Stereoselective synthesis of tetrahydropyran-4-ones from dioxinones catalyzed by scandium(III) triflate

Article abstract of DOI:10.1021/ol050093v

(Chemical Equation Presented) A scandium triflate catalyzed, diastereoselective cyclization between aldehydes and β-hydroxy dioxinones has been discovered. This process capitalizes on the untapped nucleophilicity of the embedded enol ether within the dioxinone core. The bicyclic compounds from the resulting cyclization can be isolated, or alternatively, alkoxide nucleophiles can be directly added. This in situ addition fragments the dioxinone rings and delivers the 3-carboxy-substituted tetrahydropyran-4-ones in good yields with high levels of diastereoselectivity.

Full text of DOI:10.1021/ol050093v

ORGANIC
LETTERS
2005
Vol. 7, No. 6
1113-1116
Stereoselective Synthesis of
Tetrahydropyran-4-ones from Dioxinones
Catalyzed by Scandium(III) Triflate
William J. Morris, Daniel W. Custar, and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road,
EVanston, Illinois 60208
scheidt@northwestern.edu
Received January 17, 2005
ABSTRACT
A scandium triflate catalyzed, diastereoselective cyclization between aldehydes and
â-hydroxy dioxinones has been discovered. This process
capitalizes on the untapped nucleophilicity of the embedded enol ether within the dioxinone core. The bicyclic compounds from the resulting
cyclization can be isolated, or alternatively, alkoxide nucleophiles can be directly added. This in situ addition fragments the dioxinone rings
and delivers the 3-carboxy-substituted tetrahydropyran-4-ones in good yields with high levels of diastereoselectivity.
Tetrahydropyrans and related tetrahydropyran-4-ones are key
structural elements in numerous bioactive natural products
and medicinal compounds.1 Because of their prevalence,
there are multiple strategies for the construction of these six-
membered ring systems, including Prins cyclizations,2 hetero-
Diels-Alder reactions,3 and intramolecular nucleophilic
reactions.4 Inspired by the natural product targets currently
being pursued in our laboratory and encouraged by the
numerous bioactive compounds containing tetrahydropyrans,
we desired a direct method for the synthesis of various
carboxy-substituted tetrahydropyran-4-ones. Although exist-
ing methods might be employed to access these structures,
we envisioned an efficient and mild approach to our targets
that would capitalize on the previously untapped nucleophilic
character of dioxinones such as 1.5 We report herein the
realization of this strategy as a one-pot, diastereoselective
synthesis of tetrahydropyran-4-ones (4) from â-hydroxy-
dioxinones (1) and aldehydes (2) catalyzed by a Lewis acid
(Scheme 1, eq 1).
To install the desired 3-carboxy substituent directly, we
sought to capitalize on the potential nucleophilicity of the
R-position of the dioxinone ring system.6 Although an enol
ether moiety is contained within the dioxinone nucleus of 1,
a survey of the literature revealed that, surprisingly, the use
(1) (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309-3362. (b) Elliott,
M. C.; Williams, E. J. Chem. Soc., Perkin Trans. 1 2001, 2303-2340. (c)
Marmsater, F. P.; West, F. G. Chem. Eur. J. 2002, 8, 4347-4353.
(2) (a) Adams, D. R.; Bhatnagar, S. D. Synthesis 1977, 661-672. (b)
Snider, B. B. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2. (c) Cloninger, M. J.;
Overman, L. E. J. Am. Chem. Soc. 1999, 121, 1092-1093. (d) Jasti, R.;
Vitale, J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2004, 126, 9904-9905
and references therein. (e) Hart, D. J.; Bennett, C. E. Org. Lett. 2003, 5,
1499-1502 and references therein.
(4) For examples in total syntheses, see: (a) Williams, D. R.; Clark, M.
P.; Berliner, M. A. Tetrahedron Lett. 1999, 40, 2287-2290. (b) Christmann,
M.; Bhatt, U.; Quitschalle, M.; Claus, E.; Kalesse, M. Angew. Chem., Int.
Ed. 2000, 39, 4364-4366. (c) Williams, D. R.; Ihle, D. C.; Plummer, S. V.
Org. Lett. 2001, 3, 1383-1386. (d) Takahashi, S.; Kubota, A.; Nakata, T.
Tetrahedron 2003, 59, 1627-1638. (e) Hilli, F.; White, J. M.; Rizzacasa,
M. A. Org. Lett. 2004, 6, 1289-1292.
(3) (a) Boger, D. L.; Weinreb, S. L. Hetero Diels-Alder Methodology
in Organic Synthesis; Academic Press: San Diego, 1987. (b) Waldmann,
H. Synthesis 1994, 535-551. (c) Dossetter, A. G.; Jamison, T. F.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 1999, 38, 2398-2400 and references therein.
(5) The appended carboxy substituent significantly attenuates the reactiv-
ity of dienes related to 1, thereby rendering a hetero-Diels-Alder strategy
to compounds such as 4 currently untenable under numerous Lewis acid
catalyzed conditions surveyed.
10.1021/ol050093v CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/11/2005

Table 1. Optimization of Reaction Conditionsa
Scheme 1
entry
conditions
yield (%)b
1
2
2 equiv of BF3‚OEt2, CH2Cl2, 0 °C, 2 h
20 mol % Sc(OTf)3, H3CCN,
4Å sieves, 0 °C, 3 h
51
45
3
4
5
20 mol % Sc(OTf)3, CH2Cl2, CaSO4,c
-20 °C, 3 h
93
80
79
of dioxinones as nucleophiles is exceedingly rare.7 From a
practical perspective, the â-hydroxy-dioxinones employed
in this strategy are more stable than related â-keto esters
and can be directly accessed from catalytic asymmetric
additions of dienolates to aldehydes.8 Finally, the addition
of nucleophilic alkoxides directly to the reaction flask would
then convert intermediate 3 to the targeted 2,6-disubstituted
tetrahyrdropyran-4-ones with an appended carboxy substitu-
ent.
Our initial investigations focused on identifying optimal
carbon-carbon bond-forming conditions to generate stable
species with the general structure of 3 (Table 1, eq 2). While
stoichiometric quantities of BF3‚OEt2 promoted the cycliza-
tion of â-hydroxy-dioxinone 1a and aldehyde (2a, entry 1),
we were delighted to discover that catalytic amounts of
scandium(III) trifluoromethanesulfonate afforded high yields
of the desired heterocycle 3a (entries 2-5). Gratifyingly,
the diastereoselectivity of the overall process is excellent (20:
1), affording the 2,6-cis relative stereochemistry.9 A survey
of the catalyst loadings indicated that 10 mol % of Sc(OTf)3
was optimal in terms of yield and reaction time. The use of
other metal triflate salts in the reaction, such as Sm(OTf)3,
La(OTf)3, Mg(OTf)2, and Zn(OTf)2, did not provide signifi-
cant quantities of the desired cyclizied product, 3a. It is
important to note that the choice of dehydrating agent
(CaSO4) is crucial for obtaining high yields of the pyrone
products under catalytic conditions.10 Utilizing molecular
sieves or anhydrous magnesium sulfate consistently afforded
lower yields of 3a in a variety of solvents.
10 mol % Sc(OTf)3, CH2Cl2, CaSO4,c
-20 °C, 4 h
5 mol % Sc(OTf)3, CH2Cl2, CaSO4,c
-20 to 23 °C, 24 h
a Reactions performed at 0.2 M. b Isolated yield. c Anhydrous.
With efficient Lewis acid catalyzed conditions identified,
the influence of aldehyde structure on the transformation to
3 was probed (Table 2, eq 3). Saturated aldehydes participate
in the cyclization, with linear systems (entries 1, 2, and 8)
being superior to R-branched substrates (entry 9) in terms
of yield. The overall diastereoselectivity of the reaction is
dependent on the structure of the aldehyde. For example,
p-anisaldehyde, 1-naphthaldehyde, and isobutyraldehyde
provide reduced levels of selectivity compared to unbranched
saturated or electron-deficient substrates. Various dioxinones
(1) with alkyl chains (linear and branched) or aromatic rings
(such as phenyl) flanking the hydroxyl group are good
substrates and do not adversely impact diastereoselectivity
of the resulting bicyclic compounds.
Table 2. Scope of Sc(OTf)3-Catalyzed Cyclization
(6) For dioxinone enolate additions to carbonyl compounds, see: See-
bach, D.; Misslitz, U.; Uhlmann, P. Chem. Ber. 1991, 124, 1845-1852.
For organomagnesium reagents from dioxinones, see: Vu, V. A.; Berillon,
L.; Knochel, P. Tetrahedron Lett. 2001, 42, 6847-6850. For a photocy-
cloaddition/fragmentation approach to tetrahydropyrones utilizing dioxino-
nes, see: Dritz, J. H.; Carreira, E. M. Tetrahedron Lett. 1997, 38, 5579-
5582.
(7) For the only example of trapping an N-acyliminium electrophile with
a dioxinone ring, see: Teerhuis, N. M.; Hiemstra, H.; Speckamp, W. N.
Tetrahedron Lett. 1997, 38, 159-162. For related cyclizations that utilize
δ-hydroxy-â-keto esters and stoichiometric quantities of harsh Lewis acids,
see: (a) Clarke, P. A.; Martin, W. H. C. Org. Lett. 2002, 4, 4527-4529
(BF3‚OEt2). (b) Sabitha, G.; Reddy, G. S. K. K.; Rajkumar, M.; Yadav, J.
S.; Ramakrishna, K. V. S.; Kunwar, A. C. Tetrahedron Lett. 2003, 44,
7455-7457 (TMSI).
entry
R
R1
yield (%)b dr (cis:trans)c product
1
2
3
4
5
6
7
8
9
Ph(CH2)2 Ph(CH2)2
Ph(CH2)2 n-hexyl
Ph(CH2)2 Ph
Ph(CH2)2 4-Cl-Ph
Ph(CH2)2 4-Fl-Ph
Ph(CH2)2 4-MeO-Ph
Ph(CH2)2 1-Naphthyl
Ph(CH2)2 BnO(CH2)3
Ph(CH2)2 i-Pr
80
85
71
73
83
54
81
80
75
64
70
20:1
20:1
6:1
20:1
20:1
2:1
3:1
20:1
2:1
3a
5
6
7
8
9
10
11
12
13
14
(8) (a) Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117,
12360-12361. (b) Krueger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998,
120, 837-838. (c) Denmark, S. E.; Beutner, G. L. J. Am. Chem. Soc. 2003,
125, 7800-7801.
10 Ph
11 cyclohexyl Ph(CH2)2
Ph(CH2)2
20:1
20:1
a Reactions performed at 0.2 M. b Isolated yield after chromatographic
1
(9) As determined by H NMR (500 MHz) NOE experiments.
purification. c As determined by H NMR (500 MHz).
1
(10) Ben, A.; Yamauchi, T.; Matsumoto, T.; Suzuki, K. Synlett 2004,
225-230.
1114
Org. Lett., Vol. 7, No. 6, 2005

Table 3. One-Pot Cyclization/Ring Openinga
a Reactions performed from -10 to 0 °C at 0.2 M; 4 equiv of KOR2 added directly to reaction after conversion of 1. b Isolated yield after chromatographic
1
purification. c 2,6 relationship. d Enol/keto ratio determined by H NMR (500 MHz).
In a multicomponent reaction approach,11 3-carboxy pyran-
4-ones can be produced from a single reaction vessel by
direct addition of potassium alkoxide salts (Table 3). This
one-pot sequential process efficiently assembles three reac-
tion components and can accommodate various substitutions
on the dioxinone (1), aldehyde coupling partner (2), or
alkoxide nucleophile (KOR2). By increasing the catalyst
loading to 20 mol %, the overall process is accomplished in
less than 10 h.12 Presumably, the delivery of alkoxide
promotes fragmentation of the dioxinone ring in situ to afford
ethyl, benzyl, and trimethylsilylethyl esters in good yield (as
keto/enol tautomers).
(Scheme 2). Presumably, C-C bond formation proceeds via
a chairlike arrangement to afford dioxinone intermediate II.
The elimination of a proton from this oxocarbenium species
affords the bicyclic 2,6-cis-dioxinone 3a.13 The addition of
an alkoxide nucleophile (such as KOEt) to the reaction
fragments the dioxinone ring, and protonation of the resulting
enolate (III) upon quenching generates the thermodynami-
cally favored equatorial ester (4).14 Gratifyingly, the original
stereocenter of the â-hydroxy-dioxinone is completely
conserved in 3a when enantioenriched 1a9c is utilized in the
Our current working model of the reaction begins with
the Lewis acid catalyzed formation of oxocarbenium ion I
Scheme 2. Proposed Reaction Pathway
(11) For reviews on multicomponent reactions, see: (a) Moser, W. H.
Tetrahedron 2001, 57, 2065-2084. (b) Ugi, I. Pure Appl. Chem. 2001, 73,
187-191. (c) Orru, R. V.; de Greef, M. Synthesis 2003, 1471-1499.
(12) Lower catalysts loadings (5 and 10 mol %) increase reaction time
but do not adversely affect yield or selectivity.
(13) An alternative mechanism may involve an oxonia-Cope rearrange-
ment of I followed by ring closure; see: (a) Semeyn, C.; Blaauw, R. H.;
Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997, 62, 3426-3427. (b)
Rychnovsky, S. D.; Marumoto, S.; Jaber, J. J. Org. Lett. 2001, 3, 3815-
3818 and references therein. (c) Roush, W. R.; Dilley, G. J. Synlett 2001,
955-959. Further investigations to probe the operative reaction pathway
are ongoing in our laboratory.
Org. Lett., Vol. 7, No. 6, 2005
1115

the synthetic potential of these rigid reaction scaffolds should
provide access to significant chemical diversity initiated by
this new cyclization methodology.16
Scheme 3. Synthetic Transformations of Dioxinone 3aa
In summary, â-hydroxy-dioxinones and aldehydes undergo
mild and stereoselective cyclizations in the presence of
catalytic amounts of Sc(OTf)3. This novel construction of
the pyrone heterocycle capitalizes on the intrinsic, yet
previous unexploited, nucleophilicity of the dioxinone moi-
ety. The direct addition of a range of alkoxide nucleophiles
to the reaction flask can convert the resulting bicyclic pyrans
into carboxy-substituted tetrahydropyran-4-ones, thereby
accessing a highly efficient three-component process. Al-
ternatively, the intermediate pyrans can be isolated in good
yield and converted into the related carboxamide or unsub-
stituted tetrahydropyran-4-ones by trapping the easily gener-
ated acylketenes. Applications of this new catalytic cycliza-
tion reaction to the synthesis of bioactive pyrones are in
progress in our laboratory.
a (a) DMSO, H2O, 130 °C; (b) xylenes, reflux, H2NCH2Ph.
reaction. This stereochemical fidelity provides the foundation
to synthesize desired optically active bicycles (such as 3a)
or carboxy-substituted tetrahydropyran-4-ones (such as 15)
from enantioenriched â-hydroxy-dioxinones.
A significant advantage to this methodology is that the
dioxinone products 3a-14 are highly versatile platforms for
further synthetic manipulations (Scheme 3). One avenue of
transformation employs the exposure of the dioxinone core
to heat, which presumably generates a reactive acylketene
(A) via thermal reversion.15 Differentially trapping the
acylketene from 3a cleanly affords either unsubstituted
tetrahydropyran-4-one 21 (71%) or â-keto amide 22 (63%)
without affecting the diastereoselectivity established in 3a.
Interestingly, compounds such as 3a-14 have not been
reported in the literature to date, and a full investigation of
Acknowledgment. The authors thank Northwestern Uni-
versity, the National Science Foundation (CAREER Award
0348979), and Amgen (New Faculty Award) for financial
support. W.J.M. thanks Abbott Laboratories for a graduate
fellowship.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL050093V
(14) As a mixture of enol and keto tautomers. The configuration of this
stereocenter is assigned based on large 1H-1H coupling values (J g 10
Hz) indicating a diaxial vicinal proton disposition.
(15) Clemens, R. J.; Hyatt, J. A. J. Org. Chem. 1985, 50, 2431-2435
and references therein.
(16) (a) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004,
43, 46-58. (b) Burke, M. D.; Berger, E. M.; Schreiber, S. L. J. Am. Chem.
Soc. 2004, 126, 14095-14104.
1116
Org. Lett., Vol. 7, No. 6, 2005