Operationally simple, efficient, and diastereoselective synthesis of cis-2,6-disubstituted-4-methylene tetrahydropyrans catalyzed by triflic acid

Article abstract of DOI:10.1021/ol060430f

A highly efficient (0.01 mol % of TfOH), operationally simple (room temperature, inexpensive, and commercially available catalyst), and diastereoselective (up to >98% de) method for Bronsted acid-catalyzed reaction of enol ethers to form cis-2,6-disubstit

Full text of DOI:10.1021/ol060430f

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1871-1874
Operationally Simple, Efficient, and
Diastereoselective Synthesis of
cis-2,6-Disubstituted-4-Methylene
Tetrahydropyrans Catalyzed by Triflic
Acid
Alessandra Puglisi,†,§ Ai-Lan Lee,† Richard R. Schrock,# and Amir H. Hoveyda*,†
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467, and Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
amir.hoVeyda@bc.edu
Received February 18, 2006
ABSTRACT
A highly efficient (0.01 mol % of TfOH), operationally simple (room temperature, inexpensive, and commercially available catalyst), and
diastereoselective (up to >98% de) method for Brønsted acid-catalyzed reaction of enol ethers to form cis-2,6-disubstituted tetrahydropyrans
is disclosed.
Practical, environmentally friendly, and efficient methods for
stereoselective synthesis of heterocycles are critical to the
synthesis of medicinally relevant organic molecules. An
important class of heterocyclic synthesis targets is function-
alized chiral pyrans.1 Accordingly, a number of synthesis
strategies have been recently developed that involve stereo-
selective conversions of appropriately functionalized acyclic
O-containing precursors to 2,6-disubstituted pyrans. In one
set of transformations, a highly electrophilic oxocarbenium
ion, generated from reaction of an alcohol and an aldehyde
in the presence of a Lewis acid, is intramolecularly trapped
by an electron-rich neighboring alkene through an oxonium-
ene process (Prins-type cyclizations).2 The above strategy
requires sub-stoichiometric (0.5 equiv) or super-stoichio-
metric (2 equiv) amounts of strong Brønsted or Lewis acids.
In a related study, the only catalytic method disclosed thus
far in this general class of transformations, 5-20 mol % of
a Lewis acid catalyst (In(OTf)3), is used in the presence of
1.2-2.5 equiv of trimethyl silyl halides to promote inter-
molecular oxonium-ene cyclizations; these diastereoselective
transformations afford cis-2,6-disubstituted pyrans that bear
a C-halide bond at the C4 position.3 In another set of
investigations, electron-donating silyl units are installed to
enhance the reactivity of the nucleophilic olefin (allylsi-
lanes).4 The latter approach delivers excellent yields of pyrans
in high diastereoselectivities. However, additional operations
† Boston College.
(2) (a) Cloninger, M. J.; Overman, L. E. J. Am. Chem. Soc. 1999, 121,
1092-1093. (b) Sabitha, G.; Reddy, K. B.; Reddy, G. S. K. K.; Fatima,
N.; Yadav, J. S. Synlett 2005, 2347-2351.
# Massachusetts Institute of Technology.
§ Present address: Universita’ degli Studi di Milano, Dipartimento di
Chimica Organica ed Industriale, via Golgi, 19-20133 Milano, Italy.
(1) For representative examples, see: (a) Evans, D. A.; Carter, P. H.;
Carreira, E. M.; Charette, A. B.; Prunet, J. A.; Lautens, M. J. Am. Chem.
Soc. 1999, 121, 7540-7552. (b) Smith, A. B., III; Razler, T. M.; Ciavarri,
J. P.; Hirose, T.; Ishikawa, T. Org. Lett. 2005, 7, 4399-4402. (c) Sohn,
J.-H.; Waizumi, N.; Zhong, H. M.; Rawal, V. H. J. Am. Chem. Soc. 2005,
127, 7290-7291.
(3) (a) Loh, T.-P.; Yang, J.-Y.; Feng, L.-C.; Zhou, Y. Tetrahedron Lett.
2002, 43, 7193-7196. (b) Chan, K.-P.; Loh, T.-P. Org. Lett. 2005, 7, 4491-
4494.
(4) (a) Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2001, 123,
8420-8421. (b) Leroy, B.; Marko, I. E. Tetrahedron Lett. 2001, 42, 8685-
8688. (c) Keck, G. E.; Covel, J. A.; Schiff, T.; Yu, T. Org. Lett. 2002, 4,
1189-1192. (d) Hansen, E. C.; Lee, D. Tetrahedron Lett. 2004, 45, 7151-
10.1021/ol060430f CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/04/2006

must be carried out to incorporate the requisite silyl group,
and the use of 1-2 equiv of a strong acid (e.g., camphor-
sulfonic acid, TMSOTf) is often required.5
In the course of these studies, we noted that, when 1 is
subjected to a particular batch of Mo-based alkylidene 3,10
unsaturated pyrans 2a, 2b, and 2c are formed efficiently and
diastereoselectively (>98% de, as judged by analysis of 400
MHz 1H NMR spectra) instead of the expected ring-closing
metathesis (RCM) product (Scheme 1).
An alternative protocol, developed by Hart and Rych-
novsky,6 involves the formation of oxocarbenium ions,
generated by reaction of an enol ether with an acid, that is
then intercepted by an unfunctionalized alkene (i.e., not
activated by an R-silyl group); such a strategy is attractive
since it does not require silyl group activation. To the best
of our knowledge, an example of an efficient catalytic variant
of the latter approach has not yet been reported.
Scheme 1. Initial Observations with Mo-Based Alkylidenes
Research in these laboratories, during the past several
years, has focused on the design and development of a range
of new metal-based chiral catalysts and methods for dia-
stereo- and enantioselective synthesis of chiral pyrans.7 In
this communication, we report an efficient, practical, and
highly stereoselective protocol that involves the use of a
simple and inexpensive Brønsted superacid catalyst for
conversion of unsaturated enol ethers to cis-2,6-disubstituted-
4-methylene tetrahydropyrans: six-membered heterocyclic
units found in a variety of biologically active natural
products, such as dactylolide and zampanolide (shown
below).8 Thus, low catalyst loadings (e0.01 mol %; turnover
number ) 10 000) of commercially available triflic acid
(TfOH, pKa ) -13 to -14) initiate stereoselective formation
of the desired pyrans. Catalytic reactions are typically carried
out at room temperature (22 °C) and proceed to >98%
conversion in only a few minutes.
Despite the appreciable Lewis acidity of Mo-based alkyli-
denes, particularly those bearing electron-deficient ligands,
such as dichloroaryl imidate 3,11 we suspected that this and
related olefin metathesis precatalysts may not be responsible
for promoting cyclizations. Accordingly, we systematically
investigated the reaction of 1 in the presence of a range of
Mo-based alkylidenes (5 mol % loading in all cases),
including freshly prepared chiral complexes 3, which only
promote RCM. In contrast, their Mo triflate precursors (e.g.,
4, Scheme 1) proved to be effective cyclization catalysts.
Next, we established that other metal triflates, such as
Ag(OTf), Hg(OTf)2, Zn(OTf)2, Mg(OTf)2, Sn(OTf)2, and
Al(OTf)3, can be used as catalysts, whereas Yb(OTf)3, which
is relatively stable to hydrolytic decomposition12 (does not
readily generate TfOH through exposure with moisture), fails
to promote conversion of 1 to 2a-c (<2% conv). Finally,
we determined that, in the above studies, cyclization ef-
ficiency (% conv) and reaction times are dependent on the
age and quality of the metal triflate used. Collectively, the
The present protocol was discovered inadvertently during
investigations concerning the development of Mo-catalyzed
asymmetric ring-closing metathesis (ARCM) of enol ethers.9
7155. (e) Bolla, M. L.; Patterson, B.; Rychnovsky, S. D. J. Am. Chem.
Soc. 2005, 127, 16044-16045. (f) Shin, C.; Chavre, S. N.; Pae, A. N.;
Cha, J. H.; Koh, H. Y.; Chang, M. H.; Choi, J. H.; Cho, Y. S. Org. Lett.
2005, 7, 3283-3285.
(5) For catalytic Prins reactions that involve acetals as oxocarbenium
ion precursors, see: Aubele, D. L.; Lee, C. A.; Floreancig, P. E. Org. Lett.
2003, 5, 4521-4523 and references therein.
(6) (a) Hart, D. J.; Bennett, C. E. Org. Lett. 2003, 5, 1499-1502. (b)
Patterson, B.; Marumoto, S.; Rychnovsky, S. D. Org. Lett. 2003, 5, 3163-
3166. (c) Bolla, M. L.; Patterson, B.; Rychnovsky, S. D. J. Am. Chem.
Soc. 2005, 127, 16044-16045.
(8) For recent stereoselective total syntheses of zampanolide and dac-
tylolide, see: (a) Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am.
Chem. Soc. 2002, 124, 11102-11113. (b) Hoye, T. R.; Hu, M. J. Am. Chem.
Soc. 2003, 125, 9576-9577. (c) Aubele, D. L.; Wan, S.; Floreancig, P. E.
Angew. Chem., Int. Ed. 2005, 44, 3485-3488. (d) Jennings, M. P.; Ding,
F. Org. Lett. 2005, 7, 2321-2324. (d) Sanchez, C. C.; Keck, G. E. Org.
Lett. 2005, 7, 3053-3056.
(7) For representative examples, see: (a) Morken, J. P.; Didiuk, M. T.;
Visser, M. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1994, 116, 3123-3124.
(b) Johannes, C. W.; Visser, M. S.; Weatherhead, G. S.; Hoveyda, A. H. J.
Am. Chem. Soc. 1998, 120, 8340-8347. (c) Zhu, S. S.; Cefalo, D. R.; La,
D. S.; Jamieson, J. Y.; Davis, W. M.; Hoveyda, A. H.; Schrock, R. R. J.
Am. Chem. Soc. 1999, 121, 8251-8259. (d) Weatherhead, G. S.; Ford, J.
G.; Alexanian, E. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2000, 122, 1828-1829. (e) Cefalo, D. R.; Kiely, A. F.; Wuchrer, M.;
Jamieson, J. Y.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2001,
123, 3139-3140. (f) Gillingham, D. G.; Kataoka, O.; Garber, S. B.;
Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 12288-12290. (g) Brown,
M. K.; Degrado, S. J.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2005, 44,
5306-5310.
(9) Lee, A.-L.; Malcolmson, S. J.; Puglisi, A.; Schrock, R. R.; Hoveyda,
A. H. J. Am. Chem. Soc. 2006, 128, 5153-5157.
(10) Weatherhead, G. S.; Houser, J. H.; Ford, J. G.; Jamieson, J. Y.;
Schrock, R. R.; Hoveyda, A. H. Tetrahedron Lett. 2000, 41, 9553-9559.
(11) For a comprehensive review of chemistry of early transition metal
alkylidenes, see: Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2003, 42, 4592-4633.
(12) (a) Kobayashi, S.; Hachiya, I. J. Org. Chem. 1994, 59, 3590-3596.
(b) Kobayashi, S.; Nagayama, S.; Busujima, T. J. Am. Chem. Soc. 1998,
120, 8287-8288.
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Org. Lett., Vol. 8, No. 9, 2006

above findings suggested that small amounts of TfOH are
likely responsible for the observed catalytic activity.
On the basis of the above findings, we examined the effect
of pure TfOH on promoting the conversion of enol ether 1
to pyrans 2. As the data in entries 1 and 2 of Table 1 indicate,
Table 2. Diastereoselective TfOH-Catalyzed Synthesis of
cis-2,6-Disubstituted-4-Methylene Tetrahydropyransa
Table 1. Effect of Catalyst Loading on Product Distributiona
entry
mol % TfOH
2a:2b:2cb
1
2
3
4
5
10
5
1
0.1
0.01
(polymer)
(polymer)
1:3:3
1.5:1:1
4:1:1
a All conversions and de >98%, determined by 400 MHz 1H NMR
analysis of the unpurified product. b Determined by 400 MHz 1H NMR
analysis of the unpurified product.
treatment of 1 with 5 or 10 mol % of TfOH gives rise to
rapid polymerization (<2% 2). However, upon decreasing
the catalyst loading considerably (e1 mol %), the desired
tetrahydropyrans 2 can be isolated (entries 3-5, Table 1).
The ratio of the olefin isomers is affected by catalyst loading,
with 0.01 mol % of TfOH providing a 4:1:1 ratio of 2a:2b:
2c. Attempts at improving the above product distribution by
further lowering the catalyst loading resulted in >98%
recovery of the starting material.
Next, we examined the scope of the cyclization process.
The results of these studies are summarized in Table 2. As
shown in entry 1, we established that pyran 2a, from the
reaction of enol ether 1, can be obtained in the pure form in
55% isolated yield. Similar levels of reactivity and diaste-
reoselectivity are observed with diene 5 (entry 2); dihydro-
pyran 6a is obtained in 64% isolated yield. The acid-cata-
lyzed cyclization of enol ethers 7 and 9, where the 1,1-disub-
stituted olefins bear a longer alkyl chain (vs Me in 1), leads
to the formation of 8a and 10a as 1.6-1:1 mixtures of olefin
stereoisomers in 53 and 75% isolated yields. The transforma-
tions depicted in entries 3 and 4 proceed with improved levels
of product selectivity (a:b:c ) 10-11:1:1), presumably
because isomerization of the trisubstituted exocyclic alkene
is now thermodynamically less favored (vs with disubstituted
exocyclic olefins in 2a and 6a). Desymmetrization of triene
11 proceeds smoothly to afford dihydropyran 12a in 60%
isolated yield and >98% de. Catalytic cyclization of 1,1-
disubstituted enol ether 13 (entry 6, Table 2) is noteworthy
as it affords 14a, bearing a tertiary ether site, in 90% de and
46% isolated yield. The acid-catalyzed transformation of 15,
which carries a sterically more hindered and electron-
deficient enol ether, requires 18 h to proceed to completion,
delivering 16a-c in reduced selectivity (2:2:1); diastereo-
merically pure 16a was isolated in 27% yield.
a Conditions: 0.01 mol % of TfOH for entry 1 and 0.1 mol % of TfOH
for entries 2-7, C6H6, 22 °C, 10 min, N2 atm. All conversions and de >98%,
determined by 400 MHz 1H NMR analysis of the unpurified product.
b Determined by 400 MHz 1H NMR analysis of the unpurified product.
c Isolated yields after chromatography on silica gel impregnated with AgNO3
(5% w/w). d Diastereomeric excess ) 90%. e Reaction time ) 18 h.
can be carried out efficiently in various other common
solvents, such as pentane, toluene, Et2O, THF, dichlo-
romethane, and dimethoxyethane with similar levels of
efficiency as that observed in benzene; however, product
selectivity (a:b:c) is consistently higher in benzene. For
example, with 0.1 mol % of TfOH at 22 °C, a 1:1:1 mixture
of 2a:2b:2c is formed when catalytic cyclization of 1 is
carried out in THF; a 3:1:1 selectivity is observed with Et2O
as solvent. (2) Catalytic cyclizations can be carried out at
-78 °C (toluene). Under these conditions, reactions proceed
to completion (0.01 mol % of TfOH) but without any
improvement in product selectivity (a:b:c). (3) Longer
reaction times lead to an increase in the amount of endocyclic
products; for example, after 5 days, 1 is converted to 2b
and 2c with <2% 2a remaining (established by analysis of
400 MHz 1H NMR). Moreover, when pure 2a is re-subjected
to the reaction conditions, it is converted to 2b and 2c in
the presence of 0.01 mol % of TfOH after 1 h at 22 °C. The
above observations indicate that products a are likely the
Several other noteworthy points regarding the acid-
catalyzed cyclization merit mention. (1) Catalytic cyclizations
Org. Lett., Vol. 8, No. 9, 2006
1873

exclusive kinetic products which then isomerize to b and c
olefin isomers. (4) One limitation of the present catalytic
protocol is that there is <2% conv with substrates bearing a
terminal alkene.
phenyl acetate; 15 (entry 7, Table 2) was accessed through
a conjugate addition6a method. It is important to note that
the more substituted and functionalized oxocarbenium ions
generated from enol ether precursors, such as 13 and 15
(entries 6 and 7, Table 2), cannot be readily prepared in situ
through Prins-type protocols.2-4
Examination of other Brønsted and Lewis acids as catalysts
for this class of cyclization reactions clearly indicates that
TfOH is unique in its ability to promote efficient and
selective C-C bond formations. Thus, when enol ether 1 is
subjected to camphorsulfonic acid or trifluoroacetic acid (5
mol %), <2% of the desired product is obtained (>98%
recovered starting material). In contrast, Amberlyst 15E (0.5
g resin/mmol substrate) gives rise to >98% conversion after
1 h (22 °C) to afford 2a:2b:2c, albeit with diminished product
selectivity (1:1:1) and diastereoselectivity (33 vs >98% de
with TfOH in favor of the cis diastereomer). Lewis acids
BF3‚Et2O and TiBr4 induce cyclization, but significantly less
efficiently: with 5 mol % of BF3‚Et2O, >98% conv to an
equimolar mixture of 2a, 2b, and 2c is observed (18 h),
whereas TiBr4 (∼90% conv after 18 h) provides a complex
mixture of products, including 2a, 2b, and 2c and ∼10%
unreacted starting material.
The starting vinyl ethers required for TfOH-catalyzed
cyclizations can be accessed from the corresponding homo-
allylic alcohols in one Pd-catalyzed step; the procedure
shown in eq 1 is representative.13 Subjection of homo-
allylic alcohol 17 to 0.5 mol % of commercially available
Pd(OCOCF3)2 and 4,7-diphenyl-1,10-phenanthroline in the
presence of 0.75 equiv of Et3N and 20 equiv of n-butyl vinyl
ether (75 °C, 24 h) gives rise to the formation of 5 in 71%
yield after silica gel chromatography (eluted with 1% Et3N).
Because a variety of homoallylic alcohols are available in
highly optically enriched form,14 the present protocol can
be easily applied to the enantioselective synthesis of cis-
2,6-disubstituted-4-methylene tetrahydropyrans.
In summary, we present a method for catalytic and
diastereoselective cyclizations of unsaturated enol ethers that
afford cis-2,6-disubstituted-4-methylene tetrahydropyrans.
The overall process is direct and operationally simple: vinyl
ether substrates can be accessed from easily available
homoallylic alcohols, and cyclizations are readily promoted,
typically in less than 10 min, in the presence of 0.01-0.1
mol % of commercially available TfOH (∼$6/gram) at room
temperature. The effectiveness of the present protocol and
the significance of 2,6-disubstituted pyrans in chemical
synthesis should render the present method of synthetic
utility. Moreover, the recent emergence of chiral Brønsted
acid catalysts16 suggests that a highly efficient approach for
an enantioselective variant of the present process may be
achievable. Studies along these lines are in progress and will
be disclosed in due course.
Acknowledgment. Financial support was provided by the
NIH (GM-59426 to R.R.S. and A.H.H.). In addition, post-
doctoral fellowships to A.P. (Universita’ degli Studi di
Milano) and A.-L.L. (Lindemann Trust) are acknowledged.
We are grateful to Steven J. Malcolmson for experimental
assistance, and to Drs. Constantin Czekelius and Monica
Duval for helpful discussions.
1,1-Disubstituted vinyl ether 13 (entry 6, Table 2) was
prepared through Tebbe olefination15 of the corresponding
(13) Bosch, M.; Schlaf, M. J. Org. Chem. 2003, 68, 5225-5227.
(14) For representative procedures for enantioselective synthesis of
homoallylic alcohols, see: (a) Keck, G. E.; Krishnamurthy, D.; Grier, M.
C. J. Org. Chem. 1993, 58, 6543-6544. (b) Yanagisawa, A.; Nakashima,
H.; Ishiba, A.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 4723-4724.
(c) Bode, J. W.; Gauthier, D. R.; Carreira, E. M. Chem. Commun. 2001,
2560-2561. (d) Denmark, S. E.; Wynn, T. J. Am. Chem. Soc. 2001, 123,
6199-6200. (e) Kinnard, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.;
Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 7920-7921. (f) Gung, B.
W.; Xue, X.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 10692-10697.
(g) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763-2794. (h) Lachance,
H.; Lu, X.; Gravel, M.; Hall, D. G. J. Am. Chem. Soc. 2003, 125, 10160-
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K. Chem.sEur. J. 2003, 9, 4405-4413. (j) Gravel, M.; Lachance, H.; Lu,
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(15) (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611-3613. (b) Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs,
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Supporting Information Available: Experimental pro-
cedures and spectral data for products (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
OL060430F
(16) For example, see: (a) Uraguchi, D.; Terada, M. J. Am. Chem. Soc.
2004, 126, 5356-5357. (b) Uraguchi, D.; Sorimachi, K.; Terada, M. J.
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