Asymmetric synthesis of dihydropyranones from ynones by sequential copper(I)-catalyzed direct aldol and silver(I)-catalyzed oxy-michael reactions

Article abstract of DOI:10.1002/anie.201109209

Ynones as diene surrogates: The asymmetric synthesis of enantiomerically enriched substituted dihydropyranones is described. The products are obtained in two steps by a copper(I)-catalyzed direct aldol reaction of ynones followed by a silver-catalyzed oxy-Michael reaction. This easy method is compatible with both aromatic and aliphatic substrates, and provides excellent chemoselectivity under mild reaction conditions. Copyright

Full text of DOI:10.1002/anie.201109209

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Angewandte
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DOI: 10.1002/anie.201109209
Asymmetric Synthesis
Asymmetric Synthesis of Dihydropyranones from Ynones by
Sequential Copper(I)-Catalyzed Direct Aldol and Silver(I)-Catalyzed
Oxy-Michael Reactions**
Shi-Liang Shi, Motomu Kanai,* and Masakatsu Shibasaki*
Chiral dihydropyranones are versatile intermediates for the
synthesis of tetrahydropyrans and spiroketals, which are
ubiquitous structural motifs in biologically active molecules.
The asymmetric hetero-Diels–Alder reaction[1] between car-
bonyl compounds and Danishefsky-type siloxy dienes is one
of the most reliable methods of accessing optically active
dihydropyranones [Scheme 1, Eq. (1)]. However, this method
requires additional steps for the preparation of siloxy dienes,
and the stereoselective synthesis of multisubstituted siloxy
dienes is generally difficult. Considering the fact that enolates
derived from ynones 2[2] are in the same oxidation state as
Danishefsky-type dienes, we envisioned that a stepwise
catalytic asymmetric direct aldol reaction of ynones, followed
by an intramolecular oxy-Michael reaction would produce
enantiomerically enriched dihydropyranones [Scheme 1,
Eq. (2)]. This sequential pathway would be atom-econom-
ical[3] and require fewer steps.[4] Herein, we report the
catalytic asymmetric synthesis of 2,6-disubstituted and 2,3,6-
trisubstituted dihydropyranones by a sequential aldol-oxy-
Michael reaction using stable and easily accessible ynones.
Despite the high synthetic utility of the products, to date
Scheme 1. Two methods for the catalytic asymmetric synthesis of
dihydropyranones. TMS=trimethylsilyl.
there have been only three reports of direct catalytic
enantioselective aldol reactions[5] between aldehydes and
ynones.[6,7] However, the substrate scope of these previous
examples is not satisfactory, being limited to either unenoliz-
able a,a-disubstituted aliphatic aldehydes[6a–d] or aromatic
aldehydes with strong electron-withdrawing groups.[6e] In
addition, intramolecular oxy-Michael reactions of ynones
producing dihydropyranones have not been studied exten-
sively.[8,9] The high susceptibility of aldol intermediates
derived from ynones to the retro-aldol reaction is the most
common reason for this lack of research into the use of ynones
in aldol and oxy-Michael reactions. To enhance the feasibility
of sequential dihydropyranone synthesis, potential catalysts
should promote the aldol and oxy-Michael steps under very
mild conditions.
[*] Dr. S.-L. Shi, Prof. Dr. M. Kanai
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: kanai@mol.f.u-tokyo.ac.jp
Homepage: http://www.f.u-tokyo.ac.jp/~kanai/index.html
Prof. Dr. M. Kanai
Kanai Life Science Catalysis Project
ERATO (Japan) Science and Technology Agency
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
We envisioned that soft metal catalysts, which preferen-
ꢀ
tially interact with the C C bond moiety of ynones, would
effectively suppress the undesired retro-aldol reaction in this
sequential process (Scheme 1). There are three main advan-
tages to using soft metal catalysts in this process. First, the
interaction of these catalysts with the substrate facilitates the
selective deprotonation of ynones, even in the presence of
enolizable aliphatic aldehydes under weakly basic condi-
tions.[10] Second, the intermediate soft metal aldolate is
stabilized due to the additional metal–p interaction, allowing
for retardation of the undesired retro-aldol reaction. Third,
Prof. Dr. M. Shibasaki
Institute of Microbial Chemistry, Tokyo
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021 (Japan)
E-mail: mshibasa@bikaken.or.jp
[**] Financial support was provided by the Funding Program for Next
Generation World-Leading Researchers from JSPS and ERATO from
JST. We thank Dr. Ludovic Drouin for his contribution at the initial
stage of this project. S.-L.S. thanks the JSPS for research fellowships.
ꢀ
the interaction activates the C C bond, and facilitates the
intramolecular oxy-Michael reaction under non-basic condi-
tions. M1 and M2 can either be the same metal (preferably) or
different metals.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201109209.
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Based on our previous findings,[10b–e] we began by exam-
ining the asymmetric aldol addition of 3-hexyn-2-one (2a)
and isobutyraldehyde (1a) using copper alkoxide- or phen-
oxide-phosphine complexes (M1 = Cu, Table 1) as catalysts.
Initial ligand screening[11] indicated that a catalyst derived
the copper catalyst and 40 mol% of TFE at À408C gave 96%
yield and 88% ee (Table 1, entry 7). Alternatively, 3aa could
be obtained in 91% yield and 89% ee using a less basic
catalyst, CuOCH(CF3)2 (5 mol%), derived from more acidic
hexafluoroisopropanol (HFIP; pKa in DMSO = 17.9)
(Table 1, entry 8).[11] Lithium was not essential in this
reaction, and comparable results were obtained (82% yield
and 88% ee) using a lithium-free copper alkoxide catalyst
prepared from mesitylcopper (3 mol%) and excess TFE
(43 mol%). On the other hand, a markedly lower yield was
obtained when using CF3CH2OLi as a catalyst without any
copper source (3 mol% tBuOLi and 43 mol% TFE; 47%
yield), indicating the critical role of copper in promoting this
aldol reaction.
Table 1: Optimization of CuI alkoxide-catalyzed asymmetric aldol reac-
tion of an aliphatic aldehyde.[a]
Aromatic aldehydes are even more challenging substrates,
because the b-aryl-b-hydroxyynone products have a greater
susceptibility to both the retro-aldol reaction and dehydration
than b-alkyl-b-hydroxyynones.[12] Indeed, the optimized con-
ditions for aliphatic aldehydes were unsatisfactory for ben-
zaldehyde (1e) (Table 2, entries 1 and 2). Excess amounts of
Entry
Cu source (x)[b]
R
y
Yield [%][c]
ee [%]
1[d]
2
3
4
5
CuPF6 (10)
CuPF6 (10)
CuPF6 (10)
CuClO4 (10)
CuClO4 (10)
CuClO4 (10)
CuClO4 (3)
CuClO4 (5)
p-MeO-C6H4
p-MeO-C6H4
p-MeO-C6H4
p-MeO-C6H4
CF3CH2
CF3CH2
CF3CH2
(CF3)2CH
0
0
84
69
65
76
86
100
96
91
30
81
88
88
33
81
88
89
15
15
15
200
40
5
Table 2: Optimization of CuI alkoxide-catalyzed asymmetric aldol reac-
tion of an aromatic aldehyde.[a]
6
7[e]
8[f]
[a] Reactions conducted at À308C for 13 h, unless otherwise noted.
[b] Tetraacetonitrile complexes were used. [c] Determined by 1H NMR
spectroscopy using 1,1,2,2-tetrachloroethane as an internal standard.
[d] At À208C. [e] At À408C for 20 h. [f] For 36 h.
Entry
R
x
y
Yield [%][b]
ee [%]
1
CF3CH2
(CF3)2CH
CF3CH2
3
5
5
40
5
200
70
80
100
79
61
93
2[c]
3[d]
from CuPF6, Li(OC6H4-p-OMe), and (R)-5,5’-bis[di(3,5-di-
tert-butyl-4-methoxyphenyl)phosphino]-4,4’-bi-1,3-benzo-
dioxole (DTBM-Segphos) at À208C gave promising results,
affording b-hydroxyynones 3aa in 84% yield and 30% ee
(Table 1, entry 1). The subsequent oxy-Michael reaction did
not proceed under those conditions. Therefore, we first
optimized the direct catalytic asymmetric aldol reaction.
Notably, either lowering the temperature to À308C (Table 1,
entry 2) or using an additional 15 mol% of p-MeO-C6H4OH
(pKa in DMSO = 19.1, Table 1, entry 3) significantly
improved the enantioselectivity to greater than 80%,
although the yield of 3aa was moderate. The effects of the
copper source were minor, although the use of CuClO4
instead of CuPF6 slightly improved the yield without changing
the enantioselectivity (Table 1, entry 4).
[a] CuOR catalyst was prepared from CuClO4·4CH3CN and LiOR (1:1).
Reaction time was 36 h for entries 1 and 2, and 72 h for entry 3.
[b] Determined by 1H NMR spectroscopy using 1,1,2,2-tetrachloroethane
as an internal standard. [c] At À308C. [d] Using 3 equiv of 2a.
alcohol were added to more effectively suppress the retro-
aldol reaction. Using 2 equiv of TFE and 5 mol% of catalyst,
product 3ea was obtained in quantitative yield and 93% ee
(Table 2, entry 3). The optimization studies shown in Tables 1
and 2 demonstrated the critical importance of the balance
between the basicity of the catalyst (to promote the aldol
reaction) and the amount of alcohol (to suppress the retro-
aldol reaction).
To improve the yield further, we used a more basic
catalyst containing trifluoroethoxide (pKa of trifluoroethanol
(TFE) in DMSO = 23.5). As expected, the yield was higher
(86%), but the enantiomeric excess dropped to 33% (Table 1,
entry 5). This dramatic decrease in enantioselectivity when
using a catalyst with higher basicity is likely due to the basic
conditions facilitating the retro-aldol reaction through
a metal aldolate intermediate.[6c] Excess alcohol was added
to prevent the retro-aldol reaction by decreasing the concen-
tration of metal aldolate (Table 1, entry 6). A marked
improvement in enantioselectivity to 81% was observed.
Finally, optimized results were obtained by balancing the
basicity and the amount of the alcohol additive: 3 mol% of
Having established the optimized conditions for the aldol
reaction step, we next investigated the oxy-Michael reaction
step. Using purified aldol product 3aa, we screened Lewis
acids and identified AgOTf[8c] and AuCl[8a] as excellent
catalysts. The reaction rate was significantly enhanced under
microwave conditions (1008C, 1 h). CuOTf also promoted the
oxy-Michael reaction, but the reaction rate was lower than
with AgOTf and AuCl.
The optimized conditions for the aldol reaction and oxy-
Michael reaction were then combined for the sequential
dihydropyranone synthesis (Scheme 2). After the aldol reac-
tion, using 5 mol% of CuOCH(CF3)2 and HFIP (Table 1,
entry 8), was complete, AgOTf (10 mol%) was added and the
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Table 3: Catalytic asymmetric synthesis of dihydropyranones from
aldehydes and ynones.
Scheme 2. Sequential catalytic enantioselective aldol-oxy-Michael reac-
tion of an aliphatic aldehyde. OTf=triflate.
Entry Aldehyde:
R1
Ynone:
R2, R3
x
Cond.[a] Prod. Yield ee
[%][b] [%]
1
2
iPr (1a)
cHex (1b)
tBu (1c)
Ph(CH2)2 (1d) Et, H (2a)
tBu (1c)
tBu (1c)
Et, H (2a)
Et, H (2a)
Et, H (2a)
5
5
3
3
3
3
A[c]
A[c]
A
4aa 81
4ba 75
4ca 88
4da 55
4cb 65
4cc 73
88
88
93
75
95
93
mixture was heated by microwave irradiation at 1008C for
1 h. Cyclized product 4aa was obtained in 81% yield and
88% ee. The enantiomeric excess of 4aa was slightly lower
(86%) when using CuOCH2CF3 and TFE conditions for the
aldol reaction (Table 1, entry 7). For the more sensitive aldol
product 3ea, derived from an aromatic aldehyde, the
sequential one-pot procedure was not successful. Aqueous
workup after the aldol reaction involving oxidation of the
phosphine by dilute aqueous H2O2 was found to be crucial in
this case. Thus, an AgOTf-catalyzed oxy-Michael reaction
using crude 3ea at room temperature produced 4ea in 99%
yield and 91% ee (Scheme 3).
3[d]
4
A[e]
A[f]
A[f]
5
6
Ph, H (2b)
(CH2)2OH, H
(2c)
Et, H (2a)
Me, H (2d)
Et, H (2a)
7
Ph (1e)
Ph (1e)
2-naph (1 f)
5
5
5
B
B
B
4ea 99
4ed 94
91
90
88
8[g]
9
4 fa
89
10
11
Et, H (2a)
5
3
B[h]
4ga 75
4ha 56
83
87
Et, H (2a)
Et, H (2a)
B[i]
12
13
3
5
3
B[i]
B
4ia
4ja
61
63
93
76
85
=
(E)-PhCH CH Et, H (2a)
(1j)
14[j] tBu (1c)
Ph, Me (2e)
A[k]
4ce 63
Scheme 3. Sequential catalytic enantioselective aldol-oxy-Michael reac-
tion of an aromatic aldehyde. OTf=triflate.
[a] Conditions: A=CuOCH2CF3/(R)-DTBM-Segphos (3 mol%) and
CF3CH2OH (40 mol%) in THF at À408C for 20 h (for the aldol reaction);
AgOTf (OTf=triflate; 10 mol%) in CH2Cl2 at 1008C (microwave) for 1 h
(for cyclization). B=CuOCH2CF3/(R)-DTBM-Segphos (5 mol%) and
CF3CH2OH (200 mol%) in THF at À608C for 72 h (for the aldol
reaction); AgOTf (10 mol%) in CH2Cl2 at RT for 18 h (for cyclization).
See the Supporting Information for details. [b] Yield of isolated product.
[c] Conditions given in Table 1, entry 8 were used. [d] Performed on
a 10 mmol scale. [e] À608C (for the aldol reaction). [f] At RT for 18 h (for
cyclization). [g] The absolute configuration was determined to be S.
[h] AuCl (10 mol%) in CH2Cl2 at RT for 72 h (for cyclization).
[i] CuOCH2CF3/(R)-DTBM-Segphos (3 mol%) and CF3CH2OH
(120 mol%; for the aldol reaction). [j] Diastereomeric ratio of the
product=6.7:1 (cis/trans). [k] At À608C in THF/DMF (1:1) for 48 h (for
the aldol reaction); using 20 mol% of AgOTf at RT for 18 h (for
cyclization). cHex=cyclohexyl, 2-naph=2-naphthyl.
The substrate scope of the sequential dihydropyranone
synthesis was investigated under the optimized conditions
(Table 3). The method was applicable to both aliphatic and
aromatic aldehydes. Of particular note, the reaction was
effective on linear aldehyde 1d, which is susceptible to self-
condensation under basic conditions (Table 3, entry 4). Both
ketone and ester functionalities were tolerated (Table 3,
entries 11 and 12). For enal 1j, 1,2-addition to the aldehyde
moiety was the exclusive pathway (Table 3, entry 13). The
range of functional ynones was also broad. Specifically, ynone
2c, containing a free hydroxy group, produced 4cc in high
yield and enantioselectivity (Table 3, entry 6). The method
was also applicable to a-substituted ynones. The use of ethyl
ketone 2e promoted the facile synthesis of 2,3,6-trisubstituted
dihydropyranone 4ce, affording the product with high
diastereo- and enantioselectivity (Table 3, entry 14, 6.7:1
d.r., 85% ee, 63% yield). Therefore, the current method,
which starts from stable and easily accessible ynones, is
noteworthy with regard to the synthetic value of the products,
broad substrate scope, easy operation under mild reaction
conditions, and excellent chemoselectivity. The products,
enantiomerically enriched 2,6-disubstituted dihydropyra-
nones, are generally difficult to synthesize through previously
established catalytic asymmetric hetero-Diels–Alder reac-
tions using the corresponding Danishefsky-type siloxy
dienes.[13]
ically-enriched substituted dihydropyranones. The process
involves two sequential steps with unstable aldol intermedi-
ates derived from ynones. Three main characteristics of the
chiral CuI-conjugated base catalyst favorably contributed to
the success of the reaction: 1) alkyne affinity leading to
chemoselective enolization, 2) tuneable basicity through the
alkoxide, and 3) tolerance of excess protic agents that are
needed to suppress the retro-aldol reaction. In addition, soft
I
ꢀ
electrophilic p-activation of the C C bond by the Ag catalyst
was also critical. Expansion of these concepts to other
important bond formations is ongoing.
Received: December 29, 2011
Revised: February 3, 2012
Published online: March 2, 2012
In summary, we have developed a facile and general
catalytic asymmetric method for the synthesis of enantiomer-
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2004, 37, 580; b) R. Mahrwald, Modern Aldol Reactions, Wiley-
Keywords: aldol reactions · asymmetric catalysis ·
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[11] See the Supporting Information.
[12] The pKa (in DMSO) values were calculated using Jaguar version
7.0, which revealed that the hydroxy group in 3ea is significantly
more acidic than that of 3aa. See the Supporting Information.
[13] The corresponding siloxy dienes are difficult to synthesize.
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