Chiral ruthenium lewis acid catalyzed intramolecular diels - Alder reactions

Article abstract of DOI:10.1021/ol1019103

Single point binding ruthenium Lewis acid catalysts [Ru(acetone)(S,S)- BIPHOP-F)Cp][SbF₆] ((S,S)-1b) and [Ru(acetone)(S,S)-BIPHOP-F) (indenyl)][SbF₆] ((S,S)-1c) efficiently catalyze intramolecular Diels - Alder (IMDA) reactions under mild conditions to afford the endo cycloaddition products as the major product in excellent yields with high diastereo- and enantioselectivities.

Full text of DOI:10.1021/ol1019103

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5604-5607
Chiral Ruthenium Lewis Acid Catalyzed
Intramolecular Diels-Alder Reactions
Sirinporn Thamapipol, Ge´rald Bernardinelli, Ce´line Besnard, and E. Peter Ku¨ndig*
Department of Organic Chemistry, UniVersity of GeneVa, Quai Ernest Ansermet 30,
1211 GeneVa 4, Switzerland
peter.kundig@unige.ch
Received August 13, 2010
ABSTRACT
Single point binding ruthenium Lewis acid catalysts [Ru(acetone)(S,S)-BIPHOP-F)Cp][SbF6] ((S,S)-1b) and [Ru(acetone)(S,S)-BIPHOP-F)-
(indenyl)][SbF6] ((S,S)-1c) efficiently catalyze intramolecular Diels-Alder (IMDA) reactions under mild conditions to afford the endo cycloaddition
products as the major product in excellent yields with high diastereo- and enantioselectivities.
Cycloaddition reactions with their potential for a high degree
of stereo- and regio-control are arguably the most versatile
reactions for the construction of five- and six-membered
rings. Spectacular asymmetric versions have been achieved
by using chiral Lewis acid catalysts.1 Our studies in this area
focused on one-point binding chiral iron and ruthenium
Lewis acids that are based on structurally well-defined
monocationic half-sandwich complexes that incorporate a C2-
Figure 1. Single-point binding chiral Ru Lewis acid catalysts.
symmetric perfluoroaryl phosphinite ligand (Figure 1).
These mild chiral Lewis acids proved to be excellent
catalysts for the conjugate addition of thiophenols to enones,2
intermolecular Diels-Alder reactions of dienes with enals3
and enones,4 and 1,3-dipolar cycloadditions with nitrones5
and nitrile oxides.5a,6
In this communication, we extend the application of
catalysts (S,S)-1b and (S,S)-1c to the intramolecular
(3) (a) Ku¨ndig, E. P.; Alezra, V.; Bernardinelli, G.; Corminboeuf, C.;
Frey, U.; Merbach, A. E.; Saudan, C. M.; Viton, F.; Weber, J. J. Am. Chem.
Soc. 2004, 126, 4843. (b) Ku¨ndig, E. P.; Anil Kumar, P. G.; Pregosin, P. S.;
Vallet, M.; Bernardinelli, G.; Jazzar, R. F.; Viton, F. Organometallics 2004,
23, 5410. (c) Ku¨ndig, E. P.; Saudan, C. M.; Alezra, V.; Viton, F.;
Bernardinelli, G. Angew. Chem., Int. Ed. 2001, 40, 4481. (d) Ku¨ndig, E. P.;
Saudan, C. M.; Viton, F. AdV. Synth. Catal. 2001, 343, 51. (e) Ku¨ndig,
E. P.; Saudan, C. M.; Bernardinelli, G. Angew. Chem., Int. Ed. 1999, 38,
1220. (f) Ku¨ndig, E. P.; Bruin, M. E. Chem. Commun. 1998, 2635. (g)
Ku¨ndig, E. P.; Bourdin, B.; Bernardinelli, G. Angew. Chem., Int. Ed. 1994,
33, 1856.
(1) (a) Reymond, S.; Cossy, J. Chem. ReV. 2008, 108, 5359. (b) Shen,
J.; Tan, C.-H. Org. Biomol. Chem. 2007, 6, 3229. (c) Corey, E. J. Angew.
Chem., Int. Ed. 2002, 41, 1650. (d) Dias, L. C. J. Braz. Chem. Soc. 1997,
8, 289. (e) Ishihara, K.; Yamamoto, H. AdVances in Catalytic Process;
Doyle, M., Ed.; JAI Press: London, United Kingdom, 1995; Vol. 1, pp 29.
(f) Evans, D. A.; Johnson, J. S. ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, Germany,
1999; Vol. 3, Chapter 33.1.
(2) Ku¨ndig, E. P.; Ba˘doiu, A.; Bernardinelli, G.; Besnard, C. Org.
Biomol. Chem. 2010, 8, 193.
(4) Ku¨ndig, E. P.; Rickerby, J.; Vallet, M.; Bernardinelli, G.; Viton, F.
Chem.sEur. J. 2007, 13, 3354.
10.1021/ol1019103  2010 American Chemical Society
Published on Web 11/17/2010

Scheme 1
.
Synthesis of Bridgehead Adduct 8
Scheme 3. Synthesis of Trienes 5 and 6
Diels-Alder (IMDA) reaction. A first example was
reported previously and involved trienone 2 and (R,R)-
1b as catalyst to construct the bicyclic adduct (R)-8
(Scheme 1).4,7 This result encouraged us to explore the
IMDA reaction of trienes 3-7 (Figure 2).
The keto-triene 7 was prepared from ester 10 in high yield
via the Weinreb amide 18 and reaction with MeMgBr
(Scheme 4).
Figure 2. Trienes for the asymmetric IMDA reaction.
Scheme 4. Synthesis of Triene 7
Horner-Wadsworth-Emmons reaction of aldehyde 98a,b
with methyldiethylphosphonoacetate and triethylphospho-
nopropionate, respectively, afforded R,ꢀ-(E)-unsaturated
esters 108c and 11 in good yield (Scheme 2). A reduction/
oxidation sequence afforded trienes 39a,b and 49c in excellent
yield.
The results of IMDA reactions catalyzed by Lewis acids
(S,S)-1b and (S,S)-1c are detailed in Table 1. Trienes 3 and
4 gave the cycloadducts 19 and 20 (entries 1-4), in good
yields with high enantioselectivities albeit long reaction times
were required. Whereas 19 was obtained with excellent endo-
diastereoselectivity, the endo/exo ratio was somewhat lower
for 20 (entries 3-4). Both catalysts gave similar results
though reaction times to completion were generally shorter
for catalyst (S,S)-1c.
Scheme 2.
Synthesisa of Trienes 39a,b and 49c
a Reagents and conditions: (a) NaH, THF, rt, then methyl dieth-
ylphosphonoacetate for 10 or triethylphosphono-propionate for 11; (b)
DIBALH, Et2O, 0 °C, 2 h; (c) MnO2, CH2Cl2, rt, 1 h.
As expected, the IMDA reactions of trienes 5 and 6 were
more efficient (Thorpe-Ingold effect11) (entries 5-8) and
reaction times were reduced from days to hours. Trienes 3
Trienes 5 and 6 were synthesized by using two sequential
alkylations of dimethylmalonate followed by selective sa-
ponification and oxidation (Scheme 3).10
(8) (a) Spino, C.; Crawford, J.; Bishop, J. J. Org. Chem. 1995, 60, 844.
(b) Spino, C.; Crawford, J. Tetrahedron Lett. 1994, 35, 5559. (c) Roush,
W. R.; Gillis, H. R.; Ko, A. I. J. Chem. Am. Soc. 1982, 104, 2269.
(9) (a) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Am. Chem. Soc.
1998, 120, 6920. (b) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Am. Chem.
Soc. 1996, 118, 3049. (c) Furuta, K.; Kanematsu, A.; Yamamoto, H.
Tetrahedron Lett. 1989, 30, 7231.
(5) (a) Ku¨ndig, E. P.; Ba˘doiu, A.; Brinkmann, Y.; Viton, F. Pure. Appl.
Chem. 2008, 80, 1013. (b) Ku¨ndig, E. P.; Ba˘doiu, A.; Bernardinelli, G.;
Mareda, J.; Viton, F. Chem. Asian. J. 2008, 3, 1298. (c) Ku¨ndig, E. P.;
Viton, F.; Bernardinelli, G. J. Am. Chem. Soc. 2002, 124, 4969.
(6) Ku¨ndig, E. P.; Brinkmann, Y.; Madhushaw, R. J.; Jazzar, R.;
Bernardinelli, G. Tetrahedron 2007, 63, 8413.
(10) Carrying out the synthesis of 17 analoguously to that of 15 afforded
an inseparable mixture of SN2, SN2′, and SN2′′ reaction products, hence the
modification.
(11) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc., Trans.
1915, 107, 1080.
(7) Rac-8 was a key intermediate in the synthesis of Ledol: (a) Gwaltney,
S. L.; Sakata, S. T.; Shea, K. J. J. Org. Chem. 1996, 61, 7437. (b) Gwaltney,
S. L.; Shea, K. J. Tetrahedron Lett. 1996, 37, 949.
Org. Lett., Vol. 12, No. 24, 2010
5605

Table 1. Enantioselective IMDA Reaction with Chiral Ru Lewis Acids
entry
triene
catalyst
2,6-lutidine (mol %)
timeb
productc
yield (%)d
endo/exo
ee (%)
1
2
3
4
5
6
7
8
9
3
3
4
4
5
5
6
6
7
7
(S,S)-1b
(S,S)-1c
(S,S)-1b
(S,S)-1c
(S,S)-1b
(S,S)-1c
(S,S)-1b
(S,S)-1c
(S,S)-1b
(S,S)-1c
2
2
2
2
5
5
5
5
2
2
9 d
7 d
7 d
6 d
5 h
4 h
5 h
4 h
7 d
7 d
19 R ) R1 ) R2 ) Z ) H
82
92
82
85
quant
quant
quant
quant
10
99/1
99/1
84/16
81/19
99/1
99/1
99/1
99/1
99/1
99/1
72e
19 R ) R1 ) R2 ) Z ) H
84e
20 R ) R1 ) Z ) H, R2 ) Me
20 R ) R1 ) Z ) H, R2 ) Me
21 R ) R1 ) R2 ) H, Z ) CO2Me
21 R ) R1 ) R2 ) H, Z ) CO2Me
22 R ) R2 ) H, R1 ) Me, Z ) CO2Me
22 R ) R2 ) H, R1 ) Me, Z ) CO2Me
23 R ) Me, R1 ) R2 ) Z ) H
23 R ) Me, R1 ) R2 ) Z ) H
92, 91f
84, 90f
43g
84g
55h
56h
0i
10
12
0i
a All reactions were carried out in 0.15-0.30 M concentration. 2,6-Lutidine (2-5 mol %) was added to scavenge acid impurities. Results shown are the
average of a minimum of three experiments. b IMDA reactions of 3, 4, and 7 were followed by TLC and 5 and 6 by IR. c Racemic reactions of 3, 4, and
7 were performd with AlEt2Cl and 5 and 6 with SiO2. d Isolated yield. e ee of endo-isomer, determined by GC analysis. f ee of exo-isomer, determined by
g
1
GC analysis. ee, determined by H NMR of its chiral amine derivative (see Supporting Information); 4% conversion was observed for the background
reaction in the absence of catalyst. h Twenty-six percent conversion was observed for the background reaction in the absence of catalyst. i Eight percent
conversion was observed for the background reaction in the absence of catalyst.
and 5 provided adducts 19 and 21 with higher ee using (S,S)-
1c than with (S,S)-1b. In the case of triene 6, both Ru
catalysts afforded adduct 22 with modest ee because of the
high background reaction of this triene as mentioned in
footnote h of Table 1.
(R)-1-phenylethanamine as crystallization partner (Figure
3). The structure shows that the ring junction is trans-
configured and consequently, 19 is the endo-isomer with
(3aR,4R,7aS)-configuration.
IMDA reaction conditions of triene 7 (entries 9-10) were
screened but under all conditions adduct 23 was obtained in
racemic form. This presumably reflects the lower reactivity
of keto-dienophiles compared to the aldehyde substrates.
Trienals 3 and 4 were used previously by Yamamoto and
co-workers in the IMDA reaction with the chiral boron Lewis
acids BLA9a,b and CAB.9c The absolute configuration of
adduct 19 (with (S,S)-1c, 84% ee) was initially established
by comparison with the literature data9b in which the endo-
isomer was described as the major adduct.12 But the aldehyde
protons of endo and exo-isomers of 19 are extremely close
(δexo 9.67 and δendo 9.69) and difficult to distinguish. Bicyclic
aldehyde 19 was therefore submitted to Pinnick oxidation13
(Scheme 5). In addition to oxidizing the aldehyde function,
Figure 3.
X-ray structure of carboxylate salt 24.14
Scheme 5. Synthesis of Carboxylate 24
Adducts 19-22 were converted to their corresponding
hydrazones 25-28 (Scheme 6) because their CD spectra
could not be measured due to the overlap of the aldehyde
peak with the solvent peak. The absolute configurations of
26-28 were assigned based on comparison of their the CD
spectra with that of 25 (see Supporting Information).
(12) Lit. correction: The structure and the name of the endo product in
the Supporting Information of ref 9b was interchanged and the wrong
structure was accidently drawn in ref 9a. E-mail correspondance with K.
Ishihara.
we observed concomitant chlorohydroxylation of the alkene.
Crystals suitable for X-ray analysis of 24 were obtained using
5606
Org. Lett., Vol. 12, No. 24, 2010

Scheme 6. Synthesis of Hydrozones 25-28
X-ray structures of chiral Ru Lewis acid/substrate com-
plexes were instrumental for the interpretation of observed
selectivities in cycloaddition reactions.2-6 For the IMDA
reaction involving triene 3 the diene approach leading to the
observed endo product 19 was modeled using the X-ray
structure of (S,S)-1c. It is proposed that the enal dienophile
(orange) coordinates to the Ru in an anti-s-trans conforma-
tion and the diene (blue) approaches the Re-face of the enal
moiety in an endo mode. The Si-face is shielded by the
pentafluorophenyl moiety of the (S,S)-BIPHOP-F ligand
(Figure 4). This results in the observed product stereochem-
istry of 19.
Figure 4. Modeled approach of trienal 3 coordinated to Ru in (S,S)-
1c in an anti-s-trans orientation (catalyst part taken from the X-ray
structure of [Ru(acetone)(S,S)-BIPHOP-F)Ind][SbF6] ((S,S)-1c).3c
Projection onto the CR-Re face of the enal and showing the endo
approach of diene. This model rationalizes the product’s (3aR,4R,7aS)-
configuration.
Background reactions apart, we presume the product ee
to reflect the competition between the two possible orienta-
tions of the coordinated dienophile (anti-s-trans or syn-s-
trans). In intramolecular DA reactions of enals, the anti-s-
trans conformation always dominates, though syn-s-trans
coordination in the transition state is operative in conjugate
addition of thiophenols to enones,2 and in intermolecular DA
reactions of some diene/enone reactions4 with these catalysts.
IMDA reaction of trienes 3 and 5 catalyzed by (S,S)-1b
afford adducts 19 and 21, respectively, in lower ee than the
reactions catalyzed by (S,S)-1c (compare entries 1 and 2,
respectively 5 and 6). It can be argued that this is because
the indenyl roof of 1c more strongly disfavors a reaction
occurring Via a syn-s-trans coordinated dienophile.
The favored anti-s-trans conformation then leads to a
product in higher ee. For triene 4 (entries 3 and 4), the
R-methyl substituent enforces the anti-s-trans conformation.
In conclusion, the chiral Ru Lewis acids (S,S)-1b and (S,S)-
1c can satisfactorily catalyze diastereo- and enantioselective
IMDA reactions of suitable trienes. This method allows the
formation of highly enantiomerically enriched bicyclic
products of potential use in synthesis.
Acknowledgment. We thank the Swiss National Science
Foundation and the University of Geneva for financial
support and Dr. Bettina Bressel for help with the manuscript.
Supporting Information Available: Details of experi-
mental procedures and spectroscopic characterization (1H and
13C NMR, IR, and HRMS) of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981,
37, 2091.
(14) CCDC-789209 contains the supplementary crytallographic data for
24. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre (CCDC) via http://www.ccdc.cam.ac.uk/
data_reguest/cif.
OL1019103
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