Gold catalysis: Enantiotopos selection

Article abstract of DOI:10.1002/chem.200901695

"Chemical Equation Presented" Selecting one out of two enantiotopic alkynes: A furan-diyne substrate with enantiotopic alkynyl groups was prepared and the gold-catalyzed cyclo isomerization by a series of different chiral cationic gold(I) complexes was in

Full text of DOI:10.1002/chem.200901695

DOI: 10.1002/chem.200901695
Gold Catalysis: Enantiotopos Selection
A. Stephen K. Hashmi,*[a] Melissa Hamzic´,[a] Frank Rominger,[a] and Jan W. Bats[b]
Homogeneous gold catalysis has made a major contribu-
tion to organic synthesis in the past decade[1] and, apart
from significant methodology work in the meantime, it has
become an efficient tool in total synthesis.[2] It has almost
been forgotten that enantioselective gold catalysis was the
origin of homogenous gold catalysis.[3] After significant ini-
tial success,[4] stereoselective gold catalysis was neglected for
some time. As recently predicted,[5] enantioselective gold
catalysis revived in the last years and significant success has
been achieved with a number of different enantiomerically
pure gold complexes[6] and even enantiomerically pure coun-
terions.[7]
Common for these enantioselective reactions is that the
new stereocenters are formed by the transformation of a sp2
center of a C=C double bond (in an allene or alkene 1,
Scheme 1) to a chiral center with sp3 hybridization in the
product 2. Alternatively, a C=O double bond (in an alde-
hyde) is transformed. So far only an enantiofacial selection
in the selectivity determining step has been exploited for
enantioselective homogeneous gold catalysis.
With mono-alkynes, such a facial selection is not possi-
ble—the typical addition reactions initially form alkenes
that do not possess a stereocenter. Dialkynes 3 with symme-
try equivalent, enantiotopic alkynyl groups would allow ste-
reoselective conversions. If, after the coordination (an inter-
molecular process) of the alkyne to the enantiomerically
pure gold catalyst, the subsequent intramolecular addition is
fast for both diastereomeric p complexes (leading to the two
enantiomeric products 4 and ent-4; in general, gold-cata-
lyzed reactions are fast compared to other catalysts). The
stereoselection would be quite difficult, as the p coordina-
tion of one of the two alkynes to the gold catalyst would
become the selectivity determining step (in general, the sub-
sequent addition reactions are not reversible).
Here we report our findings with regard to this concept in
the gold-catalyzed phenol synthesis.[8]
As the test substrate for this investigation, we used the
furyldialkyne 8. It was easily prepared from 5-methylfurfural
(5) by an aldol condensation with tert-butyl acetate to deliv-
er the furylacrylate 6, followed by chemoselective transfer
hydrogenation to give 7 and twofold addition of propargyl
magnesium bromide to the ester group (Scheme 2).
With 5 mol% AuCl3 this substrate 8 readily and chemose-
lectively underwent cycloisomerization to the phenol rac-9
Scheme 1. Generation of stereocenters by asymmetric gold catalysis
+
´
[a] Prof. Dr. A. S. K. Hashmi, Dr. M. Hamzic, Dr. F. Rominger
Organisch-Chemisches Institut
Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax : (+49) 6221-544205
E-mail: hashmi@hashmi.de
[b] Dr. J. W. Bats+
Institut fꢁr Organische Chemie und Chemische Biologie
Johann Wolfgang Goethe-Universitꢀt Frankfurt
Marie-Curie-Str. 11, 60439 Frankfurt (Germany)
[+] Crystallographic investigation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901695.
Scheme 2. Synthesis of the test substrate 8.
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COMMUNICATION
in 91% yield after only 30 min (Table 1, entry 1); no side-re-
actions were observed and the second alkyne unit did not
initiate any undesired competing reactions (for example,
Table 2. (Continued)
Ligand
Mol% of
catalyst
Yield
of 9 [%]
% ee[a]
Table 1. Conversion of 8 by different achiral gold catalysts.
3
4
5
14
15
16
0.6
0.6
0.6
91
90
93
0.7
1.2
Catalyst/Solvent
AuCl3/MeCN
NaACHTUNGTRENNUNG[AuCl4]/MeCN
10/MeCN
11/MeCN
t [h]
Yield of rac-9 [%]
1
2
3
4
0.5
24
4
66
63
74
85
0.66
8
cyclization reactions of the 1,6-diyne substructure). Both en-
antiomers could readily be detected by GC with a Amidex B
column, a prerequisite for the subsequent investigation of
enantioselective catalysis. Other goldACHTUNGTREN(NUGN III) catalysts like
Na[AuCl4] and 10 show longer reaction times and similar
ACHTUNGTRENNUNG
6
17
1
95
8
yields (entries 2 and 3), the Schmidbaur–Bayler gold(I) cata-
lyst 11[9] (entry 4) gave an excellent yield after 40 min.
7
8
18
19
0.6
90
90
30
1
41[b]
Then we investigated a number of different enantiomeri-
cally pure gold(I) complexes (Table 2). From the work of
Ito, Sawamura, and Hayashi as well as Togni it was known
that reactions catalyzed by gold complexes with chiral ferro-
cene ligands proceed at room temperature.[10] Under similar
9
20
1
95
41[b]
Table 2. Phenol synthesis with enantiomerically pure gold complexes.
10
11
12
21
22
23
1
1
1
54
90
70
1
5
1
Ligand
Mol% of
catalyst
Yield
of 9 [%]
% ee[a]
1
2
12
13
0.6
0.6
97
95
8
[a] ee of the product—the stereoisomer with the longer retention time on
the GC column always dominated. [b] Complete conversion after 10 h.
5.9
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A. S. K. Hashmi et al.
conditions the gold-catalyzed conversion of 8 to 9 was
tested. From 0.6 mol% tetrahydrothiophenegold(I) chloride
[AuClACHTUNGTRENNUNG(tht)] as catalyst precursor and 0.6 mol% JodyPhos
Since this gave no further improvement of the ee value,
we turned to another ligand type: (R)-3,5-tBu-4-MeO-MeO-
BIPHEP (25) gave a respectable ee of 55% (Table 3). The
other ligands 26–29 of this family gave inferior results with
respect to the ee (entries 2–5); BINAP (entry 6) and the
phosphoramidite ligands 30–32 gave reduced yields and no
detectable ee (entries 7–9).
ligand 12 in [D2]dichloromethane, a gold complex was
formed. After five minutes in the NMR tube, the complex
formed in situ was activated by the addition of AgBF4 and
the test substrate was added. The conversion was monitored
1
by H NMR spectroscopy. After 24 h 8 had been completely
converted to 9, but the ee was only 8% (Table 2, entry 1).
With the ligands 13–17, (entries 2–6) the ee could not be im-
proved; a much better value was only observed with the
MandyPhos ligand 18 (30% ee, entry 7). With the other
MandyPhos ligands 19 and 20 an ee of 41% could be ach-
ieved (entries 8 and 9). The ligands 21–23 (entries 10–12)
did not yield any better ee values for this product with the
carbon of the tertiary alcohol being the stereogenic center.
The MandyPhos gold(I) chloro complex 24 unexpectedly
delivered single crystals for a crystal structure analysis by
spontaneous crystallization from one of the reaction runs
(Figure 1).[11] As expected, the P-Au-Cl angle is close to line-
arity (1758), the distance between the gold centers is too
large for an aurophilic interaction.
Table 3. Enantioselective catalysis with gold complexes of the BIPHEP
family and phosphoramidites.
Ligand
Yield
% ee[a]
of 9 [%]
1
2
3
25
26
27
99
87
98
55
1
3
4
28
29
98
7
5
6
99
94
18
BINAP
0.5
7
8
9
30
31
32
40
45
41
–
–
–
[a] ee of the product—the stereoisomer with the longer retention time on
the GC column always dominated.
Figure 1. a) Complex 24 and b) its solid-state structure.
For the two optimal ligands from Table 1, the effect of the
counterion was investigated. When the activation was done
with AgOTs, satisfactory results were not obtained when the
reaction was carried out in toluene or dichloromethane.
Only AgBARF with the gold complex of 19 (i.e., compound
24) in dichloromethane gave a detectable ee of 10%. Focus-
ing on this ligand then gave 43% ee with AgSbF6 and
31% ee with AgPF6.
Although 25 and 28 differ by only one methyl group, the
ee value for 28 is much lower. In analogy to published
work,[12] for 25 we tried AgOPNB (OPNB=para-nitroben-
zoate). With one equivalent of the complex, the results were
identical to entry 1, while two equivalents AgOPNB inhibit-
ed the catalysis.
Again, some of the complexes could be characterized by a
crystal structure analysis. Figure 2 shows the solid-state
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Gold Catalysis
COMMUNICATION
AHCTUNGTRENNUNG
To test whether these observations are of general nature,
we prepared the substrate 38 with a phenyl substitutent in
the 5-position of the furan ring (starting from 35, Scheme 3).
The only difference to the synthesis of substrate 8 is that a
Reformatski and not an aldol reaction was used in the inital
condensation step. With AuCl3, the substrate readily provid-
ed 39 in 87% yield. When 38 was subjected to the most suc-
cessful catalyst for 8, the BIPHEB ligand 25, again only
53% ee (81% yield) were observed for 39. The Mandyphos
ligand 20 also gave only 37% ee (79% yield) for 39.
In conclusion, the enantiotopos selection of dialkynes in
homogenoeous gold catalysis is a difficult synthetic problem
and it is investigated here for the first time. While the che-
moselectivity is good and no disturbing alkyne–alkyne reac-
tions were observed, for the enantioselectivity only a ee
value of 55% could be reached. This could indicate a fast
and irreversible cycloisomerization, indicating that the p-co-
ordination of the alkyne would be relevant in the selectivity
determining step, and for such a step the stereoselectivity is
respectable albeit not synthetically useful for the formation
of the chiral tertiary alcohols. The influence of the counter-
ions is minor.
Figure 2. Plot of the (R)-3,5-tBu-4-MeO-MeOBIPHEP gold complex 33.
structure of ligand 25 coordinated to gold chloride (complex
33) and Figure 3 shows the structure of ligand 30 coordinat-
ed to gold chloride (complex 34). The structure of the bis-
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (HA
1932/9-1). We are grateful to Dr. H.-U. Blaser and Solvias AG as well as
Dr. M. Scalone and F. Hoffmann-La Roche AG for donations of chiral li-
gands. Some gold salts were provided by Umicore AG & Co. KG. The li-
gands 30–32 were generously donated by Prof. Dr. Gꢁnter Helmchen,
Dr. Mathias Schelwies, Dr. Pierre Dꢁbon and Andreas Farwick.
Keywords: alkynes · arenes · furans · gold · homogeneous
catalysis · stereoselective synthesis
Figure 3. a) Complex 34 and b) ORTEP plot of its solid-state structure.
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Scheme 3. Synthesis and gold-catalyzed conversion of the substrate 38.
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Received: June 20, 2009
Published online: November 6, 2009
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