Catalytic Michael reactions of ketoesters with a camphor-derived acrylate equivalent: Stereoselective access to all-carbon quaternary centers

Article abstract of DOI:10.1021/ol800564d

(Chemical Equation Presented) A camphor-based α′-hydroxy enone reagent acts as a chiral acrylate equivalent in copper-catalyzed Michael reactions of β-keto esters and affords products that possess all-carbon quaternary stereocenters of high enantiomeric purity.

Full text of DOI:10.1021/ol800564d

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2637-2640
Catalytic Michael Reactions of
Ketoesters with a Camphor-Derived
Acrylate Equivalent: Stereoselective
Access to All-Carbon Quaternary
Centers
Claudio Palomo,*,† Mikel Oiarbide,† Jesu´s M. Garc´ıa,‡ Patricia Ban˜uelos,‡
,§
Jose´ M. Odriozola,‡ Jesu´s Razkin,‡ and Anthony Linden
Departamento de Qu´ımica Orga´nica I, Facultad de Qu´ımica, UniVersidad del Pa´ıs
Vasco, Apdo. 1072, 20080 San Sebastia´n, Spain, Departamento de Qu´ımica Aplicada,
UniVersidad Pu´blica de NaVarra, Campus de Arrosad´ıa, 31006 Pamplona, Spain, and
Institute of Organic Chemistry, UniVersity of Zurich, Winterthurerstrasse 190,
CH-8057 Zurich, Switzerland
claudio.palomo@ehu.es
Received March 11, 2008
ABSTRACT
A camphor-based r′-hydroxy enone reagent acts as a chiral acrylate equivalent in copper-catalyzed Michael reactions of ꢀ-keto esters and
affords products that possess all-carbon quaternary stereocenters of high enantiomeric purity.
All-carbon quaternary stereocenters pose a particular chal-
lenge for synthesis because of steric repulsion between the
carbon substituents in the product and the difficulty in
achieving good stereocontrol.1 Nowadays the construction
of a quaternary stereocenter remains the touchstone of every
stereoselective procedure and a significant challenge in the
total synthesis of natural products. One versatile access to
all-carbon quaternary stereocenters relies on the conjugate
addition reaction of soft C-nucleophiles to acceptor-activated
olefins,2 and within this strategy both asymmetric catalysis
with preformed silyl enolates3 and metal-catalyzed reactions
involving preformed chiral enamides4 have been reported.
Direct catalytic methods involving stabilized enolates have
also been documented recently by using both asymmetric
X-ray analyses.
† Universidad del Pa´ıs Vasco.
‡ Universidad Pu´blica de Navarra.
§ University of Zurich.
(1) For recent reviews, see: (a) Christoffers, J.; Baro, A. Angew. Chem.,
Int. Ed. 2001, 40, 4591–4597. (b) Denissova, I.; Barriault, L. Tetrahedron
2003, 59, 10105–10146. (c) Douglas, C. J.; Overman, L. E. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5363–5367. (d) Christoffers, J.; Baro, A. AdV.
Synth. Catal. 2005, 347, 1473–1482. (e) Christoffers, J.; Baro, A. Quaternary
Stereocenters: Challenges and Solutions for Organic Synthesis; Wiley-VCH:
Weinheim, 2005. (f) Trost, B. M.; Chunhui, S. Synthesis 2006, 369–396.
(g) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007,
5969–5994.
(2) For reviews, see: (a) Christoffers, J.; Baro, A. Angew. Chem. Int.
Ed 2003, 42, 1688–1690. (b) Christoffers, J. Chem. Eur. J. 2003, 9, 4862–
4867.
(3) (a) Liu, D.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128,
8160–8161. (b) Takenaka, N.; Abell, J. P.; Yamamoto, H. J. Am. Chem.
Soc. 2007, 129, 742–743.
10.1021/ol800564d CCC: $40.75
Published on Web 06/03/2008
2008 American Chemical Society

organocatalysts5 and metal catalysts.6 Despite these advances,
currently available methods are restricted to certain combina-
tions of substrate nucleophile and electrophile, most often
involving vinyl ketones, vinyl sulfones, enals, nitroalkenes,
and substituted acrylonitriles as the electrophilic component.
Although the corresponding conjugate addition products from
acrylic acid derivatives bear significant synthetic interest, this
process is virtually undeveloped yet.7 Here we present a
highly stereoselective direct Michael reaction of R-substituted
ꢀ-keto esters and a chiral acrylate equivalent,8 easily prepared
from camphor, as a new entry to all-carbon quaternary
stereocenters of high enantiomeric purity.
Scheme 1
We have previously documented that R′-hydroxy enone
1, accessible from (1R)-(+)-camphor in multigram quantities
through a one-pot two-step sequence, Scheme 1, is able to
impart remarkable levels of diastereofacial selectivity in
Diels-Alder reactions of inherently poor reactivity and
diastereoselectivity.9 Further demonstration of the potential
of the R′-hydroxy enone template in metal-assisted trans-
formations10 was ascribed to the capacity of the ketol moiety
for 1,4-metal binding.11 We argued that such a stereochem-
ical constrain might be effective for substrate activation and
chirality transfer during generation of quaternary stereo-
centers.
To evaluate this assumption, initial screening reactions
were carried out with 1 and ethyl 2-methylacetoacetate 2 in
the presence of several metal triflates, Table 1. Data revealed
(4) (a) Christoffers, J.; Mann, A. Chem. Eur. J. 2001, 7, 1014–1027.
(b) Christoffers, J.; Scharl, H. Eur. J. Org. Chem. 2002, 1505–1508. (c)
Kreidler, B.; Baro, A.; Christoffers, J. Eur. J. Org. Chem. 2005, 5339–
5348. Ni catalysis: (d) Christoffers, J.; Ro¨bler, U.; Werner, T. Eur. J. Org.
Chem. 2000, 701–705. Zn catalysis: (e) Tour, M.; Tan, K.; Jankowski, R.;
Cave´, C. Tetrahedron: Asymmetry 2001, 12, 765–769.
(5) For recent works, see: (vinyl ketones) (a) Li, H.; Song, J.; Liu, X.;
Deng, L. J. Am. Chem. Soc. 2005, 127, 8948–8949. (b) Wu, F.; Li, H.;
Hong, R.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 947–950. (c) Liu,
T.-Y.; Li, R.; Chai, Q.; Long, J.; Li, B.-J.; Wu, Y.; Ding, L.-S.; Chen, Y.-
C. Chem. Eur. J. 2007, 13, 319–327(enals) (d) Wu, F.; Hong, R.; Khan, J.;
Liu, X.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 4301–4305. (e) Bell,
M.; Frisch, K.; Jørgensen, K. A. J. Org. Chem. 2006, 71, 5407–
5410(maleimides) (f) Bartoli, G.; Bosco, M.; Carlone, A.; Cavalli, A.;
Locatelli, M.; Mazzanti, A.; Ricci, P.; Sambri, L.; Melchiorre, P. Angew.
Chem. Int. Ed. 2006, 45, 4966–4970(acrylonitriles) (g) Liu, X.; Wang, Y.;
Deng, L. J. Am. Chem. Soc. 2006, 128, 3928–3930. (h) Wang, B.; Wu, F.;
Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2007, 129, 768–769(vinyl
sulfones) (i) Alema´n, J.; Reyes, E.; Richter, B.; Overgaard, J.; Jørgensen;
K., A. Chem. Commun. 2007, 3921–3923(nitroalkenes) (j) Li, H.; Wang,
Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew.
Chem., Int. Ed. 2005, 44, 105–108. (k) Lalonde, M. P.; Chen, Y.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2006, 45, 6366–6370(vinyl phosphonates) (l)
Capuzzi, M.; Perdicchia, D.; Jørgensen, K. A. Chem. Eur. J. 2008, 14, 128–
135. Addition to alkynones/alkynoates: (m) Bella, M.; Jørgensen, K. A.
J. Am. Chem. Soc. 2004, 126, 5672–5673. (n) Wang, X.; Kitamura, M.;
Maruoka, K. J. Am. Chem. Soc. 2007, 129, 1038–1039.
Table 1. 1,4-Addition of Ethyl 2-Methylacetoacetate to
R′-Hydroxy Enone 1 Catalyzed by Metal Triflatesa
entry
M(TfO)x
additive
solvent
drb
yield, %c
1
2
3
4
1
2
5
6
7
Cu(TfO)2
CH2Cl2
86:14
76:24
80:20
90:10
50:50
60:40
60:40
50:50
55:45
78
4Å MS
4Å MS
CH2Cl2
91
81
85
80
92
80
Mg(TfO)2
Zn(TfO)2
Yb(TfO)3
La(TfO)3
Sc(TfO)3
(6) (vinyl ketones) (a) Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.;
Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506–6507. (b)
Nakajima, M.; Yamaguchi, Y.; Hashimoto, S. Chem. Commun. 2001, 1596–
1597. (c) Suzuki, T.; Torii, T. Tetrahedron: Asymmetry 2001, 12, 1077–
1081. (d) Sodeoka, M.; Hotta, D.; Hamashima, Y. J. Am. Chem. Soc. 2002,
124, 11240–11241. (e) Takenaka, K.; Uozumi, Y. Org. Lett. 2004, 6, 1833–
1835. (f) Kumaraswamy, G.; Jena, N.; Sastry, M. N. V.; Padmaja, M.;
Markondaiah, B. AdV. Synth. Catal. 2005, 347, 867–871. (g) Mori, K.;
Oshiba, M.; Hara, T.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Tetrahedron
Lett. 2005, 46, 4283–4286. (h) Ogawa, C.; Kizu, K.; Shimizu, H.; Takeuchi,
M.; Kobayashi, S. Chem. Asian J. 2006, 1-2, 121–124. (i) Hamashima,
Y.; Hotta, D.; Umebayashi, N.; Tsuchiya, Y.; Suzuki, T.; Sodeoka, M. AdV.
Synth. Catal. 2005, 347, 1576–1586(cyclic enones) (j) Majima, K.; Tosaki,
S.-Y.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2005, 46, 5377–
5381(Acrolein) (k) Motoyama, Y.; Koga, Y.; Kobayashi, K.; Aoki, K.;
Nishiyama, H. Chem. Eur. J. 2002, 8, 2968–2975.
a All reactions were run at 0.5 mmol scale until consumption of starting
enone. b Diastereomeric ratios were determined by 13C NMR. c Product
purified by column chromatography.
that Cu(TfO)2 gave the best results, and the addition adduct
3 could be obtained as an isomeric mixture with a ratio of
(10) (a) Palomo, C.; Oiarbide, M.; Garc´ıa, J. M.; Gonza´lez, A.; Arceo,
E. J. Am. Chem. Soc. 2003, 125, 13942–13943. (b) Palomo, C.; Oiarbide,
M.; Halder, R.; Kelso, M.; Go´mez-Bengoa, E.; Garc´ıa, J. M. J. Am. Chem.
Soc. 2004, 125, 9188–9189. (c) Palomo, C.; Oiarbide, M.; Kardak, B. G.;
Garc´ıa, J. M.; Linden, A. J. Am. Chem. Soc. 2005, 127, 4154–4155. (d)
Palomo, C.; Oiarbide, M.; Arceo, E.; Garc´ıa, J. M.; Lo´pez, R.; Gonza´lez,
A.; Linden, A. Angew. Chem., Int. Ed. 2005, 44, 6187–6190. (e) Palomo,
C.; Pazos, R.; Oiarbide, M.; Garc´ıa, J. M. AdV. Synth. Catal. 2006, 348,
1161–1164. Also, see: (f) Lee, S.; Lim, C. J.; Kim, S.; Subramaniam, R.;
Zimmerman, J.; Sibi, M. P. Org. Lett. 2006, 8, 4311–4313. (g) Monge, D.;
(7) For remarkable exceptions, see: (a) Taylor, M. S.; Jacobsen, E. N.
J. Am. Chem. Soc. 2003, 125, 11204–11205. (b) Balskus, E.; Jacobsen,
E. N. J. Am. Chem. Soc. 2006, 128, 6810–6812. See also ref 3b.
(8) A chiral acrylate derived from (-)-8-phenylmenthol has been used
in the asymmetric 1,4-addition of ethyl 2-oxocyclohexanecarboxylate
catalyzed by trifluoromethanesulfonic acid (dr 69:31). Kotsuki, H.; Arimura,
K.; Ohishi, T.; Maruzasa, R. J. Org. Chem. 1999, 64, 3770–3773.
(9) Palomo, C.; Oiarbide, M.; Garc´ıa, J. M.; Gonza´lez, A.; Lecumberri,
A.; Linden, A. J. Am. Chem. Soc. 2002, 124, 10288-10289. For an
application in synthesis, see: (b) Pfeiffer, M. W. B.; Phillips, A. J. J. Am.
Chem. Soc. 2005, 127, 5334–5335.
´
Mart´ın-Zamora, E.; Va´zquez, J.; Alcarazo, M.; Alvarez, E.; Ferna´ndez, R.;
Lassaletta, J. M. Org. Lett. 2007, 9, 2867–2870.
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Org. Lett., Vol. 10, No. 13, 2008

86:14. The reactions were typically carried out in dichlo-
romethane as solvent using 10 mol % catalyst at -20 °C,
with lower temperatures giving no significant changes. Other
solvents tested, such as THF, Et2O, or toluene, led to lower
selectivity, and the reaction did not proceed at all in
acetonitrile. When the reaction was carried out without added
solvent and using the ꢀ-keto ester as the solvent media, an
isomeric mixture with a ratio of 76:24 was produced. Metal
Lewis acids other than triflates, such as ReCl5, AuCl,
Ni(ClO4)2·6H2O, FeCl3·6H2O, PdCl2(CH3CN)2, Zn(ClO4)2·
6H2O, and RuCl3·nH2O, were also tested, but poor yields
and stereoselectivities were attained. Because of the fact that
molecular sieves have shown high efficiency in a variety of
Lewis acid catalyzed stereoselective processes,12 we carried
out the reaction with Cu(TfO)2 in the presence of this
additive. In this case the diastereomeric ratio decreased to
80:20, but surprisingly, when the ꢀ-keto ester was used as
solvent, the isomeric mixture obtained rose to a 90:10 ratio.
To define the scope of this reaction, we next examined
various ꢀ-keto esters. Table 2 shows the results obtained in
the Michael reaction of R′-hydroxy enone 1 with several
cyclic and acyclic R-substituted ꢀ-keto esters using dichlo-
romethane as the solvent (method A) or the ꢀ-keto ester as
the solvent in the presence of molecular sieves (method B).13
In general, Michael adducts were obtained in good yields
and with diastereomeric ratios ranging from 85:15 to 95:5
for the acyclic R-substituted ꢀ-keto esters. Noteworthy is
the use of the sterically demanding R-alkyl tert-butyl ꢀ-keto
esters 6 and 7, which afforded products with diastereomeric
ratios of 93:7 and 95:5, respectively, whereas tert-butyl
2-benzylacetoacetate 8 yielded a mixture of isomers in an
88:12 ratio. The configuration of adduct 14a was established
by single-crystal X-ray structure analysis,14 and the con-
figurations of the remaining acyclic adducts 3 and 15-18
were assigned by analogy.
Table 2. 1,4-Addition of Acyclic and Cyclic ꢀ-Keto Esters to
R′-hydroxy Enone 1 Catalyzed with Copper Triflatea
Cyclic ꢀ-keto esters 9-13 behave similarly, and as shown
in Table 2, tert-butyl esters 11 and 13 afforded the corre-
sponding adducts with excellent diastereomeric ratios (95:
5). Likewise, a single-crystal X-ray structure analysis of
compound 23a corroborated the assigned configurations of
the adducts.
a Methods A and B as defined in ref 13. b Diastereomeric ratios were
determined by 13C NMR. c Yield of isomeric mixture purified by column
chromatography.
The excellent diastereoselectivity observed in these reac-
tions is of particular interest in that it provides, through
oxidative cleavage of the acyloin moiety, carboxylic acids
with a quaternary stereocenter in good chemical yields and
enantiomeric purities. For example, treatment of isomeric
mixtures of adducts 14, 16, and 23 with cerium ammonium
nitrate (CAN) gave the corresponding carboxylic acids 24,
25, and 26 in high yields and ee’s, Scheme 2. On the other
hand, separation of diastereomeric adducts through crystal-
lization or chromatography opens a route to final products
of almost perfect enantiopurity. For instance, separation of
23a by column chromatography and subsequent acyloin
cleavage led to 26 in essentially optically pure form. The
whole transformation represents a formal 1,4-addition to
acrylic acid derivatives with concomitant generation of all-
carbon quaternary stereocenters in high selectivity. In addi-
tion, both carboxy groups in the products are orthogonal.
Importantly, in each case, the starting source of chiral
information, (1R)-(+)-camphor, is easily recovered from the
reaction mixture almost quantitatively and without loss of
optical integrity.15
(11) See ref 10a,b. For early formulation of the 1,4-metal binding
activation model of ketols, see: Masamune, S.; Reed, L. A., III; Davis,
J. T.; Choy, W. J. Org. Chem. 1983, 48, 4441–4444.
(12) (a) Posner, G. H.; Dai, H. Y.; Bull, D. S.; Lee, J. K.; Eydoux, F.;
Ishihara, Y.; Welsh, W.; Pryor, N. J. Org. Chem. 1996, 61, 671–676. (b)
Mikami, K.; Motoyama, Y.; Terada, M. J. Am. Chem. Soc. 1994, 116, 2812–
2820. (c) Kanemasa, S.; Oderaotoshi, Y.; Tanaka, J.; Wada, E. J. Am. Chem.
Soc. 1998, 120, 12355–12356. (d) Desimoni, D.; Faita, G.; Mortoni, A.;
Righetti, P. Tetrahedron Lett. 1999, 40, 2001–2004. (e) Gothelf, K. V.;
Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 1998, 63, 5483–5488. (f)
Evans, D. A.; Song, H-J.; Fandrick, K. R. Org. Lett. 2006, 8, 3351–3354.
(g) Reference 10e.
(13) Experimental Procedure. Method A. A solution of vinyl ketone
1 (0.1042 g, 0.5 mmol) in CH2Cl2 (0.6 mL) was added dropwise to a mixture
of copper(II) triflate (0.0181 g, 0.05 mmol) and the ꢀ-keto ester (1 mL) in
0.4 mL of CH2Cl2 at -20°C. The reaction mixture was stirred at the same
Org. Lett., Vol. 10, No. 13, 2008
2639

Scheme 2
Scheme 3
Finally, we decided to assess the possibility of implement-
ing an enantioselective version of the method by using the
achiral R′-hydroxy enone 2710 and a chiral copper catalyst.
Initial exploration revealed chiral diamines as the best-suited
ligands for this catalytic process. For example, the copper-
catalyzed reaction of 27 and both acyclic ketoesters 6 and
7, and cyclic ketoester 11, using diamine 28 as a ligand16 in
toluene at 0 °C, afforded the corresponding Michael adducts
29, 30, and 31 with high yield and enantiomeric ratios,
Scheme 3. Oxidation of the products with CAN as above
yielded the corresponding carboxylic acids with acetone
being the only byproduct formed, an additional aspect of
the approach that is of practical interest.
In summary, a copper-catalyzed highly diastereoselective
direct 1,4-addition of R-substituted ꢀ-keto esters to a chiral
acrylate equivalent derived from (1R)-(+)-camphor is pre-
sented. Upon smooth removal of the auxiliary, which can
be reused, differently functionalized molecules bearing all-
carbon quaternary stereocenters are obtained in high enan-
tiomeric purity. Extension of this model to other Michael
reactions is currently underway in our laboratory.
temperature overnight. Then, CH2Cl2 (5 mL) was added, and the resulting
solution was washed twice with 5 mL of water. The organic layer was
dried over MgSO4 and filtered, and the solvent was removed under reduced
pressure. The crude product was purified by column chromatography (eluant
EtOAc/hexane 1:10). The diastereomeric ratio was determined in each case
by 13C NMR analyses and in some cases by HPLC analyses. Purification
to obtain the major diastereomer was effected by flash column chromatog-
raphy, using a 1:20 EtOAc/hexane mixture as the eluant. Method B. Vinyl
ketone 1 (0.1042 g, 0.5 mmol) was added to a mixture of copper(II) triflate
(0.0181 g, 0.05 mmol), molecular sieves 4Å powder (100 mg), and the
ꢀ-keto ester (1 mL) at -20°C. The reaction mixture was stirred at the same
temperature overnight. The same workup and purification procedure of
Method A was followed.
Acknowledgment. This work was financially supported
by Universidad del Pa´ıs Vasco, Gobierno Vasco, and by
MEC. A grant to P.B. from UPNA is acknowledged.
Supporting Information Available: Experimental pro-
cedures; characterization data for compounds 1, 3a,
1
14a-23a, 24-26, and 29-31; representative H and 13C
NMR spectra and HPLC chromatograms; X-ray data for 14a
and 23a in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) See Supporting Information.
(15) (1R)-(+)-Camphor: Aldrich [R]25D +42.2 (c 1.0 in EtOH). Recov-
ered material, [R]25 +41.5 (c 1.0 in EtOH).
D
(16) Hamada, T.; Manabe, K.; Kobayashi, S. Angew. Chem., Int. Ed.
2003, 42, 3927–3920.
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