Chirality Transfer in Gold(I)-Catalysed Hydroalkoxylation of 1,3-Disubstituted Allenes

Article abstract of DOI:10.1002/chem.201603918

Gold(I)-catalysed intermolecular hydroalkoxylation of enantioenriched 1,3-disubstituted allenes was previously reported to occur with poor chirality transfer due to rapid allene racemisation. The first intermolecular hydroalkoxylation of allenes with efficient chirality transfer is reported here, exploiting conditions that suppress allene racemisation. A full substrate scope study reveals that excellent regio- and stereoselectivities are achieved when a σ-withdrawing substituent is present.

Full text of DOI:10.1002/chem.201603918

DOI: 10.1002/chem.201603918
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Chirality Transfer |Hot Paper|
Chirality Transfer in Gold(I)-Catalysed Hydroalkoxylation of
1,3-Disubstituted Allenes
Stacey Webster, Daniel R. Sutherland, and Ai-Lan Lee*[a]
Abstract: Gold(I)-catalysed intermolecular hydroalkoxylation
of enantioenriched 1,3-disubstituted allenes was previously
reported to occur with poor chirality transfer due to rapid
allene racemisation. The first intermolecular hydroalkoxyla-
tion of allenes with efficient chirality transfer is reported
here, exploiting conditions that suppress allene racemisa-
tion. A full substrate scope study reveals that excellent
regio- and stereoselectivities are achieved when a s-with-
drawing substituent is present.
Introduction
The gold-catalysed[1] hydroalkoxylation of allenes[2,3] is one of
the earliest homogenous gold(I)-catalysed reactions to be re-
ported.[4] The ability of gold(I) to act as a soft, p-Lewis acid
makes it an ideal catalyst, and since the turn of the century,
many excellent publications have emerged in the area.[5] To
date, however, much of the attention has been focused on in-
tramolecular hydroalkoxylations to form cyclic ether products,
including with excellent regio- and enantioselectivity.[2e,6] Far
less attention has been paid to the intermolecular variant, and
it was not until 2008 when Widenhoefer,[7] Yamamoto[8] and
Horino[9] revealed the first examples of the gold-catalysed in-
termolecular hydroalkoxylation of allenes (e.g., reaction (1),
Scheme 1).[10–12] Following these seminal reports, Paton and
Maseras proposed, based on DFT calculations, that the regiose-
lectivity observed by Widenhoefer and Yamamoto is due to
isomerisation of the kinetic tertiary allylic ether 3 to the ther-
modynamic primary allylic ether 2, rather than preferential acti-
vation of 1 at the less-hindered double bond, as originally as-
sumed (reaction (2), Scheme 1).[13] Drawing on previous success
in controlling the regioselectivity of gold-catalysed alcohol ad-
ditions to cyclopropenes,[14] we subsequently developed condi-
tions to suppress isomerisation of 3 to 2, thereby switching
the regioselectivity to the kinetic, tertiary allylic ether product
3 (reaction (3), Scheme 1).[15] The use of DMF as solvent was
the crucial difference, possibly because it reduces the activity
Scheme 1. Previous work on intermolecular gold-catalysed hydroalkoxylation
of allenes.
of the active cationic gold catalyst (IPr)Au+ (IPr=1,3-bis(2,6-di-
isopropylphenyl)imidazol-2-ylidene) by means of reversible co-
ordination.[16]
In contrast to 1-substituted and 1,1-disubstituted allenes 1,
1,3-disubstituted allenes 4 have been far less studied, presum-
ably due to regioselectivity issues when R1 and R2 are not elec-
tronically differentiated. 1,3-Disubstituted allenes 4, however,
are extremely interesting due to the possibility of axis to point
chirality transfer during the hydroalkoxylation reaction
(Scheme 2).[17] Surprisingly, Yamamoto et al. observed that,
while the related gold-catalysed hydramination reaction with
allene 4a occurred with good chirality transfer,[18,19] the corre-
sponding hydroalkoxylation, using less nucleophilic alcohols in-
stead of anilines as nucleophiles, produced only racemic prod-
uct (reaction (1), Scheme 3).[8b] In his seminal work, Widenhoe-
fer et al. also reported chirality transfer reaction on one sub-
strate, allene 4b, and obtained a much more promising
[a] S. Webster, D. R. Sutherland, Dr. A.-L. Lee
Institute of Chemical Sciences
School of Engineering and Physical Sciences
Heriot-Watt University
Edinburgh EH14 4AS (UK)
E-mail: A.Lee@hw.ac.uk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201603918.
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This is an open access article under the terms of the Creative Commons At-
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medium, provided the original work is properly cited.
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proach would allow us to finally realise efficient chirality trans-
fers. In this full article, we describe our endeavours and dis-
close for the first time a method for intermolecular hydroalkox-
ylation of allenes with high degree of chirality transfer, along
with full substrate scope studies.
Scheme 2. 1,3-Disubstituted allenes can in principle undergo chirality trans-
fer.
Results and Discussion
We initiated our investigations using the allene 4b, since regio-
selectivity is not an issue with this substrate[7] (see below), and
also in order to readily compare our results with previous stud-
ies (Scheme 3). Working on the assumption that any erosion of
chirality transfer originates from rapid racemisation of the
allene substrate, as suggested by Widenhoefer and Yamamoto,
while not ruling out racemisation of the allylic ether product
through isomerisation (see reaction (2), Scheme 1), it is clear in
either case that the conditions need to be modified in order to
retard the racemisation step while still actively catalysing the
desired hydroalkoxylation reaction. Based on our previous re-
lated studies mentioned above, we hypothesised that our two
previous sets of conditions could potentially be solutions:
1) conditions in reaction (3), Scheme 1 (DMF, 08C, excess alco-
hol), which was found to suppress any further isomerisation of
the allylic ether products, and 2) conditions using molecular
sieves, as shown in Scheme 4, which was also shown to favour
the kinetic products.[23] Pleasingly, our initial results were prom-
ising and are summarised in Scheme 5. Addition of molecular
sieves did indeed result in higher chirality transfer (97:3 e.r.),
however, at the cost of a drop in yield (30%, reaction (1),
Scheme 5). Unfortunately, further attempts at optimisation by
increasing the time, temperature and catalyst loading did not
significantly improve the yield without a subsequent drop in
e.r. Therefore, we turned to our previous conditions shown in
reaction (3), Scheme 1 instead: (IPr)AuCl/AgOTf (Tf=triflate)
pre-catalyst at 08C in DMF, with excess alcohol. To our delight,
high chirality transfer (98:2 e.r.) is observed and in a much
better 65% yield of 6bb (reaction (2), Scheme 5).
Scheme 3. Previous reported attempts at chirality transfer in gold-catalysed
hydroalkoxylation of allenes.
result.[7] Nevertheless, the reaction still proceeded with sub-
stantial erosion of enantiomeric excess (97!79% ee, reac-
tion (2), Scheme 3). In both cases, it is thought that rapid race-
misation of the allene[20] under the hydroalkoxylation condi-
tions is to blame.[7,8] Thus far, this remains an unsolved prob-
lem and represents a clear limitation in the area.
Meanwhile, we recently carried out a full investigation into
chirality transfer in gold-catalysed allylic etherification reac-
tions; this reaction is related to the title reaction by virtue of
forming similar allylic ether products 6, though with different
substrate and mechanism. Surprisingly, we discovered that the
addition of molecular sieves (MS) was crucial for both regiose-
lectivity and efficient chirality transfer (Scheme 4).[21,22] In the
absence of molecular sieves, only racemic allylic ether products
6 were observed. Inspired by this discovery, we decided to re-
visit the gold-catalysed hydroalkoxylation of allenes (Scheme 2
and Scheme 3) in order to investigate whether a similar ap-
Scheme 4. Addition of molecular sieves (MS) affects efficiency of chirality
transfer.
Scheme 5. Initial attempts at increasing the levels of chirality transfer.
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Before proceeding to the substrate scope, we carried out
control reactions to ascertain whether erosion in enantiomeric
excess occurs through racemisation of the allylic ether product
6 or racemisation of the allene substrate 4, or both. Towards
this end, the allylic ether products 6bb and 6cb were subject-
ed to two reaction conditions: the original conditions used by
Widenhoefer in reaction (2) Scheme 3 (hereafter referred to as
Conditions A) and also our conditions shown in reaction (2),
Scheme 5 (hereafter referred to as Conditions B). As shown in
Scheme 6, there was either no or very little erosion of enantio-
meric excess, thereby suggesting that isomerisation of prod-
ucts 6 is not the major cause of ee erosion in the gold-cata-
lysed hydroalkoxylation reaction.
Having confirmed that the racemisation of the allene sub-
strate is indeed the major culprit for ee erosion under Condi-
tions A, we then proceeded to ascertain whether it is the sol-
vent (DMF versus toluene), temperature (08C versus RT) or al-
cohol concentration that is causing the stark difference in re-
sults using Conditions A versus B as shown in Table 1. Towards
this end, the racemisation control under Conditions B was in-
vestigated with toluene instead of DMF as the solvent
(Scheme 7). The resulting enantiomeric ratios are very similar
(within error): 96.5:3.5 e.r. in DMF and 97.5:2.5 e.r. in toluene,
which initially suggests that the solvent difference between
Conditions A and B is not the most crucial change with this
substrate. The temperature, however, is crucial (Scheme 7);
when the same toluene experiment is repeated at room tem-
perature, the e.r. of 4b plummets to 81:19.
Scheme 7. Effect of solvent and temperature on allene racemisation.
With these observations in hand, we then proceeded to
study the effect of the solvent in the actual gold-catalysed hy-
droalkoxylation reaction with allene 4b (Table 2). Indeed, the
change of solvent from DMF and toluene has only a small
effect on resulting enantiomeric ratios for substrate 4b (98:2
vs. 97:3), but the yield is slightly better with toluene as solvent
(65 vs. 81%, entries 1 and 2). Sticking with toluene, the alcohol
equivalents was investigated next (entries 3–6). The enantio-
meric ratio appears to drop slightly as the alcohol equivalents
is decreased from 4 to 2 to 1.1 equivalents (entries 3–6). As
a result of this screen, we initially decided to use the condi-
tions shown in entry 4 (hereafter referred to as Conditions C)
Scheme 6. Control reaction to test whether the products 6 racemise under
the reaction conditions.
Next, the allene substrate 4b was subjected to similar con-
trols (Table 1). This time, however, sterically hindered tBuOH
(which is a sluggish nucleophile under these conditions, see
below) was added to these control reactions in order to repli-
cate the reaction conditions whilst avoiding hydroalkoxyla-
tion.[24] As shown in Table 1, Conditions A clearly result in
much faster racemisation of the allene 4b compared to Condi-
tions B.
Table 2. Effect of solvent and alcohol concentration on the hydroalkoxy-
lation of 4b
Table 1. Controls to test whether the allene substrate 4 racemises under
the reaction conditions.
Entry
Solvent
BnOH equiv
e.r.[a]
Yield [%]
1
2
3
4[b]
5
DMF
10
10
4
2
1.1
98:2
97:3
97:3
96:4
93:7
65
81
85
78
74
toluene
toluene
toluene
toluene
Entry
Time
Conditions A[a]
Conditions B[a]
1
2
3
20 min
2 h
24 h
98:2 e.r.
89:11 e.r.
racemic
98.5:1.5 e.r.
96.5:3.5 e.r.
no allene remaining
[a] Determined by CSP-HPLC, >20:1 E:Z by 1H NMR analysis. [b] Condi-
tions C.
[a] Determined by CSP-HPLC.
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as the optimised reaction conditions, as it provided a good
compromise between lower equivalents of alcohol nucleophile
and good e.r./yield.
Table 4. Allene scope.
However, we soon discovered to our surprise that Condi-
tions C only gave good enantiomeric ratios specifically for sub-
strate 4b, and consistently provided poorer enantiomeric
ratios for all other allenes investigated (see below, Table 4). In
fact, when applied to other allenes 4 during our substrate
scope studies, our original Conditions B consistently outper-
form Conditions A and C in chirality transfer efficiency. For ex-
ample, when 4c is used instead of 4b, Conditions B (95:5 e.r.,
entry 2, Table 3) outperform both A (81:19 e.r., entry 1) and C
(87:13 e.r., entry 3). In this case, the switch of solvent alone
from DMF (95:5 e.r., entry 2, Table 3) to toluene (92.5:7.5 e.r.,
entry 4) produces a worse result in enantiomeric ratio.
Entry Allene
Product
Result[a]
65%
98:2 e.r.[b]
1
45%
95:5 e.r.[b]
2
3
70%
93:7 e.r.[c]
Table 3. Effect of solvent and alcohol concentration on the hydroalkoxy-
lation of 4c.
78%
94:6 e.r.[c]
4
91%
97:3 e.r.[b]
5
Entry Solvent BnOH equiv T [8C] Conditions e.r.[a]
Yield [%]
1[b]
2
3
4
toluene 4.4
RT
0
0
cond. A
cond. B
cond. C
–
81:19
95:5
87:13
37
45
61
79%
90:10 e.r.[b]
DMF
toluene
10
2
6[e]
toluene 10
0
92.5:7.5 65
81%
97:3 e.r.[b]
[a] Determined by CSP-HPLC. >20:1 E:Z by 1H NMR analysis. [b] 20 min.
7
94%
We therefore conclude that, with the exception of the initial-
ly studied allene 4b, in general, the solvent, temperature and
alcohol equivalents all cumulatively affect the efficiency of the
chirality transfer reaction when comparing Conditions B to the
previously reported Conditions A. Although the yield is lower
using DMF for this particular combination of reactants (4c with
BnOH), the yields were pleasingly all good to excellent when
Conditions B were applied to other substrates (see later,
Table 4 and Table 5).
8[g]
9[h]
10
81:19 e.r.
9:1 regioselectivity[f]
92%
97:3 e.r.[b]
71%
95:5 e.r.[b]
58%
91:9 e.r.[b]
Having ascertained that Conditions B is the most general,
we proceeded to investigate the allene substrate scope
(Table 4).[25] Suspecting that the OBz substituent plays a major
role in the excellent regioselectivity observed, we first investi-
gated the effect of various different protecting groups on the
oxygen (entries 1–4). To our delight, removing the carbonyl
(4c, entry 2) or Ph (4d, 4e, entries 3 and 4) does not seem to
significantly affect enantiomeric ratios and a high degree of
chirality transfer occurs in all cases. Replacing the Me in 4b
with a longer npentyl in 4 f also results in high yield and chiral-
ity transfer (entry 5). Inserting an extra CH2 to place the OBz
group further from the allene in 4g, however, does cause
a more noticeable drop in chirality transfer, although 6gb is
still formed in a good 79% yield and 90:10 e.r. (entry 6).
11
12
86%
90:10 e.r.[b]
[i]
13
14
–
–
79%[j]
racemic
10:1 regioselectivity
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is likely that the aryl substituent renders the allene isomerisa-
tion too rapid for successful chirality transfer under gold-cata-
lysed hydroalkoxylation conditions.[20b] Next, we investigated
whether steric differentiation in a dialkyl 1,3-substituted allene
(4n) could result in good regioselectivity. Disappointingly, this
is not the case and 6nb and 6nb’ is formed as an inseparable
regioisomeric mixture (entry 15).[26] The poor regioselectivity
with double alkyl substituents (4n) is not necessarily a major
drawback for synthetic purposes, as functionalised substituents
are much more useful as a handle for subsequent elaboration
in synthesis.
Table 4. (Continued)
Entry Allene
Product
Result[a]
71%,[j]
In order to investigate the minimum amount of functionality
required to achieve good regioselectivity, the ether allene 4o
was investigated next (entry 16). Pleasingly, the reaction is re-
gioselective, and a decent 87:13 e.r. is observed for product
6oc. It is clear that some functionality on one substituent is re-
quired for good regio- and stereoselectivities, and the heteroa-
tom (4o) and carbonyls (4b, 4d–l) all seem to play a role in
the observed selectivity.
1:0.7 regioselectivity
15
94%
87:13 e.r.[d]
16
[a] Isolated yields, >20:1 E:Z and regioselectivity by 1H NMR analysis
unless otherwise stated. 5c was used when the product using 5b is not
separable by CSP-HPLC, CSP-GC or chiral shift reagents. [b] Determined
The alcohol nucleophile scope was investigated next using
allene substrate 4b (Table 5). Primary benzyl (5b) and pheneth-
yl alcohol (5 f), as well as alkyl alcohols MeOH (5c) and n-buta-
nol (5e) all react smoothly to furnish the desired allylic ethers
in good yields and enantioselective ratios (entries 1–4). Primary
alkyl alcohols 5g and 5h, with pendent electron withdrawing
Cl and CF3 groups respectively, also react smoothly and in high
enantioselective ratios, albeit with slightly lower yields (60 and
37%, entries 5 and 6). To our delight, the more sterically hin-
dered secondary alcohol iPrOH 5a reacts in good yield (88%)
and e.r. (97:3 e.r., entry 7). Homochiral secondary alcohols 5j
and 5k also proceed with excellent e.r. and d.r., although the
yield is higher for the less bulky 5j (78%) versus 5k (51%) (en-
tries 8–9). Unsurprisingly, therefore, the bulky tertiary alcohol
tBuOH 5l reacts sluggishly; nevertheless, 30% of the desired
product is obtained in a good 94:6 e.r. (entry 10). This differ-
ence in reactivity, however, allows for chemoselective reaction
of unprotected diol 5m at the less-hindered primary end
(entry 11). Other potentially sensitive functional groups such as
a pendent alkene (5n) and a furan (5o) are also pleasingly tol-
erated (entries 12 and 13). The less nucleophilic phenol (5p),
however, is not a viable nucleophile in this reaction (entry 14).
Finally, in order to ascertain whether the heteroatom and
carbonyl groups in 4b–l and 4o impart excellent regioselectivi-
ty through a chelation effect or a simple inductive withdrawing
effect, the reaction with allene 4p was investigated
(Scheme 8). Allene 4p contains a non-chelating electron-with-
drawing substituent (CF3) in place of the O, N or C=O with-
drawing groups in 4b–4l, 4o, but still produces a highly regio-
selective reaction (Scheme 8). This suggests that the prefer-
ence for reaction at a is purely due to electronics: The induc-
tive withdrawing effect of the functional group (CF3 in this
case) results in electronically differentiated p-bonds a and b,
with the LAu+ catalyst preferring to coordinate to the more
electron-rich p-bond at position a. It should be noted though
that allene 4m, with electronically differentiated p-bonds
through a conjugated rather than inductive withdrawing
group, performs very poorly in the reaction (entry 13, Table 4).
1
by CSP-HPLC. [c] Determined by H NMR using chiral shift reagent (R)-(ꢀ)-
1-(9-anthryl)-2,2,2-trifluoroethanol. [d] Determined by CSP-GC. [e] Condi-
tions C gives 70% yield and 78:22 e.r. [f] When (IPr)AuNTf2 used as cata-
lyst instead, regioselectivity improves to>20:1; 82:18 e.r. [g] Conditions C
gives 79% yield, 7:1 regioselectivity, 78:22 e.r. [h] Conditions C gives 63%
yield, 97:3 e.r. [i] Mainly 4m and complex mixture of products. [j] Com-
bined yield.
Next, we proceeded to replace the O in 4b with N (4h) and
pleasingly, this still gives a high 81% yield and 97:3 e.r. of 6hb
(Table 4, entry 7). Once again, placing the NPhtalate functional-
ity further from the allene in 4i results in a more noticeable
drop in enantiomeric ratio (81:19 e.r., entry 8). While all previ-
ous examples (entries 1–7) provided exclusively one regioiso-
mer, the regioselectivity with 4i is lower, albeit a still very
good 9:1 (entry 8), suggesting that the functionality on the
substituent is indeed responsible for the excellent regioselec-
tivities observed thus far. Nevertheless, when the silver free
catalyst (IPr)AuNTf2 is used, the regioselectivity is restored to
>20:1 (82:18 e.r.).
Next, the ester (4j) and Weinreb amide (4k) substituted al-
lenes were investigated (Table 4, entries 9–11). These once
again provide the expected products, with 6jc and 6jd being
formed in excellent yield and e.r. (92%, 97:3 e.r. and 71%, 95:5
e.r. respectively) and 6kb in a slightly lower but still good 91:9
e.r. Once again, moving the ester functionality one carbon
away (4l) still provides excellent regioselectivity and 90:10 e.r.
(entry 12). Having the ester directly conjugated to the allene
(4m), however, is surprisingly detrimental to the reaction
(entry 13).
Having successfully demonstrated good regioselectivities
and enantiomeric ratios with a wide range of functionalised al-
lenes, we next turned our attention to unfunctionalised ones.
Aryl substituted allene 4a, originally investigated by Yamamo-
to (reaction (1), Scheme 3), gave a good 10:1 regioselectivity
but still racemised under these conditions (Table 4, entry 14). It
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Table 5. Alcohol scope.
Entry
1
Alcohol
Product
Result[a]
Scheme 8. Reaction to ascertain that regioselectivity is due to inductive ef-
fects.
65%
98:2 e.r.[b]
81%
>95:5 e.r.[c]
ing substituents have the opposite effect and allow for excel-
lent transfer of chirality.
2
3
4
5
6
7
8
68%
It should be noted that the reaction is highly stereoselective
both in terms of chirality transfer as well as E selectivity
97.5:2.5 e.r.[b]
1
(>20:1 E:Z by H NMR analysis). A plausible reason for the ob-
62%
98:2 e.r.[c]
served selectivity is shown in Scheme 9. The gold catalyst can
60%
97:3 e.r.[b]
37%
99:1 e.r.[b]
88%
97:3 e.r.[b]
78%
81:19 e.r.[b]
51%
97:3 e.r.[b]
9
30%
94:6 e.r.[b]
10
11
12
13
60%
98:2 e.r.[b]
66%
99.8:0.2 e.r.[b]
Scheme 9. Postulated origin of stereoselectivity.
64%
99:1 e.r.[b]
coordinate to either face of the allene (I and I’), with a low bar-
rier of interconversion between I and I’.[27] Because nucleo-
philes typically approach anti to the AuI,[1] the approach of the
alcohol onto I should have the lower energy barrier as it ap-
proaches from the less hindered face of the allene. This leads
to intermediate II and the observed (R,E)-6 product upon pro-
todeauration. Conversely, nucleophilic attack onto I’ is predict-
ed to be kinetically unfavourable, and indeed (S,Z)-6 is never
observed experimentally.[28] Furthermore, subjecting a mixture
of E:Z isomers of an allylic ether 6 to the gold-catalysed hydro-
alkoxylation conditions (see Supporting Information) results in
no change to the E:Z ratio, suggesting that the E selectivity is
not due to thermodynamic control.
14
N/A
No reaction
[a] Isolated yields, >20:1 E:Z and regioselectivity by 1H NMR analysis unless
otherwise stated. [b] Determined by CSP-HPLC. [c] Determined by 1H NMR
using chiral shift reagent (R)-(ꢀ)-1-(9-anthryl)-2,2,2-trifluoroethanol. [d] Deter-
mined on the THP deprotected product.
Furthermore, because the unwanted and competing gold-cata-
lysed allene racemisation is thought to occur through achiral
h1-allylic cation intermediates,[20] it is possible that allenes with
substituents that stabilise these intermediates (such as Ph in
4a) undergo fast racemisation, and therefore provide poor
chirality transfer in the reaction, whereas inductive withdraw-
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[2] a) N. Krause, A. S. K. Hashmi, Modern Allene Chemistry, Wiley-VCH, Wein-
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Chem. 2000, 112, 3737–3740; for early gold-catalysed conversions of al-
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2007, 40, 91–102; c) R. K. Neff, D. E. Frantz, ACS Catal. 2014, 4, 519–
528; see also: d) X. Huang, T. Cao, Y. L. Han, X. G. Jiang, W. L. Lin, J. S.
Zhang, S. M. Ma, Chem. Commun. 2015, 51, 6956–6959; e) R. Gurubra-
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[4] M. Schulz, J. H. Teles, (BASF AG); WO-A1 9721648, 1997.
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Conclusion
Gold(I)-catalysed intermolecular hydroalkoxylation of enan-
tioenriched 1,3-disubstituted allenes was previously reported
to occur with poor chirality transfer due to rapid racemisation
of the allene substrate. We have developed conditions to over-
come this limitation and to successfully carry out gold(I)-cata-
lysed intermolecular hydroalkoxylation of allenes with high
degree of chirality transfer (up to 99:1 e.r.), excellent E selectivi-
ty and good substrate scope. The combined use of the coordi-
nating solvent DMF, lower temperatures and higher equiva-
lents of alcohol nucleophile suppresses allene racemisation
and thereby allows for the asymmetric hydroalkoxylation using
a wide range of alcohol nuceophiles, including sterically hin-
dered and acid sensitive ones. A variety of functional groups
are tolerated on the 1,3-disubstituted allene substrate, and the
former are in fact necessary for excellent regioselectivities.
Control experiments suggest that the excellent regioselectivity
is determined by inductive withdrawing effects rather than
chelation control or steric differentiation.
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Experimental Section
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General procedure
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(IPr)AuCl (10 mol%), followed by AgOTf (10 mol%) were added to
a solution of allene 4 (0.14 mmol, 1 equiv), alcohol nucleophile
(1.4 mmol, 10 equiv) and DMF (0.14 mL) at 08C. The resulting reac-
tion mixture was allowed to stir at 08C for 24 h. The crude mixture
was then filtered through two plugs of silica, washing with Et2O.
The filtrate was washed with water and brine, and the resulting or-
ganic layer was dried (MgSO4) and concentrated in vacuo. The
crude product was purified by column chromatography to yield
products 6. Full experimental procedures, characterisation for all
[13] R. S. Paton, F. Maseras, Org. Lett. 2009, 11, 2237–2240.
1
new compounds and copies of H and 13C NMR spectra are provid-
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6407; b) M. S. Hadfield, J. T. Bauer, P. E. Glen, A. L. Lee, Org. Biomol.
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ed in the Supporting Information.
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see: A. Zhdanko, M. Strçbele, M. E. Maier, Chem. Eur. J. 2012, 18,
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Acknowledgements
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We thank EPSRC (EP/K00736X/1) and Heriot-Watt University
(James Watt Scholarship for SW and DRS) for funding, and Prof.
Stuart A. Macgregor and Dr David G. Johnson for helpful dis-
cussions. Mass spectrometry data was acquired at the EPSRC
UK National Mass Spectrometry Facility at Swansea University.
Keywords: alcohols · allenes · chirality transfer · ether · gold
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[24] In the absence of any alcohol 5, complete racemisation of 4b occurs
under both conditions; however, this does not accurately reflect the re-
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Chem. Eur. J. 2016, 22, 1 – 9
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action conditions as excess alcohol is always present. Excess alcohol
has been shown to dampen unwanted side reactions in gold-catalysed
reactions, for example, see ref. [14b] and [15].
[26] Chirality transfer was not investigated in reactions with very poor regio-
selectivity, as the products were inseparable.
[27] T. J. Brown, A. Sugie, M. G. D. Leed, R. A. Widenhoefer, Chem. Eur. J.
2012, 18, 6959–6971.
[28] Any erosion of e.r. is thought to result from competing isomerisation of
the allene substrate, as described earlier, rather than by this kinetically
unfavourable pathway.
[25] Chirality transfer occurs to give the R isomer of product 6 when (S)-4 is
used (e.g., Table 4, entry 1) and S isomer of product 6 when (R)-4 is
used (e.g., Table 4, entry 10). The absolute configuration of 6bb was
determined by comparison of HPLC traces with literature known proce-
dures (see Supporting Information). All other assignments in this series
were made by analogy. The absolute configuration of 6jd was deter-
mined by Mosher ester analysis (see Supporting Information). The abso-
lute configurations of the rest of the series were assigned by analogy.
Received: August 17, 2016
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FULL PAPER
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Chirality Transfer
S. Webster, D. R. Sutherland, A.-L. Lee*
&& – &&
Chirality Transfer in Gold(I)-Catalysed
Hydroalkoxylation of 1,3-Disubstituted
Allenes
Gold(I)-catalyzed intermolecular hy-
droalkoxylation of enantioenriched 1,3-
disubstituted allenes was previously re-
ported to occur with poor chirality
transfer due to rapid allene racemiza-
tion. The first intermolecular hydroal-
koxylation of allenes with efficient chir-
ality transfer is reported, exploiting con-
ditions that suppress allene racemiza-
tion. Excellent regio- and stereoselectivi-
ties are achieved when a slightly s-with-
drawing substituent is present.
Chem. Eur. J. 2016, 22, 1 – 9
www.chemeurj.org
9
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
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These are not the final page numbers! ÞÞ