Catalytic asymmetric synthesis of cyclic ethers containing an α-tetrasubstituted stereocenter

Article abstract of DOI:10.1002/anie.201300174

'Ether' furan or pyran: The exo-selective cyclization of enantioenriched allenols is accomplished with high chirality transfer using as little as 0.02 mol % of a gold catalyst. The new method is effective in the synthesis of a wide range of enantioenriche

Full text of DOI:10.1002/anie.201300174

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DOI: 10.1002/anie.201300174
Asymmetric Synthesis
Catalytic Asymmetric Synthesis of Cyclic Ethers Containing an
a-Tetrasubstituted Stereocenter**
Nick Cox, Mycah R. Uehling, Karl T. Haelsig, and Gojko Lalic*
Cyclic ethers are an important class of heterocycles present in
a variety of biologically active molecules. For example,
tetrahydrofurans (THFs) and tetrahydropyrans (THPs) are
found in several classes of natural products, including macro-
diolides,[1] acetogenins,[2] ionophores,[3] lignans,[4] and macro-
lides,[5] while arene-fused THPs are the major structural motif
of chromans.[6] The importance of cyclic ethers as structural
elements of organic molecules has led to continued interest in
the development of new catalytic and stereoselective methods
for their synthesis.[7,8] However, despite significant progress in
the field, the asymmetric synthesis of cyclic ethers containing
tetrasubstituted stereocenters[9] is still a major synthetic
challenge. Herein we describe the development of a method
for the catalytic, asymmetric synthesis of THFs, THPs, and
chromans containing a tetrasubstituted stereocenter.
Scheme 1. Gold-catalyzed exo-selective cyclization of allenols. a) For-
Our approach is based on a catalytic method for the
mation of cyclic ethers containing an a-tetrasubstituted stereocenter.
b) Formation of cyclic ethers containing a trisubstituted stereocenter.
Ts =4-toluenesulfonyl.
synthesis of cyclic ethers developed in 2006 by Widenhoefer
and co-workers,[10] who reported a gold-catalyzed exo-selec-
tive cyclization of allenols as an efficient method for the
synthesis of THFs and THPs. This method has been applied to
the asymmetric synthesis of compounds containing trisubsti-
tuted, but not tetrasubstituted stereocenters.[10,11] We rea-
soned that cyclic ethers containing a tetrasubstituted stereo-
center could be prepared by cyclization of enantioenriched
trisubstituted allenols, as outlined in Scheme 1a.
trisubstituted allenes.[14] With the exception of the synthesis
of dihydrofurans by endo-selective hydroalkoxylation of
allenes pioneered by Marshall and Pinney,[13] and further
developed by Krause and co-workers,[15] there are only few
isolated examples of such transformations.[16]
The key aspect of this transformation is transfer of
chirality from the chiral axis of an allene to the tetrasub-
stituted stereocenter of the cyclic ether. Chirality transfer to
a trisubstituted stereocenter in exo cyclizations of allenols is
known to be compromised by the formation of a mixture of
diastereoisomers with the opposite sense of chirality (Sche-
me 1b).[10] However, chirality transfer to a tetrasubstituted
stereocenter has so far not been explored in the context of this
transformation. Furthermore, chirality transfer from enan-
tioenriched trisubstituted allenes has, in general, rarely been
used in gold-catalyzed hydrofunctionalization reactions,
despite its enormous potential[12] in the asymmetric synthesis
of tetrasubstituted stereocenters, because of the lack of
a general method for the synthesis of enantioenriched
Our group has recently reported the synthesis of enan-
tioenriched trisubstituted allenes by copper-catalyzed substi-
tution of propargylic phosphates using alkyl boranes as
nucleophiles.[17,18] As Scheme 2 illustrates, we were able to
Scheme 2. Synthesis of enantioenriched trisubstituted allenols. [a] 7
(1.5 equiv), 9-BBN (1.5 equiv), 1,4-dioxane, 608C, 12 h, then 6
(1.0 equiv), ICyCuCl (10 mol%), LiOtBu (1.0 equiv), n-pentane, 358C.
[b] Bu4NF, THF, 80% yield over two steps. 9-BBN=9-borabicyclo-
[3.3.1]nonane, THF=tetrahydrofuran, TIPS=triisopropylsilyl.
[*] N. Cox,[+] M. R. Uehling,[+] K. T. Haelsig, G. Lalic
Department of Chemistry, University of Washington
Seattle, WA 98195 (USA)
prepare the enantioenriched trisubstituted allenol 8 from the
readily available propargylic phosphate 6 and protected
allylic alcohol 7. Practical access to enantioenriched trisub-
stituted allenols gave us an opportunity to investigate chirality
transfer in the hydroalkoxylation reaction, and ensured that
the overall synthesis of cyclic ethers containing a tetrasubsti-
tuted stereocenter would be convergent and practical.
E-mail: lalic@chem.washington.edu
[+] These authors contributed equally to this work.
[**] Forrest Michael is gratefully acknowledged for helpful discussions
and suggestions. NSF (CAREER Award 1254636) is acknowledged
for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300174.
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Table 1: Chirality transfer in exo-selective cyclization of allenols.
Table 2: Asymmetric synthesis of THFs and THPs.
Entry
L
X
t [h]
Yield [%][a]
CT [%][b]
1
2
3
tBu2P(o-biphenyl)
Ph3P
Ph3P
Ph3P
Ph3P
(C6F5)3P
Cy3P
tBu3P
OTs
ClO4
BF4
OTs
OAc
OTs
OTs
OTs
OTs
1
1
1
1
100
1
1
1
1
73[c]
>95
>95
>95
70
>95
>95
>95
>95
75
0
2
95
87
83
98
99
99
4
5d
6
7
8
9e
tBu3P
[a] Yields of the product as determined by GC. [b] CT=chirality transfer.
[c] Mixture of diastereomers was obtained. [d] Reaction was performed
at 608C. [e] 1 mol% of the catalyst was used.
In the initial cyclization experiments with the allenol 8, we
explored the reactivity of Au[P(tBu)2(o-biphenyl)]OTs, which
was previously identified as effective in the exo cyclization of
allenols.[10] We observed the formation of E and Z isomers of
the exo-cyclization products, which is consistent with the
results previously obtained (Scheme 1b). However, the major
E isomer of the cyclization product was formed with low
chirality transfer (CT)[19] (Table 1, entry 1). This result is
surprising in light of a recent study, which suggests that CT
from trisubstituted allenes in gold-catalyzed reactions can be
expected to be higher than in those reactions with disubsti-
tuted allenes.[12] However, low CT could be a result of
a difference in rates of racemization of the trisubstituted and
disubstituted allenes previously observed in related trans-
formations.[20] Indeed, a control experiment showed that
racemization of the allene was responsible for the low CT
observed.[21]
Considering this result, we decided to explore the
reactivity of other gold complexes supported by monodentate
phosphine ligands. Surprisingly, we found that with a variety
of phosphine gold complexes, the E isomer of exo cyclization
is the exclusive product of the reaction (Table 1, entries 2–9).
Furthermore, in reactions promoted by triphenylphosphine
gold complexes, higher CT is obtained using more-coordinat-
ing counter ions. At a certain point however, the cyclization
becomes prohibitively slow and CT decreases (entry 5).
Overall, the best CT is obtained using a gold tosylate catalyst
supported by hindered, electron-rich phosphine ligands, such
as tBu3P. Surprisingly, excellent yield of the desired product
can be obtained within an hour with as little as 1 mol% of the
gold catalyst.
[a] Yields of isolated products are reported. [b] An allene with the
opposite sense of chirality was used.
The cyclization can also be accomplished in the presence of
a variety of functional groups including nitro, cyano, pivaloyl,
azido, formyl, and silyloxy groups (15–20). We found that the
presence of an additional stereocenter in the allenol affects
the selectivity of the cyclization reaction (21 and 22).
However, reasonable selectivity (85:15 d.r.) is obtained even
in the mismatched case (22). Considering the results de-
scribed in Scheme 1b, we were surprised to find that our
catalyst also provides excellent results in a reaction with
a disubstituted allenol. The cyclization product 23 was
obtained in 95% yield, as a single diastereoisomer, and with
excellent CT. Overall, in most examples, THFs and THPs
were obtained in excellent yields (> 85%) and enantiomeric
ratios greater than 95:5.[22] Furthermore, in all reactions only
the E isomer of the product was obtained.
To demonstrate the utility of the new method in a large-
scale synthesis of cyclic ethers, we performed the cyclization
of 8 on a 5 mmol scale (1.2 g) using 0.02 mol% of the catalyst
[Eq. (1)]. The cyclization product was obtained as a single
Using the optimal reaction conditions, a variety of highly
enantioenriched THFs and THPs containing tetrasubstituted
stereocenters were prepared (Table 2). As the synthesis of
compounds 9–12 demonstrates, substrates bearing various
substituents perform well in the reaction, and the selectivity
of the cyclization does not seem to depend on the size of the
R2 substituents. Similarly, both methyl and larger alkyl
substituents at the tetrasubstituted stereocenter are tolerated.
diastereoisomer, in excellent yield and with 98:2 e.r. The low
catalyst loading used in this transformation is particularly
noteworthy considering that in closely related reactions two-
hundred-fifty-fold higher catalyst loading (5 mol%) is com-
monly used.[23]
Following the exploration of the synthesis of THFs and
THPs we decided to explore the asymmetric synthesis of
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Table 4: Asymmetric synthesis of chromans.
closely related chromans, which are found in numerous
biologically active compounds.[6,24] This transformation was
particularly appealing considering that we found no previous
reports of chroman synthesis by phenol addition to allenes.
Furthermore, chromans containing a tetrasubstituted stereo-
center are found in a wide range of biologically relevant
molecules, and their asymmetric synthesis is still a major
challenge.[25]
The synthesis of the requisite phenol-containing allenes
was accomplished by an efficient two-step procedure shown
in Scheme 3. The coupling of a readily available propargylic
Scheme 3. Representative synthesis of phenol-functionalized allene.
[a] 24 (1.2 mmol), 9-BBN (1.2 equiv), 1,4-dioxane, 608C, 12 h, then 6
(1.0 equiv), ICyCuCl (10 mol%), LiOtBu (1.0 equiv), n-pentane, 358C,
24 h. [b] TBAF (1.1 equiv), THF, 258C, 1 h.
[a] 28 (1.2 equiv), 9-BBN (1.2 equiv), 1,4-dioxane, 608C, 12 h, then 29
(1.0 equiv), ICyCuCl (10 mol%), LiOtBu (1.0 equiv), n-pentane, 358C,
18 h. [b] TBAF (1.1 equiv), THF, 1 h, 258C. [c] tBu3PAuCl (2 mol%),
AgO2CC6H4(4-CO2Me) (2 mol%), toluene. [d] Yield of isolated product
after three steps is reported. Yield of the cyclization shown in
parentheses. [e] A phosphate with the opposite absolute configuration
was used. [f] Propargylic phosphate with 96:4 e.r. was used.
phosphate with a protected phenol and subsequent depro-
tection provides the substrate for the cyclization reaction in
excellent yield and with high e.r. value.
Initial experiments with the allene 25 using reaction
conditions developed for the cyclization of allenols provided
the desired chromane in excellent yield and diastereoselec-
tivity, but with an 87% CT (Table 3, entry 1). Significantly
As the results in Table 4 demonstrate, using the reaction
conditions developed for intramolecular addition of phenols
to allenes, the three-step synthesis of chromans can be
accomplished with phenols containing both an electron-
donating and an electron-withdrawing substituent (32–36).
Furthermore, both large and small substituents at the
tetrasubstituted stereocenter are tolerated (32, 37, and 38).
Most importantly, the overall process is efficient, stereo-
selective, highly convergent, and relies on readily available
starting materials. As a result, this process is a valuable
addition to the existing methods for the asymmetric synthesis
of chromans containing tetrasubstituted stereocenters.
The mechanism of the intramolecular exo hydroalkoxyla-
tion of allenes catalyzed by gold has been explored in detail
by Widenhoefer and co-workers.[10,26b] Considering these and
other investigations of the mechanism of the addition of
nucleophiles to allenes[26] we anticipated that the reaction
would proceed according to a mechanism resembling the one
outlined in Scheme 4. In an effort to gain a more detailed
understanding of the reaction mechanism, we isolated and
characterized the proposed intermediate 42 [Eq. (2)]. When
Table 3: Development of intramolecular addition of phenols to allenes.
Entry
X
Cat. loading[a]
Y
Yield [%][b] CT [%]
1
2
3
4
H
H
10 mol%
10 mol%
TsO
PhCO2
PhCO2
4-(NO2)C6H4CO2
4-(MeO2C)C6H4CO2 >95
4-(MeO2C)C6H4CO2
92
87
98
98
93
94
94
92
OMe 10 mol%
OMe 5 mol%
OMe 5 mol%
OMe 2 mol%
58[c]
>95
5
6[d]
89[e]
[a] Equimolar amount of the gold precatalyst and a silver salt was used in
all experiments. [b] Yield of the product as determined by GC analysis.
[c] 60% conversion after 48 h. [d] [allene]=1m. [e] Yield of the isolated
product.
better results were obtained using a gold(I) benzoate catalyst
(entry 2). Unfortunately, the reaction with a less reactive
substrate 26 provided the desired product in only 58% yield
after 48 hours (entry 3). A faster reaction was observed using
p-nitro and p-carbomethoxy benzoate catalysts, and the CT
remained high (entries 4 and 5). Finally, we were able to
achieve complete conversion with just 2 mol% of the catalyst
within 48 hours by increasing the concentration of the
substrate from 0.1m to 1m (entry 6).
we monitored a catalytic reaction by in situ 31P NMR
spectroscopy we observed the gold(I) alkenyl intermediate
42 and complex 39 as the resting states of the catalyst.[21] This
finding is in contrast to previous reports on closely related
gold-catalyzed reactions of allenes wherein a digold(I)
alkenyl complex is the resting state of the catalyst.[26b,e] We
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with excellent diastereoselectivity and chirality transfer. We
have also shown that in combination with the method for the
synthesis of enantioenriched trisubstituted allenes recently
developed by our group, the exo-selective cyclization of
allenols constitutes a practical and convergent approach to
the synthesis of THFs, THPs, and chromans containing
a tetrasubstituted stereocenter.
Received: January 9, 2013
Published online: April 8, 2013
Keywords: allenes · asymmetric synthesis · cyclization · gold ·
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heterocycles
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Scheme 4. Proposed mechanism.
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limiting.
In conclusion, we have developed a catalytic method for
asymmetric synthesis of cyclic ethers containing a tetrasub-
stituted stereocenter through the exo-selective cyclization of
enantioenriched trisubstituted allenols. We demonstrated that
the exo-selective cyclization is highly efficient and proceeds
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[28] A control experiment in which 42 is omitted did not result in the
formation of the cyclization product.
[29] We thank one of the reviewers for suggesting this experiment.
[30] The cyclization of the deuterium-labeled phenol (ꢀ 90% d)
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