Access to enantiopure 2,5-diaryltetrahydrofurans - Application to the synthesis of (-)-virgatusin and (+)-urinaligran

Article abstract of DOI:10.1002/ejoc.200900099

The diastereoselective Mn^m-promoted radical addition of (3- oxoesters 1 onto N-cinnamoyloxazolidinones 2 afforded 2,3- dihydrofurans 3. After catalytic hydrogenation of the C=C bond, followed by reductive removal of the chiral auxiliary, the re

Full text of DOI:10.1002/ejoc.200900099

FULL PAPER
DOI: 10.1002/ejoc.200900099
Access to Enantiopure 2,5-Diaryltetrahydrofurans – Application to the
Synthesis of (–)-Virgatusin and (+)-Urinaligran
Sophie Martinet,[a] Alain Méou,*[b] and Pierre Brun[a][†]
Keywords: Manganese / Asymmetric synthesis / Radical reactions / Total synthesis / Chiral auxiliaries
The diastereoselective MnIII-promoted radical addition of β-
oxoesters 1 onto N-cinnamoyloxazolidinones 2 afforded 2,3-
dihydrofurans 3. After catalytic hydrogenation of the C=C
bond, followed by reductive removal of the chiral auxiliary,
the resulting enantiopure tetrahydrofurans 5 were trans-
formed in two steps into naturally occurring (–)-virgatusin
and (+)-urinaligran and two other, nonnatural, tetrasubsti-
tuted THF lignans.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
2,5-Diaryltetrahydrofuran (2,5-diaryl-THF) lignans con-
stitute an important subgroup of the extended family of
natural lignans.[1] A great number of these THF lignans
possess interesting biological and pharmacological proper-
ties (antitumor, antibacterial, antifungal, antioxidant).[2]
They differ from each other by the substitution pattern on
Ar1 and Ar2, the nature of R1 and R2, and by the stereo-
chemistry (relative and absolute) about the four contiguous
stereocenters (Figure 1). To this day, 2,5-diaryl-THF lig-
nans possessing the trans,trans,cis relative stereochemistry
have received the most attention and constitute the major
group for which a total synthesis has been reported (Fig-
ure 1).[3] These syntheses suffer, nevertheless, from one or
two major drawbacks: they are somewhat lengthy, as they
are rather linear and/or they are not totally diastereoselec-
tive, which results in poor overall yield in the desired target.
In order to overcome these shortcomings, we envisioned
to prepare enantiopure 2,5-diaryl-THF lignans possessing
the trans,trans,cis relative stereochemistry (taking virgatusin
as a model compound) by a shorter (more convergent) and
highly stereocontrolled route according to the initial retro-
synthetic analysis depicted in Scheme 1 (path a). This
scheme rested upon our previous works concerning the
asymmetric synthesis and utilization of enantiopure tetra-
substituted 2,3-dihydrofurans.[4] The two key steps, each in-
volving the concomitant creation of two stereocenters, are
the radical oxidative addition[5] of methyl benzoylacetate
1[6] to phenyl-substituted cinnamic acid 2 bearing a chiral
auxiliary[7] followed by the reduction of the prochiral C=C
Figure 1. General structure of 2,5-diaryl-THF lignans and struc-
tures of previously synthesized trans,trans,cis-2,5-diaryl-THF lig-
nans.
bond of the 2,3-dihydrofuran thus formed, after removal of
the chiral auxiliary. As already shown, the absolute configu-
ration at C2 and C3 can be controlled by the chiral auxil-
iary.[4,8] For this purpose, 4-substituted 1,3-oxazolidin-2-
ones have proven their efficacy and their versatility: they
can be readily grafted onto the cinnamic moiety, they toler-
ate the harsh conditions of the oxidative addition step, and
they can be smoothly removed from the adduct to furnish
at will an acid, an ester, or a primary alcohol. Besides, the
absolute configuration at C4 and C5 could be controlled by
catalytic hydrogenation performed on an enantiopure dihy-
drofuran precursor.
A preliminary study conducted on racemic dihydrofurans
with a methoxycarbonyl group at C3 (H2, 10% Pd/C,
EtOAc, 1 bar, r.t.) showed that this step was not totally dia-
stereoselective, giving predominantly the expected dia-
stereomer accompanied by a minor one (10–20%, de-
pending on Ar1 and Ar2), which could not be separated
either at this stage or in a subsequent step. This fact has
also been reported, during the course of our work, in the
[a] GCOM2, UMR 6114, Faculté des Sciences de Luminy,
163 Avenue de Luminy, 13288 Marseille Cedex 9, France
[b] CINaM, UPR 3118, Faculté des Sciences de Luminy,
163 Avenue de Luminy, 13288 Marseille Cedex 9, France
Fax: +33-4-91829304
E-mail: meou@cinam.univ-mrs.fr
[†] Deceased.
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Eur. J. Org. Chem. 2009, 2306–2311

Access to Enantiopure 2,5-Diaryltetrahydrofurans
Scheme 1. Initial (a) and modified (b) retrosynthetic analyses of (–)-virgatusin and congeners.
synthesis of a closely related compound.[9] We thus decided LiAlH4 reduction of the methyl ester. In all cases, it ap-
to reinvestigate this crucial step. Fortunately, when we per- peared that the two-step procedure gave consistently a bet-
formed the catalytic hydrogenation by using the same exper- ter overall yield of the desired diol. Accordingly, we modi-
imental conditions on a dihydrofuran with an achiral N- fied our initial retrosynthetic analysis: to accommodate
oxazolidinylcarbonyl substituent at C3, it could be rendered these new findings, the chiral auxiliary had to be removed
entirely diastereoselective, furnishing quantitatively the sin- after the hydrogenation step and by reductive cleavage
gle trans,trans,cis diastereomer (Scheme 2).[10]
(Scheme 1, path b).
The synthesis of (Ϯ)-virgatusin 6AB[12] was then realized
uneventfully according to this scheme. It nevertheless al-
lowed us to find out that the overall yield of 6AB could be
optimized by conducting the dimethylation reaction on the
crude diol immediately after LiAlH4 reduction and that
only two chromatographic purifications were required: one
after the first step and one after the last step (Scheme 3).
With our final retrosynthetic analysis thus validated, in
order to obtain (–)-virgatusin we had next to focus on the
first step and find a chiral auxiliary able to furnish desired
adduct 3AB in optimal yield and diastereoselectivity. We
already knew that to access (2R,3S,4S,5S)-(–)-virgatusin we
had to employ a (S)-4-substituted oxazolidinone.[4] We
therefore screened three of them that had previously given
the best diastereoselectivity in the oxidative addition step
(Table 1 and Scheme 4). As expected, the diphenylmethyl-
oxazolidinone chiral auxiliary gives the best result in
terms of diastereoselectivity but the two diastereomers
3ABd/3ЈABd could not be efficiently separated by silica-gel
chromatography. However, tert-butyloxazolidinone as a chi-
Scheme 2. Diastereoselectivity of the hydrogenation step.
Results and Discussion
At this stage, we could prepare the requisite diol by two ral auxiliary was also efficient, and in this case, major dia-
possible routes: either simultaneous reduction of the two stereomer 3ABc could be obtained pure in a significantly
C=O groups by LiAlH4 or initial reductive removal better yield (45%) after careful chromatography. The hydro-
(NaBH4, THF/H2O) of the oxazolidinone[11] followed by genation step was then carried out by using the same condi-
Eur. J. Org. Chem. 2009, 2306–2311
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S. Martinet, A. Méou, P. Brun
FULL PAPER
Scheme 3. Synthesis of (Ϯ)-virgatusin (6AB).
tions employed in the racemic synthesis (Scheme 3) to give
quantitatively a single compound (4ABc), which was trans-
formed into (–)-virgatusin (6AB; Scheme 5).
Table 1. Addition of methyl benzoylacetate 1A to N-cinnamoyl-
oxazolidinones 2Bb–d.
2B
Time [h]
Unchanged
3AB +
3ЈAB
[%]
3AB/3ЈAB
2B [%]
b (R = Bn)
c (R = tBu)
d (R = Ph2CH)
4
3
5
27
30
20
58
52
40
75:25
88:12
90:10
Scheme 4. Addition of methyl benzoylacetate 1A to N-cinnamoyl-
oxazolidinones 2Bb–d.
Scheme 5. Total synthesis of (–)-virgatusin (6AB), (+)-urinaligran (6AA), (+)-6BA, and (–)-6BB.
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Access to Enantiopure 2,5-Diaryltetrahydrofurans
or 2B (1 mmol), and Mn(OAc)3·2H2O (590 mg, 2.2 mmol) in
AcOH (10 mL) was heated at 70 °C until complete discoloration.
After cooling, H2O (5 mL) was added, and the mixture was ex-
tracted with Et2O (3ϫ10 mL). The combined organic layer was
washed with saturated aqueous NaHCO3 and dried with MgSO4.
Evaporation of the solvent afforded the crude product, which was
purified by flash chromatography.
Having successfully achieved the total synthesis of (–)-
virgatusin (6AB)[13] in five steps and 20% overall yield from
1A and 2Bc, we extended this approach to the preparation
of three of its congeners by employing consistently (S)-4-
tert-butyl-1,3-oxazolidin-2-one as the chiral auxiliary for
the oxidative addition step (Table 2). We thus obtained
enantiopure (+)-urinaligran (6AA),[14] (+)-6BA, and (–)-
6BB in 8.2, 12.4, and 25.4% overall yield, respectively, over
five steps (Scheme 5).
Dihydrofuran 3ABb: The general procedure was applied starting
from 1A (222 mg, 1 mmol) and 2Bb (367 mg, 1 mmol). The crude
product was purified by flash chromatography (hexane/EtOAc, 9:1
to 1:1) to give first 3ABb (190 mg, 0.32 mmol, 32% yield) then a
mixture of 3ABb and 3ЈABb (82 mg, 0.14 mmol, 14% yield), and
finally pure 3ЈABb (71 mg, 0.12 mmol, 12% yield). Data for 3ABb:
Table 2. Addition of methyl benzoylacetate 1A or 1B to N-cinnam-
oyloxazolidinone 2Ac or 2Bc.
1/2c
Time
[h]
Unchanged
2c [%]
3c + 3Јc
[%]
3c/3Јc
1
[α]2D5 = –43.5 (c = 1.00, CHCl3). H NMR (250 MHz, CDCl3): δ =
2.81 (dd, J = 13.3, 9.0 Hz, 1 H), 3.20 (dd, J = 13.3, 3.4 Hz, 1 H),
3.56 (s, 3 H), 3.81 (s, 3 H), 3.83 (s, 3 H), 4.10–4.30 (m, 2 H), 4.85
(m, 1 H), 5.65 (d, J = 6.9 Hz, 1 H), 5.78 (d, J = 6.9 Hz, 1 H), 5.95
(s, 2 H), 6.80 (m, 2 H), 6.96 (m, 3 H), 7.10 (m, 4 H), 7.40 (m, 2 H)
ppm. 13C NMR (62 MHz, CDCl3): δ = 38.15, 51.31, 53.90, 54.33,
55.96, 56.03, 66.38, 86.21, 101.53, 102.12, 107.77, 109.53, 110.04,
111.02, 119.02, 122.74, 124.95, 127.48, 128.98 (2 C), 129.49 (2 C),
130.97, 134.94, 147.12, 149.21, 149.47, 149.92, 153.32, 164.62,
166.67, 173.42 ppm. C32H29NO10 (587.58): calcd. C 65.41, H 4.97,
1A/2Ac
4.5
2Ac [25]
2Ac [13]
2Bc [23]
3AAc +
3ЈAAc
[30]
3BAc +
3ЈBAc
[31]
3BBc +
3ЈBBc
[45]
3AAc/3ЈAAc
88:12
3BAc/3ЈBAc
1B/2Ac
1B/2Bc
4
77:23
3BBc/3ЈBBc
4
87:13
N 2.38; found C 65.48, H 4.92, N 2.44. Data for 3ЈABb: [α]2D5
=
1
+131.4 (c = 1.00, CHCl3). H NMR (250 MHz, CDCl3): δ = 2.66
(dd, J = 13.3, 10.3 Hz, 1 H), 3.28 (dd, J = 13.3, 2.7 Hz, 1 H), 3.61
(s, 3 H), 3.81 (s, 3 H), 3.83 (s, 3 H), 4.12 (d, J = 4.7 Hz, 2 H), 4.65
(m, 1 H), 5.63 (d, J = 6.8 Hz, 1 H), 5.83 (d, J = 6.8 Hz, 1 H), 5.95
(s, 2 H), 6.80 (m, 3 H), 6.96 (m, 2 H), 7.10 (m, 4 H), 7.40 (m, 2 H)
ppm. 13C NMR (62 MHz, CDCl3): δ = 37.41, 51.27, 54.16, 54.35,
55.99, 56.03, 66.00, 86.20, 101.51, 102.18, 107.77, 109.62, 110.01,
111.02, 119.10, 122.68, 124.93, 127.38, 129.04 (2 C), 129.44 (2 C),
130.92, 135.41, 147.13, 149.22, 149.53, 149.91, 153.32, 164.51,
166.69, 173.54 ppm. C32H29NO10 (587.58): calcd. C 65.41, H 4.97,
N 2.38; found C 65.27, H 5.02, N 2.35.
Conclusions
We have devised a short synthesis of enantiopure 2,5-
diaryl-THF lignans possessing the trans,trans,cis relative
stereochemistry. We have thus prepared in five steps two
natural, (–)-virgatusin and (+)-urinaligran, and two nonnat-
ural THF lignans from readily available starting com-
pounds. This convergent, modular, and versatile strategy
could be extended to the synthesis of other enantiopure 2,5-
diaryl-THF lignans endowed with the same stereochemistry
or of other diastereomers provided that the C=C bond
could be reduced by a means other than the catalytic hydro-
genation employed in this work, which we are currently in-
vestigating.
Dihydrofuran 3ABc: The general procedure was applied starting
from 1A (222 mg, 1 mmol) and 2Bc (333 mg, 1 mmol). The crude
product was purified by flash chromatography (hexane/EtOAc, 9:1
to 1:1) to give first 3ABc (249 mg, 0.45 mmol, 45% yield) then a
mixture of 3ABc and 3ЈABc (38.7 mg, 0.07 mmol, 7% yield). Data
for 3ABc: [α]2D5 = –35.1 (c = 1.13, CHCl3). 1H NMR (250 MHz,
CDCl3): δ = 0.85 (s, 9 H), 3.55 (s, 3 H), 3.81 (s, 6 H), 4.24 (d, J =
5.0 Hz, 2 H), 4.82 (d, J = 5.0 Hz, 1 H), 5.72 (d, J = 8.0 Hz, 1 H),
5.86 (d, J = 8.0 Hz, 1 H), 5.93 (s, 2 H), 6.75 (m, 2 H), 6.96 (m, 2
H), 7.29 (d, J = 1.6 Hz, 1 H), 7.38 (dd, J = 8.2, 1.6 Hz, 1 H) ppm.
13C NMR (62 MHz, CDCl3): δ = 25.64 (3 C), 35.60, 51.28, 53.61,
55.95 (2 C), 61.68, 65.42, 86.95, 101.52, 102.53, 107.73, 109.30,
109.98, 111.03, 118.94, 122.75, 124.87, 130.86, 147.07, 149.18,
149.41, 149.84, 154.80, 164.62, 166.45, 173.63 ppm. C29H31NO10
(553.56): calcd. C 62.92, H 5.64, N 2.53; found C 62.78, H 5.72, N
2.55.
Experimental Section
General Remarks: All NMR spectra were recorded with a Bruker
AC 250 spectrometer (1H 250 MHz; 13C 62 MHz). Chemical shifts
are reported in ppm. The following abbreviations are used in re-
porting spectra: s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, dd = doublet of doublets, br. s = broad singlet.
Optical rotations were measured with a Perkin–Elmer 241 polari-
meter in a 1-dm cell.
Materials: All experiments were conducted under an atmosphere
of nitrogen unless indicated otherwise, and the reaction mixtures
were stirred magnetically. Mn(OAc)3·2H2O (Aldrich) and 10% Pd/
C (Aldrich) were used as received. THF was distilled from sodium
benzophenone–ketyl immediately prior to use. Flash chromatog-
raphy was performed with Merck silica-gel 60 H. Thin-layer
chromatography (TLC) was carried out on Merck silica-gel 60 F254
aluminum-backed-plates. TLC visualization was done with a
254 nm UV lamp and phosphomolybdic acid staining solution.
Dihydrofuran 3ABd: The general procedure was applied starting
from 1A (222 mg, 1 mmol) and 2Bd (443 mg, 1 mmol). The crude
product was purified by flash chromatography (hexane/EtOAc, 9:1
to 1:1) to give first 3ABd (133 mg, 0.20 mmol, 20% yield) then a
mixture of 3ABd and 3ЈABd (132 mg, 0.20 mmol, 20% yield). Data
for 3ABd: [α]2D5 = +10.0 (c = 1.00, CHCl3). 1H NMR (250 MHz,
CDCl3): δ = 3.55 (s, 3 H), 3.80 (s, 3 H), 3.83 (s, 3 H), 4.30–4.40
(m, 2 H), 4.61 (d, J = 6.8 Hz, 1 H), 5.14 (d, J = 6.5 Hz, 1 H), 5.40
(m, 1 H), 5.64 (d, J = 6.8 Hz, 1 H), 5.93 (s, 2 H), 6.70–7.40 (m, 16
H) ppm. 13C NMR (62 MHz, CDCl3): δ = 51.28, 51.64, 53.54,
55.96, 56.03, 60.44, 65.53, 85.91, 101.51, 101.87, 107.73, 109.47,
General Procedure for the Oxidative Addition: A mixture of methyl
benzoylacetate 1A or 1B (1 mmol), N-cinnamoyloxazolidinone 2A
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S. Martinet, A. Méou, P. Brun
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109.99, 110.99, 118.95, 122.74, 124.89 (2 C), 127.17, 127.92 (2 C),
128.47 (2 C), 128.69 (2 C), 129.04, 129.25, 131.14, 138.05, 139.30,
147.09, 149.12, 149.36, 149.86, 153.39, 164.64, 166.63, 172.97 ppm.
C38H33NO10 (663.68): calcd. C 68.77, H 5.01, N 2.11; found C
68.88, H 4.96, N 2.03.
81.12, 84.14, 100.02, 106.49, 106.92, 109.70, 109.79, 119.21, 119.46,
129.16, 130.12, 146.28, 146.40, 147.98, 148.35, 152.62, 171.26,
172.38 ppm.
1
Tetrahydrofuran 4AAc: H NMR (250 MHz, CDCl3): δ = 0.75 (s,
9 H), 3.27 (s, 3 H), 3.60 (dd, J = 8.2, 5.0 Hz, 1 H), 4.11 (m, 2 H),
4.24 (m, 1 H), 4.39 (dd, J = 8.0, 5.6 Hz, 1 H), 5.10 (d, J = 8.2 Hz,
1 H), 5.20 (d, J = 7.8 Hz, 1 H), 5.87 (s, 2 H), 5.90 (s, 2 H), 6.65–
6.95 (m, 6 H) ppm. 13C NMR (62 MHz, CDCl3): δ = 24.50 (3 C),
34.70, 50.87, 51.83, 54.83, 60.06, 64.03, 81.27, 83.82, 100.02,
100.10, 106.12, 106.81, 106.95, 107.04, 119.10, 120.19, 129.78,
131.05, 146.28, 146.40, 146.91, 146.96, 152.64, 170.32, 171.34 ppm.
Dihydrofuran 3AAc: The general procedure was applied starting
from 1A (222 mg, 1 mmol) and 2Ac (317 mg, 1 mmol). The crude
product was purified by flash chromatography (hexane/EtOAc, 9:1
to 1:1) to give first 3AAc (129 mg, 0.24 mmol, 24% yield) then a
mixture of 3AAc and 3ЈAAc (32 mg, 0.06 mmol, 6% yield). Data
for 3AAc: [α]2D6 = –38.3 (c = 1.00, CHCl3). 1H NMR (250 MHz,
CDCl3): δ = 0.87 (s, 9 H), 3.55 (s, 3 H), 4.25 (m, 2 H), 4.44 (m, 1
H), 5.63 (d, J = 7.5 Hz, 1 H), 5.73 (d, J = 7.5 Hz, 1 H), 5.91 (s, 2
H), 5.94 (s, 2 H), 6.65–6.85 (m, 6 H) ppm. 13C NMR (62 MHz,
CDCl3): δ = 25.68 (3 C), 36.63, 51.30, 54.07, 61.71, 65.45, 86.75,
101.32, 101.52, 102.23, 106.58, 107.73, 108.31, 110.01, 120.09,
122.67, 124.92, 132.71, 147.05, 148.11, 148.19, 149.86, 154.73,
164.61, 166.50, 173.56 ppm. C28H27NO10 (537.58): calcd. C 62.56,
H 5.06, N 2.62; found C 62.42, H 5.13, N 2.65.
Tetrahydrofuran 4BAc: 1H NMR (250 MHz, CDCl3): δ = 0.75 (s, 9
H), 3.22 (s, 3 H), 3.61 (dd, J = 7.6, 5.6 Hz, 1 H), 3.80 (s, 3 H), 3.82
(s, 3 H), 4.10 (m, 2 H), 4.20 (m, 1 H), 4.39 (dd, J = 8.0, 5.6 Hz, 1
H), 5.05 (d, J = 7.6 Hz, 1 H), 5.25 (d, J = 8.0 Hz, 1 H), 5.90 (s, 2
H), 6.70–6.95 (m, 6 H) ppm. 13C NMR (62 MHz, CDCl3): δ =
24.48 (3 C), 34.68, 50.83, 52.15, 54.79, 54.85, 54.90, 60.03, 63.99,
81.23, 82.42, 100.06, 106.63, 107.00, 108.86, 109.67, 118.80, 120.04,
127.36, 131.48, 146.31, 147.20, 148.14, 148.25, 152.63, 170.40,
172.29 ppm.
Dihydrofuran 3BAc: The general procedure was applied starting
from 1B (238 mg, 1 mmol) and 2Ac (317 mg, 1 mmol). The crude
product was purified by flash chromatography (hexane/EtOAc, 9:1
to 1:1) to give first 3BAc (120 mg, 0.22 mmol, 22% yield) then a
mixture of 3BAc and 3ЈBAc (50 mg, 0.09 mmol, 9% yield). Data
for 3BAc: [α]2D3 = –46.6 (c = 1.00, CHCl3). 1H NMR (250 MHz,
CDCl3): δ = 0.87 (s, 9 H), 3.56 (s, 3 H), 3.83 (s, 3 H), 3.85 (s, 3 H),
4.10 (m, 2 H), 4.40 (m, 1 H), 5.62 (d, J = 7.5 Hz, 1 H), 5.80 (d, J
= 7.5 Hz, 1 H), 5.90 (s, 2 H), 6.65–6.85 (m, 6 H) ppm. 13C NMR
(62 MHz, CDCl3): δ = 25.68 (3 C), 35.63, 51.23, 54.24, 55.94, 56.00,
61.71, 65.43, 86.73, 101.32, 102.08, 106.64, 108.30, 110.07, 112.80,
120.12, 121.44, 123.44, 132.77, 147.96, 148.11, 148.20, 151.33,
154.73, 164.67, 166.69, 173.69 ppm. C29H31NO10 (553.56): calcd. C
62.92, H 5.64, N 2.53; found C 63.01, H 5.68, N 2.48.
Tetrahydrofuran 4BBc: 1H NMR (250 MHz, CDCl3): δ = 0.70 (s, 9
H), 3.23 (s, 3 H), 3.60 (dd, J = 6.7, 5.1 Hz, 1 H), 3.75 (s, 3 H), 3.77
(s, 3 H), 3.80 (s, 3 H), 3.81 (s, 3 H), 4.15 (m, 1 H), 4.22 (m, 2 H),
4.38 (dd, J = 8.5, 5.1 Hz, 1 H), 5.22 (d, J = 6.7 Hz, 1 H), 5.45 (d,
J = 8.5 Hz, 1 H), 6.25 (dd, J = 8.6, 2.8 Hz, 1 H), 6.70–7.00 (m, 5
H) ppm. 13C NMR (62 MHz, CDCl3): δ = 24.48 (3 C), 34.68, 50.82,
52.23, 54.72, 54.80, 54.85, 54.88, 54.91, 60.03, 63.99, 81.16, 83.86,
108.54, 109.58, 109.67, 109.73, 119.12 (2 C), 127.36, 130.18, 147.52,
147.59, 148.13, 148.25, 152.63, 170.55, 171.18 ppm.
General Procedure for the Reductive Removal of the Oxazolidinone:
A mixture of compound 4c (0.50 mmol) and NaBH4 (76 mg,
2 mmol) in THF (2 mL) and H2O (0.5 mL) was stirred at room
temperature for 6 h. Aqueous HCl (2 , 5 mL) was added, and the
mixture was extracted with EtOAc (3ϫ5 mL). The combined or-
ganic layer was washed with saturated aqueous NaCl and dried
with MgSO4. Evaporation of the solvent afforded crude tetra-
hydrofuran 5 in quantitative yield and of sufficient purity to be
directly used in the next step.
Dihydrofuran 3BBc: The general procedure was applied starting
from 1B (238 mg, 1 mmol) and 2Bc (333 mg, 1 mmol). The crude
product was purified by flash chromatography (hexane/EtOAc, 9:1
to 1:1) to give first 3BBc (210 mg, 0.37 mmol, 37% yield) then a
mixture of 3BBc and 3ЈBBc (45 mg, 0.08 mmol, 8% yield). Data
for 3BBc: [α]2D6 = –18.5 (c = 1.00, CHCl3). 1H NMR (250 MHz,
CDCl3): δ = 0.85 (s, 9 H), 3.56 (s, 3 H), 3.81 (s, 6 H), 3.83 (s, 3 H),
3.85 (s, 3 H), 4.20 (m, 2 H), 4.40 (m, 1 H), 5.73 (d, J = 8.1 Hz, 1
H), 5.89 (d, J = 8.1 Hz, 1 H), 6.78–6.84 (m, 2 H), 6.94–7.00 (m, 2
H), 7.44–7.50 (m, 2 H) ppm. 13C NMR (62 MHz, CDCl3): δ =
24.62 (3 C), 36.63, 51.23, 52.76, 54.91 (2 C), 54.96 (2 C), 60.64,
64.38, 85.90, 101.31, 108.32, 109.00, 110.00, 111.71, 117.99, 120.48,
122.38, 129.88, 146.91, 148.15, 148.38, 150.25, 153.78, 163.70,
165.66, 172.73 ppm. C30H35NO10 (569.67): calcd. C 63.25, H 6.19,
N 2.46; found C 63.31, H 6.11, N 2.51.
1
Tetrahydrofuran 5AB: H NMR (250 MHz, CDCl3): δ = 2.55 (br.
s, 1 H), 2.85 (m, 1 H), 3.23 (s, 3 H), 3.40 (dd, J = 8.7, 7.0 Hz, 1
H), 3.50 (m, 2 H), 3.82 (s, 3 H), 3.87 (s, 3 H), 4.60 (d, J = 9.0 Hz,
1 H), 5.10 (d, J = 8.7 Hz, 1 H), 5.87 (s, 2 H), 6.70–6.90 (m, 4 H),
7.00 (dd, J = 8.2, 1.8 Hz, 1 H), 7.15 (d, J = 1.8 Hz, 1 H) ppm. 13C
NMR (62 MHz, CDCl3): δ = 51.63, 52.21, 53.72, 55.92 (2 C), 61.50,
81.65, 82.90, 100.98, 107.24, 107.81, 110.28, 110.93, 119.64, 120.14,
132.19 (2 C), 147.11, 147.33, 149.00, 150.01, 172.82 ppm.
1
Tetrahydrofuran 5AA: H NMR (250 MHz, CDCl3): δ = 2.60 (br.
General Procedure for the Hydrogenation Step: A solution of 3c
(0.10 mmol) in EtOAc (5 mL) was stirred with 10% Pd on charcoal
(60 mg). The mixture was thoroughly deoxygenated by bubbling H2
for 10 min and kept under H2 (1 bar) at room temperature for 48 h.
Pd was filtered through Celite, which was then rinsed with EtOAc
(3ϫ10 mL). Evaporation of the solvent afforded crude tetra-
hydrofuran 4c in quantitative yield and of sufficient purity to be
directly used in the next step.
s, 1 H), 2.78 (m, 1 H), 3.21 (s, 3 H), 3.40 (m, 1 H), 3.65 (m, 2 H),
4.58 (d, J = 9.0 Hz, 1 H), 5.10 (d, J = 8.7 Hz, 1 H), 5.87 (s, 2 H),
5.90 (s, 2 H), 6.66–6.84 (m, 4 H), 6.90 (dd, J = 8.0, 1.6 Hz, 1 H),
7.08 (d, J = 1.6 Hz, 1 H) ppm. 13C NMR (62 MHz, CDCl3): δ =
50.65, 51.39, 52.63, 60.14, 80.56, 81.73, 99.99, 100.09, 106.21,
106.46, 106.82, 107.09, 119.11, 119.79, 130.99, 132.62, 146.09,
146.29, 146.56, 146.94, 171.87 ppm.
Tetrahydrofuran 4ABc: 1H NMR (250 MHz, CDCl3): δ = 0.70 (s, 9
H), 3.27 (s, 3 H), 3.61 (dd, J = 7.6, 5.4 Hz, 1 H), 3.81 (s, 3 H), 3.87
Tetrahydrofuran 5BA: H NMR (250 MHz, CDCl3): δ = 2.63 (br.
1
s, 1 H), 2.80 (m, 1 H), 3.17 (s, 3 H), 3.40 (m, 1 H), 3.79 (s, 3 H),
(s, 3 H), 4.10 (m, 2 H), 4.20 (m, 1 H), 4.39 (dd, J = 7.8, 5.4 Hz, 1 3.82 (s, 3 H), 4.15 (d, J = 5.8 Hz, 2 H), 4.60 (d, J = 9.0 Hz, 1 H),
H), 5.05 (d, J = 7.6 Hz, 1 H), 5.10 (d, J = 7.8 Hz, 1 H), 5.89 (s, 2
5.15 (d, J = 8.6 Hz, 1 H), 5.90 (s, 2 H), 6.65–6.95 (m, 5 H), 7.10
H), 6.65–7.05 (m, 6 H) ppm. 13C NMR (62 MHz, CDCl3): δ = (d, J = 1.5 Hz, 1 H) ppm. 13C NMR (62 MHz, CDCl3): δ = 50.62,
24.46 (3 C), 34.66, 50.82, 52.00, 54.77, 54.84, 54.87, 60.00, 63.94, 51.44, 52.67, 54.84, 54.87, 60.46, 80.70, 81.79, 100.08, 106.49,
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2306–2311

Access to Enantiopure 2,5-Diaryltetrahydrofurans
107.08, 108.81, 109.56, 118.07, 119.82, 129.74, 132.83, 146.56,
146.96, 147.44, 147.53, 171.94 ppm.
1 H), 2.55 (m, 1 H), 3.05 (m, 2 H), 3.00 (s, 3 H), 3.30 (s, 3 H), 3.49
(m, 2 H), 3.81 (s, 3 H), 3.82 (s, 3 H), 3.83 (s, 3 H), 3.85 (s, 3 H),
4.68 (d, J = 8.0 Hz, 1 H), 5.06 (d, J = 7.2 Hz, 1 H), 6.70–7.05 (m,
6 H) ppm. 13C NMR (62 MHz, CDCl3): δ = 45.66, 49.67, 54.74,
54.81, 54.87, 56.97, 57.53, 57.78, 72.07, 72.18, 81.58, 81.65, 106.85,
107.04, 108.00, 108.71, 118.57, 119.00, 131.64, 134.54, 145.56,
145.98, 146.38, 146.74 ppm. C24H32O7 (432.51): calcd. C 66.65, H
7.46; found C 66.54, H 7.52.
1
Tetrahydrofuran 5BB: H NMR (250 MHz, CDCl3): δ = 2.58 (br.
s, 1 H), 2.80 (m, 1 H), 3.16 (s, 3 H), 3.40 (dd, J = 8.5, 6.7 Hz, 1
H), 3.50 (m, 2 H), 3.78 (s, 3 H), 3.79 (s, 3 H), 3.80 (s, 3 H), 3.88
(s, 3 H), 4.65 (d, J = 8.9 Hz, 1 H), 5.15 (d, J = 8.5 Hz, 1 H), 6.65–
6.90 (m, 4 H), 7.00 (dd, J = 8.2, 1.8 Hz, 1 H), 7.18 (d, J = 1.8 Hz,
1 H) ppm. 13C NMR (62 MHz, CDCl3): δ = 50.58, 51.37, 52.73,
54.75, 54.82, 54.90 (2 C), 59.45, 80.68, 81.83, 108.74, 109.25,
109.51, 109.83, 118.02, 118.58, 129.77, 131.57, 147.39, 147.49,
147.96, 148.03, 172.00 ppm.
[1] R. S. Ward, Nat. Prod. Rep. 1999, 16, 75–96.
[2] M. Saleem, H. J. Kim, M. S. Ali, Y. S. Lee, Nat. Prod. Rep.
2005, 22, 696–716.
General Procedure for the Transformation 5 Ǟ 6: A solution of 5
(0.25 mmol) in dry THF (6 mL) was added dropwise to a suspen-
sion of LiAlH4 (19 mg, 0.50 mmol) in dry THF at 0 °C. After
30 min at 0 °C, H2O (27 µL), 15% aqueous NaOH (27 µL), and
H2O (54 µL) were successively added. The resulting cloudy suspen-
sion was filtered through Celite, which was then rinsed with CH2Cl2
(3ϫ5 mL). The filtrate was concentrated to afford quantitatively
the diol, which was immediately dimethylated without further puri-
fication. A suspension of oil-free NaH (67 mg, 1.4 mmol) in dry
THF (5 mL) containing the diol (0.14 mmol) was stirred at room
temperature for 1 h. CH3I (0.087 mL, 1.4 mmol) was added. After
stirring for another 3 h, the reaction mixture was cooled to 5 °C
and quenched with H2O (10 mL). The aqueous layer was extracted
with Et2O (3ϫ5 mL). The combined organic layer was washed
with H2O (3ϫ5 mL) and dried with MgSO4. Evaporation of the
solvent afforded the crude product, which was purified by flash
chromatography (hexane/EtOAc, 9:1 to 1:1) to give pure 6.
[3] a) H. Yoda, M. Mizutani, K. Takabe, Tetrahedron Lett. 1999,
40, 4701–4702; b) S. Yamauchi, M. Okazaki, K. Akiyama, T.
Sugahara, T. Kishida, T. Kashiwagi, Org. Biomol. Chem. 2005,
3, 1670–1675; c) T. Akindele, S. P. Marsden, J. G. Cumming,
Org. Lett. 2005, 7, 3685–3688; d) T. Esumi, D. Hojyo, H. Zhai,
Y. Fukuyama, Tetrahedron Lett. 2006, 47, 3979–3983; e) S.
Hanessian, G. J. Reddy, Synlett 2007, 475–479; f) H. Kim,
C. M. Wooten, Y. Park, J. Hong, Org. Lett. 2007, 9, 3965–3968;
g) M. Maruyama, S. Yamauchi, K. Akiyama, T. Sugahara, T.
Kishida, Y. Koba, Biosci. Biotechnol. Biochem. 2007, 71, 677–
680; h) K. Akiyama, S. Yamauchi, T. Nakato, M. Maruyama,
T. Sugahara, T. Kishida, Biosci. Biotechnol. Biochem. 2007, 71,
1028–1035; i) S. Yamauchi, T. Sugahara, J. Matsugi, T. So-
meya, T. Masuda, T. Kishida, K. Akiyama, M. Maruyama,
Biosci. Biotechnol. Biochem. 2007, 71, 2283–2290; j) T. Nakato,
R. Tago, K. Akiyama, M. Maruyama, T. Sugahara, T. Kishida,
S. Yamauchi, Biosci. Biotechnol. Biochem. 2008, 72, 197–203;
k) K. Matcha, S. Ghosh, Tetrahedron Lett. 2008, 49, 3433–
3436.
(–)-Virgatusin (6AB): Yield 63 mg (0.15 mmol, 60% over two
steps). [α]2D5 = –12.2 (c = 1.10, CHCl3) {ref.[13] [α]2D5 = –12.7 (c =
[4] F. Garzino, A. Méou, P. Brun, Eur. J. Org. Chem. 2003, 1410–
1414.
1
0.50, CH2Cl2)}. H NMR (250 MHz, CDCl3): δ = 2.25 (m, 1 H),
[5] For general reviews about the mechanism and scope of MnIII
-
2.55 (m, 1 H), 2.92 (m, 2 H), 3.02 (s, 3 H), 3.28 (s, 3 H), 3.45 (m,
2 H), 3.81 (s, 3 H), 3.85 (s, 3 H), 4.65 (d, J = 8.0 Hz, 1 H), 5.00 (d,
J = 7.2 Hz, 1 H), 5.88 (s, 2 H), 6.68–7.02 (m, 6 H) ppm. 13C NMR
(62 MHz, CDCl3): δ = 45.50, 49.85, 54.82, 54.89, 57.66, 58.05,
71.98, 72.00, 80.42, 81.58, 99.88, 106.03, 106.84, 108.85, 109.88,
117.74, 118.60, 131.73, 133.00, 145.52, 146.34, 147.45, 147.86 ppm.
C23H28O7 (416.47): calcd. C 66.33, H 6.78; found C 66.23, H 6.84.
promoted reactions of active methylene compounds with al-
kenes, see: a) G. G. Melikyan, Org. React. 1997, 49, 425–675;
b) B. B. Snider in Radicals in Organic Synthesis (Eds.: P. Re-
naud, M. P. Sibi), Wiley-VCH, Weinheim, 2001, vol. 3, pp. 198–
218.
[6] Prepared from 3,4-methylenedioxy- or 3,4-dimethoxybenzoyl
chloride and potassium monomethyl malonate according to:
R. J. Clay, T. A. Collom, G. L. Karrick, J. Wemple, Synthesis
1993, 290–292.
(+)-Urinaligran (6AA): Yield: 41 mg (0.10 mmol, 40% over two
steps). [α]2D5 = +18.2 (c = 1.10, CHCl3) {ref.[14] [α]2D5 = +19.0 (c =
1.00, CHCl3)}. 1H NMR (250 MHz, CDCl3): δ = 2.20 (m, 1 H),
2.50 (m, 1 H), 2.90 (m, 2 H), 3.00 (s, 3 H), 3.30 (s, 3 H), 3.40 (m,
2 H), 4.60 (d, J = 8.0 Hz, 1 H), 5.00 (d, J = 7.3 Hz, 1 H), 5.85 (s,
4 H), 6.60–6.95 (m, 6 H) ppm. 13C NMR (62 MHz, CDCl3): δ =
45.44, 50.37, 57.63, 58.03, 71.90, 72.17, 80.37, 81.57, 99.88, 99.95,
105.94, 106.03, 106.85, 107.04, 118.57, 119.00, 131.64, 134.54,
145.56, 145.98, 146.38, 146.76 ppm. C22H24O7 (400.43): calcd. C
65.99, H 6.04; found C 66.08, H 5.99.
[7] Prepared from (E)-3,4-methylenedioxy- or 3,4-dimethoxycin-
namic chloride and the appropriate 4-substituted 1,3-oxazoli-
din-2-one according to: V. A. Soloshonok, H. Ueki, C. Jiang,
C. Cai, V. J. Hruby, Helv. Chim. Acta 2002, 85, 3616–3623.
[8] For an overview of auxiliary-controlled radical reactions, see:
D. P. Curran, N. A. Porter, B. Giese, Stereochemistry of Radical
Reactions, VCH, Weinheim, 1996, pp. 178–241.
[9] P. F. Schatz, J. Ralph, F. Lu, I. A. Guzei, M. Bunzel, Org. Bio-
mol. Chem. 2006, 4, 2801–2806.
[10] S. Martinet, A. Méou, P. Brun, Magn. Reson. Chem. 2007, 45,
182–184.
(+)-6BA: Yield: 75 mg (0.18 mmol, 72% over two steps). [α]2D5
=
[11] M. Prashad, D. Har, H.-Y. Kim, O. Repic, Tetrahedron Lett.
1998, 39, 7067–7070.
+2.4 (c = 1.00, CHCl3). 1H NMR (250 MHz, CDCl3): δ = 2.20 (m,
1 H), 2.48 (m, 1 H), 2.90 (m, 2 H), 3.00 (s, 3 H), 3.30 (s, 3 H), 3.40
(m, 2 H), 3.82 (s, 3 H), 3.83 (s, 3 H), 4.60 (d, J = 8.0 Hz, 1 H),
5.00 (d, J = 7.2 Hz, 1 H), 5.85 (s, 2 H), 6.60–6.96 (m, 6 H) ppm.
13C NMR (62 MHz, CDCl3): δ = 46.57, 51.14, 55.88 (2 C), 58.63,
59.03, 72.93, 73.13, 81.44, 82.63, 100.96, 106.96, 108.03, 109.80,
110.75, 118.58, 120.05, 131.39, 135.63, 147.00, 147.77, 148.08,
148.58 ppm. C23H28O7 (416.47): calcd. C 66.33, H 6.78; found C
66.10, H 6.76.
[12] For the sake of coherence, we have chosen, when numbering
each compound, to indicate the nature first of Ar1 (A = 3,4-
methylenedioxyphenyl or B = 3,4-dimethoxyphenyl), then of
Ar2 (A or B), and finally (when pertinent) of the affixed oxazol-
idinone [R = H (a), Bn (b), tBu (c), or Ph2CH (d)].
[13] Y. L. Huang, C. C. Chen, F. L. Hsu, C. F. Chen, J. Nat. Prod.
1996, 59, 520–521.
[14] C. C. Chang, Y.-C. Lien, K. C. S. Chen Liu, S.-S. Lee, Phyto-
chemistry 2003, 63, 825–833.
(–)-6BB: Yield: 78 mg (0.18 mmol, 72% over two steps). [α]2D5
–4.2 (c = 1.00, CHCl3). 1H NMR (250 MHz, CDCl3): δ = 2.30 (m,
=
Received: January 29, 2009
Published Online: March 27, 2009
Eur. J. Org. Chem. 2009, 2306–2311
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2311