Copper(I)-catalyzed asymmetric desymmetrization: Synthesis of five-membered-ring compounds containing all-carbon quaternary stereocenters

Article abstract of DOI:10.1021/ja3032345

A highly stereoselective catalytic alkylation sequence for the synthesis of highly functionalized and versatile five-membered-ring compounds bearing all-carbon quaternary stereocenters was developed. Enantioselective desymmetrization of achiral cyclopentene-1,3-diones was thus executed by chiral Cu-phosphoramidite catalysts. A variety of complicated cyclopentane derivatives can be synthesized with excellent stereoselectivities using a low catalyst loading in a one-pot operation.

Full text of DOI:10.1021/ja3032345

Communication
pubs.acs.org/JACS
Copper(I)-Catalyzed Asymmetric Desymmetrization: Synthesis of
Five-Membered-Ring Compounds Containing All-Carbon Quaternary
Stereocenters
Kohsuke Aikawa, Tatsuya Okamoto, and Koichi Mikami*
Department of Applied Chemistry, Tokyo Institute of Technology, Tokyo 152-8552, Japan
S
* Supporting Information
Scheme 1. Asymmetric Desymmetrization of Various
Cyclopentene-1,3-diones Based on Chiral Cu Catalysts
ABSTRACT: A highly stereoselective catalytic alkylation
sequence for the synthesis of highly functionalized and
versatile five-membered-ring compounds bearing all-
carbon quaternary stereocenters was developed. Enantio-
selective desymmetrization of achiral cyclopentene-1,3-
diones was thus executed by chiral Cu−phosphoramidite
catalysts. A variety of complicated cyclopentane derivatives
can be synthesized with excellent stereoselectivities using a
low catalyst loading in a one-pot operation.
synthesis of a precursor of madindolines A and B11,12
containing their chiral cyclopentene-1,3-dione motif.
or fine-chemicals and materials science, efficient synthetic
Initially, we designed symmetrical cyclopentene-1,3-dione 2a
containing methyl and benzyloxymethyl groups as an achiral
substrate for enantioselective desymmetrization. In the
presence of a Cu salt (4 mol %) and phosphoramidite ligand
1b (8 mol %) at −40 °C with Et2Zn as an alkylation reagent,
the reaction proceeded smoothly and afforded the alkylated
product 3a and its diastereomer 4a in good to high yields
(Table 1). In toluene and CH2Cl2 as noncoordinating solvents,
the reaction gave high yields with low enantioselectivities and
diastereomeric ratios similar to that obtained under the reaction
conditions without 1b (entries 2 and 3 vs 1). In this catalytic
system, the solvent has a significant effect on not only the
catalytic activity of the Cu complex but also the stereocontrol of
the 1,4-addition (entries 2−8). Indeed, ether-type solvents
increased the diastereo- and enantioselectivity (entries 5−8).
Particularly, diethyl ether led to the best results, giving 3a (dr >
95:5) in 91% yield and 60% ee within 30 min (entry 8). The
effect of the Cu salt was also surveyed. Cu(OAc)2 and
(CuOTf)·C6H6 showed slightly decreased enantioselectivities
but gave almost the same results as Cu(OTf)2 (entries 9 and
10). The use of cationic Cu(CH3CN)4(BF4) led to lower
stereocontrol (entry 11). CuBr·SMe2 provided excellent
diastereoselectivity but racemic product (entry 12). These
data suggest that OTf− and OAc−, which can form chelates with
Cu and Zn, play a key role in the enantio- and
diastereoselection by the catalytic active species.8a,13
F
methods for versatile building blocks in enantiopure forms
have attracted much attention.1 In comparison with the
formation of quaternary stereocenters bonded to a heteroatom
(e.g., tertiary alcohols or amines), the formation of all-carbon
quaternary stereocenters poses a particular challenge due to the
inherent steric congestion.2 Thus, reliable and divergent
methods for the catalytic formation of all-carbon quaternary
stereocenters with excellent enantioselectivities are quite
limited even in modern synthetic organic chemistry.2 On the
other hand, asymmetric desymmetrization,3 especially using
chiral transition-metal catalysts, is an efficient and powerful
method for synthesizing optically active substances with
complex structures. Through differentiation of two enantiotopic
groups on readily prepared meso or achiral substrates, this
process can afford chiral/nonracemic compounds bearing
multiple chiral centers in a controlled fashion.4,5
Enantiomerically enriched five-membered-ring compounds
such as cyclopentane and cyclopentene derivatives are highly
important building blocks for the basic structural motifs of
many natural products and bioactive compounds.6 The
development of synthetic methods for the preparation of
these compounds has been strongly desired.7 For this objective,
we envisioned using enantioselective Cu-catalyzed conjugate
additions because of the reliable and practical catalytic
systems.2c,8 Herein we report that asymmetric syntheses of
complicated but versatile five-membered-ring compounds
bearing all-carbon quaternary stereocenters can be achieved
through desymmetrization of achiral cyclopentene-1,3-diones
using Cu catalysts with chiral phosphoramidite ligands9
(Scheme 1).10 The advantage of this method is that various
five-membered-ring compounds can be readily prepared with
excellent stereoselectivity using not only a low catalyst loading
(up to 0.5 mol %) but also a simple one-pot operation. The
process can also be applied as a powerful tool for the concise
A number of phosphoramidite ligands9 were next assayed
with the aim of increasing the enantioselectivity (Table 2).
Indeed, the investigation of the effect of a variety of substituents
at the 3- and 3′-positions of the binaphthol backbone led to a
remarkable improvement in the enantioselectivity. Ligand 1a
Received: April 3, 2012
Published: June 5, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
a
backbone is very important for control of the stereochemistry.
On the other hand, commercially available ligand 1j with two
centers of chirality and one center of S-axial chirality performed
poorly concerning both yield and stereoselectivity (entries 10
and 11). The use of BINAP (1k) as a bidentate ligand led to
decomposition of the substrate (entry 12). In the case of the
reaction using 1i, the absolute and relative configurations of the
product (+)-3a were determined to be 2R,4S by X-ray analysis
of a single crystal of 6a (see below).
Table 1. Cu-Catalyzed Enantioselective Desymmetrization
With the effective catalyst system identified via screening of
phosphoramidite ligands in hand, the substrate scope with
respect to the substituents of the quaternary carbon center was
explored (Table 3). Reactions with Me2Zn and nBu2Zn instead
of Et2Zn provided the corresponding products 3a-Me and 3a-
Bu in excellent yields and stereoselectivities (entries 2 and 6).
For Me2Zn in particular, even with a lower catalyst loading (0.5
mol %), the excellent yield and stereoselectivity were
maintained (entry 3). High enantioselectivity was also achieved
in the presence of a 1:1 ratio of Cu(OTf)2 and ligand 1i (entry
a
Conditions: 2a (0.1 mmol), Et2Zn (0.15 mmol), Cu salt (0.004
mmol), and chiral ligand 1b (0.008 mmol) in solvent (1 mL) at −40
b
c
d
a
°C. Chiral ligand 1b was not used. Isolated yields. Determined by
Table 3. Use of a Variety of Cyclopentene-1,3-diones 2a−k
e
1H NMR analysis. Determined by chiral HPLC analysis.
a
Table 2. Effects of Chiral Ligands 1a−k
a
Conditions: 2a (0.1 mmol), Et2Zn (0.15 mmol), Cu(OTf)2 (0.004
mmol), and chiral ligand 1 (0.008 mmol) in Et2O (1 mL) at −40 °C
b
c
for 30 min. Isolated yields. Determined by 1H NMR analysis.
d
e
Determined by chiral HPLC analysis. Me2Zn instead was used of
Et2Zn. Decomposition of substrate 2a.
f
without substituents at the 3- and 3′-positions gave almost
racemic product (entry 1). In addition, 1c and 1d with ortho-
and meta-substituted phenyl rings, respectively, afforded lower
enantioselectivities, probably because of increased steric
repulsion (entries 3 and 4). In sharp contrast, the use of 1f
with para-substituted aryl rings increased the enantioselectivity
(82% ee), and interestingly, the absolute configuration of the
obtained product, (2R,4R)-(+)-3a, was opposite to that of
(2S,4S)-(−)-3a obtained by the reactions using 1a−d (entry 6).
Moreover, the use of 1g−i dramatically increased the
enantioselectivity, with 1i giving the highest enantiomeric
excess (97% ee) and an excellent yield (entry 9). These results
definitely indicate that appropriate steric hindrance by the
substituents at the 3- and 3′-positions of the binaphthol
a
Conditions: 2 (0.1 mmol), R2Zn (0.15 mmol), Cu(OTf)2 (0.004
mmol), and chiral ligand 1i (0.008 mmol) in Et2O (1 mL) at −40 °C
for 30 min. Substrate/catalyst (2a or 2b/Cu) = 100. Substrate/
b
c
d
e
catalyst (2a/Cu) = 200. 6 mol % 1i was used. 4 mol % 1i was used.
f
g
Ligand (aS,S,S)-1j was used instead of 1i. Ligand 1d was used instead
h
i
j
of 1i. Isolated yields. Determined by 1H NMR analysis. Determined
k
by chiral HPLC or GC analysis. Enantiopurity of diastereomer 4
determined by chiral HPLC analysis.
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Communication
5). Almost complete stereoselectivity through the methylation
was obtained with a p-methoxybenzyl (PMB)-substituted
substrate (entry 7). The catalyst system could tolerate the
presence of an ester group, providing highly enantioenriched
product 3c (entry 8). The catalyst system could also permit
more sterically demanding groups on the all-carbon quaternary
Scheme 3. Proposal for the Sense of the Diastereoselectivity
i
stereocenter: reactions with 2d−f bearing Et, Pr, and Ph
groups instead of the Me group maintained the high catalytic
activity and stereoselectivity (entries 9−11). While substrate 2g
with benzyl and methyl groups produced the product with high
stereoselectivity, substrates 2h and 2i with 2-naphthyl and spiro
groups gave decreased diastereoselectivities (entries 12−14).
The reactions using 2j and 2k with phenyl and 2-naphthyl
groups, respectively, on the quaternary carbon center also
afforded the corresponding products in high yields with good
diastereo- and enantioselectivities (entries 15 and 16).
Interestingly, the products 3a−k were obtained with high to
good diastereoselectivities via the syn addition to the more
hindered BnOCH2, ArCH2, and Ar groups, probably because of
BnO- and π-directing effects. Thus, the reaction using 2l
bearing a TBDPSOCH2 group, which is less capable of
chelation, provided the diastereomer 4l through opposite
diastereofacial selection (i.e., anti addition by the steric effect),
albeit in lower yield and enantioselectivity (entry 17). The use
of 1d instead of 1i increased the yield of the product with the
opposite absolute configuration (entry 18). The absolute
configuration of (+)-3a-Me was determined to be 2R,4S by
comparison of the optical rotation to 15 in the literature value
(see below).12c The relative configurations of 3a-Me, 3g, and 3l
were determined by nuclear Overhauser effect experiments of
their derivatives.14 The relative configuration of 3j was
determined by X-ray analysis of a single crystal of 6d, but the
absolute configuration could not be determined (see below).
Enticed by these results, we investigated the effect of using
different alkylation reagents.15 For the reaction using Me3Al,
higher enantioselectivity was obtained in THF (dr > 95:5, 94%
ee; eq 1 in Scheme 2) than in Et2O (−78 °C for 30 min; >99%
bidentate TC ligand would interact with the double bond
without the chelate control (eq 2 in Scheme 3). Indeed, a
nonlinear effect (NLE)16 was not observed using either Me2Zn
or Me3Al with a 1:1 Cu(OTf)2/1i ratio (see Table 3, entry
5).14,17 Thus, a rational choice of ligand can lead to selective
production of either 3a-Me or 4a-Me.
As a great advantage of the Cu-catalyzed alkylation of α,β-
unsaturated ketones, the zinc enolate intermediate can be
employed for tandem reactions. The reactions with various
electrophiles (e.g., aldehydes) can furnish short syntheses of
complicated chiral cyclopentane derivatives. Additions of the
zinc enolate to benzaldehyde derivatives were smoothly
promoted, providing the corresponding adducts 6a−c with
excellent diastereoselectivities and yields. Thus, four new chiral
centers were created in a one-pot operation (Scheme 4a).
Scheme 4. Asymmetric Syntheses of Complicated
Cyclopentane Derivatives via One-Pot Operation
Scheme 2. Enantioselective Desymmetrization Using Me3Al
yield, dr > 95:5, 75% ee). Significantly, the use of 1k-Cu(TC)
(TC = thiophene-2-carboxylate) provided (2R,4R)-(−)-4a-Me
as the major product with 10:90 dr, albeit with low
enantioselectivity (eq 2 in Scheme 2). In contrast, the substrate
decomposed in the reaction using Me2Zn under the same
conditions.
Although the reason for the observed diastereoselectivity has
not yet been clarified, we propose that the alkylated Cu(I)/Zn
and Cu(I)/Al species A bearing monodentate ligand 1i before
oxidative addition interacts with the double bond via
coordination of the benzyloxy group to the Cu center (eq 1
in Scheme 3).8,13 The alkylated Cu(I)/Al species B bearing the
Further treatment of 6c with DIBAL led to highly oxygenated
cyclopentane 7 containing six continuous chiral centers and an
all-carbon quaternary stereocenter in only two steps. Also, one-
pot enol triflate and enol silyl ether formation gave synthetically
useful building blocks 5a and 5b, respectively (Scheme 4a).
Moreover, we succeeded in converting enol triflate 5a into
various five-membered-ring compounds 8−13 containing all-
carbon quaternary setereocenters (see pp S31−S36 in the
Supporting Information). In addition, the use of 2j and 2k with
phenyl and 2-naphthyl groups produced the corresponding
aldol products with high diastereoselectivities (Scheme 4b).
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Journal of the American Chemical Society
Communication
Hoboken, NJ, 2007. (c) Catalytic Asymmetric Synthesis, 3rd ed.; Ojima,
I., Ed.; Wiley: Hoboken, NJ, 2010.
Finally, the Cu-catalyzed enantioselective alkylation was
applied to the concise synthesis of a precursor of madindolines
A and B (Scheme 5).11,12 The reaction of butyraldehyde with
(2) For reviews of catalytic enantioselective formation of all-carbon
quaternary stereocenters, see: (a) Corey, E. J.; Guzman-Perez, A.
Angew. Chem., Int. Ed. 1998, 37, 388. (b) Douglas, C. J.; Overman, L.
E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363. (c) Christoffers, J.;
Baro, A. Adv. Synth. Catal. 2005, 347, 1473. (d) Trost, B. M.; Jiang, C.
Synthesis 2006, 369. (e) Hawner, C.; Alexakis, A. Chem. Commun.
2010, 46, 7295.
Scheme 5. Concise Synthesis of a Precursor of Madindolines
(3) For reviews of catalytic enantioselective desymmetrization, see:
(a) Ward, R. S. Chem. Soc. Rev. 1990, 19, 1. (b) Mikami, K.; Yoshida,
A. J. Synth. Org. Chem., Jpn. 2002, 60, 732. (c) Rovis, T. In New
Frontiers in Asymmetric Catalysis; Mikami, K., Lautens, M., Eds.; Wiley:
Hoboken, NJ, 2007; p 275.
(4) For examples of catalytic enantioselective desymmetrization for
construction of all-carbon quaternary stereocenters, see: (a) Lebsack,
A. D.; Link, J. T.; Overman, L. E.; Stearns, B. A. J. Am. Chem. Soc.
2002, 124, 9008. (b) Willis, M. C.; Powell, L. H. W.; Claverie, C. K.;
Watson, S. J. Angew. Chem., Int. Ed. 2004, 43, 1249. (c) Mori, K.;
Katoh, T.; Suzuki, T.; Noji, T.; Yamanaka, M.; Akiyama, T. Angew.
Chem., Int. Ed. 2009, 48, 9652. (d) Lee, J. Y.; You, Y. S.; Kang, S. H. J.
Am. Chem. Soc. 2011, 133, 1772.
(5) For selected recent examples of catalytic enantioselective
desymmetrization, see: (a) Lewis, C. A.; Gustafson, J. L.; Chiu, A.;
Balsells, J.; Pollard, D.; Murry, J.; Reamer, R. A.; Hansen, K. B.; Miller,
S. J. J. Am. Chem. Soc. 2008, 130, 16358. (b) Dickmeiss, G.; De Sio, V.;
Udmark, J.; Poulsen, T. B.; Marcos, V.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2009, 48, 6650. (c) Ito, H.; Okura, T.; Matsuura, K.;
Sawamura, M. Angew. Chem., Int. Ed. 2010, 49, 560. (d) Takebayashi,
S.; John, J. M.; Bergens, S. H. J. Am. Chem. Soc. 2010, 132, 12832.
(6) For a review, see: Silva, L. F., Jr. Tetrahedron 2002, 58, 9137.
(7) (a) Hong, A. Y.; Krout, M. R.; Jensen, T.; Bennett, N. B.; Harned,
A. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2011, 50, 2756. (b) Hong,
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the zinc enolate gave 14 with excellent diastereo- and
enantioselectivity. Treatment of 14 with DBU in toluene
afforded cyclopentene-1,3-dione (S)-15 bearing an all-carbon
quaternary stereocenter in 99% yield with >99% ee in two
steps. The Cu catalyst with ent-1i bearing the opposite S-axial
chirality produced the other enantiomer, (R)-15. Reduction of
15 using Zn(BH4)2 stereoselectively provided diol 16, which
was converted into 17, the important intermediate11a,12b for
madindolines A and B, via TBS protection of the diol moiety
followed by deprotection of the benzyl group.
In summary, we have succeeded in the asymmetric synthesis
of versatile five-membered-ring compounds bearing all-carbon
quaternary stereocenters through desymmetrization of achiral
cyclopentene-1,3-diones in the presence of chiral Cu catalysts
with phosphoramidite ligands. This straightforward process can
offer excellent stereoinduction not only with low catalyst
loading (up to 0.5 mol %) but also in a one-pot operation. In
addition, the catalytic process can be also applied to the concise
synthesis of a precursor of madindolines A and B. Further
synthetic studies of complicated compounds via the catalytic
asymmetric desymmetrization are underway.
(8) For reviews, see: (a) Alexakis, A.; Backvall, J.-E.; Krause, N.;
̈
̀ ́
Pamies, O.; Dieguez, M. Chem. Rev. 2008, 108, 2796. (b) Harutyunyan,
S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L. Chem.
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(9) For a review, see: Teichert, J. F.; Feringa, B. L. Angew. Chem., Int.
Ed. 2010, 49, 2486.
(10) For an example of Cu-catalyzed enantioselective desymmetriza-
tion using Et2Zn, see: Imbos, R.; Brilman, M. H. G.; Pineschi, M.;
Feringa, B. L. Org. Lett. 1999, 1, 623.
(11) Total syntheses of madindolines A and B have been reported by
four groups. See: (a) Sunazuka, T.; Hirose, T.; Shirahata, T.; Harigaya,
Y.; Hayashi, M.; Komiyama, K.; Omura, S.; Smith, A. B., III. J. Am.
̅
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, compound characterization data, and
a CIF file. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
Chem. Soc. 2000, 122, 2122. (b) Hosokawa, S.; Sekiguchi, K.; Hayase,
K.; Hirukawa, Y.; Kobayashi, S. Tetrahedron Lett. 2000, 41, 6435.
(c) McComas, C. C.; Perales, J. B.; Van Vranken, D. L. Org. Lett. 2002,
4, 2337. (d) Wan, L.; Tius, M. A. Org. Lett. 2007, 9, 647.
S
(12) (a) Hirose, T.; Sunazuka, T.; Shirahata, T.; Yamamoto, D.;
Harigaya, Y.; Kuwajima, I.; Omura, S. Org. Lett. 2002, 4, 501.
(b) Hirose, T.; Sunazuka, T.; Yamamoto, D.; Kojima, N.; Shirahata,
̅
AUTHOR INFORMATION
■
T.; Harigaya, Y.; Kuwajima, I.; Omura, S. Tetrahedron 2005, 61, 6015.
(c) Hosokawa, S.; Sekiguchi, K.; Enemoto, M.; Kobayashi, S.
Tetrahedron Lett. 2000, 41, 6429.
(13) Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem.
Soc. 2002, 124, 5262.
̅
Corresponding Author
mikami.k.ab@m.titech.ac.jp
Notes
The authors declare no competing financial interest.
(14) See the Supporting Information.
(15) Gremaud, L.; Alexakis, A. Angew. Chem., Int. Ed. 2012, 51, 794
ACKNOWLEDGMENTS
■
and references therein.
We thank Dr. K. Yoza (Bruker AXS K.K.) for X-ray analysis and
Takasago International Co. for providing BINOL and BINAP.
(16) For reviews, see: (a) Girard, C.; Kagan, H. B. Angew. Chem., Int.
Ed. 1998, 37, 2922. (b) Kagan, H. B. In New Frontiers in Asymmetric
Catalysis; Mikami, K., Lautens, M., Eds.; Wiley: Hoboken, NJ, 2007; p
207.
(17) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz,
R.; Feringa, B. L. Tetrahedron 2000, 56, 2865.
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