Highly enantioselective alkynylation of trifluoropyruvate with alkynylsilanes catalyzed by the BINAP - Pd complex: Access to -trifluoromethyl-substituted tertiary alcohols

Article abstract of DOI:10.1021/ol102541s

A highly enantioselective alkynylation catalyzed by the dicationic (S)-BINAP - Pd complex with a variety of alkynylsilanes and trifluoropyruvate is described. The catalytic reaction is applicable to highly enantioselective addition of polyyne to trifluoro

Full text of DOI:10.1021/ol102541s

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5716-5719
Highly Enantioselective Alkynylation of
Trifluoropyruvate with Alkynylsilanes
Catalyzed by the BINAP-Pd Complex:
Access to r-Trifluoromethyl-Substituted
Tertiary Alcohols
Kohsuke Aikawa, Yu¯ta Hioki, and Koichi Mikami*
Department of Applied Chemistry, Tokyo Institute of Technology,
Tokyo 152-8552, Japan
mikami.k.ab@m.titech.ac.jp
Received October 20, 2010
ABSTRACT
A highly enantioselective alkynylation catalyzed by the dicationic (S)-BINAP-Pd complex with a variety of alkynylsilanes and trifluoropyruvate
is described. The catalytic reaction is applicable to highly enantioselective addition of polyyne to trifluoropyruvate to construct r-trifluoromethyl-
substituted tertiary alcohols as enantiomerically enriched forms. The alkynyl products can be converted into a chiral allene bearing a
trifluoromethyl group.
Organofluorine compounds have currently attracted widespread
interest in the fields of biological and material sciences.
Therefore, the development of a novel method to efficiently
introduce the fluorine unit is strongly desired in modern organic
synthesis.1 Especially, the synthesis of optically active R-tri-
fluoromethyl-substituted secondary and tertiary alcohols has
received much attention due to their unique properties with
unusual biological activities as drugs and its candidates, such
as Efavirenz (anti-HIV agents),2a CF3 analogues of MMPs
inhibitors2b and DHA (antimalarial agents),2c a nonsteroidal
(2) (a) Corbett, J. W.; Ko, S. S.; Rodgers, J. M.; Gearhart, L. A.; Magnus,
N. A.; Bacheler, L. T.; Diamond, S.; Jeffrey, S.; Klabe, R. M.; Cordova,
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Viitanen, S. K. J. Med. Chem. 2000, 43, 2019. (b) Sani, M.; Belotti, D.;
Giavazzi, R.; Panzeri, W.; Volonterio, A.; Zanda, M. Tetrahedron Lett. 2004,
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Schottelius, A.; Do¨cke, W.-D.; Strehlke, P.; Jaroch, S.; Schmees, N.;
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2004, 101, 227. (e) Betageri, R.; Zhang, Y.; Zindell, R. M.; Kuzmich, D.;
Kirrane, T. M.; Bentzien, J.; Cardozo, M.; Capolino, A. J.; Fadra, T. N.;
Nelson, R. M.; Paw, Z.; Shih, D.-T.; Shih, C.-K.; Zuvela-Jelaska, L.;
Nabozny, G.; Thomson, D. S. Bioorg. Med. Chem. Lett. 2005, 15, 4761.
(f) Moseley, J. D.; Brown, D.; Firkin, C. R.; Jenkin, S. L.; Patel, B.; Snape,
E. W. Org. Process Res. DeV. 2008, 12, 1044.
(1) (a) Ojima, I.; McCarthy, J. R.; Welch, J. T., Eds. Biomedical
Frontiers of Fluorine Chemistry; American Chemical Society: Washington
DC, 1996. (b) Chambers, R. D., Ed. Organofluorine Chemistry; Springer:
Berlin, 1997. (c) Soloshonok, V. A., Ed. Enantiocontrolled Synthesis of
Fluoro-Organic Compounds; Wiely: Chichester, 1999. (d) Hiyama, T.;
Kanie, K.; Kusumoto, T, Morizawa, Y.; Shimizu, M., Eds. Organofluorine
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Chemistry of Fluorine; Wiley: Hoboken, 2008.
10.1021/ol102541s  2010 American Chemical Society
Published on Web 11/16/2010

philes by the Lewis acidic Pd catalyst.9,10 A variety of
catalytic enantioselective alkynylations of not only carbonyls
but also imines with terminal alkynes have been reported to
provide the excellent enantioselectivities.11 However, all the
alkynylations previously reported proceed via in situ genera-
tion of metal acetylides as reactive nucleophiles and, hence,
can not be applied for the polyyne system.12,13
Table 1. Catalytic Enantioselective Alkynylation with Alkynylsilane
2a and Trifluoropyruvate 3 by Chiral Lewis Acid Catalysts
Figure 1. Biologically active compounds bearing chiral R-triflu-
oromethyl-substituted tertiary alcohols.
selective GR agonist (ZK216348),2d,e and a PDK inhibitor
(AZD7545)2f (Figure 1).
yield ee
There are two general strategies for synthesizing enantio-
merically enriched R-trifluoromethyl-substituted alcohols:
one is the direct addition of the trifluoromethyl group to
carbonyl compounds using the Ruppert-Prakash reagent,
CF3SiMe3.3 Some successes of the catalytic asymmetric
reaction have been reported, but the high enantioselectivity
and substrate generality have not been established yet.4 On
the other hand, the building block methods using trifluoro-
methyl carbonyl compounds in particular can be expected
to provide excellent yield and enantioselectivity by appropri-
ate chiral Lewis acid catalysts. However, only catalytic
asymmetric ene,5 aldol,6 Friedel-Crafts,7 and enamine-
trifluoropyruvate condensation-cyclization reaction8 with
trifluoropyruvate, which is one of the most versatile com-
mercially available reagents, have been reported so far. Since
other transformations of trifluoropyruvate remain unexplored,
the exploitation of novel catalytic asymmetric syntheses of
R-trifluoromethyl-substituted tertiary alcohols has been re-
quired. Herein, we report the highly enantioselective alky-
nylation of trifluoropyruvate with alkynylsilanes as nucleo-
entry
cat.
(S)-SEGPHOS-Pd
Si
solvent (%)b (%)c
1
1
SiMe3
SiMe3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
85
82
61
69
0
14
79
22
32
61
40
31
64
99
99
82
78
-
23
99
98
99
97
73
21
99
2
3
(S)-DTBM-SEGPHOS-Pd SiMe3
4
(S)-BINAP-Pt
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
5
(S,S)-Box-Cu
6
(S,S)-Pybox-Sc
CH2Cl2
CHCl3
Et2O
7
1
1
1
1
1
1
1
8
9
toluene
10
11
12
13a
SiMe2Ph CH2Cl2
SiMe2tBu CH2Cl2
Si(OEt)3 CH2Cl2
SiMe3
CH2Cl2
a Reaction was examined with 2 mol % of catalyst. b Isolated yield.
c Enantiopurity was determined by chiral GC analysis.
Table 1 outlines the preliminary experiments to show the
feasibility of the present alkynylation of trifluoropyruvate 3 with
alkynylsilane 2a using various chiral Lewis acid catalysts.14
After evaluation of atropisomeric diphosphine ligands, the chiral
cationic Pd complex (1)5a,g,14b bearing (S)-BINAP was identi-
fied as the best catalyst providing high yield and enantiose-
lectivity (entries 1 vs 2 and 3). The use of not only
(3) (a) Ruppert, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984,
25, 2195. (b) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem.
Soc. 1989, 111, 393.
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19, 2633. (d) Ma, J.-A.; Cahard, D. Chem. ReV. 2008, 108, PR1.
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(a) Aikawa, K.; Kainuma, S.; Hatano, M.; Mikami, K. Tetrahedron Lett.
2004, 45, 183. (b) Mikami, K.; Kakuno, H.; Aikawa, K. Angew. Chem.,
Int. Ed. 2005, 44, 7257. (c) Doherty, S.; Knight, J. G.; Smyth, C. H.;
Harrington, R. W.; Clegg, W. J. Org. Chem. 2006, 71, 9751. (d) Doherty,
S.; Knight, J. G.; Smyth, C. H.; Harrington, R. W.; Clegg, W. Organome-
tallics 2007, 26, 5961. (e) Doherty, S.; Knight, J. G.; Smyth, C. H.;
Harrington, R. W.; Clegg, W. Organometallics 2007, 26, 6453. (f) Doherty,
S.; Knight, J. G.; Smyth, C. H.; Harrington, R. W.; Clegg, W. Org. Lett.
2007, 9, 4925. (g) Mikami, K.; Kawakami, Y.; Akiyama, K.; Aikawa, K.
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Kuenkel, A.; Koenigs, R. M. Angew. Chem., Int. Ed. 2008, 47, 6798. (i)
Zhao, J.-F.; Tjan, T.-B. W.; Tan, B.-H.; Loh, T.-P. Org. Lett. 2009, 11,
5714.
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pyruvate, see: (a) Gathergood, N.; Zhuang, W.; Jørgensen, K. A. J. Am.
Chem. Soc. 2000, 122, 12517. (b) Zhuang, W.; Gathergood, N.; Hazell,
R. G.; Jørgensen, K. A. J. Org. Chem. 2001, 66, 1009. (c) Corma, A.; Garc´ıa,
H.; Moussaif, A.; Sabater, M. J.; Zniber, R.; Redouane, A. Chem. Commun.
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2005, 7, 901. (e) To¨ro¨k, B.; Abid, M.; London, G.; Esquibel, J.; To¨ro¨k, M.;
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2008, 49, 1476. (j) Nakamura, S.; Hyodo, K.; Nakamura, Y.; Shibata, N.
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Kashikura, W.; Itoh, J.; Mori, K.; Akiyama, T. Chem. Asian J. 2010, 5,
(6) For catalytic asymmetric aldol-type reactions using trifluoropyruvate,
see: (a) Bogevig, A.; Kumaragurubaran, N.; Jørgensen, K. A. Chem.
Commun. 2002, 620. (b) Gathergood, N.; Juhl, K.; Poulsen, T. B.; Thordrup,
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470
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.
.
Org. Lett., Vol. 12, No. 24, 2010
5717

BINAP-Pt but also Box-Cu and Pybox-Sc, which are
often used as chiral Lewis acid catalysts, gave lower catalytic
activity and enantioselectivity (entries 1 vs 4-6). Chloroform
gave a similar result, but diethyl ether and toluene led to a
decrease in both yields and enantioselectivities because of
low solubility of the catalyst (entries 1 vs 7-9). The use of
sterically more demanding SiMe2Ph and SiMe2tBu and the more
electron-rich Si(OEt)3 substituent resulted in a decrease of yields
and enantioselectivities (entries 10-12). The catalyst loading could
be reduced to 2 mol % to obtain 4a with an equally high level of
enantioselectivity in a decreasing yield (entry 13). The absolute
configuration of the product 4a was determined to be R by X-ray
crystallographic analysis.15
in high enantioselectivity (entry 2). Using more reactive 2c,d
also gave the high level of enantioselectivity (entries 3-4).
The reaction occurred in a highly enantioselective fashion
with various alkynylsilanes 2e-j bearing aliphatic substit-
uents (entries 4-9). Especially, 2e and 2h provided almost
complete enantioselectivity (entries 4 and 7). The use of 2j
required the elevated reaction temperature probably due to
the coordination of palladium to propargyl ether (entry 9).
We also investigated the reaction with enyne, endiyne, and
diyne to provide satisfactory levels of enantiocontrol
(91f>99% ee) (entries 10-14).
The alkynyl products bearing central chirality can be
converted into the optically active trifluoromethyl-substituted
allenes bearing an axial chirality (Scheme 1). For example,
Under the optimized conditions, the 1-catalyzed reactions
of 3 and various alkynylsilanes 2 bearing TMS were
investigated (Table 2). We were encouraged to find that low
Scheme 1
. Syntheses of Optically Active Allene 6 and E-Allyl
Alcohol 7 Bearing a Trifluoromethyl Group
Table 2. Catalytic Enantioselective Alkynylation with Various
Alkynylsilanes 2b-o and 3 under the Optimized Conditions
treatment of the product 4f (99% ee) with NaBH4 followed
by silylation and mesylation of primary and secondary
alcohols gave an 80% yield of 5 in three steps. The product
5 was transformed to the corresponding allene 6 (95% ee)
by using Et2Zn reagent in DMSO.16 The reaction of 4 equiv
of LiAlH4 with 4f produced E-allyl alcohol 7 in a 94% yield.
With these successes in terms of the wide scope of alkynyl
substrates, we attempted catalytic enantioselective addition
of polyyne to trifluoropyruvate 3 (Scheme 2). Alkynylation
using nucleophiles 2p or 2q bearing two or three trimeth-
ylsilyl acetylene units on a benzene ring gave the single
diastereomer 4p or 4q with almost complete enantioselec-
tivity (eqs 1 and 2). Significantly, tetrayne 2r, which is
capped at the terminus by trimethylsilyl and phenyl groups,
afforded the corresponding product 4r with high enantiose-
lectivity despite lower catalytic activity, probably due to the
coordination of palladium to the tetrayne portion (61%, 96%
a (S)-DTBM-SEGPHOS was used instead of (S)-BINAP. b Dichloroethane
was used as a solvent. c 10 mol % of catalyst was used. d Isolated yield. e NMR
yield. f Enantiopurity was determined by chiral HPLC or GC analysis.
(11) For review, see: (a) Lu, G.; Li, Y.-M.; Li, X.-S.; Chan, A. S. C.
Coord. Chem. ReV. 2005, 249, 1736. (b) Trost, B. M.; Weiss, A. H. AdV.
Synth. Catal. 2009, 351, 963. (c) de Armas, P.; Tejedor, D.; Garc´ıa-Tellado,
F. Angew. Chem., Int. Ed. 2010, 49, 1013.
reactive 2b with an electron-withdrawing CF3 substituent
provided a good yield of the desired alkynylation product
(12) Reber, S.; Kno¨pfel, T. F.; Carreira, E. M. Tetrahedron 2003, 59,
6813.
(13) For catalytic enantioselective addition of 1,3-diynes to aldehyde,
see: Trost, B. M.; Chan, V. S.; Yamamoto, D. J. Am. Chem. Soc. 2010,
132, 5522.
(9) Catalytic enantioselective alkynylation of trifluoromethyl ketones and
trifluoromethyl pyruvate: (a) Motoki, R.; Kanai, M.; Shibasaki, M. Org. Lett.
2007, 9, 2997. (b) Nishiyama, H.; Ito, J. Chem. Commun. 2010, 46, 203.
(10) Only one example of enantioselective additions with alkynylsilanes
using the Pybox-Sc complex as chiral Lewis acid catalysts was reported:
Evans, D. A.; Aye, Y. J. Am. Chem. Soc. 2006, 128, 11034.
(14) (a) Long, M. J. C.; Aye, Y. Chem.sEur. J. 2009, 15, 5402. (b)
Aikawa, K.; Hioki, Y.; Mikami, K. J. Am. Chem. Soc. 2009, 131, 13922.
(15) See Supporting Information.
(16) Kobayashi, K.; Naka, H.; Wheatley, A. E. H.; Kondo, Y. Org. Lett.
2008, 10, 3375.
5718
Org. Lett., Vol. 12, No. 24, 2010

Scheme 2
.
Catalytic Enantioselective Addition of Polyyne
Scheme 3. Plausible Reaction Mechanism
complex via transmetalation was not observed in 1H and 31
P
NMR spectroscopic analyses in CD2Cl2 by the combination
of alkynylsilane 2a with a stoichiometric (S)-BINAP-Pd (1).
In summary, we have developed a highly enantioselective
catalytic alkynylation with trifluoropyruvate and alkynylsi-
lanes using chiral dicationic Pd complex 1. Compared to the
previous alkynylations with terminal alkynes via the metal
acetylides, this catalytic reaction can also be applied to
enantioselective addition of polyynes to the carbonyl group.
Further investigations using a variety of electrophiles are
currently in progress.
Acknowledgment. We are grateful to Takasago Interna-
tional Co. for providing BINAP and SEGPHOS derivatives.
This research was supported in part by a grant program
“Collaborative Development of Innovative Seeds” from the
Japan Science and Technology Agency.
ee) (eq 3). To the best of our knowledge, there is no report
describing catalytic enantioselective addition of polyyne as
a nucleophile to carbonyl compounds, except for diyne.
As a proposed reaction mechanism, the attack of alky-
nylsilane 2 to trifluoropyruvate 3 through the coordination
of chiral Lewis acid catalyst (S)-BINAP-Pd (3/cat.) followed
by the intramolecular transfer of the silyl group and desi-
lylation upon acidic workup provide the corresponding
product 4 (Scheme 3). Indeed, the alkynyl-palladium
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and CIF file. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL102541S
Org. Lett., Vol. 12, No. 24, 2010
5719