A versatile stereocontrolled approach to chiral tetrahydrofuran and tetrahydropyran derivatives via sequential asymmetric horner-wadsworth-emmons and palladium-catalyzed ring closure reactions

Article abstract of DOI:10.1021/ol006135r

(equation presented) In approach to chiral tetrahydrofuran and tetrahydropyran derivatives is reported which is based on the sequential use of an asymmetric Horner-Wadsworth-Emmons desymmetrization of a meso-dialdehyde and a palladium-catalyzed intramolec

Full text of DOI:10.1021/ol006135r

ORGANIC
LETTERS
2000
Vol. 2, No. 17
2611-2614
A Versatile Stereocontrolled Approach
to Chiral Tetrahydrofuran and
Tetrahydropyran Derivatives via
Sequential Asymmetric
Horner−Wadsworth−Emmons and
Palladium-Catalyzed Ring Closure
Reactions
,†
Lauri Vares†,‡,§,| and Tobias Rein*
Department of Organic Chemistry, Building 201, KemitorVet, Technical UniVersity of
Denmark, DK-2800 Kgs. Lyngby, Denmark, Department of Chemistry, Organic
Chemistry, Royal Institute of Technology, S-10044 Stockholm, Sweden, and Department
of Bioorganic Chemistry, Institute of Chemistry at Tallinn Technical UniVersity,
Akadeemia tee 15, EE-12618 Tallinn, Estonia
oktr@pop.dtu.dk
Received May 31, 2000
ABSTRACT
An approach to chiral tetrahydrofuran and tetrahydropyran derivatives is reported which is based on the sequential use of an asymmetric
Horner−Wadsworth−Emmons desymmetrization of a meso-dialdehyde and a palladium-catalyzed intramolecular allylic substitution. The strategy
is versatile in that either a cis- or a trans-relation between the stereocenters adjacent to the ring oxygen can be obtained.
The development of stereoselective syntheses of substituted
tetrahydrofuran (THF) and tetrahydropyran (THP) derivatives
is an important challenge because of the frequent occurrence
of such oxacycles as substructures in biologically active
substances, such as the annonaceous acetogenins1 and several
groups of macrolides.2 The need for appropriately function-
alized synthetic building blocks has motivated the develop-
ment of many different synthetic approaches.3 In this Letter,
we describe a stereochemically versatile approach to certain
(2) For a review, see: Norcross, R. D.; Paterson, I. Chem. ReV. 1995,
95, 2041.
(3) For reviews, see: (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309.
(b) Harmange, J.-C.; Figade`re, B. Tetrahedron: Asymmetry 1993, 4, 1711.
Selected recent examples: (c) Berninger, J.; Koert, U.; Eisenberg-Ho¨hl,
C.; Knochel, P. Chem. Ber. 1995, 128, 1021, and references therein. (d)
Ram´ırez, M. A.; Padro´n, J. M.; Palazo´n, J. M.; Mart´ın, V. S. J. Org. Chem.
1997, 62, 4584, and references therein. (e) Sinha, S. C.; Keinan, E.; Sinha,
S. C. J. Am. Chem. Soc. 1998, 120, 9076, and references therein. (f) Ley,
S. V.; Brown, D. S.; Clase, J. A.; Fairbanks, A. J.; Lennon, I. C.; Osborn,
H. M. I.; Stokes, E. S. E.; Wadsworth, D. J. J. Chem. Soc., Perkin Trans.
1 1998, 2259. (g) Morimoto, Y.; Iwai, T.; Kinoshita, T. J. Am. Chem. Soc.
1999, 121, 6792. (h) Pilli, R. A.; Riatto, V. B.; Vencato, I. Org. Lett. 2000,
2, 53. (i) Micalizio, G. C.; Roush, W. R. Org. Lett. 2000, 2, 461.
† Technical University of Denmark.
‡ Royal Institute of Technology.
§ Institute of Chemistry.
| Present address: National Institute of Chemical Physics and Biophysics,
Akadeemia tee 23, EE-12618, Tallinn, Estonia.
(1) For a review, see: Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J.
Nat. Prod. 1999, 62, 504.
10.1021/ol006135r CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/04/2000

THF and THP derivatives which is based on the sequential
use of an asymmetric Horner-Wadsworth-Emmons (HWE)
reaction4 and an intramolecular palladium-catalyzed allylic
substitution.5 An attractive feature of this approach is the
fact that as a result of the stereospecificity of the Pd(0)-
catalyzed reaction, control of the alkene geometry in the
HWE product translates into control of the relative config-
uration of the ring-closed product.
We have recently reported that meso-dialdehydes of type
1 can be efficiently desymmetrized by use of asymmetric
HWE reactions4g to give either (E)-alkenes 2 or (Z)-alkenes
5 with good to excellent levels of geometric selectivity and
asymmetric induction. The protective group P can be chosen
so that the PO group can act as a leaving group in a Pd(0)-
catalyzed allylic substitution6 (Scheme 1). After reduction
with overall retention of configuration; (Z)-allylic com-
pounds, on the other hand, might undergo a π-σ-π
rearrangement of the intermediate palladium complex before
the nucleophilic attack takes place, resulting in overall
inVersion of configuration and simultaneous conversion of
the (Z)-alkene to an (E)-alkene.7 We therefore anticipated a
possibility for versatility of stereocontrol: whereas (E)-
substrates 3 would give cis-products 4, ring closure of (Z)-
substrates 6 could provide access to trans-products 7.
Precedence for ring closure by Pd(0)-catalyzed allylic
substitution with an oxygen nucleophile does exist,5 but the
opportunities for simultaneously controlling the stereochem-
istry to obtain, at will, either retention or inversion of
configuration appear to be previously unexplored.
To apply this strategy to the preparation of THF deriva-
tives, we investigated asymmetric HWE reactions with meso-
dialdehyde 88 (Scheme 2). Pivaloyl protective groups were
chosen because allylic carboxylates are known to be good
precursors of η3-allylpalladium complexes. To our delight,
asymmetric HWE reactions between 8 and phosphonates 9
gave essentially complete geometric selectivities as well as
excellent diastereoselectivities.9,10
Scheme 1
Subsequent reduction of the aldehyde functionalities in 10
and 14, followed by acyl group migration, gave 12 and 16,
respectively.11 When compound 12 was treated with catalytic
amounts of Pd2(dba)3 in the presence of neocuproine,12 it
readily ring-closed at room temperature to give the 2,5-cis-
disubstituted THF derivative 13,13 with complete retention
of configuration at the allylic stereocenter.
The (Z)-alkene 16, on the other hand, required elevated
temperatures (refluxing THF) under otherwise similar condi-
(5) For selected examples of use of an intramolecular Pd(0)-catalyzed
allylic substitution as the ring-closing step in approaches to oxygen
heterocycles, see: (a) Trost, B. M.; Tenaglia, A. Tetrahedron Lett. 1988,
29, 2927. (b) Suzuki, T.; Sato, O.; Hirama, M.; Yamamoto, Y.; Murata,
M.; Yasumoto, T.; Harada, N. Tetrahedron Lett. 1991, 32, 4505. (c)
Mizuguchi, E.; Achiwa, K. Chem. Pharm. Bull. 1997, 45, 1209. (d) Fournier-
Nguefack, C.; Lhoste, P.; Sinou, D. Tetrahedron 1997, 53, 4353. (e) Trost,
B. M.; Asakawa, N. Synthesis 1999, 1491. (f) Labrosse, J.-R.; Poncet, C.;
Lhoste, P.; Sinou, D. Tetrahedron: Asymmetry 1999, 10, 1069.
(6) For a general reference, see: Tsuji, J. Palladium Reagents and
Catalysts: InnoVations in Organic Synthesis; Wiley & Sons: New York,
1995; pp 290-340.
(7) For examples, see: (a) Hayashi, T.; Yamamoto, A.; Hagihara, T. J.
Org. Chem. 1986, 51, 723. (b) Sugiura, M.; Yagi, Y.; Wei, S.-Y.; Nakai,
T. Tetrahedron Lett. 1998, 39, 4351.
(8) See Supporting Information for details on how compound 8 was
prepared.
(9) Both geometric selectivities and diastereomer ratios for the HWE
products were determined by 1H NMR spectroscopy. The absolute
configurations of compounds 12 and 16 were assigned on the basis of NMR
analyses of the corresponding Mosher esters (see Supporting Information
for details).
(10) From the reaction between 8 and 9a, bisaddition products were also
isolated in ca. 40% yield, which explains the modest yield of compound
10.
(11) Depending on the specific conditions used, varying ratios between
the secondary alcohols (12, 16, 20, and 23) and the isomeric primary
alcohols (11, 15, 19, and 22, respectively) could be obtained from reduction
of the corresponding HWE products. The primary alcohols could be
separated and converted to mixtures of secondary/primary, thereby increas-
ing the overall yield of the desired secondary alcohols to ca. 70% after one
iteration (see Supporting Information for details).
of the unreacted formyl group in the HWE product, migration
of the one protective group P which is adjacent to the primary
alcohol will give compounds 3 and 6, respectively, in which
the stage is now set for a Pd(0)-catalyzed ring closure in
which the liberated secondary OH group can act as the
nucleophile. In general, (E)-allylic substrates are known to
undergo Pd(0)-catalyzed substitution with O-nucleophiles
(4) For a review, see: Rein, T.; Reiser, O. Acta Chem. Scand. 1996, 50,
369. Selected recent examples: (b) Abiko, A.; Masamune, S. Tetrahedron
Lett. 1996, 37, 1077. (c) Kumamoto, T.; Koga, K. Chem. Pharm. Bull. 1997,
45, 753. (d) Dai, W.-M.; Wu, J.; Huang, X. Tetrahedron: Asymmetry 1997,
8, 1979. (e) Mizuno, M.; Fujii, K.; Tomioka, K. Angew. Chem. 1998, 110,
525; Angew. Chem., Int. Ed. Engl. 1998, 37, 515. (f) Vaulont, I.; Gais,
H.-J.; Reuter, N.; Schmitz, E.; Ossenkamp, R. K. L. Eur. J. Org. Chem.
1998, 805. (g) Tullis, J. S.; Vares, L.; Kann, N.; Norrby, P.-O.; Rein, T. J.
Org. Chem. 1998, 63, 8284. (h) Arai, S.; Hamaguchi, S.; Shioiri, T.
Tetrahedron Lett. 1998, 39, 2997. (i) Tanaka, K.; Watanabe, T.; Shimamoto,
K.-Y.; Sahakitpichan, P.; Fuji, K. Tetrahedron Lett. 1999, 40, 6599. (j)
Pedersen, T. M.; Jensen, J. F.; Humble, R. E.; Rein, T.; Tanner, D.;
Bodmann, K.; Reiser, O. Org. Lett. 2000, 2, 535.
(12) Neocuproine ) 2,9-dimethyl-1,10-phenanthroline.
(13) Assignments of relative configuration in the ring-closed products
are based on NOE experiments on compounds 13, 17, and 24. The
assignment for compound 21 is based on 13C NMR analysis of a derivative
(see Supporting Information for details).
2612
Org. Lett., Vol. 2, No. 17, 2000

Scheme 2a
Scheme 3a
a Reaction conditions: (a) imidazole, EtOH, 75 °C; 59% 20, 28%
recovered 19 (see footnote 11); (b) Pd2(dba)3‚CHCl3 (0.1 equiv),
neocuproine (0.4 equiv), THF, 25 °C; 80%; (c) DMAP, EtOH, 75
°C; 48% 23, 42% recovered 22 (see footnote 11); (d) Pd2(dba)3‚
CHCl3 (0.15 equiv), neocuproine (0.4 equiv), THF, 50 °C; 59%.
a Reaction conditions: (a) 1.3 equiv of 8, 1.1 equiv of 9a, 1.0
equiv of KHMDS, 5 equiv of 18-crown-6, THF, -85 °C; 55%; (b)
NaBH4, MeOH/THF, 0 °C; 85%; (c) DMAP, EtOH, 75 °C; 63%
12, 27% recovered 11 (see footnote 11); (d) Pd2(dba)3‚CHCl3 (0.05
equiv), neocuproine (0.2 equiv), THF, 25 °C; 76%; (e) 1.3 equiv
of 8, 1.1 equiv of 9b, 1.0 equiv of KHMDS, 5 equiv of 18-crown-
6, THF, -85 °C; 71%; (f) LiBH4, i-PrOH/THF, 0 °C; 49% 16,
To summarize, we have demonstrated efficient stereocon-
trolled routes for the preparation of various functionalized
THF and THP derivatives, using a strategy involving an
asymmetric HWE reaction in sequence with a palladium-
catalyzed intramolecular allylic substitution as key steps. The
relative configuration of the stereocenters adjacent to the ring
oxygen is controlled by the combined influence of the
geometric selectivity of the HWE reaction and the ste-
reospecificity of the palladium-catalyzed process, while the
absolute configuration is controlled in the asymmetric HWE
reaction. We are currently investigating possible extensions
of this strategy to the preparation of other heterocyclic and
carbocyclic systems.
•
38% 15 (see footnote 11); (g) Pd2(dba)3 CHCl3 (0.15 equiv),
neocuproine (0.4 equiv), THF, 65 °C; 79%.
tions for the ring closure to occur. The major product was
the 2,5-trans-disubstituted THF derivative 17,13 containing
an (E)-alkene, an outcome which is completely consistent
with the anticipated π-σ-π rearrangement. Use of phos-
phine ligands in place of neocuproine in reactions with 16
caused elimination to form a diene to prevail over the desired
ring closure.
Starting from compounds 19 and 22, which are available
via asymmetric HWE desymmetrization of meso-dialdehyde
18 followed by NaBH4 reduction,4g THP derivatives 21 and
24 were synthesized using a similar approach (Scheme 3).
Pivaloyl group migration afforded the secondary alcohols
20 and 23 from 19 and 22, respectively.11 When the (E)-
alkene 20 was subjected to the ring closure conditions, we
were pleased to see that the desired 2,6-cis-THP derivative
21 could be obtained diastereomerically pure, even though
the starting material 20 contained minor amounts (ca. 5%)
of another isomer. Ring closure of the (Z)-alkene 23 gave,
as expected, the 2,6-trans-derivative 24, in analogy to the
formation of compound 17 from 16.
Acknowledgment. We thank the Danish Technical Sci-
ence Research Council (STVF), the Danish Natural Science
Research Council (SNF), the Swedish Natural Science
Research Council (NFR), the Swedish Institute, the Sale´n
Foundation (Sweden), the Royal Institute of Technology, the
Estonian Science Foundation (Grant 4230), the Estonian
Ministry of Education (Grant 0350315s98), and the Nordic-
Baltic Scholarship Scheme for financial support. Dr Ivar
Martin, Institute of Chemistry at Tallinn Technical Univer-
sity, and Professor Paul Helquist, University of Notre Dame,
are acknowledged for helpful discussions and continuous
support. We are grateful to Professor Christian Pedersen and
Mr. Torben M. Pedersen, Technical University of Denmark,
and Professor To˜nis Pehk, National Institute of Chemical
Physics and Biophysics, Tallinn, for skilful assistance with
Org. Lett., Vol. 2, No. 17, 2000
2613

NMR experiments. Mrs. Nonka Sevova, University of Notre
Dame, is gratefully acknowledged for assistance with HRMS
analyses.
material is available free of charge via the Internet at
http://pubs.acs.org.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
OL006135R
2614
Org. Lett., Vol. 2, No. 17, 2000