Enantioselective gold catalysis: Opportunities provided by monodentate phosphoramidite ligands with an acyclic TADDOL backbone

Article abstract of DOI:10.1002/anie.200906550

(Chemical Equation Presented) The tail makes the difference: Removing the isopropylidene acetal unit from well-known TADDOL ligands improved the performance of the derived phosphoramidite ligands in asymmetric gold catalysis (see scheme; Ts=4-toluenesulfonyl). X-ray crystallography showed that the binding pocket has an effective three-fold symmetry, with through-space interactions between the arene rings of the ligand and the gold center.

Full text of DOI:10.1002/anie.200906550

Angewandte
Chemie
DOI: 10.1002/anie.200906550
Asymmetric Catalysis
Enantioselective Gold Catalysis: Opportunities Provided by
Monodentate Phosphoramidite Ligands with an Acyclic TADDOL
Backbone**
Henrik Teller, Susanne Flꢀgge, Richard Goddard, and Alois Fꢀrstner*
Electrophilic activation of p systems using platinum and gold
complexes is an active frontier of contemporary catalysis
research.[1,2] These exceedingly practical carbophilic Lewis
acids allow readily available substrates to be converted into
diverse carbocyclic or heterocyclic scaffolds with a significant
increase in molecular complexity.[3] Although inherently apt
for asymmetric synthesis, the development of effective chiral
gold catalysts poses considerable challenges,[4] not least
because of the strong preference of AuI for linear dicoordi-
nation. This geometry precludes the chelation of a bidentate
chiral ligand to a single metal center, which arguably
constitutes the most successful strategy in asymmetric catal-
ysis to date.[5] Moreover, the reacting substrate is forced to
approach the reactive gold center trans to the ancillary ligand
(L*), which further hinders the transfer of chiral informa-
tion.
Two different approaches have been reported to over-
come these problems.[4,6] First, the use of chiral counterions as
an escort for a cationic gold template has been successful in
certain cases (see complex 1).[7] Second, dinuclear diphos-
phine complexes, such as 2–5, have proven effective, even
though careful optimization is necessary to match substrate
and catalyst.[8] However, the bis(phosphine) ligands in 2–5 are
elaborate, difficult to modify, and can be more expensive than
the noble metal they bind to; therefore, alternative design
principles are highly desirable. Herein, we report our
approach, which exploits a previously unrecognized oppor-
tunity in TADDOL chemistry[9] for the development of
powerful phosphoramidite gold catalysts.[10]
Early attempts to use the BINOL-derived phosphorami-
dite containing complex [6·AuCl] in asymmetric gold-catal-
ysis essentially met with failure (< 2% ee),[11] and only
recently has this class of ligands been re-utilized. Mascareꢀas
et al. showed that the highly crowded variant [7·AuCl]
successfully effected the [4+2] cycloadditions of allene–
dienes in good to excellent enantioselectivity.[12] In parallel
studies, our research group found that complex [8·AuCl],[13,14]
which also contains bulky substituents at the 3,3’-positions of
the BINOL core, is useful for the enantioselective cyclo-
propanation of styrene derivatives (Scheme 1).[8a]
Although this result merits further investigation, a catalyst
screen gave another promising hit. Complex 12a,[15] which
contains a much simpler TADDOL-derived phosphorami-
dite, furnished cycloadduct 14[16] with 84% ee (Table 1).
Variation of the ligand constituents showed that: 1) bis(1-
phenylethyl)amine 15 performed best amongst all amine
components investigated,[14] and 2) (R,R)-15 and (R,R)-
TADDOL form a matched pair.[14] Moreover, the arene
moiety exerted a striking influence on the outcome. Whereas
12a (Ar= Ph) and 12b (Ar= C6H4OMe) gave similar results,
phenyl groups containing electron-withdrawing substituents
at the meta or para positions afforded higher reaction rates
but significantly lower enantioselectivities (Table 1, entries 3–
5). A through-bond effect seems unlikely to explain these
striking differences in selectivity and reactivity because the
31P NMR shifts of the corresponding gold complexes do not
change much within the entire series (Table 1); rather, a
through-space interaction between the arenes and the elec-
tron deficient Au+ center is more plausible.[17] In this case, a
higher electron density at the aromatic periphery should
tighten the chiral pocket, but also lower the electrophilicity,
and hence decrease the activity of the gold complex after
ionization with AgBF4.
[*] H. Teller, Dr. S. Flꢀgge, Dr. R. Goddard, Prof. A. Fꢀrstner
Max-Planck-Institut fꢀr Kohlenforschung
45470 Mꢀlheim/Ruhr (Germany)
Fax: (+49)208-306-2994
E-mail: fuerstner@mpi-muelheim.mpg.de
[**] Generous financial support by the MPG and the Fonds der
Chemischen Industrie (Kekulꢁ fellowships to H.T. and S.F.) is
gratefully acknowledged. We thank the NMR, X-ray, and Chroma-
tography Departments of our Institute for their excellent support,
and Umicore AG & Co KG, Hanau, for a gift of noble metal salts.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906550.
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Figure 1. Structure of complex 12a in the solid state in two orienta-
Scheme 1. BINOL-derived phosphoramidites for asymmetric gold
catalysis. Piv=pivaloyl.
ꢀ
ꢀ
ꢀ ꢀ
tions: a) perpendicular to the P Au Cl axis and b) along the P Au Cl
axis. These structures show the binding pocket around the gold center,
which is formed from three phenyl groups of the ligand (red).
Ellipsoids are drawn at the 50% probability level and hydrogen atoms
are omitted for clarity.[14]
Table 1: Influence of remote substituents on the arene part of the
TADDOL ligand 12 on the enantioselectivity and reaction rate of gold-
catalyzed [2+2] cycloaddition reactions.[18]
arenes orientate one edge toward the AuCl unit, even though
the contacts are not uniformly close (the distances from the
gold center to the Cipso atoms are 3.230(1), 3.284(1), and
3.971(1) ꢁ). One of the phenyl rings of the TADDOL part is
slightly bent away from the metal, which presumably under-
mines the enantioselective binding event of the substrate to
the gold center. The crystal structure of the analogous
complex 12b, which contains para-methoxyphenyl rather
than unsubstituted phenyl rings on the TADDOL, shows very
similar structural features.[14] Importantly, however, the
Entry
Ar
t
[h]
Yield
[%]
ee
[%]
dP
(ppm, C6D6)
1
2
3
4
12a
12b
12c
12d
2
16
1
93
90
95
84
84
86
75
39
113.5
112.5
113.6
113.8
ꢀ
corresponding Au Cipso distances in 12b are shortened to
3.196(1), 3.292(1), and 3.766(1) ꢁ, thus lending credence to
the notion that a more electron-rich periphery in the ligand
maintains closer interactions with the metal,[17] and thereby
possibly improves the asymmetric induction at the expense of
the reaction rate (Table 1, entries 1 and 2).[14]
1
We envisaged that this apparently important secondary
interaction between the peripheral arenes and the metal
would be reinforced if the third phenyl ring is moved closer to
the metal. To this end, the isopropylidene acetal was removed
from the TADDOL backbone and replaced with a dimethyl
ether motif (Scheme 2). We expected that the seven-mem-
bered ring of the resulting phosphoramidite 19, relieved from
the constraints of annulation, would be sufficiently flexible, to
bring the third arene ring into a truly axial orientation. To the
best of our knowledge, TADDOL derivatives containing an
acyclic skeleton have so far not been successfully used in
asymmetric catalysis,[9,19] even though compounds 18a,b and
the derived phosphoramidites 19a,b are readily accessi-
5
6
12e
12 f
1
88
71
20
63
117.3
112.7
>16
The structure of gold complex 12a in the solid state
supports this view. Two phenyl rings of the TADDOL and one
phenyl substituent of the amine form a cone-shaped binding
pocket of approximate C3 symmetry (red; Figure 1). All three
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lysts. The structure of 20a in the solid state (Figure 2) retains
the favorable features of parent compound 12a; however, its
seven membered ring is slightly more puckered, bringing the
third phenyl group into significantly closer contact with the
ꢀ
gold center (the corresponding Au Cipso distance is shortened
from 3.971(1) ꢁ (12a) to 3.505(1) ꢁ in 20a); this tighter and
more regular binding pocket crafts what appears to be an
effective C3-symmetric chiral environment.
Provided that the structure of 20 in the solid state is
maintained in solution, this precatalyst should furnish higher
enantioselectivities than the original catalyst 12a. In fact, the
ee value for the [2+2] cycloaddition product 14 was improved
from 84% (12a) to 94% (20a), and ꢁ 99% ee was obtained
with complex 20b, which contains tert-butyl substituents on
the phenyl rings (Table 2).[21] This result clearly surpasses the
selectivity obtained with the much more expensive and
elaborate dinuclear SEGPHOS complex 4 (95% ee).[16]
Gratifyingly, the outstanding level of selectivity was retained
throughout the entire series; even the N-tosyl derivative 23
showed excellent optical purity (95% ee), although complex 4
furnished this product in only 54% ee.[16] Moreover, the novel
Scheme 2. Preparation of phosphoramidite gold complexes 20a,b that
have a TADDOL subunit with an acyclic backbone. a) NaH, dimethyl
sulfate, Et2O, 08C!RT, quant. yield; b) ArMgBr (5 equiv), THF,
08C!RT, 57% yield (Ar=Ph), 67% yield (Ar=tBuC6H4); c) PCl3, Et3N,
toluene (0.02m), 4 ꢂ M.S., 08C!608C; d) 15, nBuLi, THF,
ꢀ788C!RT, 58% yield (19a), 67% yield (19b); e) NaAuCl4·2H2O,
2,2’-thiodiethanol, CHCl3/H2O (1:5), 99% yield (20a), 95% yield
(20b).
Table 2: [2+2] Cycloaddition reactions[a] catalyzed by different gold–
phosphoramidite complexes.[18]
Product
Gold complex
Yield
[%][e]
12a
20a
20b
14
84% 94%
82% 96%
ꢁ99%
ꢁ99%
91
98
X=C(COOMe)2
21
X=C(COOBn)2
22
79% 95%
99%
94
X=C(COOtBu)2
23 X=NTs
86%[b] 87%[b]
95%[b] 52[c]
24
25
84%[b] 92%[b] ꢁ99%[b] 93
87% 91%
99%[d] 94
Figure 2. a) Structure of complex 20a in the solid state.[14] b) Overlay
of the crystal structures of complex 12a (black) and 20a (red) along
ꢀ
ꢀ
the Cl Au P axis. This comparison shows that the acyclic TADDOL
backbone in 20a affords a tighter binding pocket about the gold atom
by bringing the third phenyl ring into closer contact (see arrow).
Ellipsoids are drawn at the 50% probability level and hydrogen atoms
are omitted for clarity.
26
88% 92%
98%
87
[a] All reactions were performed at 08C unless otherwise stated. [b] At
room temperature. [c] 65% yield, based on recovered starting material.
[d] According to HPLC, the product contains 6.7% of an unknown isomer.
[e] Yield obtained using complex 20b.
ble.[14,20] Like their annulated analogues 12, the corresponding
gold complexes 20a (dP = 112.8 ppm) and 20b (dP =
113.7 ppm) are air-stable and therefore convenient precata-
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Communications
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selectivity to [7·AuCl].[12a,c,22,23] Importantly, this [4+2] cyclo-
addition is mechanistically distinct from the [2+2] cyclo-
additions that are summarized in Table 2; strong evidence has
been reported suggesting that the former cycloaddition occurs
in a concerted manner, whereas the latter proceed by a
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Scheme 3. Comparison of two gold phosphoramidite complexes in the
asymmetric [4+2] cycloaddition of allene–diene 27: a) [7·AuCl]
(2 mol%), AgSbF6 (2 mol%), CH2Cl2, ꢀ158C, 92% yield, 92% ee
(Ref. [12a]), or b) 20b (5.5 mol%), AgBF4 (5 mol%), CH2Cl2, 08C, 90%
yield, 91% ee.
stepwise, cationic mechanism.[24] Therefore, we conclude that
the new phosphoramidite complexes described herein repre-
sent cheap, practical, stable, and highly enantioselective
alternatives to the established ligands in the field of asym-
metric gold catalysis. Our rational approach was made
possible by the first productive use of a TADDOL derivative
with an acyclic backbone in asymmetric catalysis. We intend
to develop this design concept further, investigate the
preparative scope of the new complexes and their congeners
in more detail, and establish a better understanding of the
underlying mechanisms.[25]
[11] M. P. Muꢀoz, J. Adrio, J. C. Carretero, A. M. Echavarren,
Organometallics 2005, 24, 1293 – 1300.
Received: November 20, 2009
Revised: December 16, 2009
Published online: February 19, 2010
[12] a) I. Alonso, B. Trillo, F. López, S. Montserrat, G. Ujaque, L.
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R. M. Zeldin, A. Z. Gonzµlez, F. D. Toste, J. Am. Chem. Soc.
2009, 131, 6348 – 6349; c) while this manuscript was under
review, another closely related 3,3’-disubstituted BINOL-
derived phosphoramidite as well as a C3-symmetric phosphite
ligand were reported; see: A. Z. Gonzµlez, F. D. Toste, Org. Lett.
2010, 12, 200 – 203.
Keywords: asymmetric catalysis · cycloaddition · gold ·
.
phosphoramidites · TADDOLs
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[14] For crystallographic data, further screening results and the full
experimental
data,
see
the
Supporting
Informa-
tion. CCDC 754596 [8·AuCl], 754597 (12a), 754598 (12b), and
754599 (20a) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Center via www.ccdc.
cam.ac.uk/data_request/cif.
[15] a) This and related TADDOL-derived phosphoramidites are
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Rosset, Eur. J. Org. Chem. 2000, 4011 – 4027. For an improved
synthesis, see the Supporting Information; b) for a recent
application of related phosphoramidites in a cycloaddition
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