Development of 5-silylethynyl-1,3-dioxolan-4-one as a new prochiral template for asymmetric phase-transfer catalysis

Article abstract of DOI:10.1039/c0cc02334e

Phase-transfer catalyzed asymmetric alkylation and Michael addition of 5-silylalkynyl-1,3-dioxolan-4-one were developed as a novel strategy to provide highly modular tertiary α-alkyl-α-hydroxy acids bearing an alkyne moiety.

Full text of DOI:10.1039/c0cc02334e

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Development of 5-silylethynyl-1,3-dioxolan-4-one as a new prochiral
template for asymmetric phase-transfer catalysisw
Takuya Hashimoto, Kazuhiro Fukumoto, Naoyuki Abe, Kazuki Sakata and Keiji Maruoka*
Received 2nd July 2010, Accepted 23rd August 2010
DOI: 10.1039/c0cc02334e
Phase-transfer catalyzed asymmetric alkylation and Michael
addition of 5-silylalkynyl-1,3-dioxolan-4-one were developed as
a novel strategy to provide highly modular tertiary a-alkyl-
a-hydroxy acids bearing an alkyne moiety.
Scheme
1
Reagents and conditions (Si = SiPh3): (a) BuLi,
a-Chiral acetylenes serve as an invaluable building block
owing to the synthetic versatility of the alkynyl moiety utilizable
in a variety of carbon–carbon and carbon–heteroatom bond
formations as well as reductive and oxidative manipulations.1
In the last decade, catalytic asymmetric alkynylations have
been playing a dominant role as a means to access optically
enriched a-chiral acetylenes.2 In this context, phase-transfer
catalyzed asymmetric alkylation of a-alkyl-a-alkynyl esters
has recently emerged from this laboratory as an alternative
approach, wherein the a-chiral acetylenes with an all-carbon
quaternary stereocenter could be easily constructed.3,4 In an
effort to extend this concept, we embarked on the phase-
transfer catalyzed functionalization of a-alkynyl-a-hydroxy
acid derivatives as a means to provide chiral tertiary alcohols
bearing an alkynyl and ester functionalities (Fig. 1).5 The clear
advantage of this protocol compared to the corresponding
asymmetric alkynylation of a-keto esters6,7 is the feasibility of
introducing various functionalities at the tertiary alcohol
moiety (R1 in Fig. 1) simply by changing electrophiles.8
Ph3SiCRCH, THF, À78 1C; (b) LiBH4, THF, À78 to 0 1C, 76%
(2 steps); (c) HCO2H, CH2Cl2, rt; (d) PPTS, Me2C(OMe)2, cyclo-
hexane, reflux, 61% (2 steps).
a silylethynyl moiety, would increase the acidity of the a-hydrogen
and facilitate the catalytic generation of the corresponding
ammonium enolate under the phase-transfer conditions.
After establishment of the synthetic protocol of the requisite
substrates 2 in multigram quantities as shown in Scheme 1, we
set out to investigate the phase-transfer catalyzed alkylation of
thus-obtained 5-(triphenylsilyl)ethynyl-1,3-dioxolan-4-one 2a
(Si = SiPh3) (Table 1). The initial experiment employing the
Table 1 Optimization of the reaction conditionsa
As
a suitable protecting group for the fundamental
a-alkynyl-a-hydroxy acid motif tolerant to the basic phase-
transfer condition, we opted for the use of a 1,3-dioxolan-4-one,
considering its facile deprotection as well as the advantage of its
cyclic structure forming only Z-enolate rigorously as a key
prochiral intermediate. Although such a 1,3-dioxolan-4-one
structure is commonly utilized in Seebach’s diastereoselective
self-regeneration of stereocenters strategy,9 the harsh basic
conditions required to generate the corresponding enolates are
considered inadequate to be applied in catalytic asymmetric
synthesis.10 Nevertheless, we anticipated that the highly
electron-withdrawing character of an alkynyl moiety, especially
Yieldb eec
Entry cat. Si
Solvent
1C, h
0, 3
(%)
(%)
1
1a Ph3Si (2a)
Toluene
Toluene
TBME
TBME
TBME
TBME
TBME
TBME
—
—
18
—
35
30
38
81
84
—
—
68
78
84
89
89
2
3
4
5
6
7
8
1a Ph3Si
1a Ph3Si
1a Ph3Si
1b Ph3Si
1c Ph3Si
1d Ph3Si
1e Ph3Si
À20, 21 43
À20, 6
—
À30, 15 49
À30, 19 51
À30, 23 66
À30, 24 64
À30, 20 83
9
1e tBuMe2Si (2b) TBME
1e PhMe2Si (2c) TBME
1e Ph2MeSi (2d) TBME
1e Ph3Si
1e Ph3Si
1e Ph3Si
À30, 24
À30, 24
—
—
10
11
12
13d
14d
À30, 17 43
CPME
À30, 3 28
Fig. 1 Strategies for the asymmetric synthesis of a-chiral acetylenes
having a tertiary alcohol.
TBME : CPME À30, 9 79
TBME : CPME À40, 46 84
TBME : CPME À40, 9 71
15d,e 1e Ph3Si
a
Reactions were performed with 2 (0.10 mmol) and benzyl bromide
(0.12 mmol) in the presence of 1 mol % (S)-1 (0.001 mmol) and
b
powdered KOH (0.25 mmol). Isolated yield. Determined by
Department of Chemistry, Graduate School of Science,
Kyoto University, Sakyo, Kyoto, 606-8502, Japan.
E-mail: maruoka@kuchem.kyoto-u.ac.jp; Fax: +81 75-753-4041;
Tel: +81 75-753-4041
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c0cc02334e
c
d
chiral HPLC. TBME : CPME
e
=
1 : 1. Powdered CsOHÁH2O
(0.25 mmol).
c
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Chem. Commun., 2010, 46, 7593–7595 7593

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conventional phase-transfer catalyzed alkylation conditions
using (S)-1a as catalyst failed to give the desired compound
in a meaningful yield (entry 1). Since decomposition of the
substrate was assumed to predominate over alkylation, the
reaction was then conducted at lower temperatures to give
the alkylated compound 3aa in 43% yield with 18% ee
(entry 2). When TBME (tert-butyl methyl ether) was utilized
as ethereal solvent, rapid decomposition of the substrate was
again observed even at À20 1C (entry 3). This issue could be
solved by further lowering the reaction temperature to À30 1C,
furnishing the alkylated compound in 49% yield with 35% ee
(entry 4). Screening of the aryl substituents of the quaternary
ammonium salt revealed the superior activity of the catalyst
(S)-1d (entries 5–7). Fine-tuning of the right hand of the
catalyst identified the use of newly developed N,N-diisopentyl
ammonium salt (S)-1e as the optimal catalyst (entry 8).
Replacement of the silyl group of 2 led to the significant
decrease of the reactivity, probably due to the lower acidity
of the a-hydrogen of these materials (entries 9–11).
Whereas the use of less polar aromatic solvents, such as
toluene and mesitylene, resulted in a deceleration of the
reaction (data not shown), use of a more polar ethereal solvent
CPME (cyclopentyl methyl ether) led to a drastic increase of
the reactivity accompanied by the competitive degradation of
the substrate (entry 12). At this stage, we came up with the
idea of using a co-solvent system comprised of TBME and
CPME, anticipating the acceleration of the reaction without
compromising the yield or selectivity. This co-solvent system
actually worked very well (entry 13), and the reaction
proceeded even at À40 1C, giving the product with 89% ee
(entry 14). Finally, use of caesium hydroxide monohydrate as
a stronger base further enhanced the reaction rate, furnishing
3aa in 71% yield with 89% ee within 9 h at À40 1C (entry 15).
With the optimized reaction conditions in hand, the
substrate scope of this alkylation was investigated in detail
(Table 2). The alkylations with electronically unbiased
benzylic bromides proceeded with high enantioselectivities
ranging from 87 to 95% ee (entries 2–6). Use of benzylic
bromides bearing a halogen atom or a methoxy group on the
aromatic ring resulted in slightly lower enantioselectivities
(entries 7–10). Use of allylic bromides was also tolerated,
though the enantioselectivity was highly dependent on the
substitution pattern of the allylic moiety (entries 11–13). In
addition, alkylation with propargyl bromide furnished the
diyne in 84% yield with 89% ee (entry 14).11
It is worth mentioning that the attempted alkylation of
5-phenylethynyl-1,3-dioxolan-2-one 4 furnished the cyclo-
butane 6 as a major product (85% yield) probably via the
base-mediated isomerization of the alkyne to the allene 5 and
successive [2+2] cycloaddition (Scheme 2).12
To expand the synthetic utility of 5-(triphenylsilyl)ethynyl-
1,3-dioxolan-4-one 2a as a novel nucleophilic template,
asymmetric Michael addition with methyl vinyl ketone was
then investigated. Although the re-establishment of the optimal
conditions was required, use of (S,S)-7 as phase-transfer
catalyst finally furnished the Michael adduct 8 in 81% yield
with 90% ee (Scheme 3).11 In this case, a relatively weak base
like caesium carbonate was able to facilitate the reaction.
Selective deprotection of the alkylated compound could be
achieved as summarized in Scheme 4. Treatment of 3aa with
hydrochloric acid furnished the corresponding a-hydroxy-
carboxylic acid 9 without affecting the silyl moiety. On the
other hand, use of potassium carbonate in methanol led to the
simultaneous removal of the acetonide and silyl groups to give
the methyl ester 10. The silyl moiety could be selectively
cleaved to provide 11 by the treatment with Bu4NF.
Table 2 Scope of phase-transfer catalyzed enantioselective alkylation
of 5-(triphenylsilyl)ethynyl-1,3-dioxolan-4-onea
Scheme 2 Formation of [2+2] adduct.
Entry
R
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Bn
71
70
73
79
83
79
84
85
61
78
61
75
75
84
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
89
89
87
95
88
87
84
86
85
83
76
80
86
89
4-MeC6H4CH2
3-MeC6H4CH2
2-MeC6H4CH2
4-PhC6H4CH2
2-NpCH2
4-FC6H4CH2
4-BrC6H4CH2
2-ClC6H4CH2
4-MeOC6H4CH2
H2CQCHCH2
(CH3)2CQCHCH2
H2CQC(CH3)CH2
HCRCCH2
a
Reactions were performed with 2a (0.10 mmol) and alkyl halide
(0.12 mmol) in the presence of 1 mol% (S)-1e (0.001 mmol) and
b
c
powdered CsOHÁH2O (0.25 mmol). Isolated yield. Determined by
Scheme 3 Phase-transfer catalyzed enantioselective Michael addition
chiral HPLC.
of 5-(triphenylsilyl)ethynyl-1,3-dioxolan-4-one.
c
7594 Chem. Commun., 2010, 46, 7593–7595
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and C. Bolm, Chem. Commun., 2006, 4263; (d) B. M. Trost and
A. H. Weiss, Adv. Synth. Catal., 2009, 351, 963.
3 (a) T. Hashimoto, K. Sakata and K. Maruoka, Angew. Chem., Int.
Ed., 2009, 48, 5014; (b) T. Hashimoto, K. Sakata and K. Maruoka,
Adv. Synth. Catal., 2010, 352, 1653.
4 For recent reviews on asymmetric phase-transfer catalysis, see:
(a) T. Hashimoto and K. Maruoka, Chem. Rev., 2007, 107, 5656;
(b) T. Ooi and K. Maruoka, Angew. Chem., Int. Ed., 2007, 46,
4222.
5 For the phase-transfer catalyzed asymmetric alkylation of
a-hydroxy carbonyl compounds, see: (a) T. Ooi, K. Fukumoto
and K. Maruoka, Angew. Chem., Int. Ed., 2006, 45, 3839;
(b) T. Hashimoto, K. Sasaki, K. Fukumoto, Y. Murase, N. Abe,
T. Ooi and K. Maruoka, Chem.–Asian J., 2010, 5, 562;
(c) M. B. Andrus, M. A. Christiansen, E. J. Hicken,
M. J. Gainer, D. K. Bedke, K. C. Harper, S. R. Mikkelson,
D. S. Dodson and D. T. Harris, Org. Lett., 2007, 9, 4865;
(d) M. B. Andrus, E. J. Hicken, J. C. Stephens and D. K. Bedke,
J. Org. Chem., 2005, 70, 9470.
Scheme 4 Selective transformation of the protecting groups.
In summary, we demonstrated herein the asymmetric
phase-transfer catalyzed alkylation and Michael addition of
6 (a) B. Jiang, Z. Chen and X. Tang, Org. Lett., 2002, 4, 3451;
(b) P. K. Dhondi, P. Carberry, L. B. Choi and J. D. Chisholm,
J. Org. Chem., 2007, 72, 9590.
5-silylethynyl-1,3-dioxolan-4-one as
a means to provide
a-chiral acetylenes with tertiary a-hydroxycarboxylic acid
structure. This synthetic plan could be realized by building on
the sufficiently electronegative nature of the (triphenylsilyl)-
ethynyl group which facilitated the deprotonation of the
substrate bearing a less acidic hydrogen. Application of this
template in other fundamental reaction systems such as aldol
and Mannich reactions is currently underway in this laboratory.
This work was partially supported by a Grant-in-Aid for
Scientific Research from MEXT (Japan). K.F. and K.S. thank
the Research Fellowships of JSPS for Young Scientists.
7 For other leading examples of asymmetric alkynylation of ketones,
see: (a) P. G. Cozzi, Angew. Chem., Int. Ed., 2003, 42, 2895;
(b) G. Lu, X. Li, X. Jia, W. L. Chan and A. S. C. Chan, Angew.
Chem., Int. Ed., 2003, 42, 5057.
8 For an alternative approach, see: D. K. Friel, M. L. Snapper and
A. H. Hoveyda, J. Am. Chem. Soc., 2008, 130, 9942.
9 (a) D. Seebach and R. Naef, Helv. Chim. Acta, 1981, 64, 2704;
(b) G. Frater, U. Muller and W. Gunther, Tetrahedron Lett., 1981,
´
¨
22, 4221; (c) R. Nagase, Y. Oguni, T. Misaki and Y. Tanabe,
Synthesis, 2006, 3915, and references herein.
10 For
a rare example of using 1,3-dioxolan-4-one motif in
asymmetric catalysis, see: P. S. Hynes, D. Stranges, P. A. Stupple,
A. Guarna and D. J. Dixon, Org. Lett., 2007, 9, 2107.
11 For the determination of the absolute configurations by X-ray
crystallographic analysis, see ESIw.
Notes and references
1 Acetylene Chemistry, ed. F. Diederich, P. J. Stang and
R. R. Tykwinski, Wiley–VCH, New York, 2005.
12 B. Alcaide, P. Almendros and C. Aragoncillo, Chem. Soc. Rev.,
2010, 39, 783.
2 (a) L. Pu, Tetrahedron, 2003, 59, 9873; (b) P. G. Cozzi, R. Hilgraf
and N. Zimmermann, Eur. J. Org. Chem., 2004, 4095; (c) L. Zani
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 7593–7595 7595