Chirality Transfer in Gold(I)-Catalysed Direct Allylic Etherifications of Unactivated Alcohols: Experimental and Computational Study

Article abstract of DOI:10.1002/chem.201501607

Gold(I)-catalysed direct allylic etherifications have been successfully carried out with chirality transfer to yield enantioenriched, γ-substituted secondary allylic ethers. Our investigations include a full substrate-scope screen to ascertain substituent effects on the regioselectivity, stereoselectivity and efficiency of chirality transfer, as well as control experiments to elucidate the mechanistic subtleties of the chirality-transfer process. Crucially, addition of molecular sieves was found to be necessary to ensure efficient and general chirality transfer. Computational studies suggest that the efficiency of chirality transfer is linked to the aggregation of the alcohol nucleophile around the reactive π-bound Au-allylic ether complex. With a single alcohol nucleophile, a high degree of chirality transfer is predicted. However, if three alcohols are present, alternative proton transfer chain mechanisms that Erode the efficiency of chirality transfer become competitive.

Full text of DOI:10.1002/chem.201501607

DOI: 10.1002/chem.201501607
Full Paper
&
Organic Synthesis
Chirality Transfer in Gold(I)-Catalysed Direct Allylic Etherifications
of Unactivated Alcohols: Experimental and Computational Study
Graeme Barker, David G. Johnson, Paul C. Young, Stuart A. Macgregor,* and Ai-Lan Lee*[a]
Abstract: Gold(I)-catalysed direct allylic etherifications have
been successfully carried out with chirality transfer to yield
enantioenriched, g-substituted secondary allylic ethers. Our
investigations include a full substrate-scope screen to ascer-
tain substituent effects on the regioselectivity, stereoselectiv-
ity and efficiency of chirality transfer, as well as control ex-
periments to elucidate the mechanistic subtleties of the chir-
ality-transfer process. Crucially, addition of molecular sieves
was found to be necessary to ensure efficient and general
chirality transfer. Computational studies suggest that the ef-
ficiency of chirality transfer is linked to the aggregation of
the alcohol nucleophile around the reactive p-bound Au–al-
lylic ether complex. With a single alcohol nucleophile, a high
degree of chirality transfer is predicted. However, if three al-
cohols are present, alternative proton transfer chain mecha-
nisms that erode the efficiency of chirality transfer become
competitive.
Introduction
a-Chiral ethers are present in many natural products, biologi-
cally active molecules and synthetic intermediates.[1] Therefore,
much effort has been directed towards efficient routes to
enantiomerically enriched chiral ethers through allylic etherifi-
cation reactions.[2] Within this context, there is currently ongo-
ing interest in utilising unactivated allylic alcohol electrophiles
in transition-metal-catalysed allylations of various nucleo-
philes,[3] as the use of unactivated allylic alcohol electrophiles
reduces the number of synthetic steps required (by virtue of
not requiring prior derivatisation) and minimises byproduct
formation. In terms of asymmetric intermolecular etherifica-
tions, a recent notable advance by Carreira et al. uses Ir cataly-
sis to effect allylic etherifications on secondary allylic alcohols
through formal SN2 selectivity.[4]
Scheme 1. Previous work (racemic studies) and current chirality-transfer
target.
a leaving group in the former or form an alkoxide in the
latter), leading to mild reaction conditions that are tolerant of
various functional groups as well as air and moisture (Sche-
me 1a).[3a,10] We were keen to extend this methodology to
asymmetric methods by investigating various chiral, non-race-
mic g-substituted substrates, which should be amenable to
chirality transfer. In theory, an enantioenriched chiral allylic al-
cohol with g-substitution (e.g., 4, Scheme 1), which is easily ac-
cessible in good enantioselectivities by Sharpless kinetic reso-
lution[11] or enzyme resolution,[12] should be able to transfer its
chirality[13] to the allylic ether product 5, especially if a 6-mem-
One of the key research efforts within our group has been
to develop gold-catalysed[5] regioselective methods towards al-
lylic ethers[6] and allylic thioethers.[7] Within this context, we re-
cently developed a mild and air-stable gold(I)-catalysed direct
allylic etherification of allylic alcohols.[8] This dehydrative formal
SN2’ procedure[9] requires neither the allylic alcohol electrophile
nor the alcohol nucleophile to be activated (either to install
[a] Dr. G. Barker, Dr. D. G. Johnson, Dr. P. C. Young, Prof. S. A. Macgregor,
Dr. A.-L. Lee
bered ring hydrogen-bonded intermediate
I is involved
(Scheme 1b). Access to chiral, non-racemic a,g-disubstituted al-
lylic ethers such as 5 from unactivated alcohols also nicely
complements recent Ir-catalysed allylation methods by Carreira
et al.,[4a] which are confined to formation of unsubstituted sec-
ondary allylic ethers (R1 =H). It should be noted that shortly
after our initial communication,[8a] Mukherjee and Widenhoefer
disclosed an independent report on the same reaction.[14]
Using a different set of catalysts and conditions, they carried
out a substrate-scope study on the racemic reaction. In addi-
Institute of Chemical Sciences, Heriot-Watt University
Edinburgh EH14 4AS (UK)
E-mail: S.A.Macgregor@hw.ac.uk
A.Lee@hw.ac.uk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501607.
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tion, they also elegantly show one example of a chirality-trans-
fer reaction (see below). However, as the substrate scope of
their chirality-transfer reaction was not reported and there was
room for improvement with regards to the regioselectivity (5:1
of formal SN2’/SN2 5/6), we decided that it was still important
to continue with our independent studies. These are reported
here, and include optimisation to give greatly improved regio-
selectivities, full substrate-scope studies and experimental and
computational mechanistic investigations.
Table 2. Allylic alcohol scope.
Entry
1
Allylic alcohol
Product
Result[a]
78%, 7:1 E/Z
88:12 e.r. (E)[b]
16:84 e.r. (Z)[b]
Results and Discussion
71%, 11:1 E/Z
76:24 e.r. (E)[b]
16:84 e.r. (Z)[b]
2
3
Our investigation began with the optimisation of reaction con-
ditions to improve the regioselectivity for allylic etherifications,
using secondary allylic alcohol 4a as a model substrate
(Table 1). Our previously reported conditions provided a poor
78%, 5:1 E/Z
98:2 e.r. (E)[b]
16:84 e.r. (Z)[b]
77%, 10:1 E/Z
89:11 e.r. (E)[c]
46:54 e.r. (Z)[c]
4
5
6
7
Table 1. Optimisation of catalytic conditions for secondary allylic alco-
hols.
80%, 9:1 E/Z
77:23 e.r. (E)[c]
47:53 e.r. (Z)[c]
81%, 5:1 E/Z
77:23 e.r. (E)[c]
13:87 e.r. (Z)[c]
Entry
Mol% Cat.
t [h]
MS
Results[a]
74%,>20:1 E/Z
99:1 e.r. (E)[c]
1
2
3
4
5
6
7
8
10
5
48
67
None
62%, 2:1 5/6, 10:1 E/Z
42%, >20:1 5/6, 9:1 E/Z
84%, >20:1 5/6, 9:1 E/Z
81%, >20:1 5/6, 8:1 E/Z
56%, >20:1 5/6, 9:1 E/Z
90%, >20:1 5/6, 7:1 E/Z
67%, >20:1 5/6, 10:1 E/Z
84%, >20:1 5/6, 7:1 E/Z
4 ŠMS
4 ŠMS
2”4 ŠMS
3 ŠMS
3 ŠMS
3 ŠMS
3 ŠMS
2”5
2”5
5
2”5
2”2.5
2”5
24+39
24+39
66
20+20
20+20
8+16
from 4h: 67%, 14:1 E/Z
racemic
from 4i: 73%, 12:1 E/Z
racemic
8
59%, 6:1 E/Z
98:2 e.r. (E)[c]
38:62 e.r. (Z)[c]
1
[a] Isolated yields. 5/6 and E/Z ratios determined by H NMR analysis.
9
79%, 9:1 E/Z
71:29 e.r. (E)[c,d]
2:1 ratio of formal SN2’/SN2 (5aa/6aa, entry 1), which needed
to be improved drastically before chirality transfers could be
investigated. During our optimisation, we discovered that addi-
tion of molecular sieves (MS) to the reaction mixture greatly
improved the selectivity, exclusively yielding the formal SN2’
product 5aa (entries 2–8). 3 Š MS provided slightly higher
yields compared to 4 Š MS (entry 2 vs. entry 5), however, the
yields were modest when only 5 mol% of gold catalyst was
employed (42% and 56%, respectively). Portion-wise addition
of gold catalyst (2”5 mol%) greatly improved the yields (en-
tries 3 and 6), but addition of another portion of molecular
sieves makes little difference (entry 3 vs. entry 4). Finally, as
a compromise between shorter reaction times and acceptable
yield, we settled for the protocol shown in entry 8 as our opti-
mised conditions for investigating the chirality-transfer reac-
tion. Note that under these newly optimised conditions, the
formal SN2’ product 5 is formed exclusively for all subsequent
substrate-scope screens (Tables 2 and 3).
10
11
71%, >20:1 E/Z
67:33 e.r. (E)[c]
72%, >20:1 E/Z
51:49 e.r. (E)[c]
12
13
62%, >20:1 E/Z
53:47 e.r. (E)[c]
[a] Isolated yields. >20:1 5/6 (formal SN2’/formal SN2) by 1H NMR analysis
where applicable. E/Z ratios determined by 1H NMR analysis. [b] Deter-
mined by CSP-HPLC of a derivative. [c] Determined by CSP-HPLC. [d] E.r.
of Z isomer not determined.
chiral stationary phase (CSP)-HPLC enantiomer separation in
the product. Gratifyingly, our first attempt with enantioen-
riched n-butyl allylic alcohol (R)-4a gave the desired product
(E)-5ab in 88:12 e.r. from >99:1 e.r. of the starting material.
The minor (Z)-isomer (Z)-5ab was obtained in 84:16 e.r.
With these optimised conditions in hand, we turned our at-
tention to effecting chirality transfer in etherifications of
a range of enantioenriched allylic alcohols (Table 2). For this
assay, alcohol 2b was chosen as the nucleophile for ease of
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(entry 1). Alternatively, starting with (Z)-allylic alcohol 4b, the
opposite enantiomer of the product could be obtained with
good transfer of chirality (entry 2). It should be noted, howev-
er, that the Z-allylic alcohol starting materials (e.g., 4b, entry 2)
are more difficult to access in high e.r., resulting in poorer e.r.
of product 5bb, despite displaying a good degree of chirality
transfer (81:19!76:24 e.r.). Reversing the substituents at the
a- and g-positions of the allylic alcohol similarly gave high
yield of product 5cb with a high degree of chirality transfer
(entry 3). Replacing the n-butyl substituent with the sterically
more demanding cyclohexyl also works well with the Cy at the
a-position, but only moderately at the g-position (entries 4–5).
To verify that a more sterically hindered substituent at the g-
position causes a drop in chirality transfer, allylic alcohol 4 f,
with an iPr at the g-position was investigated. Indeed, moder-
ate chirality transfer of >99:1!77:23 e.r. is observed (entry 6).
Benzyl-substituted allylic alcohol 4g provided the best result
in this assay, with excellent chirality transfer (>99:1!99:1 e.r.)
and >20:1 E/Z observed (entry 7). Replacing the benzyl in 4g
(entry 7) with a Ph substituent (4h, entry 8) causes a drastic
change (racemic product 5hb). Unlike with alkyl substituents
(entries 1 vs. 3 and entries 4 vs. 5), swapping the Ph substitu-
ent around now forms the same product (4i!5hb, entry 8),
so aryl substituents appear to be detrimental to both chirality
transfer and formal SN2’ selectivity. Next, we decided to com-
pare our procedure with substrate 4j, which was the substrate
chosen by Widenhoefer et al. in their studies (entry 9).[14] The
chirality transfer is once again excellent (99:1!98:2 e.r.). It
should be noted that using our newly optimised conditions,
etherification proceeds with significantly higher formal SN2’ se-
lectivity (>20:1 vs. 5:1 formal SN2’/SN2).
Table 3. Nucleophile alcohol scope.
Entry
1
Nucleophile 2
Product
Result[a]
78%, 7:1 E/Z
88:12 e.r. (E)[b]
21:79 e.r. (Z)[b]
82%,10:1 E/Z
97:3 e.r. (E)[c]
<1:99 e.r. (Z)[c]
73%, 6:1 E/Z
87:13 e.r. (E)[b]
25:75 e.r. (Z)[b]
84%,10:1 E/Z
>95:5 e.r. (E)[d]
<5:95 e.r. (Z)[d]
76%, 4:1 E/Z
86:14 e.r. (E)[c]
9:91 e.r. (Z)[c]
76%,10:1 E/Z
98:2 e.r. (E)[c]
4:96 e.r. (Z)[c]
74%, 2:1 E/Z
93:7 e.r. (E)[e]
29:71 e.r. (Z)[e]
67%, 6:1 E/Z
94:6 e.r. (E)[e]
35:65 e.r. (Z)[e]
71%, 6:1 E/Z
98:2 e.r. (E)[c]
14:86 e.r. (Z)[c]
81%, 5:1 E/Z
86:14 (E)[c]
2
3
4
5
6
7
8
9[f]
10
9:91 e.r. (Z)[c]
83%, 1:1.1 d.r.
>20:1 E/Z
98:2 e.r. (d 1)[e]
97:3 e.r. (d 2)[e]
77%,>20:1 d.r.
10:1 E/Z
93:7 e.r. (E)[c]
10:90 e.r. (Z)[c]
76%,14:1 E/Z
>99:1 e.r. (E)[c]
7:93 e.r. (Z)[c]
Certain substituents on the allylic alcohol substrate were
found to cause the chirality transfer to proceed moderately to
poorly (entries 10–13). For example, dimethyl allylic alcohol 4k
gave a high degree of racemisation (71:29 e.r. of E-5kb from
4k of >99:1 e.r.); likewise, increasing the steric bulk of the
substituent at the alcohol centre to tert-butyl alcohol 4l also
led to some racemisation during reaction (entry 11). Substrates
with b-substituents performed the worst: 4m and 4n both
give excellent >20:1 E/Z ratios, but almost complete racemisa-
tion under these conditions (entries 12–13) and are therefore
not suitable substrates for chirality transfer.
11
12
13[g]
1
[a] Isolated yields, >20:1 5/6 (formal SN2’/formal SN2) by H NMR analysis.
E/Z ratios and d.r. values determined by 1H NMR analysis. [b] Determined
by CSP-HPLC of a derivative. [c] Determined by CSP-HPLC. [d] Determined
by chiral shift 1H NMR spectroscopy. [e] Determined by CSP-GC. [f] Using
allylic alcohol (S)-4j, >99:1 e.r. [g] Using allylic alcohol (R)-4g, >99:1 e.r.
We next turned our attention to investigating the tolerance
of a range of different nucleophile alcohols by using model al-
lylic alcohol substrate (R)-4a (Table 3).[15] Although para-bromo-
benzyl alcohol 2d (entry 3) gave a comparable result to the
original nucleophile alcohol 2b, benzyl alcohol 2c and para-
methoxybenzyl alcohol 2e yielded products 5ac and 5ae, re-
spectively, with a greater degree of chirality transfer (97:3 e.r.,
entry 2 and >95:5 e.r., entry 4).[16] Furfuryl alcohol 2 f was also
tolerated, though with a reduction of enantioenrichment in
product 5af (entry 5). We then turned our attention to alkyl al-
cohols. Extending the alkyl chain of benzyl alcohol by two
methylene units preserved yield, formal SN2’/SN2 and E/Z
alkene selectivity as well as chirality-transfer efficiency (entry 2
vs. entry 6). Next, we set out to test functional group tolerance.
Pleasingly, trifluoromethyl substitution of the nucleophile was
tolerated (entry 7) as were haloalkanes (entry 8) and unprotect-
ed terminal alkenes (entry 9). When utilising diol 2k, reaction
occurred exclusively through the primary alcohol to give 5ak
in high yield and selectivity (entry 10). No product from subse-
quent reaction through the tertiary alcohol was observed.
Acid-labile groups such as acetals 2l and 2m were also found
to be compatible with the reaction (entries 11 and 12). Finally,
we demonstrated that the reaction also proceeds very well
(>99:1 e.r.) using a more hindered secondary nucleophile alco-
hol such as cyclohexanol 2n (entry 13).
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Scheme 2. Proposed mechanism for successful chirality transfer and stereo-
specificity.
Scheme 3. Resubjection of products 5db, 5eb and 5mb to the reaction
conditions.
The mechanism that we originally proposed for the allylic
etherification reaction[8a] can also account for the chirality
transfer and stereospecificity of the reaction (Scheme 1). As
gold(I) is an excellent p-Lewis acid,[5e] it is likely to activate the
alkene functionality in the allylic alcohol towards attack by an
external alcohol nucleophile (I, Scheme 2).[10f] Demetallation
and elimination of water (enabled by intramolecular hydrogen-
bonding, II) will then regenerate the catalyst and produce the
desired allylic ether product 5. A tightly bound chair-like 6-
membered ring transition state[17] is required for efficient chir-
ality transfer, and also accounts for the stereospecificity of the
E and Z isomers. As shown in Scheme 1a, the E isomer has its
substituent R in the equatorial position, whereas the Z isomer
has R axial (Scheme 2b), thus leading to the different stereo-
chemical outcomes. Having the substituent R’ equatorial also
accounts for the E-selectivity of the reaction.
resubjection to the reaction conditions (Scheme 3c).[20] From
these results, it appears that slight erosion of ee is not caused
by isomerisation/racemisation of the product (see later and
Scheme 9 for plausible racemisation mechanism). However, in-
stances of complete racemisation, such as the formation of
5mb and 5nb from b-substituted 4m and 4n, respectively,
could be due to isomerisation and racemisation of the prod-
ucts under the reaction conditions.
Next, we wanted to ascertain the role of molecular sieves in
the reaction. It is clear from the results in Table 1 that addition
of molecular sieves is the key factor to improving the formal
SN2’/SN2 (5/:6) regioselectivity. Our next control reaction
(Scheme 4) shows that molecular sieves are also crucial for
It is clear from the proposed mechanism in Scheme 1 that
the hydrogen-bonded 6-membered transition state I is crucial
for the chirality transfer, and also the E-selectivity. Any erosion
of ee could therefore be attributed to the disruption of this hy-
drogen-bonding pattern that would allow the reaction to
occur without this 6-membered transition state I. One such
mechanism is explored in the computational section below
(see Scheme 9). However, a second possibility for erosion of ee
is the racemisation of the product 5 through isomerisation be-
tween the formal SN2’ (5) and formal SN2 (6) products, cata-
lysed by gold(I).[6b,c,17] Indeed, during our related studies using
thiols for thioetherification reactions, chirality transfer does not
occur in the thioetherification reactions.[7a,18] Experimental and
computational studies showed that the racemisation is due to
isomerisation between the formal SN2’ and SN2 thioether prod-
ucts. Clearly, using alcohol instead of thiol as a nucleophile
allows for successful chirality transfer, except in certain sub-
strates, such as b-substituted 4m and 4n (entries 12–13,
Table 2). Therefore, we carried out several control experiments
to ascertain the role of isomerisation of the products 5 and 6
in the erosion of ee.
Scheme 4. Allylic etherification of 4d without molecular sieves results in rac-
emic product.
chirality transfer and E/Z selectivities. Removing molecular
sieves from the reaction results in a completely racemic prod-
uct 5 db and a poor 3:1 E/Z ratio (vs. 89:11 e.r. and 9:1 E/Z
with molecular sieves added).[21]
Previously, Widenhoefer et al. had shown that chirality trans-
fer is possible on substrate 4j, without the need for molecular
sieves (Scheme 5).[14] Having just ascertained that molecular
sieves are crucial to avoid racemisation, we therefore thought
it important to investigate whether the conditions in Scheme 5
allow for the omission of molecular sieves in chirality-transfer
Firstly, product 5 db (entry 4, Table 2) was resubjected to the
reaction conditions and no change was observed after 24 h
(Scheme 3a). Next, 5eb was investigated, as this product was
formed with only moderate chirality transfer (77:23 e.r. , entry 5,
Table 2). Once again, no change was observed upon resubjec-
tion to the reaction conditions (Scheme 3b). Finally, product
5mb, which is formed as a racemic mixture by our method
(entry 12, Table 2) was investigated. This species, obtained in
98:2 e.r. by an alternative route,[19] was found to racemise upon
Scheme 5. Results by Widenhoefer et al.[14]
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etherification reactions. In particular, we sought to understand
why our initial expectation of chirality transfer (cf. Scheme 1
and 2) was not borne out, except in the presence of molecular
sieves. In the calculations we have studied the symmetrically
substituted dimethyl allylic alcohol 4k (as the R,E-isomer) re-
acting with ethanol (2o) to give 5ko. This choice removes the
potential complication of any subsequent SN2’ reaction at 5ko
as this would return the same 5ko product. Experimental stud-
ies indicate that the catalysis is not significantly affected by
the nature of the alcohol and so ethanol was chosen for sim-
plicity. The calculations (run with SDD pseudopotentials and
basis sets on Au and P, with d-orbital polarization on the latter,
and 6-31g** basis sets on other centres) report free energies
derived from a BP86-D3(toluene) protocol, that is, gas-phase
free energies based on BP86 optimisations, corrected for dis-
persion and toluene solvation (using Grimme’s D3 parameter
set and the PCM approach respectively, see Supporting Infor-
mation for full details).
Scheme 6. Control reactions to ascertain effects of conditions vs. substrate.
(a) Standard substrate by using the conditions of Widenhoefer et al. (b) Sub-
strate 4j by using conditions that usually result in racemisation.
reactions, or whether successful chirality transfer without mo-
lecular sieves is in fact specific to substrate 4j. Our results in
Scheme 6 show that the latter is true. Employing the condi-
tions of Widenhoefer et al. on substrate 4d (which undergoes
chirality transfer with molecular sieves under our conditions,
Table 2, but racemises in the absence of 3 Š MS, Scheme 4), re-
sults in racemic product 5 db. However, employing substrate
4j under conditions that usually result in racemisation (i.e., no
3 Š MS), results in efficient chirality transfer. Therefore, it ap-
pears that the substituent on substrate 4j plays a significant
role in allowing the chirality-transfer process to proceed effi-
ciently even without molecular sieves. For a more general sub-
strate scope, however, the addition of molecular sieves to the
reaction is crucial for successful chirality transfer.
The Au-catalysed direct allylic etherification reaction is
thought to proceed[23] via coordination of the {Au(PPh3)}+ frag-
ment at the C=C p-bond of the allylic alcohol. As shown by
Mukherjee and Widenhoefer,[14] if the alcohol nucleophile at-
tacks at the opposite face to Au then only two outcomes are
possible with an enantiopure substrate: with (R,E)-4k either
(S,E)-5ko or (R,Z)-5ko will be formed (Scheme 8). The forma-
The effect of molecular sieves in the reaction is stark as well
as puzzling. There are several possibilities regarding the mode
of action of molecular sieves in the reaction that may lead to
the observed chirality-transfer outcome. Possible reasons for
this could be: i) removal of excess water from the reaction;
ii) the slightly basic nature of molecular sieves, which may de-
activate the gold catalyst;[22] and iii) the polar surface of molec-
ular sieves may result in the reaction occurring closer to the
surface, thereby changing the aggregation levels or transition
state. However, a control reaction to test point (i) shows that
chirality transfer is observed regardless of whether the molecu-
lar sieves are activated or not, thus ruling out this possibility
(Scheme 7). In fact, the reaction occurs with even better yields
and e.r. with unactivated vs. activated sieves (67%, 94:6 e.r. vs.
90%, 98:2 e.r., Scheme 7).
Scheme 8. Possible outcomes of the Au-mediated reaction of (R,E)-4k with
ethanol (2o) to give either (S,E)- or (R,Z)-5ko. Computed product free ener-
gies are indicated in kcalmolÀ1, relative to the reactant set to 0.0 kcalmolÀ1
.
tion of both products (alongside water) is computed to be
thermodynamically downhill, with the E-isomer favoured over
the Z-form by 1.3 kcalmolÀ1. This equates to a E/Z ratio of ap-
proximately 9:1 at 298 K, fairly typical of the E/Z selectivities
seen with dialkyl-substituted allylic alcohols (Tables 1 and 2).
This result also suggests the reaction may be proceeding
under thermodynamic control.
For the computed mechanism, we consider the direct etheri-
fication to start from the p-bound adduct [(Ph3P)Au{(R,E)-4k}]+
·EtOH, I, in which the EtOH is hydrogen-bonded to the OH
group of the allylic alcohol.[24] Several arrangements of this
adduct were located in the course of this study and the most
stable of these, Ia, has the EtOH lying over the Au centre (i.e.,
syn to Au), with interactions to both the O of the allyl group
(1.86 Š) and also to one CÀH bond of the PPh3 ligand (2.26 Š,
see Figure 1, which also provides the associated labelling
scheme). The most stable adduct, where the EtOH is located
Scheme 7. Comparing results of reactions with no molecular sieves, activat-
ed sieves and unactivated sieves.
Density functional theory (DFT) calculations were therefore
employed to explore the mechanism of these direct allylic
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ing equatorial positions. Similar
structures have been reported at
a {Au(NHC)}+ fragment.[17a] From
here H+ transfer induces loss of
water and concomitant forma-
tion of the AuÀC3 bond to give
intermediate IIIb in which the al-
lylic ether product is bound
through the C2=C3 bond and
water is hydrogen-bonded to
the ether oxygen. Dissociation
will give 5ko as the S,E-form. Of
the two transition states, the
higher is TS(II–III)b at +11.1 kcal
molÀ1. An analogous series of
events accounts for the forma-
tion of (R,Z)-5ko. Starting from
Ic (G= +6.8 kcalmolÀ1), the
Figure 1. Computed structures of two forms of [(Ph3P)Au{(R,E)-4k}]+·EtOH, I, with computed free energies (kcal
molÀ1, relative to Ia set to zero) and selected distances in Š. Phosphine H atoms are omitted for clarity, with the
exception of that interacting with the EtOH molecule in Ia.
chair-like intermediate IIc is formed via TS(I–II)c at
+11.1 kcalmolÀ1. IIc is similar to IIb but now has one
methyl substituent in an axial position. Loss of H2O
via TS(II–III)c at +13.2 kcalmolÀ1 leads to IIIc from
which the allylic ether product is lost as the (R,Z)-
form. Overall, these two allylic etherification process-
es proceed with modest barriers (<14 kcalmolÀ1). In
addition, as these reactions are only marginally
downhill thermodynamically (Scheme 8), they are
likely to be reversible under the reaction conditions.
Hence, a thermodynamic distribution of products is
seen that favours the (S,E)-5ko product.
The observation of the enhanced stability of pre-
cursor Ia in which EtOH is positioned syn to Au sug-
gests the possibility of alternative syn attack mecha-
nisms and two such processes have been character-
ised (see Figure 4). Hydrogen-bonded chair-like inter-
mediates IIa and IId are located, but now with the
Au in an axial position (see Figure 3 for the structure of IIa).
Loss of water from IIa and IId then leads to the formation of
Figure 2. Key intermediates and energetics for the Au-catalysed reaction of (R,E)-4k with
ethanol (2o) through anti attack to give either (S,E)-5ko or (R,Z)-5ko (L=PPh3). Comput-
ed free energies are indicated in kcalmolÀ1 and quoted relative to Ia set to 0.0 kcal
molÀ1
.
on the other side of the C=C p-bond (i.e., anti to Au, Ib), is
6.6 kcalmolÀ1 higher in energy, with the EtOH showing close
contacts with one allylic proton,
as well as the OH group. All en-
ergies in this section will be
quoted relative to Ia set to
0.0 kcalmolÀ1.
The key steps and associated
energetics for direct etherifica-
tion through anti-attack of EtOH
are outlined in Figure 2. Starting
from Ib, CÀO bond formation
proceeds through a transition
state at +10.9 kcalmolÀ1 to give
intermediate IIb at +9.1 kcal
molÀ1. The computed structure
of this species is shown in
Figure 3 and displays the antici-
pated hydrogen-bonded chair-
Figure 3. Different forms of intermediate II: IIb and IIc are alternative species formed by anti attack of ethanol,
whereas IIa is formed by syn attack. Computed free energies (kcalmolÀ1) are quoted relative to Ia set to zero and
like structure with the Au and
both Me substituents all occupy- selected distances are in Š. Phosphine phenyl substitutents are truncated at the ipso carbon for clarity.
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comparable, the result will be the loss of chirality
transfer that is seen experimentally.
A model incorporating three ethanol molecules
was set up to test these ideas (see Figure 5), three
being the minimum number of EtOH molecules re-
quired to access pathway (ii), which requires both
faces of the allylic alcohol substrate to be engaged.
As in the single EtOH system, the most stable form of
the hydrogen-bonded precursor has one EtOH posi-
tioned over the Au centre. This species, Ia3(ii), leads
ultimately to the (R,E)-5ko product along pathway
(ii), as described below. The alternative arrangement
relevant for pathway (i) is seen in Ia3(i) and lies
8.7 kcalmolÀ1 higher in energy. Both the initial attack
of EtOH at this species (via TS(I–II)a3(i) at +12.8 kcal
molÀ1) and the subsequent loss of water (via TS(II–
Figure 4. Key intermediates and energetics for the Au-catalysed reaction of (R,E)-4k with
ethanol (2o) by syn attack to give either (S,E)-5ko or (R,Z)-5ko (L=PPh3). Computed free
energies are indicated in kcalmolÀ1 and quoted relative to Ia set to 0.0 kcalmolÀ1
.
(R,Z)-5ko and (S,E)-5ko, respectively, that is, the same
products as seen in the anti attack processes. syn
attack, however, entails barriers of 17.7 and 18.4 kcal
molÀ1, and so these processes will not be competitive
with the anti attack mechanisms described above.
The mechanisms outlined so far are consistent
with the transfer of chirality shown in Widenhoefer’s
example (Scheme 5) and anticipated prior to our
work. However, our experimental studies have shown
that in most cases such chirality transfer only occurs
in the presence of molecular sieves and that in fact
under sieve-free conditions loss of chirality domi-
nates. To account for this a mechanism, involving nu-
cleophilic attack at one face of the allylic alcohol and
loss of water from the opposite face is required. One
way to achieve this is to invoke a proton chain trans-
fer mechanism[25] involving several EtOH molecules.
This is illustrated in Scheme 9 for the case of three
EtOH molecules. Pathway (i) is equivalent to the anti
attack in Scheme 8, where a three EtOH molecule
Figure 5. Key intermediates and energetics for the Au-catalysed reaction of (R,E)-4k in
the presence of three ethanol molecules to give (i) (S,E)-5ko and (ii) (R,E)-5ko (L=PPh3).
Computed free energies are indicated in kcalmolÀ1 and quoted relative to Ia3(i) set to
0.0 kcalmolÀ1
.
III)a3(i) at +14.0 kcalmolÀ1) occur anti to the Au and hence
yield the (S,E)-5ko product. The overall barrier for pathway (i)
is 14.0 kcalmolÀ1
.
In pathway (ii), the EtOH molecule lying over the Au centre
in Ia3(ii) is linked through two hydrogen-bonded EtOH mole-
cules to the allylic hydroxyl group, which maintains a position
anti to the Au. syn attack of EtOH proceeds to give IIa3(ii) (G=
+6.0 kcalmolÀ1) via TS(I–II)a3(ii) at +15.6 kcalmolÀ1. Figure 6
shows the computed structure of IIa3(ii) and highlights the anti
arrangement of the EtOH nucleophile and the putative H2O
leaving group. In this case, the water dissociation is the easier
step and so (R,E)-5ko is formed with an overall barrier of
15.6 kcalmolÀ1. Similar barrier heights are therefore computed
Scheme 9. Possible mechanisms accounting for loss of chirality transfer in
the Au-mediated reactions of (R,E)-4k with three ethanol molecules to form
both (S,E)-5ko (pathway (i)) and (R,E)-5ko (pathway (ii)).
chain now promotes loss of water anti to Au with formation of
(S,E)-5ko. In contrast, pathway (ii) is able to accommodate
a syn attack by EtOH while still delivering a proton onto the al-
lylic hydroxyl group that is in an anti position. This leads to the
formation of (R,E)-5ko. If the barriers to pathways (i) and (ii) are
for the formation of both (S,E)-5ko (DG°calc =14.0 kcalmolÀ1
)
and (R,E)-5ko (DG°calc =15.6 kcalmolÀ1) and this, coupled with
reversibility of these transformations, means that both enantio-
mers will be formed over the timescale of the reaction, leading
to the unexpected loss of chirality transfer.[26]
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Scheme 11. Large excess of alcohol nucleophile results in racemisation with
4j, overriding the effect of the ether moiety (CH2OBn) and molecular sieves.
5ko). As, by definition, the energies of these two enantiomers
of 5kb are the same, these reversible processes will produce
a racemic mixture. This is exemplified by control experiments
shown in Scheme 12, where the product 5kb from Table 2,
entry 10 is resubjected to the reaction conditions without
Figure 6. Computed structure of intermediate IIa3(ii) located along path-
way (ii) on route to the formation of (R,E)-5ko. The computed free energy is
in kcalmolÀ1 and is relative to Ia3(i) set to zero. Selected distances are in Š
and phosphine phenyl substituents are truncated at the ipso carbon for
clarity.
A plausible explanation for the requirement of molecular
sieves for efficient chirality transfer is their role in disrupting
the type of proton chain transfer mechanism (i.e., aggregation
levels of alcohol) shown in Scheme 9, which are a potential
cause of racemisation. To test our hypothesis, the reaction was
carried out with a large excess of alcohol nucleophile[27]
(Scheme 10), which should outcompete the role of the molecu-
Scheme 12. Resubjecting 5kb to reaction conditions: racemisation without
molecular sieves and much slower erosion of e.r. with molecular sieves.
sieves to produce a racemic mixture. In contrast, in the pres-
ence of sieves, this process is considerably slowed
(Scheme 12). Although the reasons for the remarkable impact
of the molecular sieves on these transformations are currently
unclear, nevertheless, their effect in providing kinetic control
for these experiments is remarkable and, moreover, synthetical-
ly useful.
Scheme 10. Comparing results of reactions with no molecular sieves, unacti-
vated sieves and large excess of alcohol nucleophile.
Conclusion
lar sieves. Indeed, very poor enantiomeric ratios are observed
in the presence of 20 equivalents of alcohol 2i (Scheme 10),
thereby lending support to our theory. Following this train of
thought, we postulated that the reason substrate 4j does not
require molecular sieves for chirality transfer (Schemes 5 and 6)
is because the ether moiety (-CH2OBn) within the substrate
may be playing a similar role to molecular sieves: disrupting
the proton chain transfer mechanism, presumably by hydro-
gen-bonding. Indeed, when the reaction with 4j is repeated
with a large excess (20 equiv) of alcohol nucleophile, this over-
rides any effect of the ether moiety as well as molecular sieves
and produces racemic product 5jb in a poor 1:1 5jb/6jb re-
gioselectivity (Scheme 11).
We have successfully developed conditions for highly regiose-
lective, gold(I)-catalysed direct allylic etherification of alcohols
with chirality transfer to access enantioenriched g-substituted
secondary allylic ethers. A thorough substrate screen shows
that very high levels of chirality transfer can be achieved (up
to >99:1 e.r.). The reaction is very functional-group tolerant
and proceeds in the presence of unprotected groups such as
alkyl halides, tertiary alcohols, alkenes and acid-sensitive ace-
tals. Both primary and the more hindered secondary alcohol
nucleophiles are tolerated well. Furthermore, we demonstrate
that the addition of molecular sieves is crucial not only for ex-
cellent formal SN2’ selectivity, but also to ensure efficient chiral-
ity transfer. The molecular sieves need not be activated to ach-
ieve this effect, which implies that it is not aiding the selectivi-
ty by removal of water. DFT calculations suggest that chirality
transfer should proceed under conditions that promote the re-
action of a single alcohol as nucleophile. However, at higher al-
cohol concentrations proton chain transfer mechanisms
become accessible, which permit alternative pathways that will
An additional explanation for erosion of chirality transfer is
possible for allylic ether products such as 5kb. In this case,
a second formal SN2’ reaction on 5kb will lead to the same
product, but with chirality transfer to the opposite enantiomer.
Calculations indicate that the barrier for the second formal SN2’
is readily accessible (via a transition state at 9.8 kcalmolÀ1 for
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erode the chirality transfer. A plausible role of the molecular
sieves is to disrupt the aggregation of alcohol molecules in
order to prevent loss of chirality through this pathway. What-
ever the underlying reasons, the impact of molecular sieves in
controlling the outcome of these allylic etherification reactions
is remarkable and synthetically useful.
Experimental Section
General procedure
A solution of [PPh3AuNTf2] (2:1 toluene adduct, 5 mol%), allylic al-
cohol 4 (0.101 mmol), alcohol 2 (0.506 mmol) and 3 Š molecular
sieves (8 mg) in toluene (260 mL) was stirred at 508C under air for
8 h. Then, [PPh3AuNTf2] (2:1 toluene adduct, 5 mol%) was added
and the resulting solution was stirred at 508C for a further 16 h.
The resulting solution was filtered through a short plug of silica,
washing with 9:1 hexane/Et2O. The filtrate was evaporated under
reduced pressure to give the crude product, which was purified by
flash column chromatography. Full experimental procedures, char-
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1
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We thank the EPSRC (EP/K00736X/1) and EPSRC DTA student-
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Keywords: alcohols · allylations · asymmetric reactions
chirality transfer · gold
·
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an O-bound form of the reactant and found this to be higher in energy
(G= +22.6 kcalmolÀ1). See the Supporting Information.
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previous optimisation studies in order to avoid self-reaction of allylic al-
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to be a compromise between avoiding self-reaction of 4, and avoiding
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Received: April 24, 2015
Published online on August 6, 2015
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