Stereoselective synthesis of polysubstituted tetrahydrofurans by radical cyclization of epoxides using a transition-metal radical source. Application to the total synthesis of (±)-methylenolactocin and (±)-protolichesterinic acid

Article abstract of DOI:10.1021/jo971526d

Radical cyclization reactions of substituted α-(prop-2-ynyloxy) epoxides using bis(cyclopentadienyl)-titanium(III) chloride as the radical source resulted in polysubstituted tetrahydrofurans. Titanium(III) species were prepared in situ from commercially available titanocene dichloride and zinc dust in tetrahydrofuran. Upon radical cyclization, 2-aryl epoxides 3a-e afforded only trans products 4a-e whereas the 2-alkyl epoxides 3f-h formed a mixture of isomeric products 4f-h in a ratio of 5:1. Some of the aryl tetrahydrofuran derivatives have already been used for the synthesis of bioactive furofuran lignans. 2-Pentyl-3-(hydroxymethyl)-4- methylenetetrahydrofuran (4f) and 2-tridecyl-3-(hydroxymethyl)-4- methylenetetrahydrofuran (4g) have been transformed to two antitumor antibiotics (±)-methylenolactocin (1f) and (±)-protolichesterinic acid (1g), respectively, in good overall yield.

Full text of DOI:10.1021/jo971526d

J . Org. Chem. 1998, 63, 2829-2834
2829
Ster eoselective Syn th esis of P olysu bstitu ted Tetr a h yd r ofu r a n s by
Ra d ica l Cycliza tion of Ep oxid es Usin g a Tr a n sition -Meta l Ra d ica l
Sou r ce. Ap p lica tion to th e Tota l Syn th esis of
(()-Meth ylen ola ctocin a n d (()-P r otolich ester in ic Acid
Pijus Kumar Mandal, Gourhari Maiti, and Subhas Chandra Roy*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, J adavpur,
Calcutta-700 032, India
Received August 14, 1997
Radical cyclization reactions of substituted R-(prop-2-ynyloxy) epoxides using bis(cyclopentadienyl)-
titanium(III) chloride as the radical source resulted in polysubstituted tetrahydrofurans. Tita-
nium(III) species were prepared in situ from commercially available titanocene dichloride and zinc
dust in tetrahydrofuran. Upon radical cyclization, 2-aryl epoxides 3a -e afforded only trans products
4a -e whereas the 2-alkyl epoxides 3f-h formed a mixture of isomeric products 4f-h in a ratio of
5:1. Some of the aryl tetrahydrofuran derivatives have already been used for the synthesis of
bioactive furofuran lignans. 2-Pentyl-3-(hydroxymethyl)-4-methylenetetrahydrofuran (4f) and
2-tridecyl-3-(hydroxymethyl)-4-methylenetetrahydrofuran (4g) have been transformed to two
antitumor antibiotics (()-methylenolactocin (1f) and (()-protolichesterinic acid (1g), respectively,
in good overall yield.
Sch em e 1
In tr od u ction
The explosive growth in free radical chemistry in
recent years reflects its significance as a powerful tool
in modern synthetic chemistry.1 The mildness and regio-
and stereoselectivities of the 5-hexenyl radical cyclization
have been extensively used2 for the construction of
carbocyclic as well as oxacyclic compounds leading to
cyclopentane and tetrahydrofuran derivatives, respec-
tively. Although there are several methods available in
the literature for intramolecular radical cyclizations, a
bromoalkene or a bromoalkyne has extensively been used
as a radical precursor3 (Scheme 1). Newer methods for
the preparation of radical precursors required for the
intramolecular radical cyclizations are still desirable.
Epoxides are vastly used as building blocks for organic
synthesis due to their ready availability and facile
substitution reactions with predictable stereochemistry.4
Rajanbabu and Nugent have successfully established5 the
selective one-electron reduction of an epoxide to a radical
intermediate which represents an invaluable synthetic
tool as the intermediate radical can be trapped in
subsequent reactions (Scheme 2).
(1) For a general review and books, see: (a) Giese, B. Radical in
Organic Synthesis: Formation of C-C bonds; Pergamon Press: Oxford,
1986. (b) Curran, D. P. Synthesis 1988, p 417 and 489. (c) Regitz, M.,
Giese, B., Eds. Houben-Weyl, Methoden der Organischen Chemie; band
E19a, C-Radikale, Teil 1+2; Georg Tieme Verlag: Stuttgart, 1989. (d)
Curran, D. P. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Semmelhack, M. F., Eds.; Pergamon Press: Oxford, 1991;
Vol. 4, p 715 and 779. (e) Motherwell, W. B.; Crich, D. Free Radical
Chain Reactions in Organic Synthesis; Academic Press: New York,
1992. (f) Fossey, J .; Lefort, D.; Sorba, J . Free Radicals in Organic
Chemistry; Wiley: New York, 1995.
(2) See for example: Ladlow, M.; Pattenden, G. Tetrahedron Lett.
1984, 25, 4317. Stork, G.; Kahn, M. J . Am. Chem. Soc. 1985, 107, 500.
Moriya, O.; Kakihana, M.; Urata, Y.; Sugizaki, T.; Kageyama, T.; Ueno,
Y.; Endo, T. J . Chem. Soc., Chem. Commun. 1985, 1401. Stork, G.;
Sher, P. M. J . Am. Chem. Soc. 1986, 108, 303. Bhandal, H.; Pattenden,
G.; Russell, J . J . Tetrahedron Lett. 1986, 27, 2299. Pezechk, M.;
Brunetiere, A. P.; Lallemand, J . Y. Tetrahedron Lett. 1986, 27, 3715.
Ueno, Y.; Moriya, O.; Chino, K.; Watanabe, M.; Okawara, M. J . Chem.
Soc., Perkin Trans. 1 1986, 1351. Stork, G.; Sher, P. M.; Chen, H.-L.
J . Am. Chem. Soc. 1986, 108, 6384. Morikawa, T.; Nishiwaki, T.; Iitaka,
Y.; Kobayashi, Y. Tetrhedron Lett. 1987, 28, 671. Hutchinson, J . H.;
Pattenden, G.; Myers, P. L. Tetrahedron Lett. 1987, 28, 1313. Begby,
M. J .; Bhandal, H.; Hutchinson, J . H.; Pattenden, G. Tetrahedron Lett.
1987, 28, 1317. Keck, G. E.; Burnett, D. A. J . Org. Chem. 1987, 52,
2958. Audin, C.; Lancelin, J .-M.; Beau, J .-M. Tetrahedron Lett. 1988,
29, 3691. Harrison, T.; Pattenden, G.; Myers, P. L. Tetrahedron Lett.
1988, 29, 3869. De Mesmalker, A.; Hoffmann, P.; Ernst, B. Tetrahedron
Lett. 1989, 30, 57. Chapleur, Y.; Moufid, N. J . Chem. Soc., Chem.
Commun. 1989, 39. Bonini, C. Tetrahedron Lett. 1990, 31, 5369.
Ishiyama, T.; Murata, M.; Suzuki, A.; Miyaura, N. J . Chem. Soc., Chem.
Commun. 1995, 295. Srikrishna, A.; Viswajanani, R.; Sattigeri, J . A.
J . Chem. Soc., Chem. Commun. 1995, 469. Srikrishna, A.; Viswajanani,
R.; Yelamaggad, C. V. Tetrahedron Lett. 1995, 36, 1127. Giese, B.;
Kopping, B.; Gobel, T.; Dickhauf, J .; Thoma, G.; Kulicke, K. J .; Trach,
F. Org. React. 1996, 48, 301.
Thus, epoxides can provide an excellent source of
functionalized radicals.6 The regio- and stereochemis-
tries of the epoxide cleavage via C-O homolysis are
guided by the relative stability of the intermediate
radicals rather than the ease of approach to the epoxide
termini. Very recently Engman and Gupta reported7 the
ring opening of epoxides by arenetellurolate or arene-
(3) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.; Okawara, M. J .
Am. Chem. Soc. 1982, 104, 5564. Stork, G.; Mook, R., J r.; Biller, S. A.;
Rychnovskyu, S. D. J . Am. Chem. Soc. 1983, 105, 3741.
(4) Rao, A. S.; Paknikar, S. K.; Kirtane, J . G. Tetrahedron 1983,
39, 2323. Smith, J . G. Synthesis 1984, 629. Chini, M.; Crotti, P.;
Flippin, L. A.; Gardelhi, C.; Giovani, E.; Macchia, F.; Pineschi, M. J .
Org. Chem. 1993, 58, 1221 and references therein.
(5) Rajanbabu, T. V.; Nugent, W. A. J . Am. Chem. Soc. 1994, 116,
986 and references therein.
(6) Rawal, V. H.; Newton, R. C.; Krishnamurthy, V. J . Org. Chem.
1990, 55, 5181. Merlic, C. A.; Xu, D. J . Am. Chem. Soc. 1991, 113,
9855. Rawal, V. H.; Dufour, C. J . Am. Chem. Soc. 1994, 116, 2613.
(7) Engman, L.; Gupta, V. J . Org. Chem. 1997, 62, 157.
S0022-3263(97)01526-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/15/1998

2830 J . Org. Chem., Vol. 63, No. 9, 1998
Mandal et al.
Sch em e 2
Sch em e 4
Sch em e 3
Resu lts a n d Discu ssion
P r ep a r a tion of Ep oxid es a n d P r op a r gyla tion of
Ep oxy Alcoh ols. Epoxy alcohols 2 were prepared from
the corresponding vinyl alcohols by treatment with
MCPBA in CHCl3.14 The epoxides 2a -h were found to
be a mixture of two isomers in a ratio of 1:1. The ratio
1
was determined from the H NMR signals for the proton
adjacent to the hydroxy group, e.g., for 2a the particular
signals appeared as two multiplets at δ 4.88 for one
isomer and at δ 4.44 for the other. Epoxide 2i was
isolated as a single isomer. Since the isomers in 2a -h
could not be separated by usual chromatographic meth-
ods, the mixture of isomers was used for the propargyl-
ation step (Scheme 4). The epoxy alcohols 2a -i were
O-prop-2-ynylated by treatment with propargyl bromide
in the presence of NaH in THF-DMSO (10:1) to furnish
3a -h (Table 1) as an inseparable mixture of two isomers
in a ratio of 1:1 and 3i as a single isomer. These prop-
2-ynylated derivatives 3a -i were used as precursors to
3-oxa-5-hexynyl radicals finally leading to polysubsti-
tuted tetrahydrofurans. Since the isomers could not be
separated by usual chromatographic methods, the crude
isomeric mixtures were used for the radical cyclization
reactions.
Ra d ica l Cycliza tion s of Ep oxid es Usin g a Tita -
n iu m Ra d ica l Sou r ce. For homolytic cleavage of ep-
oxides, a titanium(III) reagent, bis(cyclopentadienyl)-
titanium(III) chloride,5 was used at room temperature.
The reagent was easily generated in situ from inexpen-
sive Cp2TiCl2 and is compatible with many organic
functional groups. A satisfactory reagent can be pre-
pared by stirring a red THF solution of Cp2TiCl2 with
activated Zn dust (eq 1). After 15 min, the solution turns
lime green and the formation of Cp2TiCl is complete.
selenide ion and the preparation of tetrahydrofuran
derivatives by a hexabutyltin/light-induced group trans-
fer cyclization reaction of the O-allylated telluride and
Bu3SnH-induced radical cyclization of selenide precursors
(Scheme 3).
Although the intramolecular radical cyclizations of
epoxides using a titanium radical source were reported
for the synthesis of cyclopentane derivatives years ago,5
application toward the stereoselective preparation of
polysubstituted tetrahydrofuran derivatives or natural
products are still unexplored. We report here a full
account8 of the stereoselective synthesis of polysubsti-
tuted tetrahydrofuran derivatives some of which are
valuable precursors for biologically active furano lignans.9
This epoxide radical cyclization strategy has also been
applied to the total synthesis of two densely functional-
ized antitumor antibiotics, (()-methylenolactocin (1f)10
and (()-protolichesterinic acid (1g).11 Compound 1f was
isolated from the culture filtrate of Pencillium sp., and
it shows selective antibacterial activity against Gram-
positive bacteria.12 Protolichesterinic acid (1g) was iso-
lated from various types of moss Cetraria13 and found to
be effective in inhibiting the growth of Gram-positive
bacteria.
2Cp2TiCl2 + Zn f 2Cp2TiCl + ZnCl2
(1)
In a preliminary experiment, 2 molar equiv of Cp2TiCl
in THF was added dropwise to a THF solution of the
epoxide 3a . The initial green color of the titanium(III)
species instantly discharged to red upon exposure to the
epoxide. Quenching the mixture with 10% H2SO4 in H2O
afforded the tetrahydrofuran 4a in 71% yield as a single
isolable product (Scheme 5). This cyclization/protonolysis
was applied to a series of substituted epoxyalkynes
containing synthetically useful functionalities. The re-
sults are tabulated in Table 1. It is noteworthy that the
R-aryl epoxides 3a -e upon radical cyclization formed
only trans products (4a -e) whereas the R-alkyl epoxides
3f-h led to an inseparable mixture of two isomeric
products (4f-h ), in a ratio of 5:1. The ratio of the isomers
(8) For preliminary communication, see: Maiti, G.; Roy, S. C. J .
Chem. Soc., Perkin Trans. 1 1996, 403.
(9) Adhikari, S.; Roy, S. Tetrahedron Lett. 1992, 33, 6025. Maiti,
G.; Adhikari, S.; Roy, S. C. Tetrahedron Lett. 1994, 35, 3985. Maiti,
G.; Adhikari, S.; Roy, S. C. Tetrahedron Lett. 1994, 35, 6731. Maiti,
G.; Adhikari, S.; Roy, S. C. Tetrahedron 1995, 51, 8389.
(10) (a) Azevedo, de M. B. M.; Murta, M. M.; Greene, A. E. J . Org.
Chem. 1992, 57, 4567. (b) Zhu, G.; Lu, X. J . Org. Chem. 1995, 60, 1087.
(c) Vaupel, A.; Knochel, P. Tetrahedron Lett. 1995, 36, 231. Sarkar,
S.; Ghosh, S. Tetrahedron Lett. 1996, 37, 4809.
(11) (a) Murta, M. M.; Azevedo, de M. B. M.; Greene, A. E. J . Org.
Chem. 1993, 58, 7587. (b) Sibi, M. P.; Despande, P. K.; Loggia, La A.
J . Synlett 1996, 343.
(12) Park, B. K.; Nakagawa, M.; Hirota, A.; Nakayama, M. J .
Antibiot. 1988, 41, 751.
(13) Zopf, W. Liebigs Ann. Chem. 1902, 324, 39. Zopf, W. Liebigs
Ann. Chem. 1904, 336, 46. Cavallito, C. J .; Fruehauf, D. M.; Bailey, J .
H. J . Am. Chem. Soc. 1948, 70, 3724.
(14) Chavdarian, C. G.; Heathcock, C. H. Synth. Commun. 1996, 6,
277.

Stereoselective Synthesis of Polysubstituted Tetrahydrofurans
J . Org. Chem., Vol. 63, No. 9, 1998 2831
Ta ble 1. Ra d ica l Cycliza tion of Ep oxid es Usin g
Tita n iu m (III) Ra d ica l Sou r ce
F igu r e 1.
transition complex for 1,5-intramolecular addition in
hex-5-enyl radical will comprise a structure somewhat
similar in dimensions to cyclohexane and existing pref-
erentially in a chairlike conformation. Consequently, in
our case, for 1,5-ring closure of 2-substituted hex-5-ynyl
radical, four “chairlike” transition complexes, A and B
where CH2OTi(IV) moiety lies up and C and D where
CH2OTi(IV) lies down, are possible (Figure 1). Here, the
transition complexes A and C which are equatorially
substituted R to the radical should be of lower free energy
than the axially substituted complexes B and D. Since
the R-substituent R and CH2OTi(IV) in the complex C
are cis, they will have some steric interactions as we
observe from the difference in the product distributions
upon cyclization by changing R from an aryl to an alkyl
group. It seems from the model that there might also
be some steric interaction between CH2OTi(IV) and
OCH2CtCH moieties since they come closer in the
complex C compared to A. The transition complex A will
have the lower free energy than C and therefore lies on
the pathway to the more stable product. Thus, prefer-
ential formation of trans product 4a -e derived from A
should occur. When the aryl group is replaced by an
alkyl group in 3f-h , a mixture of isomeric products in
4f-h is formed, probably through transition complexes
such as A and C, though one isomer always predomi-
nated. Therefore, the radical cyclization occurs without
retention of the stereochemistry of the epoxide. The
trans stereochemistry in 4b-c is precedented in our
earlier work9 and also from the published literature.17
The tetrahydrofurans 4b-c prepared by other methods
in our laboratory have already been used for the total
synthesis of furofuran lignans.9
Ster eoselective Tota l Syn th esis of (()-Meth ylen o-
la ctocin (1f) a n d (()-P r otolich ester in ic Acid (1 g).
The crude tetrahydrofuran derivatives 4f and 4g were
converted to two antitumor antibiotics, (()-methyleno-
lactocin (1f) and (()-protolichesterinic acid (1g), respec-
tively, in good overall yield. The inseparable isomeric
mixtures were used for this purpose (Scheme 6). It
seemed to us that probably the oxidation of the hy-
droxymethyl group as well as allylic oxidation of 4 might
occur in one pot, giving rise to the target molecules 1.
However, various methods for double oxidation were
unsuccessful, resulting only in an intractable mass. For
the successful approach, the free alcohol in 4 was
protected with 3,4-dihydro-2H-pyran in the presence of
a catalytic amount of pyridinium toluene-p-sulfonate
in 4f-h was determined from two distinguishable mul-
1
tiplets in the H NMR spectra for 3-H, e.g., for 4h two
multiplets centered at δ 2.45 for the major isomer and
at δ 2.65 for the minor one.
Sch em e 5
Since two isomers could not be separated, it was not
clear at this stage which isomer is which. The observed
stereochemistries of the products can be rationalized by
invoking well-known conformational effects in the inter-
mediates.15,16 It is well established that the intimate
(15) Beckwith, A. L. J .; Easton, C. J .; Lawrence, T.; Serelis, A. K.
Aust. J . Chem. 1983, 36, 545.
(16) Rajanbabu, T. V. Acc. Chem. Res. 1991, 24, 139.
(17) Andrey, O.; Ducry, L.; Landais, Y.; Planchenault, D.; Weber,
V. Tetrahedron 1997, 53, 4339.

2832 J . Org. Chem., Vol. 63, No. 9, 1998
Mandal et al.
Sch em e 6
tetrahydrofuran derivatives. Aryl epoxides 3a -e on
radical cyclization afforded the trans products 4a -e as
the only isolable compounds, whereas alkyl epoxides
3f-h led to a mixture of isomeric products 4f-h in a ratio
of 5:1. Some of these 2-aryl-3-(hydroxymethyl)-4-meth-
ylenetetrahydrofuran derivatives are important precur-
sors for biologically active natural lignans.8 We also
demonstrated here the use of tetrahydrofuran derivatives
4f and 4g by converting them to antitumor antibiotics
(()-methylenolactocin (1f) and (()-protolichesterinic acid
(1g), respectively, in good overall yield. Since R-substi-
tuted enantiomerically pure epoxides can be easily
prepared by Sharpless epoxidation, enantioselective syn-
thesis of several tetrahydrofuran derivatives as well as
oxacyclic natural products will not be very difficult. Work
in this direction is already ongoing in our laboratories.
Exp er im en ta l Section
(PPTS) to afford the tetrahydropyranyl (THP) ether 5 as
an inseparable diastereomeric mixture in 98% yield.
Crude 5 was oxidized with pyridinium dichromate (PDC)
in DMF18 to give the lactone 6 (63-66% yield) which was
treated with toluene-p-sulfonic acid (PTSA) in MeOH to
afford the lactone 7 in 93-94% yield as an inseparable
mixture of two diastereomers in a ratio of 5:1. The
presence of the γ-lactone moiety was confirmed by a
strong absorption at 1770 cm-1 for 7f and at 1760 cm-1
for 7g in the IR spectra. The ratio of the isomers in crude
The compounds described are all racemates. Melting points
were determined in open capillary tubes and are uncorrected.
Although some of the epoxides used are commercially avail-
able, we prepared all epoxides in our laboratory from the
corresponding vinyl alcohols according to the published pro-
cedure.14 1H and 13C NMR spectra were recorded in CDCl3
on 300 and 200 MHz NMR spectrometers. Diethyl ether and
tetrahydrofuran were distilled from sodium-benzophenone
ketyl. Dimethyl sulfoxide was freshly distilled from calcium
hydride. Elemental analyses were performed in our analytical
laboratories. Light petroleum of boiling range 60-80 °C was
used for chromatography.
1
7f was determined from the distinctive signals in the H
Typ ica l P r oced u r e for th e P r ep a r a tion of Ep oxy
Alcoh ols. P r ep a r a tion of 1-(3,4-(Meth ylen ed ioxy)p h en -
yl)-2,3-ep oxyp r op a n -1-ol (2b). To a stirred solution of
3-(3,4-(methylenedioxy)phenyl)-1-propen-3-ol (1 g, 5.6 mmol)
in chloroform (30 mL) at 0 °C was added portionwise m-
chloroperoxybenzoic acid (3.1 g, 40%, 7.3 mmol) over 30 min.
The resulting mixture was stirred at 0 °C for an additional 1
h and then left overnight at room temperature. It was diluted
with chloroform (20 mL), washed with a 10% aqueous sodium
sulfite solution (3 × 25 mL) followed by saturated aqueous
sodium bicarbonate (3 × 25 mL), and dried (Na2SO4). Solvent
was removed under reduced pressure and the residue obtained
was chromatographed over silica gel (15% ethyl acetate/light
petroleum) to yield the epoxide 2b (0.95 g, 88%) as a viscous
NMR spectrum for 4-H and 5-H which appeared as
multiplets centered at δ 2.87 and 4.38 for the major
isomer and at δ 3.22 and 4.57 for the minor isomer,
respectively. The ratio of isomers in 7g was determined
from four distinguishable doublets for the two olefinic
1
protons in the H NMR spectrum at δ 5.71 and 6.33 (J )
2.7 Hz) for the major isomer and at δ 5.69 and 6.29 (J )
2.1 Hz) for the minor isomer, respectively. All attempts
to separate the isomers at every stage by usual chro-
matographic methods were unsuccessful, and NOE ex-
periments or decoupling techniques could not help to
elucidate the stereochemistry of the two isomers of crude
7. Interestingly, on J ones oxidation, the crude lactone
7f afforded 1f as the only isolable product in 80% yield.
Similarly, the crude lactone 7g, upon J ones oxidation,
furnished only 1g as isolable compound in 80% yield.
Probably, isomerization of the epimerizable C-4 centers
in 7f and 7g under the strongly acidic J ones oxidation
conditions produced only the thermodynamically more
stable isomers of methylenolactocin 1f and protoliches-
terinic acid 1g, respectively, which were spectroscopically
and chromatographically identical with previously re-
ported samples.12,13
1
liquid: IR (neat) 3420 (br), 1500 cm-1; H NMR δ 2.61-2.91
(m, 2H), 3.05-3.09 (m, 1H), 4.25 (t, J ) 5 Hz, 1/2 H for one
isomer), 4.69 (s, 1/2 H for the other isomer), 5.85 (s, 2H), 6.68-
6.82 (m, 3H).
Compounds 1-phenyl-2,3-epoxypropan-1-ol (2a ), 1-(3,4-
dimethoxyphenyl)-2,3-epoxypropan-1-ol (2c), 1-(3-methoxy-4-
(benzyloxy)phenyl)-2,3-epoxypropan-1-ol (2d ), 1-naphthyl-2,3-
epoxypropan-1-ol (2e), 1-pentyl-2,3-epoxypropan-1-ol (2f),
1-tridecyl-2,3-epoxypropan-1-ol (2g), 1-isopropyl-2,3-epoxypro-
pan-1-ol (2h ), and 1,1-diphenyl-2,3-epoxypropan-1-ol (2i) were
prepared by the same procedure. For yields, see Table 1.
Typ ica l P r oced u r e for O-P r op -2-yn yla tion of Ep oxy
Alcoh ols. P r ep a r a tion of 1-(3,4-(Meth ylen ed ioxy)p h en -
yl)-1-(pr op-2-yn yloxy)-2,3-epoxypr opan e (3b). To a stirred
suspension of sodium hydride (0.32 g, 60% dispersion, 6.70
mmol) in dry tetrahydrofuran-dimethyl sulfoxide (10:1) (20
mL) was added dropwise a solution of epoxy alcohol 2b (1 g,
5.14 mmol) in dry tetrahydrofuran (10 mL) at room temper-
ature under nitrogen. After evolution of hydrogen ceased, a
solution of propargyl bromide (0.74 g, 6.16 mmol) in dry
tetrahydrofuran (10 mL) was added dropwise at 0 °C over 30
min. The reaction mixture was then stirred at room temper-
ature for 4 h and carefully quenched with ice-water. After
removal of most of the tetrahydrofuran under reduced pres-
sure, the resulting residue was extracted with diethyl ether
(3 × 30 mL). The ether extract was washed with saturated
brine and dried (Na2SO4). Removal of solvent under reduced
Con clu sion s
In the present paper, we have demonstrated the use
of radical cyclization of epoxides using a transition-metal
radical source for the construction of a variety of polysub-
stituted tetrahydrofuran derivatives. The radical cy-
clization reactions are stereo- and regioselective in
nature. Although simple-looking, this radical cyclization
sequence has, to the best of our knowledge, not been
previously applied to the preparation of polysubstituted
(18) Corey, E. J .; Schmidt, G. Tetrahedron Lett. 1979, 399.

Stereoselective Synthesis of Polysubstituted Tetrahydrofurans
J . Org. Chem., Vol. 63, No. 9, 1998 2833
pressure afforded a viscous liquid which was purified by
column chromatography over silica gel (5% ethyl acetate/light
petroleum) to furnish 3b (0.85 g, 82%) as a viscous liquid: IR
P r ep a r a tion of 2-Tr id ecyl-3-((tetr a h yd r op yr a n yloxy)-
m eth yl)-4-m eth ylen etetr a h yd r ofu r a n (5g). Compound 5g
was prepared from 4g using a procedure similar to that
described for 5f. Yield 98%.
1
(neat) 1600, 1490, 1440 cm-1; H NMR δ 2.43-2.44 (m, 1H),
2.61-2.82 (m, 2H), 3.16-3.20 (m, 1H), 3.93-4.08 (m, 1H),
4.16-4.29 (m, 11/2 H), 4.48 (d, J ) 4.2 Hz, 1/2 H), 5.85 (s,
2H), 6.68-6.83 (m, 3H). Anal. Calcd for C13H12O4: C, 67.23;
H, 5.21. Found: C, 67.37; H, 5.37.
Compounds 1-phenyl-1-(prop-2-ynyloxy)-2,3-epoxypropane
(3a ), 1-(3,4-dimethoxyphenyl)-1-(prop-2-ynyloxy)-2,3-epoxypro-
pane (3c), 1-(3-methoxy-4-(benzyloxy)phenyl)-1-(prop-2-ynyl-
oxy)-2,3-epoxypropane (3d ), 1-naphthyl-1-(prop-2-ynyloxy)-2,3-
epoxypropane (3e), 1-pentyl-1-(prop-2-ynyloxy)-2,3-epoxypropane
(3f), 1-tridecyl-1-(prop-2-ynyloxy)-2,3-epoxypropane (3g), 1-iso-
prpyl-1-(prop-2-ynyloxy)-2,3-epoxypropane (3h ), and 1,1-di-
phenyl-1-(prop-2-ynyloxy)-2,3-epoxypropane (3i) were prepared
by the same procedure. For yields, see Table 1.
P r ep a r a tion of 4-((Tetr a h yd r op yr a n yloxy)m eth yl)-3-
m eth ylen e-5-pen tyltetr ah ydr ofu r an -2-on e (6f). To a stirred
solution of tetrahydropyranyl ether 5f (0.6 g, 2.24 mmol) in
dry DMF (18 mL) was added pyridinium dichromate (8.43 g,
22.4 mmol) portionwise at room temperature during 1 h. The
reaction mixture was further stirred for 24 h, diluted with
water (25 mL), and extracted with ethyl acetate (4 × 25 mL).
The organic layer was washed with water (3 × 25 mL) and
dried (Na2SO4). The solvent was removed under reduced
pressure, and the residue obtained was chromatographed over
silica gel (10% ethyl acetate/light petroleum) to furnish the
lactone 6f (0.4 g, 63%) as a light yellow viscous liquid: IR
1
(neat) 1770, 1470 cm-1; H NMR δ 0.89 (t, J ) 6.4 Hz, 3H),
Typ ica l P r oced u r e for Ra d ica l Cycliza tion Rea ction .
P r ep a r a t ion of 2-(3,4-(Met h ylen ed ioxy)p h en yl)-3-(h y-
d r oxym eth yl)-4-m eth ylen etetr a h yd r ofu r a n (4b). A solu-
tion of titanocene dichloride (1 g, 4.02 mmol) in dry tetrahy-
drofuran (50 mL) was stirred with activated zinc dust (0.8 g,
12.1 mmol) for 1 h under argon (activated zinc dust was
prepared by washing 20 g of commercially available zinc dust
with 60 mL of 4 N HCl and thorough washing with water and
finally with dry acetone and then drying in vacuo). The
resulting green solution was then added dropwise to a stirred
solution of the epoxide 3b (0.47 g, 2 mmol) in dry tetrahydro-
furan (50 mL) at room temperature under argon during 30
min. The reaction mixture was stirred for an additional 1 h
and decomposed with 10% H2SO4 (100 mL). Most of the
solvent was removed under reduced pressure, and the residue
was extracted with diethyl ether (4 × 30 mL). The ether layer
was washed with saturated NaHCO3 (2 × 25 mL) and dried
(Na2SO4). After removal of solvent, the crude residue was
purified by column chromatography over silica gel (20% ethyl
acetate/light petroleum) to afford the alcohol 4b (0.36 g, 76%)
1.16-1.76 (several peaks, 14H), 2.90-3.0 (m, 1H), 3.37-3.57
(m, 2H), 3.70-3.94 (m, 2H), 4.30-4.38 (m, 1H), 4.55-4.63 (m,
1H), 5.65-5.72 (m, 1H), 6.24-6.30 (m, 1H). Anal. Calcd for
C
16H26O2: C, 68.05; H, 9.28. Found: C, 67.95; H, 9.22.
P r ep a r a tion of 4-((Tetr a h yd r op yr a n yloxy)m eth yl)-3-
m eth ylen e-5-tr id ecyltetr a h yd r ofu r a n -2-on e (6g). Com-
pound 6g was prepared from 5g by using a procedure similar
to that described for 6f. Yield 66%.
P r ep a r a tion of 4-(Hyd r oxym eth yl)-3-m eth ylen e-5-p en -
tyltetr a h yd r ofu r a n -2-on e (7f). To a stirred solution of
lactone 6f (0.2 g, 0.71 mmol) in methanol (4 mL) was added
p-toluenesulfonic acid monohydrate (15 mg, 0.08 mmol), and
the reaction mixture was stirred for 3 h at room temperature.
Most of the solvent was removed in vacuo, and the residue
was diluted with water (3 mL) and extracted with diethyl ether
(3 × 20 mL). The ether extract was washed with saturated
NaHCO3 and brine and dried (Na2SO4).
After removal of solvent, the residue obtained was purified
by column chromatography over silica gel (20% ethyl acetate/
light petroleum) to afford the hydroxy lactone 7f (0.13 g, 93%)
as a viscous oil: IR (neat) 3450 (br), 1770, 1470 cm-1; 1H NMR
δ 0.89 (t, J ) 6.6 Hz, 3H), 1.27-1.77 (m, 8H), 2.82-2.92 (m,
5/6 H), 3.18-3.30 (m, 1/6 H), 3.75 (d, J ) 6.2 Hz, 2H), 4.35-
4.41 (m, 5/6 H), 4.55-4.64 (m, 1/6 H), 5.69 (d, J ) 2.4 Hz, 1/6
H), 5.71 (d, J ) 2.3 Hz, 5/6 H), 6.30 (d, J ) 2.4 Hz, 1/6 H),
6.34 (d, J ) 2.4 Hz, 5/6 H). Anal. Calcd for C11H18O3: C, 66.64;
H, 9.15. Found: C, 66.51; H, 9.13.
1
as a viscous liquid: IR (neat) 3420 (br), 1610, 1490 cm-1; H
NMR δ 1.81 (brs, OH), 2.71-2.73 (m, 1H), 3.76 (dq, J ) 11.1,
4.8 Hz, 2H), 4.49 (q, J ) 12.6 Hz, 2H), 4.75 (d, J ) 7.2 Hz,
1H), 5.04-5.09 (m, 2H), 5.93 (s, 2H), 6.75-6.89 (m, 3H); 13C
NMR δ 53.9, 61.8, 71.2, 83.2, 100.9, 104.9, 106.6, 108.0, 119.8,
134.9, 147.1, 147.8, 148.5. This compound (4b) is identical
with the authentic sample prepared earlier in our labora-
tory.9
Compounds 2-phenyl-3-(hydroxymethyl)-4-methylenetetra-
hydrofuran (4a ), 2-(3,4-dimethoxyphenyl)-3-(hydroxymethyl)-
4-methylenetetrahydrofuran (4c),9 2-(3-methoxy-4-(benzyloxy)-
phenyl)-3-(hydroxymethyl)-4-methylenetetrahydrofuran (4d ),
2-naphthyl-3-(hydroxymethyl)-4-methylenetetrahydrofuran (4e),
2-pentyl-3-(hydroxymethyl)-4-methylenetetrahydrofuran (4f),
2-tridecyl-3-(hydroxymethyl)-4-methylenetetrahydrofuran (4g),
2-isopropyl-3-(hydroxymethyl)-4-methylenetetrahydrofuran (4h ),
and 2,2-diphenyl-3-(hydroxymethyl)-4-methylenetetrahydro-
furan (4i) were prepared by the same procedure. For yields,
see Table 1.
P r ep a r a tion of 4-(Hyd r oxym eth yl)-3-m eth ylen e-5-tr i-
d ecyltetr a h yd r ofu r a n -2-on e (7g). Compound 7g was pre-
pared from 6g by using a procedure similar to that described
for 7f. Yield 94%.
P r ep a r a tion of (()-Meth ylen ola ctocin (1f). A solution
of the hydroxy lactone 7f (90 mg, 0.45 mmol) in acetone (3
mL) was treated with freshly prepared J ones reagent at 0 °C
until a persistent orange color was observed. After 2 h of
stirring at 0 °C (progress of the reaction was monitored by
TLC), 2-propanol was added to destroy the excess reagent. The
reaction mixture was diluted with water (2 mL), and acetone
was removed under reduced pressure. The residue was
extracted with methylene chloride (4 × 10 mL). The organic
extract was washed with brine and dried (Na2SO4). Evapora-
tion of the solvent afforded a residue which was purified by a
short column of silica gel (chloroform-ethyl acetate-acetic
acid, 90:8:2) to give methylenolactocin (1f) (77 mg, 80%) as a
thick liquid: IR (neat) 3460, 1750, 1660, 1470 cm-1; 1H NMR
δ 0.80 (t, J ) 6.6 Hz, 3H), 1.15-1.55 (m, 6H), 1.62-1.74 (m,
2H), 3.54-3.59 (m, 1H), 4.75 (q, J ) 6 Hz, 1H), 5.96 (d, J )
2.6 Hz, 1H), 6.39 (d, J ) 3 Hz, 1H); 13C NMR δ 13.8, 22.3,
24.4, 31.3, 35.6, 49.5, 79.0, 125.8, 132.5, 168.4, 173.9.
P r ep a r a tion of (()-P r otolich ester in ic Acid (1 g). Com-
pound 1g was prepared from 7g by using a procedure similar
to that described for 1f. Yield 80%. 1f: crystalline solid; mp
105-107 °C; IR (KBr) 3460, 1750, 1660 cm-1; 1H NMR δ 0.87
(t, J ) 6.3 Hz, 3H), 1.25 (brs, 22H), 1.67-1.77 (m, 2H), 3.60-
3.64 (m, 1H), 4.80 (q, J ) 6 Hz, 1H), 6.01 (d, J ) 2.7 Hz, 1H),
6.46 (d, J ) 3 Hz, 1H); 13C NMR δ 13.9, 22.5, 24.6, 29.1, 29.2,
29.3, 29.5, 31.8, 35.6, 49.3, 78.7, 125.5, 132.4, 168.0, 173.1.
P r ep a r a tion of 2-P en tyl-3-((tetr a h yd r op yr a n yloxy)-
m eth yl)-4-m eth ylen etetr a h yd r ofu r a n (5f). A solution of
the alcohol 4f (0.7 g, 3.8 mmol), 3,4-dihydro-2H-pyran (0.48 g,
5.7 mmol), and pyridinium-p-toluenesulfonate (95 mg, 0.38
mmol) in dry methylene chloride (15 mL) was stirred for 5 h
at room temperature under nitrogen. The resulting reaction
mixture was diluted with methylene chloride, washed with
saturated NaHCO3 (3 × 25 mL), and dried (Na2SO4). After
evaporation of the solvent, the crude residue was purified by
column chromatography over silica gel (2% ethyl acetate/light
petroleum) to afford 5f (1 g, 98%) as a viscous liquid: IR (neat)
1
1470, 1450 cm-1; H NMR δ 0.87 (t, J ) 6.6 Hz, 3H), 1.16-
1.83 (m, 14H), 2.49-2.58 (m, 1H), 3.45-3.52 (m, 2H), 3.73-
3.87 (m, 3H), 4.29 (dq, J ) 10.6, 2.1 Hz, 2H), 4.54-4.82 (m,
1H), 4.93-5.01 (m, 2H); 13C NMR δ 13.9, 19.1, 19.3, 19.7, 22.5,
22.6, 25.3, 25.4, 25.6, 25.7, 30.4, 30.5, 30.6, 31.7, 31.8, 34.5,
34.6, 48.5, 48.8, 61.7, 62.1, 62.8, 68.6, 68.8, 70.4, 70.5, 83.3,
83.6, 94.5, 98.3, 99.0, 104.6, 104.8, 149.6, 149.7. Anal. Calcd
for C16H28O3: C, 71.60; H, 10.51. Found: C, 71.28; H, 10.45.

2834 J . Org. Chem., Vol. 63, No. 9, 1998
Mandal et al.
5f-g, 6f-g, and 7f-g and 13C NMR spectral data of com-
pounds 1f-g, 3f-g, 4a , 4c-i, 5f-g, and 7g (4 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
Ack n ow led gm en t. We thank CSIR, New Delhi, for
financial support. P.K.M. is a Senior Research Fellow
under that project. G.M. thanks UGC, New Delhi, for
awarding a Senior Research Fellowship.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectral
data for compounds 1f-g, 2a , 2c-i, 3a , 3c-i, 4a , 4c-i,
J O971526D