Tungsten-promoted [3+2]- and [3+3]-cycloaddition of epoxides with alkynes. A facile enantiospecific synthesis of bicyclic lactones [3]

Full text of DOI:10.1021/ja0106016

J. Am. Chem. Soc. 2001, 123, 7427-7428
7427
Scheme 1
Tungsten-Promoted [3+2]- and [3+3]-Cycloaddition
of Epoxides with Alkynes. A Facile Enantiospecific
Synthesis of Bicyclic Lactones
Reniguntala J. Madhushaw, Chien-Le Li, Kuo-Hui Shen,
Chu-Chen Hu, and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua UniVersity
Hsinchu, Taiwan, ROC
ReceiVed March 6, 2001
The cycloaddition of alkynes and alkenes with organic sub-
strates is widely used for the synthesis of carbocyclic and
heterocyclic compounds.1,2 Epoxides and aziridines are important
substances, and the cycloaddition of these molecules with alkenes
and alkynes is an interesting topic in organic synthesis. Scheme
1 shows two types for [3+2]-cycloaddition of alkenes and alkynes
with epoxides or aziridines via cleavage of their C-C and C-X
bonds, respectively.3,4 The former (eq 1) involves 1,3-dipolar
cycloaddition of electron-deficient alkynes and alkenes with a
zwitterionic intermediate A produced by the thermal and photo-
lytic activation of epoxides and aziridines. The presence of an
electron-withdrawing group R2 (R2 ) CN, CO2R) is crucial for
formation of this intermediate.3,4 This system has been thoroughly
studied and is useful in organic synthesis. An alternative route5
involves the use of a Lewis acid to cleave of the C-X bond, to
give the intermediate B (eq 2). Despite its synthetic significance,
there have been very few successful examples of this system
despite its synthetic significance. It is only applicable to special
types of functionalized olefins.5 Yamamoto6 recently reported the
synthesis of tetrahydrofuran derivatives from vinyloxirane with
activated alkenes using palladium catalyst. Normally, addition
products are formed exclusively when epoxides and aziridienes
are treated with activated alkenes or alkynes in the presence of a
Lewis acid.7,8 [3+2]-Cycloaddition of epoxides and aziridines with
alkynes remains unknown to our best knowledge. In this study,
we describe two new cycloadditions for common epoxides and
functionalized alkynes. These methods are applicable to the
enantiocontrolled synthesis of complex bicyclic lactones.
Scheme 2
(1) (a) Gothelf, K. V.; Jorgensen, K. A. Chem. ReV. 1998, 98, 863. (b)
Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; John
Wiley & Sons: Chichester, 1984; Vol. 2, p 83.
a BF3‚Et2O (25 mol %), CH2Cl2, -40 °C. b Yields were reported after
purification from preparative silica TLC plate. c ee values were determined
from HPLC (Merck Chiral Sphere column.
(2) (a) Carruthers, W. Cycloaddition in Organic Synthesis; Pergamon:
Oxford, 1990. (b) Pindur, U.; Lutz, G.; Otto, C. Chem. ReV. 1993, 93, 741.
(c) Togni, A.; Venanzi, L. M. Angew. Chem., Int. Ed. Engl. 1994, 33, 497.
(3) Cycloadditions of aziridine with olefin and alkyne with cleavage of
the C-C bond; see the following examples: (a) Sisko, J.; Weinreb, S. M. J.
Org. Chem. 1991, 56, 3211. (b) Takano, S.; Iwabuchi, Y.; Ogasawara, K. J.
Am. Chem. Soc. 1987, 109, 5523. (c) DeShong, P.; Kell. D. A.; Sidler, D. R.
J. Org. Chem. 1985, 50, 2309. (d) Metra, P.; Hemelin, J. J. Chem. Soc., Chem.
Commun. 1980, 1038. (e) Gaebert, C.; Siegner, C.; Mattay J.; Toubartz, M.;
Steenken, S. J. Chem. Soc., Perkin Trans. 2 1998, 2735. (f) Domingo, L. R.
J. Org. Chem. 1999, 64, 3922.
(4) Cycloadditions of epoxide with olefin and alkyne with cleavage of the
C-C bond; see the following examples: (a) Chou, W.-N.; White, J. B.
Tetrahedron Lett. 1991, 32, 7637. (b) Gaebert, C.; Mattaay, J. Tetrahedron
1997, 53, 14297. (c) Palomino, E.; Schaap, A. P.; Heeg, M. J. Tetrahedron
Lett. 1989. 30, 6801.
(5) Cycloadditions of aziridine or epoxide with alkene with cleavage of
the C-X bond; see: (a) Bergmeier, S. C.; Fundy, S. L.; Seth, P. P. Tetrahedron
1999, 55, 8025. (b) Schneider, M. R.; Mann, A.; Taddei, M. Tetrahedron
Lett. 1996, 37, 8493. (c) Nakagawa, M.; Kawahara, M. Org, Lett. 2000, 2,
953. (e) Sugita, Y.; Kimura, Y.; Yokoe, I. Tetrahedron Lett. 1999, 40, 5877.
(6) Shim, J. G.; Yamamoto, Y. J. Org. Chem. 1996, 63, 3067.
(7) For review papers, see: (a) Tanner, D. Angew. Chem., Int. Ed. Engl.
1994, 33, 599. (b) Yamamoto, Y.; Asao N. Chem. ReV. 1993, 93, 2207.
(8) See the following examples: (a) Dubiois, S.; Mehta, A.; Toureet, E.;
Dodd, R. H. J. Org. Chem. 1994, 59, 434. (b) Sato, K.; Kozikowski, A. P.
Tetrahedron Lett. 1989, 30, 4073. (c) Bennani, Y. L.; Zhu, G. D.; Freeman,
J. C. Synlett 1998, 754. (d) Marson, C. M.; McGregor, J.; Khan, A. J. Org.
Chem. 1998, 63, 7833.
Scheme 2 shows a working hypothesis for the [3+2]-cycload-
dition of alkynyltungsten and epoxide. The mechanism involves
a tungsten-vinylidenium9 cation C. A catalytic amount of Lewis
acid is sufficient for the reaction. The enol ether D is highly
sensitive to the presence of a proton which accelerates its catalytic
conversion to oxacarbenium E,10 and finally to cis-fused bicyclic
lactone selectively if water is present.9 The success of this
cycloaddition relies on exo-attack at the epoxide, which normally
is considered to be problematic because the hybridization of
epoxide is somewhere between sp2 and sp3.11
Scheme 2 also shows the syntheses of various lactones based
on this mechanism. Alkynyltungsten complexes 1-10 were
prepared in yields of 75-86% from CpW(CO)3Cl, Et2NH, and
the corresponding alkyne.9 In a typical reaction, a CH2Cl2 solution
of alkynyltungsten species was treated with BF3‚Et2O (20 mol
(9) Liang, K.-W.; Li,W.-T.; Lee, G.-H.; Peng, S.-Mi.; Liu, R.-S. J. Am.
Chem. Soc. 1997, 119, 4404.
(10) McDonald, F. E.; Schults, C. C. J. Am. Chem. Soc. 1994, 169, 9363.
(11) Nicolaou, K. C.; Duggan, M. E.; Huang, C.-K.; Somers, P. K. J. Chem.
Soc., Chem. Commun. 1985, 1359.
10.1021/ja0106016 CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/03/2001

7428 J. Am. Chem. Soc., Vol. 123, No. 30, 2001
Communications to the Editor
%) at -40 °C for 2-8 h before water was added. Entries a and
b show two examples of the efficient synthesis of cis-γ-lactones
11 and 12 fused with six-membered oxaocycles, respectively. The
Scheme 3
1
cis-configurations of 11 and 12 were determined by H NOE
NMR spectra.12 In the cyclization of trans- and cis-epoxides 3
and 4 (entries c and d), the cis-fused products 13 and 14 have
1
cis-methyl and trans-propyl groups, respectively, based on H
NMR analysis.12 This information suggests that opening of the
epoxide proceeds via an inversion of stereochemistry. We also
prepared the styrene epoxide 5 which could favor the endo-attack
via the formation of a benzyl carbocation,11 but the exo-attack is
still the dominant route to yield the bicyclic lactone 15 exclusively.
Two chiral epoxides 6 (97% ee) and 7 (87% ee) were prepared
to study the enantioselective cycloadditions as depicted in entries
f and g. A small decrease in the ee value is observed for the
lactone 16 (91% ee), while a significant decrease is seen for
compound 17 (65% ee). The latter may involve a tertiary
carbocation during ring-opening of the epoxide. The absolute
configuration and [R]-value of 16 are consistent with those
reported in the literature.13 Enantiopure bicyclic lactones can be
synthesized smoothly from chiral 1,2-disubstituted epoxides14
8
and 9 in a one-pot operation. Entries h and i show the enantio-
specific synthesis of functionalized bicyclic lactones 18 and 19
with BF3‚Et2O as the catalyst. Only one stereoisomer was formed
even through three stereogenic centers are present. The enan-
tiopurities of 18-19 agree with those of the starting epoxides
8-9. We also prepared chiral epoxide 10 as a 1:1 mixture of
acetate diastereomers, and each isomer has 90% ee according to
HPLC analysis; the resulting unsaturated lactone 20 was obtained
in 63% yield with 90% ee.
a BF3‚Et2O (25 mol %), CH2Cl2 (-40 °C). b Yields were reported after
purification from silica TLC plate. c BnOH (2.0 equiv), I2 (1.1 equiv),
CH2Cl2, -40 °C.
BF3‚Et2O catalyst also effected a novel [3+3]-cycloaddition
of epoxides with propargyltungsten groups; the results are
summarized in Scheme 3. The propargyltungsten complexes 21-
26 were prepared15 in yields of 87-95% from NaCpW(CO)3 and
the corresponding chloropropargyl chlorides comprising an ep-
oxide. In a typical reaction, the propargyl complex was treated
with BF3‚Et2O (25 mol %) catalyst in cold CH2Cl2 (-40 °C) for
4-10 h before treatment with a saturated NaHCO3 solution. The
products 27-32 were obtained in 51-63% yields. Structural
assignment of the products was made based on spectroscopic data.
This cyclization induces 1,2-migration of the tungsten fragment.
Subsequent demetalation of 27-32 with I2 (1.1 equiv) and benzyl
alcohol (2.0 equiv) gave benzyl esters 33-38 in high yields (90-
97%). Entries a and b show the synthesis of tungsten-pyranyl
complexes 27 and 28 fused with five-membered carbocycles and
azacycles. This cyclization also works well for gem-disubstituted
epoxide 23 to yield compound 29 in 63% yield. Cyclizations of
cis epoxides 24 and 25 afforded trans-pyranyl compounds 30 and
31 in reasonable yields. Trans epoxide 26 gave the cis-pyranyl
complex 32 in 51% yield.
Notably, the BF3O- terminus of species F attacks the terminal
allene carbon rather than the expected central carbon.17 This
contradicts those of free allenes comprising a similar alcohol.17
The exact nature of this cyclization is uncertain at this stage. We
tentatively propose that it may be due to coordination of
CpW(CO)3 to the external dCdCH2 group to alter the carbon
hybridization close to sp3 character. This effect disfavors a [3+2]-
cycloaddition pathway given from a 5-endo-trig ring-closure.18
In summary, we have reported two tungsten-promoted [3+2]-
and [3+3]-cycloadditions of alkynes and epoxides. These two
types of cycloadditions involve the exo ring-opening of epoxide,
-
followed by counterattack of OBF3 of the intermediate at its
central vinylidenium carbon and its terminal allene carbon,
respectively. These cyclizations proceed having high diastereo-
and enantiospecificity to give bicyclic heterocycles with multiple
stereogenic centers in a one-pot operation. Further applications
of these cycloadditions to the syntheses of natural lactones with
high enantiopurities is under investigation.
The preference for [3+3]-cycloaddition can be rationalized by
the mechanism proposed in Scheme 3, which involves a tungsten-
η2-allene cation16 F produced by exo-attack on the epoxide.
Acknowledgment. The authors wish to thank the National Science
Council, Taiwan for support of this work.
(12) 1H-NOE NMR spectra of key compounds are provided in the
Supporting Information.
(13) Petit, F.; Furstoss, R. Tetrahedron: Asymmetry 1993, 4, 1341.
(14) Syntheses of chiral epoxides 6-10 are provided in the Supporting
Information.
(15) Chen C.-C.; Fan J.-S.; Shieh, S.-J.; Lee G.-H.; Peng S.-M.; Wang
S.-L.; Liu R.-S. J. Am. Chem. Soc. 1996, 118, 9279.
Supporting Information Available: Experimental procedures for the
syntheses and spectral data of new compounds 1-38 and the key chiral
epoxides (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
JA0106016
(16) [3+2]-Cycloadditions of propargylmetal complexes with reactive
olefins; see the following examples: (a) Rosenblum, M.; Raghu, S. J. Am.
Chem. Soc. 1973, 95, 3062. (b) Lichtenberg, D. L.; Wojcicki, A. J. Organomet.
Chem. 1975, 94, 311. (c) Li, C.-L.; Liu R.-S. Chem. ReV. 2000, 100, 3127.
(17) Schuster, H. F.; Coppola, G. M. Allenes in Organic Synthesis; John
Wiley & Sons: Chichester, 1985; p 79.
(18) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.