Synthesis of fused-ring and attached-ring bis-tetrahydrofurans via Pd-catalyzed carboetherification

Article abstract of DOI:10.1021/ol900594h

A five step-synthesis of fused bis-tetrahydrofurans and attached bis-tetrahydrofurans from butadiene diepoxide is described. Two sequential Pd-catalyzed carboetherification reactions between protected 1,2-diols and aryl/alkenyl bromides, each of which for

Full text of DOI:10.1021/ol900594h

ORGANIC
LETTERS
2009
Vol. 11, No. 10
2209-2212
Synthesis of Fused-Ring and
Attached-Ring bis-Tetrahydrofurans via
Pd-Catalyzed Carboetherification
Amanda F. Ward and John P. Wolfe*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue,
Ann Arbor, Michigan, 48109-1055
jpwolfe@umich.edu
Received March 20, 2009
ABSTRACT
A five step-synthesis of fused bis-tetrahydrofurans and attached bis-tetrahydrofurans from butadiene diepoxide is described. Two sequential
Pd-catalyzed carboetherification reactions between protected 1,2-diols and aryl/alkenyl bromides, each of which form both a C-O bond and
a C-C bond, are used to generate the heterocyclic rings with >20:1 dr. Installation of different R1 and R2 groups is achieved in a straightforward
fashion through use of different aryl or alkenyl bromide coupling partners.
A large number of interesting compounds contain attached-
ring or fused-ring tetrahydrofuran scaffolds (Figure 1). The
to human health (e.g., 3; antitumor activity)2 and agriculture
(e.g., 4; herbicide).3 Attached-ring tetrahydrofurans (2) are
displayed in a vast number of natural products, including
the annonaceous acetogenins,4 of which asimicin (5) is a
member.
A variety of different approaches have been developed
for the construction of these useful compounds.4,5 Many of
these strategies involve generation of the bis-tetrahydrofuran
framework via sequential (or tandem) ring-closing reactions
of 1,2-diols bearing pendant functional groups such as
alkenes, epoxides, alcohols, or allylic acetates/halides.6
Although these methods effectively form the heterocyclic
(2) Pinacho Crisostomo, F. R.; Padron, J. M.; Martin, T.; Villar, J.;
Martin, V. S. Eur. J. Org. Chem. 2006, 1910–1916.
Figure 1. Examples of biologically active bis-tetrahydrofurans.
(3) Kakimoto, T.; Koizumi, F.; Hirase, K.; Arai, K. J. Pestic. Sci. 2006,
31, 380–389.
(4) For recent reviews, see: (a) McLaughin, J. L. J. Nat. Prod. 2008,
71, 1311–1321. (b) Bermejo, A.; Figadere, B.; Zafra-Polo, M.-C.; Bar-
rachina, I.; Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269–303. (c)
Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504–
540.
2,6-dioxabicyclo[3.3.0]octane framework (1) is found in both
naturally occurring1 and synthetic molecules that are relevant
(1) (a) Suzuki, T.; Koizumi, K.; Suzuki, M.; Kurosawa, E. Chem. Lett.
1983, 1639–1642. (b) Suzuki, M.; Kurosawa, E. Phytochemistry 1985, 24,
1999–2002.
(5) For general reviews on the synthesis of tetrahydrofurans, see: (a)
Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261–290. (b) Harmange,
J.-C.; Figadere, B. Tetrahedron: Asymmetry 1993, 4, 1711–1754
.
10.1021/ol900594h CCC: $40.75
Published on Web 04/20/2009
 2009 American Chemical Society

ring, they do not allow the simultaneous construction of a
C-C bond. Thus, substituents attached to the tetrahydrofuran
C2-position, such as the side chains present in 3-5, must
be installed in separate steps either prior to or following ring-
closure.
oxide. We also prepared mono-TBS-protected10 derivatives
11 and 12 (Figure 2), as our prior studies indicated that
We felt that an alternative approach to the construction
of substituted fused-ring tetrahydrofurans with the general
structure 8 could be developed using sequential Pd-catalyzed
carboetherification reactions7,8 of unsaturated 1,2-diols such
as 6. As shown in Scheme 1, treatment of 6 with an aryl or
Figure 2. Protection of 1,2-diols.
Scheme 1. Synthetic Strategy
carboetherification reactions of mono-protected 1,2-diols are
often more efficient than transformations of the correspond-
ing unprotected diols.8
Preliminary attempts to effect selective monocyclization
of unprotected diols 6 and 9 provided unsatisfactory results
(Figure 3). Treatment of 6 with one equivalent of bromoben-
alkenyl halide in the presence of NaOtBu and a palladium
catalyst should provide 7, which could be converted to 8 in
a second catalytic transformation. This strategy could also
be applied to the synthesis of attached-ring tetrahydrofurans
(e.g., 9 to 10) by simply extending the tether between the
alcohols and the alkenes by one methylene unit. Importantly,
each carboetherification reaction would generate both a C-O
bond (to form the heterocylic ring) and a C-C bond, thus
providing a more concise approach to substituted bis-
tetrahydrofurans compared to currently available methods.
To examine the feasibility of the strategy outlined above,
we elected to examine the selective monocyclization of
known diols 66i and 9,9 which can be generated by Cu-
catalyzed addition of vinylmagnesium bromide or allylmag-
nesium bromide to commercially available butadiene diep-
Figure 3. Attempted monocyclization of 1,2-diols.
zene under our standard carboetherification conditions (NaOt-
Bu, cat. Pd2(dba)3/Dpe-Phos)11 afforded mixtures of bis-
cyclized product 13 and unreacted starting material. Treatment
of 6 with four equivalents of bromobenzene led to complete
consumption of starting material and the formation of 13
with >20:1 dr, albeit in only 30% yield. Efforts to achieve
monocyclization of 9 did lead to the formation of desired
tetrahydrofuran 14, but yields were low and isomerization
of the second alkene was problematic. Use of excess aryl
halide in this reaction failed to generate significant amounts
of the bis-tetrahydrofuran target, and instead provided an
81% combined yield of 14 and inseparable alkene isomers.
Although carboetherification reactions of 6 and 9 were
generally ineffective, transformations of TBS-protected
substrates 11 and 12 proceeded smoothly. As shown in Table
1, treatment of 11 with an aryl bromide in the presence of
NaOtBu and a catalyst composed of Pd2(dba)3 and Dpe-Phos
provided tetrahydrofurans 15 in good yields with excellent
diastereoselectivities. Cleavage of the silyl ether protecting
group was achieved under standard conditions, and carbo-
(6) For representative examples of attached-ring tetrahydrofuran syn-
thesis, see: (a) Li, P.; Wang, T.; Emge, T.; Zhao, K. J. Am. Chem. Soc.
1998, 120, 7391–7392. (b) Hoye, T. R.; Ye, Z. J. Am. Chem. Soc. 1996,
118, 1801–1802. (c) Wysocki, L. M.; Dodge, M. W.; Voight, E. A.; Burke,
S. D. Org. Lett. 2006, 8, 5637–5640. (d) Marshall, J. A.; Sabatini, J. J.
Org. Lett. 2006, 8, 3557–3560, references cited therein. (e) Carlisle, J.;
Fox, D. J.; Warren, S. Chem. Commun. 2003, 2696–2697. (f) Sinha, A.;
Sinha, S. C.; Keinan, E. J. Org. Chem. 1999, 64, 2381–2386. (g)
Beauchamp, T. J.; Powers, J. P.; Rychnovsky, S. D. J. Am. Chem. Soc.
1995, 117, 12873–12874. For representative examples of fused-ring
tetrahydrofuran synthesis, see: (h) Reference 2. (i) Wang, J.; Pagenkopf,
B. L. Org. Lett. 2007, 9, 3703–3706. (j) Duclos, A.; Fayet, C.; Gelas, J.
Synthesis 1994, 1087–1090
(7) For reviews see: (a) Wolfe, J. P. Eur. J. Org. Chem. 2007, 571–
582. (b) Wolfe, J. P. Synlett 2008, 2913–2937
.
.
(8) (a) Wolfe, J. P.; Rossi, M. A. J. Am. Chem. Soc. 2004, 126, 1620–
1621. (b) Hay, M. B.; Hardin, A. R.; Wolfe, J. P. J. Org. Chem. 2005, 70,
3099–3107. (c) Hay, M. B.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127,
16468–16476. (d) Hay, M. B.; Wolfe, J. P. Tetrahedron Lett. 2006, 47,
2793–2796
.
(9) Baylon, C.; Heck, M.-P.; Mioskowski, C. J. Org. Chem. 1999, 64,
3354–3360.
(10) Essenfeld, A. P.; Gillis, H. R.; Roush, W. R. J. Org. Chem. 1984,
49, 4674–4682.
(11) Dpe-Phos ) bis(2-diphenylphosphinophenyl)ether.
Org. Lett., Vol. 11, No. 10, 2009
2210

Table 1. Stepwise Synthesis of Fused Tetrahydrofuransa
entry
R1
yield 15 (%)b
yield 16
R2
p-F3CPh
p-PhC(O)Ph
3-pyridyl
m-MeOPh
p-PhPh
2-naphthyl
(E)-ꢀ-styryl
6-MeO-2-naphthyl
yield 8 (%)b
overall yield (%)c
1
2
3
4
5
6
7
8
Ph
86
92
86
94
91
81
87
85
67
89
68
74
75
67
43
54
27
36
p-Tol
91
71
44
91
90
92
p-tBuPh
p-PhC(O)Ph
a Conditions: Steps 1 and 3: 1.0 equiv 11 or 16, 2.0 equiv ArBr, 2.0 equiv NaOtBu, 2 mol % Pd2(dba)3, 4 mol % Dpe-Phos, THF, 65 °C. Step 2: 1.0
equiv 15, 10 equiv TBAF, THF, rt. b Isolated yields (average of two or more experiments). All products were obtained with >20:1 dr. c Yield obtained over
the three step sequence from 11 to 8.
etherification of the resulting alcohols 16 provided fused
tetrahydrofurans (8) as single stereoisomers (>20:1 dr). Both
cyclizations led to products that are trans-2,5-disubstituted
around the tetrahydrofuran ring(s), which is consistent with
our previously reported observations and stereochemical
models for the conversion of γ-hydroxy alkenes to tetrahy-
drofurans.8
broader, and a number of different aryl bromides were
effectively coupled. In addition, use of ꢀ-bromostyrene in
the second transformation was also successful (entry 7).
Diastereoselectivities were uniformly high in all of the
carboetherification reactions (>20:1 dr), and in many cases
the overall yield of 8 exceeded 50% over the three-step
sequence.
The first carboetherification reaction in this sequence (11
to 15) was sensitive to the electronic properties of the aryl
bromide, and the best yields were obtained with electron-
neutral substrates (entries 1-6). However, the scope of the
second carboetherification reaction (16 to 8) was much
The synthesis of attached-ring bis-tetrahydrofurans was
achieved by subjecting protected diol 12 to an analogous
sequence of carboetherification (12 to 17), deprotection (17
to 18), and carboetherification (18 to 10). As observed in
the transformations of 11, the scope of the second carboet-
Table 2. Stepwise Synthesis of Attached Tetrahydrofuransa
entry
R1
yield 17 (%)b
yield 18 (%)b
R2
yield 10 (%)b
overall yield (%)c
1
2
3
4
5
6
7
8
p-tBuPh
73
89
p-Tol
p-PhPh
3-pyridyl
2-naphthyl
p-F3CPh
p-PhC(O)Ph
3,5-Cl2Ph
6-MeO-2-naphthyl
64
63
54
61
75
72
71
53
42
41
35
40
44
42
37
28
Ph
72
64
55
91
91
96
m-MeOPh
p-MeOPh
a Conditions: Steps 1 and 3: 1.0 equiv 12 or 18, 2.0 equiv ArBr, 2.0 equiv NaOtBu, 2 mol % Pd2(dba)3, 4 mol % Dpe-Phos, Toluene or THF, 65 or 110
°C. Step 2: 1.0 equiv 17, 10 equiv TBAF, THF, rt. b Isolated yields (average of two or more experiments). All products were obtained with >20:1 dr. c Yield
obtained over the three step sequence from 12 to 10.
Org. Lett., Vol. 11, No. 10, 2009
2211

herification step is considerably broader than the first (with
respect to the aryl bromide component). Yields of attached-
ring tetrahydrofurans were slightly lower than the corre-
sponding fused-ring products described above. However,
diastereoselectivities were excellent, and all products were
obtained with >20:1 dr favoring 2,5-trans-stereochemistry
around both tetrahydrofuran rings.
Scheme 2
.
Synthesis of a Highly Substituted
bis-Tetrahydrofuran
To further probe the synthetic utility of these transforma-
tions, we sought to determine if nonracemic starting materials
could be converted to bis-tetrahydrofuran products without
loss of enantiomeric purity. To this end, (-)-12 was prepared
in 96% ee via asymmetric dihydroxylation of commercially
available trans-1,5,9-decatriene12 followed by mono-TBS-
protection of the resulting diol. This substrate was converted
to (-)-10h using a sequence of reactions identical to that
shown in Table 2, entry 8, and the product was obtained
with >20:1 dr and 95% ee (Figure 4).
In conclusion, we have developed a concise approach to
the construction of both attached-ring and fused-ring bis-
tetrahydrofurans using sequential Pd-catalyzed carboetheri-
fication reactions. This strategy allows for preparation of
derivatives bearing different substituents at the 2-position
of each tetrahydrofuran ring, and provides access to deriva-
tives that could not be easily generated with existing methods.
Further studies on the application of these reactions to the
synthesis of natural products and molecules of medicinal
interest are currently underway.
Figure 4. Synthesis of an enantioenriched bis-tetrahydrofuran.
Acknowledgment.WethanktheNIH-NIGMS(GM071650)
for financial support of this work. Additional support was
provided by the Camille and Henry Dreyfus Foundation
(Camille Dreyfus Teacher Scholar Award), GlaxoSmithKline,
Eli Lilly, Amgen, and 3M. We also thank Ms. Jody Canapp
for performing preliminary experiments in this area.
The synthesis of more elaborate tetrahydrofuran products
is also feasible using this method. For example, protected
tetraol derivative 19 was generated from D-mannitol using
standard transformations.13 This substrate was converted to
bis-tetrahydrofuran 22 with >20:1 dr using the same reaction
sequence described above (Scheme 2).
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of 1H and 13C NMR
spectra for all new compounds reported in the text. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Braddock, D. C.; Cansell, G.; Hermitage, S. A.; White, A. J. P.
Tetrahedron: Asymmetry 2004, 15, 3123–3129.
(13) (a) Kajiwara, M.; Miyazawa, M.; Nakazawa, M.; Shimayama, T.;
Takatori, K.; Takahashi, T.; Yamada, H. Tetrahedron Lett. 1992, 33, 5973–
5976. (b) Depezay, J. C.; Dure´ault, A.; LeMerrer, Y.; Greck, C.; Micas-
Languin, D.; Gravier, C. Heterocycles 1987, 25, 541–548.
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