Synthesis of polysubstituted tetrahydrofurans via Pd-catalyzed carboetherification reactions

Article abstract of DOI:10.1016/j.tetlet.2006.02.066

Pd-catalyzed carboetherifications of 1-, 2-, or 3-substituted γ-hydroxy internal alkenes afford tetrahydrofuran products bearing three stereocenters in good yield with moderate to good stereoselectivity.

Full text of DOI:10.1016/j.tetlet.2006.02.066

Tetrahedron Letters 47 (2006) 2793–2796
Synthesis of polysubstituted tetrahydrofurans via Pd-catalyzed
carboetherification reactions
Michael B. Hay and John P. Wolfe*
University of Michigan, Department of Chemistry, 930 North University Avenue, Ann Arbor, MI 48109-1055, USA
Received 31 January 2006; accepted 10 February 2006
Available online 3 March 2006
Abstract—Pd-catalyzed carboetherifications of 1-, 2-, or 3-substituted c-hydroxy internal alkenes afford tetrahydrofuran products
bearing three stereocenters in good yield with moderate to good stereoselectivity.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Multiply substituted tetrahydrofuran moieties are found
in a broad array of biologically active molecules and
natural products.1 In many of these molecules, including
the antifungal agents gambieric acids A–D,2 the antipara-
sitic agent tetronasin (1),3 and the cytotoxic agent
simplakidine A (2),4 stereocenters are displayed both
around and also adjacent to the tetrahydrofuran ring.
Thus, the development of methods that provide stereo-
controlled access to polysubstituted tetrahydrofurans is
of significant importance, and many strategies have been
explored for the construction of such molecules.5 How-
ever, few methods allow for the generation of the hetero-
cyclic ring with simultaneous formation of a C–O bond,
a C–C bond, and control of relative stereochemistry be-
tween two ring stereocenters and one exocyclic stereo-
center.6 Moreover, the applicability of these methods
to the generation of 2-benzyl or 2-allyl tetrahydrofuran
moieties of the type found in 1 and 2 has not been
demonstrated.6
We have recently developed a new method for the stereo-
selective synthesis of substituted tetrahydrofurans via
Pd-catalyzed carboetherification reactions of c-hydroxy-
alkenes with aryl bromides.7,8 These transformations
lead to ring closure with generation of a C–O bond, a
C–C bond, and up to two stereocenters in a single step.
We have found that transformations of acyclic internal
alkene substrates provide products resulting from syn-
addition of the arene and the oxygen atom across the
double bond with diastereoselectivities of ca. 5:1 (Eq.
1). In addition, reactions of terminal alkene substrates
bearing substituents at the 1-, 2-, or 3-position afford
disubstituted tetrahydrofurans with diastereoselectivities
up to >20:1 (Eq. 2). Thus, these transformations have
the potential to provide highly substituted tetrahydro-
furan products from simple substrates in a stereocon-
trolled fashion.
O
O
OH
H
O
1
H
OH
O
O
ArBr
H
O
H
H
H
H
OMe
Pd2(dba)3/P(o-tol)3
O
OH
NaOtBu, Tol, 110 oC
ð1Þ
ð2Þ
Ar
CO H
2
syn-addition
~5:1 dr
2
O
–
H
C
OH
OH
1
2
ArBr
2
3
O
2
Pd2(dba)3/DPE-Phos
N
Me
5
+
R
Ar
R
3
2,5-trans: >20:1 dr
2,3-trans: 3–8:1 dr
2,4-cis: 1.5–2:1 dr
*
Corresponding author. Tel.: +1 734 763 3432; fax: +1 734 615
3790; e-mail: jpwolfe@umich.edu
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.066

2794
M. B. Hay, J. P. Wolfe / Tetrahedron Letters 47 (2006) 2793–2796
Although transformations of simple alcohols such as
those shown in Eqs. 1 and 2 provided efficient access
to tetrahydrofuran derivatives bearing two stereocen-
ters, many key questions about the applicability of this
methodology to more complex systems remained unans-
wered. It was not clear that substrates containing both
an internal alkene and a substituent at C1, C2, or C3
would still afford products derived from syn-addition
with synthetically useful levels of selectivity, or whether
increased substitution would lead to a change in reac-
tion mechanism to afford products resulting from anti-
addition. In this letter we describe our preliminary
studies on the stereoselective synthesis of tetrahydrofuran
products bearing three stereocenters via Pd-catalyzed
carboetherification reactions of c-hydroxy alkenes with
aryl bromides. These studies illustrate the potential util-
ity of this methodology for the construction of complex
heterocyclic molecules, and further support our stereo-
chemical and mechanistic model for the carboetherifica-
tion process.
(entries 3 and 6). Transformations of b-bromostyrene
also afforded substituted tetrahydrofurans in good
yields with useful levels of stereoselectivity (entries 4
and 7).
In our previous studies on carboetherification reactions
of substrates bearing terminal alkenes and substituents
at C2 we observed that cis-2,4-disubstituted tetra-
hydrofurans were formed in very good yield, but with
low diastereoselectivity (ca. 2:1).7a,b This modest selec-
tivity was also observed in reactions of 2-substituted
alcohols 16 and 21, which contain internal alkene moie-
ties. As shown in Eq. 4, treatment of 16 with b-bromo-
styrene under our standard reaction conditions afforded
a 65:17:14:4 mixture of diastereomers. As expected, the
major product (17) resulted from syn-addition and con-
tained a cis-2,4-disubstituted tetrahydrofuran ring. Simi-
lar results were obtained in the cyclization of Z-alkene
substrate 21 (Eq. 5).
Ph
Ph
Ph
Ph
Ph
OH
In a representative experiment, we examined the reac-
tion of E-2-phenylhept-5-en-2-ol 3 (1.0 equiv) with 1-
bromo-4-tert-butylbenzene (2.0 equiv) in the presence
of NaOt-Bu (2.0 equiv) and catalytic amounts of
Pd2(dba)3 (1 mol%) and P(o-tol)3 (4 mol%).9 These reac-
tion conditions were derived from our earlier studies on
Pd-catalyzed carboetherification reactions of internal
alkenes.7c As shown in Eq. 3, this transformation pro-
vided a 75:25 mixture of tetrahydrofurans 4 and 5 in
74% yield.10 Both diastereomers contained a trans-2,5-
disubstituted tetrahydrofuran ring, and the major dia-
stereomer derives from syn-addition across the alkene.11
Br
Pd2(dba)3/P(o-tol)3
+
+
+
NaOtBu, Tol,110 oC
O
O
O
O
65:17:14:4
81%
16
17
18
19
20
ð4Þ
Ph
Ph
Ph
Ph
Ph
OH
Br
Pd2(dba)3/P(o-tol)3
+
+
+
NaOtBu, Tol, 110 oC
58:24:10:8
O
O
O
O
21
OH
4-t-BuC6H4Br
77 %
H
H
Me
Ph
19
20
17
18
Ph
Me
Ph
Pd2(dba)3/P(o-tol)3
O
O
+
Ar
Ar
NaOtBu, Tol., 110 oC
74%, 75:25
ð5Þ
3
4
5
Ar = 4-t-BuC6H4
The stereochemical outcome of the reactions described in
Eqs. 3–5 and Table 1 is consistent with our previously re-
ported mechanistic hypothesis.7 As shown in Scheme 1,
oxidative addition of the aryl halide to Pd(0) would
generate 22, which could undergo transmetalation
with the in situ generated sodium alkoxide to afford
palladium(aryl)alkoxide complex 23.13 syn-Oxypalla-
dation7,14 would provide 24, which could undergo
carbon–carbon bond-forming reductive elimination to
generate the observed product. The relative stereochem-
istry between C2 and C10 would derive from the syn-oxy-
palladation step,7a,c whereas the stereochemistry around
the tetrahydrofuran ring is likely controlled by a prefer-
ence for pseudoequatorial orientation of bulky substitu-
ents in the transition state between 23 and 24.7a,b
ð3Þ
With this result in hand, we proceeded to examine the
Pd-catalyzed reactions of several different unsaturated
alcohols bearing stereocenters at C-1 or C-3 with vari-
ous aryl bromides. The results of these experiments are
shown in Table 1. As expected, the transformations
proved to be both stereoselective and stereospecific.
For example, the reaction of E-alkene 3 with 1-bromo-
4-tert-butylbenzene afforded 4 as the major product
(Eq. 3), whereas the analogous reaction of Z-alkene 6
provided 5 as the predominant isomer (entry 2). Similar
stereospecificity was observed in reactions of 3-substi-
tuted substrates 7 and 8 (entries 3–8). However, in con-
trast to reactions of 3 and 6, which provided only two
isomeric products, transformations of 7 and 8 gave more
complex mixtures of stereoisomers along with small
amounts (ca. 1–3%) of unidentified isomeric products.12
In all cases examined, the major products resulted from
syn-addition across the double bond, and contained the
expected 2,5-trans- or 2,3-trans-tetrahydrofuran stereo-
chemistry. Similar yields and selectivities were obtained
with a number of different aryl halides including deriva-
tives that were heterocyclic (entry 1) or o-substituted
In conclusion, we have demonstrated that Pd-catalyzed
carboetherification reactions of 1-, 2-, or 3-substituted
c-hydroxy internal alkenes provide access to tetrahydro-
furan products bearing three stereocenters in good yields
with moderate to good stereoselectivities. These studies
suggest that the syn-addition manifold is the dominant
mechanistic pathway in transformations of a variety of
substrates with different substitution patterns. Further
studies directed toward expanding the scope and dia-

M. B. Hay, J. P. Wolfe / Tetrahedron Letters 47 (2006) 2793–2796
Table 1. Synthesis of tetrahydrofurans via Pd-catalyzed carboetherificationa
2795
Entry
Alcohol
Aryl/vinyl halide
Major product
Selectivityb (%)
Isomer ratio (isolated)
Yieldc (%)
Br
OH
Ph
Me
Ph
O
1
75
75:25
60
N
Bn
9
N
3
Bn
OH
Me
Ph
O
Br
Ph
2
3
80
81
80:20
68
70
t-Bu
6
5
t-Bu
OH
O
Br
81:12:7
10
7
O
Br
4
5
6
79
71
86
79:9:5:4d
71:13:11:4
86:9:5
60
68
70
Ph
Ph
Ph
11
O
Br
Ph
12
OH
O
Br
8
13
O
Br
7
8
79
79
79:7:7:6d
86
68
Ph
Ph
Ph
14
O
Br
79:21
15
Ph
a Conditions: 1.0 equiv alcohol, 2.0 equiv aryl or vinyl bromide, 2.0 equiv NaOtBu, 1 mol % Pd2(dba)3, 4 mol % P(o-tol)3, toluene (0.25 M), 110 ꢁC.
b Percentage of major isomer present in isolated mixture.
c Average isolated yield of isomers obtained from two or more reactions.
d An additional unidentified isomeric product (1–3%) was also observed.
ArBr
LnPd(0)
stereoselectivity of these reactions along with applica-
tions toward the synthesis of biologically active natural
products are currently underway.
4
Ph
H
Ar
O
Ar
Br
24
LnPd
Acknowledgments
LnPd
Me
22
H
This research was supported by the NIH-NIGMS (GM
071650) and the University of Michigan. J.P.W. thanks
the Camille and Henry Dreyfus Foundation for a new
faculty award, Research Corporation for an innovation
award, and Eli Lilly for a Grantee Award. Additional
unrestricted support was provided by Amgen, Eli Lilly,
and 3M.
Ph
H
O
3, NaOtBu
Ar
LnPd
Me
23
H
Scheme 1. Catalytic cycle.

2796
M. B. Hay, J. P. Wolfe / Tetrahedron Letters 47 (2006) 2793–2796
8. For examples of Pd-catalyzed carboamination reactions
Supplementary data
that afford pyrrolidine products see: (a) Bertrand, M. B.;
Wolfe, J. P. Tetrahedron 2005, 61, 6447–6459, and
references cited therein; (b) Ney, J. E.; Wolfe, J. P. Angew.
Chem., Int. Ed. 2004, 43, 3605–3608.
Experimental procedures, characterization data for new
compounds reported in Eqs. 3–5 and Table 1, and
descriptions of stereochemical assignments. Supplemen-
tary data associated with this article can be found, in the
online version, at online at doi:10.1016/j.tetlet.
2006.02.066.
9. General procedure for palladium catalyzed reactions: A
flame dried or oven dried Schlenk tube equipped with a
magnetic stir bar was cooled under a stream of argon and
charged with Pd2(dba)3 (4.6 mg, 0.005 mmol), P(o-tol)3
(6.1 mg, 0.02 mmol), sodium tert-butoxide (96 mg,
1.0 mmol), and the aryl or vinyl bromide (1.0 mmol).
The tube was purged with argon and toluene (2 mL), the
alcohol substrate (0.5 mmol) and additional toluene
(2 mL) were added. The reaction mixture was heated to
110 ꢁC with stirring until the alcohol substrate was
consumed as judged by GC analysis. The reaction mixture
was cooled to rt and saturated aqueous NH4Cl (2 mL) and
ethyl acetate (10 mL) were added. The layers were
separated and the aqueous layer was extracted with ethyl
acetate (2 · 10 mL). The combined organic layers were
dried over anhydrous Na2SO4, decanted, and concen-
trated in vacuo. The crude material was purified by flash
chromatography on silica gel.
10. The ratios of isomers observed in crude reaction mixtures
were similar to the isomeric ratios obtained upon
purification.
11. The stereochemistry of the tetrahydrofuran products was
determined through a combination of 1H NMR NOE
experiments and correlation of 1H and 13C NMR chemical
shifts with those of previously reported compounds of
known configuration. See the Supplementary data for
complete details. See also Ref. 7.
References and notes
1. (a) Faul, M. M.; Huff, B. E. Chem. Rev. 2000, 100, 2407–
2474; (b) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J.
Nat. Prod. 1999, 62, 504–540; (c) Hou, X.-L.; Yang, Z.;
Wong, H. N. C. Prog. Heterocycl. Chem. 2002, 14, 139–
179; (d) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75–96; (e)
Nicotra, F. Top. Curr. Chem. 1997, 187, 55–83.
2. Morohashi, A.; Satake, M.; Nagai, H.; Oshima, Y.;
Yasumoto, T. Tetrahedron 2000, 56, 8995–9001.
3. (a) Keller-Julsen, C.; King, H. D.; Kuhn, M.; Loosli, H.
R.; Pache, W.; Petcher, T. J.; Weber, H. P.; von Wartburg,
A. J. Antibiot. 1982, 35, 142; (b) Bourque, E.; Kocienski,
P. J.; Stocks, M.; Yuen, J. Synthesis 2005, 3219–3224.
4. Campagnuolo, C.; Fattorusso, C.; Fattorusso, E.; Ianaro,
A.; Pisano, B.; Taglialatela-Scafati, O. Org. Lett. 2003, 5,
673–676.
5. (a) Elliott, M. C. J. Chem. Soc., Perkin Trans. 1 2002,
2301–2323; (b) Harmange, J. C.; Figadere, B. Tetrahedron:
Asymmetry 1993, 4, 1711–1754.
12. For further discussion of the possible origin of other
isomers, see Ref. 7c.
13. (a) Widenhoefer, R. A.; Buchwald, S. L. J. Am. Chem.
Soc. 1998, 120, 6504–6511; (b) Mann, G.; Hartwig, J. F. J.
Am. Chem. Soc. 1996, 118, 13109–13110.
14. (a) Hamed, O.; Thompson, C.; Henry, P. M. J. Org.
Chem. 1997, 62, 7082–7083; (b) Hayashi, T.; Yamasaki,
K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004,
126, 3036–3037; (c) Trend, R. M.; Ramtohul, Y. K.;
Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778–17788.
6. (a) Semmelhack, M. F.; Bodurow, C. J. Am. Chem. Soc.
1984, 106, 1496–1498; (b) Semmelhack, M. F.; Zhang, N.
J. Org. Chem. 1989, 54, 4483–4485; (c) McCormick, M.;
Monahan, R., III; Soria, J.; Goldsmith, D.; Liotta, D. J.
Org. Chem. 1989, 54, 4485–4487; (d) Mikami, K.; Shimizu,
M. Tetrahedron 1996, 52, 7287–7296.
7. (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.