Enantioselective Synthesis of 4H-Pyrans Through Organocatalytic Asymmetric Formal [3+3] Cycloadditions of 2-(1-Alkynyl)-2-alken-1-ones with β-Keto Esters

Article abstract of DOI:10.1002/adsc.201600591

4H-Pyran units are frequently present in molecules with significant biological and pharmaceutical activities. Herein, we present the first enantioselective formal [3+3] cycloaddition between 2-(1-alkynyl)-2-alken-1-ones and β-keto esters catalyzed by a cyclohexyldiamine-based thiourea-tertiary amine bifunctional catalyst. Under the mild and eco-friendly conditions, a wide range of polysubstituted 4H-pyrans were obtained in moderate yields with good enantioselectivities. (Figure presented.).

Full text of DOI:10.1002/adsc.201600591

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DOI: 10.1002/adsc.201600591
Very Important Publication
Enantioselective Synthesis of 4H-Pyrans Through Organocatalytic
Asymmetric Formal [3+3]Cycloadditions of 2-(1-Alkynyl)-2-
alken-1-ones with b-Keto Esters
Zhenting Yue,a Wenbo Li,a Lu Liu,a Cuihong Wang,a,* and Junliang Zhanga,*
a
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering,
East China Normal University, 3663 N. Zhongshan Road, Shanghai 200062, Peopleꢀs Republic of China
Fax : (+86)-21–6223-5039; e-mail: chwang@chem.ecnu.edu.cn or jlzhang@chem.ecnu.edu.cn
Received: June 6, 2016; Revised: June 29, 2016; Published online: && &&, 0000
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/adsc.201600591.
Abstract: 4H-Pyran units are frequently present in
molecules with significant biological and pharma-
ceutical activities. Herein, we present the first enan-
tioselective formal [3+3]cycloaddition between 2-
(1-alkynyl)-2-alken-1-ones and b-keto esters cata-
lyzed by a cyclohexyldiamine-based thiourea-terti-
ary amine bifunctional catalyst. Under the mild and
eco-friendly conditions, a wide range of polysubsti-
tuted 4H-pyrans were obtained in moderate yields
with good enantioselectivities.
[4+2]cycloaddition between allenic esters and elec-
tron-deficient enones under amine catalysis, deliver-
ing the corresponding tetrasubstituted 4H-pyrans in
moderate yields with good enantioselectivies. Recent-
ly, Yuan[5e] and others demonstrated a Cinchona-de-
rived bifunctional catalyst-catalyzed formal [3+3]cy-
cloaddition of b-carbonyl ketones and enenitriles (or
in situ formed) to deliver pentasubstituted 2-amino-
4H-pyrans in DCM (Scheme 1c). However, the enan-
tioselective synthesis of chiral penta-carbon substitut-
ed 4H-pyrans remains elusive and poses a considerable
challenge. In 2008, we disclosed the DBU (1,8-diaza-
Keywords: bifunctional catalysts; [3+3] cycloaddi-
tion; eco-friendly reactions; enantioselectivities;
4H-pyrans
bicyclo[5.4.0.]undecen-7-ene)-catalyzed
formal
[3+3]cycloaddition of 2-(1-alkynyl)-2-alken-1-ones
with 1,3-dicarbonyl compounds to synthesize diversely
pentasubstituted 4H-pyrans.[4b] Herein, we report the
asymmetric version of this reaction by the employ-
ment of a tertiary amine-thiourea bifunctional catalyst
Polyfunctionalized 4H-pyran scaffolds are important (Scheme 1d).
building blocks in organic synthesis and widely exist
in biologically and pharmacologically active molecules
(Figure 1).[1] For example, these compounds contain-
ing 4H-pyran units are utilized as anticoagulants, anti-
cancer agents, antianaphylactics, spasmolytics, specific
IKCa channel blockers as well as serving as valuable
photoactive materials.[2]
Recently, organocatalytic cascade reactions[3,4] have
been intensively investigated as one of the most pow-
erful tools for the quick construction of diversely and
À
complexly chiral molecules via multiple C C bond
formations in a single step. Thus, significant progress
has been made in the synthesis of enantiomerically
enriched 4H-pyrans by several groups via this strat-
egy.[5] For example, Zhao[5a] developed a chiral amine-
catalyzed inverse-electron-demand formal [4+2]cyclo-
addition of malononitrile with electron-deficient
enones to synthesize chiral 4H-pyran derivatives
Figure 1. 4H-Pyrans in natural products and bioactive mole-
(Scheme 1a). Shi[5h] reported an alternative formal cules.
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Figure 2. Organocatalysts tested in this study.
62% yield with 20% ee under the catalysis of Cincho-
na alkaloid 4a in dichloromethane (Table 1, entry 1).
When the bifunctional catalysts[6] 4b–4d (entries 2–4)
derived from Cinchona alkaloids were used, catalyst
4b could give the highest yield while catalyst 4c bear-
ing with the thiourea moiety for enhancing H-bonding
could deliver a much better ee (Table 1, entry 3, 73%
ee), even though the yield of the product was not sat-
isfactory. The different results of 4c and 4d indicated
that the distance between the thiourea and tertiary
amine might be crucial to the enantioselectivity in
this transformation. Thus, the thiourea-tertiary amine
bifunctional catalysts (4e–4i) based on chiral 1,2-di-
AHCTUNGTRENNUNG
amines,[7] possessing a similar distance between two
nitrogen atoms with 4c, were conducted in this trans-
formation. The natural amino acids derived 4e and 4f
could not deliver better enantioselectivity compared
to 4c (Table 1, entries 5–6). The commonly-used cy-
clohexyldiamine derived bi-functional catalysts 4g–4i
were examined (Table 1, entries 7–9). When the R
groups on the tertiary amine were replaced by diiso-
pentyl (4i), the best enantioselectivity (88% ee) was
obtained (Table 1, entry 9) but the yield was very low.
Scheme 1. Organocatalytic asymmetric synthesis of 4H-
pyrans.
2-(1-Alkynyl)-2-alken-1-one 1a and benzyl 3-oxobu- The addition of base decreased the stereoselectivity.
tanoate 2a were selected as model substrates for Compared to the reaction carried out in dichlorome-
screening the chiral organocatalysts and reaction con- thane (DCM), a similar result was observed in DCE
ditions. Various chiral tertiary amine-based organoca- (Table 1, entry 12). Further solvent screening with,
talysts 4a–4i were tested (Figure 2). To our delight, e.g., 1,4-dioxane, toluene, THF, EtOAc, CH3CN etc.
the desired product 4H-pyran 3aa was obtained in did not bring better results (entries 13–19). Gratify-
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Table 1. Optimization of the reaction conditions.[a]
Table 2. Scope of various enynes.[a]
Entry
Catalyst
Solvent
Yield[b] [%]
ee[c] [%]
Entry R1/R2/R3 (1)
3
Yield[b] [%] ee[e] [%]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4i
4i
4i
4i
4i
4i
4i
4i
4i
4i
4i
4i
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
1,4-dioxane
toluene
THF
CH3CN
Et2O
62
80
27
53
42
6
6
34
14
70
16
15
N.R.
trace
trace
20
26
N.R.
13
20
55
73
33
43
58
70
84
88
9
78
88
–
–
–
1
2
3
4
Me/Ph/Ph
3aa 55
3ba 45
3ca 50
3da 80
81
80
85
85
82
86
81
77
88
84
86
78
82
84
76
81
Me/Ph/4-MeC6H4
Me/Ph/4-BrC6H4
Me/Ph/4-NCC6H4
Me/Ph/4-MeO2CC6H4 3ea 64
Me/Ph/4-MeCOC6H4 3fa 59
Me/Ph/4-NO2C6H4
Me/Ph/4-FC6H4
Me/Ph/4-CF3C6H4
Me/Ph/4-ClC6H4
Me/Ph/4-OCHC6H4
Ph/Ph/Ph
Me/4-NCC6H4/Ph
Me/4-ClC6H4/Ph
Me/4-BrC6H4/Ph
Me/4-CF3C6H4/Ph
5
6[d]
7[d]
8[d]
9
3ga 78
3ha 49
9
3ia
3ja
62
47
10[d]
11[e]
12
13
14
15
16
17
18
19
20
21[f]
10[d]
11
12
13
14[d]
15
16
3ka 65
3la 61
3ma 78
3na 77
3oa 56
3pa 62
74
73
–
57
85
85
[a]
EtOAc
CHCl3
neat
The reactions were carried out with 0.2 mmol of 1,
0.6 mmol of 2a and 10 mol% of catalyst at room temper-
ature for 5–9 days.
Isolated yield.
Determined by HPLC analysis.
51
55
[b]
[c]
[d]
neat
[a]
Unless noted, all reactions were carried out with
0.2 mmol of 1a, 0.6 mmol of 2a and 10 mol% of catalyst
at room temperature for 7 days.
Isolated yield.
Determined by HPLC analysis.
20 mol% of K2CO3 were added.
20 mol% of Na2CO3 were added.
20 mol% of catalyst were used.
20 mol% catalyst were used.
[b]
[c]
[d]
[e]
[f]
(Table 2, entries 13–16). In general, those substrates
with electron-withdrawing groups could facilitate the
transformation and deliver better yields.
We then turned to investigate the scope of b-keto
esters 2 for this transformation (Scheme 2). Gratify-
ingly, the best result was obtained when the reaction ingly, the reaction of yne-enone 1a with various b-
was carried out in neat condition and the catalyst keto esters 2 worked well, furnishing the desired 4H-
loading was increased to 20 mol% (Table 1, entry 21). pyrans 3ab–3ag in moderate yields with good enantio-
We next investigated the yne-enone scope of the selectivities. The reactions involving the b-keto esters
asymmetric [3+3]cycloaddition under the optimal re- 2 with ethyl and n-propyl on the ketone side (2b–2d)
action conditions (Table 2). Benzyl 3-oxobutanoate 2a delivered higher ees (3ab–3ad, up to 91% ee) than the
reacted with a variety of yne-enones 1 with aromatic methyl ketone 2a. Meanwhile, the keto ester 2e with
or aliphatic substituents on the terminus of the alkyn- a phenyl group on the ketone part was also applicable
yl group (R3), leading to the corresponding pyrans 4 to the present transformation, producing the 4H-
in moderate yield with good enantioselectivities pyran product 3ae in 86% ee. The reactions of the
(Table 2, entries 1–11). Various substituents, including keto esters with a bulky group on the ester (2f and
halogen, cyano, even formyl group were compatible 2g) displayed a slightly better enantioselectivity but
with this transformation. The reaction of 1l with relatively lower reactivity (3af and 3ag). Further re-
a phenyl group on the ketone showed a slightly lower sults demonstrated that the cycloaddition reaction of
enantioselectivity than that of 1a (Table 2, entry 12). symmetrical 1,3-diketones with yne-enone 1a also
The reaction of 1 with various substituents on the al- work, but deliver lower yields and ee (3ah and 3ai).
kenyl group (R2) also afforded similar results The absolute configuration of product (R)-3ag was
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Scheme 3. X-ray crystal structure of (R)-3ag.
To gain insight into the reaction pathway, several
control experiments were carried out (Scheme 4).
When the reaction of 1a and 2g was run under the
standard conditions for 2 days, 1a was consumed com-
pletely and allene 6,[9] dihydropyran 5ag and desired
product 3ag were isolated in 66%, 15% and 17%
yields, respectively [Eq. (1)]. This indicated that 6 and
5ag should be the key intermediates for this transfor-
mation. The resulting mixture was then subjected to
treatment with DBU. After 14 h, 3ag was isolated in
85% yield along with 9% 5ag, indicating that allene 6
was the precursor of 5ag. The cyclization of 6 and
subsequent isomerization of 5ag into the final product
3 are much slower under the catalysis of the chiral bi-
functional catalyst than the stronger base DBU [Eq.
(2) and (3)].
Scheme 2. Various b-keto ester compounds. Reactions were
carried out with 0.2 mmol of 1, 0.6 mmol of 2 and 20 mol%
catalyst at room temperature. Isolated yields.
Based on the above-mentioned control experiments
determined by single-crystal X-ray diffraction analysis and our previous studies, a possible reaction mecha-
(Scheme 3),[8] and all other adducts were tentatively nism that accounts for this [3+3]cycloaddition is pro-
assigned.
posed (Scheme 5). Under the catalysis of 4i, TS-
Scheme 4. Control experiments.
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CH2Cl2 was removed by vacuum oil pump. The mixture was
stirred at room temperature until complete consumption of
2-(1-alkynyl)-2-alken-1-one as indicated by TLC, after com-
pletion of the reaction, the reaction mixture was directly pu-
rified by silica gel chromatography using petroleum ether/
EtOAc as the eluent to afford the desired product 3aa;
yield: 55% (82% ee); [a]2D0: À14.8 (c=0.5, CHCl3). IR
(neat): n=3029, 1692, 1494, 1454, 1199, 946, 1063, 696 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=7.30–7.20 (m, 7H), 7.20-
7.09 (m, 6H), 7.09–7.04 (m, 2H), 5.04 (dd, J=29.6, 12.4 Hz,
2H), 4.71 (s, 1H), 3.96 (dd, J=29.2, 14.4 Hz, 2H), 2.19 (s,
3H), 2.08 (s, 3H); 13C NMR (100 MHz, CDCl3): d=198.98,
166.39, 158.83, 157.46, 144.18, 137.07, 135.73, 128.87, 128.51,
128.50, 128.45, 128.31, 128.19, 127.02, 126.67, 116.33, 108.23,
66.43, 39.28, 37.00, 29.75, 18.85; enantiomeric excess: 82%,
determined by HPLC (Chiralpak ADH, hexane/2-propa-
nol=95/5; flow rate 0.8 mLminÀ1
; 258C; 254 nm): tr
(major)=10.87 min, tr (minor)=15.31 min; MS (EI): m/z
(%)=438 (M+, 12.78), 91 (100); HR-MS: m/z=438.1828,
calcd. for C29H26O4: 438.1831.
Acknowledgements
We are grateful to 973 Programs, Shanghai Pujiang Program
(14PJ1403100), the National Natural Science Foundation of
China (21572065, 21425205), and Changjiang Scholars and
Innovative Research Team in University (PCSIRT) for finan-
cial support.
Scheme 5. Proposed mechanism.
References
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In conclusion, we have developed an organocatalyt-
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esters and 2-(1-alkynyl)-2-alken-1-ones under mild
conditions, leading to diversely penta-carbon-substi-
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The salient features of this transformation include
readily available starting materials, good substrate
scope, solvent-free and mild conditions. Further stud-
ies including the application of chiral organocatalyst
4i to other formal cyclizations of enynes with bisnu-
cleophiles are underway in the laboratory and will be
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ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!

COMMUNICATIONS
Enantioselective Synthesis of 4H-Pyrans Through
Organocatalytic Asymmetric Formal [3+3]Cycloadditions of
2-(1-Alkynyl)-2-alken-1-ones with b-Keto Esters
7
Adv. Synth. Catal. 2016, 358, 1 – 7
Zhenting Yue, Wenbo Li, Lu Liu, Cuihong Wang,*
Junliang Zhang*
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!