Organocatalytic asymmetric syn-selective direct aldol reactions in water

Article abstract of DOI:10.1016/j.tetlet.2009.06.037

A practical and convenient organocatalytic strategy is developed to provide a direct route to syn-selective aldol products in the presence of water. The siloxy serine organocatalyst mediates the direct aldol reaction of TBSO-protected hydroxyacetone with

Full text of DOI:10.1016/j.tetlet.2009.06.037

Tetrahedron Letters 50 (2009) 4854–4856
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Tetrahedron Letters
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Organocatalytic asymmetric syn-selective direct aldol reactions in water
b
b
b
Yong-Chua Teo a, , Guan-Leong Chua , Chin-Yee Ong , Chai-Yun Poh
*
a Natural Sciences and Science Education, National Institute of Education, Nanyang Technological University, 1 Nanyang Walk, Singapore 637616, Singapore
b Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and convenient organocatalytic strategy is developed to provide a direct route to syn-selective
aldol products in the presence of water. The siloxy serine organocatalyst mediates the direct aldol reac-
tion of TBSO-protected hydroxyacetone with a variety of aldehydes to provide the aldol products in good
yields and enantioselectivities up to 92%.
Received 17 February 2009
Revised 25 May 2009
Accepted 5 June 2009
Available online 11 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Enantioselective organocatalysis has emerged as a powerful
strategy in organic synthesis since it employs small organic mole-
cules that are relatively non-toxic, inexpensive and stable to both
air and moisture.1 The organocatalytic asymmetric direct aldol reac-
tion via enamine intermediates generated in situ is one of the most
effective carbon–carbon bond-forming reactions for synthesizing
enantiomerically enriched b-hydroxy carbonyl compounds.2 The
potential of this reaction to generate diversity and to construct use-
ful building blocks for pharmaceuticals and natural products has at-
tracted attention from synthetic chemists and the pharmaceutical
industry.3
b-hydroxy carbonyl scaffolds.13 The reaction proceeded via a bi-
phasic system, furnishing a wide variety of aldol products in good
yields and excellent enantioselectivities. Based on this precedent
and as part of our programme to develop organocatalytic direct al-
dol reactions to install syn-configured 1,2-diols, we investigated
protected forms of hydroxyketones as donors. Herein, we report
on efficient syn-selective syntheses of aldol products based on
the protected monohydroxy acetone donors catalyzed by the siloxy
serine organocatalyst in the presence of water.
In our initial study, tert-butyldimethylsiloxy hydroxyacetone
and 4-nitrobenzaldehyde were chosen as model substrates. Using
the optimized conditions developed for the previous protocol,13a
Organic reactions in water have attracted significant attention,
not only because unique reactivity is often observed in water, but
also due to its low-cost, safety and environmentally benign nature.4
The synthesis of organic molecules via organocatalytic reactions in
water5 is an extensively investigated topic which entails the addi-
tional challenges of water tolerance for the catalyst6 and the associ-
ated problem of substrate solubilities and reactivities. Barbas
reported the direct asymmetric aldol reaction of ketones and aryl
aldehydes in water catalyzed by proline-derived hydrophobic
organocatalysts7 and an amide catalyst derived from threonine that
mediated the synthesis of syn-aldol products from protected dihy-
droxyacetone in aqueous media.8 Hayashi reported that siloxypro-
line catalyzes effectively the highly diastereo- and enantioselective
aldol reaction of ketones and aldehydes in the presence of water,9
and that a combined proline-surfactant organocatalyst promotes
the asymmetric aqueous direct cross-aldol reaction of two different
aldehydes.10 Numerous examples of organocatalytic direct aldol
reactions utilizing amino acid derivatives and polymer-supported
organocatalysts in the presence of water have been reported.11,12
Recently, we reported a siloxy serine organocatalyst that uses a
cyclic ketone, predominantly cyclohexanone as the aldol donor, in
the presence of water to facilitate the synthesis of anti-configured
Table 1
Optimization studies on the siloxy-L-serine-catalyzed asymmetric direct aldol
reactiona
NH2
O
O
OH
1'
O
TBDPSO
COOH
2
+
H
+ anti- isomer
NO2
H2O, RT
OTBS
OTBS
NO2
20 h
Entry
Cat. loading (mmol %)
H2O (mL)
Yieldb (%)
syn:antic
eed (%)
1
2
3
4
10
10
10
5
0.1
0.3
0.3
0.3
82
83
70
74
91:9
92:8
91:9
88:12
84
88
86e
84
a
Unless otherwise shown, the reaction was performed with aldehyde
(0.5 mmol), ketone (1.0 mmol) and catalyst (0.05 mmol) in H2O at room tempera-
ture for 20 h.
b
Combined yield of isolated diastereomers.
c
Diastereoselectivity was determined by 1H NMR analysis of the reaction
mixture.
d
Enantiomeric excess refers to the syn isomer and was determined by HPLC
analysis on a chiral phase.
* Corresponding author. Tel.: +65 6790 3846; fax: +65 6896 9414.
E-mail address: yongchua.teo@nie.edu.sg (Y.-C. Teo).
e
The reaction was performed with 1.1 equiv of ketone donor.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.037

Y.-C. Teo et al. / Tetrahedron Letters 50 (2009) 4854–4856
4855
Table 2
the direct aldol reaction catalyzed by 10 mol % of the TBDPS-
L
-ser-
The asymmetric direct aldol reactiona catalyzed by siloxy-L-serine organocatalyst in
water
ine organocatalyst proceeded in the presence of water to afford the
product in a good yield of 82% and enantiomeric excess of 84% (Ta-
ble 1, entry 1). With an increased amount of water in the reaction
mixture, the aldol product was isolated in a comparable yield of
83% and higher enantiomeric excess of 88% (entry 2). To enhance
the atom economical value of the current synthetic approach, the
reaction was repeated using a reduced amount of the aldol donor.
In this experiment, the aldol product was obtained in a good yield
of 70% and enantiomeric excess of 86% (entry 3). It is worth noting
10 mol%
NH2
O
OH
R1
OTBS
TBDPSO
O
COOH
O
+
+ anti- isomer
H
R1
H2O, RT
20 h
OTBS
Entry
1
Product
Yieldb (%)
syn:antic (%)
eed (%)
that the siloxy-L-serine organocatalyst can also catalyze the reac-
tion at 5 mol % catalyst loading, affording the aldol product in good
enantiomeric excess, albeit with a slight decrease in yield (entry 4).
In summary, the optimum conditions required the use of 10 mol %
of the siloxy serine organocatalyst, ketone donor (2 equiv) and
water (0.6 ml mmolÀ1) at room temperature for 20 h (entry 2).
A series of aromatic aldehydes were used to explore the general-
ity of this catalytic system and the results are summarized in Table 2.
In most cases, the expected b-hydroxy carbonyl compounds were
obtained in good yields and high diastereo- and enantioselectivities.
The more reactive aldehydes afforded the aldol products in good to
excellent enantioselectivities and high syn-selectivities (Table 2, en-
tries 1–3). Aldehyde substrates with a para-substituted halogen
moiety underwent the catalytic process to afford the aldol products
in moderate yields and good enantioselectivities (entries 4 and 5).
The direct aldol reaction between benzaldehyde and tert-butyldim-
O
OH
83
84
90
71
80
62
64
78
92:8
88
OTBS
NO2
NO2
O
O
OH
2
3
4
5
6
7
87:13
90:10
84:16
87:13
88:12
81:19
80:20
86
90
92
76
92
74
80e
OTBS
OH
ethylsiloxy hydroxyacetone catalyzed by the siloxy-L-serine organo-
OTBS
CN
catalyst gave the corresponding product in high enantio- and
diastereoselectivity (entry 6). However, only moderate enantiose-
lectivity was obtained in the case of 2-naphthaldehyde as the aldol
acceptor (entry 7). The catalytic process was also efficient for a rep-
resentative aldehydewith apara-electron-donatinggroup, affording
the product in good yield and enantioselectivity (entry 8). Currently,
the catalytic system is limited only to aryl aldehydes as acceptors as
we were unable to obtain satisfactory results with aliphatic alde-
hydes. The stereochemistry of the b-hydroxy group of the aldol ad-
O
O
OH
OTBS
Cl
Br
OH
ducts derived from the acyclic siloxy-L-serine catalysis was
determined as S by chiral-phase HPLC analysis and by comparison
with the literature.11
OTBS
In conclusion, we have demonstrated an efficient direct asym-
metric syn-selective aldol reaction between a variety of aromatic
aldehydes and tert-butyldimethylsiloxy hydroxyacetone as donor
in the presence of water, catalyzed by a siloxy-L-serine organocat-
O
OH
alyst.14 Features worth noting include (1) the direct aldol reaction
proceeded efficiently in the presence of water to afford a variety of
valuable compounds from commercially available substrates; (2)
the procedure is simple to perform and requires mild conditions;
OTBS
(3) the siloxy-L-serine organocatalyst is prepared easily and eco-
O
O
OH
nomically from commercially available sources, with both enanti-
omers readily available; (4) a 5 mol % catalyst loading is sufficient
to furnish the aldol products in good yields and enantioselectivi-
ties. Further extension of the siloxy serine organocatalyst to other
asymmetric reactions is ongoing in our laboratory and the results
will be reported in due course.
OTBS
OH
8
Acknowledgements
OTBS
Me
We would like to thank the National Institute of Education
(RP5/06 TYC), Nanyang Technological University for their generous
financial support.
a
Unless otherwise noted, the reaction was performed with aldehyde (0.5 mmol),
ketone (1.0 mmol) and siloxy serine organocatalyst (0.05 mmol) in H2O (0.3 mL) at
room temperature.
b
Combined yield of isolated diastereomers.
c
Diastereoselectivity was determined by 1H NMR analysis of the reaction
Supplementary data
mixture.
d
Enantiomeric excess refers to the syn isomer and was determined by HPLC
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.06.037.
analysis on a chiral phase.
e
Reaction was carried out using 20 mol % catalyst loading.

4856
Y.-C. Teo et al. / Tetrahedron Letters 50 (2009) 4854–4856
11. (a) Córdova, A.; Zou, W.; Ibrahem, I.; Reyes, E.; Engqvist, M.; Liao, W.-W. Chem.
References and notes
Commun. 2005, 3586; (b) Zou, W.; Ibrahem, I.; Dziedzic, P.; Sundén, H.;
Córdova, A. Chem. Commun, 2005, 4946; (c) Hayashi, Y. Angew. Chem., Int. Ed.
2006, 45, 8103; (d) Mase, N.; Wattanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F., III J. Am. Chem. Soc. 2006, 128, 4966; (e) Jiang, Z.-Q.; Liang, Z.; Wu,
X.-Y.; Lu, Y.-X. Chem. Commun. 2006, 2801; (f) Córdova, A.; Zou, W.; Dziedzic,
P.; Ibrahem, I.; Reyes, E.; Xu, Y. Chem. Eur. J. 2006, 12, 5383; (g) Dziedzic, P.;
Zou, W.; Ibrahem, I.; Sundén, H.; Córdova, A. Tetrahedron Lett. 2006, 47, 6657;
(h) Chimni, S. S.; Mahajan, D. Tetrahedron: Asymmetry 2006, 17, 2108; (i)
Dziedzic, P.; Zou, W.; Hffren, J.; Cordova, A. Org. Biomol. Chem. 2006, 4, 38; (j)
Luo, S.; Mi, X.; Liu, S.; Xu, H.; Cheng, J.-P. Chem. Commun. 2006, 3687; (k) Wu,
Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8, 4417; (l) Guillena, G.;
Hita, M. D. C.; Tjera, C. N. Tetrahedron: Asymmetry 2006, 17, 1493; (m) Pihko, P.
M.; Laurikainen, K. M.; Usano, A.; Nyberg, A. I.; Kaavi, J. A. Tetrahedron 2006, 62,
317; (n) Font, D.; Jimeno, C.; Pericas, M. A. Org. Lett. 2006, 8, 4653; (o) Guilenna,
G.; Hita, M. C.; Najera, C. Tetrahedron: Asymmetry 2006, 17, 729; (p) Zhang, S.-
H.; Tang, M.-S. Tetrahedron: Asymmetry 2006, 17, 3351; (q) Guizzetti, S.;
Benaglia, M.; Raimondi, L.; Celentano, G. Org. Lett. 2007, 9, 1247; (r) Hayashi, Y.;
Aratake, S.; Itoh, T.; Okano, T.; Sumiya, T.; Shoji, M. Chem. Commun. 2007, 957;
(s) Wu, X.; Jiang, Z.; Shen, M.; Lu, Y. Adv. Synth. Catal. 2007, 349, 812; (t)
Rodríguez, B.; Bruckmann, A.; Bolm, C. Chem. Eur. J. 2007, 13, 4710; (u) Huang,
J. M.; Zhang, X. T.; Armstrong, D. W. Angew. Chem., Int. Ed. 2007, 46, 9073; (v)
Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593; (w) Luo, S.; Mi, X.; Zhang,
L.; Liu, S.; Xu, H.; Cheng, J.-P. Tetrahedron 2007, 63, 1923; (x) Giacalone, F.;
Gruttadauria, M.; Marculescu, A. M.; Noto, R. Tetrahedron Lett. 2007, 48, 255;
(y) Amedjkouh, M. Tetrahedron: Asymmetry 2007, 18, 390.
1. (a) Alexakis, A.; Bernardinelli, G.; Andrey, O. Org. Lett. 2003, 5, 2559; (b) Barbas,
C. F., III; Chowdari, N. S.; Suri, J. T. Org. Lett. 2004, 6, 2507; (c) Northrup, A. B.;
Mangion, I. K. F.; Hettche, F.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2004, 43,
4138; (d) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (e) List, B.
Chem. Commun. 2006, 819; (f) Berkssel, A.; Groger, H. Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, 2005; (g) Marigo, M.; Jørgensen, K.
A. Chem. Commun. 2006, 2001; (h) Lelais, G.; MacMillan, D. W. C. Aldrichim. Acta
2006, 39, 79; (i) Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug
Discovery Today 2007, 12, 8; (j) Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev.
2007, 107, 5416; (k) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471; (l) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713; (m)
Davie, E. A. C.; Mennen, S. M.; Xu, Y.; Miller, S. Chem. Rev. 2007, 107, 5759.
2. (a) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352; (b)
Sathivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc. 2001, 123, 5260;
(c) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798; (d)
List, B. Tetrahedron 2002, 28, 5573; (e) Suzuki, N.; Hayashi, Y.; Shoji, M.; Tsuboi,
W. J. Am. Chem. Soc. 2003, 125, 11208; (f) Zhong, G. Angew. Chem. Int. Ed. 2003,
42, 4247; (g) Notz, W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004, 37, 580;
(h) Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem. Soc. Rev. 2004, 33, 65; (i) Suri, J.
T.; Ramachary, D. B.; Barbas, C. F., III Org. Lett. 2005, 7, 1383; (j) Guillena, G.;
Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249; (k) Mukherjee,
S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471; (l) Schwab, R.
S.; Galetto, F. Z.; Azeredo, J. B.; Braga, A. L.; Lüdtke, D. S.; Paixão, M. W.
Tetrahedron Lett. 2009, 49, 5094.
12. (a) Gryko, D.; Saletra, W. J. Org. Biomol. Chem. 2007, 5, 2148; (b) Wang, C.; Jiang,
Y.; Zhang, X.; Huang, Y.; Li, B.; Zhang, G. Tetrahedron Lett. 2007, 48, 4281; (c)
Aratake, S.; Itoh, T.; Okano, T.; Usui, T.; Shoji, M.; Hayashi, Y. Chem. Commun.
2007, 24, 2524; (d) Chen, X.-H.; Luo, S.-W.; Tang, Z.; Cun, L.-F.; Mi, A.-Q.; Jiang,
Y.-Z.; Gong, L.-Z. Chem. Eur. J. 2007, 13, 689; (e) Carrie, E. A.; Scott, J. M. J. Am.
Chem. Soc. 2007, 129, 256; (f) Nagamine, T.; Inomata, K.; Enso, Y.; Paquette, L. A.
J. Org. Chem. 2007, 72, 123.
13. (a) Teo, Y.-C. Tetrahedron: Asymmetry 2007, 18, 1155; (b) Teo, Y.-C.; Lau, J.-J.;
Wu, M.-C. Tetrahedron: Asymmetry 2007, 19, 186; (c) Teo, Y.-C.; Chua, G.-L.
Tetrahedron Lett. 2008, 49, 4235.
14. Representative procedure for the direct asymmetric aldol reaction: A catalytic
amount of siloxyserine (0.05 mmol, 0.1 equiv) was added to a vial containing
the aldehyde (0.5 mmol, 1.0 equiv), tert-butyldimethyl-siloxyhydroxyacetone
(1.0 mmol, 2.0 equiv) and water (0.3 mL) under air in a closed system. The
reaction mixture was stirred at room temperature for 20 h and subsequently
poured into an extraction funnel containing brine (5 mL) and water (5 mL). The
reaction vial was also washed with ethyl acetate (5 mL). The aqueous phase
was extracted with ethyl acetate (3 Â 15 mL). The combined organic extracts
were dried with anhydrous MgSO4 and the solvent was removed under
reduced pressure. The crude aldol product was purified by silica gel column
chromatography (hexane–ethyl acetate, 9:1) to afford the product. The
diastereomeric anti-syn ratio for 1a was determined by 1H NMR analysis of
the crude reaction mixture: d 4.17 (d, 1H, J = 2.8 Hz, syn, major), 4.10 (d, 1H,
J = 6.2 Hz, anti, minor). Enantiomeric excess was determined by HPLC with a
Chiralcel OD-H column (hexane/i-PrOH = 90:10, 0.5 mL/min, k = 254 nm,
20 °C): tR = 14.5 min (minor) and 15.7 min (major).
3. (a) Trost, B. M. Science 1991, 254, 147; (b) Trost, B. M. Angew. Chem., Int. Ed.
1995, 34, 259; (c)Modern Aldol Reactions; Marhrwald, R., Ed.; Wiley-VCH:
Weinheim, 2004; Vols. 1–2, (d) Kim, B. M.; Williams, S. F.; Masamune, S.. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.;
Pergamon: Oxford, 1991; Vol. 2,.
4. (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159; (b) Gajewski, J. J. Acc. Chem. Res.
1997, 30, 219; (c)Organic Synthesis in Water; Grieco, P., Ed.; Blackie: London,
1998; (d) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751; (e) Kobayashi, S.;
Manabe, K. Acc. Chem. Res. 2002, 35, 209; (f) Li, C.-J. Chem. Rev. 2005, 105, 3095;
(g) Pirrung, M. C. Chem. Eur. J. 2006, 12, 1312. and references cited therein.
5. (a) Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P. Angew. Chem., Int. Ed.
2006, 45, 3093; (b) Palomo, C.; Vera, S.; Mielgo, A.; Gomez Bengoa, E. Angew.
Chem., Int. Ed. 2006, 45, 5984; (c) Mosse, S.; Laars, M.; Kriis, K.; Kanger, T.;
Alexakis, A. Org. Lett. 2006, 8, 2559; (d) Mosse, S.; Alexakis, A. Org. Lett. 2006, 8,
3577; (e) Reyes, E.; Vicario, J. L.; Badia, D.; Carrillo, L. Org. Lett. 2006, 8, 6135; (f)
McCooey, S. H.; Connon, S. J. Org. Lett. 2007, 9, 599; (g) Barros, M. T.; Phillips, A.
M. F. Eur. J. Org. Chem. 2007, 178; (h) Mosse, S.; Alexakis, A. Chem. Commun.
2007, 3123.
6. Sinou, D. Adv. Synth. Catal. 2002, 344, 221.
7. Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III J.
Am. Chem. Soc. 2006, 128, 734.
8. Ramasastry, S. S. V.; Albertshofer, K.; Utsumi, N.; Barbas, C. F., III Org. Lett. 2008,
10, 1621.
9. Hayashi, Y.; Sumiya, T.; Takashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew.
Chem., Int. Ed. 2006, 45, 958.
10. Hayashi, Y.; Aratake, S.; Okano, T.; Takahashi, J.; Sumiya, T.; Shoji, M. Angew.
Chem., Int. Ed. 2006, 45, 5527.