Proline-mediated enantioselective construction of tetrahydropyrans via a domino aldol/acetalization reaction

Article abstract of DOI:10.1021/ol8002223

(Chemical Equation Presented) Highly enantioselective synthesis of tetrahydropyrans was accomplished via a domino proline-mediated aldol reaction/intramolecular acetal formation from an aldehyde and inexpensive aqueous tetrahydro-2H-pyran-2,6-diol as a five-carbon unit.

Full text of DOI:10.1021/ol8002223

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1445-1448
Proline-Mediated Enantioselective
Construction of Tetrahydropyrans via a
Domino Aldol/Acetalization Reaction
Damien Hazelard,† Hayato Ishikawa,† Daisuke Hashizume,‡
Hiroyuki Koshino,‡ and Yujiro Hayashi*,†
Department of Industrial Chemistry, Faculty of Engineering, Tokyo UniVersity of
Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan, and RIKEN, 2-1 Hirosawa,
Wako, Saitama 351-0198, Japan
hayashi@ci.kagu.tus.ac.jp
Received January 31, 2008
ABSTRACT
Highly enantioselective synthesis of tetrahydropyrans was accomplished via a domino proline-mediated aldol reaction/intramolecular acetal
formation from an aldehyde and inexpensive aqueous tetrahydro-2H-pyran-2,6-diol as a five-carbon unit.
Tetrahydropyrans are found in many biologically active mol-
ecules and natural products.1 Much effort has been devoted
to the development of enantioselective syntheses of these
heterocycles,1 and several methods, including the Prins
cyclization from optically active homoallylic alcohol,2 an
asymmetric catalytic hetero-Diels-Alder reaction,3 and 1,5-
cyclization,4 have been reported. It is desirable to synthesize
the tetrahydropyran moiety with high enantioselectivity in a
minimum of steps from the readily available starting materi-
als.
Organocatalysis is a rapidly expanding field in organic
synthesis, and many organocatalyst-mediated reactions have
been developed in recent years.5 Domino reaction is a
powerful method for the synthesis of complex molecules in
a short sequence, and several enantioselective domino
reactions have been developed.6 Recently, organocatalysts
have also been applied to the synthesis of complex molecules
by domino reactions from simple starting materials.7 We have
reported the highly enantioselective synthesis of optically
active cyclohexane derivatives by a domino Michael-Henry
reaction of commercially available aqueous tetrahydro-2H-
pyran-2,6-diol and nitroalkenes catalyzed by diphenyl-
prolinolsilyl ether.8 Because pentane-1,5-dial, a synthetically
useful five-carbon unit, is generated under equilibrium
conditions from inexpensive aqueous tetrahydro-2H-pyran-
2,6-diol, this reagent would be successfully utilized for
the formation of optically active tetrahydropyrans by the
domino aldol9/acetal formation catalyzed by organocatalysis
in the presence of water,10 as shown in Scheme 1. That is,
† Tokyo University of Sceince.
‡ RIKEN.
(1) For reviews, see: (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309.
(b) Clarke, P. A.; Santos, S. Eur. J. Org. Chem. 2006, 2045.
(2) (a) Dalgard, J. E.; Rychnovsky, S. D. Org. Lett. 2005, 7, 1589. (b)
Jasti, R.; Rychnovsky, S. D. J. Am. Chem. Soc. 2006, 128, 13640. (c)
Biermann, U.; Lutzen, A.; Metzger, J. O. Eur. J. Org. Chem. 2006, 2631.
(3) (a) Gademann, K.; Chavez, D. E.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2002, 41, 3059. For organocatalysis-mediated hetero-Diels-Alder
reaction, see: (b) Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003,
42, 1498. (c) Huang, Y.; Unni, A. K.; Tadani, A. N.; Rawal, V. H. Nature
2003, 424, 140. (d) Samanta, S.; Krause, J.; Mandal, T.; Zhao, C.-G. Org.
Lett. 2007, 9, 2745. (e) For a review, see: Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2000, 39, 3558.
(4) Evans, P. A.; Cui, J.; Gharpure, S. J. Org. Lett. 2003, 5, 3883.
(5) For reviews of organocatalysis, see: (a) Berkessel, A.; Groger, H.
Asymmetric Organocatalysis; Wiley-VCH: Weinheim, 2005. (b) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (c) Hayashi, Y. J.
Synth. Org. Chem. Jpn. 2005, 63, 464. (d) List, B. Chem. Commun. 2006,
819. (e) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006, 2001. (f)
Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79. (g) Gaunt,
M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug DiscoVery Today
2007, 12, 8. (h) EnantioselectiVe Organocatalysis; Dalko, P. I., Ed.; Wiley-
VCH: Weinheim, 2007.
10.1021/ol8002223 CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/01/2008

Scheme 1. Reaction Mechanism of Proline-Mediated Aldol, Followed by Acetal Formation
pentane-1,5-dial, generated from tetrahydro-2H-pyran-2,6-
and L-proline (1) was employed as an organocatalyst. Be-
cause the adduct 7a (R ) 4-NO2Ph) was found to be unstable
and some degradation occurred during the purification by
column chromatography, 7a was converted to the stable
methyl acetal 8a, which was isolated. After completion of
the aldol/cyclization reaction, an aqueous workup was carried
out to remove the catalyst. Treatment of the crude mixture
with MeOH in the presence of p-toluenesulfonic acid gave
methyl acetal 8a. Because four isomers (anti, syn aldol
products and R and â anomers) are formed, R,â-methyl
acetals of the major aldol product (anti isomer, vide infra)
can be separated and their enantiomeric excesses can be
determined. Both enantioselectivities of R and â anomers
had the same value.
diol under equilibrium conditions, would react with an
organocatalyst such as proline (1) to generate enamine 4.
Enamine 4 would react with an aldehyde to generate 5 via
an aldol reaction, followed by acetal formation to provide
tetrahydropyran 7 with regeneration of proline (1). Because
tetrahydro-2H-pyran-2,6-diol is available as an aqueous
solution,11 these reactions have to be carried out in the
presence of water or under aqueous conditions. We12 and
other groups13,14 have shown that some of the aldol reactions
proceed enantioselectively in the presence of water or under
aqueous conditions. Thus, it is expected that aqueous
tetrahydro-2H-pyran-2,6-diol would be employed directly in
the domino aldol/acetal formation reaction. Successful
realization of this scenario will be described in this paper.
First, we chose a reaction of p-nitrobenzaldehyde and
aqueous tetrahydro-2H-pyran-2,6-diol as a model reaction,
The activity of the organocatalyst was examined in detail.
Siloxyproline 212a,e and surfactant-proline conjugated cata-
lyst 312b (Figure 1), which promote highly enantioselective
(6) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim,
2006.
(7) For selected examples of organocatalytic domino reactions, see: (a)
Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Angew. Chem., Int.
Ed. 2003, 42, 4233. (b) Yamamoto, Y.; Momiymama, N.; Yamamoto, H.
J. Am. Chem. Soc. 2004, 126, 5962. (c) Yang, J. W.; Fonseca, M. T. H.;
List, B. J. Am. Chem. Soc. 2005, 127, 15036. (d) Huang, Y.; Walji, A. M.;
Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051.
(e) Brandau, S.; Maerten, E.; Jørgensen, K. A. J. Am. Chem. Soc. 2006,
128, 14986. (f) Enders, D.; Hu¨ttl, M. R. M.; Raabe, G. Nature 2006, 44,
861. (g) Sunde´n, H.; Ibrahem, I.; Zhao, G.-L.; Eriksson, L.; Co´rdova, A.
Chem. Eur. J. 2007, 13, 574. (h) Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang,
W. J. Am. Chem. Soc. 2007, 129, 10886. (i) Reyes, E.; Jiang, H.; Milelli,
A.; Elsner, P.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2007,
46, 9202. (j) Enders, D.; Hu¨ttl, M. R. M.; Raabe, G.; Bats, J. W. AdV.
Synth. Catal. 2008, 350, 267. (k) For a review see; Enders, D.; Grondal,
C.; Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570.
Figure 1. Organocatalysts examined in the present study.
aldol reaction in the presence of water, are found to be as
effective as proline, producing slightly higher diastereo- and
enantioselectivities (Table 1, entries 2 and 4). Because proline
is inexpensive and both enantiomers are readily available,
(8) Hayashi, Y.; Okano, T.; Aratake, S.; Hazelard, D. Angew. Chem.,
Int. Ed. 2007, 46, 4922.
1446
Org. Lett., Vol. 10, No. 7, 2008

the presence of p-TsOH, acetals 10a were generated in 80%
yield in an 8:1 ratio. The configuration of the major isomer
was determined as an anti isomer by analysis of its NMR
spectrum.
Table 1. Effect of Catalyst and Solvent in the Reaction of
p-Nitrobenzaldehyde and Aqueous
Tetrahydro-2H-pyran-2,6-diola
Because such good results were obtained with the model
reaction, the generality of the reaction was investigated, with
the results summarized in Table 2. A catalytic amount (10
entry cat. solvent time (h) yield (%)b
dec
ee (%)d
Table 2. Organocatalytic Reaction of Aqueous
Tetrahydro-2H-pyran-2,6-diol with Aldehydes for the Formation
of Optically Active Tetrahydropyransa
1
2
3
4
5
6
7
1
2
2
3
1
1
1
DMF
DMF
e
DMF
DMSO
CH2Cl2
MeOH
12
12
20
20
16
24
20
78
74
<10
70
72
nr
7/1
10/1
94
98
9/1
5/1
96
94
27
2/1
79
a Conditions: p-nitrobenzaldehyde (1.0 mmol), aqueous tetrahydro-2H-
time yield
conditions (h)
ratio
ee
entry
R
(%)b dec R/âd (%)e
pyran-2,6-diol (1.2 mmol), catalyst (0.1 mmol), solvent (1.0 mL), rt.
b Isolated yield of four diastreomers. c Diastereoselectivity of the aldol
reaction determined by 1H NMR of the intermediate aldehyde before acetal
protection by integration of aldehyde peaks. d The enantiomeric excess of
the major isomer of the methyl acetal. e No organic solvent.
1
2
3
4
5
6
7
8
9
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CF3C6H4
4-CNC6H4
4-TfOC6H4
2-ClC6H4
4-BrC6H4
Ph
A
A
A
A
A
A
B
B
B
12
14
24
16
16
24
48
48
48
78
60
50
71
63
52
67
59
42
7/1 60/40 94
4/1 65/35 99
4/1 60/40 93
7/1 65/35 97
4/1 60/40 95
4/1 60/40 97
4/1 65/35 99f
4/1 60/40 95
4/1 60/40 97
screening of the solvent was conducted using proline (1) as
a catalyst, which showed that DMF is a good choice. The
reaction was found to proceed in the presence of 10 mol %
of proline in DMF, to produce methyl acetal 8a in 78% yield
with 94% enantiomeric excess after treatment of the aldol
product with MeOH and p-TsOH (entry 1).
a Condition A: 1.2 equiv of aqueous tetrahydro-2H-pyran-2,6-diol, 10
mol % proline. Condition B: 3 equiv aqueous tetrahydro-2H-pyran-2,6-
diol, 30 mol % proline. b Isolated yield (after 2 steps). c Diastereoselectivity
(anti:syn) of the aldol reaction. Calculated from crude 1H NMR of first
step. d Calculated from crude 1H NMR after acetalization step. e Determined
by chiral HPLC. f Determined after reduction of chloro by LiAlH4.
To determine the relative configuration of 8a, the follow-
ing transformation was performed as shown in Scheme 2.
Scheme 2. Determination of Relative Configuration
mol %) of proline can promote the reaction efficiently in
the cases of electron-deficient aldehydes such as p-, m-, and
o-nitrobenzaldehydes and p-trifluoromethyl-, p-cyano-, and
(12) (a) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima,
T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958. (b) Hayashi, Y.; Aratake,
S.; Okano, T.; Takahashi, J.; Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed.
2006, 45, 5527. (c) Hayashi, Y.; Aratake, S.; Itoh, T.; Okano, T.; Sumiya,
T.; Shoji, M. Chem. Commun. 2007, 957. (d) Aratake, S.; Itoh, T.; Okano,
T.; Usui, T.; Shoji, M.; Hayashi, Y. Chem. Commun. 2007, 2524. (e)
Aratake, S.; Itoh, T.; Okano, T.; Nagae, N.; Sumiya, T.; Shoji, M.; Hayashi,
Y. Chem. Eur. J. 2007, 13, 10246.
(13) For organocatalysis-mediated asymmetric aldol reaction in aqueous
solvent, see: (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto,
H. Angew. Chem., Int. Ed. 2004, 43, 198. (b) Nyberg, A. I.; Usano, A.;
Pihko, P. M. Synlett 2004, 1891. (c) Tang, Z.; Yang, Z.-H.; Cun, L.-F.;
Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org. Lett. 2004, 6, 2285. (d) Casas,
J.; Sunde´n, H.; Co´rdova, A. Tetrahedron Lett. 2004, 45, 6117. (e) Ward,
D. E.; Jheengut, V. Tetrahedron Lett. 2004, 45, 8347. (f) Ibrahem, I.;
Co´rdova, A. Tetrahedron Lett. 2005, 46, 3363. (g) Amedjkouh, M.
Tetrahedron: Asymmetry 2005, 16, 1411. (h) Co´rdova, A.; Zou, W.;
Ibrahem, I.; Reyes, E.; Engqvist, M.; Liao, W.-W. Chem. Commun. 2005,
3586. (i) Wu, Y.-S.; Chen, Y.; Deng, D.-S.; Cai, J. Synlett 2005, 1627. (j)
Dziedzic, P.; Zou, W.; Hafren, J.; Co´rdova, A. Org. Biomol. Chem. 2006,
4, 38. (k) Pihko, P. M.; Laurikainen, K. M.; Usano, A.; Nyberg, A. I.; Kaavi,
J. A. Tetrahedron 2006, 62, 317. (l) Co´rdova, A.; Zou, W.; Dziedzic, P.;
Ibrahem, I.; Reyes, E.; Xu, Y. Chem. Eur. J. 2006, 12, 5383.
(14) For the reaction in the presence of water, see: (a) Jiang, Z.; Liang,
Z.; Wu, X.; Lu, Y. Chem. Commun. 2006, 2801. (b) Wu, Y.; Zhang, Y.;
Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8, 4417. (c) Font, D.; Jimeno,
C.; Pericas, M. A. Org. Lett. 2006, 8, 4653. (d) Guillena, G.; Hita, M. C.;
Najera, C. Tetrahedron: Asymmetry 2006, 17, 1493. (e) Wu, X.; Jiang, Z.;
Shen, H.-M.; Lu, Y. AdV. Synth. Catal. 2007, 349, 812. (f) Maya, V.; Raj,
M.; Singh, V. K. Org. Lett. 2007, 9, 2593.
After the first aldol reaction, inseparable anti and syn isomers
7a were formed. The mixture was reduced with NaBH4 in
MeOH, producing the triol 9a in 62% yield as a diastereo-
meric mixture. When triol 9a was treated with acetone in
(9) For reviews on asymmetric aldol reaction catalyzed by organoca-
talysis, see: (a) List, B. In Amine-catalyzed Aldol Reaction in Modern Aldol
Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004; Vol. 1,
Chapter 4. (b) List, B. Tetrahedron 2002, 58, 5573. (c) List, B. Acc. Chem.
Res. 2004, 37, 548. (d) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37,
570. (e) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004,
37, 580. (f) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719.
(10) (a) Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 8103. (b) Brogan,
A. P.; Dickerson, T. J.; Janda, K. D. Angew. Chem., Int. Ed. 2006, 45,
8100.
(11) Sigma-Aldrich, 50 wt % solution in water, catalogue no. G6403.
Org. Lett., Vol. 10, No. 7, 2008
1447

p-trifluoromethanesulfonylbenzaldehydes, to produce the
corresponding tetrahydropyran derivatives with excellent
enantioselectivity (entries 1-6, conditions A).
In the reaction of arylaldehydes without strong electron-
withdrawing substituents, such as o-chlorobenzaldehyde,
p-bromobenzaldehyde, and benzaldehyde, the reaction pro-
ceeds in the presence of 30 mol % of the catalyst using three
equivalents of aqueous tetrahydro-2H-pyran-2,6-diol to
produce the tetrahydropyran derivatives with excellent enan-
tioselectivity (entries 7-9, conditions B).
from both R,â-cis anomers without compromising the
enantioselectivity. Thus, by a combination of the present
domino reaction and a successive isomerization reaction, both
trans- and cis-substituted tetrahydropyran derivatives are
obtained with excellent optical purities.
Scheme 3. Isomerization of Tetrahydropyran 8a
The absolute configuration was determined by X-ray
crystallographic analysis of the â-methyl acetal 8a derived
from p-nitrobenzaldehyde (Figure 2).15 This absolute con-
In summary, we have developed an enantioselective
synthetic method for substituted tetrahydropyrans via a
domino proline-mediated aldol reaction/acetal cyclization
reaction. Pentane-1,5-dial, a useful five-carbon unit, is
generated from inexpensive aqueous tetrahydro-2H-pyran-
2,6-diol under equilibrium conditions. It is a noteworthy
advantage of the organocatalyst that the reaction proceeds
efficiently with excellent enantioselectivity under aqueous
conditions. Because the obtained cis-substituted tetrahydro-
pyran derivative can be transformed into the trans isomer
without compromising the enantioselectivity, the present
method would be an effective method for the preparation of
substituted chiral tetrahydropyran derivatives.
Figure 2. ORTEP drawing of 8a-â. Displacement ellipsoids are
drawn at the 50% probability level.
figuration is in accordance with that expected from the
L-proline-mediated aldol reaction.16
Tetrahydropyrans 8 have two dialkyl acetal moieties. One
is the dimethyl acetal and the other is the monomethyl acetal.
From a synthetic point of view, selective discrimination of
these two moieties has to be achieved. The dimethyl acetal
moiety of both R and â anomers 8a (R ) 4-NO2Ph) is
deprotected selectively to the corresponding monomethyl
acetal 11 by treatment with p-toluenesulfonic acid in acetone
at 30 °C in good yield. When 11 was treated with base
(DBU) in CH2Cl2 at room temperature, isomerization oc-
curred to produce the trans isomer predominantly, starting
Acknowledgment. This work was partially supported by
the Toray Science Foundation and a Grant-in-Aid for
Scientific Research from The Ministry of Education, Culture,
Sports, Science, and Technology (MEXT). D. Hazelard is
grateful to the Japan Society for the Promotion of Science
(JSPS) for a postdoctoral fellowship.
Supporting Information Available: Detailed experi-
(15) A CIF file for 8a-â was deposited to the Cambridge Crystallographic
Data Centre with the deposition number CCDC 678278. Copies of the data
can be obtained free of charge via http://www.ccdc.cam.ac.uk or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax +44(1223)336033; deposit@ccdccam.ac.uk.
(16) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.
2000, 122, 2395. (b) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 6798.
1
mental procedures, full characterization, and copies of H
and 13C NMR and IR spectra of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL8002223
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Org. Lett., Vol. 10, No. 7, 2008