The direct asymmetric vinylogous aldol reaction of furanones with α-ketoesters: Access to chiral γ-Butenolides and glycerol derivatives

Article abstract of DOI:10.1002/anie.201006316

Twice as good: The title reaction using the tryptophan-derived bifunctional organic catalyst 1 has been developed. The reported method led to the synthesis of chiral γ-substituted butenolides in excellent yields, with high diastereo- and enantioselectivit

Full text of DOI:10.1002/anie.201006316

DOI: 10.1002/anie.201006316
Asymmetric Synthesis
The Direct Asymmetric Vinylogous Aldol Reaction of Furanones with
a-Ketoesters: Access to Chiral g-Butenolides and Glycerol
Derivatives**
Jie Luo, Haifei Wang, Xiao Han, Li-Wen Xu, Jacek Kwiatkowski, Kuo-Wei Huang, and
Yixin Lu*
The creation of quaternary stereogenic centers is still a
challenge in organic synthesis even though significant prog-
ress has been made in the past few decades.[1] As part of our
ongoing research efforts towards the efficient generation of
quaternary stereogenic centers,[2] we were interested in
organic molecules containing a tertiary hydroxy group.
Scheme 1. Construction of g-butenolides and glycerol derivatives
Structures that contain tertiary alcohols are very important
in the biological sciences and pharmaceutical industry.[3] In
particular, enantiomerically pure glycerol derivatives having
a quaternary center are key chiral structural motifs that are
present in many pharmaceuticals, and they are also versatile
synthetic intermediates.[4] Although many excellent methods
have been devised for the synthesis of chiral tertiary
alcohols,[5] the asymmetric preparation of glycerol derivatives
having a quaternary center is still a formidable task. To the
best of our knowledge, only two examples have been reported
in the literature. In 1992, Harada, Oku, and co-workers
reported a synthetic approach utilizing menthone as a chiral
auxiliary.[6] Very recently, Kang and co-workers elegantly
employed chiral copper complexes to carry out the enantio-
selective desymmetrization of meso-2-substituted glycerols,
and obtained 2-substituted 1,2,3-propanetriols with excellent
enantioselectivity.[7] It is thus our goal to develop an efficient
organocatalytic variant to allow easy access to 2-substituted
chiral glycerol derivatives.
through the vinylogous aldol reaction.
converted into tertiary-alcohol-containing glycerol deriva-
tives. The vinylogous aldol reaction has been investigated
intensively in the past few decades,[9] and although it is
commonplace to employ 2-silyloxyfurans as nucleophiles,[10]
the direct utilization of 2-furanone derivatives in the vinyl-
ogous aldol reactions is rare, probably because of their low
reactivity. Zhang and co-workers first utilized a,b-dichloro-g-
butenolides in the direct vinylogous aldol reaction.[11]
Recently, Terada and co-workers reported an enantioselec-
tive vinylogous aldol reaction of furanone derivatives with
aldehydes catalyzed by a chiral guanidine.[12] Feng and co-
workers subsequently disclosed a thiourea-catalyzed direct
vinylogous aldol reaction of furanones with aldehydes.[13]
Herein, we document the first direct asymmetric vinylogous
aldol reaction of 3,4-dichlorofuran-2(5H)-one with a-keto-
esters, catalyzed by an l-tryptophan-derived bifunctional
catalyst, that leads to an efficient synthesis of chiral g-
butenolides and 2-substituted glycerol derivatives.
We recently introduced a novel tertiary amine/thiourea
bifunctional catalyst derived from l-tryptophan, and showed
its effectiveness in the Mannich reaction of fluorinated
ketoesters.[2b] To extend the applications of these amino-
acid-based bifunctional catalysts,[14] we prepared a number of
l-tryptophan-derived organic catalysts and examined their
catalytic effects in the vinylogous aldol reaction of 3,4-
dichlorofuran-2(5H)-one (1a) with the phenylglyoxylates 2
(Table 1). The reaction was quite slow in the presence of Trp-1
alone (Table 1, entry 1), but the rate of the reaction could be
substantially improved with the addition of molecular sieves
(4 ꢀ; Table 1, entry 2). An examination of the ester moieties
in the different a-ketoesters revealed that tert-butyl phenyl-
glyoxylate (2c) offered the best diastereoselectivity and
enantioselectivity (Table 1, entry 4). Changing the concen-
tration of the reaction mixture yielded the product with a
91% ee (Table 1, entry 6). Notably, in contrast to the high
stereoselectivity induced by the tryptophan-derived organic
catalysts, quinidine QD-1, 6’-demethylated quinidine QD-
2,[15] quinidine-derived sulfonamide QD-3,[16] and quinidine-
We focused on the vinylogous aldol reaction between
furanones and a-ketoesters (Scheme 1). The g-butenolides
that would result from these reactions are common structural
motifs in bioactive molecules.[8] Moreover, they can be readily
[*] J. Luo, H. Wang, X. Han, J. Kwiatkowski, Prof. Dr. Y. Lu
Department of Chemistry & Medicinal Chemistry Program
Life Sciences Institute, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
Fax: (+65)6779-1691
E-mail: chmlyx@nus.edu.sg
Prof. Dr. L.-W. Xu
Key Laboratory of Organosilicon Chemistry and Material Technology
of Ministry of Education, Hangzhou Normal University (P R China)
Prof. Dr. K.-W. Huang
KAUST Catalysis Center and Division of Chemical and Life Sciences
and Engineering, King Abdullah University of Science and
Technology (Kingdom of Saudi Arabia)
[**] We thank the National University of Singapore and the Ministry of
Education (MOE) of Singapore (R-143-000-362-112) for generous
financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006316.
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1861

Communications
Table 1: Catalyst screening for the asymmetric vinylogous aldol reaction
of 1a with 2.[a]
Table 2: Scope of Trp-2-catalyzed direct vinylogous aldol reaction.[a]
Entry
1
R’
t [h] Yield [%][b] d.r.[c]
ee [%][d]
1
2
1a 4-PhC6H4
1a 2-naphthyl
1a 4-MeC6H4
1a 3-MeC6H4
1a 4-tBuC6H4
1a 4-OMeC6H4
1a 4-ClC6H4
1a 3-ClC6H4
1a 4-BrC6H4
1a 4-FC6H4
1a 4-CNC6H4
1a 4-CO2MeC6H4 3p
1a
1a
1a
1a
3e
3 f
3g
3h
3i
3j
3k
3l
24 92
40 86
48 86
48 81
72 80
72 76
24 85
24 84
24 93
36 81
20 93
20 86
20 86
96:4
94:6
95:5
96:4
95:5
94:6
97:3
93:7
95:5
94:6
92:8
97:3
92:8
93
94
95
94
94
95
92
88
90
92
82
87
85
3[e]
4[e]
5[e]
6[e]
7
8
9
10
11[f]
12[f]
13
3m
3n
3o
Entry
Cat.
R
t [h]
Yield [%][b]
d.r.[c]
82:18
80:20
81:19
>91:9
91:9
>91:9
>91:9
>91:9
>91:9
>91:9
>91:9
>91:9
>91:9
>91:9
>91:9
95:5
ee [%][d]
3q
3r
3s
3t
14
15[g]
20 87
10 41
12 73
90:10 81
88:12 90
89:11 88
1[e]
2
3
4
Trp-1
Trp-1
Trp-1
Trp-1
Trp-1
Trp-1
QD-1
QD-2
QD-3
QD-4
Trp-2
Trp-3
Trp-4
Trp-5
Trp-6
Trp-2
Trp-2
Trp-2
Trp-2
Me (3a)
Me (3a)
Et (3b)
48
15
24
24
24
24
24
24
24
24
24
24
24
24
24
40
24
24
40
<50
83
89
92
79
85
84
85
<50
92
91
87
89
84
87
83
89
88
73
75
74
82
87
61
91
À11
12
0
À65
92
80
71
65
29
90
88
93
93
16
17
18
19
20
1a PhCH2
1a PhCH2CH2
1a
3u
3v
3w
8
5
61
53
85:15 80
86:14 85
87:13 80
tBu (3c)
Ph (3d)
tBu (3c)
tBu (3c)
tBu (3c)
tBu (3c)
tBu (3c)
tBu (3c)
tBu (3c)
tBu (3c)
tBu (3c)
tBu (3c)
tBu (3c)
tBu (3c)
tBu (3c)
tBu (3c)
5
6[f]
12 70
7[f]
1b Ph
3x 144 69
91:9
82
8[f]
[a] Reaction conditions:
1
(0.1 mmol),
2
(0.05 mmol), Trp-2
9[f]
(0.005 mmol), molecular sieves (4 ꢀ), 1:1 mixture of THF/acetone
(0.2 mL), room temperature. [b] Yield of the isolated product. [c] Deter-
mined by 1H NMR analysis. [d] Determined by HPLC analysis on a chiral
stationary phase. [e] With 20 mol% of catalyst. [f] The reaction was
performed in 0.35 mL of solvent. [g] The double bond in the allyl group
was shifted to yield the 2-methyl-vinyl-substituted product.
10[f]
11[f]
12[f]
13[f]
14[f]
15[f]
16[f,g]
17[g,h]
18[g,i]
19[g,j]
94:6
97:3
97:3
well-tolerated, and high d.r. and ee values were attainable
(Table 2, entries 13–14). Alkyl-substituted ketoesters were
suitable substrates as well, and stereoselectivities were
maintained (Table 2, entries 16–19). The nonhalogenated
furanone could also be used, although a much longer reaction
time was required (Table 2, entry 20).
The vinylogous aldol reaction described here represents a
novel asymmetric preparation of biologically important g-
substituted butenolides.[8] Furthermore, these aldol products
are versatile chiral building blocks as is demonstrated in
Scheme 2. Reduction of the g-substituted butenolide 3c
afforded the chiral g-butyrolactone[18] 4, and subsequent
selective reduction of the tert-butyl ester using LiAl-
(OtBu)3H[19] yielded lactone 5, which contains an adjacent
tertiary hydroxy group. Chiral glycerol derivatives were
accessed by treating 4 with LiBH4 at 608C to effect a global
reduction and give the 2-substituted glycerol derivative 6.
Alternatively, exposing 4 to LiBH4 at 08C selectively reduced
the lactone to triol 7, which could be elaborated to yield the
antifungal agent 10.[20]
[a] Reaction conditions: 1 (0.1 mmol), 2 (0.05 mmol), the catalyst
(0.01 mmol), molecular sieves (4 A), THF (0.35 mL), room temperature.
´
˚
[b] Yield of the isolated product. [c] Determined by 1H NMR analysis.
[d] Determined by HPLC analysis on a chiral stationary phase. [e] With-
out molecular sieves (4 ꢀ). [f] Reaction was performed in 0.5 mL of
solvent. [g] With 10 mol% catalyst. [h] Reaction was performed in 0.2 mL
of THF. [i] Reaction was performed in 0.2 mL of acetone/THF (1:1).
[j] Reaction was performed in 0.2 mL of acetone. Ts=p-toluenesulfonyl
derived thiourea QD-4[17] were all found to be poor catalysts
(Table 1, entries 7–10). Among the various tryptophan-based
catalysts, Trp-2 gave the best results (Table 1, entry 11). To
make the method more practical, the catalyst loading was
lowered to 10 mol%, and under the optimized reaction
conditions, the desired vinylogous aldol product could be
obtained in excellent yield and with 97:3 d.r. and 93% ee
(Table 1, entry 18).
With these optimized reaction conditions in hand, the
reaction scope was studied next (Table 2). Consistently high
diastereo- and enantioselectivities were observed for a wide
range of aromatic-substituted a-ketoesters (Table 2,
entries 1–12). Vinylic substituents on the a-ketoesters were
To account for the stereochemical outcome of the vinyl-
ogous aldol reaction, a plausible transition-state model is
proposed in Scheme 3. The tertiary amine of the catalyst
deprotonates the dichlorofuranone to yield an ammonium ion
and an enolate. Hydrogen-bonding interactions between the
ketoester and the thiourea moiety play a key role in the
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Angew. Chem. Int. Ed. 2011, 50, 1861 –1864

dibromofuranone (1c) was employed
in the vinylogous aldol reaction
under otherwise identical reaction
conditions, a 98:2 d.r. was observed,
as compared to a 95:5 d.r. with 3,4-
dichlorofuranone (1a).
In conclusion, we have developed
the first highly diastereo- and enan-
tioselective direct vinylogous aldol
reactions between furanones and a-
ketoesters catalyzed by a tryptophan-
derived bifunctional organic catalyst.
The synthetic method reported pro-
vides easy access to biologically
important g-substituted butenolides
and chiral glycerol derivatives con-
taining a tertiary alcohol moiety.
Investigations into the extension of
this method to other asymmetric
vinylogous reactions are ongoing
and will be reported in due course.
Scheme 2. Preparation of chiral g-substituted butenolides and 2-substituted glycerol derivatives.
DMAP=4-dimethylaminopyridine, Ms=methanesulfonyl, TFA=trifluoroacetic acid, TMS=tri-
methylsilyl, Tr=trityl.
Received: October 8, 2010
Revised: December 3, 2010
Published online: January 11, 2011
Keywords: aldol reaction · asymmetric synthesis · butenolides ·
.
glycerol derivatives · organocatalysis
Scheme 3. Proposed transition-state model.
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