Asymmetric Diels-Alder reactions of unsaturated β-ketoesters catalyzed by chiral ruthenium PNNP complexes

Article abstract of DOI:10.1021/ja910039e

Chemical equation presented Cyclic α-unsaturated β-ketoesters undergo cycloaddition with di- and trisubstituted butadienes to give tetrahydro-1-indanone derivatives with up to 93% ee in the presence of a ruthenium catalyst formed by activation of [RuCl2(PNNP)] with (Et3O)PF6 (2 equiv) (PNNP = (1S,2S)-N,N -bis[o-(diphenylphosphino)benzylidene]cyclohexane-1, 2-diamine). The protocol has been used to prepare the estrone derivative (8R,13S,14S)-13-tert-butoxycarbonyl-3-methoxy- 7,8,12,13,15,16-hexahydro-6H- cyclopenta[a]phenanthren-17(14H)-one as a single diastereoisomer with 85% yield and 99% ee after one crystallization step. Its absolute configuration, which has been determined by X-ray diffraction after reduction to the alcohol and esterification with camphanic chloride, is in agreement with the attack of the diene onto the open enantioface of the β-keto ester (O-O) in the ruthenium complex [Ru(O-O)(PNNP)]2+, whose X-ray structure has been determined.

Full text of DOI:10.1021/ja910039e

Published on Web 01/12/2010
Asymmetric Diels-Alder Reactions of Unsaturated ꢀ-Ketoesters Catalyzed by
Chiral Ruthenium PNNP Complexes
Christoph Schotes and Antonio Mezzetti*
Department of Chemistry and Applied Biosciences, ETH Zu¨rich, CH-8093 Zu¨rich, Switzerland
Received December 2, 2009; E-mail: mezzetti@inorg.chem.ethz.ch
Scheme 1. Diels-Alder Reactions of Unsaturated ꢀ-Ketoesters
The enantioselective formation of all-carbon quaternary centers
is an area of intense research in which Diels-Alder reactions play
a major role.1 As a possible alternative to R,ꢀ-unsaturated alde-
hydes, doubly activated R-methylene ꢀ-ketoesters have been
employed as dienophiles.2 However, more bulky unsaturated
ꢀ-ketoesters, such as cyclic carboxypentenones, are much less
reactive dienophiles and challenge the known protocols due to their
tendency to polymerization and keto-enol tautomerization.3 Ad-
ditionally, the corresponding tetrahydro-1-indanones are formed in
low yield under harsh conditions,4 and to the best of our knowledge,
no enantioselective synthesis has been reported yet. We report here
that our dicationic ruthenium PNNP complexes,5 which efficiently
catalyze the asymmetric Michael addition,6 hydroxylation,7 and
fluorination8 of saturated ꢀ-ketoesters, also promote the enantiose-
lective Diels-Alder reaction of R-methylene ꢀ-keto esters to give
tetrahydro-1-indanones. In particular, we show that the methodology
gives access to enantiomerically pure ent- (or nat-) estrone
derivatives, which is interesting in view of the application potential
of these compounds, including the treatment of breast cancer.9
Table 1. Asymmetric Diels-Alder Reaction with 3a-c and Dienes
4-6a
entry
dienophile
diene
product
R1
R2
yield
ee
1
2
3
3a
3b
3c
3a
3b
3c
3a
3b
3c
3a
3c
4
4
4
5
5
5
6
6
7a
7b
7c
8a
8b
8c
9a
9b
9c
11a
11c
tBu
Et
Me
tBu
Et
Me
tBu
Et
Me
tBu
Me
OBn
OBn
OBn
OMe
OMe
OMe
Me
91
99
90
86
92
62
82
87
88
85d
56d
93
77
76
64
84
66
67
60
69
99d
99d
4b
5b
6b
7c
8c
10c
11
12
The catalyst is formed in situ by double chloride abstraction from
[RuCl2(PNNP)] (1) with (Et3O)PF6 (2 equiv) in dichloromethane,
which gives the putative dicationic species [Ru(OEt2)2(PNNP)]-
(PF6)2 (2).6 Complex 2 catalyzes the Diels-Alder reaction of the
unsaturated ꢀ-ketoesters of type 3 with dienes 4-6, to give the
alkoxycarbonyltetrahydro-1-indanone derivatives 7-9 (Scheme 1).
This is the first enantioselective synthesis of 7-9, which are
versatile intermediates as they contain multiple, separately addres-
sable reaction sites besides the ꢀ-ketoester functionality.10 Of these
products, only 9c has been previously prepared, though with low
yield and using harsh conditions.4 Preliminary studies showed that
2,3-dimethylbutadiene (6) can be used as a diene, but the best results
were obtained with 2,3-(dibenzyloxy)butadiene (4) and 2,3-
dimethoxybutadiene (5). With diene 4, cyclopentanone derivatives
of type 7 were formed with enantioselectivity of up to 93% ee
(Table 1).11
Me
Me
6
10
10
a A Et2O solution (1 mL) of 3a-c (0.12 mmol) and, after 10 min, the
diene 4 or 6 (0.13-1.2 mmol) were added to catalyst 2 (prepared from
1 (12.1 µmol) and Et3OPF6 (25.0 µmol) overnight in CH2Cl2 (1 mL)).
All reactions were quenched after 24 h by addition of Bu4NCl and were
run at least twice with identical results (within experimental error).
b Diene 5 was added in three portions of 0.12 mmol (see Supporting
Information). c In pure CH2Cl2. d After crystallization from 2-propanol.
Scheme 2. Synthesis of the Estrone Precursor 11
A useful application of this method is the synthesis of the estrone
derivative 11 from 3a (or 3c) and the unsymmetrical Dane’s diene
10 (Scheme 2). Catalyst 2 gave crude 11a as a single regioisomer
of the ester-exo diastereoisomer (as determined by X-ray; see
Supporting Information) in quantitative yield and 86% ee. Enan-
tiomerically pure 11a was obtained in 85% yield (based on 3a,
after recrystallization from 2-PrOH). The exo/endo ratio of crude
11a is 27:1 (145:1 after one crystallization) as compared to methyl
As Corey has recently reported a procedure to convert the 18-
C-methyl analogue of 11 (R2 ) Me) (prepared with high enanti-
oselectivity via a chiral boron catalyst) to estrone methyl ether,13
the reaction in Scheme 2 is potentially useful in the synthesis of
enantiomerically pure estrone derivatives functionalzed at the
R-carbonyl bridghead position, which are of biomedical interest.
Although such molecules are known from nature, the difficulty of
introducing substituents at the bridgehead position, as opposed to
other locations in the molecule, has restricted the number of
synthetically available estrones of this class in comparison to those
in other steroid classes.14
t
analogue 11c (3:1), which indicates that the Bu ester moiety on
3a is pivotal to give excellent diastereoselectivity for the ester exo
product. The absolute configuration of 11a was shown to be
8R,13S,14S by reducing the enantiomerically pure product with
NaBH4 to the corresponding alcohol 13. Esterification with (1S,4R)-
(-)-camphanic chloride gave (1S,4R,8′R,13′S,14′S,17′S)-14, whose
X-ray structure was determined (Scheme 3).12
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3652 J. AM. CHEM. SOC. 2010, 132, 3652–3653
10.1021/ja910039e  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Determination of the Absolute Configuration of 11a
The highly regio- and diastereoselective formation of 11a
indicates that diene 10 approaches with the bicyclic moiety directed
away from the PNNP ligand and away from the bulky Bu group
t
of the dienophile. This arrangement in the pericyclic transition state
leads to the observed ester exo product.
In conclusion, we have described a ruthenium/PNNP-catalyzed
asymmetric Diels-Alder reaction that converts unsaturated ꢀ-ke-
toesters into multifunctional tetrahydro-1-indanone derivatives, most
of which have not been reported before, under mild conditions and
with high regio-, diastereo-, and enantioselectivity. This approach
allows the first enantioselective synthesis of both nat- and ent-
entiomers of an estrone derivative bearing an ester functionality at
the R-carbonyl bridgehead position.
To gain mechanistic insight into the reaction, we studied the
coordination of substrates 3a-c (1 equiv) to the ruthenium/ PNNP
moiety. Double chloride abstraction from 1 with (Et3O)PF6 (2
equiv), followed by addition of the ꢀ-keto ester (1 equiv), yields
the dicationic ruthenium(II) complexes [Ru(3,κO,O)(PNNP)]2+ (12).
We isolated and fully characterized 12a,15 which is formed from
substrate 3a as a single diastereoisomer (Scheme 4).16
Acknowledgment. We thank Dr. Martin Althaus for the
synthesis and characterization of complex 12a and Mrs. Katrin
Niedermann, Mr. Pietro Butti, and Mr. Raphael Aardoom for the
X-ray structure determinations.
Supporting Information Available: Detailed experimental proce-
dures and CIF files of 12a and (1S,4R,8′R,13′S,14′S,17′S)-14. This
material is available free of charge via the Internet at http://pubs.acs.org.
Scheme 4. Dicationic Adduct 12a of ꢀ-Ketoester 3a
References
(1) Trost, B. M.; Jiang, C. Synthesis 2006, 369.
(2) (a) Honda, Y.; Date, T.; Hiramatsu, H.; Yamauchi, M. Chem. Commun.
1997, 1411. (b) Yamauchi, M.; Aoki, T.; Li, M. Z.; Honda, Y. Tetrahedron:
Asymmetry 2001, 12, 3113.
(3) Bernardi, A.; Colombo, G.; Scolastico, C. Tetrahedron Lett. 1996, 37, 8921.
(4) Marx, J. N.; Cox, J. H.; Norman, L. R. J. Org. Chem. 1972, 37, 4489.
(5) PNNP ) (1S,2S)-N,N′-bis[o-(diphenylphosphino)benzylidene]cyclohexane-
1,2-diamine.
(6) (a) Althaus, M.; Bonaccorsi, C.; Mezzetti, A.; Santoro, F. Organometallics
2006, 25, 3108. (b) Santoro, F.; Althaus, M.; Bonaccorsi, C.; Gischig, S.;
Mezzetti, A. Organometallics 2008, 27, 3866.
The X-ray structure of 12a shows that the lower face of the
substrate is shielded by one of the phenyl rings of the PNNP ligand
(Figure 1).17 In combination with the absolute configurations of
9c and 11a, we conclude that the diene attacks the open re
enantioface of the metal-bound dienophile in a higly enantioselective
fashion. An analogous shielding of the si enantioface of the
coordinated substrate has been observed in the ruthenium/PNNP
complexes of saturated ꢀ-keto esters.6,8
(7) Toullec, P. Y.; Bonaccorsi, C.; Mezzetti, A.; Togni, A. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5810.
(8) Althaus, M.; Becker, C.; Togni, A.; Mezzetti, A. Organometallics 2007,
26, 5902.
(9) (a) Review article: Biellmann, J. F. Chem. ReV. 2003, 103, 2019. (b) Seminal
paper: Terenius, L. Acta Endrocrinol. 1971, 66, 43.
(10) Benetti, S.; Romagnoli, R.; De Risi, C.; Spalluto, G.; Zanirato, V. Chem.
ReV. 1995, 95, 1065.
(11) Preliminary tests with cyclopentadiene gave racemic Diels-Alder products
along with poly- or oligomers of the diene (see Supporting Information).
(12) The absolute configuration of 9c was determined similarly (see Supporting
Information); those of the remaining products are assigned by analogy.
(13) (a) Yeung, Y. Y.; Chein, R. J.; Corey, E. J. J. Am. Chem. Soc. 2007, 129,
10346. (b) Canales, E.; Corey, E. J. Org. Lett. 2008, 10, 3271.
(14) See Pillai, K. M. R.; Murray, W. V.; Shooshani, I.; Williams, D. L.; Gordon,
D.; Wang, S. Y.; Johnson, F. J. Med. Chem. 1984, 27, 1131, and ref 1
therein.
(15) Data of 12a: 31P NMR (101.3 MHz, CH2Cl2): δ 63.4 (d, 1P, JP,P′ ) 31.2
Hz), 52.5 (d, 1P, JP,P′ ) 31.2 Hz). Analysis calcd for C54H55F6N2O3P3Ru:
C, 59.61; H, 5.09; N, 2.57. Found: C, 59.86; H, 5.20; N, 2.54.
(16) Addition of 3b or 3c to a solution of 2 results in the formation of one
additional species, which is believed to be a different diasteroisomer of
the corresponding complexes 12b and 12c (see Supporting Information).
j
(17) Crystal data of 12a: C56H88Cl4F12N2O3P4Ru, triclinic, P1, a ) 11.5110(7)
Å, b ) 13.8903(8) Å, c ) 20.6616(12) Å, R ) 96.886(1)°, ꢀ ) 93.755(1)°,
γ ) 113.085(1)°, V ) 2994.2(3) Å3, Z ) 2, T ) 200 K, Dc ) 1.555 Mg/
m3, µ ) 0.630 mm-1 (Mo KR, graphite monochromated), λ ) 0.710 73 Å,
F(000) ) 1424, 26 500 data collected at 200 K on a Bruker AXS SMART
APEX platform in the θ range 1.00°-26.02°, 11 770 independent reflections
(Rint ) 0.0252), R1 ) 0.0504 (for 10 527 reflections with I > 2σ(I)) and
wR2 ) 0.133724 (all data), GOF ) 1.021. Max and min difference peaks
+1.26 and-0.76 eÅ-3, largest and mean ∆/σ ) 0.001 and 0.000.
Figure 1. ORTEP drawing of 12a. Selected distances (Å): Ru-P(1)
2.2973(8), Ru-P(2) 2.2692(8), Ru-N(1) 2.047(3), Ru-N(2) 2.083(3),
Ru-O(1) 2.107(2), Ru-O(2) 2.172(2), C(48)-C(49) 1.339(5) Å.
JA910039E
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