Highly enantioselective copper-catalyzed alkylation of β-ketoesters and subsequent cyclization to spirolactones/bi-spirolactones

Article abstract of DOI:10.1021/ja211859w

Cu-catalyzed enantioselective alkylation of β-ketoesters using alcohols for in situ preparation of alkylating reagents is reported. A number of functionalized β-ketoesters containing a quaternary carbon stereocenter are obtained with up to 99% ee. The alkylation products derived from 2-substituted allylic alcohols or their corresponding iodides can then be converted to spirolactones, bi-spirolactones, and related chiral target products.

Full text of DOI:10.1021/ja211859w

Communication
pubs.acs.org/JACS
Highly Enantioselective Copper-Catalyzed Alkylation of β-Ketoesters
and Subsequent Cyclization to Spirolactones/Bi-spirolactones
Qing-Hai Deng, Hubert Wadepohl, and Lutz H. Gade*
Anorganisch-Chemisches Institut, Universitat Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
̈
S
* Supporting Information
Scheme 1. Chiral Pincer Ligands Boxmi (1) and the
Synthesis of Copper Complex 2
ABSTRACT: Cu-catalyzed enantioselective alkylation of
β-ketoesters using alcohols for in situ preparation of
alkylating reagents is reported. A number of functionalized
β-ketoesters containing a quaternary carbon stereocenter
are obtained with up to 99% ee. The alkylation products
derived from 2-substituted allylic alcohols or their
corresponding iodides can then be converted to
spirolactones, bi-spirolactones, and related chiral target
products.
nantioselective construction of organic target molecules
E
containing all-carbon quaternary stereogenic centers is a
challenge in organic synthesis1 due to steric repulsion between
the carbon substituents. Catalytic stereoselective alkylation of
β-ketoesters generates chiral quaternary stereocenters with
diverse substituents, which themselves offer manifold possibil-
ities for further derivatization.2 Several methods have been
developed, such as Pd-catalyzed asymmetric allylic alkylation
with allylic esters or analogues3,4 and alkylation with halides by
phase-transfer catalysis.5,6 From a conceptual point of view,
using alcohols7,8 to generate alkylating reagents in situ is of
particular interest because alcohols are among the most
abundant and common organic feedstock.
molecular structure, established by X-ray diffraction, reveals a
planar (rmsd 0.07 Å) T-shape coordination of the Cu(II) by
the three N donors, augmented by O(3) of the acetate to a
somewhat distorted square planar arrangement (rmsd 0.12 Å)
(Figure 1).
Spirolactone frameworks are present in many biologically
active natural products and pharmaceuticals.9 However, their
stereocontrolled synthesis, particularly generating an enantio-
pure spiro-quaternary stereocenter, poses a challenge.10
Recently, Marini et al. reported the first organocatalyzed
enantioselective synthesis of spirolactones starting from racemic
cyclic β-ketoesters11 and using a vinyl selenone as an alkylating
agent.
We recently developed a class of chiral pincer ligands, boxmi
(1, Scheme 1), which have shown great promise as stereo-
directing ligands for transition metal catalysts.12 Here we report
highly enantioselective alkylation of β-ketoesters catalyzed by
boxmi-Cu(II) catalysts, using benzylic and allylic alcohols to
prepare the corresponding iodides in situ as alkylating reagents
without further purification. The primary chiral alkylation
products are then cyclized in a one-pot procedure to generate
spirolactones or bi-spirolactones by adding BF3·Et2O in the
presence of a Cu complex.
Although the Cu(II) catalysts employed in this study were
generated in situ, Cu complexes bearing the chiral pincer ligand
were readily isolable. Direct complexation of the protioligand
1a with Cu(OAc)2·H2O in methanol at room temperature gave
the corresponding Cu(II) acetato complex 2 (Scheme 1). The
Figure 1. Molecular structure of [Cu(lig)(OAc)] (2); hydrogen atoms
omitted for clarity.
In a first test reaction, the isolated Cu complex 2 catalyzed
the enantioselective alkylation of β-ketoester 3a with benzyl
iodide to obtain the product 4a with 87% ee in 94% yield
(Scheme 2).
Since benzyl iodide can be prepared from benzyl alcohol by
treatment with CsI and BF3·Et2O in MeCN,13 we used benzylic
alcohol, converted in situ to benzyl iodide and quenched by
diisopropylethylamine, without further purification to obtain
Received: December 20, 2011
Published: January 26, 2012
© 2012 American Chemical Society
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Scheme 2. Initial Test of Alkylation
Scheme 3. Enantioselective Alkylation of β-Ketoesters with
Benzyl Alcohol
a
the desired alkylation product with the same enantioselectivity
(Table 1, entry 1). The same result was obtained upon in situ
Table 1. Optimization of Reaction Conditions for the
Alkylation of 3a
a
Yields refer to isolated products; ee's were determined by HPLC
analysis; absolute configurations of the products were determined by
comparison with αD values reported in the literature.
membered rings and acyclic ketoesters proved to be unreactive
under these reaction conditions.
We next investigated the scope with respect to various
benzylic alcohols (Table 2, entries 1−6) as well as naphthyl-
Table 2. Enantioselective Alkylation of 3a with Various
Benzylic Alcohols
a
b
c
Isolated yields. Determined by HPLC analysis. No reaction.
generation of the catalyst (entry 2), demonstrating that the
catalyst system tolerates a variety of additional components
without a significant effect on its performance. Cu(OTf)2 was
found to be optimal in terms of yield and enantioselectivity,
while solvent screening showed that CH2Cl2 gave the best
results (entries 4 and 6−8). Other organic bases led to much
reduced catalyst activity. Finally, screening of a series of boxmi
ligands revealed that higher selectivity was obtained with
derivatives that contained 4-phenyloxazolinyl units at the “wing
tips” of the pincer ligand (cf. entry 4 with entries 12 and 13).
Furthermore, the appropriate substitution pattern in the ligand
backbone14 slightly improved the enantioselectivity (cf. entry 4
with entries 14 and 15). Ligand 1d, which contained two
methyl groups in the backbone, gave the product with the
highest enantioselectivity (98% ee) in combination with a high
yield (entry 14).
With these optimized reaction conditions we explored the
generality of the protocol for different β-ketoesters by reaction
with benzyl alcohol 5a. As summarized in Scheme 3, indanone-
derived tert-butyl β-ketoesters were found to be suitable for this
catalytic transformation and provided products 4a−4f in high
yields and excellent enantioselectivities. Cyclopentanone-
derived tert-butyl β-ketoesters were also successfully employed
in the process to generate 4g−4k with high selectivities. In
contrast, the corresponding ethyl ester led to a significant
decrease in enantioselectivity (4l). Substrates with six-
a
b
Isolated yields. Determined by HPLC analysis.
derived substrates (entries 7 and 8). All catalytic reactions
provided the desired products in high yields and with excellent
enantioselectivities.
The catalytic alkylation could also be readily extended to a
range of substituted allylic alcohols (Table 3). Thus, treating β-
ketoester 3a with different substituted allylic alcohols yielded
the target products 4u−4z again in high yields and with
excellent enantioselectivities (up to 99%). It is notable that the
configuration of the double bond in products 4y and 4z is fully
retained (entries 5 and 6) when using Cu complexes, whereas
the use of nonligated Cu salts had previously given rise to
mixtures resulting from double bond isomerization.16
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Table 3. Enantioselective Alkylation of 3a with Various
Allylic Alcohols
Scheme 5. Proposed Mechanism of the CuII-Catalyzed
Alkylation of Cyclic β-Ketoesters
a
b
Isolated yields. Determined by HPLC analysis.
The chiral allylation products obtained by using 2-substituted
allylic alcohols 7 could be converted to bi-spirolactones 9 by
adding 8 equiv of BF3·Et2O17 in a one-pot procedure (Scheme
4). We found that the Cu complex played a key role in the
face of the substrate, consistent with the absolute configuration
of products 4d and 4k (Scheme 3).
Occasionally, allyl iodides cannot be prepared from the
corresponding alcohol by the CsI/BF3·Et2O/MeCN protocol.
This is the case for 3-iodo-2-methylpropene (10), for which the
primary alkylation products were subsequently converted to
spirolactones 11 upon addition of 6 equiv of BF3·Et2O using a
one-pot procedure (Scheme 6).
a
Scheme 4. Enantioselective Synthesis of Bi-spirolactones 9
Scheme 6. Enantioselective Synthesis of Spirolactones 11
a
Using 10 as the Allylating Reagent
a
Yields refer to isolated products based on substrate 3; ee's were
determined by HPLC analysis. b8a was the product of the second step.
cyclization.18 In a control test without the Cu complex, only
trace amounts of 9a were obtained when the isolated pure
alkylation product 8a16 was reacted with BF3·Et2O alone.
Indanone-derived tert-butyl β-ketoester 3a yielded products
9a,9b with moderate enantioselectivities; however, cyclo-
pentanone-derived tert-butyl β-ketoesters were converted to
the corresponding bi-spirolactones 9c−9h with excellent
enantioselectivities.
Based on the results described above, a mechanism for this
catalytic reaction is proposed in Scheme 5. In the initial step,
two carbonyl oxygen atoms of the β-ketoester substrate
coordinate to the Cu complex to give intermediate A, followed
by deprotonation with DIPEA to form the key ester enolate
intermediate B. This reacts with the benzyl or allyl iodide,
generated in situ from the alcohol, to give intermediate C.
Finally, de-coordination from intermediate C liberates the
product and regenerates the catalyst. Based on the X-ray
structure analysis of Cu complex 2, we assume a molecular
structure of intermediate B in which the Si face of the substrate
is blocked by the phenyl group in the oxazolinyl unit and the
alkylating agents therefore preferentially approach from the Re
a
Yields refer to isolated products on the basis of substrates 3; ee's were
determined by HPLC analysis.
This methodology also can be extended to the reaction of 3
with 3-iodo-2-[(trimethylsilyl)methyl]propene (12)19 to pro-
vide the corresponding allylsilanes 13 with excellent enantio-
selectivities. The longer reaction times may be due to the steric
hindrance of the bulky trimethylsilyl group in 12. Combination
of 13, 4 equiv of BF3·Et2O, and 5 mol % of Cu(OTf)2 in
dichloromethane at room temperature gave rise to spirolac-
tones 11, whereas reaction with 3 equiv of tetra-n-
butylammonium fluoride in THF at room temperature
provided the desilylative cyclization products 14 in high yields
and enantioselectivities (Scheme 7).20 Single-crystal X-ray
structure analysis of rac-14a (see Supporting Information)
showed that 14 was diastereoselectively generated as a syn-
diastereomer.
In conclusion, Cu(II) complexes bearing the chiral pincer
ligands boxmi (1) have been found to be highly efficient for the
enantioselective alkylation of cyclic β-ketoesters. Benzyl and
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Scheme 7. Stereoselective Synthesis of Allylsilanes 13 and
Their Subsequent Transformations
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0.10 mmol of 13 was used in the further transfer. Yields refer to
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allylic alcohols may be employed for the in situ preparation of
iodides, which then act as alkylating reagents. This strategy has
been extended to the one-pot asymmetric synthesis of
spirolactones and bi-spirolactones by subsequent cyclization
promoted by BF3·Et2O, in which the Cu complex appeared to
play a key role in both the alkylation and cyclization steps.
Finally, β-ketoester-substituted allylsilanes were converted to
spirolactones and bicyclic cyclopentanols with excellent
enantioselectivities by subsequent treatment of the primary
chiral allylation products.
ASSOCIATED CONTENT
* Supporting Information
■
S
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AUTHOR INFORMATION
Corresponding Author
lutz.gade@uni-hd.de
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Q.-H.D. acknowledges support by the Alexander von
Humboldt Foundation. Funding was also provided by the
Deutsche Forschungsgemeinschaft (SFB 623, TP B6).
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