Tandem ruthenium-catalyzed redox isomerization-O-conjugate addition: An atom-economic synthesis of cyclic ethers

Article abstract of DOI:10.1021/ol9007876

An atom-economical method for the convenient synthesis of tetrahydropyrans and tetrahydrofurans is reported. Enones and enals derived from the [lndRu(PPh₃)₂CI]-catalyzed redox isomerization of primary and secondary propargyl alcohols

Full text of DOI:10.1021/ol9007876

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2539-2542
Tandem Ruthenium-Catalyzed Redox
Isomerization-O-Conjugate Addition: An
Atom-Economic Synthesis of Cyclic
Ethers
Barry M. Trost,* Alicia C. Gutierrez, and Robert C. Livingston
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received April 10, 2009
ABSTRACT
An atom-economical method for the convenient synthesis of tetrahydropyrans and tetrahydrofurans is reported. Enones and enals derived
from the [IndRu(PPh3)2Cl]-catalyzed redox isomerization of primary and secondary propargyl alcohols undergo a subsequent intramolecular
conjugate addition to provide cyclic ethers in excellent yields.
A primary focus in our laboratory is the invention and
use of atom-economical reactions for the rapid construc-
tion of molecular complexity from relatively simple
starting materials. Toward this end, we have frequently
employed alkynes as the key building blocks from which
an array of functionalities can be accessed.1 Alkynes are
particularly well-suited to this strategy because of the
exceptional ease and chemoselectivity with which they
can be installed, particularly when they are substituted
with propargyl alcohols, and the diversity of functional
groups (including 1,3- and 1,4-dienes, enones, enals,
dienones, dienals, vinyl halides, and vinyl silanes) to
which they can be converted.2 When used as synthetic
equivalents of more reactive moieties, their robust nature
obviates the need for protecting groups.
(2) Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH:
Weinheim, Germany, 1995.
(3) Examples of tetrahydropyran- and tetrahydrofuran-containing natural
products include Bryostatin, Salinomcin, Latrunculin A, Spongistatin 1,
Swinholide A, Hemibrevitoxin B, Glabrescol, Pamamycin 607, and Scle-
rophytin A.
(4) For reviews containing leading references on the development of
methods for the synthesis of tetrahydropyrans, tetrahydrofurans, and
oxepanes, see: (a) Piccialli, V. Synthesis 2007, 17, 2585. (b) Elliot, M. C.
J. Chem. Soc., Perkin. Trans. 1 2002, 2301. (c) Boivin, T. L. Tetrahedron
1987, 43, 3309. Recent advances: (d) Zhu, H.; Wickenden, J. G.; Campbell,
N. E.; Leung, J. C. T; Johnson, K. M.; Sammis, G. M. Org. Lett. 2009, 11,
2019. (e) Fu, G. C.; Chung, Y. K. Angew. Chem., Int. Ed. 2009, 48, 2225.
(f) Dzudza, A.; Marks, T. Org. Lett. 2009, 11, 1523. (g) Gonzlez-Rodrguez,
C.; Escalante, L.; Varela, J. A.; Castedo, L.; Saa, C. Org. Lett. 2009, 11,
1531. (h) Samanta, S.; Mohapatra, H.; Jana, R.; Ray, J. K. Tetrahedron
Lett. 2008, 49, 7153. (i) Kimishima, A.; Nakata, T. Tetrahedron Lett. 2008,
49, 6563. (j) Jamison, T. F.; Vilotijevic, I. Science 2007, 317, 1189. (k)
Kartika, R.; Taylor, R. E. Angew. Chem., Int. Ed. 2007, 46, 6874. (l) Yadav,
J. S.; Rajasekhar, K.; Murty, M. S. Synlett 2005, 12, 1945. (m) Trost, B. M.;
Yang, H.; Wuitschik, G. Org. Lett. 2005, 7, 4761.
(1) Reviews containing leading references in this area: (a) Trost, B. M.;
Frederiksen, M. U.; Rudd, M. T. Angew. Chem., Int. Ed. 2005, 44, 6630.
(b) Trost, B. M. Acc. Chem. Res. 2002, 35, 695. (c) Trost, B. M.; Toste,
F. D. ; Pinkerton, A. B. Chem. ReV. 2001, 101, 2067. Recent advances: (d)
Trost, B. M.; Bertogg, A. Org. Lett. 2009, 11, 511. (e) Trost, B. M.; Ashfeld,
B. L. Org. Lett. 2008, 10, 1893. (f) Trost, B. M.; Ferreira, E. M.; Gutierrez,
A. C. J. Am. Chem. Soc. 2008, 130, 16176. (g) Trost, B. M.; Xie, J.; Maulide,
N. J. Am. Chem. Soc. 2008, 130, 17258. (h) Trost, B. M.; Machacek, M. R.;
Faulk, B. D. J. Am. Chem. Soc. 2006, 128, 6745. (i) Trost, B. M.; McClory,
A. Org. Lett. 2006, 8, 3627. (j) Trost, B. M.; Huang, X. Chem. Asian J.
2006, 1, 469.
10.1021/ol9007876 CCC: $40.75
Published on Web 05/18/2009
 2009 American Chemical Society

Functionalized tetrahydropyrans (THPs) and tetrahydro-
furans (THFs) are ubiquitous motifs in biologically signifi-
cant natural products and medicinal agents.3 Due to the
structural diversity of these units in targets of interest,
numerous methods have been developed for their synthesis.4
Previously we have shown that catalyst 1, along with
cocatalysts indium(III) triflate and camphorsulfonic acid
(CSA), can effect the redox isomerization of propargyl
alcohols to enals and enones.5 We envisioned that hetero-
cycles such as THPs and THFs could be constructed from
propargyl alcohols such as 2 utilizing a redox isomerization-
conjugate addition sequence (Scheme 1). The proposed
Indeed, when propargyl alcohol 11, which bears a pendant
hydroxy group, was submitted to the redox isomerization
conditions, THP 12 was obtained along with the uncyclized,
isomerized product 13 in a 21:65 ratio (Table 1, entry 1).
Table 1. Optimization of Reaction Conditions
time convn
entry mol % 1 cocatalyst
acid
(h) (%)a yieldb
1
5
40% InCl3 10% Et3NHPF6 1.25 100 21% 12,
65% 13
Scheme 1
.
Tandem Redox Isomerization-Conjugate Addition to
Generate Cyclic Aldehydes
2
5
5
5
5
40% InCl3 10% Et3NHPF6
4
100 70% 12
100 78% 12
3c
4d
5
40% InCl3 10% Et3NHPF6 1.5
40% InCl3 10% Et3NHPF6 1.5
40% InCl3 10% Et3NHPF6 1.5
20% CSA
100
100
-
-
6
7
8
5
5
5
20% InCl3 10% Et3NHPF6 1.5
20% CSA
93
86
94
-
-
-
-
10% Et3NHPF6
50% CSA
10% Et3NHPF6
100% CSA
3
-
3
9
2
3
5% In(OTf)3 10% CSA
5% In(OTf)3 5% CSA
5% In(OTf)3 10% CSA
5% In(OTf)3 5% CSA
3% In(OTf)3 20% CSA
10% AgOTf 40% TsOH
5% AgOTf 20% TsOH
0.25
0.25
0.25
1
1.5
6
6
87
98
92
-
-
-
sequence involves the isomerization of a propargyl alcohol
containing a pendant alcohol (2) to furnish the corresponding
enal (4), capable of spontaneous cyclization to cyclic ether
5.6
10
11
12
13
14
15
3
3
100 75% 12
100 80% 12
100
35
3
10
5
-
-
If successful, this method would provide quick access to
cyclic ethers, allowing for their introduction via simple
addition chemistry. Several groups,7 including ours,8 have
developed enantioselective methods for constructing chiral
propargyl alcohols. With chiral propargyl moiety 7 in hand,
isomerization of the internal alkyne to the terminal alkyne
using the base-promoted “acetylene zipper” reaction9 fol-
lowed by deprotonation and addition of terminal alkyne 8
into an aldehyde (R′CHO) would provide the requisite
precursor 9 for the formation of cyclic ether 10 (Scheme 2).
a Conversion refers to the consumption of 11; determined by GC and
NMR. b Isolated yield. c Addition of 40% TsOH and continued reflux (15
min) after completion of isomerization. d Addition of 40% CSA and
continued reflux (15 min) after completion of isomerization.
Increasing the reaction time allowed complete cyclization
to the THP (entry 2). It was also found that the degree of
cyclization was pH-dependent and that the addition of strong
acids allowed isolation of the cyclized product exclusively
(entries 3-15). Under the indium(III) trichloride conditions,
addition of p-toluenesulfonic acid (TsOH) and continued
reflux after the isomerization was complete gave good yields
of the corresponding THP (entry 3). Additional studies
revealed that the procedure could be reduced to one step by
including a stronger Brønsted acid during the isomerization
(entries 5-13). The essential role of the indium cocatalyst
was revealed by adding high-to-stoichiometric amounts of
CSA without the indium cocatalyst; in these cases, the
Scheme 2. Facile Access to Cyclic Ethers
(7) For reviews, see: (a) Pu, L. Tetrahedron 2003, 59, 9873. (b) Pu, L.;
Yu, H. B. Chem. ReV. 2001, 101, 757. Recent advances: (c) Xu, Z.; Mao,
J.; Zhang, Y. Org. Biomol. Chem. 2008, 6, 1288. (d) Asano, Y.; Hara, K.;
Ito, H.; Sawamura, M. Org. Lett. 2007, 9, 3901. (e) Yang, F.; Xi, P.; Yang,
L.; Lan, J.; Xie, R.; You, J. J. Org. Chem. 2007, 72, 5457. (f) Hsieh, S.-H.;
Gau, H.-M. Synlett 2006, 12, 1871.
We anticipated that this method would form THPs with high
diastereoselectivity, given the thermodynamic preference for
cis- over trans-substitution in 2,6-disubstituted THPs, and
form THFs with reduced diastereoselectivity.2,10,11
(8) Trost, B. M.; Weiss, A. H.; Jacobi von Wangelin, A. J. Am. Chem.
Soc. 2006, 128, 8.
(9) (a) Brown, C. A.; Yamashita, A. J. Am. Chem. Soc. 1975, 97, 891.
(b) Midland, M. M.; Halterman, R. L.; Brown, C. A.; Yamaichi, A.
Tetrahedron Lett. 1981, 22, 4171.
(5) (a) Trost, B. M.; Livingston, R. B. J. Am. Chem. Soc. 1995, 117,
9586. (b) Trost, B. M.; Livingston, R. B. J. Am. Chem. Soc. 2008, 130,
11970.
(10) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry Part
A, 3rd ed.; Plenum Press: New York, 1990; Chapter 3.
(6) While preparing the current manuscript, this was demonstrated by
our group with nitrogen nucleophiles: Trost, B. M.; Maulide, N.; Livingston,
R. C. J. Am. Chem. Soc. 2008, 130, 16502.
(11) Similar diastereoselectivities have been observed by ourselves and
others in the formation of saturated heterocycles under thermodynamic
conditions: Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 10819.
2540
Org. Lett., Vol. 11, No. 12, 2009

reaction failed to reach quantitative conversion (entries 7 and
8). Further examination of cocatalysts revealed that in-
dium(III) triflate could be used in significantly lower amounts
(entries 9-13) than indium(III) trichloride (entries 3-6) to
achieve higher conversion with shorter reaction times.
Replacing indium triflate with silver triflate slowed down
the reaction significantly and typically led to inferior results
(entries 14 and 15). Ultimately, the indium(III) triflate
conditions proved capable of effecting the tandem isomer-
ization and cyclization in good yields with low loadings of
all components (entry 13). Thus, with 3% indium(III) triflate
and 20% CSA, 12 could be obtained as the sole product. As
anticipated, the product THP was formed with complete
selectivity for the cis diastereomer (eq 1).12
conjugate acceptors, furnishing THPs with pendant ketone
moieties in high yields (entries 3-6). Keto-ether 15b was
formed from 15a in 71% yield (entry 3). Bicyclic products
such as 14b and 16b were obtained in moderate to high yields
(50% and 85%, entries 2 and 4) and excellent dr (>40:1).
Ynols containing pendant alkynes were also tolerated,
providing cyclized products in high yields (entries 5 and 6).
We were pleased to find the electrophilic ynoate moiety
present in 18a and 18b was maintained; products derived
from conjugate addition to the pendant alkyne were not
observed.
To investigate the formation of tetrahydrofurans using this
method, 19a was prepared and subjected to the optimized
reaction conditions; as expected, THF 19b was formed in
77% yield (Table 3, entry 1). Sterically unencumbered esters
Table 3. Scope of Redox Isomerization-Conjugate Addition in
the Formation of Tetrahydrofuransa
Employing these optimized conditions, we were able to
construct a variety of functionalized tetrahydropyrans (Table
2). As demonstrated by 12 and 14b, aldehyde acceptors are
transformed in good yields to the corresponding THPs
(entries 1 and 2). In addition to enals, enones are competent
Table 2. Scope of Redox Isomerization-Conjugate Addition in
the Formation of Tetrahydropyransa
a All reactions run as in eq 1.
were also compatible; ester-ynol 20a formed THF 20b in
77% yield (entry 2). To examine the inherent diastereose-
lectivity in the formation of tetrahydrofurans, 21a was
synthesized and tested. While 21b was formed in an excellent
72% yield, cyclization occurred without the diastereocontrol
observed for the THPs (entry 3). This can be ascribed to the
reduced energy difference between the cis- and trans-2,5-
disubstituted THF system, as compared to the analogous cis-
and trans-2,6-disubstituted THP system.
a All reactions run as in eq 1 for a period of 2 h unless otherwise stated.
b Reaction run for 4 h with 40% CSA.
We were pleased to find that substrates such as 22a, a
1,6-enyne, and 23a, a 1,6-diyne, were tolerated (entries 4
Org. Lett., Vol. 11, No. 12, 2009
2541

and 5). This is particularly impressive as the two points of
unsaturation in the substrate are positioned so that they might
tightly bind to the cationic ruthenium catalyst in a bidentate
fashion and prevent catalyst turnover. When 24a was exposed
to the redox isomerization conditions, a mixture of linear
and cyclized products was obtained, albeit in 73% overall
yield (eq 2). We had surmised that the strained 6,5-ring
system might be difficult to form, and it was therefore not
surprising that the linear product 24b was favored over THF
24c, in contrast to the 6,6-trans-fused system (Table 2, entry
Unfortunately, efforts to form oxepanes via the isomeriza-
tion-conjugate addition sequence did not generate the
desired cyclic products. Extended reaction times and higher
acid loadings did not effect the cyclization; only the linear,
isomerized product 26b was isolated from diol 26a in 67%
yield (eq 5).
1
2). While the H NMR spectrum of the crude reaction
The tandem redox isomerization-O-conjugate addition
allows for the facile construction of THFs and THPs from
readily accessible starting materials. The reaction is simple,
robust, and exceptionally mild, a quality demonstrated by
its tolerance of a wide variety of functional groups. Low
catalyst loadings and short reaction times further enhance
the utility of this transformation. Additionally, the cyclic
ethers derived from this sequence contain a pendant carbonyl
that can be used for further elaboration. Currently our efforts
are focused on improving the diastereoselectivity of the
reaction to form disubstituted THFs and investigations of
synthetic applications.
the ratio of cyclized to linear products to be 1:3.2, respec-
tively, only 9% of the cyclized product was isolated, along
with 64% of 24b. Doubling the reaction time increased the
ratio to 1:1.5 (cyclized/linear), concomitant with the forma-
tion of several decomposition products. The reluctance of
24b to undergo the conjugate addition could be overcome
by use of a two-step, one-pot protocol. Upon completion of
the redox isomerization (30 min), addition of ethylene glycol,
trimethyl orthoformate, and TsOH followed by continued
stirring at room temperature afforded acetal 25 in 67%
isolated yield (eq 3).
Acknowledgment. We thank the National Science Foun-
dation and the National Institutes of Health, General Medical
Sciences Institute (GM-13598), for their generous support
of our programs.
In an effort to determine the degree of catalyst participation
in the conjugate addition, linear product 24b was exposed
to 1 and indium(III) triflate in the absence of CSA. After
2 h, none of the cyclized product was observed (eq 4). In
contrast, treating 24b with catalytic CSA in the absence of
both 1 and indium(III) triflate resulted in conversion of 29%
of 24b to 24c. Thus, it is unlikely that the ruthenium catalyst
is involved in the cyclization event.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL9007876
(12) Diastereomer determined by diagnostic value of coupling constants
(J).
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Org. Lett., Vol. 11, No. 12, 2009