Asymmetric synthesis of 1,3-dioxolanes by organocatalytic formal [3 + 2] cycloaddition via hemiacetal intermediates

Article abstract of DOI:10.1021/ol3003755

A novel asymmetric formal [3 + 2] cycloaddition reaction for the synthesis of 1,3-dioxolanes using cinchona-alkaloid-thiourea-based bifunctional organocatalysts is reported. The reaction proceeds via the formation of hemiacetal intermediates between γ-hyd

Full text of DOI:10.1021/ol3003755

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1620–1623
Asymmetric Synthesis of 1,3-Dioxolanes
by Organocatalytic Formal [3 þ 2]
Cycloaddition via Hemiacetal
Intermediates
Keisuke Asano* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510, Japan
keisuke.asano@t03kr913mk.mbox.media.kyoto-u.ac.jp; matsubar@orgrxn.mbox.
media.kyoto-u.ac.jp
Received February 15, 2012
ABSTRACT
A novel asymmetric formal [3 þ 2] cycloaddition reaction for the synthesis of 1,3-dioxolanes using cinchona-alkaloid-thiourea-based bifunctional
organocatalysts is reported. The reaction proceeds via the formation of hemiacetal intermediates between γ-hydroxy-R,β-unsaturated ketones
and aldehydes.
Optically active cyclic acetals are important in various
biologically active agents and natural products.1 They
are also known as versatile intermediates for asymmetric
synthesis:2ꢀ4 they can be used as chiral auxiliaries to
Scheme 1. Asymmetric Cycloetherification by Bifunctional
Aminothiourea Catalyst
control the reaction of a proximal prochiral center2,3 and
can also be used as chiral templates for stereospecific
cleavage of their ring in the presence of nucleophiles and
Lewis acid reagents.2,4 Therefore, asymmetric synthesis
methods of chiral cyclic acetals would be particularly
useful as approaches to various chiral building blocks.
Nevertheless, optically active acetals are largely prepared
from chiral starting materials or by the use of stoichio-
metric chiral reagents,2ꢀ6 and there have been only a few
(1) (a) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105,
4406. (b) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617. (c) Felix,
examples of catalytic asymmetric syntheses.7ꢀ9 Moreover,
W.; Rimbach, G.; Wengenroth, H. Arzeim.-Forsch. 1969, 19, 1860. (d)
Mavragani, C. P.; Moutsopoulos, H. M. Clinic Rev. Allerg. Immunol.
2007, 32, 287.
(2) For reviews, see: (a) Alexakis, A.; Mangeney, P. Tetrahedron:
Asymmetry 1990, 1, 477. (b) Carreira, E. M.; Kvaerno, L. Classics in
Stereoselective Synthesis; Wiley-VCH: Weinheim, 2009; Chapter 6.
(3) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2708.
catalytic asymmetric cycloaddition has remained under-
developed despite its advantage in terms of the ability to
construct multiplebonds ina single step, thereby leading to
divergent synthesis.
Recently, we reported an asymmetric cycloetherification
reaction of ε-hydroxy-R,β-unsaturated ketones A mediated
r
10.1021/ol3003755
Published on Web 03/02/2012
2012 American Chemical Society

by cinchona-alkaloid-thiourea-based bifunctional organo-
catalysts (Scheme 1, eq 1).10 In this reaction, concerted
catalysis due to the bifunctional nature of the catalyst led to
highly enantioselective cyclization, which afforded chiral
oxacyclic compounds. The results of our previous work
motivated us to exploit this efficient cyclization route in the
development of a formal cycloaddition reaction starting
from γ-hydroxy-R,β-unsaturated ketones with aldehydes
or ketones via hemiacetal intermediates B (Scheme 1,
eq 2).5,11 Herein we present a novel catalytic asymmetric
formal [3 þ 2] cycloaddition reaction for the synthesis of
chiral 1,3-dioxolanes using bifunctional organocatalysts
derived from cinchona alkaloids.12,13
Table 1. Optimization of Conditionsa
(4) For selected examples, see: (a) Johnson, W. S.; Harbert, C. A.;
Stipanovic, R. D. J. Am. Chem. Soc. 1968, 90, 5279. (b) Bartlett, P. A.;
Johnson, W. S.; Elliott, J. D. J. Am. Chem. Soc. 1983, 105, 2088. (c)
Johnson, W. S.; Elliott, R.; Elliott, J. D. J. Am. Chem. Soc. 1983, 105,
2904. (d) McNamara, J. M.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 7371.
(e) Sekizaki, H.; Jung, M.; McNamara, J. M.; Kishi, Y. J. Am. Chem.
Soc. 1982, 104, 7372. (f) Mori, A.; Maruoka, K.; Yamamoto, H.
Tetrahedron Lett. 1984, 25, 4421. (g) Mori, A.; Ishihara, K.; Yamamoto,
H. Tetrahedron Lett. 1986, 27, 987. (h) Ishihara, K.; Hanaki, N.;
Yamamoto, H. J. Am. Chem. Soc. 1991, 113, 7074. (i) Ghribi, A.;
Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1984, 25, 3083. (j)
Alexakis, A.; Mangeney, P.; Normant, J. F. Tetrahedron Lett. 1985,
26, 4197. (k) Mangeney, P.; Alexakis, A.; Normant, J. F. Tetrahedron
Lett. 1986, 27, 3143. (l) Matsutani, H.; Ichikawa, S.; Yaruva, J.;
Kusumoto, T.; Hiyama, T. J. Am. Chem. Soc. 1997, 119, 4541. (m)
Fukuzawa, S.; Tsuchimoto, T.; Hotaka, T.; Hiyama, T. Synlett 1995,
1077. (n) Zhao, Y.-J.; Chng, S.-S.; Loh, T.-P. J. Am. Chem. Soc. 2007,
129, 492. (o) Li, H.; Loh, T.-P. Org. Lett. 2010, 12, 2679. (p) Richter,
W. J. J. Org. Chem. 1981, 46, 5119. (q) Mashraqui, S. H.; Kellogg, R. M.
J. Org. Chem. 1984, 49, 2513. (r) Yamamoto, Y.; Nishi, S.; Yamada, J.
J. Am. Chem. Soc. 1986, 108, 7116. (s) Yamamoto, K.; Ando, H.;
Chikamatsu, H. J. Chem. Soc., Chem. Commun. 1987, 334. (t) Kano,
S.; Yokomatsu, T.; Iwasawa, H.; Shibuya, S. Chem. Lett. 1987, 16, 1531.
(u) Kato, K.; Suemune, H.; Sakai, K. Tetrahedron Lett. 1993, 34, 4979.
(v) Sugimura, T.; Fujiwara, Y.; Tai, A. Tetrahedron Lett. 1997, 38, 6019.
(w) Takayama, Y.; Okamoto, S.; Sato, F. J. Am. Chem. Soc. 1999, 121,
3559. (x) Fujioka, H.; Kitagawa, H.; Matsunaga, N.; Nagatomi, Y.;
Kita, Y. Tetrahedron Lett. 1996, 37, 2245. (y) Andrus, M. B.; Lepore,
S. D. Tetrahedron Lett. 1995, 36, 9149.
yield
(%)b
ee
entry
catalyst
solvent
drc
(%)d
1
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
CH2Cl2
benzene
THF
83
89
56
85
81
86
95
88
91
87
2.9:1
2.3:1
3.7:1
2.4:1
2.9:1
3.0:1
3.0:1
2.7:1
4.0:1
3.4:1
93
2
94
3
96
4
Et2O
95
5
TBMEf
CPMEg
CPMEg
CPMEg
CPMEg
CPMEg
96
6
96
7e
8e
9e
10e
96
95
ꢀ93
ꢀ93
a Reactions were run using 1a (0.25 mmol), 2a (0.25 mmol), and the
catalyst (0.025 mmol) in the solvent (0.5 mL). b Isolated yields. c Diaste-
reomeric ratios were determined by 1H NMR. d Values are for the
major diastereomer of 3aa. e Reactions were run using 0.3 mmol of 2a.
f TBME = tert-butyl methyl ether. g CPME = cyclopentyl methyl ether.
(5) For examples of diastereoselective cyclic acetal syntheses by
intramolecular oxy-Michael addition via hemiacetal formation, see:
(a) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446.
(b) Evans, P. A.; Grisin, A.; Lawler, M. J. J. Am. Chem. Soc. 2012, 134,
2856. (c) Watanabe, H.; Machida, K.; Itoh, D.; Nagatsuka, H.; Kitahara, T.
Chirality 2001, 13, 379.
(6) (a) Spantulescu, M. D.; Boudreau, M. A.; Vederas, J. C. Org.
Lett. 2009, 11, 645. (b) Uchiyama, M.; Satoh, S.; Ohta, A. Tetrahedron
Lett. 2001, 42, 1559. (c) Davies, S. G.; Correia, L. M. A. R. B. Chem.
Commun. 1996, 1803. (d) Rychnovsky, S. D.; Bax, B. M. Tetrahedron
Lett. 2000, 41, 3593.
We initiated our investigations using (E)-4-hydroxy-
1-phenylbut-2-en-1-one (1a) and cyclohexanecarboxalde-
hyde (2a) with 10 mol % of quinidine-derived bifunctional
catalyst 4a in CH2Cl2 at 25 °C. As expected, 1,3-dioxolane
3aa was obtained stereoselectively in 83% yield (Table 1,
entry 1). Through a process of solvent optimization, ethe-
real solvents were identified as being efficient for stereo-
selectivity, and cyclopentyl methyl ether (CPME) was
identified as the most suitable solvent from the viewpoints
of both yield and enantioselectivity (Table 1, entries 1ꢀ6).
The use of 1.2 equiv of 2a further improved the yield with-
out decreasing the stereoselectivity (Table 1, entry 7).
Catalyst screening identified 4c also as an efficient catalyst
for obtaining the opposite enantiomer of 3aa in good yield
with high enantioselectivity (Table 1, entry 9).
(7) (a) Fletcher, S. J.; Rayner, C. M. Tetrahedron Lett. 1999, 40, 7139.
(b) Hoveyda, A. H.; Schrock, R. R. Chem.;Eur. J. 2001, 7, 945. (c)
Weatherhead, G. S.; Houser, J. H.; Ford, J. G.; Jamieson, J. Y.; Schrock,
R. R.; Hoveyda, A. H. Tetrahedron Lett. 2000, 41, 9553. (d) Burke, S. D.;
€
Muller, N.; Beaudry, C. M. Org. Lett. 1999, 1, 1827. (e) Frauenrath, H.;
Philipps, T. Angew. Chem., Int. Ed. Engl. 1986, 25, 274. (f) Frauenrath,
H.; Reim, S.; Wiesner, A. Tetrahedron: Asymmetry 1998, 9, 1103.
(8) Nagano, H.; Katsuki, T. Chem. Lett. 2002, 31, 782.
ꢀ
ꢀ
ꢁ
ꢁ
(9) (a) Coric, I.; Vellalath, S.; List, B. J. Am. Chem. Soc. 2010, 132,
€
8536. (b) Coric, I.; Muller, S.; List, B. J. Am. Chem. Soc. 2010, 132,
17370.
(10) Asano, K.; Matsubara, S. J. Am. Chem. Soc. 2011, 133, 16711.
(11) Reactions between γ-hydroxy-R,β-unsaturated ketones and
boronic acids via boronic acid hemiester intermediates have been
previously reported; see: Li, D. R.; Murugan, A.; Falck, J. R. J. Am.
Chem. Soc. 2008, 130, 46.
(12) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003,
125, 12672. (b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto,
Y. J. Am. Chem. Soc. 2005, 127, 119. (c) Vakulya, B.; Varga, S.;
ꢁ
ꢁ
Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967. (d) Hamza, A.; Schubert,
Withthe optimized conditions and using4a asa catalyst,
we next explored the substrate scope. γ-Hydroxy-
R,β-unsaturated ketones 1 could be readily prepared from
commercially available materials by our reported proce-
dure.14 Good to excellent yields and enantioselectivities
were obtained with both electron-rich and -poor enones
ꢁ
ꢁ
G.; Soos, T.; Papai, I. J. Am. Chem. Soc. 2006, 128, 13151. (e) Connon,
S. J. Chem.;Eur. J. 2006, 12, 5418.
(13) For reviews on asymmetric catalysis based on hydrogen bond-
ing, see: (a) Hydrogen Bonding in Organic Synthesis; Pihko, P. M., Ed.;
Wiley-VCH: Weinheim, 2009. (b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev.
2007, 107, 5713. (c) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2006, 45, 1520.
Org. Lett., Vol. 14, No. 6, 2012
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good yields and high enantioselectivities (Table 2,
entries 7 and 8). In addition, we could replace 2a with
propionaldehyde (2b), isobutyraldehyde (2c), and pivalal-
dehyde (2d) to obtain the corresponding cycloadducts in
excellent enantioselectivities (Table 2, entries 9ꢀ11).15
Instead of an aldehyde, electron-deficient ketone 2e could
also be employed to furnish the cyclic acetal 3ae with a chiral
quaternary acetal carbon (Table 2, entry 12). The absolute
configurations of 3da were determined by X-ray analysis
for both diastereomers (see Supporting Information for
details),16 and the configurations of all other examples
were assigned analogously.
Table 2. Scope of Substratesa,b
To demonstrate the utility of our products as synthetic
intermediates, we performed the transformation of 3aa.
Reduction with lithium aluminum hydride in the presence
of lithium iodide afforded the corresponding alcohol 5 in
high diastereoselectivity, and subsequent deacetalization
gave optically active triol 6 (Scheme 2). In addition,
treatment of 3aa with allyltrimethylsilane in the presence
of titanium tetrachloride led to allylative ring cleavage to
provide 7 in regio- and diastereoselective fashion while
maintaining the optical purity (Scheme 3).4b
Scheme 2. Synthesis of Chiral Triol 6
Scheme 3. Stereospecific Ring Cleavage of 3aa
To gain insight into the enantiodetermining step, we
further investigated formal [3 þ 2] cycloaddition reactions
(14) Sada, M.; Ueno, S.; Asano, K.; Nomura, K.; Matsubara, S.
Synlett 2009, 724.
(15) Aryl and alkenyl aldehydes proved to be much less reactive:
reactions using benzaldehyde or cinnamaldehyde with 1a gave the
corresponding products in less than 10% yields, while electron-poor
4-(trifluoromethyl)benzaldehyde gave the acetal product in 70% yield
with moderate stereoselectivities (dr = 0.9:1, 79% ee and 82% ee,
respectively). Similar observations were also recently reported; see
ref 5b. For quantification of the electrophilic reactivity of aldehydes,
see: Appel, R.; Mayr, H. J. Am. Chem. Soc. 2011, 133, 8240.
(16) The absolute configuration of the minor diastereomer of 3da was
determined by X-ray analysis to be as follows:
a Reactions were run using 1 (0.25 mmol), 2 (0.3 mmol), and 4a
(0.025 mmol) in CPME (0.5 mL). b CPME = cyclopentyl methyl ether.
c Isolated yields. d Diastereomeric ratios were determined by 1H NMR.
e Values are for the major diastereomers of 3. See Supporting Informa-
tion for minor diastereomers. f Reaction was run for 48 h. g Reaction was
run for 96 h. h Reaction was run for 120 h.
(Table 2, entries 2 and 3). Substrates bearing p-bromo-
phenyl, o-tolyl, and 1-naphthyl groups were tolerated
(Table 2, entries 4ꢀ6). Further, enones substituted by a
heterocycle or an alkyl group also gave 1,3-dioxolanes in
(17) Although not confirmed directly, we believe the catalyst might
also be responsible for the enatioselective formation of acetal carbon,
and the diastereoselectivity might be determined kinetically.
1622
Org. Lett., Vol. 14, No. 6, 2012

using formaldehyde (2f) and acetone (2g) with1a (Scheme 4).
We found that products 3af and 3ag were obtained
enantioselectively regardless of the fact that the forming
acetal carbon was achiral. Although a precise understand-
ing of the mechanism requires additional studies, from
these results, the enantioselectivity of this reaction can be
attributed largely tothe stepcomprising oxy-Michael addi-
tion from the hemiacetal intermediates.17 This is in accor-
dance with the consistent absolute configuration (the same
(S)-configuration) at the β-position of the carbonyl group
in both diastereomers of 3da.16
In summary, we developed a novel organocatalytic
formal [3 þ 2] cycloaddition reaction leading to optically
active 1,3-dioxolanes. Bifunctional organocatalysts allowed
cyclization from hemiacetals in high enantioselectivity. This
synthetic route provides efficient access to a range of chiral
cyclic acetals. In addition, the novel potential of bifunctional
organocatalysts in chiral heterocycle synthesis was demon-
strated. Further studies on the application of this methodol-
ogy to other related transformations are currently underway
in our laboratory and will be reported in due course.
Acknowledgment. We thank Professor Takuya Kurahashi
(Kyoto University) for X-ray crystallographic analysis. This
work was supported financially by the Japanese Ministry of
Education, Culture, Sports, Science and Technology. K.A.
also acknowledges the Japan Society for the Promotion of
Science for Young Scientists for fellowship support.
Scheme 4. Formal [3 þ 2] Cycloaddition with Formaldehyde (2f)
and Acetone (2g)a
Supporting Information Available. Experimental pro-
cedures including spectroscopic and analytical data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a Reaction was run using 37% aqueous solution of formaldehyde.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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