Substituted alkenediols by alkylative double ring opening of dihydrofuran and dihydropyran epoxides

Article abstract of DOI:10.1021/ol016638c

Equation presented Dihydrofuran and dihydropyran epoxides undergo alkylative double ring opening with organolithiums to provide a new route to substituted alkenediols.

Full text of DOI:10.1021/ol016638c

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3401-3403
Substituted Alkenediols by Alkylative
Double Ring Opening of Dihydrofuran
and Dihydropyran Epoxides
David M. Hodgson,* Matthew A. H. Stent,† and Francis X. Wilson‡
,†
Dyson Perrins Laboratory, Department of Chemistry, UniVersity of Oxford,
South Parks Road, Oxford OX1 3QY, U.K., and Roche DiscoVery (Welwyn),
40 Broadwater Road, Welwyn Garden City, Herts AL7 3AY, U.K.
daVid.hodgson@chem.ox.ac.uk
Received August 23, 2001
ABSTRACT
Dihydrofuran and dihydropyran epoxides undergo alkylative double ring opening with organolithiums to provide a new route to substituted
alkenediols.
Epoxides are widely utilized as versatile synthetic intermedi-
ates.1 Their reactions are dominated by the electrophilic
nature of the epoxide, generally involve cleavage of the
strained three-membered ring, and include a wide range of
nucleophilic ring openings and acid- and base-induced
isomerization reactions. The alkylative deoxygenation of
epoxides 1 using organolithiums to give substituted alkenes
2 (Scheme 1) was originally discovered by Crandall and Lin,2
lithiums with cyclopentene- and cyclohexene-derived ep-
oxides possessing a â-methoxy substituent results in the
elimination of methoxide and formation of substituted cyclic
allylic alcohols (e.g., Scheme 2).4
Scheme 2
Scheme 1
Arising out of these previous observations, and in con-
nection with our studies concerning the reactions of organo-
lithiums with cycloalkene- and heterocycloalkene-derived
epoxides,5 we considered whether the chemistry illustrated
in Scheme 2 could be extended to elimination from a cyclic
ether 3 (Scheme 3). Both ethereal oxygens would be retained
and a number of research groups have subsequently made
contributions to this area.3
In one development of this methodology, Mioskowski and
co-workers reported in 1996 that the reaction of organo-
(3) Reviews: (a) Satoh, T. Chem. ReV. 1996, 96, 3303-3325. (b) Doris,
E.; Dechoux, L.; Mioskowski, C. Synlett 1998, 337-343.
† University of Oxford.
‡ Roche Discovery (Welwyn).
(4) Dechoux, L.; Doris, E.; Mioskowski, C. Chem. Commun. 1996, 549-
550.
(1) Erden, I. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996;
Vol. 1A, pp 97-171.
(2) (a) Crandall, J. K.; Lin, L.-H. C. J. Am. Chem. Soc. 1967, 89, 4526-
4257. (b) Crandall, J. K.; Lin, L.-H. C. J. Am. Chem. Soc. 1967, 89, 4527-
4528. (c) Crandall, J. K.; Apparu, M. Org. React. (N.Y.) 1983, 29, 345-
443.
(5) (a) Hodgson, D. M.; Lee, G. P.; Marriott, R. E.; Thompson, A. J.;
Wisedale, R.; Witherington, J. J. Chem. Soc., Perkin Trans. 1 1998, 2151-
2161. (b) Hodgson, D. M.; Robinson, L. A. Chem. Commun. 1999, 309-
310. (c) Hodgson, D. M.; Cameron, I. D. Org. Lett. 2001, 3, 441-444. (d)
Hodgson, D. M.; Cameron, I. D.; Christlieb, M.; Green, R.; Lee, G. P.;
Robinson, L. A. J. Chem. Soc., Perkin Trans. 1 2001, 2161-2174.
10.1021/ol016638c CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/25/2001

Scheme 3
Scheme 5
as hydroxyl groups in the product, and the overall process
would represent a new strategy to substituted alkenediols 4.
Initially we chose to probe the above hypothesis with
readily available 3,4-epoxytetrahydrofuran 5.6 Pleasingly,
reaction of 3,4-epoxytetrahydrofuran 5 with n-BuLi (2.5
equiv) in THF at -78 °C gave 3-butylbut-3-ene-1,2-diol 77
in excellent yield (90%, Scheme 4). As in Mioskowski’s
Scheme 4
An alkyl substituent on the epoxide ring of 3,4-epoxy-
dihydrofuran is tolerated in the reaction. Pentyl-substituted
epoxide 14,11 when treated with n-BuLi, was found to
undergo the transformation to give tertiary allylic alcohol
15 (Scheme 6), in comparable yield to that of the parent
work (Scheme 2), the current reaction proceeds via ether
cleavage rather than loss of Li2O;4 this is despite â-elimina-
tion from the presumed lithiated intermediate 6 (Scheme 4)
being the reverse of a stereoelectronically disfavored 5-endo-
trig cyclization.8
Scheme 6
The new alkylative double ring opening process exhibits
scope with respect to the type of organolithium that can be
used. Primary, secondary, and tertiary alkyllithiums, as well
as phenyllithium and (trimethylsilylmethyl)lithium, all un-
derwent successful reaction with 3,4-epoxytetrahydrofuran
5 under the above conditions (Scheme 5).7,9 Given the utility
of allylsilanes in synthesis,10 the straightforward synthesis
of allylsilane 13 (in one step from commercial materials) is
noteworthy.
system 5. The Prins-pinacol rearrangement12 of 15 to the
3-acyl-substituted tetrahydrofuran 16 (Scheme 6) demon-
strates one application of such a tertiary allylic alcohol
formed in this reaction.
A study of 2,5-disubstituted-3,4-epoxytetrahydrofurans was
undertaken to further examine the effect of substituents on
the rearrangement and as a probe of the stereospecificity3b
of the process. Methylation and epoxidation13 of cis-2,5-
bis(hydroxymethyl)-2,5-dihydrofuran (17)14 gave a chro-
matographically separable mixture of epoxides 18 and 19.15
(6) 3,4-Epoxytetrahydrofuran 5 is commercially available from Acros
Organics. It can be prepared by epoxidation of widely available 2,5-
dihydrofuran (Barili, P. L.; Berti, G.; Mastrorilli, E. Tetrahedron 1993, 49,
6263-6276).
(7) Typical experimental procedure: To a stirred solution of 3,4-
epoxytetrahydrofuran 5 (80 mg, 0.93 mmol) in THF (5.0 mL) at -78 °C
was added dropwise over 10 min n-BuLi (2.20 M in hexanes, 1.06 mL,
2.33 mmol). The reaction mixture was then allowed to warm to 25 °C over
1 h, followed by addition of MeOH (0.5 mL) and preabsorption onto silica
gel (2.5 g). Purification by column chromatography on silica gel (petroleum
ether/diethyl ether 1/9) gave 3-butylbut-3-ene-1,2-diol 7 as a colorless oil
(121 mg, 90%): Rf 0.35 (diethyl ether); IR (neat) 3368, 2957, 2930, 1458,
1
1074, 1029, 903 cm-1; H NMR (400 MHz, CDCl3) δ 5.05 (s, 1H), 4.87
(s, 1H), 4.12 (d, 1H, J ) 7.0 Hz), 3.97 (br s, 1H), 3.89 (br s, 1H), 3.62 (d,
1H, J ) 11.0 Hz), 3.44 (dd, 1H, J ) 11.0 and 7.0 Hz), 2.05-1.88 (m, 2H),
1.43-1.36 (m, 2H), 1.33-1.24 (m, 2H), 0.87 (t, 3H, J ) 7.2 Hz); 13C NMR
(100 MHz, CDCl3) δ 148.5, 110.2, 75.1, 66.2, 32.3, 30.5, 22.5, 13.9; CIMS
m/z (relative intensity) 162 (M + NH4+, 100), 128 (50); HRMS cald for
C8H20NO2 162.1494, found 162.1494.
(8) Calaza, M. I.; Paleo, M. R.; Sardina, F. J. J. Am. Chem. Soc. 2001,
123, 2095-2096.
(9) Alkenediols 8, 10, and 11 are known compounds (Schulte-Elte, K.
H.; Muller, B. L.; Pamingle, H. HelV. Chim. Acta 1979, 62, 816-829).
(10) Fleming, I.; Dunogue`s, J.; Smithers, R. Org. React. (N.Y.) 1989,
37, 57-575.
(11) Prepared in three steps from 2-methylidene heptanol (Overman, L.
E.; Lesuisse, D. Tetrahedron Lett. 1985, 26, 4167-4170): (i) Allyl bromide,
NaH, THF, 25 °C, 16 h, 96%; (ii) (PCy3)2Cl2RuCHPh, CH2Cl2, 25 °C, 5
days, 56% (91% based on recovered diene); (iii) CF3COCH3, Oxone,
NaHCO3, Na2EDTA, MeCN, H2O, 0 °C, 3 h, 73%.
(12) Hopkins, M. H.; Overman, L. E.; Rishton, G. M. J. Am. Chem.
Soc. 1991, 113, 5354-5365.
(13) Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887-
3889.
(14) Prepared via cycloaddition of furan with vinylidene carbonate: de
Micheli, C.; de Amici, M.; Grana, E.; Zonta, F.; Giannella, M.; Piergentili,
A. Farmaco 1993, 48, 1333-1348.
3402
Org. Lett., Vol. 3, No. 21, 2001

The relative stereochemistry of 18 and 19 was determined
1
by H NOE studies (Scheme 7).
Scheme 9
Scheme 7
10). Treatment of dihydropyran epoxides 2420 and 2621 with
n-BuLi yields the corresponding substituted pentene-1,3-diols
25 (70% yield) and 27 (60% yield). Formation of pentenediol
25 suggests that the “cyclic” alkoxy substituent â to the
epoxide directs the epoxide lithiation vicinal to itself.22
On treatment with n-BuLi, each diastereomeric epoxide
gave a geometric isomer of the same trisubstituted olefin.
These reactions are stereospecific: cis,trans-18 exclusively
gave the E-olefin 20 in 90% yield, and cis,cis-19 exclusively
gave the Z-olefin 21 in 65% yield (Scheme 8).16
Scheme 10
Scheme 8
In conclusion, we have demonstrated that dihydrofuran
and dihydropyran epoxides undergo alkylative double ring
opening with organolithiums to provide a new route to
substituted alkenediols. Extensions of the process to other
epoxides, organolithiums, and asymmetric transformations
and manipulation of the adducts toward targets of biological
interest are under investigation.
The above results are consistent with a reaction mechanism
which proceeds from the lithiated epoxide (e.g., 22 from 18,
Scheme 9) via a 1,2-metalate shift17 (with concomitant
epoxide opening), followed by anti-â-elimination of Li and
furanyl O from alkoxide 23.18
While the process failed with cyclic and acyclic derivatives
of the epoxide of cis-but-2-ene-1,4-diol,19 the reaction could
be successfully extended to dihydropyran epoxides (Scheme
Acknowledgment. We thank the EPSRC and Roche for
a CASE award (to M.A.H.S.) and the EPSRC National Mass
Spectrometry Service Centre for mass spectra.
Supporting Information Available: 13C NMR spectra
for previously unreported epoxides (14, 18, 19, 26) and
alkenediols (7, 9, 12, 13, 15, 20, 21, 25, 27). This material
is available free of charge via the Internet at http://pubs.acs.org.
(15) Epoxidation with mCPBA (1.1 equiv, CH2Cl2, 25 °C, 16 h) gave
epoxides 18 and 19 (18:19, 1:2) in 75% yield.
(16) Stereochemistry was determined by 1H NOESY studies on both
isomers: diol 20 showed strong correlations between the olefinic proton
and the protons R-OH, while 21 showed correlations between the olefinic
proton and the butyl chain only.
OL016638C
(17) (a) Kasatkin, A. N.; Whitby, R, J. Tetrahedron Lett. 2000, 41, 5275-
5280. (b) Boche, G.; Lohrenz, J. C. W. Chem. ReV. 2001, 101, 697-756.
(18) Assuming an early transition state for the elimination, then the
required anti alignment of bonds is easily achieved (Scheme 9). Syn
elimination is not possible.
(20) Berti, G.; Catelani, G.; Ferretti, M.; Monti, L. Tetrahedron 1974,
30, 4013-4020.
(21) Dihydropyran oxide 26 was prepared by epoxidation (mCPBA, 1.1
equiv, CH2Cl2, 25 °C, 16 h, 35% yield) of the corresponding dihydropyran
(Booth, H.; Khedhair, K. A.; Readshaw, S. A. Tetrahedron 1987, 43, 4699-
4723).
(19) The corresponding acetonide and dimethyl and bis(tBuMe2Si) ethers
all underwent decomposition. The failure of noncyclic substrates to react
via oxiranyl anion chemistry has been previously observed (refs 4 and 22).
(22) Doris, E.; Dechoux, L.; Mioskowski, C. J. Am. Chem. Soc. 1995,
117, 12700-12704.
Org. Lett., Vol. 3, No. 21, 2001
3403