Copper-catalyzed enantioselective additions to oxocarbenium ions: Alkynylation of isochroman acetals

Article abstract of DOI:10.1021/ja207585p

We have developed an enantioselective, copper(I)-catalyzed addition of terminal alkynes to racemic isochroman acetals. This method is one of the first transition-metal-catalyzed approaches to enantioselective additions to prochiral oxocarbenium ions. In this reaction, TMSOTf is used to form the oxocarbenium ion in situ under conditions compatible with simultaneous formation of the chiral copper acetylide. By using a bis(oxazoline) ligand, good yields and enantioselectivities are observed for a variety of enantioenriched 1-alkynyl isochromans.

Full text of DOI:10.1021/ja207585p

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pubs.acs.org/JACS
Copper-Catalyzed Enantioselective Additions to Oxocarbenium Ions:
Alkynylation of Isochroman Acetals
Prantik Maity, Harathi D. Srinivas, and Mary P. Watson*
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S Supporting Information
b
Scheme 1. Enantioselective Alkynylation of Acetals
ABSTRACT: We have developed an enantioselective,
copper(I)-catalyzed addition of terminal alkynes to racemic
isochroman acetals. This method is one of the first transi-
tion-metal-catalyzed approaches to enantioselective addi-
tions to prochiral oxocarbenium ions. In this reaction,
TMSOTf is used to form the oxocarbenium ion in situ
under conditions compatible with simultaneous formation
of the chiral copper acetylide. By using a bis(oxazoline)
addition of phenylacetylene (3a) to isochroman acetals in the
ligand, good yields and enantioselectivities are observed for
absence of chiral ligand (Table 1, entries 1ꢀ3). However, when
a variety of enantioenriched 1-alkynyl isochromans.
chiral ligand is added, only Cu(I) catalysts provided ether 5aa in
good yields (entries 4 vs 5ꢀ7). Further, the copper counterion
had a dramatic effect onꢀthe observed enantioselectivity with
hiral substituted benzopyrans comprise a number of im-
portant molecular targets, including the natural products
weakly coordinating PF6 being optimal (entries 5ꢀ7). Bis-
C
(oxazoline) ligands were quickly identified as promising chiral
ligands, and ligand 6 was found to provide the highest selectivities
(entries 6ꢀ15). By lowering the reaction temperature to
ꢀ22 °C, the enantioselectivity increased to 89% ee (entry 16),
but decreasing the reaction temperature further was detrimental
to yield (entry 17). Reinvestigation of the Cu salt at these colder
temperatures again showed [Cu(MeCN)4]PF6 gave the best
enantioselectivities (entries 18ꢀ20). Notably, high enantioselec-
tivities were only observed if the Cu salt and ligand were stirred in
solvent for 1 h at rt prior to the addition of the other reagents.
Because [Cu(MeCN)4]PF6 is reported to oxidize in air, we set
up these reactions in a N2-atmosphere glovebox, removing the
mixtures just before addition of TMSOTf to cool them to
ꢀ22 °C. However, we found that setting up the alkynylation outside
the glovebox, including weighing [Cu(MeCN)4]PF6 in air, resulted
in 68% isolated yield of ether 5aa in 88% ee. This benchtop
procedure offers an alternative to our usual glovebox procedure.12,13
Under the optimized conditions (see Table 1, entry 16), a
variety of aryl acetylenes react with acetal 1a (Table 2). In some
cases, we found that mixing the Cu salt and ligand at higher
concentration resulted in higher enantioselectivites.12 Increased
steric bulk was well tolerated (entries 2ꢀ5). Good enantioslec-
tivity was observed for aryl acetylenes with both electron-
donating and -withdrawing groups at the para position (entries 4,
6ꢀ8), but a p-methoxy substituent led to diminished enantio-
selectivity (61% ee, entry 9), and a p-dimethylamino substituent
resulted in racemic ether 5 (not shown). For substituents in the
meta position, more strongly electron-withdrawing groups led to
lower enantioselectivities (entries 10, 11), but the addition of
m-fluorophenyl acetylene resulted in ether 5al with 88% ee (entry 12).
Notably, in contrast to the result with p-methoxyphenylacetylene, the
aposphaerin A and cytosporone C and synthetic U-101387, a
selective dopamine D4 receptor agonist.1 Nucleophilic addition
to a prochiral, cyclic oxocarbenium ion intermediate would offer a
highly efficient route to such bioactive molecules.2 Li has reported
the oxidative coupling of isochromans with alkynes and ketones,
proposed to proceed via oxocarbenium ions.3 In addition, achiral
transition metal catalysts and Lewis acid promoters have been used
for the addition of silyl and boronic carbon nucleophiles to acetals.4
However, only a few enantioselective additions to such substrates
have been achieved.5 Jacobsen reported an impressive method for
the catalytic enantioselective addition of silyl ketene acetals to
1-chloroisochromans using a chiral thiourea catalyst.6 More recently,
Schaus described the addition of vinyl- and arylboronic esters to
chromene acetals using chiral diol catalysts with a Lewis acid
cocatalyst.7 Braun has also reported a Lewis acid-catalyzed allylation
of a single dihydropyranyl acetal, but stoichiometric Lewis acid was
required for high enantioselectivity.8
In contrast, enantioselective addition of chiral metal acetylides
to aldehydes and ketones is a well-developed and powerful
method for the preparation of chiral alcohols.9 We envisioned
that an analogous alkynylation of oxocarbenium ions would be
possible if the metal acetylide could be catalytically generated
under conditions compatible with oxocarbenium formation.
Noting Downey’s report that trimethylsilyl triflate (TMSOTf)
can be used to enable catalytic turnover in the alkynylation of
aldehydes,10 we have developed an enantioselective, copper(I)-cata-
lyzed addition of terminal alkynes to isochroman acetals in the
presence of TMSOTf (Scheme 1). By using (ꢀ)-2,20-isopropylidene-
[(4S)-4-benzyl-2-oxazoline] (6) as ligand, high enantioselectivities in
the formation of chiral benzopyrans 5 were obtained.
Isochroman acetal 1a, readily prepared from isochroman,6,11
and phenylacetylene 3a were selected as model substrates for
optimization of the alkynylation. We quickly found that both
zinc(II) and copper(I) compounds are effective catalysts for the
Received: August 11, 2011
Published: October 11, 2011
r
2011 American Chemical Society
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Table 1. Optimization of Alkynylation of Acetal 1aa
Table 2. Scope of Alkynea
entry
[M]
L*
yield (%)b
ee (%)c
1d,e
2 d,e
3
ZnBr2
CuI
ꢀ
ꢀ
ꢀ
6
84
ꢀ
(95)
12
ꢀ
[Cu(MeCN)4]PF6
ZnBr2
ꢀ
4
5g
15
n.d.f
26
60
80
50
7
CuI
6
78
6
[Cu(MeCN)4]BF4
[Cu(MeCN)4]PF6
[Cu(MeCN)4]PF6
[Cu(MeCN)4]PF6
[Cu(MeCN)4]PF6
[Cu(MeCN)4]PF6
[Cu(MeCN)4]PF6
[Cu(MeCN)4]PF6
[Cu(MeCN)4]PF6
[Cu(MeCN)4]PF6
[Cu(MeCN)4]PF6
[Cu(MeCN)4]PF6
6
57
7
6
(90)
81
8
7
9
8
70
10
11h
12h
13
14
15
16h
17i
18j
19j
20j
9
60
2
10
11
12
13
14
6
60
75
78
36
50
34
89
n.d.f
72
68
82
30
70
85
65
(90)
<5
87
6
[CuOTf]2 PhMe
6
3
Cu(OTf)2
6
85
CuOt-Bu
6
79
a Conditions: Acetal 1 (0.12 mmol, 1.0 equiv), [M] (0.012 mmol, 10 mol
%), L* (0.014 mmol, 12 mol %), alkyne 3 (0.13 mmol, 1.1 equiv), i-Pr2NEt
(0.16 mmol, 1.3 equiv), TMSOTf (0.15 mmol, 1.2 equiv), Et2O, rt, 12 h,
1
unless otherwise noted. b Determined by H NMR analysis using 1,3,5-
trimethoxybenzene as internal standard. Numbers in parentheses are isolated
c
yields. Determined by chiral HPLC analysis. d NEt3 replaced i-Pr2NEt.
e CH2Cl2 replaced Et2O. f n.d. = Not determined. g 1.1 equiv of TMSOTf, 1.2
of equiv i-Pr2NEt. h Reaction was cooled to ꢀ22 °C. i Reaction was cooled to
ꢀ30 °C. j Reaction was cooled to ꢀ20 °C.
a Conditions: Acetal 1 (0.30 mmol, 1.0 equiv), [Cu(MeCN)]4PF6
(0.030 mmol, 10 mol %), (S,S)-6 (0.036 mmol, 12 mol %), alkyne 3
(0.34 mmol, 1.1 equiv), i-Pr2NEt (0.396 mmol, 1.3 equiv), TMSOTf
(0.365 mmol, 1.2 equiv), Et2O, ꢀ22 °C, 12 h, unless otherwise noted.
b Average isolated yield from duplicate experiments ((3%). c Average ee
from duplicate experiments as determined by chiral HPLC analysis
((2%). d 20 mol % [Cu] and 23 mol % 6, 0 °C. e (R,R)-6 was used as
ligand, forming (S)-5 as product. f 12 mol % [Cu], 14 mol % 6. g Results
of a single experiment. h 20 mol % [Cu] and 23 mol % 6, PhMe, 0 °C.
i Performed on 0.1 mmol scale. j n.d. = not determined.
reaction of m-methoxyphenylacetylene proceeded in much better
enantioselectivity (entry 9 vs 13). Alkynes with nonaromatic substit-
uents were less successful. Using 20 mol % Cu catalyst, cyclohexenyl-
and cyclopropylacetylene reacted, but with lower yields and selectiv-
ities (entries 14, 15). Under the optimized conditions, the addition of
1-octyne proceeded in poor yield (entry 16).
Good yields and high enantioselectivies were achieved in the
alkynylation of a variety of acetal substrates (Table 3). In
particular, the alkynylation of naphthopyranyl acetals provided
ether products in high enantioselectivites (entires 1ꢀ3). Both
electron-donating and -withdrawing substituents were tolerated
on the acetal, although bromoether 5gc was formed in somewhat
reduced enantioselectivity (entry 8).
Some of the ether products slowly decompose under ambient
conditions to give lactone and benzoic acid,14 but most products
are fairly stable when stored as solutions in Et2O at ꢀ26 °C.
However, dimethoxybenzopyran 5hc decomposes quickly even
with these precautions. Reduction of unpurified alkyne 5hc
provided stable ether 15hc in 85% ee and 50% yield from acetal
1h (Scheme 2). The analogous reduction of alkyne 5aa pro-
ceeded with minimal loss of enantioselectivity, showing that the
preparation of enantioenriched alkyl-substituted ethers is also
possible via a two-step alkynylation/hydrogenation procedure. Re-
duction of 5aa also allowed assignment of the absolute configuration
by comparison to ether 15aa independently prepared with known
absolute configuration.12 The absolute configurations of the other
propargylic ether products were assigned by analogy.
Preliminary results suggest that this strategy will also enable
the preparation of other classes of enantioenriched ethers. Under
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COMMUNICATION
Table 3. Scope of Acetal Substratea
Scheme 2. Reduction of Alkynes
Scheme 3. Proposed Mechanistic Hypothesis and Stereo-
chemical Rationale
a Conditions: Acetal 1 (0.30 mmol, 1.0 equiv), [Cu(MeCN)]4PF6
(0.030 mmol, 10 mol %), (S,S)-6 (0.036 mmol, 12 mol %), alkyne 3
(0.34 mmol, 1.1 equiv), i-Pr2NEt (0.396 mmol, 1.3 equiv), TMSOTf (0.365
mmol, 1.2 equiv), Et2O, ꢀ22 °C, 12 h, unless otherwise noted. b Average
isolated yield from duplicate experiments ((3%). c Average ee from
duplicate experiments as determined by chiral HPLC analysis ((2%).
d Results of a single experiment. e Yield (over two steps) and ee of 15hc.
Because π-backbonding is significant in such Cuꢀolefin structures,
we propose that the Cu may bind either the arene (22) or the CdO
(23), or slip between these binding modes. At this point, it is unclear
whether the CꢀC bond formation occurs via initial single-electron
transfer or nucleophilic attack.
Analysis of the CꢀC bond forming step suggests a preliminary
model for enantioinduction. Approach of Cu acetylene to the re
face of the oxocarbenium ion minimizes steric interactions
between the benzyl group of ligand 6 and the aromatic ring of
the oxocarbenium ion (TS-a, Scheme 3). Significant steric
hindrance between the aromatic ring of the oxocarbenium ion
and the benzyl group destabilizes the diastereomeric transition
state (TS-b). This model is consistent with the observed absolute
stereochemistry of the major enantiomer and also explains the
lack of enantioselectivity in the alkynylation of acyclic oxocarbe-
nium ions (Scheme 4). For an E-configured acyclic oxocarbe-
nium ion, there appears little difference in the stability of TS-c
and TS-d. However, we must note that this steric-hindrance
model does not explain why benzyl-substituted 6 is better than
ligands 7 and 9 with i-Pr and t-Bu substituents, respectively. We
have ruled out cationꢀπ interactions as a possible explanation;
increasing the π-donating capacity of the Bn group does not
increase enantioselectivity (Table 1, entry 16 vs 11 and 12),
suggesting that this group does not participate in cationꢀπ
interactions with the oxocarbenium ion.20 Further, we do not
observe a linear free-energy relationship between enantioselec-
tivity and either the electronic or steric nature of substituents on
the acetal or alkyne.12 Mechanistic investigations to explain these
details are underway and will be reported in due course.
modified conditions, the Cu-catalyzed alkynylation of acetal 167
resulted in efficient formation of benzopyran 17 in 71% yield and
63% ee (eq 1).12,15
As a working mechanistic hypothesis, we propose the catalytic
cycle shown in Scheme 3.16 The reaction likely proceeds via initial
formation of Cu acetylide 19. Although silylacetylene 20 is observed
as a minor byproduct under certain conditions, we have determined
that it is not a competent nucleophile in the alkynylation. In the
presence of 10 mol % [Cu(MeCN)4]PF6, 12 mol % 6, i-Pr2NEt,
and TMSOTf in Et2O at rt, only 3% yield of5aa was observed when
phenyl acetylene was replaced with trimethylsilyl acetylene 20.
Further, the addition of copper phenylacetylide17 (1 equiv) to acetal
1a and TMSOTf resulted in 92% yield (determined by 1H NMR
analysis), showing that Cu acetylide is a competent nucleophile.18
From the 18-electron Cu acetylide complex 19, dissociation of
neutral ligand (L) likely occurs to allow approach of the oxocarbe-
nium ion. Formation of the CꢀC bond may then occur either directly
from trivalent 21 or via π-complexation of the oxocarbenium to Cu.19
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Scheme 4. Alkynylation of Acyclic Oxocarbenium Ion
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As described above, we have developed a highly enantioselective
method for the direct alkynylation of benzopyranyl acetals to form
chiral cyclic ethers. This method allows facile access to a variety of
1-alkynyl isochromans, as well as 1-alkyl isochromans via reduction.
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of a variety of cyclic oxocarbenium ion intermediates. Efforts to
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, char-
b
acterization data, and spectra of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
mpwatson@udel.edu
’ ACKNOWLEDGMENT
To Alyssa Hellreich (University of Delaware) for synthetic assis-
tance, Prof. Joseph Fox (University of Delaware) for insightful sugges-
tions, Kaitlin Papson (University of Delaware) for HRMS, and Ram
Selvaraj (University of Delaware) for assistance with LRMS. Acknowl-
edgement is also made to the Donors of the American Chemical
Society Petroleum Research Fund, the University of Delaware Research
Fund, and the University of Delaware for partial support of this research.
NMR and other data were acquired at UD on instruments obtained
with the assistance of NSF and NIH funding (NSF MIR 0421224, NSF
CRIF MU CHE0840401 and CHE0541775, NIH P20 RR017716).
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