Phase-transfer catalyzed asymmetric conjugate additions of β-ketoesters to acetylenic ketones

Article abstract of DOI:10.1021/op100014v

Asymmetric conjugate addition of cyclic β-keto esters to acetylenic ketones has been achieved with high enantioselectivity and moderate E/Z selectivity under the influence of a binaphthyl-modified 3,5-bis[3,5- bis(trifluoromethyl)phenyl]phenyl-substituted phase-transfer catalyst.

Full text of DOI:10.1021/op100014v

Organic Process Research & Development 2010, 14, 684–686
Phase-Transfer Catalyzed Asymmetric Conjugate Additions of ꢀ-Ketoesters to
Acetylenic Ketones
Quan Lan, Xisheng Wang, Seiji Shirakawa, and Keiji Maruoka*
Laboratory of Synthetic Organic Chemistry and Special Laboratory of Organocatalytic Chemistry, Department of Chemistry,
Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Scheme 1
Abstract:
Asymmetric conjugate addition of cyclic ꢀ-keto esters to acetylenic
ketones has been achieved with high enantioselectivity and moder-
ate E/Z selectivity under the influence of a binaphthyl-modified
3,5-bis[3,5-bis(trifluoromethyl)phenyl]phenyl-substituted phase-
transfer catalyst.
Introduction
Development of methods for stereoselective construction of
quaternary stereocenters is one of the most important challenges
in organic synthesis for efficient synthesis of complex natural
products and drugs.1 Asymmetric conjugate additions of carbon
nucleophiles to R,ꢀ-unsaturated carbonyl systems constitute a
useful carbon-carbon bond formation technique and have been
used widely in asymmetric synthesis,2 such as for generation
of quaternary carbon centers in a stereoselective manner. A
variety of different vinyl carbonyl compounds have been found
useful for these conjugate addition reactions.3 In contrast, there
are only several reports dealing with the analogous conjugate
addition reaction to the corresponding acetylenic acceptors.4 An
advantage of the conjugate addition to acetylenic acceptors is
that the products obtained from the reaction possess a CdC
double bond making them versatile building blocks for further
transformation. Accordingly, we recently reported our case study
on this subject by suitably designing certain chiral phase-transfer
catalysts as promising organocatalysts.5,6 Indeed, a new spiro-
type phase-transfer catalyst (S)-1a has been designed for
effecting a hitherto unknown asymmetric conjugate addition
of R-alkyl-R-cyanoacetates to acetylenic esters6a and acetylenic
ketones6b with high enantioselectivities (Scheme 1). This
observation led us to examine the conjugate addition of ꢀ-keto
esters to acetylenic ketones for construction of all-carbon
quaternary stereocenters. Here, we report asymmetric conjugate
additions of cyclic ꢀ-keto esters to acetylenic ketones under
phase-transfer conditions.
Results and Discussion
Attempted reaction of tert-butyl 2-oxocyclopentanecarboxy-
late 2a and 3-butyn-2-one 3a with K2CO3 (0.5 equiv) in the
presence of a catalytic amount (1 mol %) of (S)-1a in toluene
at 0 °C for 2 h gave rise to conjugate adducts 4aa in 99% yield
(5) For representative reviews on asymmetric phase-transfer catalysis, see:
(a) Shioiri, T. In Handbook of Phase-Transfer Catalysis; Sasson, Y.,
Neumann, R., Eds.; Blackie Academic & Professional: London, 1997;
Chapter 14, p 462. (b) Nelson, A. Angew. Chem., Int. Ed. 1999, 38,
1583. (c) Shioiri, T.; Arai, S. In Stimulating Concepts in Chemistry;
Vo¨gtle, F., Stoddart, J. F., Shibasaki, M., Eds.; Wiley-VCH: Weinheim,
2000; p. 123. (d) O’Donnell, M. J. In Catalytic Asymmetric Syntheses,
2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; Chapter 10, p
727. (e) O’Donnell, M. J. Aldrichimica Acta 2001, 34, 3. (f) Maruoka,
K.; Ooi, T. Chem. ReV. 2003, 103, 3013. (g) O’Donnell, M. J. Acc.
Chem. Res. 2004, 37, 506. (h) Lygo, B.; Andrews, B. I. Acc. Chem.
Res. 2004, 37, 518. (i) Vachon, J.; Lacour, J. Chimia 2006, 60, 266.
(j) Ooi, T.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 4222. (k)
Ooi, T.; Maruoka, K. Aldrichimica Acta 2007, 40, 77. (l) Hashimoto,
T.; Maruoka, K. Chem. ReV. 2007, 107, 5656. (m) Maruoka, K. Org.
Process Res. DeV. 2008, 12, 679. (n) Maruoka, K., Ed. Asymmetric
Phase Transfer Catalysis; Wiley-VCH: Weinheim, 2008.
(6) (a) Wang, X.; Kitamura, M.; Maruoka, K. J. Am. Chem. Soc. 2007,
129, 1038. (b) Lan, Q.; Wang, X.; Maruoka, K. Tetrahedron Lett.
2007, 48, 4675. See also (c) Kitamura, M.; Shirakawa, S.; Maruoka,
K. Angew. Chem., Int. Ed. 2005, 44, 1549. (d) Kitamura, M.;
Shirakawa, S.; Arimura, Y.; Wang, X.; Maruoka, K. Chem. Asian J.
2008, 3, 11702. (e) Wang, Y.-G.; Kumano, T.; Kano, T.; Maruoka,
K. Org. Lett. 2009, 11, 2027. (f) Hashimoto, T.; Sakata, K.; Maruoka,
K. Angew. Chem., Int. Ed. 2009, 48, 5014. (g) He, R.; Shirakawa, S.;
Maruoka, K. J. Am. Chem. Soc. 2009, 131, 16620. (h) Wang, X.; Lan,
Q.; Shirakawa, S.; Maruoka, K. Chem. Commun. 2010, 46, 321.
* To whom correspondence should be addressed. Telephone: +81 75 753
4041. Fax: +81 75 753 4041. E-mail: maruoka@kuchem.kyoto-u.ac.jp.
(1) For representative reviews on quaternary stereocenter, see: (a) Corey,
E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. (b)
Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105. (c) Douglas,
C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363.
(d) Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim,
2005. (e) Bella, M.; Gasperi, T. Synthesis 2009, 1583.
(2) (a) Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds. ComprehensiVe
Asymmetric Catalysis I-III; Springer: Berlin, 1999. (b) Ojima, I., Ed.
Catalytic Asymmetric Synthesis, 2nd ed.; Wiley-VCH: New York,
2000. (c) Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds. Compre-
hensiVe Asymmetric Catalysis, Suppl. 1; Springer: Berlin, 2004.
(3) For examples of asymmetric conjugate addition under the influence
of chiral phase-transfer catalyst, see: (a) Corey, E. J.; Noe, M. C.;
Xu, F. Tetrahedron Lett. 1998, 39, 5347. (b) Kim, D. Y.; Huh, S. C.;
Kim, S. M. Tetrahedron Lett. 2001, 42, 6299. (c) Arai, S.; Tsuji, R.;
Nishida, A. Tetrahedron Lett. 2002, 43, 9535. (d) Ohshima, T.;
Shibuguchi, T.; Fukuta, Y.; Shibasaki, M. Tetrahedron 2004, 60, 7743.
(e) Ooi, T.; Ohara, D.; Fukumoto, K.; Maruoka, K. Org. Lett. 2005,
7, 3195. (f) Kano, T.; Kumano, T.; Maruoka, K. Org. Lett. 2009, 11,
2023.
(4) Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 5672.
684
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Vol. 14, No. 3, 2010 / Organic Process Research & Development
10.1021/op100014v  2010 American Chemical Society
Published on Web 02/25/2010

Table 1. Catalytic enantioselective conjugate addition of
tert-butyl 2-oxocyclopentanecarboxylate to 3-butyn-2-onea
to the known compound 5 with the catalytic hydrogenation (cat.
Pd/C, H2, MeOH).7
entry catalyst solvent conditions % yieldb (E/Z)c % eed
With the optimum reaction conditions determined, we further
studied the generality of the asymmetric conjugate addition to
various acetylenic ketones 3 using cyclic ꢀ-keto esters 2a-d
as nucleophiles, and some selected examples are listed in Table
2. Among cyclic ꢀ-keto esters, both five- and six-membered
cyclic ꢀ-keto esters exhibited high enantioselection.8 Acetylenic
ketones 3 possessing secondary- and tertiary- as well as
primary-alkyl groups also exhibited moderate to excellent
enantioselectivities. Phenyl-substituted acetylenic ketone 3c is
also a viable substrate when aqueous 33% K2CO3 was used as
a base in toluene (entries 3, 4, 8, and 10). In particular, the
combination of tert-butyl indanonecarboxylate 2c and acetylenic
ketone 3b (R3 ) c-Hex) gave rise to the highest enantioselec-
tivity (entry 7). Although the current E/Z selectivity is only
moderate,9 an all-carbon quaternary stereocenter can be con-
structed in this asymmetric transformation, and the (E)- and
(Z)-4 products can be easily separated by simple column
chromatography.
We are further exploring the applicability of these catalysts
to related systems. For instance, the asymmetric conjugate
addition of tert-butyl 2-oxocyclopentanecarboxylate 2a to tert-
butyl propiolate 6 with aqueous 33% K2CO3 in the presence of
a catalyst (S)-1b in toluene at 0 °C for 20 h afforded the
corresponding conjugate adduct 7 in 85% yield with good
enantioselectivity (Scheme 2). Further results will be reported
in due course.
1
2
3
4
5
6
7
8
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1b
(S)-1b
toluene
0 °C, 2 h
99 (3.1/1)
99 (2.6/1)
94 (3.4/1)
99 (2.4/1)
99 (1.5/1)
99 (2.2/1)
99 (2.0/1)
97 (1.5/1)
99 (1.7/1)
98 (1.2/1)
99 (1.2/1)
69/51
76/57
72/57
55/33
25/17
77/67
76/65
81/75
87/79
90/85
91/84
m-xylene 0 °C, 1 h
o-xylene 0 °C, 1 h
CF3-Ph 0 °C, 1 h
THF
0 °C, 1 h
t-BuOMe 0 °C, 1 h
CPMEe
Et2O
0 °C, 1 h
0 °C, 1 h
-40 °C, 2.5 h
-40 °C, 3 h
-40 °C, 8 h
9
Et2O
Et2O
Et2O
10
11f
a Unless otherwise specified, the reaction was carried out with 1.5 equiv of
3-butyn-2-one 3a and 0.5 equiv of K2CO3 in the presence of 1 mol % of (S)-1
under the given reaction conditions. b Isolated yield. c Determined by 1H NMR
analysis. d Determined by HPLC analysis. e CPME ) Cyclopentyl methyl ether.
f Use of 0.1 equiv of K2CO3.
with the E/Z ratio of 3.1:1. The enantiomeric excesses of (E)-
and (Z)-4aa were found to be 69% and 51%, respectively, as
shown in Table 1 (entry 1). The solvent effect was studied in
detail as indicated for entries 2-8, and among several solvents,
Et2O gave the best results in terms of the enantioselectivity
(entry 8). By using a lower temperature (-40 °C), the
enantioselectivity was increased to 87% ee and 79% ee for (E)-
and (Z)-4aa, respectively (entry 9). In contrast, the 1-phenylpip-
erazine-derived catalyst (S)-1b exhibited a slightly higher
enantioselectivity (90% ee and 85% ee for (E)- and (Z)-4aa,
respectively) than morpholine-derived catalyst (S)-1a (entry 10
vs 9). The amount of K2CO3 as a base could be reduced to
even 0.1 equiv without any decrease of yield and enantiose-
lectivity, though a prolonged reaction time was required (entry
11). The absolute configuration of the conjugate adducts, (E)-
4aa and (Z)-4aa was firmly determined to be S by conversion
Conclusions
Asymmetric conjugate addition of cyclic ꢀ-keto esters 2 to
acetylenic ketones 3 has been achieved with high enantiose-
Table 2. Catalytic enantioselective conjugate addition of cyclic ꢀ-keto esters to various acetylenic ketonesa
entry
2
3 (R3)
conditions
% yieldb (E/Z)c
% eed
1
2a
2a
2a
2b
2b
2c
2c
2c
2c
2d
2d
3a (R3 ) Me)
3b (R3 ) c-Hex)
3c (R3 ) Ph)
-40 °C, 3 h
-40 °C, 2 h
-20 °C, 1 h
-20 °C, 24 h
-40 °C, 40 h
-40 °C, 1.5 h
-40 °C, 2 h
-20 °C, 1 h
-40 °C, 2 h
-20 °C, 2 h
-40 °C, 24 h
98 (1.2/1); 4aa
99 (1.3/1); 4ab
95 (2.3/1); 4ac
65 (2.0/1); 4bc
90 (1/2.0); 4bd
99 (1/1.1); 4ca
99 (1/5.5); 4cb
99 (2.0/1); 4cc
99 (1/3.6); 4cd
90 (2.0/1); 4dc
68 (3.2/1); 4dd
90/85
91/83
90/60
84/61
77/84
81/62
93/85
82/56
83/79
85/81
85/74
2
3e
4e
5f
6
3c (R3 ) Ph)
3d (R3 ) t-Bu)
3a (R3 ) Me)
3b (R3 ) c-Hex)
3c (R3 ) Ph)
7
8e
9
3d (R3 ) t-Bu)
3c (R3 ) Ph)
10e
11
3d (R3 ) t-Bu)
a Unless otherwise specified, the reaction was carried out with 1.0 equiv of cyclic ꢀ-keto ester 2, 1.5 equiv of acetylenic ketone 3 and 0.5 equiv of K2CO3 in the presence
of 1 mol % of (S)-1b under the given reaction conditions. b Isolated yield. c Determined by 1H NMR analysis. d Determined by HPLC analysis. e Use of aqueous 33% K2CO3
and toluene as a solvent. f Use of 1.2 equiv of Cs2CO3.
Vol. 14, No. 3, 2010 / Organic Process Research & Development
•
685

to be 1.2:1 by 1H NMR analysis of the crude sample. Separation
by column chromatography on silica gel with hexane/ethyl
acetate (8:1-4:1) afforded (E)-4aa and (Z)-4aa in 98%
combined yield. The enantiomeric excess of these (E)-4aa and
(Z)-4aa was determined by chiral HPLC analysis [(E)-4aa:
DAICEL CHIRALPAC AS-H, isopropanol/hexane ) 1:10,
flow rate ) 0.5 mL/min, λ ) 220 nm, retention time: 19.4 min
(minor) and 25.4 min (major); (Z)-4aa: DAICEL CHIRALCEL
OD-H, isopropanol/hexane ) 1:10, flow rate ) 0.5 mL/min, λ
) 220 nm, retention time: 10.2 min (minor) and 11.6 min
(major)].
Scheme 2
lectivity and moderate E/Z selectivity under the influence of a
binaphthyl-modified 3,5-bis[3,5-bis(trifluoromethyl)phenyl]phe-
nyl-substituted phase-transfer catalyst 1b. The products should
prove to be useful synthetic intermediates as much as otherwise
difficult to prepare all-carbon quaternary stereocenters.10
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific
Research from MEXT, Japan.
Experimental Section
A Typical Experimental Procedure of Catalytic Enan-
tioselective Conjugate Addition. ꢀ-Keto ester 2a (55 mg, 0.30
mmol) and chiral ammonium salt (S)-1b (4.6 mg, 0.0030 mmol,
1 mol %) in Et2O (3.0 mL) under Ar were treated with 3-butyn-
2-one 3a (35 µL, 0.45 mmol, 1.5 equiv). After the reaction
system was cooled to -40 °C, K2CO3 (21 mg, 0.15 mmol, 0.50
equiv) was added in a single portion. The reaction mixture was
stirred vigorously at -40 °C for 3 h, quenched with saturated
aqueous NH4Cl (10 mL), extracted with Et2O (10 mL), dried
over Na2SO4, and concentrated. The E/Z ratio was determined
Received for review January 20, 2010.
OP100014V
(9) The Z isomer of compound 4ac could isomerize to the corresponding
E isomer without loss of enantioselectivity, see: Poulsen, T. B.;
Bernardi, L.; Bell, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2006,
45, 6551.
(10) Asymmetric phase-transfer reactions on a large scale, see: (a) Patterson,
D. E.; Xie, S.; Jones, L. A.; Osterhout, M. H.; Henry, C. G.; Roper,
T. D. Org. Process Res. DeV. 2007, 11, 624. (b) Wang, Y.-G.;
Maruoka, K. Org. Process Res. DeV. 2007, 11, 628. (c) Scott, J. P.;
Ashwood, M. S.; Brands, K. M. J.; Brewer, S. E.; Cowden, C. J.;
Dolling, U.-H.; Emerson, K. M.; Gibb, A. D.; Goodyear, A.; Oliver,
S. F.; Stewart, G. W.; Wallace, D. J. Org. Process Res. DeV. 2008,
12, 723.
(7) (a) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002,
124, 11240. (b) Hamashima, Y.; Hotta, D.; Umebayashi, N.; Tsuchiya,
Y.; Suzuki, T.; Sodeoka, M. AdV. Synth. Catal. 2005, 347, 1576.
(8) Acyclic ꢀ-keto esters as nucleophiles showed moderate reactivity and
enantioselectivity (∼40% ee).
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Vol. 14, No. 3, 2010 / Organic Process Research & Development