Catalytic asymmetric domino michael addition - Alkylation reaction: Enantioselective synthesis of dihydrofurans

Article abstract of DOI:10.1021/ol102499r

A catalytic enantioselective synthesis of dihydrofurans has been developed. 1,3-Dicarbonyl derivatives react with (E)-β,β-bromonitrostyrenes in the presence of a chiral bifunctional thiourea catalyst providing mild and efficient access to diverse polysubs

Full text of DOI:10.1021/ol102499r

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5680-5683
Catalytic Asymmetric Domino Michael
Addition-Alkylation Reaction:
Enantioselective Synthesis of
Dihydrofurans
Magnus Rueping,* Alejandro Parra, Uxue Uria, Franc¸ois Besselie`vre, and
Est´ıbaliz Merino
Institute of Organic Chemistry, RWTH Aachen UniVersity, Landoltweg 1,
D-52074 Aachen, Germany
Magnus.Rueping@rwth-aachen.de
Received October 15, 2010
ABSTRACT
A catalytic enantioselective synthesis of dihydrofurans has been developed. 1,3-Dicarbonyl derivatives react with (E)-ꢀ,ꢀ-bromonitrostyrenes
in the presence of a chiral bifunctional thiourea catalyst providing mild and efficient access to diverse polysubstituted dihydrofurans in good
yields and enantioselectivities.
Dihydrofurans are found in many naturally occurring com-
pounds and are attractive starting materials for the synthesis of
highly valuable tetrahydrofurans.1,2 Many syntheses of enan-
tiomerically enriched dihydrofurans have been described, but
most rely on the use of multistep diastereoselective strategies
using chiral auxiliaries, including oxazolidinones,3a
sulfoximines,3b or sulfonium salts.3c Further elegant ap-
proaches include the retro-Claisen photo rearrangement of
enantiopure norbornane derivatives4a and the nickel-catalyzed
rearrangement of cyclopropanes to provide enantioenriched
hydrofurans.4b
In view of the importance of this class of molecules,
and building on our previous investigations, we decided
to develop a new metal-free enantioselective reaction for
the fast and efficient synthesis of hydrofurans. Recently,
Gouverneur and co-workers described a proline-catalyzed
aldol reaction to efficiently generate acyclic chiral keto-
alcohols which upon a phosphine-catalyzed cyclization
provided the desired 5-membered ring.6a In addition,
Calter et al. reported an enantioselective interrupted Feist-
Benary reaction employing a cinchona catalyst.6b,c
Our group reported the synthesis of multisubstituted
hydrofurans using a Brønsted acid catalyzed Mannich-
ketalization reaction.7 Guided by our studies on the use of
diketones 1 in cascade transformations,8 we envisioned that
In addition, examples of asymmetric transition metal-
catalyzed reactions employing different chiral ligands have
also been described.5
(3) (a) Garzino, F.; Me´ou, A.; Brun, P. Eur. J. Org. Chem. 2003, 1410.
(b) Gais, H. J.; Reddy, L. R.; Babu, G. S.; Raabe, G. J. Am. Chem. Soc.
2004, 126, 4859. (c) Zheng, J.; Zhu, C.; Sun, X.; Tang, Y.; Dai, L. J. Org.
Chem. 2008, 73, 6909.
(1) For occurrence of dihydrofurans in Nature, see: (a) Fraga, B. M.
Nat. Prod. Rep. 1992, 9, 217. (b) Merrit, A. T.; Ley, S. V. Nat. Prod. Rep.
1992, 9, 243
.
(2) Tetrahydrofuran is a very important scaffold: (a) Lipshutz, B. H.
(4) (a) Xia, W.; Yang, C.; Patrick, B.; Scheffer, J. R.; Scott, C. J. Am.
Chem. Soc. 2005, 127, 2725. (b) Bowman, R. K.; Johnson, J. S. Org. Lett.
2006, 8, 573.
Chem. ReV. 1986, 86, 795. (b) Faul, M. M.; Huff, B. E. Chem. ReV. 2000,
100, 2407
.
10.1021/ol102499r  2010 American Chemical Society
Published on Web 11/23/2010

the reaction between this type of dinucleophile and
bromonitrostyrene8d 2 could lead to the targeted dihydrofuran
3 (Scheme 1). The proposed reaction sequence would involve
was obtained when the bifunctional thiourea 4 was used as
the catalyst in chloroform at -20 °C (Table 1, entry 1).
Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Synthetic Approach to Dihydrofurans
entry
base
None
KOAc
K2CO3
Pyridine
Lutidine
DMAP
DABCO
Et2NH
Et3N
TMEDA
TMEDA
TMEDA
yield (%)
ee (%)
1
2
3
4
5
6
7
8
20
54
86
59
63
78
68
59
58
82
89
88
77
6
the enantiocontrolled Michael addition of diketone 1 to the
(E)-ꢀ,ꢀ-bromonitrostyrene 2a, followed by the diastereose-
lective cyclization requiring nucleophilic substitution of the
bromide to yield the desired polysubstituted dihydrofurans.
Furthermore, it was hoped that the chiral induction may be
achieved by activation of the bromonitrostyrene employing
a hydrogen bond donor catalyst.9
78
58
74
70
0
68
66
82
81
80
9
To verify this hypothesis, we conducted a series of
reactions between the dimedone 1a and the (E)-ꢀ,ꢀ-bro-
monitrostyrene 2a using different bifunctional cinchona
alkaloid catalysts.10,11 In all cases formation of the product
3a was observed but the best enantioselectivity (77% ee)
10
11b
12c
a Reactions were run on 0.4 mmol scale using diketone (1.0 equiv),
bromonitrostyrene (1.0 equiv), thiourea catalyst 4 (10 mol %), base (10
mol %) in CHCl3 (0.2 M) at -20 °C for 48 h. b TMEDA (20 mol %) was
used. c TMEDA (20 mol %) and 20 mol % catalyst 4 were used.
(5) (a) Evans, D. A.; Sweeney, Z. K.; Rovis, T.; Tedrow, J. S. J. Am.
Chem. Soc. 2001, 123, 12095. (b) Son, S.; Fu, G. C. J. Am. Chem. Soc.
2007, 129, 1046. (c) Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi, T.
Organometallics 1993, 12, 4188. Both metal and chiral auxiliary are used
in this example: (d) Davies, H. M. L.; Ahmed, G.; Calvo, R. L.; Churchill,
M. R.; Churchill, D. G. J. Org. Chem. 1998, 63, 2641. (e) Mu¨ller, P.;
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S. Y. Chin. Chem. Lett. 2010, 21, 167.
However, the yields and conversions to the cyclic com-
pound 3a remained poor. Furthermore, lower temperatures
caused the reaction to proceed slowly without increasing
(11) Selected recent examples for the use of cinchona alkaloid derived
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(10) For pioneering work in the field of cinchona alkaloid derived
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Org. Lett. 2005, 7, 1967. (b) Ye, J.; Dixon, D. J.; Hynes, P. Chem. Commun.
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.
Org. Lett., Vol. 12, No. 24, 2010
5681

Table 2. Reaction between Dimedone 1a and Various
ꢀ,ꢀ-Bromonitrostyrenesa
Table 3. Reaction between 1,3-Diketone Derivatives and
ꢀ,ꢀ-Bromonitrostyrene 2aa
a Reactions were run on 0.4 mmol scale using diketone (1 equiv),
bromonitrostyrene (1 equiv), thiourea catalyst 4 (10 mol %), TMEDA (20
mol %) in CHCl3 (0.2 M) at -20 °C. b ee values in brackets are obtained
after one recrystallization using isopropanol. c Obtained as a 1:1 mixture
of regioisomeres. d Reaction was carried out at 0 °C without base.
either the enantiomeric excesses or the yields. Looking closer
at the reaction mechanism, we considered that the liberation
of bromhydric acid in the reaction medium could be
detrimental to the good activity of the catalyst due to the
possible protonation of its basic sites. Thus, many different
base additives were used in order to trap the liberated acid.
When one equivalent was used, a significant drop in
enantioselectivity was observed yet the conversion increased.
Therefore, we investigated the amount and nature of the base
needed for the reaction. Interestingly the best results were
obtained when 20 mol % of tetramethylethylenediamine
(TMEDA) were used in combination with either 10 mol %
(Table 1, entry 11) or 20 mol % (Table 1, entry 12) of the
bifunctional thiourea.12-14 This resulted in the formation of
a Reactions were run on 0.4 mmol scale using diketone (1 equiv),
bromonitrostyrene (1 equiv), thiourea catalyst (10 mol %), TMEDA (20
mol %) in CHCl3 (0.2 M) at -20 °C. b ee values in brackets are obtained
after one recrystallization using isopropanol.
5682
Org. Lett., Vol. 12, No. 24, 2010

the desired product as a single diastereoisomer in 89% yield
and with 81% enantiomeric excess.
The versatile inorganic base K2CO3 can also be used in
20 mol % quantity as it gives similar results with regard to
yield and enantioselectivity (Table 1, entry 3). With the
optimal conditions in hand, we carried out a series of
experiments using variously substituted bromonitrostyrenes
(Table 2). Both electron-rich and electron withdrawing
groups were well tolerated at the ortho, meta or para position
of the phenyl ring. In general the yields were consistently
good; the lowest of which was 70% for the m-bromo
substituted styrene (Table 2, entry 6). Enantiomeric excesses
were all in the 80-90% range. Only in the case of the bulky
2-naphthyl substituent was a slight decrease observed.
The above enantioselectivies were obtained from the
compounds when they were fully dissolved. When we
initially carried out our analysis with the typical HPLC
sample solvent, isopropanol, crystallization occurred and the
enantiomeric excess increased to more than 97% ee. There-
fore, we recrystallized all the compounds using isopropanol
and obtained the dihydrofurans in good yields and with
excellent enantioselectivities throughout.
To explore the scope of the reaction, further experiments
were conducted using different dicarbonyl derivatives. The
results are reported in Table 3.
The simple cyclohexanedione 1b (Table 3, entry 1) gave
results comparable with dimedone 1a. The hydroxy coumarin
1c (Table 3, entry 2) and its lactam analog 1d (Table 3, entry
3) reacted well with the bromonitrostyrene to give the
tricyclic compounds 6 (71% yield, 77% ee) and 7 (67% yield,
Figure 1. Molecular structure of 3e. The single crystal has been
obtained from isopropanol. Ellipsoids set at 50% probability.
86% ee) respectively. The lactone 8 (Table 3, entry 4) was
obtained in lower yield (45%) but the enantiomeric excess
remained good. When the hydroxyquinone 1f was used in
the reaction two products were obtained in a 1:1 ratio. These
compounds were identified as the two regioisomers 9a and
9b and they were isolated in 37 and 42% yields and with
excellent enantioselectivies of 90 and 92% ee, respectively.
To determine the absolute configuration of the products,
X-ray analysis was performed on a single crystal of
compound 3e bearing a bromine atom on the para position
of the phenyl ring. The configuration was assigned as
(2R,3R).
In summary, we have developed a new enantioselective
Michael addition-nucleophilic substitution reaction that
enables the formation of trans-tetrasubstituted dihydrofuranes
from easily accessible diketones and (E)-ꢀ,ꢀ-bromonitrosty-
renes. The reactions proceed in good yields, with good
enantioselectivities and with high functional group tolerance.
Furthermore, this methodology demonstrates that ꢀ,ꢀ-bro-
monitrostyrenes are useful dielectrophilic synthons in the
field of asymmetric organocatalysis.
(12) Selected examples for the applications of other bifunctional thiourea
catalysts: (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120,
4901. (b) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003,
125, 12672. (c) Berkessel, A.; Cleemann, F.; Mukherjee, S.; Mu¨ller, T. N.;
Lex, J. Angew. Chem., Int. Ed. 2005, 44, 653. (d) Marcelli, T.; van der
Haas, R. N. S.; Van Marseveen, J. H.; Hiemstra, H. Angew. Chem., Int.
Ed. 2006, 45, 929. (e) Tsogoeva, S. B.; Wie, S. Chem. Commun. 2006,
1451. (f) Li, L.; Glauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2008, 130,
12248. (g) Kanta De, C.; Glauber, E. G.; Seidel, D. J. Am. Chem. Soc.
2009, 131, 17060. (h) Bui, T.; Syed, S.; Barbas, C. F., III J. Am. Chem.
Soc. 2009, 131, 8758. (i) Uehara, H.; Barbas, C. F., III Angew. Chem., Int.
Ed. 2009, 48, 9848. (j) Flock, A. M.; Krebs, A.; Bolm, C. Synlett 2010,
1219. (k) Schmitt, E.; Schiffers, I.; Bolm, C. Tetrahedron 2010, 66, 6349.
(l) Vecchione, M. K.; Li, L.; Seidel, D. Chem. Commun. 2010, 46, 4604.
(13) For recent reviews on the application of bifunctional thiourea
catalysts, see: (a) Connon, S. J. Chem. Commun. 2008, 2499. (b) Connon,
S. J. Synlett 2009, 354. (c) Takemoto, Y. Chem. Pharm. Bull. 2010, 58,
593. (d) Kotke, M.; Schreiner, P. R. (Thio)urea organocatalysts. In Hydrogen
Bonding in Organic Synthesis; Pihko, P. M., Ed., Wiley VCH: Weinheim,
2009; pp 141-351.
Acknowledgment. We gratefully acknowledge the DFG
for financial support. A.P. thanks Spanish “Ministerio de
Educacio´n” and U.U. thanks ”Eusko Jaurlaritza-Gobierno
Vasco” for a postdoctoral fellowship.
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(14) Increasing the amount of base additive resulted in lower enanti-
oselectivities.
OL102499R
Org. Lett., Vol. 12, No. 24, 2010
5683