of
L-ribulose, L-lyxose, D-ribose, D-tagatose, 1-amino-1-deoxy-D-
lyxitol, and other carbohydrates was accomplished via the use
of 1 and proline. Many of the aldol acceptors aldehydes used
in our study have not been reported in studies of the natural
enzymes. Attempts to use (S)-alanine as a catalyst were
8c
unsatisfactory. Unlike the natural aldolase derivates, the scope
of proline-catalyzed reactions extends to ketone acceptors and
highly protected sugars. Our studies have also revealed effective
methodologies for accessing anti- or syn-1,3-diols, expanding
the scope of synthons and carbohydrates and their derivatives
that are accessible with our approach. Further studies are
underway to explore the synthesis of higher carbon sugars via
organocatalysis.
a
b
1
Isolated yield after column chromatography. Determined by H NMR
and HPLC analysis. Determined by chiral-phase HPLC analysis. d Reaction
c
conducted at room temperature.
Experimental Section
high dr’s can be obtained upon the addition of water to the
reaction (entries 6 and 7). To the best of our knowledge, this is
the first time that the aldol adduct 17 has been prepared; it may
possess interesting biological properties because of its unique
trifluoro-substituted polyhydroxy structure.21
General Experimental Procedure for the Aldol Reaction. To
a glass vial charged with DMF (200 µL) were added ketone (0.5
mmol), aldehyde (0.1 mmol), and (S)-proline (0.02 mmol, 2.3 mg),
and the reaction was stirred at ambient temperature or at 4 °C until
the reaction was complete as shown by TLC. Then, a half-saturated
NH
the layers were separated, and the organic phase was washed with
brine. The organic phase was dried (MgSO ), concentrated, and
4
Cl solution and ethyl acetate were added with vigorous stirring,
Conclusions
4
Dihydroxyacetone variants have been explored as donors in
organocatalytic aldol reactions with various aldehyde and ketone
acceptors. The protected form of dihydroxyacetone that was
chosen for in-depth study was 2,2-dimethyl-1,3-dioxan-5-one
purified by flash column chromatography (silica gel, mixtures of
hexanes/ethyl acetate) to afford the desired aldol product.
General Procedure for Derivatization of Aliphatic Substrates
for HPLC Analysis. The aldol adduct (1 equiv) in CH
2 2
Cl (1 mL/
0.5 mmol) was treated with 3,5-dinitrobenzoyl chloride (1.1 equiv)
1
because of its well-developed chemistry and commercial
and DMAP (1.1 equiv) and stirred for 1 h. The solution was filtered
through a small plug of silica gel and analyzed by HPLC.
22
availability. Among the catalysts surveyed here, proline proved
(
4R,5R)-4-((R)-1-Hydroxy-2,2-dimethoxyethyl)-2,2-dimethyl-
,3-dioxan-5-ol (4a). To a solution of 3f (20.0 mg, 0.0854 mmol)
in CH Cl (0.25 mL) were added AcOH (0.050 mL) and NaBH-
OAc) (27.1 mg, 0.128 mmol) at -20 °C. After stirring for
5 h, the mixture was poured into saturated NaHCO and extracted
(
21) Baasner, B.; Hagemann, H.; Tatlow, J. C.; Eds. Organofluorine
1
compounds. In Houben-Weyl, Methods of Organic Chemistry; Thieme-
Verlag: Stuttgart, 1999/2000; Vol. E 10a-c and papers cited therein.
2
2
(
3
(22) For a recent review on dihydroxyacetone derivatives, see: Enders,
D.; Voith, M.; Lenzen, A. Angew Chem., Int. Ed. 2005, 44, 2-23.
3
J. Org. Chem, Vol. 71, No. 10, 2006 3827

Suri et al.
with EtOAc. The combined organic layer was washed with brine,
dried over Na SO , and concentrated in vacuo. The obtained residue
was purified on silica gel to give 4a (15.1 mg, 69%). H NMR
400 MHz, CDCl ): δ 1.38 (s, 3H), 1.47 (s, 3H), 3.49 (s, 3H),
.52 (s, 3H), 3.64 (dd, J ) 8.8, 11.2 Hz, 1H), 3.73 (dd, J ) 6.4,
.2 Hz, 1H), 3.81-3.86 (m, 2H), 3.93 (dd, J ) 5.2, 11.2 Hz, 1H),
.46 (d, J ) 3.2 Hz, 1H). 13C NMR (100 MHz, CDCl
): δ 19.5,
8., 29.70, 55.9, 56.5, 63.9, 65.3, 72.3, 75.0, 103.3. HRMS C10
(M + Na): calcd 259.1152, obsd 259.1149. [R]D25 ) -7.3
c ) 0.52, MeOH).
S)-4-((R)-1-(tert-Butyldimethylsilyloxy)-2,2-dimethoxyethyl)-
,2-dimethyl-1,3-dioxan-5-one (5). To a solution of compound 3f
(400 MHz, CD
3
OD): δ 3.30-3.32 (m, 3H), 3.60 (m, 1H), 4.22
2
4
(dd, J ) 7.2, 8.0 Hz, 1H), 5.06 (s, 2H), 7.27-7.36 (m, 5H), 7.50
1
13
(d, J ) 7.2 Hz, 1H). C NMR (100 MHz, CD
3
OD): δ 64.5, 70.4,
(
3
71.7, 73.4, 76.8, 128.8, 129.3, 129.4, 139.2, 152.8. HRMS for
+
D
3
9
4
2
NaO
(
C
12
H
17NNaO
0.27 (c ) 1.0, MeOH).
2-((2S,3S)-2,3,5-Trihydroxy-4-oxopentyl)isoindoline-1,3-di-
one (7). Compound 3c (0.05 mmol, 18 mg) dissolved in H O (200
µL) and THF (300 µL) was stirred with Dowex 50WX2-100 resin
(prewashed with H O) for 12 h at room temperature. The solution
5
(MNa ): calcd 278.0999, obsd 278.1004. [R] 25 )
3
H
20
-
2
6
2
(
was filtered and the filtrate was concentrated to give the final
product without purification (yield 99%). H NMR (d-DMSO, 500
1
2
(
(
0.174 mg, 0.744 mmol) in DMF (2.0 mL) were added imidazole
0.127 g, 1.87 mmol) and TBS-Cl (0.168 g, 1.11 mmol) at room
MHz): δ 7.88-7.82 (m, 4H), 5.70 (d, J ) 5.3 Hz, 1H), 5.31 (d, J
) 5.4 Hz, 1H), 4.90 (t, J ) 5.9 Hz, 1H) 4.32 (dq, J
1
) 6.0 Hz, J
2
temperature. After stirring for 24 h, the mixture was poured into
saturated NH Cl and extracted with EtOAc. The combined organic
layer was washed with brine, dried over Na SO , and concentrated
in vacuo. The obtained residue was purified on silica gel to give
) 19.4 Hz, 2H), 4.03-3.96 (m, 2H), 3.73 (dd, J
1
) 9.2 Hz, J
2
)
1
3
4
13.8 Hz, 1H), 3.56 (dd, J ) 3.13 Hz, J ) 13.1 Hz, 1H).
1
2
C
2
4
NMR (d-DMSO, 125 MHz) δ 211.0, 167.9, 134.1, 131.7, 122.8,
+
76.3, 69.0, 66.4, 41.0. HRMS for C13
H
13NNaO
6
(MNa ): calcd
O, 1:1).
1
302.0635, obsd 302.0634. [R]D25 ) -23.9 (c ) 1.0, THF/H
the target product (0.170 g, 66%). H NMR (400 MHz, CDCl
3
): δ
.09 (s, 3H), 0.11 (s, 3H), 0.88 (s, 9H), 1.44 (s, 3H), 1.47 (s, 3H),
.40 (s, 3H), 3.46 (s, 3H), 3.89 (d, J ) 16.0 Hz, 1H), 4.06 (dd, J
2.0, 7.2 Hz, 1H), 4.22 (dd, J ) 1.6, 16.0 Hz, 1H), 4.34 (dd, J )
.6, 3.2 Hz, 1H), 4.59 (d, J ) 7.2 Hz, 1H). 13C NMR (100 MHz,
CDCl ): δ -4.9, -4.6, 18.1, 22.9, 24.9, 25.8, 55.6, 56.0, 67.1,
3.5, 77.7, 100.2, 105.4, 202.1. HRMS C16 Si (M + Na):
calcd 371.1866, obsd 371.1856. [R] 25 ) -88.3 (c ) 0.69, MeOH).
2S,3S,4R,E)-2,3,4,5-Tetrahydroxypentanal O-Benzyl Oxime
6a). Dowex 50W2-100 (54.0 mg) was added to a solution of 4a
83.0 mg, 0.351 mmol) in H O (2.0 mL). After stirring at room
2
0
3
)
1
Compound 12. Commercially available 1,2:3,4-di-O-isopropyl-
idene-R-D-galactopyranose (2.5 g, 9.61 mmol) was dissolved in
23
EtOAc (70 mL), and IBX (28.8 mmol, 8.1 g) was carefully added.
The suspension was heated to reflux for 4 h, and then the precipitate
3
was removed via filtration. The EtOAc was concentrated in vacuo
1
7
H32NaO
6
to give aldehyde 12 in quantitative yield. HNMR (CDCl
3
, 500
D
MHz): δ 9.618 (1H), 5.67 (d, J ) 4.9 Hz, 1H), 4.62 (ddd, J
2.45 Hz, J ) 7.80 Hz, J ) 11.5 Hz, 2H), 4.38 (q, J ) 2.45 Hz,
1H), 4.19 (d, J ) 2.13 Hz, 1H), 1.51 (s,3H), 1.44 (s,3H), 1.35 (s,
3H), 1.31 (s, 3H). 13C NMR (CDCl
, 125 MHz): δ 24.2, 24.8,
25.8, 26.0, 70.4, 70.5, 71.7, 73.2, 96.2, 109.0, 110.0, 200.3. HRMS
1
)
(
2
3
(
(
2
3
temperature for 6.5 h, the resin was removed by filtering through
a glass filter. The solution was concentrated in vacuo. The residue
+
19 6
for C12H O (MH ) calcd 259.1176, obsd 259.1182.
(
51.4 mg, 0.342 mmol) was dissolved in EtOH (1.0 mL), and
pyridine (0.042 mL, 0.513 mmol) and benzyloxyamine HCl salt
82.0 mg, 0.513 mmol) were added to the solution. After stirring
for 24 h, the mixture was diluted with EtOAc and saturated NH Cl
and extracted with EtOAc. The organic layer was washed with
saturated NaHCO and brine, dried over Na SO , and evaporated.
The obtained residue was purified on silica gel to give the target
Acknowledgment. This study was supported by the Skaggs
Institute for Chemical Biology.
(
Note Added after ASAP Publication. There was an error
in the page range of ref 8a and ref 8f was missing in the version
published ASAP April 6, 2006; the revised version was
published April 12, 2006.
4
3
2
4
1
product (74% over two steps). H NMR (400 MHz, CD
3
5
3
OD): δ
Supporting Information Available: Product characterization
.56-3.68 (m, 3H), 3.77 (m, 1H), 4.35 (dd, J ) 4.8, 7.2 Hz, 1H),
1
13
1
3
data of 2k-n, 3d, 3f, 4a, 13, 15, 17; H and C NMR spectra of
.07 (s, 2H), 7.27-7.36 (m, 5H), 7.51 (d, J ) 7.2 Hz, 1H).
C
2
k-n, 3d, 3f, 4a, 5, 6a, 6b, 13, 15, 17; X-ray ortep diagram and
NMR (100 MHz, CD
3
OD): δ 64.8, 68.4, 72.7, 74.6, 77.1, 128.9,
+
CIF file of 11. This material is available free of charge via the
1
2
29.2, 129.4, 139.2, 153.8. HRMS for C12
H
17NNaO
78.0999, obsd 278.1004. [R] 25 ) 62.2 (c ) 1.0, MeOH).
2S,3S,4S,E)-2,3,4,5-Tetrahydroxypentanal O-Benzyl Oxime
6b). The standard sample was prepared from 4b by the same
5
(MNa ): calcd
D
Internet at http://pubs.acs.org.
(
JO0602017
(
1
method as described for 6a; yield 52% over two steps. H NMR
(23) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001-3003.
3828 J. Org. Chem., Vol. 71, No. 10, 2006