Au(I)-catalyzed enantioselective 1,3-dipolar cycloadditions of muenchnones with electron-deficient alkenes

Article abstract of DOI:10.1021/ja074824t

The first catalytic enantioselective 1,3-dipolar cycloaddition of muenchnone dipoles with electron-deficent alkenes is described. The reaction is catalyzed by chiral bis(phosphine)gold(I) benzoate complexes and provides Δ¹-pyrrolines with excellent regio-, diastereo-, and enantioselectivity. The reaction is proposed to proceed througha 1,3-dipole generated by deprotonation of a gold(I)-activated azlactone. Copyright

Full text of DOI:10.1021/ja074824t

Published on Web 09/28/2007
Au(I)-Catalyzed Enantioselective 1,3-Dipolar Cycloadditions of Mu2nchnones
with Electron-Deficient Alkenes
Asa D. Melhado, Marco Luparia, and F. Dean Toste*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received July 17, 2007; E-mail: fdtoste@berkeley.edu
Table 1. Development of the Au(I)-Catalyzed Cycloadditiona
Synthetic methods relying on gold complexes as catalysts have
recently been the focus of intense development.1 Despite numerous
advances, relatively few enantioselective gold-catalyzed transforma-
tions have been described. The earliest example of an enantiose-
lective gold(I)-catalyzed transformation, the Hayashi-Ito aldol
reaction, was proposed to rely on activation of the nucleophile as
a chiral monophosphineAu(I) enolate.2 In contrast, the majority of
recently reported methods rely on the electrophilic nature of cationic
bisphosphinegold(I) complexes to activate π-bonds toward addition
of nucleophiles.3 Therefore, the utility of chiral bisphosphinegold-
(I) complexes would be signficantly extended if they could be
employed as catalysts for enantioselective transformations that are
not predicated on π-bond activation. To this end, herein we describe
the development of a bisphosphinegold(I)-catalyzed enantioselective
1,3-dipolar cycloaddition4 reaction of mesoionic azomethine ylides
(mu¨nchnones) with alkenes.
We were inspired by Tepe’s recent report of silver(I)acetate-
catalyzed mu¨nchnone/alkene 1,3-dipolar cycloadditions,5,6 to con-
sider the use of our recently developed bisphosphinegold(I)
carboxylate complexes as catalysts for this transformation.3c
Gratifyingly, treatment of a THF solution of azlactone 1a and 1.5
equiv of N-phenylmaleimide (3) with 2 mol % triphenylphosphi-
negold(I) benzoate at room temperature, followed by in situ
esterification, afforded the desired ∆1-pyrroline (()-2a in 85% yield
with excellent diastereoselectivity (Table 1, entry 1).
time
(h)
yield
(%)b
ee
entry
catalyst
(%)c
1
2
3
4
5
6
7
8
9
PPh3AuOBz
0.5
2
3
3
3
3
3
7
2
85
78
81
56
80
62
63
81
70
76
-
-8
-40
-44
-5
(R)-BINAP(AuOBz)2
(R)-SEGPHOS(AuOBz)2
(R)-DIFLUOROPHOS(AuOBz)2
(R)-Cl-MeO-BiPHEP(AuOBz)2
(R)-SYNPHOS(AuOBz)2
(R)-3,5-xylyl-BINAP(AuOBz)2
(R)-DTBM-SEGPHOS(AuOBz)2
(S)-Cy-SEGPHOS(AuOBz)2, (4)
4
-55
-24
-83
88
10
5
95d
a Reactions run with 0.33 mmol 1a; for conditions concerning in situ
ester formation see Supporting Information (SI). b Isolated yield. c Absolute
configuration determined by X-ray crystallography on the corresponding
R-methylbenzylamide (see SI). d Reaction performed at 0.5 M in PhF.
Table 2. Reaction of 1a with Various Acyclic Alkenesa
Having established an achiral phosphinegold(I) benzoate as a
catalyst for the formation for 2a, we next focused on the
enantioselective reaction of 1a and 3 (Table 1). In general, the
diphenyl-substituted biarylphosphinegold(I) benzoate complexes
successfully employed in the hydroamination gave modest selectiv-
ity for the reaction of 1a and 3 (entries 2-5). While substitution
on the phosphine aryl ring resulted in improved selectivity (entry
8), we were pleased to find the (S)-Cy-SEGPHOS(AuOBz)2
(4)7-catalyzed cycloaddition gave 2a with a notable increase in
enantioselectivity (88% ee) (entry 9). Further optimization of
reaction conditions revealed that the reaction performed similarly
in various solvents;8 however, employing fluorobenzene (PhF) as
the solvent produced a further improvement and provided 2a in
76% yield and 95% ee (entry 10).9 Notably, in all cases only the
exo-adduct was observed.
entry
product
time (h)
yield (%)b
ee (%)
t
1
2
3
4
5
7a, X ) CO2 Bu
R ) OMe
7b, X ) CO2 Bu R ) NHCH2Ph
7c, X ) CO2Et R ) OMe
7d, X ) CO2Me R ) OMe
7e, X ) CN R ) NHCH2Ph
24
14
14
14
14
56
74
66
89d
68
99c
95
90
93
76
t
a Reactions run with 0.33 mmol 1a at 0.5 M; for conditions concerning
in situ ester/amide formation see SI. b Isolated yield unless otherwise noted.
c Reaction run with 10 equiv of alkene and 2% mol 4. d Yield determined
1
by H NMR.
87% ee (eq 1).10 Acyclic alkenes could also be employed as partners
in the gold(I)-catalyzed cycloaddition (Table 2). Generally, the
reactions performed best using a 3:1 mixture of THF and PhF and
slightly higher catalyst loading (3.5%). Notably, in all cases the
reactions proceeded with excellent diastereo- and regioselectivity.
Various azlactones (1b-j) were prepared, and the results of their
gold(I) benzoate-catalyzed enantioselective cycloaddition with
N-phenylmaleimide are shown in Table 3. Substitution at the para
position of the azlactone aromatic ring was well tolerated (entries
1-4). While increasing the steric demand at the azlactone C2 or
C4 position resulted in decreased reactivity in PhF, switching the
solvent to a mixture of THF and PhF permitted isolation of the
cycloadducts in good yields (entries 5, and 7-9). The use of this
solvent mixture allowed for smooth reaction of azlactone 1f, bearing
A variety of electron-deficient alkenes were found to be viable
dipolarophiles in the gold(I)-catalyzed mu¨nchnone cycloaddition.
For example, 2 mol % gold(I) benzoate 4-catalyzed the reaction of
1a with maleic anhydride (5), under conditions similar to those
used with N-phenylmaleimide to afford acid 6 in 79% yield and
9
12638
J. AM. CHEM. SOC. 2007, 129, 12638-12639
10.1021/ja074824t CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Reaction of N-Phenylmaleimide (3) with Azlactonesa
activated azlactone and therefore represents an important departure
from the mechanistic paradigm of π-activation most commonly
proposed in contemporary asymmetric catalysis with gold com-
plexes. The development of enantioselective reactions relying on
gold(I)-catalyzed generation of nucleophiles is ongoing and will
be reported in due course.
entry
product
time (h)
yield (%)b
ee (%)
Acknowledgment. We gratefully acknowledge NIHGMS (R01
GM073932), Merck Research Laboratories, Bristol-Myers Squibb,
Amgen Inc., DuPont, GlaxoSmithKline, Eli Lilly & Co., Pfizer,
and AstraZeneca for funding. M.L. thanks Italian MIUR for a
graduate fellowship. We thank Takasago International Corporation
for their generous donation of SEGPHOS ligands.
1
2
3
4
5
6
7
8
9
b, R ) Me
c, R ) Me
d, R ) Me
e, R ) Me
f, R ) Me
g, R ) H
Ar ) p-MeO-C6H4-
Ar ) p-Br-C6H4-
Ar ) p-Cl-C6H4-
Ar ) p-NO2C6H4-
Ar ) o-Me-C6H4-
Ar ) Ph
18
15
15
1.5
4
24
8
1.5
36
77
75
72
98
73
84
86
35
71
95
93
92
91
86c
-98d
87c
78e
68c
h, R ) allyl Ar ) Ph
Supporting Information Available: Experimental procedures and
compound characterization data; X-ray crystallgraphic data. This
material is available free of charge via the Internet at http://pubs.acs.org.
i, R ) Ph
j, R ) Bn
Ar ) Ph
Ar ) Ph
a Reactions run with 0.33 mmol azlactone; for conditions concerning in
situ ester formation see SI. b Isolated yield. c Run at 0.5 M in 3:1 THF/
PhF. d At 0.5 M in aceteone, using (R)-DTBM-SEGPHOS(AuOBz)2; note
also the change in the sense of ligand chirality. e Run at 0.25 M in 3:1
THF/PhF at 0 °C with 5% mol 4.
References
(1) For recent reviews see: (a) Jime´nez-Nu´n˜ez, E.; Echavarren, A. M. Chem.
Commun. 2007, 333. (b) Furstner, A.; Davies, P. W. Angew. Chem., Int.
Ed. 2007, 46, 2. (c) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395.
Scheme 1. Proposed Mechanism of Au(I)-Catalyzed 1,3-DCR
(2) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405.
(3) (a) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007,
317, 496. (b) Liu, C.; Widenhoefer, R. A. Org. Lett. 2007, 9, 1935. (c)
LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. J. Am. Chem.
Soc. 2007, 129, 2452. (d) Zhang, Z.; Widenhoefer, R. A. Angew. Chem.,
Int. Ed. 2007, 46, 283. (e) Johansson, M. J.; Gorin, D. J.; Staben, S. T.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 18002. (f) Munoz, M. P.; Adrio,
J.; Carretero, J. C.; Echavarren, A. M. Organometallics 2005, 24, 1293.
(4) For reviews on asymmetric 1,3-dipolar cycloaddition reactions see: (a)
Pellissier, H. Tetrahderon 2007, 3235. (b) Kanemassa, S. Synlett 2002,
1371. (c) Gothelf, K. V. Synthesis 2002, 211. (d) Gothelf, K. V.; Jorgensen,
K. A. Chem. ReV. 1998, 98, 863.
(5) Peddibhotla, S.; Tepe, J. J. Am. Chem. Soc. 2004, 126, 12776.
(6) For selected reports of transition-metal-catalyzed asymmetric azomethine
ylide cycloadditions see: (a) Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am.
Chem. Soc. 2007, 129, 5364. (b) Zeng, W.; Chen, G.-Y.; Zhou, Y.-G.;
Li, Y.-X. J. Am. Chem. Soc. 2007, 129, 705. (c) Cabrera, S.; Arrayas, R.
G.; Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 16394. (d) Zeng, W.;
Zhou, Y.-G. Org. Lett. 2005, 7, 5055. (e) Gao, W.; Zhang, X.; Raghunath,
M. Org. Lett. 2005, 7, 4241. (f) Oderaotoshi, Y.; Cheng, W.; Fujimoto,
S.; Kasano, Y.; Minkata, S.; Komatsu, M. Org. Lett. 2003, 5, 5043. (g)
Chen, C.; Li, X.; Schreiber, S. J. Am. Chem. Soc. 2003, 125, 10174. (h)
Longmire, J.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400.
For a review see: (i) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. ReV.
2006, 106, 4484.
a 2-methylphenyl C2 substituent, providing product 2f in good yield
with 86% ee.11 Similarly, C4 allyl-substituted azlactone 1h under-
went gold(I)-catalyzed cycloaddition to furnish 2h in 86% yield
and 87% ee; however, a decrease in enantioselectivity was observed
with a further increase in the size of the C4 substituent to benzyl
(entry 9). The reaction of 3 with glycine-derived azlactone 1g
catalyzed by 4 produced 2g with only 81% ee. Fortunately,
switching the catalyst to (R)-DTBM-SEGPHOS(AuOBz)2 allowed
for the isolation of cycloadduct 2g in 84% yield and 98% ee
(entry 6).
A proposed catalytic mechanism, paralleling those postulated for
reactions of acyclic azomethine ylides, is shown in Scheme 1.6
Dissociation of a carboxylate counterion from 8 provides an open
coordination site for azlactone binding. Deprotonation of the
activated substrate, presumably by benzoate, generates N-aurated-
dipole 9. Reaction of 9 with the dipolarophile produces initial
cycloadduct 10. Subsequent C-O bond cleavage and protonation
followed by dissociation of the ∆1-pyrroline regenerates the
catalyst.12
(7) See Supporting Information (SI) for an X-ray structure of (S)-Cy-
SEGPHOS(AuCl)2.
(8) THF (2 h, 70%, 88% ee), acetone (2 h, 82%, 85% ee), DME (3 h, 79%,
87% ee), CH2Cl2 (5 h, 59%, 88% ee), benzene (5 h, 64%, 88% ee), toluene
(5 h, 62%, 87% ee).
(9) Under these conditions, the choice of carboxylate counterion had no
notable effect on the reaction. (benzoate, 5 h, 76%, 95% ee; p-
nitrobenzoate, 5 h, 70%, 95% ee; acetate, 5 h, 71%, 95% ee).
(10) Cycloadduct 6 was not isolated; yield determined by 1H NMR (see SI).
(11) Reaction of 2,4-dimethyl-2-oxazolin-5-one with 3, catalyzed by 4, gave
the cycloadduct in 39% ee.
(12) Maryanoff, C. A.; Turchi, I. J. Heterocycles 1993, 649.
(13) Reaction of 1a and 3 catalyzed by 10% AgOAc, 10% (S)-QUINAP6g
afforded 2a in 14% yield and 5% ee after 12 hr at -20 °C in THF.
(14) For recent examples of metal-catalyzed processes proceeding through
mu¨nchnones, see: (a) Dhawan, R.; Arndtsen, B. J. Am. Chem. Soc. 2004,
126, 468. (b) Dhawan, R.; Dghaym, R. D.; Arndtsen, B. J. Am. Chem.
Soc. 2003, 125, 1474.
(15) For examples of gold-catalyzed processes proposed to proceed via reaction
of a C-aurated 1,3-dipole generated by activation of an alkyne, see: (a)
Asao, N.; Aikawa, H. J. Org. Chem. 2006, 71, 5253. (b) Kim, N.; Kim,
Y.; Park, W.; Sung, D.; Gupta, A. K.; Oh, C. H. Org. Lett. 2005, 7, 5289.
(c) Asao, N.; Sato, K.; Menggenbateer; Yamamoto, Y. J. Org. Chem.
2005, 70, 3682. (d) Asao, N.; Aikawa, H.; Yamamoto, Y. J. Am. Chem.
Soc. 2004, 126, 7458. (e) Straub, B. F. Chem. Commun. 2004, 1726. (f)
Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am. Chem. Soc. 2003,
125, 10921. (g) Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto,
Y. J. Am. Chem. Soc. 2002, 124, 12650. For the sole example concerning
azomethine ylides, see: (h) Kusama, H.; Miyashita, Y.; Takaya, J.;
Iwasawa, N. Org. Lett. 2006, 8, 289.
In summary, we have developed the first catalytic enantioselec-
tive reaction of azlactones with alkenes to provide ∆1-pyrrolines.13,14
Notably, the gold-catalyzed cycloadditions proceed with excellent
diastereo- and regioselectivity. The reaction is proposed to proceed
through a 1,3-dipole15 generated by deprotonation of a gold(I)-
JA074824T
9
J. AM. CHEM. SOC. VOL. 129, NO. 42, 2007 12639