One-pot formation of chiral polysubstituted 3,4-dihydropyrans via a novel organocatalytic domino sequence involving alkynal self-condensation

Article abstract of DOI:10.1021/ol3032285

The self-condensation of alkynals was for the first time implemented under mild organocatalytic conditions and was successfully linked with a domino organocatalytic inverse-electron-demand oxa-Diels-Alder reaction, which led to the development of a facile one-pot method to produce a wide variety of polysubstituted chiral 3,4-dihydropyrans with good to high yields and diastereoselectivities and high enantioselectivities. The unprecedented alkynal self-condensation was revealed to pass through secondary amine-catalyzed C-C triple bond hydration and subsequent aldol condensation.

Full text of DOI:10.1021/ol3032285

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
One-Pot Formation of Chiral
Polysubstituted 3,4-Dihydropyrans via a
Novel Organocatalytic Domino Sequence
Involving Alkynal Self-Condensation
Li-Jin Dong,†,‡ Tian-Tian Fan,†,‡ Chao Wang,† and Jian Sun*,†
Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences,
Chengdu 610041, China, and Graduate University of the Chinese Academy of Sciences,
Beijing 100049, China
sunjian@cib.ac.cn.
Received November 28, 2012
ABSTRACT
The self-condensation of alkynals was for the first time implemented under mild organocatalytic conditions and was successfully linked with a
domino organocatalytic inverse-electron-demand oxa-DielsꢀAlder reaction, which led to the development of a facile one-pot method to produce a
wide variety of polysubstituted chiral 3,4-dihydropyrans with good to high yields and diastereoselectivities and high enantioselectivities. The
unprecedented alkynal self-condensation was revealed to pass through secondary amine-catalyzed CꢀC triple bond hydration and subsequent
aldol condensation.
Organocatalytic asymmetric domino reactions have
proven to be powerful tools for the efficient construction
of complex chiral molecules under mild, environmentally
benign conditions.1,2 In recent years, various protocols
have been developed, mainly based on the iminium/enam-
ine activation strategy.2 Many reactions have been incor-
porated into the domino sequences of these protocols,3 for
instance, the Michael addition, the Henry reaction, the
Aldol reaction, the Mannich reaction, the FriedelꢀCrafts,
etc. Nonetheless, it remains necessary to search for new
organocatalytic reactions applicable in domino sequences,
which could result in new domino protocols and thus useful
new chiral products or new synthetic routes toward structur-
ally complex molecules. Herein, we report our discovery that
the self-condensation of alkynal could be activated by an
organocatalyst and be incorporated into an organocatalytic
domino protocol that leads to an easy access to polysubsti-
tuted chiral 3,4-dihydropyrans with good to high yields and
diastereoselectivities and high enantioselectivities.
Activation of a carbonyl-conjugated CꢀC double bond
through an iminium intermediate has proven to be a
† Chinese Academy of Sciences.
‡ Graduate University of the Chinese Academy of Sciences.
(1) For recent reviews on domino reactions for construction of
complex chiral molecules: (a) Nicolaou, K. C.; Edmonds, D. J.; Bulger,
P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (b) Grondal, C.; Jeanty, M.;
Enders, D. Nat. Chem. 2010, 2, 167. (c) Jones, S. B.; Simmons, B.;
Mastracchio, A.; MacMillan, D. W. C. Nature 2011, 475, 183.
(2) For recent reviews on organocatalytic asymmetric domino reac-
(3) For selected examples: (a) Bui, T.; Barbas Iii, C. F. Tetrahedron
Lett. 2000, 41, 6951. (b) Huang, Y.; Walji, A. M.; Larsen, C. H.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051. (c) Xie, H.;
Zu, L.; Li, H.; Wang, J.; Wang, W. J. Am. Chem. Soc. 2007, 129, 10886.
(d) Reyes, E.; Jiang, H.; Milelli, A.; Elsner, P.; Hazell, R. G.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2007, 46, 9202. (e) Wang, Y.; Han, R.-G.;
Zhao, Y.-L.; Yang, S.; Xu, P.-F.; Dixon, D. J. Angew. Chem., Int. Ed.
2009, 48, 9834. (f) Hayashi, Y.; Okano, T.; Aratake, S.; Hazelard, D.
Angew. Chem., Int. Ed. 2007, 46, 4922. (g) Hayashi, Y.; Yasui, Y.;
Kawamura, T.; Kojima, M.; Ishikawa, H. Angew. Chem., Int. Ed. 2011,
€
tions: (a) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int.
Ed. 2007, 46, 1570. (b) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6,
2037. (c) Ruiz, M.; Lopez-Alvarado, P.; Giorgi, G.; Menendez, J. C.
Chem. Soc. Rev. 2011, 40, 3445. (d) Pellissier, H. Adv. Synth. Catal. 2012,
354, 237. (e) Alba, A.-N.; Companyo, X.; Viciano, M.; Rios, R. Curr.
Org. Chem. 2009, 13, 1432.
€
~
50, 2804. (h) Enders, D.; Goddertz, D. P.; Beceno, C.; Raabe, G. Adv.
Synth. Catal. 2010, 352, 2863.
r
10.1021/ol3032285
XXXX American Chemical Society

powerful strategy with frequent applications in asymmetric
organocatalysis in the past years.4 Recently, others and we
have shown that the CꢀC triple bond could also be activated
for asymmetric reactions through the same strategy.5ꢀ8 In our
continuing efforts to explore the reactivity and selectivity of
carbonyl-conjugated CꢀC triple bonds under organocatalytic
conditions, we observed the self-condensation of alkynals
(1) under the catalysis of diphenyl L-prolinol (I) to generate
an interesting type of alkynyl-bearing 1,3-dicarbonyl com-
pounds 2 (Scheme 1). We envisioned that this novel reaction
could be linked with another secondary amine-catalyzed
inverse-electron-demand oxa-DielsꢀAlder reaction and fur-
nish a novel one-pot domino protocol to deliver polyfunction-
alized new chiral 3,4-dihyropyrans 4.9,10
Next, we tried to combine the two separate reactions
and operate them in a one-pot fashion. In the presence of
20 mol % catalyst I, 2.0 equiv of phenylacetylenyl
aldehyde 1a was mixed with propanal 3a at rt. Delight-
fully, 4a and syn-4a were still obtained as the major
products with high yield (88%); the stereoselectivities
were similar to those observed in the stepwise reactions
(4:1 dr, 91% ee) (Table 1, entry 1). Interestingly, the
possible intermediate 7 and products 8 stemming from
the cross condensation of 1a and 3a were not observed
(Figure S1, Supporting Information (SI)), suggesting
that this reaction system has perfect chemical selectivity.
Thus, we concentrated our efforts on the development of
the one-pot domino protocol.
To implement this design, we first subjected the isolated
intermediate 2a (R1 = Ph, E/Z = 4:1) to the inverse-
electron-demand oxa-DielsꢀAlder10 reaction with propa-
nal 3a (R2 = Me) in the presence of catalyst I. As expected,
the desired 3,4-dihydropyran hemiacetal 4a and its diaste-
reomer syn-4a were furnished as the major products in good
yield (80%) with moderate diastereoselectivity (dr = 4:1)
and excellent enantioselectivity (92% ee for 4a) (Scheme 2).
Due to the fast equilibrium of 4a and syn-4a with 5a and
syn-5a, respectively, the analysis of stereoselectivity became
complicated. Thus, the products 4a and syn-4a were then
Some other catalysts were also tested for the domino
reactions of 1a and 3a. Diarylprolinol analogues IIꢀV, VII,
and VIII all displayed good reactivities and stereoselectiv-
ities (Table 1, entries 2ꢀ5, 7, and 8), but none of them gave
better results than I. The other typical catalysts diphenyl-
prolinoltrimethylsilyl (TMS) ether VI, imidazolidine IX,
Table 1. Optimization of Reaction Conditionsa
reduced with Et3SiH/BF3 Et2O to give products 6a and
syn-6a, which were stable and easy to analyze by HPLC.
3
Scheme 1. Design of an Organocatalytic Domino Sequence
Incorporating Self-Condensation of Alkynal and
Inverse-Electron-Demand Oxa-DielsꢀAlder Reaction
drc
(6a/
ee
yield
[%]b
[%]c
(6a)
entry
cat.
additive
solvent
syn-6a)
1
I
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
-
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CHCl3
Toluene
MeCN
DMF
THF
88
74
4:1
3:1
4:1
3:1
3:1
ꢀ
91
92
80
88
91
ꢀ
2
II
III
IV
V
VI
VII
VIII
IX
X
3
59
4
50
5
83
6
<5
7
43
3:1
3:1
ꢀ
73
74
ꢀ
8
53
9
<20
<5
10
11
12
13
14
15
16
17
18
19
20
21d
ꢀ
ꢀ
Scheme 2. Oxa-DielsꢀAlder Reaction between Isolated 2a and
Aldehyde 3a
I
<5
ꢀ
ꢀ
I
AcOH
PhCO2H
MeSO3H
TfOH
HCl
<20
<20
<20
<20
<20
54
ꢀ
ꢀ
I
ꢀ
ꢀ
I
ꢀ
ꢀ
I
ꢀ
ꢀ
I
ꢀ
ꢀ
I
TFA
TFA
TFA
TFA
TFA
3:1
3:1
ꢀ
93
88
ꢀ
I
55
I
<5
I
<5
ꢀ
ꢀ
I
<5
ꢀ
ꢀ
a Unless otherwise noted, all reactions were performed with 1a
(0.2 mmol), 3a (0.16 mmol), catalyst (0.04 mmol), and additive
(0.04 mmol) in 1.0 mL of solvent at rt for 72 h. b Combined yield of 4a
and 5a. c Determined by HPLC analysis. d The reaction was carried out
at 0 °C. TMS = trimethylsilyl, Bn = benzyl, TFA = trifluoroacetic
acid, TfOH = trifluoromethanesulfonic acid, THF = tetrahydrofuran,
DMF = N,N-dimethylformamide.
€
(4) For reviews: (a) Erkkila, A.; Majander, I.; Pihko, P. M. Chem.
Rev. 2007, 107, 5416. (b) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed.
2008, 47, 4638. (c) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G.
Angew. Chem., Int. Ed. 2008, 47, 6138. (d) Bertelsen, S.; Jorgensen, K. A.
Chem. Soc. Rev. 2009, 38, 2178.
B
Org. Lett., Vol. XX, No. XX, XXXX

and primary amine X were all found to have little reactivity
(Table 1, entries 6, 9, and 10).
Table 2. Substrate Scope of the Domino Sequencea
To optimize the catalytic performance of I, different
reaction conditions were examined. TFA proved to be a
crucial additive; its absence or replacement with other
Brønsted acids such as acetic acid, trifluoromethane/
sulfonicacid(TfOH),andhydrochloride all led to a dramatic
loss in reactivity (Table 1, entries 11ꢀ16). Solvents were
also found to be an important factor. Switching THF to
chloroform or toluene resulted in a significant decrease in
yield, albeit only with marginal effects on the stereoselec-
tivities (Table 1, entries 17 and 18). When acetonitrile or
DMF was used as the solvent, the reactivity was com-
pletely suppressed (Table 1, entries 19 and 20). In addition,
lowering the reaction temperature from rt to 0 °C caused a
complete loss of reactivity (Table 1, entry 21).
Having established optimal conditions, we explored the
generality of the present domino reaction system. As
shown in Table 2, this reaction system exhibited a broad
substrate spectrum. Various aryl alkynals underwent
smooth reactions with either propional or butanal, afford-
ing the desired chiral 3,4-dihydropyran products (6aꢀk)
with high yields (82ꢀ88%), moderate diastereoselectivities
(4:1ꢀ2:1 dr), and excellent enantioselectivities (90ꢀ92%
ee) (Table 2, entries 1ꢀ11). Relatively electron-rich aryl
alkynals gave slightly lower enantioselectivities (Table 2,
entries 12ꢀ14). Besides propional and butanal, benzyl
acetaldehyde could also furnish the reaction to give pro-
duct 6o with high yield and enantioselectivity (Table 2,
entry 15). In this case, high diastereoselectivity (9:1 dr) was
achieved. Notably, a simple recrystallization of the ob-
tained mixture products 6e and its diastereomer and their
enantiomers was demonstrated to improve the optical
purity and give virtually pure product 6e with >99:1 dr
and >99% ee (entry 5).
yield
[%]b
drc
ee [%]c
entry
product
R5/R6
(6/syn-6)
(6)
1
C6H5/Me (6a)
C6H5/Et (6b)
88
80
80
82
83
84
82
81
80
88
82
83
86
72
82
81
79
4:1
91
2
2:1
3:1
4:1
91
91
91
3
4-CF3C6H4/Me (6c)
4-COOMeC6H4/Me (6d)
4-CNC6H4/Me (6e)
4-FC6H4/Me (6f)
4
5
4:1 (>99:1)d 92 (>99)d
6
4:1
3:1
3:1
2:1
3:1
2:1
2:1
3:1
3:1
9:1
4:1
6:1
90
90
91
92
90
91
83
88
82
91
85
91
7
2,4-FC6H3/Me (6g)
4-ClC6H4/Me (6h)
4-BrC6H4/Et (6i)
8
9
10
11
12
13
14
15
16
17
2-naphthyl/Me (6j)
3-MeC6H4/Et (6k)
4-MeC6H4/Me (6l)
4-tBuC6H4/Me (6m)
4-MeOC6H4/Me (6n)
C6H5/Bn (6o)
C6H5/EtOOCCH2(6p)
C6H5/allyl (6q)
a Unless otherwise noted, all reactions were performed with 1
(0.2 mmol), 3 (0.16 mmol), catalyst I (0.04 mmol), and TFA (0.04 mmol)
in 1.0 mL of THF at rt for 72 h. b Combined yield of 4 and 5.
c Determined by HPLC. d The data in parentheses were obtained by
recrystallization of 4 in a mixture solvent of petroleum ether and ethyl
acetate. Me = methyl, Et = ethyl, tBu = tert-butyl, Bn = benzyl.
the products obtained in the present reaction system,
a single crystal of 4e was successfully achieved. X-ray
crystallography analysis revealed that it has a (3R,4S)-
configuration11 (Figure S3, SI).
To illustrate the utility of the present domino reaction,
the chiral products were converted into several potentially
useful new compounds in good to high yields with com-
plete preservation of the stereo- and enantiopurity
(Scheme 3). To determine the absolute stereochemistry of
Scheme 3. Transformation of the Domino Products 4a
(5) Jones, S. B.; Simmons, B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2009, 131, 13606.
(6) (a) Zhang, X.; Zhang, S.; Wang, W. Angew. Chem., Int. Ed. 2010,
49, 1481. (b) Liu, C.; Zhang, X.; Wang, R.; Wang, W. Org. Lett. 2010, 12,
4948. (c) Zhang, X.; Song, X.; Li, H.; Zhang, S.; Chen, X.; Yu, X.; Wang,
W. Angew. Chem., Int. Ed. 2012, 51, 7282.
ꢀ
ꢀ~
(7) (a) Aleman, J.; Nunez, A.; Marzo, L.; Marcos, V.; Alvarado, C.;
ꢀ
Garcıa Ruano, J. L. Chem.;Eur. J. 2010, 16, 9453. (b) Aleman, J.;
Fraile, A.; Marzo, L.; Ruano, J. L. G.; Izquierdo, C.; Dıaz-Tendero, S.
Adv. Synth. Catal. 2012, 354, 1665.
(8) Cai, X.; Wang, C.; Sun, J. Adv. Synth. Catal. 2012, 354, 359.
(9) For examples of synthesis of chiral 3,4-dihydropyrans: (a) Fehr,
M. J.; Consiglio, G.; Scalone, M.; Schmid, R. J. Org. Chem. 1999, 64,
5768. (b) Evans, D. A.; Thomson, R. J.; Franco, F. J. Am. Chem. Soc.
2005, 127, 10816.
a Reaction conditions: (a) Et3SiH, BF3 Et2O, DCM, 0 °C, 12 h; (b)
H2O, Tf2NH, DCM, rt, 2 h; (c) PCC, DCM, rt, 24 h; (d) Ac2O, DIPEA,
DCM, 0 °C, 1 h; (e) Sn(OTf)2, MeOH, rt, 12 h.
3
(10) For selected examples of organocatalytic inverse-electron-
demand oxa-DielsꢀAlder rection: (a) Juhl, K.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2003, 42, 1498. (b) Samanta, S.; Krause, J.; Mandal, T.;
Zhao, C.-G. Org. Lett. 2007, 9, 2745. (c) Xie, H.; Zu, L.; Oueis, H. R.; Li,
H.; Wang, J.; Wang, W. Org. Lett. 2008, 10, 1923. (d) Yao, W.; Pan, L.;
Wu, Y.; Ma, C. Org. Lett. 2010, 12, 2422. (e) Wang, J.; Yu, F.; Zhang,
X.; Ma, D. Org. Lett. 2008, 10, 2561. (f) Gallier, F.; Hussain, H.; Martel,
A.; Kirschning, A.; Dujardin, G. Org. Lett. 2009, 11, 3060. (g) Xu, Z.;
Liu, L.; Wheeler, K.; Wang, H. Angew. Chem., Int. Ed. 2011, 50, 3484.
(h) Li, J.-L.; Liu, T.-Y.; Chen, Y.-C. Acc. Chem. Res. 2012, 45, 1491.
As for the mechanistic aspects associated with the pre-
sent domino reaction system, we initially suspected that the
(11) CCDC 899100 contains the supplementary crystallographic
data for 4e. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Catalytic Pathway for the Formation of 2
Scheme 5. Proposed Mechanism Model for the Formation of
the Final Product 4
self-condensation of alkynal 1 for the formation of 2 passes
through an oxa [2 þ 2] cycloaddition pathway (Figure S4,
SI). But meanwhile, there also exists another possibility
that the formation of 2 goes through an alkyne hydration
pathway (Scheme 4). In the latter case, the hydration of
the iminium-activated CꢀC triple bond gives rise to enol
D, of which the resonance form E undergoes an aldol
condensation to generate intermediate F. The elimination
of a molecule of H2O from F followed by hydrolysis
furnishes 2. These two unprecedented pathways both seem
plausible.12,13 To determine which pathway is truly
more active as an electrophile toward the aldol reaction
than alkyl aldehyde.
For the mechanism of the reaction between 2 and
aldehyde 3 to generate the final product 4, a plausible
reaction model is also depicted as in Scheme 5. The oxa-
DielsꢀAlder reaction of 2 with the enamine 13 formed
from aldehyde 3 and the catalyst gives the cyclized inter-
mediate 14, which releases the end product 4 upon hydro-
lysis. The observed stereochemistry is consistent with the
plausible transition state model 15,10a whereby the (S)-
diphenylprolinol moiety shields the Si face of the enamine
and makes the attack of the enal from the Re face much
more energetically favorable.
In conclusion, we have developed a novel organocata-
lytic hydration/aldol/oxa-DielsꢀAlder domino reaction
methodtoimplement the facileone-pot formation of chiral
polyfunctionalized 3,4-dihydropyrans under mild condi-
tions. In the presence of (S)-diphenylprolinol as the cata-
lyst, a broad range of alkynl aldehydes were reacted with
several alkyl aldehydes to furnish the chiral 3,4-dihydro-
pyrans products with good to high yields, moderate to
good diastereoselectivities, and high enantioselectivities.
This method not only for the first time implemented the
organocatalytic alkynal self-condensation, which proved
to be initiated by an unprecedented organocatalytic alkyne
hydration followed by aldol condensation, but also pro-
vided a novel straightforward pathway for the construc-
tion of chiral polyfunctionalized 3,4-dihydropyrans.
1
adopted, we first monitored the reaction of 1a by H
NMR spectroscopy (Figure S5, SI). Two distinct triplet
peaks at 5.6 and 3.7 ppm, respectively, were observed soon
after the initiation of the reaction, which became major
peaks in the course of the reaction and disappeared at the
end. This observation seems to suggest that the reaction
should go through the hydration pathway because only the
intermediate F can match with these two peaks. To find
further evidence for this pathway, we used another com-
pound, 3-oxo-3-phenylpropanal, to react with 1a in the
presence of catalyst I. Since this compound could easily
react with the catalyst to generate the active enamine
species E, the same sequence from E to 2 could be followed.
As expected, the same product 2a was formed as the major
product, and the same peaks at 5.6 and 3.7 ppms were
observed during the reaction and disappeared at the end.
Thus, the hydration pathway is unequivocally proven for
the formation of 2 and the oxa [2 þ 2] cycloaddition
pathway could be excluded. The observed excellent che-
mical selectivity of the self-condensation of alkynal 1 vs
the cross condensation of 1 with 3 can also be well
explained by the hydration pathway because alkynal is
(12) For examples of oxa-[2 þ 2] cycloaddition of alkynes promoted
€
by light irridiation and Lewis acids: (a) Buchi, G.; Kofron, J. T.; Koller,
Acknowledgment. We are grateful for financial support
from the National Natural Science Foundation of China
(Project Nos. 21272227 and 91013006).
E.; Rosenthal, D. J. Am. Chem. Soc. 1956, 78, 876. (b) Middleton, W. J.
J. Org. Chem. 1965, 30, 1307. (c) Miyamoto, T.; Shigemitsu, Y.; Odaira,
Y. J. Chem. Soc., Chem. Commun. 1969, 1410. (c) Yu, H.; Li, J.; Kou, Z.;
Du, X.; Wei, Y.; Fun, H.- K.; Xu, J.; Zhang, Y. J. Org. Chem. 2010, 75,
2989. (d) Wang, L.; Zhang, Y.; Hu, H.-Y.; Fun, H. K.; Xu, J.-H. J. Org.
Chem. 2005, 70, 3850.
(13) For recent reviews on hydration of alkynes by other means: (a)
Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079. (b)
Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004,
43, 3368. (c) Hintermann, L.; Labonne, A. Synthesis 2007, 1121.
Supporting Information Available. Full experimental
data. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX