Silver-catalysed enantioselective addition of O-H and N-H bonds to allenes: A new model for stereoselectivity based on noncovalent interactions

Article abstract of DOI:10.1002/chem.201200547

The ability of silver complexes to catalyse the enantioselective addition of O-H and N-H bonds to allenes is demonstrated for the first time by using optically active anionic ligands that were derived from oxophosphorus(V) acids as the sources of chiralit

Full text of DOI:10.1002/chem.201200547

FULL PAPER
DOI: 10.1002/chem.201200547
À
À
Silver-Catalysed Enantioselective Addition of O H and N H Bonds to
Allenes: A New Model for Stereoselectivity Based on Noncovalent
Interactions
Jannine L. Arbour,[a] Henry S. Rzepa,[a] Julia Contreras-Garcꢀa,*[b] Luis A. Adrio,[a]
Elena M. Barreiro,[a] and King Kuok (Mimi) Hii*[a]
Abstract: The ability of silver com-
plexes to catalyse the enantioselective
an of low ee to be unambiguously as-
signed by comparison of the chiroptical
ORD and VCD measurements with
calculated spectra. In the second part
of the work, the origin of the stereose-
lectivity was probed by DFT free-
energy calculations of the transition
states. A new model of enantiomeric
differentiation was developed that was
based on noncovalent interactions. This
model allowed us to identify the source
of stereoselectivity as weak attractive
interactions; such dispersive forces are
often overlooked in asymmetric cataly-
sis. A new computational approach was
developed that represents these inter-
actions as colour-coded isosurfaces that
are characterised by the reduced densi-
ty-gradient profile.
À
À
addition of O H and N H bonds to al-
lenes is demonstrated for the first time
by using optically active anionic ligands
that were derived from oxophosphor-
us(V) acids as the sources of chirality.
The intramolecular addition of acids,
alcohols, and amines to allenes can be
achieved with up to 73% ee. The ex-
Keywords: allenes
·
asymmetric
catalysis · computational chemistry ·
noncovalent interactions · stereose-
lectivity
À
ploitation of a C H anomeric effect al-
lowed the absolute configuration of
a sample of 2-substituted tetrahydrofur-
Introduction
transition states, which also exerted significant influence on
the reaction rate. This observation led us to postulate that
asymmetric catalysis may be feasible by employing optically
active anions. Subsequently, a study was performed with
a number of silver salts of chiral acids (see the Supporting
Information, Table S1). Herein, we report that notable
enantioselectivity can be obtained by using oxophosphor-
us(V) acids 1-H and 2-H (Scheme 1, Figure 1). As far as we
are aware, this is the first time that chiral silver complexes
Many metal complexes have been reported to catalyse the
À
À
addition of O H and N H bonds to allenes, but enantiose-
lective examples of such transformations are rare.[1,2] In this
regard, the discovery of cationic gold(I) complexes as enan-
tioselective catalysts for these reactions is particularly signif-
icant, because excellent levels of stereoselectivity can be at-
tained by using optically active diphosphine ligands and/or
counterions.[3] More recently, the use of chiral Brønsted
has been shown to facilitate the enantioselective additions
[6,7]
À
À
À
acids for enantioselective intramolecular N H additions to
of O H and N H bonds to prochiral allenes as a catalyst.
1,2- and 1,3-dienes was also reported, but those reactions
were comparatively sluggish (required 10 mol% catalyst
loading and 48 h).[4]
In our earlier study on the Ag-catalysed cyclisation of g-
À
À
allenols,[5] certain counteranions (CF3SO3 and CF3CO2 )
were found to be intimately involved in the stereodefining
[a] Dr. J. L. Arbour, Prof. H. S. Rzepa, Dr. L. A. Adrio,
Dr. E. M. Barreiro, Prof. K. K. Hii
Department of Chemistry, Imperial College London
Exhibition Road, South Kensington, London SW7 2AZ (UK)
E-mail: mimi.hii@imperial.ac.uk
À
À
Scheme 1. Sequential C X and C H bond-forming processes.
[b] Dr. J. Contreras-Garcꢀa
Laboratoire de Chimie Thꢁorique
Universitꢁ Pierre et Marie Curie, 75005 Paris (France)
E-mail: julia.contreras66@gmail.com
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200547.
Figure 1. Chiral oxophosphorus(V) acids used in this work.
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During the course of this study, DFT calculations were em-
ployed for the stereochemical assignment of the cyclised
products by comparison of their chiroptical properties with
predicted values. Finally, a new computational model was
developed to reveal the origin of the stereoselectivity, which
may be attributed to weakly attractive noncovalent interac-
tions between the ligand and the substrate in the transition-
state structures.
ed acid catalysis can be categorically excluded from control
experiments (Table 1, entries 7 and 8).[4a,11,12]
Subsequently, the cyclisation reactions of a series of alle-
nols and allenoic acids was performed under the optimised
conditions by using 5 and 15 mol% of compounds 1-Ag and
2-Ag, respectively (Scheme 3, Table 2). Overall, the reac-
tions that are catalysed by compound 2-Ag appear to be
Results and Discussion
Silver(I) complexes 1-Ag and 2-Ag were prepared from the
reactions of Ag2CO3 with b-CgPOOH (1-H)[8,9] and
TADDOL-POOH (2-H),[10] respectively. These complexes,
which were isolated as white solids and were soluble in most
organic solvents, were fully characterised. Elemental analy-
sis revealed a metal-to-ligand ratio of 1:1 and the observa-
tion of oligomeric mass ions ([nM]+, where n=1, 2, 3) in the
MS (ESI) spectra suggested that they likely existed as aggre-
gates/polymers. By using 2,2-diphenyl-substituted g-allenol
(3a) as a model substrate, the catalytic activity of these
silver complexes was initially assessed in DCE under differ-
ent reaction conditions (Scheme 2, Table 1).
Scheme 3. Intramolecular cyclisation of allenols and allenoic acids.
Table 2. Ag-catalysed hydroACHTNUGRTNEUNG
(acy)alkoxylation reactions.[a]
Entry
Product
L*Ag
t [h] Yield [%][b] e.r.[c]
1
2
1-Ag (5)
2-Ag (15)
2
8
97
98
33:67[d]
32:68[d]
3
4
1-Ag (5)
2-Ag (15)
2
8
99
98
42:58
29.5:70.5
5
6
1-Ag (5)
2-Ag (15)
2
8
96
99
16.5:83.5[d]
13.5:86.5[d]
Scheme 2. Cyclisation of model substrate 3a.
7
8
1-Ag (5)
15 95
28.5:71.5
33:67
2-Ag (15) 168 33[e]
Table 1. Cyclisation of compound 3a in the presence of silver catalysts.[a]
9
10
1-Ag (5)
2-Ag (15)
5
98
41:59[d]
56:44
Entry [Ag] (mol%) T [8C] t [h]
Conversion [%][b] e.r.[c]
12 91
1
2
3
4
5
6
7
8
1-Ag (15)
2-Ag (15)
1-Ag (5)
1-Ag (2.5)
1-Ag (15)
1-Ag (15)
1-H (15)
2-H (15)
23
23
23
23
0
0.5
8
2
7
4
17
168
168
100
100
100
100
100
100
–
36:64
41:59
36:64
36:64
33.5:66.5
33.5:66.5
–
11
12
1-Ag (5)
2-Ag (15)
2
3
99
97
54:46
38.5:61.5
À10
23
23
–
–
13
14
1-Ag (5)
2-Ag (15)
2
3
96
98
59:41
46.5:53.5
[a] Reaction conditions: Compound 3a (0.1 mmol), catalyst, DCE
(0.5 mL); [b] Determined by 1H NMR spectroscopy. [c] Determined by
chiral HPLC. The S-enantiomer predominated in all cases.
15
16
1-Ag (5)
2-Ag (15)
2
3
98
96
57.5:42.5
48:52
The reaction that is catalysed by phosphinate salt 1-Ag is
faster than that mediated by phosphate 2-Ag (Table 1, en-
tries 1 and 2), thereby confirming the effect of the counter-
anion on the rate-determining step. As a consequence, the
reactions that are catalysed by compound 1-Ag can be per-
formed at lower catalytic loading (Table 1, entries 3 and 4)
or temperature (Table 1, entries 5 and 6) without any ad-
verse effects. For substrate 3a, compound 1-Ag is slightly
more selective (33% ee) than compound 2-Ag (28% ee),
with the formation of the S-enantiomer being favoured in
both cases. Last but not least, the operation of chiral Brønst-
17
18
1-Ag (5)
2-Ag (15)
2
3
98
98
62:38
42.5:57.5
[a] Reaction conditions: Substrate (0.1 mmol), DCE (0.5 mL), 238C;
[b] yield of isolated product after purification by column chromatography
on silica gel. [c] Determined by chiral HPLC, according to the order of
eluting peaks. [d] The major isomer was S (see the Supporting Informa-
1
tion). [e] Conversion determined by H NMR spectroscopy.
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Ag-Catalysed Addition of O H and N H Bonds to Allenes
FULL PAPER
more sensitive than those catalysed by compound 1-Ag to-
wards structural changes on the substrates; whilst similar
levels of enantioselectivity were obtained for compounds 4a
and 4b with either catalyst (Table 1 and Table 2, entries 1
and 2), the TADDOL-derived catalyst showed higher selec-
tivity for compounds 4c and 4d (Table 2, entries 3–6), there-
by affording ee values of up to 73%. Conversely, changing
the substitution pattern on the alkyl chain appears to have
little effect: the reaction of the sterically demanding 2,2-di-
phenyl-substituted allenol to compound 4e was much slower
but gave similar level of enantioselectivity to that attained
for compound 4b (Table 2, entries 1, 2, 7, and 8). The forma-
tion of six-membered pyran 4 f also proceeded in high yield
but was fairly unselective (Table 2, entries 9 and 10). In
comparison, the cyclisation of b-allenoic acids into lactones
5a–5d was facile but provided low enantioselectivities
(Table 2, entries 11–18). In all cases, the hydroalkoxylation
reactions produced optically active 1-alkenyl-substituted tet-
rahydrofurans 4b–4e in good yields. In terms of stereoin-
duction, the formation of the same S enantiomer is favoured
by both catalysts in the cyclisation of g-allenols, whilst the
opposite selectivity applies in the formation of lactones.
The cyclisation of g-aminoallenes was also examined
(Scheme 4, Table 3); on the whole, these reactions are
ing the decreased reactivity to slow proton transfer, a selec-
tion of inorganic and organic bases was investigated as co-
catalysts (see the Supporting Information, Table S2). For the
reaction that is catalysed by compound 1-Ag, inorganic
bases, such as Cs2CO3, have an accelerative effect but de-
stroy the selectivity (Table 3, entry 2). We postulate that this
effect is due to the replacement of the chiral anion by a car-
bonate moiety, thereby forming a more-active, yet unselec-
tive, catalyst. On the other hand, no reaction occurred in
the presence of a bulky non-nucleophilic base (Table 3,
entry 3), thus suggesting that the reaction is inhibited by ir-
reversible deprotonation. Eventually, pyridine was found to
be the optimal additive, which accelerated the reaction sig-
nificantly to afford the product (7a) in 68% ee (Table 3,
entry 4).
However, the effect of the pyridine additive is not univer-
sal because it only has a marginal effect on the reaction of
Cbz-derivative 6 f (Cbz=benzyloxycarbonyl; Table 3, en-
tries 9 and 10), whilst the catalytic activity of compound 2-
Ag was inhibited by its presence (Table 3, entries 12 and
13). Thus, it appears that judicious matching between the
base and substrate/catalyst is required. Notably, neither the
level nor sense of stereoinduction (for compounds 7a and
7 f) were affected by the presence of pyridine (Table 3, cf.
entries 1 and 4 and entries 9 and 10), which supports the hy-
À
slower than their corresponding O H additions. For the cyc-
À
lisation of compound 6a, catalyst 2-Ag is more active than
catalyst 1-Ag, although the latter catalyst is more selective
(Table 3, entries 1 versus 12), furnishing an encouraging
64% ee for the N-tosyl-protected pyrrolidine (7a). Attribut-
pothesis that the stereodefining (C N bond formation) and
rate-limiting steps (protonolysis) operate independently of
each other (Scheme 1).[5] The system appears to be fairly tol-
erant of different N-protecting groups, including sulfon-
AHCTUNGTREGaNNNU mides, carbamates, and benzyl groups (Table 3, entries 4–
11).[13] Comparing the reactivity of different sulfonamides
(6b–6e), the electronic nature of the N-substituent appears
to override steric effects: The use of a nosyl protecting
group led to dramatic erosion in the reaction rate and selec-
tivity (Table 3, entry 5), which were recovered with meth-
ane, mesitylene, and napthyl sulfonyl groups (Table 3, en-
tries 6–8). Conversely, the reaction of the nucleophilic N-
benzyl substrate (6g) was fast but unselective, whilst Cbz-
protected 6 f afforded the second-highest selectivity in this
series (Table 3, entries 9 and 10).
À
Scheme 4. Intramolecular N H addition to allenes.
Table 3. Ag-catalysed hydroamination of aminoallenes.[a]
Entry
6/7
Cat.*
Additive[b]
t
Conversion e.r.[d]
[h] [%][c]
To delineate the origin(s) of the enantioselectivity, it is
first necessary to ascertain the absolute configuration of the
major isomers that are observed in the formation of com-
1
2
3
6a/7a 1-Ag
6a/7a 1-Ag
none
Cs2CO3
60
24
100
100
–
18:82
50:50
–
16:84
43:57
24:76
30.5:69.5
73:27
76:24
75:25
À
pounds 4a and 7c (as representative compounds of the O
6a/7a 1-Ag proton sponge[e] 24
À
H and N H addition reactions, respectively). The [a]D
4
5
6
7
8
9
10
11
12
13
6a/7a 1-Ag
6b/7b 1-Ag
6c/7c 1-Ag
6d/7d 1-Ag
6e/7e 1-Ag
6 f/7 f 1-Ag
6 f/7 f 1-Ag
6g/7g 1-Ag
6a/7a 2-Ag
6a/7a 2-Ag
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
none
pyridine
none
pyridine
24
24
24
24
24
24
24
24
24
24
100
60
values for compounds 4a (À358, 26% ee) and 7c (À3.48,
53% ee) are both levorotatory but differ widely in magni-
tude, which can be extrapolated to À1348 and À6.48 for the
pure enantiomers, respectively. Initially, the wavelength-de-
pendent optical rotatory dispersion (ORD) spectra of these
samples were recorded in CHCl3; tetrahydrofuran 4a dis-
played negative optical rotations across the whole wave-
length range (275–800 nm, Figure 2a). In contrast, pyrroli-
dine 7a displayed small negative optical rotations between
345–800 nm, which tuned into positive rotations at <345 nm
(Figure 2b).
57
38
85
84
76
100
100
4
52.5:47.5
21.5:78.5
37:63
[a] Reaction conditions: Compound 6a–6g (0.1 mmol), catalyst, DCE,
0.5 mL, 238C. [b] 15 mol%. [c] Determined by 1H NMR spectroscopy.
[d] Determined by chiral HPLC, according to the order of eluting peaks.
The major isomer was S, see reference [3d]. [e] 1,8-Bis(dimethylamino)-
naphthalene.
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J. Contreras-Garcꢀa, K. K. Hii et al.
lute configuration at the stereogenic centre was negative
(see Web Table 1), the next two higher-energy conforma-
tions had positive rotations. The principle chromophore
over this wavelength range is the gem-diphenyl group and
the optical rotation clearly depends on the relative orienta-
tion of these two aryl rings, coupled to the conformation of
the five-membered ring. Therefore, an unambiguous assign-
ment of the absolute configuration would depend on a reli-
AHCTUNGTREGaNNUN ble identification of the dominant conformation and, whilst
DFT calculations with included dispersion terms are proba-
bly reliable at this level, other evidence would be required
to support these results.
Calculation of the electronic circular dichroism (ECD)
spectra suggested that there would be no useful diagnostic
features and so our attention turned to vibrational circular
dichroism (VCD), which is still a relatively unexploited
technique,[17] in part owing to the challenges in reliably pre-
dicting its features theoretically[18] and also to low sensitivity
when enantiomerically pure (>98% ee) samples are not
available, such as for compound 4a (26% ee). To help im-
prove the sensitivity of this technique, we focused on the
À
region of C H vibrations to exploit what might be termed
À
the C H anomeric effect, whereby an electronegative group
X (X=O, N) that contains a lone pair can selectively
À
weaken adjacent C H bonds (Scheme 5). This effect helps
À
Scheme 5. Operation of the C H anomeric effect.
À
to decrease the mixing of anomeric C H stretching modes
with any non-CH-anomeric groups present, thereby result-
ing in a localised mode at lower wavenumber; in this in-
stance, an anomeric effect is observed for the three bonds
À
À
À
(C Ha, C Hb, and C Hc) that are adjacent to the stereogen-
ic carbon atom of compound 4a (for animations of these
modes, see Web Table 1). The anomeric effect operates to
Figure 2. ORD spectra of compounds 4a (top, 26% ee) and 7c (bottom,
52% ee) in CHCl3. Each measurement was repeated twice (red and
green lines).
À
a different extent for each of these three C H groups, de-
pending on their conformation. Thus, for conformation 2 of
À
To help interpret this behaviour, conformational analysis
compound 4a, the orientation of each C H bond with re-
spect to either of the two lone pairs on the adjacent oxygen
was performed at the wB97XD/6-311G(d,p) DFT level, in-
G
cluding a continuum solvent correction (SCRF=CPCM).
The DFT functional was selected[14] because it included the
dispersion energy corrections that are now recognised as
being key to successful conformational analysis; moreover,
this functional has also been shown to reliably predict
a range of chiroptical properties.[15] For compound 4a, the
calculations revealed at least four conformations within the
range DG298 =2 kcalmolÀ1 (see Web Table 1), with the
lowest values separated by about 1.0 kcalmolÀ1 from the
next two. The geometry of the lowest-energy conformation
corresponded to the crystal structure that was reported for
a closely related derivative.[16] Although the calculated
[a]250–880 value for this conformation with an assigned S abso-
atom (the positions of which were located as centroids of
monosynaptic ELF basins[19]) controls the value of the C H
À
stretching wavenumber, the bond length, and the NBO-in-
À
teraction energy between the lone-pair donor and the C H*
acceptor (Table 4).
À
Thus, a VCD spectrum that focuses on the anomeric C H
region should exhibit less ambiguity owing to conformation-
al dependence than that predicted for the optical rotation.
The calculated VCD spectra for conformations 1 and 2 of
compound 4a (for which opposite optical rotations had
been predicted) show very similar and apparently clear-cut
À
Cotton effects in DA for these anomeric C H stretching
modes (see the Supporting Information, Web Table 1). A
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Ag-Catalysed Addition of O H and N H Bonds to Allenes
FULL PAPER
[a]
À
Table 4. Computed C H anomeric effects in compound 4a.
Table 1) and so it is more than likely that the measurements
will be made on a mixture of multiple conformers. The pre-
dicted optical rotations for all of the conformations of the
S configuration are positive over the entire wavelength
range, which agrees with the measured ORD below 350 nm,
but the assignment becomes less clear-cut at higher wave-
lengths, where the measured rotation is very small. For the
À
À
C H bond
n
q
[8][b]
C H
[ꢃ]
NBO E2 energy
[cmÀ1
]
[kcalmolÀ1
]
Hc
Ha
Hb
3015
3070
3129
157
113
85
1.0985
1.0945
1.0908
10.89
6.25
1.42
[a] See the Supporting Information, Web Table
[b] Angle between the C H bond and the lone pair.
1 for animations.
À
À
vibrational C H spectrum, nitrogen (X=N) is a weaker
À
electron donor than oxygen and hence, the induced C H
anomeric effect would be expected to be smaller. Moreover,
multiply populated conformations significantly lower the
signal-to-noise ratio for a given concentration because the
signal is distributed amongst more peaks. Indeed, the mea-
sured VCD spectrum for compound 7c shows a very much-
weaker signal than for compound 4a, despite the higher ee
value of the sample. Whilst there is a perceptibly better
match to that predicted for the S configuration (Figure 4),
the confidence level of assignment as (S)-7c is lower than
that for compound 4a.
Figure 3. Observed (anharmonic, black) and calculated VCD spectra
À
(harmonic, purple) in the C H region for compound 4a. The calculated
spectrum was offset by 168 cmÀ1 to compensate for anharmonic effects.
À
comparison with the measured VCD spectrum in the C H
stretching region for compound 4a (Figure 3) shows a better
qualitative match over the five observed peaks for the
S configuration than to the mirror-image spectrum of the
R enantiomer. This result provides further supporting evi-
dence for the assignment of the predominant enantiomer of
compound 4a as S.
Finally, the association of compound (S)-4a, as assigned
by using chiroptical ORD and VCD methods, with an
(enantiopure) rotation of À1348 can be verified by literature
data, based on synthetic transformations and the absolute
configuration of a derivative by Flack analysis of the crystal
structure.[3g,16,20]
For the nitrogen heterocycles, compound 7c (52% ee)
was chosen for assignment because it contains fewer atoms,
thereby reducing the number of bond rotations and confor-
mational complexity. The absolute configuration of com-
pound 7 f has been previously determined by chemical trans-
formation into a known compound.[3c] By comparison of the
HPLC data, the assignment of an S configuration can be
made. We assume that this assignment applies to all of the
other major enantiomers that are produced by the Ag-cata-
lysed reactions.
Figure 4. Measured (red) and calculated VCD spectra (blue) for com-
pound 7c.
One of the most-intriguing aspects of these reactions is
the level of enantioselectivity that can be achieved with
compound 1-H, which contains relatively few steric/chiral el-
ements. We have previously modelled the transition state
for the cyclisation of g-allenols with achiral counteranions.[5]
In addition to including the chiral anion, we also incorporat-
ed some changes to the computational procedure. As
before, the basis set was cc-VDZ on all elements except Ag,
which was aug-cc-pVDZ-pp. The functional was changed to
wB97XD, which has been shown to reproduce reaction bar-
riers well and which also accounts for dispersion interac-
tions.[21] Moreover, the effect of solvent by using a continuum
model is now included in the modelling.
However, the stereochemical assignment for compound
7c is more challenging than for compound 4a. There are
still at least four conformations that are predicted to be
spanned by as little as DG298 =0.2 kcalmolÀ1 (see Web
For the formation of both compounds 4a and 7c, two dia-
stereomeric transition states were located that corresponded
to both the R and S enantiomers in the presence of the
chiral anion (1R,3S,5S,7R)-tetramethyl-2,4,6-trioxa-8-phos-
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J. Contreras-Garcꢀa, K. K. Hii et al.
phatricyclo[3.3.1.13.7]decan-8-ol-8-oxide[8] (for transition-
state 3D model coordinates and animations of the normal
reaction modes, see Web Table 2). The calculated discrimi-
nation for compound 4a (0.2 kcalmolÀ1) favours the assign-
ment (R)-4a, but such a small magnitude merely confirms
that the reaction proceeds with a low ee value. The discrimi-
nation for compound (S)-7c was rather more significant
(0.70 kcalmolÀ1), which corresponds to 54% ee, similar to
that found experimentally. This result is further evidence,
albeit only indirect, in favour of the assignment of (S)-7c as
the major enantiomer.
With the enantiomers assigned, it is now possible to com-
ment on the stereochemistry of the catalyst system. Previ-
ously, the absolute stereoinduction of gold-catalysed systems
was dependent upon the nature of the nucleophile, rather
than on the source of chirality or on the degree of substitu-
tion on the allene; that is, by using either a chiral diphos-
Figure 5. NCI reduced-gradient isosurfaces for the transition state that in-
volves compound (S)-7c; the colour coding is graded over the range
blue=attractive, green=weakly attractive, yellow=weakly repulsive,
and red=strongly repulsive. The most-relevant interactions for the stabil-
ity of the transition state are highlighted. The inset shows the difference
between these noncovalent interactions for the R and the S enantiomers
phine ligand or a chiral counteranion, opposite enantiomers
[3a,d]
À
À
were preferred for O H and N H addition reactions.
In
contrast, these silver catalysts favour the same sense of ste-
À
in the s(1) space, which can be associated to the Ag CH3 interactions.
reoinduction (S) in both the hydroalkoxylation and hydro-
ACHTUNGTRENNUNGamination reactions (Table 1, entries 1, 2, 5, and 6 and
Table 3, entries 9 and 10). On the other hand, for certain re-
actions, such as the formation of pyran 4 f and lactones 5a–
5d, opposite enantioselectivities were observed with com-
pounds 1-Ag and 2-Ag, thus indicating a synergistic relation-
ship between the catalyst and the substrate.
Table 5. Energy differences between the (R/S)-4a-Ag-H-1 and (R/S)-7c-
Ag-H-1 transition states.[a]
System
DG298 [kcalmolÀ1
]
Digital repository identifier
(R)-4a
(S)-4a
(R)-7c
(S)-7c
0.0
0.2
0.0
À0.70
10042/to-8399
10042/to-9255
10042/to-8503
10042/to-9256
From the chemist’s point of view, the origin of the enan-
tiomeric excess has to be traced back to preferable interac-
tions in the formation of one of the enantiomers to the det-
riment of the other. More specifically, following transition-
state theory, other procedures should be evaluated to help
identify the factors that lead to differential stabilization of
the diastereomeric transition-state complexes. This stabiliza-
tion turns out to be a delicate balance of numerous weak
noncovalent interactions; a balance that can be very difficult
to achieve by using DFT calculations based on free energies
that were derived from covalent terms (i.e., normal vibra-
tional modes). Recently, it has been shown that, although
the energetic balance of weak interactions is cumbersome to
establish from energetics alone, the (electron) density recon-
struction by using these methods is accurate enough to
reveal the interactions that are present in the system.[22] This
principle is behind the recently reported index for detecting
noncovalent interactions (NCIs; for more technical details
on the method, see Supporting Information).[22] This index
enables the identification and characterisation of weak inter-
actions of various strengths as chemically intuitive isosurfa-
ces that reveal both stabilizing (hydrogen-bonding interac-
tions in blue, van der Waals interactions in green) and de-
stabilizing interactions (steric clashes in red).[23]
[a] See Web Table 2 for animated transition states.
of dispersion interactions (green) in the stabilization of the
complex: the bond-formation and bond-rupture process is at
its highest peak and multiple van der Waals interactions are
observed (for example, see the interactions between the Ph
rings). A clear example of steric repulsion can be found
inside the anionic ligand, where the cage is known to give
rise to an important steric clash. However, these interactions
are located within each reactant and they are expected not
to suffer many changes along the reaction; thus they should
not have a big influence on the kinetics and the enantiose-
lectivity. In this sense, it is more interesting to look at the in-
teractions that link the anionic ligand and the substrate
(Figure 5, highlighted). Firstly, the interaction between the
catalysing Ag cation and the reactants clearly appears as
À
two blue regions between them. A stabilizing X C interac-
tion also appears that is being broken in step 1 of the reac-
tion (Scheme 1). Finally, an important hydrogen bond is
found between P=O and H-X (X=O, N). These interactions
in both complexes 4a and 7c form a closed cycle that is
behind the stability of the transition states (indicated as
green plane in Figure 5).
By depicting NCIs for the most-stable conformers of the
(R/S)-4a-Ag-H-1 and (R/S)-7c-Ag-H-1 diastereomeric tran-
sition states that were located by DFT methodology (see
Web Table 2), important chemical features can be identified
that explain the stability of the complex of compound (S)-
7c (Figure 5 and Table 5). Immediately obvious is the role
The enantiomeric effects are subtle and the small differ-
ences that are revealed by transition energies alone
(Table 5) are not able to discriminate between the different
enantiomers to determine which is more favoured (for other
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Ag-Catalysed Addition of O H and N H Bonds to Allenes
FULL PAPER
figures, see the Supporting Information). To have a more-
quantitative look at the interactions that stabilise the com-
plexes, it is useful to compare their NCI profiles in terms of
the density. When we compare the plots for the 7c-Ag-H-
1 complex, a new peak appears in the S enantiomer that is
not present in the R enantiomer (Figure 5, inset, pink
arrow), which identifies an enhanced interaction at the C=
CH2 enantiomeric source. When the corresponding 4a-Ag-
H-1 complexes are compared, a similar feature is found in
the S enantiomer. Although in this case it is not as clear in
the 2D plot, it does indeed project us to the same part of
molecular space (see the Supporting Information, Figur-
es S17 and S18). In other words, NCI analysis is able to
highlight the differential interactions that explain the (S)
enantiomeric excess, where the comparison of energy differ-
ences is ambiguous.
Experimental Section
Synthesis of 1-Ag (method 1): Ag2CO3 (0.5 equiv) was added in a single
portion to a solution of 1-H[8,25] (1 equiv) in EtOH (5 mL). The resulting
mixture was protected from light and stirred vigorously overnight. The
mixture was centrifuged and the solvent was decanted. A further portion
of EtOH (5 mL) was added to the remaining solid and the mixture was
centrifuged and decanted again. The organic extracts were combined and
concentrated under vacuum. The resulting silver salt was dried overnight
in vacuo. Compound 1-Ag was obtained as a fluffy white solid (96%).
M.p.>3008C (dec.); [a]D25 =+39.08 (c=0.5, CHCl3); H NMR (400 MHz,
1
CDCl3, 258C): d=2.43 (dd, J=13.2, 1.9 Hz, 2H), 1.96 (dd, J=23.6,
13.2 Hz, 2H), 1.43 (s, 6H), 1.34 ppm (6H, d, J=11.5 Hz); 13C NMR
(100 MHz, CDCl3, 258C): d=96.5, 72.2, 71.2, 43.4, 27.2, 18.9 ppm;
31P NMR (162 MHz, CDCl3, 258C): d=31.0 ppm (br s); IR: n˜ =3001,
2921, 1638, 1451, 1378, 1343, 1202, 1136, 1087, 1023, 977, 890, 678 cmÀ1
;
MS (FAB): m/z (%): 1527 (40) [(M)4Ag5]+, 1173 (89) [(M)3Ag4]+, 355
(15) [(M)Ag]+; elemental analysis calcd (%) for C10H16AgO5P: C 33.83,
H 4.54; found: C 34.01, H 4.54.
The formation of this interaction is facilitated by the pro-
tocycle around the Ag+ cation in the transition state, medi-
ated by the X proton donors (X=O and N). This observa-
tion explains the fact that both X atoms promote the same
enantiomer. Moreover, this is a purely quantum effect, be-
cause the distances remain the same in both conformers.
Only the density is able to distinguish between the R and S
configurations.
Finally, interestingly, the NCI features extend beyond the
plane of interaction: they spread to the O-P-O part of the
anion and to the N-substituent in complex 7c. This “cooper-
ative” interaction explains their ability to tune the enantio-
selectivity. We feel that the procedure outlined herein is
a general one for establishing the regions of a molecule that
are primarily responsible for transition-state diastereoselec-
tivity, which will be the target of our future work.
Synthesis of 2-Ag (method 2): Ag2CO3 (0.5 equiv) was added in a single
portion to a solution of 2-H[10] (1 equiv) in CH2Cl2 (5 mL) followed by
H2O (5 mL). The resulting mixture was protected from light and stirred
vigorously for 2 h. After this time, the mixture was diluted with CH2Cl2
(10 mL) and H2O (10 mL). The biphasic suspension were separated and
the aqueous layer was extracted with further portions of CH2Cl2 (2ꢄ
15 mL). The combined organic extracts were filtered through celite and
concentrated under vacuum. The resulting silver salt was dried overnight
in vacuo. Compound 2-Ag was obtained as a fluffy white solid (92%).
M.p.>2348C (decomp); [a]D25 =À219.08 (c=1.0, CHCl3); 1H NMR
(400 MHz, CDCl3, 258C): d=7.61 (d, J=7.6 Hz, 4H), 7.52 (d, J=7.6 Hz,
4H), 7.37–7.06 (m, 12H), 5.18 (s, 2H), 0.82 ppm (s, 6H); 13C NMR
(100 MHz, CDCl3, 258C): d=143.5, 139.6 (d, J=9.2 Hz), 128.8, 128.2,
128.1, 127.6, 127.2, 126.9, 113.7, 87.9 (d, J=7.0 Hz), 79.4, 26.5 ppm;
31P NMR (162 MHz, CDCl3, 258C): d=À0.15 ppm (br s); IR: n˜ =3057,
2991, 2344, 1493, 1447, 1210, 1051, 1036, 897, 740, 967 cmÀ1; MS (FAB):
m/z (%): 635 (31) [M]+, 431 (45), 179 (100); elemental analysis calcd (%)
for C31H28AgO6P: C 58.60, H 4.44; found: C 58.45, H 4.36.
Typical procedure for the Ag-catalysed reactions: A screw-capped vial
was charged with a magnetic stirrer bar, compound 1-Ag or 2-Ag (5 or
15 mol%), the requisite substrate (0.1 mmol), and an additive (if used,
0.1 mmol). 1,2-Dichloroethane (DCE, 0.5 mL) was added and the mix-
ture was stirred at RT in the dark. Conversions were monitored by
1H NMR spectroscopy. Upon completion, the solvent was evaporated
and the product was purified by column chromatography on silica gel.
Conclusion
This work demonstrates, for the first time, that chiral silver
À
complexes can be used to facilitate the addition of O H and
À
N H bonds to C=C bonds with significant levels of enantio-
selectivity. Encouraging ee values of up to 73% and 68%
Acknowledgements
À
À
can be achieved for the addition of O H and N H groups,
respectively. Although the stereoselectivity is modest at
present, the combination of silver with a chiral counteranion
is a new catalyst system for this type of asymmetric catalysis,
which justifies further research in this area.
We thank the EPSRC for studentship support (J.L.A.). We thank the
Ministerio de Educaciꢅn EspaÇol, the Xunta Galicia (Angeles AlvariÇo
program), and the Fundaciꢅn Barriꢁ de la Maza for postdoctoral fellow-
ships to J.C.G., L.A.A., and E.M.B., respectively. We thank Professor Wi-
denhoefer (Duke University) for providing the HPLC conditions for
compound 4a and Professor Mikami (Tokyo Institute of Technology) for
clarification on the stereochemical assignment of compound 4a.
We also applied new theoretical methods to uncover sev-
eral important aspects regarding the stereochemistry of the
reaction, including the assignment of absolute configurations
À
based on C H anomeric effects in the VCD spectra and the
[1] a) V. M. Arredondo, F. E. McDonald, T. J. Marks, Organometallics
1999, 18, 1949–1960; b) R. W. Bates, V. Satcharoen, Chem. Soc. Rev.
2002, 31, 12–21; c) X. H. Yu, S. Seo, T. J. Marks, J. Am. Chem. Soc.
2007, 129, 7244–7245; d) T. Bai, S. M. Ma, G. C. Jia, Coord. Chem.
Rev. 2009, 253, 423–448; e) C. J. Weiss, T. J. Marks, Dalton Trans.
2010, 39, 6576–6588.
[2] The enantioselective hydroamination of aminoallenes was first ach-
ieved by using a titanium catalyst of chiral amino alcohols and, very
recently, by using sulfonamide–alcohol complexes (including tanta-
lum). However, only up to 16% ee has been achieved: a) J. M.
delineation of stereoselectivity through free-energy differen-
ces and subtle noncovalent interactions in the computed
transition states for the reactions. This study highlights the
significance of weak effects on reaction selectivity, which is
often overlooked in asymmetric synthesis.[24] Further devel-
opment and exploitation of this NCI method has the poten-
tial to deliver unique semi-quantitative insight into the ori-
gins of catalytic stereoselectivity.
Chem. Eur. J. 2012, 00, 0 – 0
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www.chemeurj.org
&
7
&
ÞÞ
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J. Contreras-Garcꢀa, K. K. Hii et al.
Hoover, J. R. Petersen, J. H. Pikul, A. R. Johnson, Organometallics
2004, 23, 4614–4620; b) A. J. Hickman, L. D. Hughs, C. M. Jones, H.
Li, J. E. Redford, S. J. Sobelman, J. A. Kouzelos, A. R. Johnson, Tet-
rahedron: Asymmetry 2009, 20, 1279–1285; c) K. E. Near, B. M.
Chapin, D. C. McAnnally-Linz, A. R. Johnson, J. Organomet. Chem.
2011, 696, 81–86.
[10] A. Voituriez, A. B. Charette, Adv. Synth. Catal. 2006, 348, 2363–
2370.
[11] J. G. Taylor, L. A. Adrio, K. K. Hii, Dalton Trans. 2010, 39, 1171–
1175.
[12] Triflic acid catalyses the cyclisation of compound 4a in a 6-endo
manner, see: K. Mori, S. Sueoka, T. Akiyama, Chem. Lett. 2009, 38,
628–629.
[3] a) G. L. Hamilton, E. J. Kang, M. Mba, F. D. Toste, Science 2007,
317, 496–499; b) R. L. LaLonde, B. D. Sherry, E. J. Kang, F. D.
Toste, J. Am. Chem. Soc. 2007, 129, 2452–2453; c) Z. Zhang, C. F.
Bender, R. A. Widenhoefer, J. Am. Chem. Soc. 2007, 129, 14148–
14149; d) Z. B. Zhang, C. F. Bender, R. A. Widenhoefer, Org. Lett.
2007, 9, 2887–2889; e) Z. B. Zhang, R. A. Widenhoefer, Angew.
Chem. 2007, 119, 287–289; Angew. Chem. Int. Ed. 2007, 46, 283–
285; f) K. Aikawa, M. Kojima, K. Mikami, Angew. Chem. 2009, 121,
6189–6193; Angew. Chem. Int. Ed. 2009, 48, 6073–6077; g) K.
Aikawa, M. Kojima, K. Mikami, Adv. Synth. Catal. 2010, 352, 3131–
3135; h) R. L. LaLonde, Z. J. Wang, M. Mba, A. D. Lackner, F. D.
Toste, Angew. Chem. 2010, 122, 608–611; Angew. Chem. Int. Ed.
2010, 49, 598–601; i) H. Li, S. Du Lee, R. A. Widenhoefer, J. Orga-
nomet. Chem. 2011, 696, 316–320.
[4] a) N. D. Shapiro, V. Rauniyar, G. L. Hamilton, J. Wu, F. D. Toste,
Nature 2011, 470, 245–249; b) L. Ackermann, A. Althammer, Syn-
lett 2008, 995–998.
[5] J. L. Arbour, H. S. Rzepa, A. J. P. White, K. K. Hii, Chem. Commun.
2009, 7125–7127.
[6] The axis-to-centre transfer of chirality from optically active precur-
sors to the products has previously been achieved by using silver
catalysis, see: a) D. Lathbury, T. Gallagher, J. Chem. Soc. Chem.
Commun. 1986, 114–115; b) N. J. S. Huby, R. G. Kinsman, D. Lath-
bury, P. G. Vernon, T. Gallagher, J. Chem. Soc. Perkin Trans. 1 1991,
145–155.
[13] So far, gold-catalysed reactions have only been reported with certain
sulfonamides, carbamates, and ureas.
[14] J.-D. Chai, M. Head-Gordon, Phys. Chem. Chem. Phys. 2008, 10,
6615–6620.
[15] F. Cherblanc, Y. P. Lo, E. De Gussem, L. Alcazar-Fuoli, E. Bignell,
Y. He, N. Chapman-Rothe, P. Bultinck, W. A. Herrebout, R. Brown,
H. S. Rzepa, M. J. Fuchter, Chem. Eur. J. 2011, 17, 11868–11875.
[16] Y. K. Chung, G. C. Fu, Angew. Chem. 2009, 121, 2259–2261; Angew.
Chem. Int. Ed. 2009, 48, 2225–2227.
[17] For a review, see L. A. Nafie, Nat. Prod. Commun. 2008, 3, 451–
466.
[18] V. P. Nicu, E. J. Baerends, Phys. Chem. Chem. Phys. 2009, 11, 6107–
6118.
[19] C. S. M. Allan, H. S. Rzepa, J. Chem. Theory Comput. 2008, 4,
1841–1848.
[20] The absolute stereochemical assignments as reported in referen-
ce [3g] have since been reassigned: K. Aikawa, M. Kojima, K.
Mikami, Adv. Synth. Catal. 2011, 353, 2882.
[21] H. S. Rzepa, Chem. Commun. 2011, 47, 1851–1853.
[22] E. R. Johnson, S. Keinan, P. Mori-Sꢆnchez, J. Contreras-Garcꢀa, A. J.
Cohen, W. Yang, J. Am. Chem. Soc. 2010, 132, 6498–6506.
[23] J. Contreras-Garcꢀa, W. Yang, E. R. Johnson, J. Phys. Chem. A 2011,
115, 12983–12990.
[24] Also see: A. M. R. Smith, H. S. Rzepa, A. J. P. White, D. Billen,
K. K. Hii, J. Org. Chem. 2010, 75, 3085–3096.
[7] For the recent use of chiral silver–phosphate complexes for the ki-
netic resolution of racemic allenic alcohols, see: Y. Wang, K. Zheng,
R. Hong, J. Am. Chem. Soc. 2012, 134, 4096–4099.
[25] J. H. Downing, J. Floure, K. Heslop, M. F. Haddow, J. Hopewell, M.
Lusi, H. Phetmung, A. G. Orpen, P. G. Pringle, R. I. Pugh, D. Zam-
brano-Williams, Organometallics 2008, 27, 3216–3224.
[8] J. Hopewell, P. Jankowski, C. L. McMullin, A. G. Orpen, P. G. Prin-
gle, Chem. Commun. 2010, 46, 100–102.
[9] Compound 1-H was kindly provided by Professor Paul G. Pringle
(the University of Bristol, U.K.).
Received: February 19, 2012
Revised: April 12, 2012
Published online: && &&, 0000
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Ag-Catalysed Addition of O H and N H Bonds to Allenes
FULL PAPER
Come on allene: The enantioselective
Asymmetric Catalysis
À
À
addition of O H and N H bonds to
allenes was achieved by using chiral
silver complexes. A new computational
method revealed that the stereoselec-
tivity resulted from weak noncovalent
interactions.
J. L. Arbour, H. S. Rzepa,
J. Contreras-Garcꢀa,* L. A. Adrio,
E. M. Barreiro, K. K. Hii* . . &&&& — &&&&
Silver-Catalysed Enantioselective
À
À
Addition of O H and N H Bonds to
Allenes: A New Model for Stereose-
lectivity Based on Noncovalent Inter-
actions
Chem. Eur. J. 2012, 00, 0 – 0
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