Chiral silver phosphate catalyzed transformation of ortho-alkynylaryl ketones into 1H-isochromene derivatives through an intramolecular-cyclization/ enantioselective-reduction sequence

Article abstract of DOI:10.1002/anie.201307371

The transformation of ortho-alkynylaryl ketones through a cyclization/enantioselective-reduction sequence in the presence of a chiral silver phosphate catalyst afforded 1H-isochromene derivatives in high yield with fairly good to high enantioselectivity. An asymmetric synthesis of the 9-oxabicyclo[3.3.1]nona-2,6-diene framework, which has been found in some biologically active molecules, is presented as a demonstration of the synthetic utility of this method. Dependent on its other half: The title reaction of ortho-alkynylaryl ketones in the presence of a silver catalyst with a chiral counteranion afforded 1H-isochromene derivatives in high yield with good to high enantioselectivity (see scheme; R¹=alkyl, aryl; R²=aryl; R³=H, F). An asymmetric synthesis of the 9-oxabicyclo[3.3.1]nona-2,6- diene framework found in biologically active molecules highlights the synthetic utility of this method. Copyright

Full text of DOI:10.1002/anie.201307371

Angewandte
Chemie
DOI: 10.1002/anie.201307371
Asymmetric Catalysis
Chiral Silver Phosphate Catalyzed Transformation of ortho-
Alkynylaryl Ketones into 1H-Isochromene Derivatives through an
Intramolecular-Cyclization/Enantioselective-Reduction Sequence**
Masahiro Terada,* Feng Li, and Yasunori Toda
Abstract: The transformation of ortho-alkynylaryl ketones
through a cyclization/enantioselective-reduction sequence in
the presence of a chiral silver phosphate catalyst afforded 1H-
isochromene derivatives in high yield with fairly good to high
enantioselectivity. An asymmetric synthesis of the 9-
oxabicyclo[3.3.1]nona-2,6-diene framework, which has been
found in some biologically active molecules, is presented as
a demonstration of the synthetic utility of this method.
of metal catalysts with electronically neutral chiral ligand(s).[6]
Hence, the development of enantioselective transformations
involving the isobenzopyrylium ion as a reactive intermediate
is still a challenging topic in synthetic organic chemistry.[8,9] To
develop such a catalytic enantioselective transformation, we
took advantage of the chemical properties of the isobenzo-
pyrylium ion; notably, the formation of ion-pair salts between
the isobenzopyrylium ion and less nucleophilic counteranions.
In principle, the use of a chiral instead of an achiral
counteranion should enable reactions to take place in an
enantioselective fashion.[9]
Chiral-counteranion-induced enantioselective transfor-
mations in metal-catalyzed reactions, namely, chiral-anion
catalysis,[10] has emerged as a powerful and attractive tool in
asymmetric synthesis in recent years owing to its distinct
advantages over conventional methods that rely on metal
complexes coupled with electronically neutral chiral
ligand(s). Chiral-anion catalysis offers another approach to
the enantioselective reaction of isobenzopyrylium ions with
a controlled stereochemical outcome.[8a,9] In this context, we
envisioned an enantioselective sequential transformation
based on chiral-anion catalysis in which the key intermediate,
the isobenzopyrylium ion, is generated in situ through metal-
I
sobenzopyrylium ions are stable oxonium cations owing to
their aromaticity as a 10 p-electron system. In general, these
cationic species have been generated in situ by various
methods for further manipulation, although the correspond-
ing salts can be isolated as air-stable solids with less
nucleophilic anions, such as BF4À, and are utilized both for
the characterization of these distinctive species and in
electrophilic transformations.[1–5] Their high and unique
reactivity has attracted great attention during the past
decade, because these oxonium species undergo a diverse
array of transformations, including Diels–Alder reactions and
nucleophilic addition reactions,[2–4] and can be applied to the
synthesis of natural products and biologically relevant
molecules.[5] However, catalytic enantioselective reactions of
the isobenzopyrylium ions remain largely unexploited despite
their unique reactivity and synthetic utility, presumably owing
to the planar structure of the isobenzopyrylium ion, which
lacks apparent coordination sites that can interact with chiral
metal catalysts or organocatalysts.[6,7] Indeed, successful
examples are quite limited and have been based on the use
[*] Prof. Dr. M. Terada, F. Li, Dr. Y. Toda
Department of Chemistry, Graduate School of Science
Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: mterada@m.tohoku.ac.jp
Homepage: http://www.orgreact.sakura.ne.jp/index.html
Prof. Dr. M. Terada
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
[**] This research was partially supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Transforma-
tions by Organocatalysts” from MEXT (Japan) and a Grant-in-Aid
for Scientific Research (Grant No. 23655077) from the JSPS. We
gratefully acknowledge Prof. T. Iwamoto and Prof. S. Ishida
(Graduate School of Science, Tohoku University) for their kind
assistance with X-ray crystallographic analysis. We also thank the
JSPS for a research fellowship for Young Scientists (Y.T.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307371.
Scheme 1. Enantioselective transformation involving an isobenzopyry-
lium cation as the reactive intermediate.
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complex-catalyzed intramolecular cyclization of ortho-alky-
nylaryl ketones 2. The proposed sequence involves a two-step
transformation (Scheme 1): 1) intramolecular cyclization of 2
catalyzed by a p-Lewis acidic metal complex with a binol-
derived phosphate 1 (binol = 1,1’-binaphthalene-2,2’-diol) as
the chiral counteranion[11] to generate an ion pair comprised
of the isobenzopyrylium intermediate A and chiral phosphate
1À, and 2) enantioselective reduction of this key intermediate
A with a Hantzsch ester 3[12] to afford the final product 4 in an
enantioselective manner under the influence of 1À. Herein,
we report the enantioselective transformation of ortho-
alkynylaryl ketones 2 into optically active 1H-isochromene
derivatives 4 through a cyclization/enantioselective reduction
sequence with a chiral silver phosphate catalyst and 3 as the
reducing agent.
entry 7). As expected, this strong Brønsted acid did not afford
any product, and the starting material 2a was almost
completely recovered. As the catalyst AgOTf exhibited
exclusive formation of the 6-endo product 4a and higher
reactivity than Cu(OTf)2, AgI was chosen as the metal species
for further studies on an enantioselective variant of the
present sequential transformation.
The enantioselective variant of the reaction was con-
ducted with the chiral silver phosphate Ag[(R)-1] (10 mol%),
2a, and 3a (1.1 equiv) in THF at room temperature. Ag[(R)-
1] was preprepared from Ag2CO3 and the corresponding
binol-derived phosphoric acid (R)-1 (2 equiv).[11a,13] We
screened a range of chiral silver phosphates by changing the
substituents at the 3- and 3’-positions of the binaphthol
backbone (Table 2, entries 1–4). The pentafluorophenyl-sub-
We began our investigation by exploring achiral p-Lewis
acidic metal complexes with the ortho-alkynylaryl ketone 2a
(R1 = Me, R2 = phenyl, R3 = H) as the primary substrate for
the precursor of the isobenzopyrylium ion. The sequential
transformation was performed with 10 mol% of the metal
catalyst and 1.1 equivalents of Hantszch ester 3a in THF at
room temperature. The reactivity and mode of cyclization
were highly dependent on the metal catalyst employed
(Table 1). AgI and CuII catalysts afforded the desired 6-endo
cyclization product 4a exclusively in excellent yield (Table 1,
entries 1 and 2, respectively). In contrast, the reactions with
PtII, AuIII, and AuI catalysts afforded not only the desired 6-
endo product 4a, but also the 5-exo product 5a (Table 1,
entries 3, 4, and 6, respectively), although the AuIII and AuI
catalysts exhibited higher catalytic activity than that of the
AgI catalyst (Table 1, entries 4 and 6 versus entry 1). To verify
the participation of the p-Lewis acidic metal species in this
reaction, trifluoromethanesulfonic acid (TfOH) was
employed as a metal-free Brønsted acid catalyst (Table 1,
Table 2: Screening of chiral silver catalysts for the cyclization/enantio-
selective reduction of 2a to 4a and control experiments.[a]
Entry
Catalyst
t [h]
Additive
Yield [%][b]
ee [%][c]
1
2
3
4
5
Ag[(R)-1a]
Ag[(R)-1b]
Ag[(R)-1c]
Ag[(R)-1d]
Ag2CO3
(R)-1a
Ag2CO3/(R)-1a
Ag[(R)-1a]
Ag[(R)-1a]
Ag[(R)-1a]
4
9
7
–
–
–
–
–
–
–
94
84
94
77
85
37
66
41
–
5
[d]
24
24
5
48
54
6
trace[e]
trace[e]
94
6
–
7[f]
8[g]
9[g]
10[g]
83
86
77
87
3 ꢀ MS
4 ꢀ MS
5 ꢀ MS
80[h]
32[i]
95
Table 1: Initial screening of p-Lewis acidic metal catalysts for the
cyclization/reduction of 2a.[a]
[a] Reaction conditions (unless otherwise noted): catalyst (0.02 mmol,
10 mol%), 2a (0.2 mmol), 3a (0.22 mmol, 1.1 equiv), THF (1 mL), room
temperature. [b] Yield of isolated 4a. The consumption of 2a was
monitored by TLC. [c] The ee value of 4a was determined by chiral-
stationary-phase HPLC analysis. [d] The reaction was carried out with
Ag2CO3 (0.01 mmol, 5 mol%). [e] Ketone 2a was recovered in nearly
quantitative yield. [f] The catalyst was generated in situ from Ag2CO3
(0.01 mmol, 5 mol%) and (R)-1a (0.02 mmol, 10 mol%). [g] The
reaction was carried out with MS (75 mg), Ag[(R)-1a] (0.015 mmol,
10 mol%), 2a (0.15 mmol), and 3a (0.165 mmol, 1.1 equiv) in THF
(0.75 mL). [h] Ketone 2a was recovered in 19% yield. [i] Ketone 2a was
recovered in 66% yield.
Entry Metal catalyst
t [h] Conversion Yield
Yield
of 2a [%][b] of 4a [%][b] of 5a [%][b]
1
2
3
4
5
6
7
AgOTf
Cu(OTf)2
PtCl2
3
24
24
1
100
96
35
96
96
18
38
–
–
–
5
50
–
58
–
stituted chiral silver phosphate Ag[(R)-1a] was found to
provide the highest chemical yield and enantioselectivity
(Table 2, entry 1). Ag[(R)-1a] promoted the consecutive
reactions smoothly to afford the desired product 4a in 94%
yield with fairly good enantioselectivity (85% ee). The use of
Ag2CO3 or the chiral phosphoric acid alone did not afford any
product, and the starting ketone 2a was recovered in a nearly
quantitative manner (Table 2, entries 5 and 6). These control
experiments strongly suggest that Ag[(R)-1] is essential for
this reaction sequence to proceed in an enantioselective
AuCl3
100
AuCl/AgOTf
[AuCl(PPh3)]/AgOTf
TfOH
24 trace
100
24 trace
1
24
–
[a] Reaction conditions: transition-metal catalyst (0.02 mmol, 10 mol%),
2a (0.2 mmol), 3 (0.22 mmol, 1.1 equiv), THF (1 mL), room temper-
ature. [b] Determined by 1H NMR spectroscopic analysis of the crude
product. Tf=trifluoromethanesulfonyl.
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manner. The chiral silver phosphate generated in situ from
(R)-1a and Ag2CO3 was also examined (Table 2, entry 7).
However, preprepared Ag[(R)-1a] displayed slightly higher
enantioselectivity than that of the catalyst generated in situ.
We then explored the use of other additives to improve the
enantioselectivity of the reaction (Table 2, entries 8–10). The
addition of 3 ꢀ and 4 ꢀ molecular sieves (MS) significantly
retarded the reaction, and the starting ketone 2a was not
consumed completely, even after 2 days (Table 2, entries 8
and 9, respectively). In particular, a considerable reduction in
both the chemical yield and the ee value was observed in the
presence of 4 ꢀ MS. In contrast, when 5 ꢀ MS were used as
an additive, even higher enantioselectivity was observed
without any detrimental effect on the chemical yield (Table 2,
entry 10).
exchange, regenerates the catalytic species and releases the
isochromene product 4.[15,16]
Having identified the sequential process involving an
isobenzopyrylium reactive intermediate, the scope of the
reaction was then investigated with a range of alkynylaryl
ketones 2 under the optimized reaction conditions. A broad
range of alkynylaryl ketones are applicable to the present
sequential transformation, although reactivity and enantiose-
lectivity are highly dependent on the nature of the substitu-
ents (Table 3). When alkyl and aryl groups were introduced at
Table 3: Scope of the chiral silver phosphate catalyzed transformation of
2 into 4.[a]
Next, we explored the mechanism of the silver phosphate
catalyzed sequential transformation of 2 into 4 to confirm the
participation of the isobenzopyrylium ion as the reactive
intermediate. From a mechanistic viewpoint, it can be
considered that there are two possible reaction pathways.
One pathway involves intramolecular cyclization followed by
enantioselective reduction of the isobenzopyrylium inter-
mediate (Scheme 1). However, the same product would be
obtained if the reactions occurred in the reverse order, that is,
reduction to the alcohol, followed by cyclization.[14] To verify
the order of the reaction sequence, we conducted a control
Entry 2 (R1, R2, R3)
t [h]
4
Yield [%][b] ee [%][c]
1
2
3
2b (Me, 4-MeC6H4-, H)
11
10
5
9
6
6
2
24
26
26
30
4b
4c
4d
4e
4 f
4g
4h
4i
98
87
92
95
89
89
89
85
81
81
84
81
67
80
81
82
87
22
92
90
91[d]
91
91
88
90
49
2c (Me, 4-CF3C6H4-, H)
2d (Me, 4-MeOC6H4-, H)
2e (nPr, Ph, H)
4
experiment with alcohol
6 as a possible intermediate
5
2 f (iBu, Ph, H)
(Scheme 2). When compound 6 was subjected to the catalytic
6
2g (Me, Ph, F)
7
2h (Me, nBu, H)
8
2i (Ph, Ph, H)
9
2j (4-MeOC6H4-, Ph, H)
2k (4-BrC6H4-, Ph, H)
2l (4-CF3C6H4-, Ph, H)
2m (3-MeOC6H4-, Ph, H) 29
2n (2-TBSOC6H4-, Ph, H) 24
4j
4k
4l
10
11
12
13
14
15
4m 81
4n
4o
4p
90
68
86
2o (Ph, Ph, F)
2p (Ph, nBu, H)
28
8
Scheme 2. Mechanistic study: control experiment.
[a] Reactions were carried out with Ag[(R)-1a] (0.015 mmol, 10 mol%), 2
(0.15 mmol), and 3 (0.165 mmol, 1.1 equiv). For 2b–h, reactions were
carried out with 3a (R=Et) in THF (0.75 mL) in the presence of 5 ꢀ MS
(75 mg). For 2i–p, reactions were carried out with 3b (R=Me) in EtOAc
(0.75 mL) in the absence of MS. [b] Yield of isolated 4. [c] The ee value of
4 was determined by chiral-stationary-phase HPLC analysis. [d] The
absolute configuration of 4k was determined to be S by X-ray crystallo-
graphic analysis.[17] See the Supporting Information for details.
reaction under the influence of Ag[(R)-1a] (10 mol%) with-
out the Hantzsch ester, the reaction proceeded with very low
conversion, even after 6 h, and product 5a of 5-exo cyclization
was obtained in 10% yield, whereas almost none of the
desired 6-endo cyclization product 4a was observed. This
behavior is in contrast to that of the present reaction of the
primary substrate 2a, which afforded the 6-endo cyclization
product 4a exclusively in excellent yield within 4 h in the
presence of the Hantzsch ester (Table 2, entry 1). Therefore,
these results strongly suggest that alcohol 6 is not involved as
an intermediate in the present sequential transformation, and
that the isobenzopyrylium species participates as the key
intermediate, as shown in Scheme 1. Thus, it was concluded
that the reaction is initiated by the coordination of Ag[(R)-1]
the R1 and R2 positions, respectively (Table 3, entries 1–6),
these substrates exhibited relatively high reactivity and
afforded isochromene derivatives 4 in high yields. However,
in terms of the enantioselectivity, the introduction of a para
substituent on the aromatic group at the R2 position
(substrates 2b–d) led to a slight decrease in enantioselectivity
as compared to that observed with the primary substrate 2a
(R2 = Ph). Substrates bearing linear or branched alkyl chains
at the R1 position (2e and 2 f, respectively) also underwent the
reaction with a slight reduction in enantioselectivity, whereas
fluoro substitution on the tethering benzene ring (2g) did not
compromise the stereochemical outcome. However, the
introduction of an alkyl substituent at the R2 position led to
À
to the C C triple bond of 2. This interaction induces
intramolecular nucleophilic attack by the carbonyl oxygen
atom to generate an ion pair consisting of the isobenzopyry-
lium ion and the chiral phosphate. Subsequent enantioselec-
tive reduction by Hantzsch ester 3, followed by metal–proton
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a
considerable decrease in enantioselectivity (Table 3,
In conclusion, we have successfully developed a cycliza-
tion/enantioselective-reduction sequence for the transforma-
tion of ortho-alkynylaryl ketones under the catalysis of
a chiral silver phosphate complex to afford 1H-isochromene
derivatives in high yields with fairly good to high enantiose-
lectivity. A mechanistic study strongly suggested that an
isobenzopyrylium cation is involved as the key intermediate
in this transformation. We also demonstrated the utility of this
methodology for the asymmetric synthesis of the 9-
oxabicyclo[3.3.1]nona-2,6-diene framework, which has been
found in some biologically active molecules. Further develop-
ment of the present methodology for application not only to
other types of nucleophiles, but also to other transformations
involving cationic species that are difficult to perform by
other conventional methods will be completed in due course.
entry 7). The reactions of substrates 2i–o bearing aromatic
substituents at the R1 position and a phenyl group at the R2
position were very sluggish under the optimized conditions
and proceeded in low chemical yields, although the ee values
of the products were around 90%. To our delight, however,
these substrates were smoothly converted under modified
reaction conditions [with 3b (R = Me) in ethyl acetate instead
of THF and in the absence of 5 ꢀ MS] to give the
corresponding isochromene products 4i–n in good yields
with high enantioselectivity (Table 3, entries 8–13). A variety
of aryl groups at the R1 position were tolerated in this reaction
(substrates 2j–n; Table 3, entries 9–13). Even with a bulky
tert-butyldimethylsilyloxy (OTBS) substituent in the ortho
position, the corresponding product 4n was obtained in 90%
yield with 88% ee (Table 3, entry 13). The introduction of
a fluoro substituent on the tethering benzene ring of a diaryl-
substituted ketone (substrate 2o) did, however, result in Experimental Section
Typical procedure for the reaction of 2a–h: MS (5 ꢀ; 75.0 mg),
a slight decrease in chemical yield, but with little detrimental
effect on the enantioselectivity (Table 3, entry 14). However,
when an alkyl substituent was introduced at the R2 position,
a considerable reduction in enantioselectivity was observed
(Table 3, entry 15).
Finally, the synthetic utility of the present method was
demonstrated (Scheme 3). 1-Allyl 1H-isochromenes, such as
4q, have been utilized as key intermediates for the synthesis
Hantzsch ester 3a (41.8 mg, 0.165 mmol), and Ag[(R)-1a] (10 mol%,
11.8 mg, 0.015 mmol) were placed in a dry test tube. The atmosphere
was replaced with argon, THF (0.75 mL) was added to the mixture,
and the resulting mixture was stirred vigorously for 10 min. Ketone 2a
(32.8 mg, 0.15 mmol) was then added, and the reaction mixture was
stirred for 6 h at room temperature and then filtered through a pad of
Al2O3 (with EtOAc as the eluent). The filtrate was concentrated, and
the crude product was purified by flash column chromatography on
silica gel with hexane/EtOAc/Et3N (100:1:1) as the eluent to afford 4a
(31.5 mg, 95%) as a white solid. The ee value was determined by
chiral-stationary-phase HPLC analysis. See the Supporting Informa-
tion for the reaction of 2i–p.
Received: August 21, 2013
Revised: October 7, 2013
Published online: November 24, 2013
Keywords: asymmetric catalysis · cyclization ·
.
enantioselective reduction · isobenzopyrylium ions · silver salts
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sulfonyl.
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regioisomer 7b in moderate overall yield for the two steps.
During the course of the acid-catalyzed annulation, no loss of
enantiomeric purity was observed.
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[15] As shown in Scheme 1, we propose that the metal species is
attached to the isobenzopyrylium ion. However, during the
reduction step, the actual structure of the cationic species has not
been confirmed yet. Before enantioselective reduction, an
exchange from the silver atom to a hydrogen atom would also
be possible, and the silver metal would then not be involved in
the stereodetermining step. We also conducted a reaction with
Cu[(R)-1a]2 as the chiral catalyst, and product 4a was obtained
with 86% ee, albeit in moderate yield. This enantioselectivity is
nearly equal to that observed upon Ag[(R)-1a] catalysis
(Table 2, entry 1: 85% ee). These results imply that the metal
species may not participate in the enantioselective reduction
step.
[16] When the 4,4-dideuterium-substituted Hantzsch ester was
employed, deuterium was introduced at the C1 position
exclusively. This result strongly suggests that the reaction
proceeded through the formation of an isobenzopyrylium ion
as the reactive intermediate. See the Supporting Information for
details.
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