Gold(I)-catalyzed enantioselective [4 + 2]-cycloaddition of allene-dienes

Article abstract of DOI:10.1021/ol902622b

"Chemical Equation Presented" An enantioselective gold(I)-catalyzed intramolecular [4 + 2]-cycloaddition of alienes and dienes is reported. The reactions allow for the asymmetric synthesis of frans-hexahydroindenes and pyrrolidine products using C₃

Full text of DOI:10.1021/ol902622b

ORGANIC
LETTERS
2010
Vol. 12, No. 1
200-203
Gold(I)-Catalyzed Enantioselective
[4 + 2]-Cycloaddition of Allene-dienes
Ana Z. Gonza´lez and F. Dean Toste*
Department of Chemistry, UniVersity of California, Berkeley,
MC 1460 Berkeley, California 94720-1460
fdtoste@berkeley.edu
Received November 12, 2009
ABSTRACT
An enantioselective gold(I)-catalyzed intramolecular [4 + 2]-cycloaddition of allenes and dienes is reported. The reactions allow for the asymmetric
synthesis of trans-hexahydroindenes and pyrrolidine products using C3-symmetric phosphitegold(I) and ortho-arylphosphoramiditegold(I)
complexes as catalysts, respectively.
The nature of the ancillary ligand can have a dramatic impact
on the course of gold(I)-catalyzed reactions.1 Gold(I) com-
plexes of N-heterocyclic carbene,2 phosphites,3 and biden-
tate,4 electron-deficient5 and bulky6 phosphines can display
dramatically different reactivity and selectivity. We recently
reported a striking example of ligand-controlled reactivity
in which allene-dienes underwent a selective [4 + 2]- or [4
+ 3]-cycloaddition catalyzed by gold complexes of phos-
phites and bulky phosphines, respectively.7 With few excep-
tions,8 enantioselective gold(I)-catalyzed transformations
(1) (a) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. ReV. 2008, 108,
3351. For general reviews, see: (b) Jime´nez-Nu´n˜ez, E.; Echavarren, A. M.
Chem. Commun. 2007, 333. (c) Gorin, D. J.; Toste, F. D. Nature 2007,
446, 395. (d) Fu¨rstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46,
3410. (e) Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180. (f) Shen, H. C.
Tetrahedron 2008, 64, 3885. (g) Shen, H. C. Tetrahedron 2008, 64, 7847.
(2) (a) de Fremont, P.; Scott, N. M.; Stevens, E. D.; Nolan, S. P.
Organometallics 2005, 24, 2411. (b) Lavallo, V.; Frey, G. D.; Donnadieu,
B.; Soleihavoup, M.; Bertrand, G. Angew. Chem., Int. Ed. 2008, 47, 5224.
(c) Marion, N.; Nolan, S. P. Chem. Soc. ReV. 2008, 37, 1776.
(3) (a) Lo´pez, S.; Herrero-Go´mez, E.; Pe´rez-Gala´n, P.; Nieto-Oberhuber,
C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 6029. (b) Gorin,
D. J.; Watson, I. D. G.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 3736.
(4) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 11260.
(5) (a) Markham, J. P.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc.
2005, 127, 9708. (b) Baskar, B.; Bae, H. J.; An, S. E.; Cheong, J. Y.; Rhee,
Y. H.; Duschek, A.; Kirsch, S. F. Org. Lett. 2008, 10, 2605.
(6) (a) Nieto-Oberhuber, C.; Lo´pez, S.; Echavarren, A. M. J. Am. Chem.
Soc. 2005, 127, 6178. (b) Horino, Y.; Luzung, M. R.; Toste, F. D. J. Am.
Chem. Soc. 2006, 128, 11364. (c) Ochida, A.; Ito, H.; Sawamura, M. J. Am.
Chem. Soc. 2006, 128, 16486.
(7) (a) Mauleo´n, P.; Zeldin, R. M.; Gonza´lez, A. Z.; Toste, F. D. J. Am.
Chem. Soc. 2009, 131, 6348. (b) Trillo, B.; Lo´pez, F.; Montserrat, S.;
Ujaque, G.; Castedo, L.; Lledo´s, A.; Mascaren˜as, J. L. Chem.sEur. J. 2009,
15, 3336. (c) Benitez, D.; Tkatchouk, E.; Gonzalez, A. Z.; Goddard, W. A.;
Toste, F. D. Org. Lett. 2009, 11, 4798.
(8) (a) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986,
108, 6405. (b) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science
2007, 317, 496.
10.1021/ol902622b  2010 American Chemical Society
Published on Web 12/04/2009

have largely relied on the use of bis(gold)-phosphine
complexes.9 Herein we report that, in the course of develop-
ing an enantioselective variant of the gold-catalyzed [4 +
2]-cycloaddition, we have uncovered two new ligand plat-
forms for asymmetric gold catalysis.9m
Table 1. Ligand Optimization for the Enantioselective
[4 + 2]-Cycloaddition of Allene-dienes
Given the success of bidentate phosphines in gold-
catalyzed enantioselective reactions, our initial efforts toward
an enantioselective [4 + 2]-cycloaddition focused on the use
of chiral diphosphonites10 as ligands. Unfortunately, the L1
and L2Au(I)-catalyzed reaction of 1 failed to produce any
of the desired cycloadduct (Table 1, entries 1 and 2).
Moreover, racemic 3 was formed in the chiraphite(L3)Au(I)-
catalyzed reaction of 1 (entry 3). As a result of the lack of
success experienced with gold complexes of bidentate
ligands, we then decided to examine the gold(I) complexes
of chiral monodentate phosphite-like ligands as catalysts.
entry substrate ligand (L)
X/solvent
yield (%) ee (%)
1
2
3
1
1
1
1
2
1
2
2
2
2
2
1
1
L1
L2
L3
SbF6/CH2Cl2
SbF6/CH2Cl2
SbF6/CH2Cl2
SbF6/CH2Cl2
SbF6/CH2Cl2
SbF6/CH2Cl2
SbF6/CH2Cl2
SbF6/C6H6
SbF6/CH2Cl2
SbF6/C6H6
BF4/C6H6
SbF6/C6H6
SbF6/CH2Cl2
NR
NR
91
--
--
0
14
10
4a
5a
6
(R)-L4
(R)-L4
(R)-L5
(S)-L5
(R)-L5
(S)-L6
(S)-L6
(S)-L6
(S)-L6
(R)-L6
88b
86
11
92
-16
66
-74
82
nd
92
While the gold(I) complex of phosphoramidite L4 did
7
8
9
10
11
12
13
90c
90
catalyze the desired transformation, it afforded cycloadducts
3 and 4 with low enantiomeric excess (entries 4 and 5).
During the course of our studies, Reetz reported the use
of configurationally stable C3-symmetric monodentate phos-
phite ligand L5 in the Rh-catalyzed enantioselective hydro-
genation of homoallylic alcohols.12 We were attracted to this
type of ligand because the ester moiety appears to extend
outward, potentially providing a chiral environment around
the gold atom (Figure 1). We were pleased to find that, while
only a low degree of enantioinduction was observed with
L5Au(I)-catalyzed reaction of 1 (entry 6), this complex
catalyzed the formation of cycloadduct 4 in an encouraging
66% ee;13 however, a small amount of the competing [4 +
3]-cycloaddition was observed (entry 7). The chemo- and
enantioselectivity of this transformation could be improved
by changing the solvent from dichloromethane to benzene
(entry 8). Employing the H8-BINOL derived ligand L6
resulted in substantially improved enantioselectivity, yielding
4 in 82% ee in dichloromethane (entry 9). In this case, the
use of benzene as solvent resulted in the formation of
substantial amounts of the [4 + 3]-cycloadduct (entry 10).
92
92d
87
86
34
76
-24
a 10 mol % L4AuCl was used. b Isolated as a 13:1 mixture of [4 +
2]- and [4 + 3]-cycloadducts. c Isolated as a 24:1 mixture of [4 + 2]-
and [4 + 3]-cycloadducts. d Isolated as a 7:1 mixture of [4 + 2]- and [4
+ 3]-cycloadducts.
-
The chemoselectivity was restored by replacing the SbF6
(9) (a) Kleinbeck, F.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 9178.
(b) Zhang, Z.; Lee, S. D.; Widenhoefer, R. A. J. Am. Chem. Soc. 2009,
131, 5372. (c) Uemura, M.; Watson, I. D. G.; Katsukawa, M.; Toste, F. D.
J. Am. Chem. Soc. 2009, 131, 3464. (d) Watson, I. D. G.; Ritter, S.; Toste,
F. D. J. Am. Chem. Soc. 2009, 131, 2056. (e) Chao, C.-M.; Vitale, M. R.;
Toullec, P. Y.; Genˆ; et, J.-P.; Michelet, V. Chem.sEur. J. 2009, 15, 1319.
(f) Luzung, M. R.; Mauleo´n, P.; Toste, F. D. J. Am. Chem. Soc. 2007, 129,
12402. (g) Tarselli, M. A.; Chianese, A. R.; Lee, S. J.; Gagne´, M. R. Angew.
Chem., Int. Ed. 2007, 46, 6670. (h) Liu, C.; Widenhoefer, R. A. Org. Lett.
2007, 9, 1935. (i) LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D.
J. Am. Chem. Soc. 2007, 129, 2452. (j) Zhang, Z.; Widenhoefer, R. A.
Angew. Chem., Int. Ed. 2007, 46, 283. (k) Johansson, M. J.; Gorin, D. J.;
Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 18002. (l) Munoz,
M. P.; Adrio, J.; Carretero, J. C.; Echavarren, A. M. Organometallics 2005,
24, 1293. (m) After submission of an earlier version of this manuscript, a
couple of examples of the asymmetric [4 + 2]-cycloaddition of N-Tos-
tethered allene-dienes utilizing phosphoramidite-based catalysts were
reported: Alonso, I.; Trillo, B.; Lo´pez, F.; Montserrat, S.; Ujaque, G.;
Castedo, L.; Lledo´s, A.; Mascareñas, J. L. J. Am. Chem. Soc. 2009, 131,
13020.
-
counterion with BF4 , allowing for the L6Au(I)-catalyzed
formation of 4 in 92% ee with complete diastereo- and
chemoselectivity (entry 11). Unfortunately, significant ero-
sion in the enantiomeric excess was observed in the L6Au(I)-
catalyzed reaction of 1, providing cycloadduct 3 with low
enantioselectivity (entries 12 and 13).
(10) Reetz, M. T.; Li, X. AdV. Synth. Catal. 2006, 348, 1157.
(11) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168.
(12) Reetz, M. T.; Guo, H.; Ma, J.-A.; Goddard, R.; Mynott, R. J. J. Am.
Chem. Soc. 2009, 131, 4136.
Given the promising results and with optimized reaction
conditions, we set out to examine the scope of the enanti-
(13) All other derivatives in which the adamantyl ester was varied gave
lower enantioselectivities (see Supporting Information).
Org. Lett., Vol. 12, No. 1, 2010
201

With the exception of the formation of 5, the reaction was
also highly selective for the [4 + 2]-cycloadduct with no
observable formation of the isomeric [4 + 3]-counterparts.
Importantly, silica gel chromatography of the crude reaction
allowed not only for the purification of the desired product but
also for the recovery of the L6AuCl complex in up to 84% yield
(Scheme 1). The recovered catalyst could be reused with no
observable erosion in the enantioselectivity of the product.
Scheme 1. Recovery of L6AuCl
Figure 1. X-ray structure of (S,S,S)-L5AuCl. Side view (top) and
view along the C3 axis of the chiral complex (bottom).
As a result of the low enantiomeric excess observed in the
cycloaddition leading to pyrrolidine 3 (Table 1, entries 12 and
13) we returned to chiral phosphoramiditegold(I) complexes
as catalysts. Our initial studies pointed to the fact that the latter
catalyst could potentially be more selective in the cycloadditions
of N-Tos tethered substrates (Table 1, entries 4 and 5). Thus,
when the phosphoramidite dimethylamine moiety was changed
to a bis(phenylethyl)amine ((S,S,S)-L7),14 the gold(I)-catalyzed
reaction produced 3 with a modest improvement in enantiose-
lectivity to 21% ee (89% yield). Examination of the X-ray
crystal structure of L4AuCl (Figure 2) suggested that ortho-
oselective gold(I)-catalyzed [4 + 2]-cycloaddition reaction.
Substitution on the diene component was well tolerated,
efficiently providing 5 and 6 in 88% and 82% ee, respectively
(Table 2, entries 2 and 3). Accordingly, a 1,1-disubstituted
Table 2. Asymmetric Gold(I)-Catalyzed Cycloadditions of
Allene-dienes with L6AuCl
entry R1
R2
R3 R4 product yield (%) ee (%)
1
2
3
4
5
6
Me Me
Me Me
Me Me
Me -(CH2)4-
Me -(CH2)5-
Bn Me
H
H
Me
H
H
H
Me
H
H
H
4
5
6
7
8
9
87
70a
50
93
92
94
92
88
82
86
82
83b
H
H
a Reaction resulted in a 85:15 mixture of [4 + 2]- and [4 +
3]-cycloaddition products. The yield is that of 5 after isolation. b Reaction
carried out in CH2Cl2 at -30 °C.
Figure 2. X-ray structure of (S)-L4AuCl.
diene underwent the gold(I)-catalyzed cycloaddition to afford
cycloadduct 6 containing a quaternary stereogenic center
(entry 3). Variation in the allene provided 7 and 8 with little
decrease in enantiomeric excess (entries 4 and 5). In all cases,
the reactions were highly diastereoselective, affording ex-
clusively the trans-fused bicyclo[4.3.0]nonane ring system.
substitution on the phosphoramidite ligands15 might provide a
steric environment similar to that found with phosphites L5 and
L6. After a systematic study of various substituents, we were
(14) The gold(I)-catalyzed reaction of 1 using (R,S,S)-L7 as the ligand
afforded 3 in 92% yield and 0% ee.
202
Org. Lett., Vol. 12, No. 1, 2010

In conclusion, we have demonstrated that high enantiose-
lectivity can be achieved for gold(I)-catalyzed intramolecular
[4 + 2] cycloaddition reactions of diene-allenes. Two comple-
mentary catalyst systems have been developed: C3-symmetric
phosphitegold(I) complexes are employed for the enantiose-
lective synthesis of trans-hexahydroindenes, and pyrrolidine
products are prepared using ortho-arylphosphoramiditegold(I)
complexes as catalysts. These studies demonstrate that, despite
the linear geometry of gold(I) complexes, chiral monodentate
phosphorus-based ligands can be employed in asymmetric
gold(I) catalysis.8 Application of these phosphite and phos-
phoramiditegold(I) complexes in other enantioselective trans-
formations is ongoing and will be reported in due course.
Figure 3. X-ray structure of (S,S,S)-L8AuCl.
Acknowledgment. We acknowledge funding from the
National Institute of General Medical Services (GM073932),
Bristol-Myers Squibb, and Novartis. A. Z. Gonza´lez thanks
the NIH for a postdoctoral fellowship. We thank R. M. Zeldin
(UC Berkeley) for preliminary experiments, Dr. B. K. Corkey
(UC Berkeley) for obtaining the X-ray structure of L4AuCl,
and Johnson Matthey for a generous gift of AuCl3.
pleased to find that the gold(I) complex of pyrenyl-substituted
ligand L8 (Figure 3) catalyzed the formation of 3 in 83% yield
and with a markedly improved 99% ee (eq 1).16 Similarly,
varying the allene moiety also produced pyrrolidine 10 in 91%
yield and an excellent 99% ee.17
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL902622B
(15) (a) de Vries, A. H. M.; Auke, M.; Feringa, B. L. Angew. Chem.,
Int. Ed. 1996, 35, 2374. (b) Arnold, L. A.; Imbos, R.; Mandoli, A.; de
Vries, A. H. M.; Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865.
(16) For additional ortho-substituted phosphoramiditegold(I) complexes
that were examined, see Supporting Information.
(17) Chiral phosphoramiditegold(I)-catalyzed reactions of 2 gave 4 with
only modest enantioselectivitity (up to 54% ee). L8AuCl/AgSbF6 catalyst
system reacted sluggishly with 2.
Org. Lett., Vol. 12, No. 1, 2010
203