Diastereoselective synthesis of 2H,5H-dihydrofurans by cobalt-mediated cycloisomerization of allyl propargyl ethers. Application to poly-THF molecules

Article abstract of DOI:10.1021/ol016768l

(Matrix Presented) Allyl propargyl ethers undergo cobalt-mediated cycloisomerization reactions to form dihydrofurans in good yield and with excellent diastereoselectivity. The reaction works with a range of substrates, and its utility in synthesis is exem

Full text of DOI:10.1021/ol016768l

ORGANIC
LETTERS
2
001
Vol. 3, No. 26
161-4164
Diastereoselective Synthesis of
H,5H-Dihydrofurans by Cobalt-Mediated
4
2
Cycloisomerization of Allyl Propargyl
Ethers. Application to Poly-THF
Molecules
Alain Ajamian and James L. Gleason*
Department of Chemistry, McGill UniVersity, 801 Sherbrooke St. West,
Montreal, QC, Canada H3A 2K6
jim@gleason.chem.mcgill.ca
Received September 17, 2001
ABSTRACT
Allyl propargyl ethers undergo cobalt-mediated cycloisomerization reactions to form dihydrofurans in good yield and with excellent
diastereoselectivity. The reaction works with a range of substrates, and its utility in synthesis is exemplified by the preparation of a
bistetrahydrofuran unit.
Tetrahydrofurans are a common subunit found in many
bioactive natural products. They are prevalent in the poly-
Scheme 1
1
ether ionophore antibiotics and in the annonaceous aceto-
2
genins. Numerous pathways for their synthesis have been
3
developed, and in recent years much work has focused on
metal-mediated approaches. Many of the metal-mediated
4
processes, including those which utilize ruthenium, rhe-
5
6
nium, and chromium oxo species, are based on oxidative
cyclizations of bishomoallylic alcohols and 1,5 dienes.
Recently, we reported a cobalt-mediated cycloisomeriza-
tion of 1,6-enynes that produces vinylcyclopentenes in high
7
yield with excellent diastereoselectivity (Scheme 1). The
reaction proceeds by an oxidative insertion into an allylic
(
1) Westley, J. W. Polyether Antibiotics: Naturally Ocurring Acid
Ionophores; Marcel Dekker: New York, 1982; Vols. I and II.
2) (a) Rupprecht, J. K.; Hui, Y.-H.; McLaughlin, J. L. J. Nat. Prod.
1
1
C-H bond to form an allylcobalt hydride (e.g., 2), followed
by sequential C-C and C-H reductive eliminations to form
the cyclopentene 3. In this letter, we report that this novel
cycloisomerization may be extended to the highly diaste-
reoselective preparation of 2H,5H-dihydrofurans. The reac-
tion provides ready access to the corresponding tetrahydro-
furans and is amenable to poly-THF synthesis.
(
990, 53, 237. (b) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod.
999, 62, 504.
(3) For reviews on tetrahydrofuran synthesis, see: (a) Boivin, T. L. B.
Tetrahedron 1987, 43, 3309. (b) Harmange, J.-C.; Figad e` re, B. Tetra-
hedron: Asymmetry 1993, 4, 1711. (c) Koert, U. Synthesis 1995, 115.
(4) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
Chem. 1981, 46, 3936.
1
0.1021/ol016768l CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/28/2001

We began the study of dihydrofuran synthesis using the
allyl propargyl ether 5, which is readily prepared from
cyclohexane carboxaldehyde in two steps. Treatment of 5
under the standard conditions developed for 1, namely,
the cyclization of 1, no alkene isomerization was observed.
However, this may be due to decomposition of the enol ether,
which would be formed by such an isomerization, under the
reaction conditions.
addition of Co
2
(CO)
8
(1.1 equiv) to a solution of 5 in toluene
The method was found to work well with a series of allyl
propargyl ethers (Scheme 2). Notably, in all cases only the
followed by thermolysis under an argon atmosphere, failed
to provide any characterizable products. In contrast, when
the reaction was conducted at 65 °C for 24 h, dihydrofuran
6
was produced as a single diastereomer in a modest 40%
Scheme 2
yield (Table 1). Allowing the reaction to go for longer periods
Table 1. Optimization of 2H,5H-dihydrofuran Formationa
entry solvent temp (°C) atmosphere additiveb yield (%)
1
2
3
4
5
6
7
8
PhMe
PhMe
PhH
DME
DME
DME
DME
DME
110
65
80
85
85
85
85
85
argon
argon
argon
argon
argon
air
0
40
5
40
63
45
58
65
NMO
air
air
NMO
TBHP
a
All reactions were conducted with 1.1 equiv of Co2(CO)8 for 24 h.
b
In all cases, 3.3 equiv of additive were used.
of time resulted in a decreased yield, presumably as a result
of decomposition of the product. Equivalent yields were
obtained if the reaction was conducted at reflux in 1,2-DME,
while very little reaction was observed in benzene at reflux.
The yield of the reaction could be improved by adding an
oxidant such as N-methylmorpholine-N-oxide or tert-butyl-
hydroperoxide (3.3 equiv) to a solution of the cobalt complex
8
in DME prior to thermolysis. The use of excess NMO (>4
equiv) in DME produces significant amounts of the Pauson-
Khand product, even at room temperature. In contrast, even
a large excess of TBHP (>10 equiv) produces only traces
of Pauson-Khand products, making it the oxidant of choice
for this reaction. Conveniently, it was found that the reaction
proceeds in air with no significant change in either yield or
stereoselectivity. The yields using this procedure are com-
parable to those obtained in the carbocyclization of 1. Unlike
trans-diastereomer was observed. The stereochemical as-
signment was made by observation of weak NOEs between
the 5-position and the vinyl group (Figure 1) and was further
substantiated by the lack of any NOE between the protons
at the 2- and 5-positions of the dihydrofuran. As with the
previous carbocyclization reaction, the dihydrofuran cycliza-
tion only proceeds with silyl-protected acetylenes. Use of
an internal alkyne pushes the reaction down the more
conventional Pauson-Khand pathway (e.g., 15 f 16).
To explore the utility of this cyclization, we sought to
utilize the dihydrofuran products in a synthesis of a simple
bis-THF unit (Scheme 3). This would require the removal
of the trimethylsilyl group, hydrogenation of the endocyclic
(5) (a) Kennedy, R. M.; Tang, S. Tetrahedron Lett. 1992, 33, 3729. (b)
Tang, S.; Kennedy, R. M. Tetrahedron Lett. 1992, 33, 5299. (c) Tang, S.;
Kennedy, R. M. Tetrahedron Lett. 1992, 33, 5303. (d) Boyce, R. S.;
Kennedy, R. M. Tetrahedron Lett. 1994, 35, 5133. (e) McDonald, F. E.;
Towne, T. B. J. Org. Chem. 1995, 60, 5750. (f) Sinha, S. C.; Sinha-Bagchi,
A.; Keinan, E. J. Am. Chem. Soc. 1995, 117, 1447. (g) Towne, T. B.;
McDonald, F. E. J. Am. Chem. Soc. 1997, 119, 6022. (h) Sinha, S. C.;
Keinan, E.; Sinha, S. C. J. Am. Chem. Soc. 1998, 120, 9076.
(
6) (a) Hammock, B. D.; Gill, S. S.; Casida, J. E. J. Agric. Food Chem.
1
974, 22, 379. (b) Walba, D. M.; Stoudt, G. S. Tetrahedron Lett. 1982, 23,
7
27.
(7) Dolaine, R.; Gleason, J. L. Org. Lett. 2000, 2, 1753.
(
8) Shambayani, S.; Crowe, W. E.; Schreiber, S. L. Tetetrahedron Lett.
1
990, 31, 5289.
4162
Org. Lett., Vol. 3, No. 26, 2001

(51%), possibly owing to reduced selectivity in the oxidation
of the diene. Some improvement was realized when the
oxidation was conducted using Sharpless’ asymmetric di-
hydroxylation conditions. Thus, treatment of 17 with AD-
mix-R at room temperature for 23 h afforded a 59% yield
9
of the diol.
Hydrogenation of the remaining olefin in 18 proved to be
less than straightforward. Isomerization of the double bond
was observed under standard conditions (Pd(OH)
(1 atm)), leading to a 1:1 mixture of the cis- and trans-
tetrahydrofurans. After examining several sets of conditions
and catalysts, it was found that using PtO as catalyst under
5 psi H provided the tetrahydrofuran in 99% overall yield
with less than 4% of the cis-tetrahydrofuran being formed.
To set the stage for the second cycloisomerization reaction,
the diol was cleaved to the corresponding aldehyde with
2
/C, EtOAc,
Figure 1. Observed NOE signals in 6.
H
2
2
alkene, and transformation of the acyclic alkene into a new
allyl propargyl ether. Direct oxidation of the terminal alkene
proved to be difficult. Ozonolysis of 6 did not lead to the
desired aldehyde, and dihydroxylation was sluggish owing
to the proximity of the trimethylsilyl group. In the end, after
conducting the dihydroxylation at reflux in acetone with
4
2
4
NaIO . Addition of the Grignard reagent formed from lithium
trimethylsilylacetylide and magnesium bromide etherate
proceeded cleanly and in high yield. However, under the best
4
NMO and catalytic OsO , only a 36% yield of the dihy-
droxylated product could be obtained. To remove the steric
hindrance to oxidation, the silyl group was removed by
treatment with TBAF (6 equiv) in THF at reflux for 6 h,
affording diene 17 in 99% yield. Dihydroxylation of 17 was
much more facile, proceeding to completion within 4 h at
room temperature. The yield of isolated diol was still modest
2 2
conditions found (5 equiv MgBr , -40 °C, Et O), the
stereoselectivity of the addition was only modest, ranging
from 1.5 to 2.5:1. As expected, the major product resulted
1
0
from a Cram-chelate attack on the aldehyde. Use of the
corresponding triisopropoxy-titanium reagent gave a modest
1
1
reversal of selectivity (1:2), whereas other metals such as
zinc and lithium gave no selectivity whatsoever. The mixture
of alcohols could be oxidized to a single ketone with Dess-
Martin periodinane in 92% yield. However reduction with a
Scheme 3
4 4 2 3
series of reducing agents such as NaBH , Zn(BH ) , LiBHEt ,
and L-Selectride gave no significant improvement in dia-
stereoselectivity relative to the Grignard reaction.
Direct separation of the alcohol diastereomers 19a and b
proved impossible by chromatography. However, conversion
to the corresponding dicobalt hexacarbonyl complexes al-
f
lowed a very easy separation by chromatography (R differ-
ence of 0.2 in 10% EtOAc/hexanes). After separation of the
isomers, the cobalt could be removed by oxidation with
NMO to afford the alcohols 19a and 19b, with a mass
balance of 95%. In several cases, we have found that the
formation of cobalt complexes allows facile separation of
diastereomeric propargylic alcohols (e.g., precursor to 13).
This may prove to be a general method for separating this
class of stereoisomers.
Allylation of the major addition product, 19a, with
n-butyllithium and allyl bromide proceeded in 70% yield.
Finally, subjection of the allyl ether to the cycloisomerization
conditions defined above readily furnished the diether 20a
in 55% yield. A similar sequence with 19b afforded 20b,
also in good yield. Both reactions proceeded with complete
stereocontrol, and NOE studies again confirmed that both
(
9) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
994, 94, 2483.
10) The stereochemistry of 19a and b was determined by coupling
1
(
constant analysis, which has been shown to be reliable for this class of
compounds. See: (a) Horton, D.; Tronchet, J. M. J. Carbohydr. Res. 1966,
2
3
1
, 315. (b) Horton, D.; Hughes, J. B.; Thomson, J. K. J. Org. Chem. 1968,
3, 728. (c) Grese, T. A.; Hutchinson, K. D.; Overman, L. E. J. Org. Chem.
993, 58, 2468.
(11) Reetz, M. T. Organotitanium Reagents in Organic Synthesis;
Springer: Berlin, 1986. See also ref 11c and Tabusa, F.; Yamada, T.; Suzuki,
K.; Mukaiyama, T. Chem. Lett. 1984, 405.
Org. Lett., Vol. 3, No. 26, 2001
4163

reactions afforded the trans-stereoisomers. Thus, the method
can be used for the preparation of both trans-syn-trans and
trans-anti-trans polyethers.
Acknowledgment. Financial support for this work from
NSERC is gratefully acknowledged.
In conclusion, we have developed a method for the
formation of polytetrahydrofurans in good yield and with
excellent diastereoselectivity using a cobalt-mediated cy-
cloisomerization of allyl propargyl ethers. The method
compliments other metal-mediated methods for the formation
of tetrahydrofurans and should find utility in the total
synthesis of poly-THF containing molecules.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL016768L
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Org. Lett., Vol. 3, No. 26, 2001