Programmable enantioselective one-pot synthesis of molecules with eight stereocenters

Article abstract of DOI:10.1038/nchembio.901

We developed an enantioselectively catalyzed tandem synthesis of structurally and stereochemically complex molecules that forms four carbon-carbon bonds and sets eight stereocenters with high regio-, diastereo- and enantioselectivity. It can be programmed to yield different stereoisomers by varying only the order of combination of a common set of reagents and catalysts. We report what is to our knowledge the first synthesis of both enantiomers of a chiral compound using the same chiral catalyst.

Full text of DOI:10.1038/nchembio.901

brief communication
published online: 18 march 2012 | doi: 10.1038/nchembio.901
programmable enantioselective one-pot synthesis
of molecules with eight stereocenters
marco potowski1,2, markus schürmann3, hans preut3, andrey p antonchick1* & herbert Waldmann1,2*
We developed an enantioselectively catalyzed tandem and in a 1:1 ratio; that is, the reaction proceeded with high diastereo-
synthesis of structurally and stereochemically complex control but low regiocontrol, which could be improved by varying
molecules that forms four carbon-carbon bonds and the reaction conditions (Supplementary Results, Supplementary
sets eight stereocenters with high regio-, diastereo- and Table 1). The relative configuration of the anti-isomer 3a was deter-
enantioselectivity. It can be programmed to yield different mined by means of crystal-structure analysis (Supplementary Fig. 1
stereoisomers by varying only the order of combination of and Supplementary Data Set 1), which revealed that the central 1,4-
a common set of reagents and catalysts. We report what cyclohexadione ring adopts a chair conformation such that cyclo-
is to our knowledge the first synthesis of both enantiomers adduct 3a has an inversion center and is achiral.
of a chiral compound using the same chiral catalyst.
Although the azomethine ylides derived from aliphatic aldehydes
The synthesis of structurally and stereochemically complex did not react, the cycloaddition has considerable scope, producing
molecular architectures is at the heart of chemical biology research. the products from imines obtained from aromatic aldehydes with
In particular, there is a high demand for methods that give efficient electron-donating or electron-accepting substituents in different
regio-, diastereo- and enantioselective access to natural product– positions (Supplementary Table 2). Attempts to isolate monocyclo-
inspired compound collections with scaffolds composed of two to adduct 5a resulted in formation of hydroquinone 6a (Scheme 1).
four rings and with multiple stereocenters1. In addition, synthetic
Given that syn-isomer 4a does not have a center of symmetry
methods that allow the construction of compound collections with (discussed below; Supplementary Fig. 2), we explored its enantio-
high structural and stereochemical diversity from a limited set of selective synthesis by varying the chiral ligands for the metal catalyst.
starting materials and catalysts are of particular value2. High levels of Exploration of a variety of copper catalysts and chiral ligands in
synthetic efficiency can be reached in one-pot, multistep sequences different solvents and in the presence of different bases revealed
that selectively form one or several stereocenters out of a much
greater number of theoretically possible isomers3–5
.
Br
Br
Br
Here we describe the development of an asymmetric one-pot
tandem synthesis of structurally complex molecular architec-
tures by two consecutive cycloadditions of azomethine ylides to
p-benzoquinone. In the tandem sequence, four new carbon-carbon
bonds and eight stereocenters are formed with very high regio-,
diastereo- and enantioselectivity, allowing the highly selective
formation of one stereoisomer from 512 possible isomers. The
sequence can readily be programmed; that is, it is possible to start
from a common set of reagents and steer all levels of selectivity
by varying only the order of reagents and/or the catalyst used. We
describe what is to our knowledge the first highly enantioselective
separate synthesis of both enantiomers of a chiral compound using,
in both cases, identical reagents and the same chiral catalyst.
For the development of an efficient programmable synthesis,
we used the enantioselectively catalyzed dipolar cycloaddition of
azomethine ylides to electron-deficient olefins because it allows the
formation of up to four stereocenters in one step and has found wide-
spread application in the synthesis of bioactive compounds, natural
products and materials6–11. We chose to use p-benzoquinone (1)
as a dipolarophile that could react twice with the 1,3-dipoles to
raise the number of simultaneously formed stereocenters to eight
and the number of possible isomers of the product to 512. p-Benzo-
quinone has been used in tandem cycloadditions before, but
O
O
O
O
O
H
H
H
H
H
H
H
H
+
HN
NH
HN
NH
O
O
O
O
O
O
O
anti-3a
syn-rac-4a
Br
Cu(I)-catalyst,
base, solvent
2a, 2.2 equiv
O
O
1
1 equiv.
2a, 1 equiv.
anti-3a + syn-rac-4a
2a, 1 equiv.
O
O
O
H
H
O
HO
OH
N
H
Br
O
SiO2
N
H
rac-5a
Br
O
rac-6a
enantioselective diannulations have not been explored yet12–16
.
Initially, alanine methyl ester imine 2a was treated with the quinone Scheme 1 | Tandem 1,3-dipolar cycloaddition. Catalytic, double 1,3-dipolar
in CH2Cl2 in the presence of base (Scheme 1). In the ensuing stepwise cycloaddition of 1,4-benzoquinone 1 and azomethine ylide 2a in the
double cycloaddition, only isomers anti-3a and syn-rac-4a were formed, presence of catalytic amounts of Cu(I) salt.
1Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Dortmund, Germany. 2Technische Universität Dortmund, Fakultät
Chemie, Chemische Biologie, Dortmund, Germany. 3Technische Universität Dortmund, Fakultät Chemie, Anorganische Chemie, Dortmund, Germany.
*e-mail: andrey.antonchick@mpi-dortmund.mpg.de or herbert.waldmann@mpi-dortmund.mpg.de
428
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NaTure chemIcal bIology doi: 10.1038/nchembio.901
Table 1 | results of the enantioselective synthesis of the chiral compounds bearing eight stereocenters
brief communication
R1
H
R1
R3
R1
R1
O
O
O
O
O
O
O
O
O
O
H
R2
R4
H
H
H
H
R4
N
+
+
N
or
or
HN
NH
R2
HN
R2
NH
R2
HN
R4
NH
R2
H
H
O
H
H
H
H
O
O
O
O
O
O
O
O
O
O
O
O
O
R1
R3
R3
1
2
2
4
8
9
product
r1
r2
r3
r4
procedurea
yield (%)b
e.e. (%)c
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-Br-C6H4
4-Me-C6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
C
C
C
C
C
C
C
C
C
C
C
C
65
54
42
65
65
73
79
84
41
66
38
54
51
56
34
70
64
72
64
57
70
50
49
44
46
54
44
49
50
49
44
40
42
98
97
98
98
97
98
98
98
96
99
98
98
98
98
98
98
98
98
98
98
98
98
98
98
98
98
98
99
99
98
98
95
94
4-Meo-C6H4
4-F-C6H4
3-F-C6H4
2-F-C6H4
Ph
2-Naphthyl
2-Cl-6-F-C6H3
4-CF3-C6H4
4-Br-C6H4
4-Br-C6H4
4-F-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-F-C6H4
4-Br-C6H4
4-Me-C6H4
4-Meo-C6H4
2-Naphthyl
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
2-Naphthyl
4-Me-C6H4
4j
4k
4l
Ph
8a
8b
8c
8d
8e
8f
8g
8h
8i
9a
9b
9c
9d
9e
9f
9g
9h
9i
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Meo-C6H4
4-F-C6H4
3-F-C6H4
2-Naphthyl
4-Meo-C6H4
4-F-C6H4
4-Me-C6H4
2-Cl-6-F-C6H3
2-Me-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
3-F-C6H4
4-F-C6H4
4-Me-C6H4
2-Naphthyl
4-Br-C6H4
4-Br-C6H4
9j
9k
9l
Ph
Me
Me
Ph
aGeneral procedures A, B and C are in Supplementary methods. bIsolated yields of the pure major regioisomer after column chromatography. Diastereomer ratio for all products is >95:5. Regioisomer ratio
for products 4 and 8 is >94:6, and for products 9 it is 75:25, on the basis of 1H-NMR analysis. cDetermined by HPlC analysis using a chiral stationary phase. Me, methyl; Ph, phenyl.
that the best result could be obtained using Cu(CH3CN)4BF4
Regardless of the substitution pattern of the aromatic ring, the
(3 mol%) as a Lewis acid in combination with the S,P-ferrocenyl asymmetric reactions of 1,4-benzoquinone 1 with various azo-
ligand (R)-Fesulphos17–19 (7g; 3 mol%) in toluene in the presence of methine ylides proceeded with moderate to good yields of 41–84%
N,N-diisopropylethylamine (DIPEA; 20 mol%) at 18–25 °C (4a–4l and high regioselectivity (94:6), diastereoselectivity (>95:5) and
in Table 1 and Supplementary Table 3). Under these conditions, enantioselectivity (96–99% e.e.) (4a–4l in Table 1). Depending on
syn-regioisomer 4a was obtained with high regioselectivity (94:6) the electronic properties of the substituents of the aromatic ring,
and diastereoselectivity (>95:5) in 65% yield and with very high slight differences in yield were observed. In the presence of electron-
enantioselectivity (98% enantiomeric excess (e.e.)). Notably, this donating substituents such as methyl or methoxy groups (4b and 4c,
reaction created eight stereocenters in a one-pot transformation. The respectively), the yield was reduced to 42–54%, whereas electron-
absolute configuration of syn-product 4a was determined by crys- withdrawing substituents such as bromine or fluorine (4a and 4d,
tal-structure analysis (Supplementary Fig. 2 and Supplementary respectively) led to higher yields. Enantioselectivity was consis-
Data Set 2), which revealed that in syn-regioisomer 4a tently high (97–98% e.e.) and was not affected by position (4d–4f)
the cyclohexa-1,4-dione adopts a twist-boat conformation.
or number (4g–4h) of substituents. An exception was 4i, which
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429

NaTure chemIcal bIology doi: 10.1038/nchembio.901
brief communication
was formed in only 41% yield but had high regio-, diastereo- and very high diastereo- and enantioselectivity. Owing to differences in
enantioselectivity. In addition, cycloadditions with other amino reaction rates of the stepwise tandem process, two different dipoles
acid ester imines (4k and 4l) showed excellent selectivity.
could successfully be used in the one-pot process. The knowledge
To expand the chemical space accessible via the double cyclo- gleaned in the syn-selective and the nonasymmetric cycloadditions
addition, we explored whether the transformation could give access further allowed us to extend the scope of the synthesis to mixed
to cycloadducts formed from two different dipoles. In the presence of anti-products. To our knowledge, it was the first time that it was
the chiral catalyst 7g carrying a bulky ligand, the second cyclization possible to synthesize both enantiomers of a chiral compound using
step proceeds with a lower reaction rate than the first reaction. Thus, identical reagents and the same chiral catalyst simply by changing
a sequence was established in which 1,4-benzoquinone 1 was treated the order of addition of the starting chemicals.
with 1 equiv. of an α-iminoester 2 in the presence of (R)-Fesulphos 7g
The tandem dipolar cycloaddition is of considerable scope and
(3 mol%), Cu(CH3CN)4BF4 (3 mol%) and DIPEA (20 mol%) in toluene promises to efficiently give access to great structural and chemical
for 1 h (Supplementary Table 4), followed by treatment with a second diversity. Thus, for instance, a 240,600-member compound library
α-iminoester 2 for 15 h to selectively yield the mixed double- that would encompass more than 1.9 million stereocenters could,
cycloaddition products syn-8 by means of a one-pot tandem reaction in principle, be selectively prepared by the described one-pot reac-
(8a–8i in Table 1) with high regio-, diastereo- and enantioselectivity. tions using only 20 amino acids, 20 aldehydes, 1,4-benzoquinone
Analogous reactions with various α-iminoesters 2 proceeded with and one chiral ligand. In a sense, such a synthetic methodology can
very high enantioselectivity (98% e.e.) to form eight stereocenters be compared with the biosynthesis of small molecules in nature,
in a one-pot tandem reaction with high stereocontrol. We note that, which also requires only variation in the combination of relatively
independently of the order of addition of the 1,3-dipoles, the absolute few building blocks under the influence of different biocatalysts.
configuration of all stereocenters in the cycloadducts is the same.
To further explore the stereochemical space defined by the Accession codes. Small-molecule crystal structures are deposited
scaffold of the double cycloadducts, we exploited the findings that in the Cambridge Crystallographic Data Centre under accession
regioselectivity can be changed by switching from the chiral to an codes 834647 and 834648.
achiral catalyst (Scheme 1 versus 4a–4l in Table 1) and that in
received 25 october 2011; accepted 23 December 2011;
the presence of the chiral catalyst with bulky ligands the velocity
published online 18 march 2012
of the second reaction is low, but in the presence of a ligand-free
catalyst (Scheme 1 and Supplementary Table 2) it is high. Thus,
references
we hypothesized that the first and faster dipolar cycloaddition is the
1. Koch, M.A. et al. Proc. Natl. Acad. Sci. USA 102, 17272–17277 (2005).
enantioselectivity-determining step and is steered by the chirality
of the ligands, whereas in the second, much slower step, the type of
the metal complex only serves to determine the regioselectivity. The
configuration of the four newly formed stereocenters is directed by
the stereogenic centers established in the first step.
2. Morton, D., Leach, S., Cordier, C., Warriner, S. & Nelson, A. Angew. Chem.
Int. Ed. Engl. 48, 104–109 (2009).
3. Enders, D., Huttl, M.R.M., Grondal, C. & Raabe, G. Nature 441, 861–863 (2006).
4. Bertelsen, S., Johansen, R.L. & Jorgensen, K.A. Chem. Commun. (Camb.)
3016–3018 (2008).
5. Rendler, S. & MacMillan, D.W.C. J. Am. Chem. Soc. 132, 5027–5029 (2010).
6. Stanley, L.M. & Sibi, M.P. Chem. Rev. 108, 2887–2902 (2008).
7. Pellissier, H. Tetrahedron 63, 3235–3285 (2007).
Accordingly, 1,4-benzoquinone 1 was initially treated with
1 equiv. of an α-iminoester 2 in the presence of (R)-Fesulphos 7g
(3mol%), Cu(CH3CN)4BF4 (3mol%)andDIPEA(20mol%)intoluene.
After completion of this initial cycloaddition, a solution of a second
α-iminoester 2, Cu(CH3CN)4PF6 (30 mol%) and triethylamine
(30 mol%) in tetrahydrofuran was added (9a–9l in Table 1). In
8. Pandey, G., Banerjee, P. & Gadre, S.R. Chem. Rev. 106, 4484–4517 (2006).
9. Adrio, J. & Carretero, J.C. Chem. Commun. (Camb.) 47, 6784–6794 (2011).
10. Yu, J., Shu, F. & Gong, L.-Z. Acc. Chem. Res. 44, 1156–1171 (2011).
11. Antonchick, A.P. et al. Nat. Chem. 2, 735–740 (2010).
12. Garratt, P.J. & Tsotinis, A. Tetrahedr. Lett. 27, 2761–2762 (1986).
the presence of a ten-fold excess of achiral copper complex rela- 13. Burnell, D.J., Goodbrand, H.B., Kaiser, S.M. & Valenta, Z. Can. J. Chem. 65,
154–165 (1987).
tive to the amount of the chiral complex, regioselectivity was
14. Brecknell, D.J., Carman, R.M. & Schumann, R.C. Aust. J. Chem. 42, 511–525
shifted to a ratio of 75:25 in favor of the mixed anti-regioisomer 9.
(1989).
Regardless of the electronic properties and positions of the imine
15. Rainbolt, J.E. & Miller, G.P. J. Org. Chem. 72, 3020–3030 (2007).
substituents, the reactions proceeded with high enantioselectivity
(98–99% e.e.) and with viable yields (43–54%) to give various mixed
anti-cycloadducts.
16. Valiulin, R.A., Arisco, T.M. & Kutateladze, A.G. Org. Lett. 12, 3398–3401 (2010).
17. Cabrera, S., Arrayas, R.G. & Carretero, J.C. J. Am. Chem. Soc. 127,
16394–16395 (2005).
18. Cabrera, S., Arrayas, R.G., Martin-Matute, B., Cossio, F.P. & Carretero, J.C.
Tetrahedron 63, 6587–6602 (2007).
19. Cabrera, S. et al. Pure Appl. Chem. 78, 257–265 (2006).
As the direction of enantioselectivity is exclusively determined
in the first step of this reaction sequence, reversing the order of
imine addition should give the opposite enantiomer. Indeed, 9i
and 9l, which were formed by using a toluyl-imine in the first step
and a bromophenyl-imine in the second step (9i) and by revers-
ing this order (9l), are enantiomers (9i and 9l in Table 1 and
Supplementary Results). By analogy, 9j and 9k are also enantiomers
(9j and 9k in Table 1 and Supplementary Fig. 3).
acknowledgments
M.P. thanks the Fonds der Chemischen Industrie for a fellowship. The research leading
to these results has received funding from the European Research Council (ERC) under
the European Union′s Seventh Framework Programme (FP7/2007-2013) and ERC grant
agreement no. 268309.
Notably, both pairs of enantiomers were obtained under iden-
tical conditions, including the use of the same chiral catalyst in
both tandem transformations, and the different enantiomers were
produced only by switching the order of imine addition.
author contributions
A.P.A. and H.W. designed experiments and supervised the project. M.P. performed
experiments. M.S. and H.P. carried out the X-ray crystallographic analysis. All authors
discussed the results, commented and wrote the manuscript.
The enantioselectively catalyzed one-pot tandem cycloaddi-
tion of azomethine ylides to p-benzoquinone proceeds with very
high regio-, diastereo- and enantioselectivity and can readily be
reprogrammed to access different anti- or syn-cycloadducts by
only varying the order of combination of a given set of reagents
and catalysts. Varying reaction conditions and the catalyst used
gave access to either achiral anti- or chiral syn-cycloadducts. By
competing financial interests
The authors declare no competing financial interests.
additional information
Supplementary information and chemical compound information are available
online at http://www.nature.com/naturechemicalbiology/. Reprints and permissions
information is available online at http://www.nature.com/reprints/index.html.
means of a chiral catalyst, the syn-isomers were synthesized with Correspondence and requests for materials should be addressed to A.P.A. or H.W.
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