Organocatalytic asymmetric aldol reaction of hydroxyacetone with β,γ-unsaturated α-keto esters: Facile access to chiral tertiary alcohols

Article abstract of DOI:10.1021/ol2021274

An efficient direct asymmetric aldol reaction between hydroxyacetone and β,γ-unsaturated α-keto esters has been successfully developed. In the presence of 9-amino-9-deoxy-epi-cinchonine and trifluoroacetic acid, the direct aldol reaction of O-protected hy

Full text of DOI:10.1021/ol2021274

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5248–5251
Organocatalytic Asymmetric Aldol
Reaction of Hydroxyacetone with β,γ-
Unsaturated r-Keto Esters: Facile Access
to Chiral Tertiary Alcohols
Chen Liu, Xiaowei Dou, and Yixin Lu*
Department of Chemistry & Medicinal Chemistry Program, Life Sciences Institute,
National University of Singapore, 3 Science Drive 3, Republic of Singapore, 117543
chmlyx@nus.edu.sg
Received August 5, 2011
ABSTRACT
An efficient direct asymmetric aldol reaction between hydroxyacetone and β,γ-unsaturated R-keto esters has been successfully developed. In the
presence of 9-amino-9-deoxy-epi-cinchonine and trifluoroacetic acid, the direct aldol reaction of O-protected hydroxyacetone proceeded in a
highly enantioselective manner, affording the desired adducts containing a chiral tertiary alcohol in high yields and with excellent
enantioselectivities. The aldol products obtained are valuable precursors for the synthesis of 2-substituted glycerol derivatives.
Creating quaternary stereogenic centers is a challenging
task in organic synthesis and has drawn enormous atten-
tion in the past few decades.1 In our continuous efforts in
developing efficient asymmetric organocatalytic methods
for the synthesis of chiral quaternary carbons, we had
recently become interested in the efficient preparation of
organic molecules containing a tertiary alcohol group.2
Tertiary alcohols play very important roles in the pharma-
ceutical industry and biological sciences.3 In this context,
glycerol derivatives containing a quaternary center are key
motifs in many pharmaceutical agents, as well as versatile
intermediates useful in organic synthesis.4 Despite their
importance, asymmetric methods for the synthesis of
glycerol derivatives bearing a quaternary center are very
limited.5 Harada and Oku described a synthesis in which
(1) For a recent book, see: Quaternary Stereocenters; Christoffers, J.,
Barw, A., Eds.; Wiley-VCH: Weinheim, 2005.
(2) For our recent examples of the synthesis of quaternary stereo-
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Ed. 2011, 50, 7837. (b) Han, X.; Wang, S.-X.; Zhong, F.; Lu, Y. Synthesis
2011, 1859. (c) Luo, J.; Wang, H.; Han, X.; Xu, L.-W.; Kwiatkowski, J.;
Huang, K.-W.; Lu, Y. Angew. Chem., Int. Ed. 2011, 50, 1861. (d) Zhong,
F.; Chen, G.-Y.; Lu, Y. Org. Lett. 2011, 13, 82. (e) Han, X; Wang, Y.;
Zhong, F.; Lu, Y. J. Am. Chem. Soc. 2011, 133, 1726. (f) Zhu, Q.; Lu, Y.
Angew. Chem., Int. Ed. 2010, 49, 7753. (g) Han, X.; Zhong, F.; Lu, Y.
Adv. Synth. Catal. 2010, 352, 2778. (h) Zhu, Q.; Lu, Y. Chem. Commun.
2010, 46, 2235. (i) Jiang, Z.; Lu, Y. Tetrahedron Lett. 2010, 51, 1884. (j)
Han, X.; Kwiatkowski, J.; Xue, F.; Huang, K.-W.; Lu, Y. Angew.
Chem., Int. Ed. 2009, 48, 7604. (k) Han, X.; Luo, J.; Liu, C.; Lu, Y.
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Chadha, N. K.; Baggiolini, E. G.; Blount, J. F.; Uskokovic, M. R. J. Am.
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(5) For selected examples on the synthesis of chiral tertiary alcohols, see:
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Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature 2008,
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r
10.1021/ol2021274
Published on Web 09/08/2011
2011 American Chemical Society

menthone was utilized as a chiral auxiliary.6 Recently,
Kang et al. employed chiral copper complexes to achieve
an enantioselective desymmetrization of meso-2-substi-
tuted glycerols and prepared highly enantioselective 2-sub-
stituted 1,2,3-propanetriols.7 Very recently, our group
disclosed a highly diastereoselective and enantioselective
vinylogous aldol reaction of furanones with R-ketoesters,
which could provide easy access to chiral glycerol deriva-
tives containing a tertiary alcohol group.2c Given the
importance of chiral glycerol derivatives and the limited
methods for their preparation, efficient synthesis of these
molecules is still highly sought.
Moreover, the aldol products possess rich functionalities,
e.g. alkene, ester, and ketone, which would allow their
ready conversion tovariousglycerol derivatives containing
a tertiary alcohol group. Herein, we document a highly
enantioselective aldol reaction between hydroxyacetone
and β,γ-unsaturated R-keto esters, which provides an
easy access to chiral glycerol derivatives containing a
quaternary stereogenic center.
Scheme 1. Construction of Glycerol Derivatives through Direct
Aldol Reaction
In designing an asymmetric process to access chiral
2-substituted glycerols, we turned our attention to the
direct aldol reaction between hydroxyacetone and β,γ-
unsaturated R-keto esters. R-Keto esters are valuable
electrophiles in organic synthesis, and they have been
extensively investigated in a range of asymmetric organic
transformationsinrecent years.8 Yet, the utilizationofβ,γ-
unsaturated R-keto esters in the direct asymmetric organo-
catalytic aldol reaction is rare. Zhao and co-workers
successfully employed cyclic ketones in an organocatalytic
aldol reaction with β,γ-unsaturated R-ketoesters.9 Subse-
quently, Chan and Kwong developed an asymmetric aldol
reaction between ketones and β,γ-unsaturated R-keto-
esters; it is noteworthy that both cyclic and acyclic ketones
bearing long carbon side chains were suitable substrates in
their studies.10 Hydroxyacetone is a useful donor, and its
applications in the aldol reaction have been well studied.11
For the construction of chiral glycerol derivatives, we
envisioned that a direct aldol reaction between hydroxy-
acetone and β,γ-unsaturated R-keto esters may be utilized
(Scheme 1). Given the availability of asymmetric organo-
catalytic synthetic methods, chiral glycerol skeletons can
be readily created via the projected direct aldol reaction.
The past few years have seen remarkable progress in the
primary amine-based enamine catalysis.12 In this context,
our group has a keen interest in developing asymmetric
catalytic processes that can be promoted by primary
amine-based organic catalysts.13 Therefore, we chose the
direct aldol reaction between 1-(benzyloxy)propan-2-one
1a14 and methyl 2-oxo-4-phenylbut-3-enoate 2a as a model
reaction to examine the catalytic effects of various primary
amine catalysts (Table 1). L-Serine-derived 4, L-threonine-
based 5, diamine 6, and cinchonidine-derived diamine 7
were found to be ineffective (entries 1ꢀ4). Cinchona
alkaloid-derived primary amines were next investigated.
9-Amino-9-deoxy-epi-cinchonine 8, in combination with
trifluoroacetic acid (TFA), afforded the products in ex-
cellent yields and with high enantioselectivity, although
with only a 2:1 diastereomeric ratio (entry 5). However,
primary amines derived from quinidine 9, cinchonidine 10,
or quinine 11 were less effective (entries 8ꢀ10). Therefore,
cinchonine-derived 8 was chosen as the catalyst for further
studies.
(6) Harada, T.; Nakajima, H.; Ohnishi, T.; Takeuchi, M.; Oku, A. J.
Org. Chem. 1992, 57, 720.
(7) (a) Jung, B. H.; Hong, M. S.; Kang, S. H. Angew. Chem., Int. Ed.
2007, 46, 2616. (b) Jung, B.; Kang, S. H. Proc. Natl. Acad. Sci. U.S.A.
2007, 104, 1471.
To further improve the stereoselectivity, we next fo-
cused on varying the ester moieties of β,γ-unsaturated R-
keto esters and installing different protective groups on
hydroxyacetone (Table 2). Among the different enone
esters 2, the ethyl ester offered improved diastereoselec-
tivity and enantioselectivity, with a slighly decreased
chemical yield, compared to the reaction employing
(8) (a) Yanagisawa, A.; Terajima, Y.; Sugita, K.; Yoshida, K. Adv.
Synth. Catal. 2009, 351, 1757. (b) Wang, F.; Xiong, Y.; Liu, X.; Feng, X.
Adv. Synth. Catal. 2007, 349, 2665. (c) Mikami, K.; Kawakami, Y.;
Akiyama, K.; Aikawa, K. J. Am. Chem. Soc. 2007, 129, 12950. (d)
Samanta, S.; Zhao, C. G. J. Am. Chem. Soc. 2006, 128, 7442. (e)
Akullian, L. C.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2006, 128, 6532. (f) Tokuda, O.; Kano, T.; Gao, W. G.; Ikemoto, T.;
Maruoka, K. Org. Lett. 2005, 7, 5103. (g) Jiang, B.; Chen, Z. L.; Tang,
X. X. Org. Lett. 2002, 4, 3451. (h) Bogevig, A.; Kumaragurubaran, N.;
Jorgensen, K. A. Chem. Commun. 2002, 620. (i) Evans, D. A.; Kozlowski,
M. C.; Burgey, C. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 1997,
119, 7893.
(9) (a) Zheng, C. W.; Wu, Y. Y.; Wang, X. S.; Zhaoa, G. Adv. Synth.
Catal. 2008, 350, 2690. For an enantioselective formal [3 þ 3] annulation
of cyclic ketones with β,γ-unsaturated R-keto esters, see: (b) Cao, C.-L.;
Sun, X.-L.; Kang, Y.-B.; Tang, Y. Org. Lett. 2007, 9, 4151.
(10) (a) Li, P.; Zhao, J.; Li, F.; Chan, A. S. C.; Kwong, F. Y. Org.
Lett. 2010, 12, 5616. (b) Li, P.; Chan, S. H.; Chan, A. S. C.; Kwong, F. Y.
Adv. Synth. Catal. 2011, 353, 1179.
(11) For our application of hydroxyacetone in a direct aldol reaction,
see ref 13d. For selective examples reported by other groups, see: (a)
Barbas, C. F., III; Heine, A.; Zhong, G.; Hoffmann, T.; Gramatikova,
S.; Bjornestedt, R.; List, B.; Anderson, J.; Stura, E. A.; Wilson, I. A.;
Lerner, R. Science 1997, 278, 2085. (b) Notz, W.; List, B. J. Am. Chem.
Soc. 2000, 122, 7386. (c) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F.,
III. J. Am. Chem. Soc. 2001, 123, 5260. (d) Tang, Z.; Yang, Z.-H.; Cun,
L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org. Lett. 2004, 6, 2285.
(12) For reviews on asymmetric catalysis mediated by amino acids
and synthetic peptides, see: (a) Xu, L.-W.; Luo, J.; Lu, Y. Chem.
Commun. 2009, 1807. (b) Xu, L.-W.; Lu, Y. Org. Biomol. Chem. 2008,
6, 2047. (c) Davie, E. A. C.; Mennen, S. M.; Xu, Y.; Miller, S. J. Chem.
Rev. 2007, 107, 5759. (d) Peng, F.; Shao, Z. J. Mol. Catal. A 2008, 285, 1.
(e) Chen, Y.-C. Synlett 2008, 1919.
(13) For our recent examples on the primary amine-mediated enam-
ine catalysis, see: (a) Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Chem. Commun.
2006, 2801. (b) Cheng, L.; Han, X.; Huang, H.; Wong, M. W.; Lu, Y.
Chem. Commun. 2007, 4143. (c) Cheng, L.; Wu, X.; Lu, Y. Org. Biomol.
Chem. 2007, 5, 1018. (d) Wu, X.; Jiang, Z.; Shen, H.-M.; Lu, Y. Adv.
Synth. Catal. 2007, 349, 812. (e) Zhu, Q.; Lu, Y. Chem. Commun. 2008,
6315. (f) Zhu, Q.; Lu, Y. Chem. Commun. 2010, 46, 2235. (g) Jiang, Z.;
Yang, H.; Han, X.; Luo, J.; Wong, M. W.; Lu, Y. Org. Biomol. Chem.
2010, 8, 1368.
(14) When the free hydroxyacetone was used as a donor in the aldol
reaction with 2a in the presence of 8/TFA, only <30% conversion was
observed after 48 h.
Org. Lett., Vol. 13, No. 19, 2011
5249

Table 1. Screening of Organocatalysts for the Aldol Reaction of
1-(Benzyloxy)propan-2-one 1a with Methyl 2-Oxo-4-phenyl-
but-3-enoate 2aa
Table 2. Optimizing the Reaction Conditionsa
entry
1
R2
3
t (d)
yield (%)b
drc
ee (%)d
1
1a
1a
1a
1a
1b
1b
1c
1d
1e
1b
1b
1b
Me
Et
tBu
Et
Et
Et
Et
Et
Et
Et
Et
Et
3a
3b
3c
3b
3d
3d
3e
3f
1
1
2
1
2
2
2
2
2
2
2
2
97
80
57
80
81
80
88
2:1
3:1
5:1
3:1
4:1
2:1
2:1
ꢀ
87/64
91-
2
3
55-
4e
5
68/64
91/-
6f
92/88
44/87
ꢀ
7
j
8
ꢀ
9
3g
3d
3d
3d
<20
82
ꢀ
ꢀ
10g
11h
12i
1:3
3:1
3:1
90/84
11/66
32/66
entry
cat.
additive
yield (%)b
drc
1:1
ee (%)d
61
<20
1
2
3
4
5
6
7
8
4
none
none
none
TFA
TFA
TFA
TFA
TFA
72
71
77
79
97
98
96
96
ꢀ5/ꢀ9
33/17
5
1:1
1:1
a Reaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), 8 (0.02 mmol),
TFA (0.04 mmol), THF (0.2 mL), room temperature. b Isolated yield.
c Determined by 1H NMR analysis of the crude reaction mixture.
d The ee values of anti- and syn-isomers, respectively, determined by
HPLC analysis on a chiral stationary phase. e (ꢀ)-CSA (0.04 mmol).
6
20/31
7
1.5:1
2:1
ꢀ24/ꢀ30
87/64
8
9
2.5:1
2:1
66/68
f
10
11
ꢀ57/ ꢀ52
ꢀ20 °C. g CHCl3 (0.2 mL). h MeOH (0.2 mL). i DMF (0.2 mL). j No
reaction.
2:1
ꢀ17/-50
a Reaction conditions: 1-(benzyloxy)propan-2-one 1a (0.1 mmol),
methyl 2-oxo-4-phenylbut-3-enoate 2a (0.12 mmol), the catalyst (0.02
mmol), TFA (0.04 mmol), THF (0.2 mL), room temperature. b Isolated
yield. c Determined by 1H NMR analysis of the crude reaction mixture.
d The ee values of anti- and syn-isomers, respectively, determined by
HPLC analysis on a chiral stationary phase.
Table 3. Aldol Reaction of 1-(Naphthalen-2-ylmethoxy)propan-
2-one 1b with Various β,γ-Unsaturated R-Keto Estersa
methyl ester (entry 2 vs 1). The aldol reaction became very
slow when tert-butyl ester was employed, likely due to the
steric hindrance induced by the bulky tert-butyl group
(entry 3). We recently showed that the primary amine/
CSA ion pair is a powerful catalytic system for the
asymmetric enamine catalysis.15 However, inclusion of
CSA in our catalytic system did not prove to be beneficial
(entry 4). For the hydroxyacetone donors bearing different
protective groups, 1-(naphthalen-2-ylmethoxy)propan-2-
one 1b was found to be the best, affording the desired aldol
products in 81% yield, with a 4:1 dr and 91% ee for the
major diastereomer (entry 5). A few other protective
groups on hydroxyacetone were shown to be ineffective
(entries 7ꢀ9). A solvent screening revealed that THF was
the best solvent, and it is interesting to note that the
diastereoselectivity was reversed when CHCl3 was utilized
as a solvent (entry 10).
To establish the reaction scope, a number of β,γ-un-
saturated R-keto esters were employed as acceptors, and
the results are summarized in Table 3. Reactions were
applicable to various γ-aryl-substituted β,γ-unsaturated
R-keto esters, and aldol products were obtained with very
high enantioselectivities and moderate diastereoselectiv-
ities (entries 1ꢀ9). Acceptors containing heterocyclic rings,
entry
R
3
yield (%)b
drc
ee (%)d
1
Ph
3d
3j
81
86
82
93
81
87
81
83
97
90
92
95
ꢀ
4:1
3:1
7:2
2:1
3:1
3:1
3:1
3:1
5:2
7:1
3:1
3:1
ꢀ
91
99
99
77
99
95
91
90
99
91
88
85
ꢀ
2
4-NO2C6H4
4-ClC6H4
4-OMeC6H4
3-OMeC6H4
3-BrC6H4
3-MeC6H4
2-FC6H4
3
3k
3l
4
5
3m
3n
3o
3p
3q
3r
3s
3t
6
7
8
9
2-MeC6H4
3-thiophenyl
2-thiophenyl
3-pyridinyl
iBu
10
11
12
13
14
e
ꢀ
hexanyl
ꢀ
ꢀ
ꢀ
ꢀ
a Reaction conditions: 1b (0.1 mmol), 2 (0.12 mmol), 8 (0.02 mmol),
TFA (0.04 mmol), THF (0.2 mL), room temperature. b Isolated yield of
both diastereomers. c Determined by 1H NMR analysis of the crude
reaction mixture. d The ee value of the major diastereomer was deter-
mined by HPLC analysis on a chiral stationary phase. e No reaction.
such as thiophene and pyridine, also worked well for the aldol
reaction, affording the desired products in excellent yields, very
(15) Liu, C.; Zhu, Q.; Huang, K.-W.; Lu, Y. Org. Lett. 2011, 13, 2638.
5250
Org. Lett., Vol. 13, No. 19, 2011

high enantioselectivities, and moderate diastereoselectivities
(entries 10ꢀ12). Notably, the two diastereomers of the above
aldol products can be easily separated by flash column
chromatography. However, our current method is not applic-
able to the acceptors with aliphatic substituents on γ-positions,
as no desired products were observed (entries 13ꢀ14). The
absolute configurations of the aldol products were assigned
unambiguously, based on a single crystal X-ray analysis of
adduct 3n (Figure 1).
carbonyl group in 3n could be reduced stereoselec-
tively to afford alcohol 6.
Scheme 2. Preparation of Various Chiral Glycerol Derivatives
In conclusion, we have developed the first highly en-
antioselective aldol reaction of protected hydroxyacetone
with β,γ-unsaturated R-keto ester, promoted by a catalytic
system comprising 9-amino-9-deoxy-epi-cinchonine 8 and
TFA. The reported method represents a novel and prac-
tical approach to access chiral tertiary alcohol skeletons
and 2-substituted glycerol derivatives. Notably, the aldol
products are rich in functionalities, offering great latitude
for further structural elaborations of biologically impor-
tant chiral glycerol derivatives.
Figure 1. X-ray structure of 3n.
The aldol products are rich in functionality, which
can be readily converted to useful chiral glycerol
derivatives. As illustrated in Scheme 2, the reduction
of 3n afforded chiral diol 4, which contains a tertiary
alcohol functionality. Further reduction with LiAlH4
then yielded 2-substituted glycerol derivate 5.16 Treat-
ment of 3n with mCPBA yielded epoxide 7 in a diaster-
eospecific manner, which was readily opened to
generate chiral glycerol derivative 8. Moreover, the
Acknowledgment. We thank the National University of
Singapore (R-143-000-469-112) for generous financial
support.
Supporting Information Available. Representative ex-
perimental procedures, HPLC chromatogram, NMR
spectra of compounds, and X-ray crystallographic data
of 3n. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) The products were obtained as a 1:1 diastereomeric mixture.
Org. Lett., Vol. 13, No. 19, 2011
5251