Asymmetric synthesis of spiro-3,4-dihydropyrans via a domino organocatalytic sequence

Article abstract of DOI:10.1021/ol1007873

A cinchona alkaloid-catalyzed domino Michael/hemiacetalization reaction of cyclic β-oxo aldehydes and aromatic β,γ-unsaturated α-keto esters, resulting in the formation of spiro-dihydropyran architectures in good yield with high stereoselectivity (up to 97% ee), is presented.

Full text of DOI:10.1021/ol1007873

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2422-2425
Asymmetric Synthesis of
Spiro-3,4-dihydropyrans via a Domino
Organocatalytic Sequence
Weijun Yao, Lianjie Pan, Yihua Wu, and Cheng Ma*
Department of Chemistry, Zhejiang UniVersity, 20 Yugu Road, Hangzhou 310027,
People’s Republic of China
mcorg@zju.edu.cn
Received April 6, 2010
ABSTRACT
A cinchona alkaloid-catalyzed domino Michael/hemiacetalization reaction of cyclic ꢀ-oxo aldehydes and aromatic ꢀ,γ-unsaturated r-keto esters,
resulting in the formation of spiro-dihydropyran architectures in good yield with high stereoselectivity (up to 97% ee), is presented.
Tetrahydropyran and dihydropyran derivatives are structural
subunits in many natural products and bioactive molecules;1
they also serve as versatile and important building blocks in
organic synthesis.2 Consequently, the formation of these
compounds especially for their stereocontrolled constructions
has enjoyed sustained attention over the past decade. Whereas
several elegant organocatalytic approaches to 3,4-dihydro-
pyrans as well as their bicyclic derivatives have been
developed,3 few synthetic methods are available to access
the spiro-bicyclic analogues having all-carbon quaternary
stereocenters.4,5
Recently, we have presented a tertiary amine-mediated
cross-cyclization reaction giving rise to functionalized spiro-
dihydropyran derivatives.6 This annulation process presum-
ably proceeds via a zwitterionic enolate (I) that undergoes a
Michael reaction-triggered domino sequence with enones 2
in a diastereoselective manner (Scheme 1).7 As the organo-
catalytic Michael reaction directly taking use of aldehyde
enolates has received little attention and still remains a rather
unexplored transformation,8 we sought to expand this
methodology to the use of ꢀ-oxo aldehydes 1 upon treatment
(4) For reviews on stereocontrolled synthesis of spirocyclics, see: (a)
Sannigrahi, M. Tetrahedron 1999, 55, 9007. (b) Pradhan, R.; Patra, M.;
Behera, A. K.; Mishra, B. K.; Behera, R. K. Tetrahedron 2006, 62, 779.
(c) Sinibaldi, M.-E.; Canet, I. Eur. J. Org. Chem. 2008, 4391. (d) Kotha,
S.; Deb, A. C.; Lahiri, K.; Manivannan, E. Synthesis 2009, 165.
(5) For reviews on enantioselective catalytic formation of quaternary
stereogenic centers, see: (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem.,
Int. Ed. 1998, 37, 388. (b) Douglas, C. J.; Overman, L. E. Proc. Nat. Acad.
Sci. U.S.A. 2004, 101, 5363. (c) Trost, B. M.; Jiang, C. H. Synthesis 2006,
369. (d) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem.
2007, 5969.
(1) Gunatilaka, A. A. L. J. Nat. Prod. 2006, 69, 509.
(2) For reviews, see: (a) Yeung, K.-S.; Paterson, I. Chem. ReV. 2005,
105, 4237. (b) Kang, E. J.; Lee, E. Chem. ReV. 2005, 105, 4348. (c) Inoue,
M. Chem. ReV. 2005, 105, 4379. (d) Aho, J. E.; Pihko, P. M.; Rissa, T. K.
Chem. ReV. 2005, 105, 4406. (e) Nakata, T. Chem. ReV. 2005, 105, 4314.
(f) Goldring, W. P. D.; Pattenden, G. Acc. Chem. Res. 2006, 39, 354. (g)
Yet, L. Chem. ReV. 2003, 103, 4283.
(3) (a) Juhl, K.; Jøgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1498.
(b) Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9662. (c) Huang,
Y.; Unni, A. K.; Thadami, A. W.; Rawal, V. H. Nature 2003, 424, 146. (d)
Unni, A. K.; Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am. Chem.
Soc. 2005, 127, 1336. (e) Du, H.-F.; Zhao, D.-B.; Ding, K.-L. Chem.sEur.
J. 2004, 10, 5964. (f) Rueping, M.; Sugiono, E.; Merino, E. Angew. Chem.,
Int. Ed. 2008, 47, 3046. (g) Rueping, M.; Sugiono, E.; Merino, E.
Chem.sEur. J. 2008, 14, 6329. (h) Franke, P. T.; Richter, B.; Jøgensen,
K. A. Chem.sEur. J. 2008, 14, 6317. (i) Samanta, S.; Krause, J.; Mandal,
T.; Zhao, C.-G. Org. Lett. 2007, 9, 2745. (j) Zhu, M-K. ; Wei, Q.; Gong,
L.-Z AdV. Synth. Catal. 2008, 350, 1281. (k) He, M.; J; Uc, G.; Bode, J. W
J. Am. Chem. Soc. 2006, 128, 15088. (l) Mangion, I. K.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2005, 127, 3696.
(6) Yao, W.; Wu, Y.; Wang, G.; Zhang, Y.; Ma, C. Angew. Chem., Int.
Ed. 2009, 48, 9713.
(7) For a minireview on conjugate additions-triggered tandem transfor-
mation, see: Guo, H.-C; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354.
(8) For reviews on organocatalyzed Michael additions, see: (a) Tsogoeva,
S. B. Eur. J. Org. Chem. 2007, 1701. (b) Sulzer-Mosse´, S.; Alexakis, A.
Chem. Commun. 2007, 3123. (c) Vicario, J. L.; Bad´ıa, D.; Carrillo, L.
Synthesis 2007, 2065. (d) Almas¸i, D; Alonso, D. A; Na´jera, C. Tetrahedron:
Asymmetry 2007, 18, 299. (e) Enders, D; Wang, C.; Liebich, J. X
Chem.sEur. J. 2009, 15, 11058.
10.1021/ol1007873  2010 American Chemical Society
Published on Web 04/29/2010

with Brønsted base.9 Given their synthetic utilities and
potential bioactivity, we report herein the first enantioselec-
tive construction of spiro-dihydropyran architectures 4 via
a cinchona alkaloid-catalyzed domino Michael addition/
hemiacetalization reaction of cyclic ꢀ-oxo aldehydes 1 and
aromatic ꢀ,γ-unsaturated R-keto esters 2 (Scheme 1).10
(DHQD)2PYR (3e) was the most effective among catalysts
3b-e, furnishng 5a with 85% ee after oxidation (Table 1,
entry 5).14 The disadvantage of the free OH group in the
catalyst structure was verified by the poor enantioselectivity
of the reaction catalyzed by quindine (entry 2). Thus,
cinchona alkaloids did not act as dual-activating organo-
catalysts herein.15 The cyclization can be run in a variety of
solvents with comparable results (Table 1, entries 5-8).
However, we found the reaction to be slightly facilitated by
the presence of t-BuOH (entry 9) and chose Tol/t-BuOH (10:
1) for further exploration.
Scheme 1. Domino Reactions Employing Aldehyde Enolates
Table 1. Catalyst Screening and Optimization of Reaction
Conditionsa
The cyclization of 2-oxocyclohexanecarbaldehyde (1a)
with ꢀ,γ-unsaturated R-keto ester 2a was initially carried
out using 10 mol % catalyst loading of tertiary amines 3 in
toluene at -20 °C (Table 1). Upon treatment with DABCO,
a mixture of two anomers of hemiacetal 4a was obtained in
an 8:1 ratio as determined by 1HNMR analysis, which
afforded R-spiropyranone 5a as a single diastereomer after
PCC oxidation (entry 1).11 On the basis of these observations,
we decided to develop an asymmetric version of this
cyclization. As cinchona alkaloids are highly useful orga-
nocatalysts for a large number of stereoselective transforma-
tions,12 a brief survey of cinchona alkaloid-derived catalysts
was conducted for this process.13 As shown in Table 1,
time
(h)
4a, yieldb
5a, eec
entry
catalyst 3
solvent
(%)
(%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3e
3e
3e
3e
toluene
toluene
toluene
toluene
toluene
THF
48
48
78
87
59
70
76
65
73
72
89
45
64
78
85
84
82
87
95
48
48
48
48
CH2Cl2
EtOAc
36
(9) For a recent review on chiral Brønsted base catalyzed reaction, see:
Palomo, C.; Oiarbide, M.; Lo´pez, R. Chem. Soc. ReV. 2009, 38, 632.
(10) For reviews on organocatalytic domino reactions, see: (a) Grondal,
C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167. (b) Alba, A.-N.;
Companyo´, X.; Viciano, M.; Rios, R. Curr. Org. Chem. 2009, 13, 1432.
(c) Enders, D.; Grondal, C.; Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007,
46, 1570. (d) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037.
(11) Attempts to determine the ee value of 4a directly proved unsuc-
cessful; therefore, product 4a was further oxidized to the corresponding
lactone derivative 5a. For synthesis of R-spiropyranone, see: (a) Kirillov,
N. F.; Gavrilov, A. G. Russ. J. Org. Chem. 2008, 44, 963. (b) Zou, Y.;
Wang, Q.; Goeke, A. Chem.sEur. J. 2008, 14, 5335.
144
48
Tol/t-BuOHd
a Reaction conditions: (i) 1a (0.4 mmol), 2a (0.2 mmol), and catalyst
3 (10 mol %) in solvent (2 mL) at -20 °C; (ii) PCC (1.5 equiv), DCM,
reflux. b Isolated yield of the mixture of two anomers 4a. c The ee value of
5a was determined by chiral HPLC. d Toluene/t-BuOH (10:1).
With the optimal reaction conditions, the scope of the
domino Michael/hemiacetalization reaction was probed by
using various R-keto esters (Table 2). Aromatic ꢀ,γ-
unsaturated R-keto esters 2 having both electron-donating
(Table 2, entries 2 and 3) and electron-withdrawing substit-
uents (Table 2, entries 4-6) can effectively be used in this
transformation; the substitution pattern of the arene had little
effect on the enantioselectivity of the reaction, although the
reactivity may be affected. Accordingly, the electron-poor
aryl R-keto esters displayed reactivity higher than that of
their electron-rich counterparts, producing the desired hemi-
acetals 4 in almost quantitatively yields (entries 4, 5 versus
(12) For reviews on chiral cinchona alkaloid catalysts, see: (a) Connon,
S. J. Chem. Commun. 2008, 2499. (b) Marcelli, T.; van Maarseveen, J. H.;
Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 7496. (c) Tian, S.-K.; Chen,
Y. G.; Hang, J. F.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004,
37, 621. (d) Chen, Y. G.; McDaid, P.; Deng, L. Chem. ReV. 2003, 103,
2965.
(13) For selected examples of cinchona alkaloid catalyzed domino
reactions via other kinds of enolates except aldehyde enolates, see: (a)
Kaneko, S.; Yoshino, T.; Katoh, T.; Terashima, S. Tetrahedron 1998, 54,
5471. (b) Dickmeiss, G; De Sio, V; Udmark, J; Poulsen, T. B; Marcos, V;
Jørgensen, K. A Angew. Chem., Int. Ed. 2009, 48, 6650. (c) Li, L.; Ganesh,
M.; Seidel, D. J. Am. Chem. Soc. 2009, 131, 11648. (d) Tan, B.; Shi, Z.;
Chua, P. J.; Zhong, G. Org. Lett. 2008, 10, 3425. (e) Shi, Z.; Yu, P.; Chua,
P. J.; Zhong, G. AdV. Synth. Catal. 2009, 351, 2797. (f) Zu, L.; Xie, H.; Li,
H.; Wang, J.; Jiang, W.; Wang, W. AdV. Synth. Catal. 2007, 349, 1882. (g)
Zu, L.; Wang, J.; Li, H.; Xie, H.; Jiang, W.; Wang, W. J. Am. Chem. Soc.
2007, 129, 1036. (h) Wang, J.; Xie, H.; Li, H.; Zu, L.; Wang, W. Angew.
Chem., Int. Ed. 2008, 47, 4177. (i) Wang, Y.; Liu, X.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 3928. (j) Wang, B.; Wu, F; Wang, Y.; Liu, X.;
Deng, L. J. Am. Chem. Soc. 2007, 129, 768. (k) Calter, M. A.; Wang, J.
Org. Lett. 2009, 11, 2205.
(14) The absolute configuration of the tandem product was assigned by
a single-crystal X-ray analysis of 5a.
(15) For the first example, see: McDaid, P.; Chen, Y.; Deng, L. Angew.
Chem., Int. Ed. 2002, 41, 338.
Org. Lett., Vol. 12, No. 10, 2010
2423

3). Additionally, heteroaromatic compounds 2g and 2h had
also successfully been employed in this process, whereas an
extended reaction time was required to get a good yield
(Table 2, entries 7 and 8). Unfortunately, (E)-methyl 5-meth-
yl-2-oxohex-3-enoate (2, R ) Me, R1 ) i-Pr), a γ-alkyl
substituted substrate, cannot undergo the annulation with 1a.
Notably, the optically pure product 5a (>99% ee) could be
obtained through a single recrystallization from CH2Cl2/
hexane (Table 2, entry 1).
Table 3. Substrate Scope for the Cyclization of Aldehydes 1
and Enone 2a
Table 2. Asymmetric Synthesis of Lactones 5a
time
(h)
4, yieldb
(%)
5, eec
(%)
entry
2
R
R1
1
2
3
4
5
6
7
8e
2a
2b
2c
2d
2e
2f
Me
Me
Me
Et
Me
Et
Ph
4-CH3Ph
48
48
72
36
42
42
72
4a, 89
4b, 97
4c, 71
4d, 99
4e, 99
4f, 94
4g, 76
4h, 67
5a, 95 (>99)d
5b, 88
5c, 90
5d, 90
5e, 90
5f, 88
5g, 92
5h, 97
4-CH3OC6H4
3-NO2C6H4
4-FC6H4
4-ClC6H4
2-thienyl
2g
2h
Et
Et
N-Tos-indol-3-yl 108
a Reaction conditions: (i) 1a (0.4 mmol), 2 (0.2 mmol), and catalyst
3e (10 mol %) in Tol/t-BuOH (10:1, 2 mL) at -20 °C; (ii) PCC (1.5 equiv),
DCM, reflux. b Yield of the mixture of two anomers after flash
chromatography. c The ee value was determined by chiral HPLC. d After a
single recystallization. e Toluene/t-BuOH (5:1, 4 mL) was used.
a Reaction conditions: (i) 1 (0.4 mmol), 2 (0.2 mmol), and catalyst 3e
(10 mol %) in Tol/t-BuOH (10:1, 2 mL) at -20 °C; (ii) PCC (1.5 equiv),
DCM, reflux. b Yield of the mixture of two anomers after flash
chromatography. c The ee value was determined by chiral HPLC. d 3e (0.5
mol %).
To further expand the synthetic utility of the reaction,
structural variation in the aldehyde partner has also been
examined (Table 3). Pleasingly, good to high enantiose-
lectivities were observed for a variety of five-, six-, and
seven-membered cyclic systems. Notably, 2-oxocyclo-
pentanecarbaldehyde (1b) accomplished the reaction with
2i quite quickly, furnishing the target compound 4i in
excellent yield after 12 h with diminished enantioselec-
tivity under the standard conditions. On the other hand,
while reducing the catalyst loading of 3e from 10 mol %
to 0.5 mol %, the reaction enantioselectivity should
significantly improve to 90% ee, albeit with a little
decrease in yield (Table 3, entries 1 and 2). Moreover,
substituents and heteroatoms were introduced onto the six-
membered scaffold without considerably affecting stere-
oinduction (Table 2, entries 4-6). To our delight, acyclic
aldehyde 1g with an ester substituent at the ꢀ-position
also provided the desired product in excellent yield with
a similar enantioselectivity (Table 3, entry 7).
75% for the major diastereomer and 93% ee for the minor
(Scheme 2).16
Scheme 2
.
Stereoselective Construction of Product 4o and 6
((DHQD)2PYR )
hydroquinidine-2,5-diphenyl-4,6-pyrimidinediyl diether)
In addition, lactone 1h reacted smoothly with ester 2f in
the presence of catalyst 3e (1 mol %), rendering the desired
product 4o in excellent yield. After acylation with acetyl
chloride in the presence of triethyl amine, as expected, only
two diastereomers of ester 6 bearing three continuous
stereogenic centers were obtained from 4o with high level
of diastereoselectivity (dr 94:6) and moderate ee value of
2424
Org. Lett., Vol. 12, No. 10, 2010

In conclusion, we have demonstrated a highly stereose-
lective domino Michael/hemiacetalization reaction of cyclic
ꢀ-oxo aldehydes and aromatic ꢀ,γ-unsaturated γ-keto esters
upon treatment with a cinchona alkaloid catalyst. High levels
of diastereoselectivities and enantioselectivities (up to 97%
ee) were observed for a broad spectrum of substrates under
mild conditions. The reaction thus offers a new and promis-
ing method for the synthesis of complicated spiro-3,4-
dihydropyran structures with potential synthetic and bio-
logical uses.
Acknowledgment. We are grateful to National Natural
Science Foundation of China and Chinese Universities
Scientific Fund (Grant Nos. 2009QNA3010) for financial
support.
Supporting Information Available: Experimental details,
spectral data, and CIF file. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) The dr and ee values were determined by chiral HPLC analyses;
the absolute configuration of 6 was not examined.
OL1007873
Org. Lett., Vol. 12, No. 10, 2010
2425