Reagent-controlled stereoselective synthesis of lignan-related tetrahydrofurans

Article abstract of DOI:10.1021/jo048971a

The reaction of ring-closing metathesis-derived cyclic allylsiloxanes 3 with aldehydes in the presence of a Lewis acid gives 2,3,4-trisubstituted tetrahydrofurans related to the furanolignan family of natural products. The reactions proceed with complete

Full text of DOI:10.1021/jo048971a

Rea gen t-Con tr olled Ster eoselective Syn th esis of Lign a n -Rela ted
Tetr a h yd r ofu r a n s
Steven M. Miles,† Stephen P. Marsden,*,‡ Robin J . Leatherbarrow,† and William J . Coates§
Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AY, U.K.,
School of Chemistry, University of Leeds, Leeds LS2 9J T, U.K., and GlaxoSmthKline, Third Avenue,
Harlow, Essex CM19 5AW, U.K.
stevem@chem.leeds.ac.uk
Received J une 18, 2004
The reaction of ring-closing metathesis-derived cyclic allylsiloxanes 3 with aldehydes in the presence
of a Lewis acid gives 2,3,4-trisubstituted tetrahydrofurans related to the furanolignan family of
natural products. The reactions proceed with complete 3,4-trans stereoselectivity, whereas the C-2
stereochemistry depends on both the aldehyde and Lewis acid used. When boron trifluoride etherate
is used with aliphatic or electronically neutral aryl aldehydes, the reactions favor the production
of the 2,3-cis isomer 8, whereas electron-rich aryl aldehydes lead to the 2,3-trans isomer 9 by Lewis
acid-mediated isomerization of the kinetically favored cis isomer. The isomerization can be avoided
by use of TMSOTf as a promoter, and hence, the stereochemistry can be tuned by appropriate
choice of reagent. Cleavage of the pendant 3-ethenyl group installs the 3-hydroxymethyl group
common to the furanolignans.
In tr od u ction
Natural products of the furanolignan family display
interesting and diverse biological activities, and as such
are popular targets for total synthesis.1 The core of these
compounds is usually a 2,3,4-trisubstituted tetrahydro-
furan. The majority of furanolignans have the substitu-
ents arranged with 2,3-trans, 3,4-cis stereochemistry, but
other stereochemical arrangements are known. The 2,3-
trans, 3,4-trans stereochemistry is found in the antimi-
crobial natural product sesaminone 1,2 for example, while
the 2,3-cis, 3,4-trans stereochemistry is observed in
sylvone 2 (Figure 1).3
We4 and others5 have previously reported the stereo-
selective synthesis of all-cis-2,3,5-trisubstituted tetrahy-
drofurans by the Lewis acid-mediated condensation of
aldehydes with 7-substituted 1-oxa-2-silacyclohept-4-enes
(cyclic allylsiloxanes). The latter species are readily
derived from ring-closing olefin metathesis (RCM) of the
corresponding acyclic homoallylic allylsilyl ethers.6 Mecha-
nistically, this reaction is presumably a form of silyl-
modified Sakurai reaction, and the stereochemical out-
F IGURE 1. Representative furanofuran lignans.
come of the reaction is consistent with such a process.7
We reasoned that a convergent synthesis of the gross
skeleton of the furanolignans could potentially be realized
in a convergent manner through a similar condensation
sequence using the isomeric 6-substituted oxasilacyclo-
hept-5-enes 3 in conjunction with an appropriate alde-
hyde 4. Further, the resulting 3-vinyl substituent of the
tetrahydrofuran 5 could serve as a direct precursor to
the hydroxymethyl group of the furanoligan 6 (Scheme
1). This would provide a complementary synthetic ap-
proach to existing methods for the assembly of 2,3,4-
trisubstituted tetrahydrofurans, which include 5-exo-
radical cyclizations of substituted allyl bromoethyl ethers,8
the reduction of aldol-derived substituted butyrolac-
tones,9 the rearrangement of 4,5-dihydro-1,3-dioxepins,10
and the Lewis-acid promoted condensation of benzyloxy-
acetaldehyde derivatives with diazoesters.11 We describe
herein the successful reduction of this scheme to practice
and discuss the stereochemical features of the reaction,
† Imperial College London.
‡ University of Leeds.
§ GlaxoSmithKline.
(1) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75-96.
(2) Chiung, Y.-M.; Hayashi, H.; Matsumoto, H.; Otani, T.; Yoshida,
K.; Huang, M.-Y.; Chen, R.-X.; Liu, J .-R.; Nakayama, M. J . Antibiot.
1994, 47, 487-491.
(7) Marko, I. E.; Mekhalfia, A.; Bayston, D. J .; Adams, H. J . Org.
Chem. 1992, 57, 2211-2213.
(8) Roy, S. C.; Guin, C.; Rana, K. K.; Maiti, G. Tetrahedron 2002,
58, 2435-2439.
(9) Yoda, H.; Kimura, K.; Takabe, K. Synlett 2001, 400-402.
(10) Takano, S.; Samiza, K.; Ogasawara, K. Synlett 1993, 785-787.
(11) Angle, S. R.; Bernier, D. S.; Chann, K.; J ones, D. E.; Kim, M.;
Neitzel, M. L.; White, S. L. Tetrahedron Lett. 1998, 39, 8195-8198.
(3) Banerji, A.; Sarkar, M.; Ghosal, T.; Pal, S. C.; Shoolery, J . N.
Tetrahedron 1984, 40, 5047-52.
(4) Cassidy, J . H.; Marsden, S. P.; Stemp, G. Synlett 1997, 1411-
1413.
(5) Meyer, C.; Cossy, J . Tetrahedron Lett. 1997, 38, 7861-7864.
(6) Chang, S. B.; Grubbs, R. H. Tetrahedron Lett. 1997, 38, 4757-
4760.
10.1021/jo048971a CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/09/2004
6874
J . Org. Chem. 2004, 69, 6874-6882

Synthesis of Lignan-Related Tetrahydrofurans
TABLE 1. Con d en sa tion of Allylsiloxa n es 3 w ith
Ald eh yd es
SCHEME 1. Retr osyn th etic An a lysis of
F u r a n olign a n s 6
yield
entry conditionsa silane
R′
n-C5H11
Ph
(%) products ratio
76 8a , 9a 91:9
78 8b, 9b 89:11
83 8c, 9c 87:13
81 8d , 9d 84:16
67 8e, 9e
76 8f, 9f
79 8g, 9g
SCHEME 2. Syn th esis of Su bstitu ted
Allylsiloxa n es
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
C
C
D
D
3a
3a
3b n-C5H11
3b Ph
3c
3c
3d n-C5H11
3d Ph
3a
3a
3a
3a
n-C5H11
Ph
90:10
88:12
85:15
68 8h , 9h 87:13
58 8i, 9i
50 8j, 9j
3,4-(OCH2O)Ph
4-MeO-Ph
3,4-(MeO)2-Ph
8:92
8:92
54 8k , 9k 10:90
8:92
3-MeO-4-HO-Ph 51 8l, 9l
3b 3,4-(OCH2O)-Ph 76 8m , 9m 11:89
3b 4-MeO-Ph
3c
3c
68 8n , 9n
3,4-(OCH2O)-Ph 52 8o, 9o
4-MeO-Ph 48 8p , 9p
8:92
8:92
8:92
which include the ability to tune the stereochemistry at
C2 by appropriate choice of reagent.
3d 3,4-(OCH2O)-Ph 47 8q, 9q
9:91
3a
3a
3a
3a
3a
3-MeO-Ph
4-Me2N-Ph
74 8r , 9r
67 8s, 9s
3,4-(OCH2O)-Ph 71 8i, 9i
4-MeO-Ph 67 8j, 9j
3,4-(OCH2O)-Ph 73 8i, 9i
82:18
57:43
50:50
39:61
90:10
Resu lts a n d Discu ssion
The requisite allylsiloxanes (3a -d ) were prepared as
shown in Scheme 2. The 2-substituted homoallylic alco-
hols (7a -d ) were prepared in two steps from ethyl
3-butenoate according to Beckwith’s general method
(enolate alkylation with the appropriate benzylic bromide
followed by LiAlH4 reduction).12 Etherification under
standard conditions with allylchlorodimethylsilane fol-
lowed by RCM with Grubbs’ second-generation catalyst
gave the target allylsiloxanes in excellent yield over two
steps. With these materials in hand, we then investigated
their cyclocondensation with a variety of aldehydes.
Treatment of the allylsiloxanes (3a -d ) under our
previously reported conditions4 (1 equiv of aldehyde, 1
equiv of boron trifluoride etherate in dichloromethane at
-78 °C and then warming to room temperature) with
hexanal or benzaldehyde gave the expected tetrahydro-
furans in good yield as an inseparable mixture of two
diastereoisomers (ca. 5-10:1 ratio) which were identified
as 8a -h and 9a -h (Table 1, entries 1-8). The major
isomer 8 from these reactions was confirmed to have 2,3-
cis, 3,4-trans stereochemistry, as predicted by our mecha-
nistic model for the reaction (vide infra), whereas the
minor isomer 9 was epimeric at C2. We next investigated
the reactions of electron-rich aromatic aldehydes as the
electrophilic reaction partner, i.e., those aldehydes which
would give rise to compounds with appropriate substitu-
tion for furanolignan synthesis. The aldehydes chosen
were piperonal, p-methoxybenzaldehyde, veratraldehyde,
and vanillin (Table 1, entries 9-17). In all cases, the
reactions were successful, although they were in general
slightly lower yielding than the reactions with benzal-
dehyde or hexanal. This may be a consequence of the
lower electrophilicity of the carbonyl groups in these
substrates. However, more significantly, in all of these
3b 3,4-(OCH2O)-Ph 74 8m , 9m 93:7
a
Conditions: (A) 1 equiv each RCHO and BF3‚OEt2, CH2Cl2,
-78 °C, 8 h, then rt; (B) as for A, but 2 equiv of BF3‚OEt2; (C) as
for A, using 0.91 equiv each of RCHO and BF3‚OEt2; (D) 1 equiv
each RCHO and TMSOTf, CH2Cl2, -78 °C, 3 h.
F IGURE 2. Diagnostic chemical shift patterns (in ppm) for
diastereomeric tetrahydrofurans 8 and 9.
examples an unexpected reversal of stereoselectivity was
observed whereby the major isomer from the reaction was
now found to be the 2,3-trans, 3,4-cis isomer 9i-q, with
8i-q as the minor (<11%) component in the mixture.
The relative stereochemical assignments of the tet-
rahydrofurans were made as follows. Extensive NOE
experiments on compounds 8a and 8b confirmed the 2,3-
cis, 3,4-trans stereochemistry of this isomer, while the
corresponding 2,3-trans, 3,4-trans stereochemistry of
compounds 9 was made on the basis of NOE experiments
on 9i and the subsequent chemical correlation of this
compound with a compound of known stereochemistry
(vide infra). The stereochemistry of those tetrahydro-
furans not subjected to NOE analysis was assigned with
confidence on the basis of the strongly consistent and
recognizable patterns of certain signals for each diaste-
1
reoisomer in their H NMR spectra. Specifically, as shown
in Figure 2, the signals corresponding to the protons at
C-5 in the 2,3-cis isomer 8 routinely present as a pair of
signals (separated by 0.56 ( 0.04 ppm) flanking those
(12) Beckwith, A. L. J .; Gerba, S. Aust. J . Chem. 1992, 45, 289-
308.
J . Org. Chem, Vol. 69, No. 20, 2004 6875

Miles et al.
SCHEME 3. Syn th esis of
Hyd r oxym eth yl-Con ta in in g Lign a n Sk eleta
F IGURE 3. Possible mechanistic pathways leading to dia-
stereomeric tetrahydrofurans 8 and 9.
for the 2,3-trans isomer 9 (which are themselves sepa-
rated by 0.23 ( 0.04 ppm). Further, the signal for H-2 in
8 (R′ ) aryl) consistently appears over 0.5 ppm downfield
of that for H-2 in isomer 9 (R′ ) aryl), presumably due
to anisotropic deshielding by the neighboring vinyl group
(the H-2 signals for 8/9, R′ ) pentyl are generally
obscured and hence no comparison can be made).
With these assignments of stereochemistry confidently
in place, we looked to rationalize the divergence in the
sense of diastereoselectivity for the different aldehydes.
The predominant formation of 2,3-cis, 3,4-trans isomer
8 with hexanal and benzaldehyde can be rationalized by
assuming that the reaction takes place by condensation
of the siloxane oxygen with the aldehyde, leading to the
formation of an (E)-oxonium ion 10 which undergoes
cyclization through a chairlike transition state with all
substituents equatorially disposed (path A, Figure 3). The
switch in selectivity in favor of the 2,3-trans, 3,4-trans
isomer 9 when electron-rich aldehydes are employed in
the reaction could potentially arise through path B,
namely Sakurai reaction between the allylsilane and a
(Z)-configured oxonium ion 11. This seems unlikely,
however, given that the steric demands of the aldehydes
have not greatly changed in the proximity of the oxonium
ion. A second possibility is that the kinetic product of the
reaction is still the 2,3-cis, 3,4-trans compound 8 but that
under the Lewis acidic reaction conditions the tetrahy-
drofuran undergoes reversible ring-opening to a stabi-
lized benzylic cation 12 (path C).13 In this event, the more
stable 2,3-trans, 3,4-trans isomer 9 would be expected to
dominate.
Further experiments were carried out to provide sup-
port for this hypothesis. The reaction of 3-methoxybenz-
aldehyde (Table 1, entry 18), which would not offer
significant stabilization to the proposed intermediate
cation 12 and hence should not suffer significant epimer-
ization, yields a mixture of diastereomeric products in
which the 2,3-cis, 3,4-trans isomer 8r does indeed domi-
nate. Interestingly, the reaction of 4-(dimethylamino)-
benzaldehyde gave an approximately equal mixture of
isomers 8s and 9s, despite the expectation that this
would lead to the most stable benzylic cation. However,
it was found necessary to employ more than 1 equiv of
Lewis acid to enable this reaction to proceed presumably
due to coordination of the Lewis acid to the anilinic
nitrogen. This would negate the electron-donating effect
of the dimethylamino substituent and hence reduce the
rate of tetrahydrofuran cleavage. The use of reduced
quantities of Lewis acid would be expected to lead to
slower epimerization, and this was indeed observed
(Table 1, entries 20 and 21). Finally, we suspected that
the epimerization was taking place only at elevated
temperatures. The tetrahydrofuran-forming reaction me-
diated by boron trifluoride is extremely slow at -78 °C,
and hence, the reaction mixtures are slowly warmed to
room temperature to effect complete reaction. Trimeth-
ylsilyl trifluoromethanesulfonate has been demonstrated
to effect these reactions at -78 °C,5 and we were
delighted to find that the use of these alternative reaction
conditions did indeed overturn the selectivity with elec-
tron-rich aldehydes, giving rise to predominantly the 2,3-
cis, 3,4-trans isomers 8i,n as the major product in those
substrates examined (Table 1, entries 22 and 23). Sig-
nificantly, this means that either stereoisomer 8 or 9 can
now be obtained as the predominant product depending
upon the selection of appropriate reaction conditions.
The conversion of the 2-ethenyl group to the hy-
droxymethyl functionality found in the furanolignans was
then investigated. Ozonolysis was found not to be com-
patible with the oxidatively sensitive electron-rich aryl
groups, but olefin cleavage could be achieved cleanly by
a two-step sequence of osmium tetraoxide-mediated
dihydroxylation followed by periodate cleavage of the
resulting diol.14 Reduction of the aldehyde with sodium
borohydride gave the desired alcohols 13/14, which are
all epimers of known lignan natural products (Scheme
3).15 Compound 13a (4-epidihydrosesamin) has previously
been prepared by Yoda,9 and the agreement of our
spectral data with their reported values allowed further
confirmation of the stereochemical assignments above.
In terms of efficiency, the Yoda synthesis of enantiopure
13a requires 16 steps (1.8% overall yield) from com-
(14) Ishibashi, F.; Taniguchi, E. Chem. Lett. 1986, 1771-1774.
(15) (a) Lin-Gen, Z.; Seligmann, O.; Lotter, H.; Wagner, H. Phy-
tochemistry 1983, 22, 265-7. (b) Vidigal, M. C. S.; Cavalheiro, A. J .;
Kato, M. J .; Yoshida, M. Phytochemistry 1995, 40, 1259-61. (c) Cuca,
L. E.; Martinez, J . C.; Delle Monache, F. Phytochemistry 1998, 47,
1437-1439.
(13) A pathway invoked in the epimerization of C-aryl nucleosides.
See, for example: J iang, Y. L.; Stivers, J . T. Tetrahedron Lett. 2003,
44, 85-88.
6876 J . Org. Chem., Vol. 69, No. 20, 2004

Synthesis of Lignan-Related Tetrahydrofurans
mercial dihydroxyacetone dimer,9,16 whereas our synthe-
sis of rac-13a proceeds in 37% overall yield over 8 total
synthetic steps from ethyl 3-butenoate. Further, the
availability of alcohols 7 in enantiomerically enriched
form17 means that application of our chemistry to either
enantiomeric series should be straightforward.
In summary, we have developed an efficient, high-
yielding and convergent synthesis of 2,3,4-trisubstituted
tetrahydrofurans utilizing allylsiloxane/aldehyde con-
densation chemistry. The stereochemical outcome is
dependent upon the aldehyde substituent and the choice
of Lewis acid. The 2,3-cis, 3,4-trans isomer 8 can be
obtained as the major product regardless of aldehyde
substituent if the appropriate Lewis acid is chosen,
whereas for electron-rich aldehydes the 2,3-trans, 3,4-
trans isomer 9 can be accessed if conditions are chosen
which permit equilibration through a stabilized benzylic
cation. Conversion of the 3-ethenyl group to a hydroxy-
methyl group can be achieved in high yield, giving access
to a range of natural lignan epimers.
s), 0.15 (3H, s), 1.38 (1H, dd, J 15.0, 8.5), 1.80 (1H, ddd, J
15.0, 6.0, 2.0), 2.59 (1H, dd, J 14.0, 8.0), 2.64 (1H, dd, J 14.0,
7.5), 2.92 (1H, m), 3.66 (1H, dd, J 11.0, 9.0), 3.85 (1H, dd, J
11.0, 3.0), 5.40 (1H, ddd, J 10.5, 6.0, 2.0), 5.76 (1H, dddd, J
10.5, 8.0, 6.0, 2.0), 7.17-7.21 (3H, m), 7.26-7.30 (2H, m); 13
C
NMR (75 MHz, CDCl3) δ -2.2 (q), -0.7 (q), 18.3 (t), 38.4 (t),
43.4 (d), 67.1 (t), 126.1 (d), 126.8 (d), 128.4 (d), 129.1 (d), 132.5
(d), 140.1 (s); MS (CI+, NH3) m/z 250 ([M + NH4]+, 100), 233
([M + H]+, 15), 141 (13), 91 (12); HRMS (CI+, NH3) for [M +
H]+ found 233.1362, C14H21OSi requires 233.1362.
6-(3-Me t h o x y p h e n y lm e t h y l)-2,2-d im e t h y l-2,3,6,7-
tetr a h yd r o[1,2]oxa silep in e (3c). Prepared according to the
general procedure above, yield 90% over two steps: IR (film,
1
cm-1) 3011, 2954, 1633, 1602; H NMR (400 MHz, CDCl3) δ
0.12 (3H, s), 0.14 (3H, s), 1.38 (1H, dd, J 15.0, 8.5), 1.80 (1H,
ddd, J 15.0, 6.0, 2.0), 2.56 (1H, dd, J 13.5, 8.0), 2.61 (1H, dd,
J 13.5, 7.5), 2.92 (1H, m), 3.66 (1H, dd, J 11.0, 9.5), 3.79 (3H,
s), 3.84 (1H, dd, J 11.0, 2.5), 5.40 (1H, ddd, J 10.5, 5.5, 2.0),
5.76 (1H, dddd, J 10.5, 8.5, 6.0, 2.0), 6.72-6.79 (3H, m), 7.19
(1H, apparent dt, J 7.5, 1.5); 13C NMR (75 MHz, CDCl3) δ -2.2
(q), -0.7 (q), 18.3 (t), 38.4 (t), 43.3 (d), 55.1 (q), 67.2 (t), 111.3
(d), 114.9 (d), 121.5 (d), 126.9 (d), 129.3 (d), 132.5 (d), 141.7
(s), 159.6 (s); MS (CI+, NH3) m/z 280 ([M + NH4]+, 100), 263
([M + H]+, 92), 141 (12), 121 (3); HRMS (CI+, NH3) for [M +
H]+ found 263.1473, C15H23O2Si requires 263.1467.
Exp er im en ta l Section
6-(3,4-Dim et h oxyp h en ylm et h yl)-2,2-d im et h yl-2,3,6,7-
tetr a h yd r o[1,2]oxa silep in e (3d ). Prepared according to the
general procedure above, yield 90% over two steps: IR (film,
cm-1) 3007, 2996, 2954, 1634, 1608; 1H NMR (500 MHz, CDCl3)
δ 0.13 (3H, s), 0.15 (3H, s), 1.39 (1H, dd, J 15.0, 8.5), 1.79 (1H,
ddd, J 15.0, 6.0, 2.0), 2.54 (1H, dd, J 14.0, 8.0), 2.59 (1H, dd,
J 14.0, 8.0), 2.88 (1H, m), 3.66 (1H, dd, J 11.0, 9.0), 3.85 (1H,
dd, J 11.0, 3.0), 3.85 (3H, s), 3.87 (3H, s), 5.40 (1H, ddd, J
11.0, 6.0, 2.0), 5.76 (1H, dddd, J 11.0, 8.5, 6.0, 2.0), 6.71 (1H,
d, J 2.0), 6.72 (1H, dd, J 8.0, 2.0), 6.78 (1H, d, J 8.0); 13C NMR
(75 MHz, CDCl3) δ -2.3 (q), -0.8 (q), 18.2 (t), 37.9 (t), 43.5
(d), 55.7 (q), 55.8 (q), 67.1 (t), 111.0 (d), 112.1 (d), 120.9 (d),
126.8 (d), 132.5 (d and s, 2 coincident peaks), 147.3 (s), 148.7
(s) [16C expected, 15C seen]; MS (CI+, NH3) m/z 310 ([M +
NH4]+, 100), 293 ([M + H]+, 22), 151 (19); HRMS (CI+, NH3)
for [M + H]+ found 293.1564, C16H25O3Si requires 293.1573.
5-[(3SR,4SR,5SR)-5-P en tyl-4-vin yltetr a h yd r ofu r a n -3-
ylm eth yl]ben zo[1,3]d ioxole (8a ). To a solution of cyclic
allylsiloxane 3a (18 mg, 0.065 mmol) in DCM (0.6 mL) at -78
°C was added boron trifluoride diethyl etherate (8.0 µL, 0.065
mmol). After 5 min, hexanal (6.5 mg, 0.065 mmol in 0.1 mL
DCM) was added dropwise. The solution was stirred at -78
°C for 8 h and then warmed slowly to room temperature with
stirring over the next 14 h before the addition of brine (2 mL)
and Et2O (5 mL). The phases were separated, and the aqueous
phase was extracted with Et2O (3 × 2 mL). The combined
organic phases were washed with water (6 mL), dried (MgSO4),
and concentrated in vacuo. Purification by flash chromatog-
raphy (5% Et2O in hexane) yielded tetrahydrofurans 8a /9a as
a colorless oil (32 mg, 76%, 91:9 inseparable mixture): IR (film,
cm-1) 3075, 2956, 1634, 1605; 1H NMR (signals for 8a , 400
MHz, CDCl3) δ 0.87 (3H, t, J 7.0), 1.25-1.46 (8H, m,), 2.28
(1H, m, 3′-H), 2.45 (1H, dd, J 14.0, 9.5), 2.46 (1H, m), 2.78
(1H, dd, J 14.0, 5.5), 3.42 (1H, dd, J 8.5, 7.5), 3.91 (1H, m),
3.96 (1H, dd, J 8.5, 7.5), 5.00 (1H, dd, J 17.0, 2.0), 5.05 (1H,
dd, J 10.0, 2.0), 5.71 (1H, apparent dt, J 17.0, 10.0), 5.92 (2H,
s), 6.59 (1H, dd, J 8.0, 1.5), 6.63 (1H, d, J 1.5), 6.71 (1H, d, J
8.0); signals for minor isomer 9a visible at δ 0.90 (3H, t, J
6.5), 3.56 (1H, apparent t, J 8.0), 3.83 (1H, dd, J 8.5, 7.5), 6.61
(1H, d, J 1.5), 6.70 (1H, d, J 8.0); 13C NMR (signals for 8a , 75
MHz, CDCl3) δ 14.1 (q), 22.7 (t), 26.2 (t), 31.6 (t), 32.0 (t), 38.4
(t), 46.9 (d), 53.0 (d), 72.3 (t), 81.6 (d), 100.9 (t), 108.2 (d), 109.1
(d), 116.4 (t), 121.5 (d), 134.2 (s), 137.4 (d), 145.9 (s), 147.7 (s);
signals for minor isomer 9a visible at δ 22.8 (t), 26.1 (t), 38.0
(t), 47.9 (d), 56.8 (d), 84.2 (d), 117.2 (t), 138.1 (s); MS (CI+,
NH3) m/z 320 ([M + NH4]+, 100), 303 ([M + H]+, 48), 285 (13),
5-(2,2-Dim e t h yl-2,3,6,7-t e t r a h yd r o[1,2]oxa sile p in -6-
ylm et h yl)ben zo[1,3]d ioxole (3a ). To a stirred solution of
allyldimethylchlorosilane (410 µL, 2.70 mmol) in CH2Cl2 (10
mL) at 0 °C was added a solution of homoallylic alcohol 7a
(567 mg, 2.75 mmol) and triethylamine (383 µL, 2.75 mmol)
in CH2Cl2 (5 mL) dropwise. The reaction mixture was stirred
at 0 °C for a further 90 min, whereupon saturated aqueous
NaHCO3 (12.5 mL) was added and the mixture was extracted
with CH2Cl2 (4 × 10 mL). The combined organic phase was
washed with water (10 mL) and brine (10 mL), dried (MgSO4),
and concentrated in vacuo. Purification by rapid filtration
through a plug of basic alumina (5.5 g alumina, 1.5 cm plug
height, eluent 10% Et2O in hexane followed by neat Et2O flush)
yielded the recovered alcohol starting material 7a (74 mg) and
the allyldimethylsilyl ether as a colorless oil (685 mg, 83%,
94% yield based on recovered starting material). To a solution
of the allyldimethylsilyl ether (600 mg, 1.97 mmol) in toluene
(99 mL) at 100 °C was added a solution of tricyclohexylphos-
phine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-
ylidene][benzylidine]ruthenium(IV) dichloride (84 mg, 98.5
µmol) in CH2Cl2 (6 mL) dropwise over 6 h (syringe pump). After
a further 12 h at 100 °C, the reaction mixture was cooled and
concentrated in vacuo. The residue was purified by filtration
through a short pad of silica (eluent 5% Et2O in hexane) to
afford compound 3a as a pale yellow oil (528 mg, 97%): IR
(film, cm-1) 3012, 2954, 1633, 1610; 1H NMR (400 MHz, CDCl3)
δ 0.12 (3H, s), 0.14 (3H, s), 1.38 (1H, dd, J 15.0, 8.5), 1.80 (1H,
ddd, J 15.0, 6.0, 1.5), 2.50 (1H, dd, J 14.0, 8.0), 2.56 (1H, dd,
J 14.0, 7.5), 2.85 (1H, m), 3.64 (1H, dd, J 11.0, 9.0), 3.84 (1H,
dd, J 11.0, 3.0), 5.38 (1H, ddd, J 11.0, 6.0, 2.0), 5.76 (1H, dddd,
J 11.0, 8.5, 6.0, 2.0), 5.92 (2H, s), 6.61 (1H, dd, J 8.0, 1.5,),
6.68 (1H, d, J 1.5), 6.72 (1H, d, J 8.0); 13C NMR (67.5 MHz,
CDCl3) δ -2.2 (q), -0.7 (q), 18.4 (t), 38.1 (t), 43.6 (d), 67.1 (t),
100.8 (t), 108.1 (d), 109.4 (d), 121.9 (d), 126.9 (d), 132.4 (d),
133.9 (s), 145.9 (s), 147.6 (s); MS (CI+, NH3) m/z 294 ([M +
NH4]+, 44), 277 ([M + H]+, 100), 141 (57), 135 (88); HRMS
(CI+, NH3) for [M + H]+ found 277.1263, C15H21O3Si requires
277.1260.
6-P h en ylm et h yl-2,2-d im et h yl-2,3,6,7-t et r a h yd r o[1,2]-
oxa silep in e (3b). Prepared according to the general procedure
above, yield 85% over two steps: IR (film, cm-1) 3086, 3063,
3026, 2956, 1634, 1604; 1H NMR (400 MHz, CDCl3) δ 0.12 (3H,
(16) (a) Yoda, H.; Mizutani, M.; Takabe, K. Synlett 1998, 855-856.
(b) Yoda, H.; Mizutani, M.; Takabe, K. Tetrahedron Lett. 1999, 40,
4701-4702.
(17) Takekawa, Y.; Shishido, K. J . Org. Chem. 2001, 66, 8490-8503.
J . Org. Chem, Vol. 69, No. 20, 2004 6877

Miles et al.
202 (9), 135 (24); HRMS (CI+, NH3) for [M + H]+ found
2.52 (1H, dd, J 13.5, 6.0), 2.85 (1H, dd, J 13.5, 5.5), 3.44 (1H,
dd, J 8.5, 7.5), 3.79 (3H, s), 3.93 (1H, m), 3.98 (1H, dd, J 8.5,
7.5), 5.01 (1H, dd, J 17.0, 2.0), 5.05 (1H, dd, J 10.0, 2.0), 5.73
(1H, apparent dt, J 17.0, 10.0), 6.69 (1H, s), 6.74 (1H, d, J
8.0), 6.74 (1H, d, J 8.0), 7.19 (1H, apparent t, J 8.0); signals
for minor isomer 9e visible at δ 0.90 (3H, t, J 7.0), 3.59 (1H,
apparent t, J 8.5), 3.82 (3H, s), 3.84 (1H, dd, J 8.5, 7.5), 7.11
(1H, apparent t, J 8.0); 13C NMR (signals for 8e, 75 MHz,
CDCl3) δ 14.1 (q), 22.7 (t), 26.2 (t), 31.6 (t), 32.0 (t), 38.7 (t),
46.5 (d), 53.2 (d), 55.2 (q), 72.3 (t), 81.6 (d), 111.4 (d), 114.6
(d), 116.4 (t), 121.2 (d), 129.4 (d), 137.4 (d), 142.0 (s), 159.7 (s);
signals for minor isomer 9e visible at δ 26.0 (t), 31.4 (t), 31.8
(t), 39.1 (t), 47.6 (d), 57.0 (d), 108.2 (d); MS (CI+, NH3) m/z
306 ([M + NH4]+, 100), 289 ([M + H]+, 53), 271 (26), 217 (3),
188 (8), 121 (6); HRMS (CI+, NH3) for [M + H]+ found
289.2165, C19H29O2 requires 289.2168.
(2RS,3SR,4SR)-4-(3-Meth oxyp h en ylm eth yl)-2-p h en yl-
3-vin yltetr a h yd r ofu r a n (8f). Prepared according to the
general procedure above, yield 24.6 mg, 76%, 88:12 inseparable
mixture of 8f/9f: IR (film, cm-1) 3078, 3029, 3003, 1639, 1602;
1H NMR (signals for 8f, 400 MHz, CDCl3) δ 2.41 (1H, m), 2.47
(1H, dd, J 13.0, 10.0), 2.81 (1H, apparent q, J 8.5), 2.90 (1H,
dd, J 13.0, 4.0), 3.70 (1H, apparent t, J 8.5), 3.80 (3H, s), 4.27
(1H, dd, J 8.5, 7.0), 4.94 (1H, dd, J 9.0, 3.0), 5.02 (1H, dd, J
17.0, 3.0), 5.08 (1H, ddd, J 17.0, 9.0, 8.5), 5.17 (1H, d, J 8.0),
6.70 (1H, dd, J 2.0, 2.0), 6.74-6.78 (2H, m), 7.17-7.34 (6H,
m); signals for minor isomer 9f visible at δ 3.80 (3H, s), 3.85
(1H, apparent t, J 8.5), 4.07 (1H, dd, J 8.5, 7.5), 4.63 (1H, d,
J 9.0), 4.97 (1H, ddd, J 17.0, 1.5, 0.5), 5.11 (1H, dd, J 10.0,
1.5), 5.78 (1H, ddd, J 17.0, 10.0, 8.5); 13C NMR (signals for 8f,
75 MHz, CDCl3) δ 37.6 (t), 45.5 (d), 55.0 (d), 55.2 (q), 73.9 (t),
83.5 (d), 111.4 (d), 114.7 (d), 117.0 (t), 121.1 (d), 126.6 (d), 127.1
(d), 127.9 (d), 129.5 (d), 137.2 (d), 140.6 (s), 141.9 (s), 159.8
(s); signals for minor isomer 9f visible at δ 38.0 (t), 47.9 (d),
59.6 (d), 73.5 (t), 85.9 (d), 118.0 (t), 125.9 (d), 127.5 (d), 128.3
(d); MS (CI+, NH3) m/z 312 ([M + NH4]+, 100), 295 ([M + H]+,
57), 277 (19), 188 (16), 121 (7), 105 (3); HRMS (CI+, NH3) for
[M + H]+ found 295.1693, C20H23O2 requires 295.1698.
(2SR,3SR,4SR)-4-(3,4-Dim eth oxyp h en ylm eth yl)-2-p en -
tyl-3-vin yltetr a h yd r ofu r a n (8g). Prepared according to the
general procedure above, yield 24.3 mg, 79%, 85:15 inseparable
mixture of 8g/9g: IR (film, cm-1) 3076, 2997, 2954, 1638, 1609;
1H NMR (signals for 8g, 400 MHz, CDCl3) δ 0.87 (3H, t, J 6.5),
1.25-1.46 (8H, m), 2.32 (1H, m), 2.45-2.52 (2H, m), 2.81 (1H,
dd, J 14.0, 5.5), 3.44 (1H, dd, J 8.5, 7.5), 3.85 (3H, s), 3.85
(3H, s), 3.92 (1H, m), 3.98 (1H, dd, J 8.5, 7.5), 4.99 (1H, dd, J
17.0, 2.0), 5.05 (1H, dd, J 10.0, 2.0), 5.73 (1H, apparent dt, J
17.0, 10.0), 6.65 (1H, d, J 2.0), 6.68 (1H, dd, J 8.0, 2.0), 6.77
(1H, d, J 8.0); signals for minor isomer 9g visible at δ 0.90
(3H, t, J 6.5), 2.86 (1H, dd, J 15.5, 4.5), 3.58 (1H, apparent t,
J 8.0); 13C NMR (signals for 8g, 75 MHz, CDCl3) δ 14.1 (q),
22.7 (t), 26.2 (t), 31.6 (t), 32.0 (t), 38.3 (t), 46.8 (d), 53.1 (d),
55.9 (q), 55.9 (q), 72.3 (t), 81.5 (d), 111.1 (d), 111.9 (d), 116.3
(t), 120.6 (d), 132.9 (s), 137.5 (d), 147.4 (s), 148.8 (s); signals
for minor isomer 9g visible at δ 22.8 (t), 26.0 (t), 47.8 (d), 56.9
(d), 72.4 (t), 84.2 (d), 110.7 (d), 132.6 (s), 138.1 (s), 147.1 (s);
MS (CI+, NH3) m/z 336 ([M + NH4]+, 100), 319 ([M + H]+, 7),
218 (7), 151 (8); HRMS (CI+, NH3) for [M + NH4]+ found
336.2544, C20H34NO3 requires 336.2539.
303.1965, C19H27O3 requires 303.1960.
5-[(3SR,4SR,5RS)-5-P h en yl-4-vin yltetr a h yd r ofu r a n -3-
ylm eth yl]ben zo[1,3]d ioxole (8b). Prepared according to the
general procedure above, yield 48 mg, 78%, 89:11 inseparable
mixture of 8b/9b: IR (film, cm-1) 3071, 3029, 2976, 1640, 1607,
1502, 1489, 1443, 1247, 1191, 1039, 925, 729; 1H NMR (signals
for 8b, 400 MHz, CDCl3) δ 2.35 (1H, m), 2.42 (1H, dd, J 13.0,
10.0), 2.78 (1H, apparent q, J 8.5), 2.83 (1H, dd, J 13.0, 3.5),
3.67 (1H, apparent t, J 8.5), 4.25 (1H, dd, J 8.5, 7.0), 4.92 (1H,
dd, J 9.0, 3.0), 5.00 (1H, dd, J 16.5, 3.0), 5.07 (1H, ddd, J 16.5,
9.0, 8.5), 5.16 (1H, d, J 8.0), 5.93 (2H, s), 6.60 (1H, dd, J 8.0,
1.5), 6.64 (1H, d, J 1.5), 6.73 (1H, d, J 8.0), 7.17-7.33 (5H, m);
signals for minor isomer 9b visible at δ 3.82 (1H, apparent t,
J 8.0), 4.04 (1H, dd, J 8.5, 7.0), 4.63 (1H, d, J 9.0), 5.83 (1H,
ddd, J 17.5, 10.0, 9.0), 6.72 (1H, d, J 8.0); 13C NMR (signals
for 8b, 75 MHz, CDCl3) δ 37.1 (t), 45.7 (d), 54.8 (d), 73.8 (t),
83.5 (d), 100.9 (t), 108.2 (d), 109.0 (d), 117.0 (t), 121.4 (d), 126.5
(d), 127.0 (d), 127.9 (d), 134.0 (s), 137.0 (d), 140.5 (s), 145.9
(s), 147.6 (s); signals for minor isomer 9b visible at δ 37.5 (t),
48.1 (d), 59.5 (d), 73.4 (t), 85.8 (d), 118.1 (t), 125.9 (d), 127.4
(d), 128.2 (d), 136.6 (d), 141.6 (s); MS (CI+, NH3) m/z 326 ([M
+ NH4]+, 100), 309 ([M + H]+, 48), 291 (19), 202 (18), 135 (21),
105 (6); HRMS (CI+, NH3) for [M + H]+ found 309.1499,
C
20H21O3 requires 309.1491.
(2SR,3SR,4SR)-2-P en tyl-4-ph en ylm eth yl-3-vin yltetr ah y-
d r ofu r a n (8c). Prepared according to the general procedure
above, yield 19 mg, 83%, 87:13 inseparable mixture of 8c/9c:
1
IR (film, cm-1) 3079, 3065, 3027, 2956, 1638, 1604; H NMR
(signals for 8c, 500 MHz, CDCl3) δ 0.87 (3H, t, J 7.0), 1.24-
1.46 (8H, m), 2.35 (1H, m), 2.49 (1H, ddd, J 10.0, 7.0, 6.5),
2.54 (1H, dd, J 14.0, 9.5), 2.87 (1H, dd, J 14.0, 5.5), 3.44 (1H,
dd, J 8.5, 7.5), 3.93 (1H, ddd, J 8.5, 7.0, 4.5), 3.97 (1H, dd, J
8.5, 7.0), 4.99 (1H, ddd, J 17.0, 2.0, 0.5), 5.04 (1H, dd, J 10.0,
2.0), 5.72 (1H, apparent dt, J 17.0, 10.0), 7.13-7.21 (3H, m),
7.25-7.29 (2H, m); signals for minor isomer 9c visible at δ
2.05 (1H, apparent q, J 9.0), 3.59 (1H, apparent t, J 8.0), 3.83
(1H, dd, J 8.0, 7.5); 13C NMR (signals for 8c, 75 MHz, CDCl3)
δ 14.1 (q), 22.7 (t), 26.2 (t), 31.6 (t), 32.0 (t), 38.7 (t), 46.7 (d),
53.1 (d), 72.3 (t), 81.6 (d), 116.4 (t), 126.1 (d), 128.5 (d), 128.8
(d), 137.4 (d), 140.4 (s); signals for minor isomer 9c visible at
δ 38.3 (t), 47.7 (d), 57.0 (d), 84.1 (d), 117.2 (t), 138.0 (d); MS
(CI+, NH3) m/z 276 ([M + NH4]+, 73), 259 ([M + H]+, 4), 241
(14), 167 (9), 158 (100), 91 (28); HRMS (CI+, NH3) for [M +
NH4]+ found 276.2334, C18H30NO requires 276.2327.
(2RS,3SR,4SR)-2-P h en yl-4-p h en ylm et h yl-3-vin ylt et -
r a h yd r ofu r a n (8d ). Prepared according to the general pro-
cedure above, yield 17 mg, 81%, 84:16 inseparable mixture of
8d /9d : IR (film, cm-1) 3083, 3063, 3003, 2976, 1640, 1603; 1H
NMR (signals for 8d , 500 MHz, CDCl3) δ 2.43 (1H, m), 2.52
(1H, dd, J 13.5, 10.0), 2.82 (1H, apparent q, J 8.5), 2.93 (1H,
dd, J 13.5, 4.5), 3.70 (1H, apparent t, J 8.5), 4.26 (1H, dd, J
8.5, 7.0), 4.93 (1H, dd, J 9.5, 2.5,), 5.02 (1H, dd, J 17.0, 2.5),
5.10 (1H, dt, J 17.0, 9.5), 5.18 (1H, d, J 8.0), 7.15-7.34 (10H,
m); signals for minor isomer 9d visible at δ 2.37 (1H, m), 3.86
(1H, apparent t, J 8.0), 4.06 (1H, dd, J 8.5, 7.5), 4.64 (1H, d,
J 9.5), 4.97 (1H, ddd, J 17.0, 1.5, 0.5), 5.11 (1H, dd, J 10.5,
1.5), 5.78 (1H, ddd, J 17.0, 10.5, 9.0); 13C NMR (signals for
8d , 75 MHz, CDCl3) δ 37.5 (t), 45.6 (d), 55.0 (d), 73.9 (t), 83.5
(d), 117.1 (t), 126.3 (d), 126.6 (d), 127.1 (d), 127.9 (d), 128.5
(d), 128.7 (d), 137.2 (d), 140.3 (s), 140.6 (s); signals for minor
isomer 9d visible at δ 37.9 (t), 48.0 (d), 59.7 (d), 73.5 (t), 85.9
(d), 118.1 (t), 125.9 (d), 127.5 (d), 128.3 (d), 136.7 (d); MS (CI+,
NH3) m/z 282 ([M + NH4]+, 100), 265 ([M + H]+, 8), 247 (16),
158 (22), 91 (19); HRMS (CI+, NH3) for [M + H]+ found
265.1595, C19H21O requires 265.1592.
(2RS,3SR,4SR)-4-(3,4-Dim eth oxyph en ylm eth yl)-2-ph en -
yl-3-vin yltetr a h yd r ofu r a n (8h ). Prepared according to the
general procedure above, yield 15.1 mg, 68%, 87:13 inseparable
mixture of 8h /9h : IR (film, cm-1) 3076, 3063, 3028, 3002, 1640,
1
1606; H NMR (signals for 8h , 400 MHz, CDCl3) δ 2.38 (1H,
m, 4-H), 2.46 (1H, dd, J 13.5, 10.0), 2.80 (1H, apparent q, J
8.5), 2.86 (1H, dd, J 13.5, 4.0), 3.70 (1H, apparent t, J 8.5),
3.87 (3H, s), 3.87 (3H, s), 4.26 (1H, dd, J 8.5, 7.0), 4.94 (1H,
dd, J 9.5, 3.0), 5.02 (1H, dd, J 17.0, 3.0), 5.09 (1H, ddd, J 17.0,
9.5, 8.5), 5.17 (1H, d, J 8.0), 6.65 (1H, d, J 2.0), 6.70 (1H, dd,
J 8.0, 2.0), 6.79 (1H d, J 8.0), 7.17-7.33 (5H, m); signals for
minor isomer 9h visible at δ 4.06 (1H, dd, J 8.5, 7.5), 4.64 (1H,
d, J 9.0), 4.96 (1H, ddd, J 17.0, 1.5, 1.0), 5.11 (1H, dd, J 10.0,
(2SR,3SR,4SR)-4-(3-Met h oxyp h en ylm et h yl)-2-p en t yl-
3-vin yltetr a h yd r ofu r a n (8e). Prepared according to the
general procedure above, yield 18.7 mg, 67%, 90:10 inseparable
mixture of 8e/9e: IR (film, cm-1) 3075, 3028, 2999, 2954, 1638,
1
1611, 1602; H NMR (signals for 8e, 400 MHz, CDCl3) δ 0.87
(3H, t, J 6.5), 1.25-1.45 (8H, m), 2.35 (1H, m), 2.49 (1H, m),
6878 J . Org. Chem., Vol. 69, No. 20, 2004

Synthesis of Lignan-Related Tetrahydrofurans
1.5), 5.78 (1H, ddd, J 17.0, 10.0, 8.5); 13C NMR (signals for
8h , 100 MHz, CDCl3) δ 37.1 (t), 45.7 (d), 55.0 (d), 55.9 (q, 2
coincident peaks), 73.9 (t), 83.5 (d), 111.2 (d), 111.9 (d), 117.1
(t), 120.6 (d), 126.6 (d), 127.1 (d), 127.9 (d), 132.8 (s), 137.2
(d), 140.6 (s), 147.5 (s), 148.8 (s) [19 C expected, 18 seen];
signals for minor isomer 9h visible at δ 37.4 (t), 48.1 (d), 73.5
(t), 85.9 (d), 118.1 (t), 127.5 (d), 128.3 (d), 136.8 (d); MS (CI+,
NH3) m/z 342 ([M + NH4]+, 100), 325 ([M + H]+, 35), 307 (7),
218 (7), 151 (15); HRMS (CI+, NH3) for [M + H]+ found
325.1801, C21H25O3 requires 325.1804.
5-[(3SR,4SR,5SR)-5-(Ben zo[1,3]d ioxol-5-yl)-4-vin yltet-
r a h yd r ofu r a n -3-ylm et h yl]b en zo[1,3]d ioxole (9i). Pre-
pared according to the general procedure above, yield 20.4 mg,
58%, 92:8 inseparable mixture of 9i/8i: IR (film, cm-1) 3076,
2972, 1641, 1608; 1H NMR (signals for 9i, 400 MHz, CDCl3) δ
2.28 (1H, apparent q, J 9.0), 2.37-2.48 (2H, m), 2.86 (1H, dd,
J 18.5, 9.5), 3.79 (1H, apparent t, J 8.5), 4.02 (1H, dd, J 8.5,
7.5), 4.52 (1H, d, J 9.0), 4.97 (1H, dd, J 17.0, 1.0,), 5.10 (1H,
dd, J 10.0, 1.0), 5.71 (1H, ddd, J 17.0, 10.0, 9.0), 5.93 (2H, s),
5.94 (2H, s), 6.60 (1H, dd, J 8.0, 1.0), 6.64 (1H, d, J 1.0), 6.72
(1H, d, J 8.0), 6.75 (2H, apparent s,), 6.84 (1H, apparent s);
signals for minor isomer 8i visible at δ 2.72 (1H, apparent q,
J 8.5), 3.62 (1H, apparent t, J 8.5), 4.20 (1H, dd, J 8.5, 7.0);
13C NMR (signals for 9i, 100 MHz, CDCl3) δ 37.6 (t), 48.0 (d),
59.5 (d), 73.3 (t), 85.9 (d), 100.9 (t), 101.0 (t), 106.5 (d), 108.0
(d), 108.3 (d), 109.1 (d), 118.2 (t), 119.5 (d), 121.5 (d), 134.0
(s), 135.4 (s), 136.5 (d), 146.0 (s), 146.9 (s), 147.7 (s, 2 coincident
peaks) [21 C expected, 20 seen]; signals for minor isomer 8i
visible at δ 37.1 (t), 45.7 (d), 55.0 (d), 73.8 (t), 83.4 (d), 107.2
(d), 107.8 (d), 117.2 (t), 119.8 (d), 134.7 (s), 137.1 (d); MS (CI+,
NH3) m/z 370 ([M + NH4]+, 27), 353 ([M + H]+, 100), 335 (30),
231 (45), 202 (18), 149 (74), 135 (37); HRMS (CI+, NH3) for [M
+ H]+ found 353.1386, C21H21O5 requires 353.1389.
(d), 133.9 (s), 134.0 (s), 136.8 (d), 145.9 (s), 147.7 (s), 148.4 (s),
148.9 (s) [22 C expected, 21 seen]; signals for minor isomer
8k visible at δ 37.1 (t), 122.0 (d); MS (CI+, NH3) m/z 386 ([M
+ NH4]+, 95), 369 ([M + H]+, 91), 351 (11), 231 (100), 202 (10),
165 (64), 135 (17); HRMS (CI+, NH3) for [M + NH4]+ found
386.1965, C22H28NO5 requires 386.1967.
4-[(2SR,3SR,4SR)-4-Ben zo[1,3]d ioxol-5-ylm et h yl-3-vi-
n yltetr a h yd r ofu r a n -2-yl]-2-m eth oxyp h en ol (9l). Prepared
according to the general procedure above, yield 11.6 mg, 51%,
92:8 inseparable mixture of 9l/8l: IR (film, cm-1) 3450 (br,
OH), 3075, 1639, 1607; 1H NMR (signals for 9l, 400 MHz,
CDCl3) δ 2.31 (1H, apparent q, J 9.0), 2.41-2.48 (2H, m), 2.87
(1H, dd, J 18.5, 9.5), 3.81 (1H, apparent t, J 8.0), 3.89 (3H, s),
4.03 (1H, dd, J 8.5, 7.5), 4.54 (1H, d, J 9.0), 4.97 (1H, dd, J
17.0, 1.0), 5.10 (1H, dd, J 10.0, 1.5), 5.59 (1H, br s), 5.74 (1H,
ddd, J 17.0, 10.0, 9.0), 5.93 (2H, s), 6.60 (1H, dd, J 8.0, 1.5),
6.65 (1H, d, J 1.5), 6.72 (1H, d, J 8.0), 6.80 (1H, dd, J 8.0, 1.5),
6.85 (1H, d, J 1.5), 6.86 (1H, d, J 8.0); signals for minor isomer
8l visible at δ 2.73 (1H, apparent q, J 9.0), 3.62 (1H, apparent
t, J 8.5), 3.86 (3H, s), 4.22 (1H, dd, J 8.5, 7.0), 5.92 (2H, s); 13
C
NMR (signals for 9l, 75 MHz, CDCl3) δ 37.7 (t), 48.0 (d), 55.9
(q), 59.2 (d), 73.2 (t), 85.8 (d), 100.9 (t), 108.2 (d′), 108.4 (d),
109.0 (d), 114.1 (d), 118.0 (t), 119.1 (d), 121.4 (d), 133.3 (s),
134.0 (s), 136.7 (d), 145.0 (s), 145.9 (s), 146.4 (s), 147.7 (s);
signals for minor isomer 8l visible at δ 37.1 (t), 45.9 (d), 54.9
(d), 73.7 (t), 83.3 (d), 109.2 (d), 109.5 (d), 113.9 (d), 116.8 (t),
119.5 (d), 122.0 (d), 132.5 (s), 137.4 (d), 139.1 (s), 144.6 (s);
MS (CI+, NH3) m/z 372 ([M + NH4]+, 100), 355 ([M + H]+, 94),
337 (14), 231 (88), 202 (14), 151 (63), 135 (18); HRMS (CI+,
NH3) for [M + H]+ found 355.1543, C21H23O5 requires 355.1543.
5-[(2SR,3SR,4SR)-4-P h en ylm eth yl-3-vin yltetr a h yd r o-
fu r a n -2-yl]ben zo[1,3]d ioxole (9m ). Prepared according to
the general procedure above, yield 18.6 mg, 76%, 89:11
inseparable mixture of 9m /8m : IR (film, cm-1) 3078, 3063,
5-[(3SR,4SR,5SR)-5-(4-Meth oxyp h en yl)-4-vin yltetr a h y-
d r ofu r a n -3-ylm eth yl]ben zo[1,3]d ioxole (9j). Prepared ac-
cording to the general procedure above, yield 20.0 mg, 50%,
92:8 inseparable mixture of 9j/8j: IR (film, cm-1) 3074, 2968,
1
3026, 2973, 1642, 1604; H NMR (signals for 9m , 500 MHz,
CDCl3) δ 2.33 (1H, apparent q, J 9.0), 2.49 (1H, m), 2.54 (1H,
dd, J 12.5, 10.0), 2.96 (1H, dd, J 12.5, 3.0), 3.82 (1H, apparent
t, J 8.5), 4.03 (1H, dd, J 8.5, 7.5), 4.54 (1H, d, J 9.0), 4.98 (1H,
ddd, J 17.0, 1.5, 0.5), 5.11 (1H, dd, J 10.0, 1.5), 5.74 (1H, ddd,
J 17.0, 10.5, 9.0), 5.94 (2H, s), 6.75 (1H, d, J 8.0), 6.78 (1H,
dd, J 8.0, 1.0), 6.85 (1H, d, J 1.0), 7.16 (2H, dd, J 7.5, 1.5),
7.19-7.31 (3H, m); signals for minor isomer 8m visible at δ
2.40 (1H, m), 2.76 (1H, apparent q, J 9.0), 3.66 (1H, apparent
t, J 9.0), 4.21 (1H, dd, J 8.5, 7.5), 4.96 (1H, dd, J 9.5, 2.0),
5.14 (1H, apparent dt, J 17.0, 9.5), 5.94 (2H, s), 6.65 (1H, dd,
J 8.0, 1.5), 6.70 (1H, d, J 1.5), 6.74 (1H, d, J 8.0); 13C NMR
(signals for 9m , 75 MHz, CDCl3) δ 37.9 (t), 47.8 (d), 59.6 (d),
73.4 (t), 85.9 (d), 101.0 (t), 106.5 (d), 108.0 (d), 118.2 (t), 119.5
(d), 126.3 (d), 128.5 (d), 128.7 (d), 135.5 (s), 136.6 (d), 140.2
(s), 147.0 (s), 147.7 (s); signals for minor isomer 8m visible at
δ 37.4 (t), 45.6 (d), 55.1 (d), 73.9 (t), 83.4 (d), 107.2 (d), 107.8
(d), 117.2 (t), 119.8 (d), 137.1 (d), 146.5 (s), 147.4 (s); MS (CI+,
NH3) m/z 326 ([M + NH4]+, 59), 309 ([M + H]+, 100), 291 (38),
217 (4), 187 (12), 158 (8), 149 (60), 91 (11); HRMS (CI+, NH3)
for [M + H]+ found 309.1500, C20H21O3 requires 309.1491.
1
1640, 1613; H NMR (signals for 9j, 400 MHz, CDCl3) δ 2.32
(1H, apparent q, J 9.0), 2.42-2.49 (2H, m), 2.86 (1H, dd, J
18.5, 9.5), 3.79 (3H, s), 3.80 (1H, m), 4.02 (1H, dd, J 8.5, 7.0),
4.56 (1H, d, J 9.0), 4.95 (1H, d, J 17.0), 5.10 (1H, d, J 10.0),
5.73 (1H, ddd, J 17.0, 10.0, 8.5), 5.92 (2H, s), 6.60 (1H, dd, J
8.0, 1.5), 6.63 (1H, d, J 1.5), 6.72 (1H, d, J 8.0), 6.86 (2H, d, J
9.0), 7.24 (2H, d, J 9.0); signals for minor isomer 8j visible at
δ 2.74 (1H, apparent q, J 8.5), 3.63 (1H, apparent t, J 8.5),
4.22 (1H, dd, J 8.5, 7.0), 7.09 (2H, d, J 8.5); 13C NMR (signals
for 9j, 75 MHz, CDCl3) δ 37.8 (t), 48.1 (d), 55.3 (q), 59.3 (d),
73.2 (t), 85.7 (d), 100.9 (t), 108.3 (d), 109.1 (d), 113.7 (d), 118.0
(t), 121.5 (d), 127.3 (d), 133.5 (s), 134.1 (s), 136.7 (d), 146.0 (s),
147.7 (s), 159.1 (s); signals for minor isomer 8j visible at δ 37.2
(t), 45.8 (d), 55.0 (d), 55.3 (q), 73.8 (t), 83.3 (d), 113.4 (d), 117.0
(t), 127.7 (d), 132.8 (s), 134.2 (s), 137.3 (d), 158.7 (s); MS (CI+,
NH3) m/z 356 ([M + NH4]+, 83), 339 ([M + H]+, 100), 321 (8),
231 (89), 202 (15), 135 (48); HRMS (CI+, NH3) for [M + H]+
found 339.1598, C21H23O4 requires 339.1596.
5-[(3SR,4SR,5SR)-5-(3,4-Dim eth oxyp h en yl)-4-vin yltet-
r a h yd r ofu r a n -3-ylm et h yl]b en zo[1,3]d ioxole (9k ). Pre-
pared according to the general procedure above, yield 16.1 mg,
54%, 90:10 inseparable mixture of 9k /8k : IR (film, cm-1) 3075,
(2SR,3SR,4SR)-2-(4-Meth oxyp h en yl)-4-p h en ylm eth yl-
3-vin yltetr a h yd r ofu r a n (9n ). Prepared according to the
general procedure above, yield 16.6 mg, 68%, 92:8 inseparable
mixture of 9n /8n : IR (film, cm-1) 3079, 3063, 3000, 1642, 1614;
1H NMR (signals for 9n , 400 MHz, CDCl3) δ 2.35 (1H, apparent
q, J 9.0), 2.48-2.58 (2H, m), 2.97 (1H, dd, J 18.5, 9.5), 3.81
(3H, s), 3.84 (1H, apparent t, J 8.5), 4.03 (1H, dd, J 8.5, 8.0),
4.58 (1H, d, J 9.0), 4.97 (1H, ddd, J 17.0, 1.5, 1.0), 5.10 (1H,
dd, J 10.0, 1.5), 5.75 (1H, ddd, J 17.0, 10.0, 9.0), 6.87 (2H, d,
J 8.5), 7.15-7.32 (7H, m, 2′-H); signals for minor isomer 8n
visible at δ 2.77 (1H, apparent q, J 9.0), 3.67 (1H, apparent t,
J 8.5), 3.80 (3H, s), 4.23 (1H, dd, J 8.5, 7.0), 6.84 (2H, d, J
8.5); 13C NMR (signals for 9n , 75 MHz, CDCl3) δ 38.0 (t), 47.8
(d), 55.3 (q), 59.5 (d), 73.3 (t), 85.7 (d), 113.7 (d), 118.0 (t), 126.2
(d), 127.3 (d), 128.5 (d), 128.7 (d), 133.5 (s), 136.7 (d), 140.3
(s), 159.1 (s); signals for minor isomer 8n visible at δ 37.5 (t),
45.6 (d), 55.1 (d), 73.8 (t), 83.3 (d), 113.3 (d), 117.0 (t), 127.7
1
2950, 1640, 1607; H NMR (signals for 9k , 400 MHz, CDCl3)
δ 2.32 (1H, apparent q, J 9.0), 2.41-2.49 (2H, m), 2.87 (1H,
dd, J 18.5, 9.5), 3.81 (1H, apparent t, J 8.0), 3.87 (3H, s), 3.89
(3H, s), 4.03 (1H, dd, J 8.5, 7.5), 4.57 (1H, d, J 9.0), 4.98 (1H,
dd, J 17.0, 1.0), 5.11 (1H, dd, J 10.0, 1.5), 5.75 (1H, ddd, J
17.0, 10.0, 9.0), 5.93 (2H, s), 6.60 (1H, dd, J 8.0, 1.5), 6.65 (1H,
d, J 1.5), 6.72 (1H, d, J 8.0), 6.81 (1H, d, J 8.0), 6.85 (1H, dd,
J 8.0, 1.5), 6.87 (1H, d, J 1.5); signals for minor isomer 8k
visible at δ 2.73 (1H, apparent q, J 9.0), 3.63 (1H, apparent t,
J 8.5), 3.85 (3H, s), 4.21 (1H, dd, J 8.5, 7.5), 5.92 (2H, s); 13C
NMR (signals for 9k , 75 MHz, CDCl3) δ 37.6 (t), 48.9 (d), 55.9
(q), 55.9 (q), 59.2 (d), 73.2 (t), 85.7 (d), 100.9 (t), 108.2 (d), 109.0
(d, 2 coincident peaks), 110.8 (d), 118.0 (t), 118.2 (d), 121.4
J . Org. Chem, Vol. 69, No. 20, 2004 6879

Miles et al.
(d), 129.1 (d), 137.3 (d); MS (CI+, NH3) m/z 312 ([M + NH4]+,
82), 295 ([M + H]+, 100), 277 (19), 203 (6), 187 (13), 158 (11),
135 (36), 91 (16); HRMS (CI+, NH3) for [M + H]+ found
295.1694, C20H23O2 requires 295.1698.
12), 351 (3), 247 (29), 218 (19), 151 (64), 149 (100); HRMS (CI+,
NH3) for [M + H]+ found 369.1696, C22H25O5 requires 369.1702.
5-[(3SR,4SR,5RS)-5-(3-Meth oxyp h en yl)-4-vin yltetr a h y-
d r ofu r a n -3-ylm eth yl]ben zo[1,3]d ioxole (8r ). Prepared ac-
cording to the general procedure above, yield 13.9 mg, 74%,
82:18 inseparable mixture of 8r /9r : IR (film, cm-1) 3075, 1640,
5-[(2S R ,3S R ,4S R )-4-(3-Me t h oxyp h e n ylm e t h yl)-3-vi-
n ylt et r a h yd r ofu r a n -2-yl]-b en zo[1,3]d ioxole (9o). Pre-
pared according to the general procedure above, yield 19.8 mg,
52%, 92:8 inseparable mixture of 9o/8o: IR (film, cm-1) 3075,
1642, 1602; 1H NMR (signals for 9o, 500 MHz, CDCl3) δ 2.31
(1H, apparent q, J 9.0), 2.47-2.52 (2H, m), 2.93 (1H, dd, J
18.5, 9.5), 3.80 (3H, s), 3.82 (1H, apparent t, J 8.5), 4.03 (1H,
dd, J 8.5, 7.5), 4.53 (1H, d, J 9.0), 4.98 (1H, ddd, J 17.0, 2.0,
0.5), 5.11 (1H, dd, J 10.0, 2.0), 5.73 (1H, ddd, J 17.0, 10.0, 9.0),
5.94 (2H, s), 6.70 (1H, dd, J 2.0, 2.0), 6.74-6.77 (4H, m), 6.85
(1H, d, J 1.5), 7.20 (1H, apparent t, J 8.0); signals for minor
isomer 8o visible at δ 2.62 (1H, dd, J 13.5, 10.0), 2.75 (1H,
apparent q, J 8.5), 3.65 (1H, apparent t, J 8.5), 4.22 (1H, dd,
J 8.5, 7.0), 4.96 (1H, dd, J 10.0, 2.0), 5.93 (2H, s), 6.64 (1H,
dd, J 8.0, 1.5), 7.21 (1H, apparent t, J 8.0); 13C NMR (signals
for 9o, 75 MHz, CDCl3) δ 37.9 (t), 47.7 (d), 55.2 (q), 59.6 (d),
73.4 (t), 85.8 (d), 101.0 (t), 106.5 (d), 108.0 (d), 111.4 (d), 114.5
(d), 118.2 (t), 119.5 (d), 121.0 (d), 129.5 (d), 135.4 (s), 136.5
(d), 141.8 (s), 147.0 (s), 147.7 (s), 159.7 (s); signals for minor
isomer 8o visible at δ 37.5 (t), 45.4 (d), 55.1 (d), 73.9 (t), 83.4
(d), 117.2 (t), 137.1 (d); MS (CI+, NH3) m/z 356 ([M + NH4]+,
100), 339 ([M + H]+, 41), 321 (6), 217 (17), 188 (7); HRMS (CI+,
NH3) for [M + H]+ found 309.1582, C21H23O4 requires 339.1596.
1
1603; H NMR (signals for 8r , 400 MHz, CDCl3) δ 2.35 (1H,
m), 2.42 (1H, dd, J 13.0, 10.0), 2.77 (1H, apparent q, J 8.5),
2.83 (1H, dd, J 13.0, 4.0), 3.66 (1H, apparent t, J 8.5), 3.79
(3H, s), 4.24 (1H, dd, J 8.5, 7.0), 4.94 (1H, dd, J 9.5, 2.5), 5.01
(1H, dd, J 17.0, 2.5), 5.10 (1H, ddd, J 17.0, 9.5, 9.0), 5.13 (1H,
d, J 8.0), 5.93 (2H, s), 6.60 (1H, dd, J 8.0, 1.5), 6.63 (1H, d, J
1.5), 6.73 (1H, d, J 8.0), 6.74-6.78 (3H, m), 7.21 (1H, apparent
td, J 8.5, 1.0); signals for minor isomer 9r visible at δ 3.81
(3H, s), 3.81 (1H, apparent t, J 8.0), 4.05 (1H, dd, J 8.5, 7.0),
4.61 (1H, d, J 9.0), 4.98 (1H, ddd, J 17.0, 1.5, 0.5), 5.77 (1H,
ddd, J 17.0, 10.0, 8.5), 5.93 (2H, s), 6.72 (1H, d, J 8.0), 6.90
(2H, m); 13C NMR (signals for 8r , 75 MHz, CDCl3) δ 37.1 (t),
45.7 (d), 54.8 (d), 55.2 (q), 73.8 (t), 83.4 (d), 100.9 (t), 108.2 (d),
109.0 (d), 112.2 (d), 112.3 (d), 117.0 (t), 119.0 (d), 121.4 (d),
128.9 (d), 134.0 (s), 137.1 (d), 142.3 (s), 145.9 (s), 147.7 (s),
159.4 (s); signals for minor isomer 9r visible at δ 37.5 (t), 48.2
(d), 59.4 (d), 73.4 (t), 85.6 (d), 111.2 (d), 112.9 (d), 118.1 (t),
129.3 (d), 136.8 (d), 143.4 (s), 159.6 (s); MS (CI+, NH3) m/z 356
([M + NH4]+, 100), 339 ([M + H]+, 52), 321 (13), 202 (11), 135
(21); HRMS (CI+, NH3) for [M + H]+ found 339.1596, C21H23O4
requires 339.1596.
5-[(3SR,4SR,5RS)- a n d 5-[(3SR,4SR,5SR)-5-(4-Dim eth -
yla m in op h e n yl)-4-vin ylt e t r a h yd r ofu r a n -3-ylm e t h yl]-
ben zo[1,3]d ioxole (8s a n d 9s). Prepared according to the
general procedure above, yield 14.3 mg, 67%, 57:43 inseparable
(2SR,3SR,4SR)-4-(3-Meth oxyp h en ylm eth yl)-2-(4-m eth -
oxyp h en yl)-3-vin yltetr a h yd r ofu r a n (9p ). Prepared accord-
ing to the general procedure above, yield 17.8 mg, 48%, 92:8
inseparable mixture of 9p /8p : IR (film, cm-1) 3075, 3028, 3000,
1
mixture of 8s/9s: IR (film, cm-1) 3075, 2972, 1640, 1615; H
1
1642, 1614, 1601; H NMR (signals for 9p , 400 MHz, CDCl3)
NMR (both diastereoisomers, asterisk denotes signal for minor
isomer 9s), 500 MHz, CDCl3) δ 2.33-2.50 (2.4H, m, 3′-H), 2.72
(0.6H, apparent q, J 9.0), 2.80-2.91 (1H, m), 2.93 (3.6H, s),
2.94* (2.4H, s), 3.63 (0.6H, apparent t, J 8.5), 3.80* (0.4H,
apparent t, J 8.0), 4.01* (0.4H, dd, J 8.0, 7.0), 4.22 (0.6H, dd,
J 8.0, 6.5), 4.54* (0.4H, d, J 9.0), 4.94 (0.6H, dd, J 10.0, 2.0),
4.97* (0.4H, ddd, J 17.0, 2.0, 0.5), 5.00 (0.6H, dd, J 17.0, 2.0),
5.07* (0.4H, dd, J 10.5, 2.0), 5.09 (0.6H, d, J 8.5), 5.15 (0.6H,
apparent dt, J 17.0, 9.5), 5.74* (0.4H, ddd, J 17.0, 10.0, 8.5),
5.93* (0.8H, s), 5.93 (1.2H, s), 6.60 (0.6H, dd, J 8.0, 1.5), 6.61*
(0.4H, dd, J 8.0, 1.5), 6.64 (0.6H, d, J 1.5), 6.65* (0.4H, d, J
1.5), 6.68-6.74 (3H, m), 7.05 (1.2H, d, J 8.5), 7.20* (0.8H, d, J
9.0); 13C NMR (both diastereoisomers, asterisk denotes signal
for minor diastereoisomer, 125 MHz, CDCl3) δ 37.2 (t), 37.8*
(t), 40.8 (q), 45.8 (d), 48.0* (d), 55.1 (d), 58.8* (d), 73.0* (t),
73.7 (t), 83.6 (d), 86.0* (d), 100.9 (t), 108.2 (d), 109.1 (d), 112.2
(d), 112.6* (d), 116.7 (t), 117.6* (t), 121.5 (d), 127.1* (d), 127.5
(d), 128.7 (s), 129.2* (s), 134.2* (s), 134.3 (s), 137.0* (d), 137.6
(d), 145.9 (s), 147.7 (s), 149.7 (s), 150.2* (s) [38C expected, 31C
seen]; MS (CI+, NH3) m/z 352 ([M + H]+, 100); HRMS (CI+,
NH3) for [M + H]+ found 352.1913, C22H26NO3 requires
352.1913.
5-[(3SR,4SR,5RS)- a n d 5-[(3SR,4SR,5RS)-5-(Ben zo[1,3]-
d ioxol-5-yl)-4-vin ylt et r a h yd r ofu r a n -3-ylm et h yl]b en zo-
[1,3]d ioxole (8i a n d 9i). Cyclic allylsilane 3a (56.4 mg, 0.204
mmol) was reacted with piperonal in the presence of boron
trifluoride diethyl etherate according to the general procedure
described above, but employing 0.91 equiv each of BF3‚OEt2
and piperonal in place of the usual 1.0 equiv. Purification by
flash chromatography (10% Et2O in hexane) yielded tetrahy-
drofurans 8i and 9i as a colorless oil (9.8 mg, 71%, 50:50
inseparable mixture of 8i and 9i).
δ 2.34 (1H, apparent q, J 9.0), 2.46-2.54 (2H, m), 2.94 (1H,
dd, J 18.5, 9.5), 3.80 (3H, s), 3.80 (3H, s), 3.83 (1H, apparent
t, J 8.5), 4.03 (1H, dd, J 8.5, 7.5), 4.57 (1H, d, J 9.0), 4.97 (1H,
ddd, J 17.0, 1.5, 0.5), 5.08 (1H, ddd, J 10.0, 1.5, 0.5), 5.74 (1H,
ddd, J 17.0, 10.0, 8.5), 6.70 (1H, dd, J 2.0, 2.0) 6.74-6.77 (2H,
m), 6.86 (2H, d, J 8.5), 7.20 (1H, apparent t, J 8.0), 7.25 (2H,
d, J 8.5); signals for minor isomer 8p visible at δ 2.76 (1H,
apparent q, J 8.5), 3.66 (1H, apparent t, J 8.5), 4.23 (1H, dd,
J 8.5, 7.0), 7.10 (2H, d, J 8.5); 13C NMR (signals for 9p , 75
MHz, CDCl3) δ 38.0 (t), 47.7 (d), 55.2 (q), 55.3 (q), 59.5 (d),
73.3 (t), 85.6 (d), 111.4 (d), 113.3 (d), 113.7 (d), 118.0 (t), 121.1
(d), 127.3 (d), 129.5 (d), 133.5 (s), 136.7 (d), 141.9 (s), 159.1
(s), 159.7 (s); signals for minor isomer 8p visible at δ 37.5 (t),
55.1 (d), 83.2 (d); MS (CI+, NH3) m/z 342 ([M + NH4]+, 73),
325 ([M + H]+, 99), 307 (11), 217 (100), 188 (25), 135 (52), 121
(26); HRMS (CI+, NH3) for [M + H]+ found 325.1805, C21H25O3
requires 325.1804.
5-[(2SR,3SR,4SR)-4-(3,4-Dim et h oxyp h en ylm et h yl)-3-
vin yltetr a h yd r ofu r a n -2-yl]ben zo[1,3]d ioxole (8q). Pre-
pared according to the general procedure above, yield 9.8 mg,
47%, 91:9 inseparable mixture of 9q/8q: IR (film, cm-1) 3072,
1
2995, 1640, 1607; H NMR (signals for 9q, 400 MHz, CDCl3)
δ 2.30 (1H, apparent q, J 9.0), 2.40-2.50 (2H, m), 2.89 (1H,
dd, J 18.5, 9.5), 3.82 (1H, apparent t, J 8.5), 3.86 (3H, s), 3.87
(3H, s), 4.02 (1H, dd, J 8.5, 7.0), 4.53 (1H, d, J 9.0), 4.97 (1H,
ddd, J 17.0, 1.5, 0.5), 5.10 (1H, dd, J 10.0, 1.5), 5.73 (1H, ddd,
J 17.0, 10.0, 8.5), 5.94 (2H, s), 6.65 (1H, d, J 2.0), 6.69 (1H,
dd, J 8.0, 2.0), 6.75 (1H, apparent s), 6.75 (1H, apparent d, J
2.0), 6.78 (1H, d, J 8.0), 6.84 (1H, m); signals for minor isomer
8q visible at δ 2.74 (1H, apparent q, J 8.5), 3.65 (1H, apparent
t, J 8.5), 4.21 (1H, dd, J 8.5, 7.0), 4.96 (1H, dd, J 10.0, 2.5),
5.01 (1H, dd, J 17.0, 2.5), 5.94 (2H, s); 13C NMR (signals for
9q, 75 MHz, CDCl3) δ 37.6 (t), 48.0 (d), 56.0 (q), 56.0 (q), 59.5
(d), 73.4 (t), 85.9 (d), 101.0 (t), 106.5 (d), 108.0 (d), 111.4 (d),
112.1 (d), 118.1 (t), 119.5 (d), 120.6 (d), 132.8 (s), 135.5 (s),
136.7 (d), 147.0 (s), 147.6 (s), 147.7 (s), 149.0 (s); signals for
minor isomer 8q visible at δ 37.0 (t), 45.7 (d), 73.8 (t), 83.4
(d), 107.2 (d), 107.8 (d), 117.1 (t), 119.8 (d), 134.7 (s), 137.2
(d); MS (CI+, NH3) m/z 386 ([M + NH4]+, 58), 369 ([M + H]+,
5-[(3SR,4SR,5SR)- a n d 5-[(3SR,4SR,5RS)-5-(4-Met h -
oxyp h en yl)-4-vin ylt et r a h yd r ofu r a n -3-ylm et h yl]b en zo-
[1,3]d ioxole (8j a n d 9j). Cyclic allylsilane 3a (10.0 mg, 0.036
mmol) was reacted with p-anisaldehyde in the presence of
boron trifluoride diethyl etherate according to the general
procedure described above, but employing 0.91 equiv each of
BF3‚OEt2 and p-anisaldehyde in place of the usual 1.0 equiv.
Purification by flash chromatography (10% Et2O in hexane)
6880 J . Org. Chem., Vol. 69, No. 20, 2004

Synthesis of Lignan-Related Tetrahydrofurans
yielded tetrahydrofurans 8j and 9j as a colorless oil (8.2 mg,
67%, 39:61 inseparable mixture of 8j and 9j).
extracted with CH2Cl2 (3 × 15 mL). The combined organic
phase was dried (Na2SO4) and concentrated in vacuo. The
resulting crude diol was taken up in methanol (0.4 mL) and
cooled to 0 °C, and a solution of sodium metaperiodate (10.9
mg, 0.051 mmol) in methanol-water (10:3, 0.82 mL) was
added dropwise over 5 min. The resulting white suspension
was warmed to room temperature and stirred for a further 70
min, whereupon the mixture was filtered and the solid was
washed with CH2Cl2 (2 mL). The filtrate was diluted with CH2-
Cl2 (5 mL), and water (3 mL) was added. The phases were
separated, and the aqueous phase was extracted with CH2Cl2
(4 × 4 mL). The combined organic phases were combined, dried
(Na2SO4), and concentrated in vacuo. The resulting crude
aldehyde was taken up in CH2Cl2 (0.4 mL), and a solution of
sodium borohydride (2.0 mg, 0.053 mmol) in methanol (0.2 mL)
was added dropwise. The reaction mixture was stirred at room
temperature for a further 30 min, whereupon water (1 mL)
was added and the mixture was extracted with CH2Cl2 (3 × 3
mL). The combined organic phase was dried (MgSO4) and
concentrated in vacuo. Purification by flash chromatography
(50% Et2O in hexane) yielded compound 13a as a colorless oil
(13 mg, 93% based upon isomeric content of starting mate-
rial): IR (film, cm-1) 3425 (br, OH), 1608; 1H NMR (400 MHz,
CDCl3) δ 1.95 (1H, ddt, J 8.0, 7.0, 5.5), 2.45 (1H, apparent
sextet, J 7.0), 2.66 (1H, dd, J 13.5, 8.5), 2.77 (1H, dd, J 13.5,
7.0), 3.62 (2H, d, J 5.5), 3.82 (1H, dd, J 8.5, 6.0), 3.94 (1H, dd,
J 8.5, 7.5), 4.59 (1H, d, J 8.0), 5.93 (2H, s), 5.96 (2H, s), 6.62
(1H, dd, J 8.0, 1.5), 6.67 (1H, d, J 1.5), 6.73 (1H, d, J 8.0), 6.77
5-[(3SR,4SR,5RS)-5-(Ben zo[1,3]d ioxol-5-yl)-4-vin yltet-
r a h yd r ofu r a n -3-ylm eth yl]ben zo[1,3]d ioxole (8i). To a so-
lution of cyclic allylsilane 3a (24.7 mg, 0.089 mmol) in DCM
(0.8 mL) at -78 °C was added trimethylsilyl trifluoromethane-
sulfonate (16.2 µL, 0.089 mmol). After 5 min, piperonal (13.4
mg, 0.089 mmol in 0.1 mL DCM) was added dropwise. The
solution was stirred at -78 °C for 3 h before the addition of
brine (3 mL) and Et2O (7 mL). The phases were separated,
and the aqueous phase was extracted with Et2O (3 × 3 mL).
The combined organic phases were washed with water (8 mL),
dried (MgSO4), and concentrated in vacuo. Purification by flash
chromatography (10% Et2O in hexane) yielded tetrahydro-
furans 8i and 9i as a colorless oil (22.9 mg, 73%, 90:10
inseparable mixture of 8i and 9i): IR (film, cm-1) 3074, 3010,
2976, 1639, 1608; 1H NMR (signals for 8i, 400 MHz, CDCl3) δ
2.32 (1H, m), 2.39 (1H, dd, J 13.0, 10.0), 2.72 (1H, apparent q,
J 8.5), 2.82 (1H, dd, J 13.0, 4.0), 3.62 (1H, apparent t, J 8.5),
4.20 (1H, dd, J 8.5, 7.0), 4.95 (1H, dd, J 9.5, 2.5), 5.01 (1H, dd,
J 17.0, 2.5), 5.07 (1H, d, J 8.0), 5.11 (1H, dt, J 17.0, 9.5), 5.93
(2H, s), 5.94 (2H, s), 6.59 (1H, dd, J 8.0, 1.5), 6.63 (1H, d, J
1.5), 6.64 (1H, dd, J 8.0, 1.5), 6.68 (1H, d, J 1.5), 6.73 (1H, d,
J 8.0), 6.74 (1H, d, J 8.0); signals for minor isomer 9i visible
at δ 3.79 (1H, apparent t, J 8.5), 4.02 (1H, dd, J 8.5, 7.5), 4.52
(1H, d, J 9.0), 5.72 (1H, ddd, J 17.0, 10.0, 9.0); 13C NMR
(signals for 8i, 75 MHz, CDCl3) δ 37.1 (t), 45.7 (d), 55.0 (d),
73.8 (t), 83.4 (d), 100.9 (t, 2 coincident peaks), 107.2 (d), 107.8
(d), 108.3 (d), 109.0 (d), 117.2 (t), 119.8 (d), 121.5 (d), 134.0
(s), 134.7 (s), 137.1 (d), 146.0 (s), 146.5 (s), 147.4 (s), 147.7 (s)
[21 C expected, 20 seen]; signals for minor isomer 9i visible
at δ 37.6 (t), 48.0 (d), 59.5 (d), 73.3 (t), 85.9 (d), 106.5 (d), 108.0
(d), 118.2 (t), 119.5 (d), 136.5 (d); MS (CI+, NH3) m/z 370 ([M
+ NH4]+, 100), 353 ([M + H]+, 97), 335 (24), 231 (41), 202 (16),
149 (70), 135 (29); HRMS (CI+, NH3) for [M + H]+ found
353.1398, C21H21O5 requires 353.1389.
(1H, d, J 8.0), 6.83 (1H, dd, J 8.0, 1.5), 6.90 (1H, d, J 1.5); 13
C
NMR (100 MHz, CDCl3) δ 39.5 (t), 44.2 (d), 55.7 (d), 62.8 (t),
73.1 (t), 84.1 (d), 101.0 (t), 101.1 (t), 106.7 (d), 108.2 (d), 108.4
(d), 109.1 (d), 119.7 (d), 121.6 (d), 134.0 (s), 136.1 (s), 146.0
(s), 147.1 (s), 147.8 (s), 148.0 (s); MS (EI+) m/z 356 (M+, 74),
135 (100); HRMS (EI+) for [M]+ found 356.1248, C20H20O6
requires 356.1260.
(2SR,3RS,4SR)-[4-Ben zo[1,3]d ioxol-5-ylm et h yl-2-(3,4-
d im eth oxyp h en yl)tetr a h yd r ofu r a n -3-yl]m eth a n ol (13b).
Vinyl tetrahydrofurans 9k and 8k (4.7 mg, 0.013 mmol, 90:10
diastereoisomeric mixture) were transformed to the corre-
sponding hydroxymethyl tetrahydrofurans according to the
procedure described above. Purification by flash chromatog-
raphy (gradient 60% Et2O in hexane to neat Et2O) yielded
compound 13b as a colorless oil (4.1 mg, 96% based upon
isomeric content of starting material): IR (film, cm-1) 3444
(br, OH), 1608; 1H NMR (400 MHz, CDCl3) δ 1.21 (1H, t, J
5.0), 2.00 (1H, ddt, J 8.0, 7.0, 5.5), 2.47 (1H, apparent sextet,
J 7.0), 2.67 (1H, dd, J 13.5, 8.5), 2.78 (1H, dd, J 13.5, 7.0),
3.64 (2H, d, J 5.5), 3.84 (1H, dd, J 8.5, 6.0), 3.88 (3H, s), 3.91
(3H, s), 3.97 (1H, dd, J 8.5, 7.5), 4.63 (1H, d, J 8.0), 5.93 (2H,
s), 6.61 (1H, dd, J 8.0, 1.5), 6.67 (1H, d, J 1.5), 6.73 (1H, d, J
8.0), 6.84 (1H, d, J 8.0), 6.92 (1H, dd, J 8.0, 2.0), 6.94 (1H, d,
J 2.0); 13C NMR (100 MHz, CDCl3) δ 39.5 (t), 44.2 (d), 55.4
(d), 55.9 (q), 56.0 (q), 63.0 (t), 73.0 (t), 84.0 (d), 100.9 (t), 108.3
(d), 109.1 (d), 109.4 (d), 111.1 (d), 118.5 (d), 121.6 (d), 134.0
(s), 134.6 (s), 146.0 (s), 147.8 (s), 148.6 (s), 149.2 (s); MS (EI+)
m/z 372 (M+, 65), 135 (100); HRMS (EI+) for [M]+ found
372.1582, C21H24O6 requires 372.1573.
5-[(2RS,3SR,4SR)-4-P h en ylm eth yl-3-vin yltetr a h yd r o-
fu r a n -2-yl]ben zo[1,3]d ioxole (8m ). Cyclic allylsilane 3b
(22.4 mg, 0.096 mmol) was reacted with piperonal in the
presence of trimethylsilyl trifluoromethanesulfonate according
to the procedure described above. Purification by flash chro-
matography (5% Et2O in hexane) yielded tetrahydrofurans 8m
and 9m as a colorless oil (21.9 mg, 74%, 93:7 inseparable
mixture of 8m and 9m ): IR (film, cm-1) 3074, 3026, 2976,
1640, 1604; 1H NMR (signals for 8m , 400 MHz, CDCl3) δ 2.40
(1H, m), 2.49 (1H, dd, J 13.5, 10.0), 2.76 (1H, apparent q, J
9.0), 2.92 (1H, dd, J 13.5, 4.0), 3.66 (1H, dd, J 9.0, 8.5), 4.21
(1H, dd, J 8.5, 7.5), 4.97 (1H, dd, J 9.5, 2.5), 5.03 (1H, dd, J
17.0, 2.5), 5.09 (1H, d, J 8.0), 5.14 (1H, dt, J 17.0, 9.5), 5.94
(2H, s), 6.65 (1H, dd, J 8.0, 1.5), 6.70 (1H, d, J 1.5), 6.74 (1H,
d, J 8.0), 7.15 (2H, dd, J 7.5, 1.5), 7.20-7.32 (3H, m); signals
for minor isomer 9m visible at δ 3.82 (1H, apparent t, J 8.5),
4.03 (1H, dd, J 8.5, 7.5), 4.54 (1H, d, J 9.0), 5.74 (1H, ddd, J
17.0, 10.5, 9.0); 13C NMR (signals for 8m , 75 MHz, CDCl3) δ
37.4 (t), 45.6 (d), 55.1 (d), 73.9 (t), 83.4 (d), 100.9 (t), 107.2 (d),
107.8 (d), 117.2 (t), 119.8 (d), 126.3 (d), 128.5 (d), 128.9 (d),
134.7 (s), 137.1 (d), 140.3 (s), 146.5 (s), 147.4 (s); signals for
minor isomer 9m visible at δ 37.9 (t), 47.8 (d), 59.6 (d), 73.4
(t), 85.9 (d), 106.5 (d), 108.0 (d), 118.2 (t), 119.5 (d), 135.5 (s),
136.6 (d); MS (CI+, NH3) m/z 326 ([M + NH4]+, 100), 309 ([M
+ H]+, 97), 291 (30), 217 (3), 187 (9), 158 (8), 149 (50), 91 (8);
HRMS (CI+, NH3) for [M + H]+ found 309.1494, C20H21O3
requires 309.1491.
(2SR,3RS,4SR)-[2-Ben zo[1,3]d ioxol-5-yl-4-(3,4-d im eth -
oxyp h en ylm eth yl)tetr a h yd r ofu r a n -3-yl]m eth a n ol (13c).
Vinyl tetrahydrofurans 9p and 8p (5.1 mg, 0.014 mmol, 91:9
diastereoisomeric mixture) were transformed to the corre-
sponding hydroxymethyl tetrahydrofurans according to the
procedure described above. Purification by flash chromatog-
raphy (gradient 60% to 70% Et2O in hexane) yielded compound
13c as a colorless oil (4.5 mg, 96% based upon isomeric content
of starting material): IR (film, cm-1) 3450 (br, OH), 3006, 1608;
1H NMR (500 MHz, CDCl3) δ 1.23 (1H, br s), 1.96 (1H, ddt, J
8.0, 7.0, 5.5), 2.50 (1H, apparent sextet, J 7.0), 2.70 (1H, dd, J
13.5, 8.5), 2.79 (1H, dd, J 13.5, 7.0), 3.63 (2H, d, J 5.5), 3.84
(1H, dd, J 8.5, 6.0), 3.86 (3H, s), 3.87 (3H, s), 3.95 (1H, dd, J
8.5, 7.5), 4.60 (1H, d, J 8.0), 5.95 (2H, s), 6.68 (1H, d, J 1.5),
6.71 (1H, dd, J 8.0, 1.5), 6.77 (1H, d, J 8.0), 6.79 (1H, d, J 8.0),
(2SR,3RS,4SR)-(2-Ben zo[1,3]d ioxol-5-yl-4-b en zo[1,3]-
d ioxol-5-ylm eth yltetr a h yd r ofu r a n -3-yl)m eth a n ol (13a ).
To a stirred solution of vinyl tetrahydrofurans 9i and 8i (15
mg, 0.043 mmol, 92:8 diastereoisomeric mixture) in THF (0.5
mL) were added successively water (50 µL), N-methylmorpho-
line N-oxide hydrate (8.1 mg, 0.060 mmol), and osmium
tetraoxide (8 µL of a 4% solution in water, 2.5 mol %). The
reaction mixture was stirred at room temperature for 15 h,
whereupon water (2 mL) was added and the mixture was
J . Org. Chem, Vol. 69, No. 20, 2004 6881

Miles et al.
6.83 (1H, dd, J 8.0, 1.5), 6.90 (1H, d, J 1.5); 13C NMR (75 MHz,
CDCl3) δ 39.4 (t), 44.2 (d), 55.8 (q), 56.0 (d & q, 2 coincident
peaks), 62.9 (t), 73.1 (t), 84.1 (d), 101.1 (t), 106.7 (d), 108.2 (d),
111.3 (d), 112.0 (d), 119.7 (d), 120.7 (d), 132.8 (s), 136.2 (s),
147.1 (s), 147.6 (s), 148.0 (s), 149.0 (s) (21C expected, 20 seen);
MS (EI+) m/z 372 (M+, 89), 151 (100); HRMS (EI+) for [M]+
found 372.1579, C21H24O6 requires 372.1573.
(2RS,3RS,4SR)-(2-Ben zo[1,3]d ioxol-5-yl-4-b en zo[1,3]-
d ioxol-5-ylm eth yltetr a h yd r ofu r a n -3-yl)m eth a n ol (14a ).
Vinyl tetrahydrofurans 8i and 9i (21.7 mg, 0.062 mmol, 50:50
diastereoisomeric mixture) were transformed to the corre-
sponding hydroxymethyl tetrahydrofurans according to the
procedure described above. Purification by flash chromatog-
raphy (50% Et2O in hexane) yielded compound 14a as a
colorless oil (10.8 mg, 99% based upon isomeric content of
starting material): IR (film, cm-1) 3433 (br, OH), 1608; 1H
NMR (400 MHz, CDCl3) δ 2.29 (1H, apparent quintet, J 6.5,
3-H), 2.44 (1H, apparent sextet, J 7.0, 4-H), 2.64 (1H, dd, J
14.0, 8.5, 5′′-CHaH), 2.82 (1H, dd, J 14.0, 6.5, 5′′-CHHb), 3.29
(2H, d, J 6.5, CH2OH), 3.57 (1H, dd, J 8.5, 8.0, 5-HaH), 4.18
(1H, dd, J 8.5, 7.5, 5-HHb), 5.03 (1H, d, J 7.0, 2-H), 5.94 (2H,
s, OCH2O), 5.95 (2H, s, OCH2O), 6.65 (1H, dd, J 8.0, 1.5, 6′′-
H), 6.69 (1H, d, J 1.5, 4′′-H), 6.74 (1H, d, J 8.0, 7′′-H), 6.78-
6.79 (2H, m, 7′-H & 4′-H or 6′-H), 6.82 (1H, apparent s, 6′-H
or 4′-H); 13C NMR (100 MHz, CDCl3) δ 38.9 (t), 43.5 (d), 51.1
(d), 62.5 (t), 73.2 (t), 81.9 (d), 101.0 (t), 101.1 (t), 106.8 (d), 108.4
(d, 2 coincident signals), 109.1 (d), 119.2 (d), 121.6 (d), 133.3
(s), 133.8 (s), 146.1 (s), 147.0 (s), 147.8 (s), 147.9 (s) [20C
expected, 19C seen]; MS (EI+) m/z 356 (M+, 90), 135 (100);
HRMS (EI+) for [M]+ found 356.1251, C20H20O6 requires
356.1260.
Ackn owledgm en t. We thank the EPSRC and Glaxo-
SmithKline for the award of an Industrial CASE stu-
dentship to S.M.M.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and compound data for alcohols 7a -d and NMR
spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O048971A
6882 J . Org. Chem., Vol. 69, No. 20, 2004