Enantioselective copper(I)-Catalyzed borylative aldol cyclizations of enone diones

Article abstract of DOI:10.1002/anie.201205899

Pina colato? In the presence of a chiral Cu^I/bisphosphine complex and B₂(pin)₂, enone diones undergo diastereo- and enantioselective desymmetrization to deliver highly functionalized bicyclic products. The products can be

Full text of DOI:10.1002/anie.201205899

Angewandte
Chemie
DOI: 10.1002/anie.201205899
Domino Reactions
Enantioselective Copper(I)-Catalyzed Borylative Aldol Cyclizations of
Enone Diones**
Alan R. Burns, Jorge Solana Gonzꢀlez, and Hon Wai Lam*
The in situ trapping of metal enolates generated by the
catalytic hydrometalation of a,b-unsaturated carbonyl com-
pounds has proven to be a mild and versatile method for
carbon–carbon bond construction.[1] Not only does this
strategy allow precise control of the site of enolization of
substrates containing several acidic sites, the use of chiral
metal/ligand complexes can also enable products to be
formed with high levels of diastereo- and enantiocontrol. In
this context, we and others have developed various copper(I)-
catalyzed or copper(I)-mediated reductive aldol,[2–5] Man-
nich,[6] and Michael[7] reactions to furnish products with high
diastereo- and enantioselectivities.
While these processes are effective, the development of
related transformations in which metal enolate generation is
initiated not by the formation of a carbon–hydrogen bond, but
by a carbon–heteroatom bond which can then be exploited in
subsequent functionalizations, should also be of high value.
Given the recent developments in enantioselective copper(I)-
catalyzed conjugate boration reactions,[8,9] we envisaged
a domino conjugate boration/aldol cyclization sequence in
which a copper enolate generated from the initial conjugate
boration is trapped by a pendant ketone to deliver cyclic
products containing multiple stereocenters (Scheme 1).
Relevant precedent for such a process is relatively
limited.[10] Hoveyda and co-workers have described racemic
N-heterocyclic-carbene-catalyzed conjugate boration of
a cyclic enone with subsequent in situ trapping of the resulting
boron enolate with benzaldehyde,[10a] whereas Kanai, Shiba-
saki, and co-workers reported a similar enantioselective
process catalyzed by a chiral copper/bisphosphine com-
plex.[10b] Recently, Riant and co-workers developed a racemic
copper-catalyzed conjugate boration/intermolecular aldol
sequence of acyclic or cyclic a,b-unsaturated carbonyl com-
pounds.[10c] However, analogous processes in which the aldol
reaction occurs in an intramolecular fashion have not, to our
knowledge, been reported, despite the potential for the
generation of useful functionalized cyclic building blocks.
In view of the precedent set by Krische and co-workers,
who described highly diastereo- and enantioselective rho-
dium-catalyzed conjugate arylation/aldol cyclizations of
enone diones,[11] we wondered whether a related process
involving copper-catalyzed conjugate boration could be
developed. Herein, we report the enantioselective copper-
catalyzed domino conjugate boration/aldol cyclization of
enone diones to give a range of highly functionalized bicyclic
products.[12–17] This desymmetrization process results in the
formation of one boron–carbon bond, one carbon–carbon
bond, and four contiguous stereocenters, two of which are
quaternary, with high levels of diastereo- and enantioselec-
tion.
Our studies commenced with evaluation of various
common chiral bisphosphine ligands (L1–L4; 5.5 mol%) in
the domino conjugate boration/aldol cyclization of the enone
dione 1a with B2(pin)2 (1.1 equiv) in the presence of CuCl
(5 mol%) and NaOtBu (7.5 mol%) in THF (0.1m) at room
temperature (Table 1, entries 1–4). Although the desired
bicyclic product 3a was formed in greater than 95:5 d.r.
[(major isomer):(ꢀ other isomers)] in several cases, appreci-
able quantities of the product 2a resulting from conjugate
boration without cyclization were often observed (Table 1,
entries 1, 2, and 4). With the Taniaphos ligand L3, 2a was the
sole product (Table 1, entry 3). Regarding enantioinduction,
the Josiphos ligand L4[8c,d] provided the best results, furnishing
3a as the major product (3a/2a = 93:7) in 85% ee (Table 1,
entry 4).[18] Additional optimization revealed that the inclu-
sion of MeOH[8c,d] (2.0 equiv; Table 1, entry 5) and halving the
concentration of the reaction (Table 1, entry 6) led to further
increases in enantioselectivity, albeit with a lower ratio of 3a/
2a (Table 1, entry 6). Fortunately, the use of more-hindered
alcohol additives improved this ratio without sacrificing
enantioselectivity (Table 1, entries 7 and 8), with iPrOH
providing the best results (entry 7). It should be noted that
there is the potential for enantioenrichment of 3a through
a ligand-controlled double asymmetric process, in which the
copper enolate containing the minor stereogenicity formed in
Scheme 1. Proposed conjugate boration/aldol cyclization.
[*] Dr. A. R. Burns, J. Solana Gonzꢀlez, Dr. H. W. Lam
EaStCHEM, School of Chemistry, University of Edinburgh
Joseph Black Building, The King’s Buildings, West Mains Road,
Edinburgh EH9 3JJ (UK)
E-mail: h.lam@ed.ac.uk
Homepage: http://homepages.ed.ac.uk/hlam/index.html
[**] We thank the EPSRC for financial support and for a Leadership
Fellowship (to H.W.L.). We thank Darryl W. Low (University of
Edinburgh) for assistance in the preparation of substrates, and
Gary S. Nichol (University of Edinburgh) for assistance with X-ray
crystallography. Solvias AG and AllyChem are gratefully acknowl-
edged for kind donations of chiral ligands and B2(pin)2, respectively.
We thank the EPSRC National Mass Spectrometry Service Centre for
providing high-resolution mass spectra.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205899.
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Table 1: Optimization of reaction conditions.[a]
Entry Ligand Conc [M] ROH
Conv [%][b] 3a/2a[b] 3a
ee [%][c]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L4
L4
L4
L4
0.1
0.1
0.1
0.1
–
–
–
–
>95
>95
56
86:14
31:69
<5:95
93:7
87:13
72:28
87:13
84:16
70
16[d]
[e]
–
>95
85
90
0.1
MeOH >95
MeOH >95
iPrOH
0.05
0.05
0.05
95
>95
94[f]
94
tBuOH >95
[a] Reactions were conducted using 1a (0.20 mmol). [b] Determined by
1H NMR spectroscopy of the unpurified reaction mixture. [c] Determined
by HPLC analysis using a chiral stationary phase. [d] Opposite enantio-
mer of 3a obtained. [e] Enantiomeric excess of 2a was 6%. [f] Uncyclized
product 2a was isolated in 12% yield with 93% ee. pin=pinacolato,
Cy =cyclohexyl.
Scheme 2. Borylative aldol cyclizations of enone diones to form decalins.
The reactions were performed with 1a–f (0.30 mmol) in THF (6 mL).
Yields are of pure isolated major diastereomers. Diastereomeric ratios
[(major isomer):(ꢀ other isomers)] were determined by 1H NMR analysis
of the unpurified reaction mixtures. Enantiomeric excesses were deter-
mined by HPLC analysis using a chiral stationary phase, and refer to the
major diastereomer. [a] Values in parentheses refer to a reaction con-
ducted using 3.15 mmol of 1b. [b] Reaction conducted with tBuOH
(2.0 equiv) in place of iPrOH.
the initial conjugate boration either does not cyclize, or
cyclizes to form an epimeric product. However, 2a and 3a
were formed with similar ee values (93% ee for 2a and 94%
ee for 3a) from the experiment of Table 1, entry 7, which
suggests that a double asymmetric process does not occur to
any significant extent in this case.
As shown in Scheme 2, a range of enone diones under-
went borylative aldol cyclization under the optimized reac-
tion conditions to furnish [6,6]-bicyclic products with high
levels of diastereoselection (> 95:5 d.r.) and enantioselection
(ꢀ 92% ee).[18] In addition to the original substrate 1a, which
gave 3a in 71% yield and 95% ee, substrates containing a 4-
chlorophenyl ketone or a 4-methoxyphenyl ketone performed
well (products 3b and 3c). Substrate 1d, containing an allyl
group rather than a methyl group at the 2-position of the
cyclic 1,3-diketone, was also a competent substrate (product
3d). The process is not limited to a,b-unsaturated aromatic
ketones; the reactions of substrates 1e and 1 f, which contain
an aliphatic ketone and an a,b-unsaturated ester, respectively,
were also highly stereoselective (products 3e and 3 f). The
reaction may also be performed on a larger scale. The
reaction of 1b on a 3.15 mmol scale provided 1.06 g (77%
yield) of 3b in 93% ee.
Scheme 3. Borylative aldol cyclizations of substrates 1g–i.
isolated in 49% yield and 86% ee, but interestingly, the
relative stereochemistry of this compound differed from those
products depicted in Scheme 2.[18] The originally expected
product 3gb was the minor component in this reaction (29%
yield, 87% ee). Two diastereomeric products were also
isolated from the reactions of substrates 1h and 1i, which
The reaction of substrate 1g, which contains a 4-nitro-
phenyl ketone, was poorly diastereoselective and gave two
separable products (Scheme 3). The major product 3ga was
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contain a 3-(trifluoromethyl)phenyl and a 2-bromophenyl
ketone, respectively.
Plausible reactive conformations that rationalize the
diastereochemical outcomes of these reactions are illustrated
in Figure 1. The formation of the products 3a–f, 3gb, 3hb, and
Figure 1. Models to explain diastereoselectivity of the reactions.
3ib may be explained by aldol cyclization through a Z enolate
in the chairlike Zimmerman–Traxler-type transition-state[19]
TS1, in which the B(pin) substituent occupies a pseudoequa-
torial position in the tether connecting the dione and enolate
components. The formation of 3ga, 3ha, and 3ia may be
accounted for on the basis of cyclization through an E enolate
in the chairlike transition-state TS2, or through a Z enolate in
the twist-boat transition-state TS3.[20] However, the reasons
that determine the propensity of a particular substrate to
react through one or more of the possible pathways are not
clear at the present time.
The scope of the enantioselective borylative cyclization
was additionally extended to the preparation of products
containing different ring sizes (Scheme 4). In these cases, the
use of tBuOH in place of iPrOH proved to be marginally
superior. Pleasingly, [5,6]-, [6,5]-, and [5,5]-bicyclic ring
systems were formed with good yields and high levels of
enantioinduction (92–99% ee for the major diastereomer).[18]
As with the decalin systems (Scheme 2), the major diastereo-
mers for the [5,6]-hydrindanes, 5a–d, have the syn-syn-anti
configuration shown, as confirmed by X-ray crystallographic
analysis of 5d.[18] Lower levels of diastereoselection were
observed with products 5e and 5 f, which were isolated as
inseparable mixtures of diastereomers.
Scheme 4. Borylative aldol cyclizations of enone diones to form
hydrindanes and diquinanes. The reactions were performed with 4a–f
(0.30 mmol) in THF (6 mL). Yields are of isolated material. Diastereo-
meric ratios [(major isomer):(ꢀ other isomers)] were determined by
1H NMR analysis of the unpurified reaction mixtures. Enantiomeric
excesses were determined by HPLC analysis using a chiral stationary
phase. [a] Isolated as an inseparable mixture of diastereomers.
[b] Enantiomeric excess values in parentheses refer to the minor
diastereomer, the stereochemistry of which was not assigned unambig-
uously.
Next, the parallel kinetic resolution[21] of a racemic chiral
enone-1,3-dicarbonyl substrate was examined.[11] Under stan-
dard conditions using iPrOH as the alcohol additive, the
substrate 6, containing a cyclic b-ketoamide, provided the
tricycle 7 in 42% yield, 83:17 d.r., and 91% ee (for the major
diastereomer), along with the uncyclized product 8 in 41%
yield, 73:27 d.r., and 90% ee (for the major diastereomer)
[Eq. (1)].[22] The formation of each of the products 7 and 8 as
an inseparable diastereomeric mixture indicates that the
parallel kinetic resolution was only moderately effective for
this substrate. When the reaction was performed with the
achiral ligand P(OEt)3, 7 and 8 were obtained in diastereo-
meric ratios similar to those indicated in Equation (1), thus
suggesting that the diastereoselectivity of the cyclization
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further transformations of the decalin 3b were conducted
(Scheme 5). Treatment of 3b with NaBO3·H2O[23] provided
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Scheme 5. Further transformations of product 3b.
the secondary alcohol 9 in 86% yield. Furthermore, forma-
tion of the potassium trifluoroborate salt 10 was readily
achieved by reaction of 3b with KHF2.[24]
In summary, we have described highly enantioselective
copper(I)-catalyzed borylative aldol cyclizations of enone
diones that result in densely functionalized decalin-, hydrin-
dane-, and diquinane-based products containing four contig-
uous stereocenters, two of which are quaternary. Work to
develop additional enantioselective metal-catalyzed domino
processes is underway in our laboratories.
Received: July 24, 2012
Published online: September 28, 2012
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Keywords: asymmetric catalysis · boron · copper ·
domino reactions · enantioselectivity
.
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herein were assigned by analogy to those of 3b, 3ia, and 5d,
which were determined by X-ray crystallography. See the
Supporting Information for full details. CCDC 891571 (3b),
891572 (3ia), and 891573 (5d) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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