Stereoselective synthesis of substituted tetrahydropyrans via domino olefin cross-metathesis/intramolecular oxa-conjugate cyclization

Article abstract of DOI:10.1021/ol100431m

(Figure Presented) A novel strategy for the stereoselective synthesis of substituted tetrahydropyrans has been developed on the basis of a domino olefin crossmetathesis/intramolecular oxa-conjugate cyclization catalyzed by the Hoveyda- Grubbs second-generation catalyst.

Full text of DOI:10.1021/ol100431m

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1636-1639
Stereoselective Synthesis of Substituted
Tetrahydropyrans via Domino Olefin
Cross-Metathesis/Intramolecular
Oxa-Conjugate Cyclization
Haruhiko Fuwa,* Kenkichi Noto, and Makoto Sasaki
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku
UniVersity, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
hfuwa@bios.tohoku.ac.jp
Received February 20, 2010
ABSTRACT
A novel strategy for the stereoselective synthesis of substituted tetrahydropyrans has been developed on the basis of a domino olefin cross-
metathesis/intramolecular oxa-conjugate cyclization catalyzed by the HoveydasGrubbs second-generation catalyst.
Domino reactions are able to build up complex molecules
by forming and/or cleaving multiple bonds in a single
reaction vessel.1 Due to their atom- and step-economical
aspects, the development of domino reactions becomes
increasingly important nowadays toward realization of
sustainable chemistry. The ruthenium alkylidene complexes,
commonly known as the Grubbs catalysts, have emerged as
an indispensable tool for olefin metathesis reactions due to
their high reactivity, ease of handling, and commercial
availability.2 The Grubbs catalysts are also known to tolerate
a wide range of functionalities, as their numerous applications
can be seen in the total synthesis of complex natural
products.3 Meanwhile, recent reports have described domino
reactions that involve nonmetathetic applications of the
Grubbs catalysts.4–10 The exceptionally high chemoselectivity
coupled with potential utility in nonmetathetic reactions
render the Grubbs catalysts as an attractive source for
inspiring domino reactions. Nevertheless, there have been
only a few reports that describe domino reactions catalyzed
solely by a Grubbs catalyst;5,6,7e,10 the use of an additive is
necessary for some of the reported domino reactions.7a-d,8,9
Substituted tetrahydropyrans are a common structural motif
that can be found in a diverse array of biologically significant
natural products, such as marine macrolides and polycyclic
(2) For recent reviews on olefin metathesis reactions, see: (a) Hoveyda,
A. H.; Zhugralin, A. R. Nature 2007, 450, 243–251. (b) Samojlowicz, C.;
Bieniek, M.; Grela, K. Chem. ReV. 2009, 109, 3708–3742. (c) van Otterlo,
W. A. L.; de Koning, C. B. Chem. ReV. 2009, 109, 3743–3782. (d) Lin,
Y. A.; Chalker, J. M.; Davis, B. G. ChemBioChem 2009, 10, 959–969. (e)
Binder, J. B.; Raines, R. T. Curr. Opin. Chem. Biol. 2009, 12, 767–773. (f)
Burtscher, D.; Grela, K. Angew. Chem., Int. Ed. 2009, 48, 442–454.
(3) For reviews, see: (a) Gradillas, A.; Perez-Castells, J. Angew. Chem.,
Int. Ed. 2006, 45, 6086–6101. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah,
D. Angew. Chem., Int. Ed. 2005, 44, 4490–4527.
(1) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006. For recent reviews, see: (a) Poulin,
J.; Grise´-Bard, C. M.; Barriault, L. Chem. Soc. ReV. 2009, 38, 3092–3101.
(b) Nicolaou, K. C.; Chen, J. S. Chem. Soc. ReV. 2009, 38, 2993–3009. (c)
Barluenga, J.; Rodr´ıguez, F.; Fan˜ana´s, F. J. Chem. Asian J. 2009, 4, 1036–
1048. (d) Alba, A. N.; Companyo, X.; Viciano, M.; Rios, R. Curr. Org.
Chem. 2009, 13, 1432–1474. (e) Vilotijevic, I.; Jamison, T. F. Angew.
Chem., Int. Ed. 2009, 48, 5250–5281.
(4) For reviews, see: (a) Alcaide, B.; Almendros, P.; Luna, A. Chem.
ReV. 2009, 109, 3817–3858. (b) Arisawa, M.; Terada, Y.; Takahashi, K.;
Nakagawa, M.; Nishida, A. Chem. Rec. 2007, 7, 238–253. (c) Alcaide, B.;
Almendros, P. Chem.sEur. J. 2003, 9, 1258–1262.
10.1021/ol100431m  2010 American Chemical Society
Published on Web 03/11/2010

ethers.11 There is a continuous demand for atom- and step-
economical methods for the synthesis of substituted tetrahy-
dropyrans. Herein, we report the development of a domino
olefin cross-metathesis/intramolecular oxa-conjugate cycliza-
tion12 by using the HoveydasGrubbs second-generation catalyst
(HG-II),13 which enables a rapid, efficient, and stereoselective
synthesis of substituted tetrahydropyrans from readily available
acyclic materials in a single flask.
Table 1. Screening of the Reaction Conditions
We envisioned that olefin cross-metathesis of a hydroxy
alkene I and an enone II catalyzed by the Grubbs second-
generation catalyst (G-II) or HG-II should generate a hydroxy
enone III, which would undergo intramolecular oxa-conjugate
cyclization to furnish a tetrahydropyran IV under suitable
conditions (Scheme 1). It is well accepted that oxa-conjugate
addition reaction of an alcohol to an enone can be accomplished
either by deprotonation with a strong base to activate a weakly
nucleophilic hydroxy group or by activation of a carbonyl group
with a Lewis or Brønsted acid. We thought a domino olefin
cross-metathesis/intramolecular oxa-conjugate cyclization would
be achievable by in situ activation of intermediate III with an
appropriate Lewis or Brønsted acid. Importantly, the product
tetrahydropyran IV is synthetically useful in subsequent trans-
formations, such as aldol reaction or acetalization, by exploiting
the carbonyl functionality.14
product(s)
3aa 4aa (%)
(%) (cis/trans)a
entry catalyst
conditions
1
2
3
4
HG-II CH2Cl2, 35 °C, 12 h
HG-II ClCH2CH2Cl, 80 °C, 15 h
G-II
88
80 (9:1)
19 31 (2:3)b
94 (7:1)
ClCH2CH2Cl, 80 °C, 15 h
HG-II CH2Cl2, 100 °C (MW), 30 min
a Ratio of 2,6-cis and 2,6-trans diastereomers was estimated by 1H NMR
analysis (500 or 600 MHz, CDCl3). b 1a was recovered in 43% yield.
vinyl ketone 2a (Table 1). Treatment of a mixture of 1a and
2a with HG-II (10 mol %) in CH2Cl2 at 35 °C for 12 h gave
hydroxy enone 3aa in 88% yield as the sole isolable product
(entry 1). In contrast, when the reaction was performed in 1,2-
dichloroethane at 80 °C for 15 h, tetrahydropyran 4aa was
directly obtained in 80% yield (2,6-cis/2,6-trans ) 9:1, entry
2). G-II was less effective than HG-II for the present purpose,
as the reaction using G-II resulted in incomplete conversion
even after 15 h at 80 °C, giving 4aa in 31% yield with poor
diastereoselectivity (entry 3). Upon microwave (MW) irradia-
tion16 of a mixture of 1a, 2a, and HG-II in CH2Cl2 at 100 °C
for 30 min, 4aa was isolated in 94% yield (2,6-cis/2,6-trans )
7:1, entry 4).
Scheme 1. Concept of the Present Work
Encouraged by these preliminary results, we examined the
use of several olefin coupling partners in the domino process
(Table 2). Coupling of 1a with enones 2b-e (1.5 equiv) under
the MW conditions (10 mol % HG-II, CH2Cl2, 100 °C, 20-30
min) provided the respective tetrahydropyrans 4ab-ae in good
yields with synthetically useful levels of diastereoselectivity
(entries 1-4).17
The scope of the domino reaction was further explored using
δ-hydroxy olefins 1b and 1c (Table 3). In all cases, the product
tetrahydropyrans 4ba-bc,ca,cb were exclusively isolated as 2,6-
cis isomers in good to excellent yields.
At this stage, we tried to figure out an actual active species
for the intramolecular oxa-conjugate cyclization process by
several control experiments (Scheme 2). When a solution of
3aa with or without HG-II (10 mol %) in CH2Cl2 was heated
at 100 °C (MW) for 30 min, 3aa was recovered almost
quantitatively with no sign of cyclization by 1H NMR analysis.
In contrast, MW heating of a mixture of 3aa, styrene (1 equiv),
We initially used δ-hydroxy olefin 1a15 as a model compound
to probe its reactivity toward olefin cross-metathesis with methyl
(5) (a) Seigal, B. A.; Fajardo, C.; Snapper, M. L. J. Am. Chem. Soc.
2005, 127, 16329–16332. (b) Faulkner, J.; Edlin, C. D.; Fengas, D.; Preece,
I.; Quayle, P.; Richards, S. N. Tetrahedron Lett. 2005, 46, 2381–2385.
(6) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 11312–11322.
(7) (a) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L.
J. Am. Chem. Soc. 2002, 124, 13390–13391. (b) Schmidt, B. Eur. J. Org.
Chem. 2003, 816–819. (c) Schmidt, B. Chem. Commun. 2004, 742–743.
(d) Schmidt, B. J. Org. Chem. 2004, 69, 7672–7687. (e) Finnegan, D.;
Seigal, B. A.; Snapper, M. L. Org. Lett. 2006, 8, 2603–2606.
(8) Kim, B. G.; Snapper, M. L. J. Am. Chem. Soc. 2006, 128, 52–53.
(9) Fustero, S.; Jime´nez, D.; Sa´nchez-Rosello´, M.; del Pozo, C. J. Am.
Chem. Soc. 2007, 129, 6700–6701.
(14) For recent examples, see: (a) O’Neil, G. W.; Ceccon, J.; Benson,
S.; Collin, M.-P.; Fasching, B.; Fu¨rstner, A. Angew. Chem., Int. Ed. 2009,
48, 9940–9945. (b) Fu¨rstner, A.; Fenster, M. D. B.; Fasching, B.; Godbout,
C.; Radkowski, K. Angew. Chem., Int. Ed. 2006, 45, 5506–5510.
(15) Fuwa, H.; Sasaki, M. Org. Lett. 2010, 12, 584–587.
(10) Chen, J.-R.; Li, C.-F.; An, X.-L.; Zhang, J.-J.; Zhu, X.-Y.; Xiao,
W.-J. Angew. Chem., Int. Ed. 2008, 47, 2489–2492.
(11) For recent reviews, see: (a) Clarke, P. A.; Santos, S. Eur. J. Org.
Chem. 2006, 2045–2053. (b) Larrosa, I.; Romea, P.; Urp´ı, F. Tetrahedron
2008, 64, 2683–2723.
(16) For a recent review on microwave-assisted olefin metathesis, see:
Coquerel, Y.; Rodriguez, J. Eur. J. Org. Chem. 2008, 1125–1132.
(17) The reaction of 1a with crotonaldehyde in the presence of HG-II
under the MW conditions gave a mixture of the corresponding hydroxy
enal (60%) and tetrahydropyran (19%, cis/trans ) 5:1), while that with
methyl acrylate gave the corresponding hydroxy enoate in 98% yield.
(12) For a recent review, see: Nising, C. F.; Bra¨se, S. Chem. Soc. ReV.
2008, 37, 1218–1228.
(13) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168–8179.
Org. Lett., Vol. 12, No. 7, 2010
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Table 2. Reaction of 1a with a Variety of Coupling Partners
Table 3. Synthesis of a Variety of 2,6-cis-Tetrahydropyransa
a All reactions were carried out using HG-II (10 mol %) and 2b-e
(1.5 equiv) in CH2Cl2 at 100 °C (MW) for 20-30 min. Ratio of 2,6-cis
and 2,6-trans diastereomers was estimated by 1H NMR analysis (500 MHz).
a All reactions were performed using HG-II (10 mol %) and 2a-c
(1.5-5 equiv) in CH2Cl2 at 100 °C (MW) for 20-30 min. The ratio of
2,6-cis and 2,6-trans diastereomers was estimated by 1H NMR analysis
(500 MHz). b Approximately 10:1 mixture of diastereomers at the C4
stereogenic center.
methyl acrylate (1.5 equiv), and HG-II (10 mol %) in CH2Cl2
at 100 °C for 30 min effected complete consumption of 3aa as
1
judged by TLC and H NMR analysis. After purification by
step of the domino reaction obviously slowed down in the
presence of 2,6-dichloro-1,4-benzoquinone (cf. Table 1, entry
4). This result suggested that the cyclization of the interme-
diary δ-hydroxy enone would be mainly promoted by the
ruthenium hydride species derived from degradation of the
thermally unstable ruthenium methylidene complex.
To probe the origin of the observed diastereoselectivity of
the cyclization process, control experiments were next per-
formed (Scheme 3). Treatment of 3aa with NaH in THF at
room temperature gave 4aa in 89% yield with a moderate
preference for the 2,6-trans product (2,6-cis/2,6-trans ) 1:2).
This product was heated in CH2Cl2 at 100 °C (MW) for 30
min together with styrene (1 equiv), methyl acrylate (1.5 equiv),
and HG-II (10 mol %). 1H NMR analysis of the crude reaction
mixture showed that the diastereomer ratio of 4aa was not
flash chromatography on silica gel, 4aa was isolated in 66%
yield (2,6-cis/2,6-trans ) 9:1) along with methyl trans-
cinnamate (90% yield based on styrene). From these experi-
ments, we assumed an active ruthenium species responsible for
the cyclization step must be generated in situ after initiation of
the cross-metathesis step. Previous related reports8,9 described
ruthenium methylidene complex [(H2IMes)(Cl)2RudCH2]
(H2IMes ) 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene) gen-
erated in the propagation step of olefin metathesis to be the
Lewis acidic species. However, the possibility that ruthenium
species resulting from decomposition of the ruthenium
methylidene complex under high temperature conditions
(e.g., ruthenium hydride species)18 may act as a Lewis acid
led us to perform the domino reaction in the presence of
2,6-dichloro-1,4-benzoquinone.19 In the event, reaction of
1a and 2a in the presence of 10 mol % of HG-II and 0.2
equiv of 2,6-dichloro-1,4-benzoquinone in CH2Cl2 at 100 °C
(MW) for 30 min gave 4aa in 17% yield along with
δ-hydroxy enone 3aa in 73% yield. Thus, the cyclization
(18) Hong, S. H.; Wenzel, A. G.; Salguero, T. T.; Day, M. W.; Grubbs,
R. H. J. Am. Chem. Soc. 2007, 129, 7961–7968.
(19) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 17160–17161.
1638
Org. Lett., Vol. 12, No. 7, 2010

methyl acetal 5 in 91% yield as a single stereoisomer after
purification by flash chromatography on silica gel. Significantly,
four bonds and two stereogenic centers were newly formed with
complete stereoselection in a single reaction vessel.
Scheme 2
. Control Experiments To Elucidate the Actual Active
Species Responsible for the Cyclization Step
Scheme 4
.
Stereoselective Synthesis of Methylene
Bis-tetrahydropyran 5
In conclusion, we developed a novel domino olefin cross-
metathesis/intramolecular oxa-conjugate cyclization, which
provides a variety of substituted tetrahydropyrans in good to
excellent yields in a stereoselective manner from readily
available acyclic precursors. Importantly, the present domino
reaction is catalyzed by HG-II alone at elevated temperatures,
which represents a new nonmetathetic application of the Grubbs
catalysts and demonstrates the power and efficiency of “tandem
catalysis” for the synthesis of complex molecules.23 Application
of the present domino reaction to the total synthesis of natural
products is currently under investigation.
changed at all. This result suggested that the 2,6-cis and 2,6-
trans products would not equilibrate under the reaction condi-
tions and that the 2,6-cis products should arise from kinetic
control.20
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Scientific Research from MEXT, Japan.
Scheme 3
.
Control Experiments To Elucidate the Origin of the
Stereoselectivity of the Cyclization Step
Supporting Information Available: Experimental proce-
1
dures and copies of H and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL100431M
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A concise synthesis of methylene bis-tetrahydropyran 5, a
common structural motif found in several marine macrolide
natural products,21 showcases the synthetic feasibility of our
domino reaction (Scheme 4). Coupling of 1c and 6 (1.5 equiv)
under the MW conditions (10 mol % HG-II, CH2Cl2, 100 °C)
cleanly provided ketone 7.22 Addition of PPTS and MeOH to
the reaction flask at room temperature smoothly effected methyl
acetalization with concomitant loss of the TES group, giving
(22) In a separate experiment, ketone 7 was isolated in 90% yield as a
single stereoisomer after purification by flash chromatography on silica gel.
Treatment of 7 with PPTS in MeOH/CH2Cl2 at room temperature gave methyl
acetal 5 in 99% yield. See the Supporting Information for details.
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Org. Lett., Vol. 12, No. 7, 2010
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