An enantioselective synthesis of (-)-4-hydroxy-6-methoxy-3a,8a- dihydrofuro[2,3-b]benzofuran: An advanced intermediate in the synthesis of (-)-aflatoxin B1 and G1

Full text of DOI:10.1016/j.tet.2010.10.003

Tetrahedron 67 (2011) 837e841
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An enantioselective synthesis of (ꢀ)-4-hydroxy-6-methoxy-3a,8a-dihydrofuro
[2,3-b]benzofuran: an advanced intermediate in the synthesis
of (ꢀ)-aflatoxin B1 and G1
,
b,
Joseph P. Marino a , Karen A. Kieler c, Min-Woo Kim b
*
a Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
b Department of Chemistry and Department of Medicinal Chemistry, The University of Michigan, Ann Arbor, MI 48109, USA
c Department of Medicinal Chemistry College of Pharmacy, USA
a r t i c l e i n f o
Article history:
Received 16 June 2010
Received in revised form 30 September 2010
Accepted 1 October 2010
Available online 13 October 2010
1. Introduction
a synthesis of Aflatoxin G1 (2) as well as an improved synthesis of
Aflatoxin B1, which employed a von Pechmann condensation of
3-bromo-2-carbethoxy cyclopentenone with racemic 4-hydroxy-6-
methoxy-3a,8a-dihydrofuro[2,3-b]benzofuran (9) in the final step.3
We chose this chiral dihydrofurobenzofuran intermediate 9 as our
target compound.
The Aflatoxins (Fig. 1), secondary metabolites of the fungus As-
pergillus, are among the most potent carcinogens known to man. The
fused dihydrobisfuran ring system of these mycotoxins contains an
electron rich double bond that undergoes metabolic activation to
an epoxide, which can then generate covalent lesions upon in-
tercalation into double stranded DNA.1 Recent reports on the pre-
paration and use of the 8,9-epoxide of Aflatoxin B1 by Harris and
co-workers1 has provided new impetus to directly investigate the
chemistryand metabolism of this highlycarcinogenic species. In this
context, the synthesis of precursors of the Aflatoxins would permit
greater accessibility to this highly reactive class of compounds.
€
Since the pioneering work of Buchi’s group, several partial and
total syntheses of Aflatoxin class of compounds have appeared in
the literature.4 Although each synthesis addresses the problem of
constructing the highly oxygenated ring system, none of these
syntheses consider the question of enantiomeric purity. The first
€
enantioselective synthesis of Buchi’s furobenzofuran 9 will be
reported in which the asymmetry is obtained through an optically
active vinyl sulfoxide 5.
€
In 1967, Buchi and co-workers devised the first total synthesis of
racemic Aflatoxin B1 (1).2 In 1971, Buchi and Weinreb reported
We had previously showed that optically active trans-vinyl
€
sulfoxides react with haloketenes to produce the trans-g-thio-g-
butyrolactones with high enantioselectivity.5 It was also demon-
strated by our group that the absolute configuration of the starting
vinyl sulfoxide controls the absolute configuration of the resulting
trans-lactone.6a Since the first report, this laconization reaction has
been used in the asymmetric synthesis of a variety of natural
products.6 We envisioned that this lactonization reaction could be
applied to the (S)-vinyl sulfoxide 5 to yield the appropriately
O
O
O
O
O
O
H
H
O
O
H
H
O
O
CH3O
CH3O
functionalized aryl-g-thio-g-butyrolactone, which would be im-
portant in construction of the naturally occurring enantiomer of the
furo[2,3-b]benzofuran ring system found in the Aflatoxins and
other natural products.
1 Aflatoxine B1
1 Aflatoxine G1
Thus, requisite vinyl sulfoxide 5 ([
a
]
25 ꢀ106ꢁ, c 1.08, CHCl3) was
Fig. 1.
D
obtained through a Stille coupling7 of the chiral trans-vinyl stan-
25
nane8 4 ([
a]
ꢀ137ꢁ, c 1.71, CHCl3) and the aromatic iodide 39
D
(Scheme 1). While several recent examples of coupling of aryl
iodides with vinyl stannanes have been reported,10 this is a unique
* Corresponding author. E-mail address: jmarino@nd.edu (J.P. Marino).
0040-4020/$ e see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.10.003

838
J.P. Marino et al. / Tetrahedron 67 (2011) 837e841
O
S
I
AcO
O
S
Tol
OAc
OAc
Tol
Pd2dba3, PPh3,
Toluene, 110 °C, (65%)
Bu3Sn
CH3O
OAc
CH3O
3
4
5
STol
O
OH
OAc
O
H
(i) Cl3CCOCl, -50 °C
3 N HCl, Acetone(1:2),
Reflux, (55%)
O
O
(ii) Zn, HOAc, reflux,
(70%, 2 Steps)
O
H
OAc
CH3O
CH3O
7
6
TBSO
OH
SPh
m-CPBA, CH Cl , -78 C, (96%);
TBS-Cl, imidazole, DMF, (98%);
H
H
°
2
2
O
DIBAL-H, CH2Cl2, -78 °C, (80%);
PBu3, N-phenylthiosuccinimide,
PhH, (78%)
O
toluene, pyridine, 110 °C, (97%);
CsF, CH3CN, 0 °C, (100%)
O
H
O
H
CH3O
CH3O
9
8
Scheme 1.
approach to chiral vinyl sulfoxides via the chiral synthon 4. Treat-
ment of the resultant trans-vinyl sulfoxide 5 with dichloroketene,
generated in situ, provided a 7:1 mixture of trans/cis dichlor-
olactones. Immediate dehalogenation of the crude dichlorolactones
The benzofuranone 7 was then protected as the tert-butyldime-
thylsilyl ether and reduced with DIBAL-H to provide a 1:1 mixture of
lactols. Treatment of lactols with N-phenylthiosuccinimide and
tributylphosphine15 yielded a 1:1 mixture of thioacetals 8. Oxida-
tion of the sulfide to sulfoxide, followed by sulfoxide elimination16
with zinc in acetic acid yielded the desired (3S,4S)-trans-lactone 6
25
([
a]
¼ꢀ72ꢁ, c 2.0, CHCl3) as the sole product. This lactone was
yielded the silyl protected dihydrobenzofuran. Final deprotection
D
25
obtained in high yield (70% over two steps) and with greater
enantioselectivity than 95% ee11 Since we observed none of the
enantiomeric (3R,4R)-trans lactone, epimerization appears to be
mediated through the action of zinc salts produced in the reaction.
Under these conditions, the more crowded (3S,4R)-cis lactone is
equilibrated to the thermodynamically stable (3S,4S)-trans product.
with cesium fluoride gave the target compound 9 ([
a]
ꢀ194ꢁ, c
D
0.67, CHCl3) in high yield and 80% ee.12
Due to their acute toxicity and carcinogenicity, the Aflatoxins
continue to attract attention from workers in many fields, including
organic synthesis. To our knowledge, this report constitutes the
€
first asymmetric synthesis of Buchi’s dihydrofurobenzofuran in-
Ring closure of the
g
-thiobutyrolactone to the furobenzofur-
termediate 9. The key steps in the synthesis involve (1) an efficient
Stille coupling of synthon 4 to form the trans vinyl sulfoxide 5 (2)
chirality transfer from an optically active vinyl sulfoxide yield the
optically active trans lactone after treatment of which with
dichloroketene, and (3) closure of the lactone to yield the furo-
benzofuranone 7 upon deprotection of the phenolic acetates. This
methodology is currently being extended to synthesize other
related natural products.
25
anone 7 ([
a
]
D
ꢀ128ꢁ, c 0.605, acetone) was accomplished during
the deprotection of the phenolic acetates in 55% yield and 80% ee12
using 3 N HCl in refluxing acetone. Many attempts were made to
increase the yield and the optical purity of the resultant
furobenzofuranone 7. One strategy involved synthesizing the aryl
iodide 3 with a more labile protecting group. A number of pro-
tecting groups were employed and for various reasons were not
suitable. Some of these groups include: 2,2,2-trifluoroethane-
sulfonate; bromomethanesulfonate; trimethylsilylethanesulfonate;
benzyl; tosyl; trifluoroacetate; ethyl carbonate. A second strategy
consisted of retaining the acetate protecting group and performing
the cleavage as a separate step before attempting ring closure. Very
2. Experimental
2.1. 2,6-Diacetoxy-4-methoxyiodobenzene (3)
quickly, the sensitivity of the
g
-thiobutyrolactone 6 to basic con-
3,5-Diacetoxyanisole (1.80 g, 8.03 mmol) and silver trifluoro-
acetate (1.86 g, 8.43 mmol) were stirred together in CH2CI2 (80 mL)
at 25 ꢁC for 1 h under a N2 atmosphere. Iodine (2.44 g, 9.63 mmol)
was added in one portion and stirring was continued for an addi-
tional 30 min. The solids were then filtered off and washed with
CH2CI2 (2ꢂ20 mL). The organic layer was then washed with aque-
ous saturated Na2S2O3 solution (3ꢂ50 mL), dried over Na2SO4, fil-
tered, and concentrated in vacuo to yield a thick yellow oil
containing the product as a 1:1 mixture of regioisomers (2.80 g,
100%) Careful crystallization with diethyl ether yielded the desired
regioisomer (3) (0.61 g, 22%) as a white solid: mp 105e106 ꢁC
ditions was displayed. Aqueous sodium bicarbonate in alcoholic
solvents3 quickly caused destruction of the lactone, most likely
through ring opening, as evidenced by the formation of p-thio-
cresol. The use of other carbonates (Ag2CO3, Cs2CO313) in ethereal
solutions (DME, THF, ether) similarly only caused destruction of the
lactone. A very efficient reagent for cleaving acetates, guanidine in
methanol,14 was also used. On model compounds, this reagent
worked quickly and cleanly. However, on the g-thiobutyrolactone
6, ring opening of the lactone with subsequent elimination of the
p-thiocresol was a major competing reaction, thus limiting the
utility of this reagent for our purposes. Other nucleophilic reagents
such as amines and thiolate ions were equally unsuccessful.
(ether); 1H NMR (CDCl3)
d C
2.36 (6H, s), 3.79 (3H, s), 6.62 (2H, s); 13
NMR (CDCl3) 21.21, 55.81, 77.26, 107.16, 152.80, 161.04, 168.16; IR
d

J.P. Marino et al. / Tetrahedron 67 (2011) 837e841
839
(KBr) 2940 (w, m), 1765 (s), 1602 (m), 1572 (m), 1466 (m), 1423 (m),
1370 (m), 1320 (m), 1320 (m), 1280 (w), 1195 (s), 1151 (s), 1065 (m),
1040 (m), 961 (w), 884 (w) cmꢀ1; MS (El, 70 eV) 350 (Mþ), 308, 266
(100%), 237, 181, 138, 110, 95, 69, 43. HRMS calcd for C11H11O5l
349.9651, found 349.9657. Anal. Calcd for C11H11051: C, 37.74; H,3.17.
Found: C, 37.68; H, 3.16.
(10 mL) was added. With strong stirring, freshly distilled tri-
chloroacetyl chloride (1.05 mL, 9.40 mmol) was added drop wise
over 5 min at ꢀ45 ꢁC. After 10 min, the solids were filtered off and
washed with ethyl acetate (2ꢂ20 mL). The organic layer was
washed with aqueous saturated NaHCO3 solution (1ꢂ20 mL), dried
over MgSO4, filtered, and concentrated to yield a 7:1 mixture of
trans and cis dichlorolactones as a brown oil, which was immedi-
ately dehalogenated.
3. (S)-(E)-p-ToIyl-2-(tri-n-butylstannyl)vinyl sulfoxide (4)
The crude dichlorolactones were heated for 6 h at 80 ꢁC in the
presence of glacial acetic acid (20 mL) and zinc dust (4.91 g,
75.2 mmol). Upon complete dehalogenation, the solids were fil-
tered off and washed with ethyl acetate (2ꢂ25 mL). The organic
layer was washed with aqueous saturated NaHCO3 solution
(5ꢂ25 mL), dried over MgSO4, filtered, and concentrated to yield
the crude trans lactone as a yellow oil. Elution with hexane/ethyl
To
a
solution of trans-1,2-bis(tri-n-butylstannyl)ethylene19
(6.1 7 g, 10.2 mmol) in THF (33 mL) at ꢀ78 ꢁC was added n-butyl-
lithium (5.00 mL, 12.2 mmol, c 2.44 M in hexane) under a N2
atmosphere. This mixture was stirred for 1 h at ꢀ78 ꢁC, after which
time it was added very rapidly to a solution of (R)-(þ)-menthol
p-tolylsulfinate (3.00 g, 10.2 mmol) in THF (100 mL) at ꢀ78 ꢁC. The
reaction mixture was stirred 15 min/at ꢀ78 ꢁC and then quenched
with a solution of aqueous saturated NH4Cl (25 mL). After warming
to room temperature, water (10 mL) and ether (100 mL) were
added and the organic layer was separated. The remaining aqueous
layer was washed with diethyl ether (2ꢂ75 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated in
vacuo to yield a crude yellow oil. Column chromatography (4:1,
hexane/ethyl acetate) provided an inseparable mixture of the
acetate (4:1) provided the dehalogenated trans lactone (6) as
25
a white foam (560 mg, 70% over two steps); [
a]
ꢀ72ꢁ (c 2.0,
D
CHCl3); 1H NMR (CDCl3)
d
2.32 (6H s), 2.33 (3H, s), 2.53 (1H, d,
J¼1.75), 2.55 (1H, d, J¼5.58), 3.75 (3H, s), 3.76 (1H, m), 5.51 (1H, d,
J¼3.87), 6.57 (2H, s), 7.14 (2H, d, J¼7.89),7.41 (2H, d, J¼8.07); 13C
NMR (CDCl3)
d 20.74, 20.99, 34.24, 37.10, 55.52, 90.83, 106.95,
117.54,126.86,129.95,134.28,139.30,149.72,159.36,168.64,175.54;
IR (film) 2944 (w), 2368 (m), 1770 (br s), 1622 (s), 1494 (s), 1435 (m),
1370 (m), 1321 (m), 1177 (s), 1036 (s) cmꢀ1; MS (Cl, NH3) 448
(MþNH4), 431 (MþH), 413, 371, 282 (100%), 263, 136; HRMS calcd
for C22H22O7SH 431.1164, found 431.1153. Anal. Calcd for
C22H22O7S: C, 61.38; H, 5.15. Found: C, 61.41; H, 5.25.
product and menthol. Sublimation of menthol at 0.1 mmHg and
25
40 ꢁC yielded the pure product (3) as yellow oil (3.02 g, 65%); [
a]
D
ꢀ137ꢁ (c 1 0.71, CHCl3; lit.8¼ꢀ140ꢁ). 1H NMR (CDCl3)
d 0.83 (9H, t),
0.95e1.05 (6H, m), 1.15e1.25 (6H, m), 1.25e1.55 (6H, m), 2.37 (3H,
s), 6.54 (1H, d, J¼18.1), 7.26 (2H, d, J¼8.0), 7.32 (1H, d, J¼18.1), 7.45
(2H, d, J¼8.0); 13C NMR (CDCl3)
d 6 10.09, 13.60, 21.39, 27.16, 28.92,
3.3. (3aS,8aS)-4-Hydroxy-6-methoxy-3a,8a-dihydrofuro[2,3-
b]benzofuran-2(3H)-one (7)
125.03, 130.05, 136.03, 140.96, 141.44, 147.80; IR (neat) 2956 (br s),
1551 (w), 1492 (w), 1465 (m), 1376 (w), 1085 (s), 1051 (m) cmꢀ1; MS
(El, 70 eV); HRMS calcd for C21H27OSSn. Anal. Calcd for C21H27OSSn:
C, 55.40; H, 7.92; S, 7.05. Found: C, 55.46; H, 7.86; S, 7.13.
3.1. (S)-(E)-2-(2,6-Diacetoxy-4-methoxyphenyl)vinyl p-tolyl
sulfoxide (5)
7
A mixture of aryl iodide (3) (1.39 g, 3.96 mmol), Pd2dba3
(182 mg, 0.20 mmol), and PPh3 (104 mg, 0.40 mmol) were dis-
solved in dry toluene (20 mL). This mixture was warmed to 110 ꢁC
and a solution of the stannyl sulfoxide (4) (2.16 g, 4.80 mmol) in
toluene (8 mL) was added via a syringe pump over a period of 2 h.
After completion of the addition, the mixture was refluxed an
additional hour, filtered through a short bed of silica gel and
concentrated in vacuo. Elution of the resulting oil (ethyl acetate/
hexane, 2:1) yielded the desired compound (5) (1.00 g, 65%) as a tan
The lactone (6) (665 mg, 1.54 mmol) was heated at 80 ꢁC with
acetone (6 mL) and 3 N aqueous HCl solution (3 mL) for 1.5e3.0 h.
Upon consumption of all starting material, the mixture was cooled
to room temperature and partitioned between ethyl acetate
(20 mL) and aqueous saturated NaCl solution (20 mL). After
removing the organic layer, the aqueous layer was washed with
ethyl acetate (3ꢂ20 mL). The combined organic layers were dried
over MgSO4, filtered, and concentrated. Chromatography of the
crude oil yielded a crystalline solid (188 mg, 55%) mp 177e179 ꢁC;
solid: mp 122e124 ꢁC; recrystallization provided an analytically
25
pure sample: mp 125e126 ꢁC (diethyl ether); [
a]
ꢀ106ꢁ (c 1.08,
D
CHCl3); 1H NMR (CDCl3)
d 2.10 (6H, s), 2.41 (3H, s), 3.79 (3H, s), 6.78
[a
]
25 ꢀ128ꢁ (c 0.605, acetone); 1H NMR (acetone-d6)
d 2.80 (1H, dd,
D
(1H, d, J¼15.6), 7.15 (1H, d, J¼15.8), 7.33 (2H, d, J¼7.88), 7.52 (2H, d,
J¼1.70, 18.0), 3.08 (1H, dd, J¼9.25, 18.0), 3.69 (3H, s), 4.24 (1H, ddd,
J¼8.18); 13C NMR (CDCl3)
d 20.61, 21.28, 55.68, 106.97,113.43,124.45,
J¼1.77, 6.05, 9.19), 6.07 (1H, d, J¼1.84), 6.08 (1H, d, J¼1.89), 6.57 (1H,
124.80,130.14,137.33,140.92,141.72,150.33,160.57,168.19; IR (film)
2940 (w), 1768 (br s), 1618 (s), 1568 (w), 1458 (w), 1436 (w), 1373
(w), 1319 (m), 1193 (s), 1164 (m), 1139 (m), 1041(s) cmꢀ1; MS (CI,
NH3) 406 (MþNH4), 389 (MþH,100%), 371, 268, 193, 164, 136, 106,
77; HRMS calcd for C20H20O6SH 389.1059, found 389.1067. Anal.
Calcd for C20H20O6S: C, 61.84; H, 5.18. Found: C, 61.65; H, 5.21.
d, J¼6.01), 8.87 (1H, br s); 13C NMR (acetone-d6)
d 33.64, 41.21,
55.72, 89.43, 96.65, 106.05, 109.48, 155.57, 160.47, 163.41, 174.84; IR
(KBr) 3288 (br s), 2978 (w), 1733 (br s), 1648 (s), 1644 (s), 1514 (s),
1477 (s), 1412 (m), 1369 (w), 1210 (m), 1134 (s), 1035 (m), 996
(s) cmꢀ1; MS (El, 70 eV) 222 (Mþ), 193 (100%), 149, 137; HRMS calcd
for C11H11O5 222.0528, found 222.0520. Anal. Calcd for C11H11O5: C,
59.46; H, 4.54. Found: C, 59.55; H, 4.43.
3.2. (3S),(4S)-3-(2,6-Diacetoxy-4-methoxyphenyl)-4-(p-tolyl)
thio-y-butyrolactone (6)
3.4. (3aS,8aS)-4-(tert-Butyldimethylsilyloxy)-3a,8a-dihydro-6-
methoxyfuro[2,3-b]benzofuran-2(3H)-one
Under a N2 atmosphere, freshly activated anhydrous zinc dust
(2.46 g, 37.6 mmol) and anhydrous cuprous chloride (3.72 g,
37.6 mmol) were refluxed together in THF (50 mL) for 1 h. The
resulting suspension of zinc/copper couple was cooled to ꢀ45 ꢁC
and a solution of the vinyl sulfoxide (5) (0.73 g, 1.88 mmol) in THF
The furanone (7) (153 mg, 0.688 mmol) was dissolved in dry
DMF (6 mL) under an N2 atmosphere. Imidazole (190 mg,
2.75 mmol) followed by TBS chloride (207 mg 1.38 mmol) were

840
J.P. Marino et al. / Tetrahedron 67 (2011) 837e841
added and the mixture was allowed to stir for 3 h at room
temperature. The organic layer was then partitioned between
ethyl acetate (10 mL) and aqueous saturated ammonium chloride
solution (10 mL). The organic layer was removed and the aqueous
layer was washed with ethyl acetate (3ꢂ10 mL). The combined
organic layers were dried over MgSO4, filtered, and concentrated.
Chromatography (hexane/ethyl acetate, 4:1) provided the pro-
131.51, 135.88, 152.54, 161.20, 161.88; IR (film) 3059 (w), 2954 (s),
2360 (s), 1734 (s), 1616 (m), 1496 (m), 1369 (m), 1254 (m), 1195 (m),
1147(m), 1082 (m) cmꢀ1; MS(El, 70 eV) 430 (Mþ), 401, 321 (100%),
293, 263, 73; HRMS calcd for C23H30O4SSi 430.1634, found
430.1632. Anal. Calcd for C23H30O4SSi: C, 64.16; H, 7.02. Found: C,
64.23; H, 7.04.
tected furanone as a thick colorless oil (220 mg, 98%); [
a
]
25ꢀ107ꢁ
3.7. (3aS,8aS)-4-(tert-Butyldimethylsilyloxy)-6-methoxy-2-
(phenylsulfinyl)2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran
D
(c 1.03, CHCI3); 1H NMR (CDCI3) 60.13 (3H, s), 0.18 (3H, s), 0.88
(9H, s), 2.83 (1H, d, J¼4.01), 2.84 (1H, d, J¼7.40), 3.64 (3H, s), 4.02
(1H, ddd, J¼4.12, 6.20, 7.13), 5.91 (1H, d, J¼2.05), 6.06 (1H, d,
J¼2.04), 6.39(1H, d, J¼6.12); 13C NMR (CDCI3) 6e4.42, ꢀ4.16,
17.94, 25.52, 33.23, 40.64, 55.55, 90.18, 98.82, 108.27, 108.66,
153.13, 159.39, 162.44, 174.18; IR (film) 2933 (s), 1791 (s), 1699 (s),
1683 (m), 1634 (s), 1558 (m), 1540 (m), 1506 (m), 1456 (m), 1143
(w) cmꢀ1; MS (El, 70 eV) 336 (Mþ), 321, 307, 291, 279, 251, 166,
97,73 (100%); HRMS calcd for C17H24O5Si 336.1393, found
336.1392. Anal. Calcd for C17H24O5Si: C, 60.71; H, 7.19. Found: C,
60.72; H, 7.29.
A mixture of the thioacetals (9) (80.0 mg, 0.186 mmol) and an-
hydrous sodium carbonate (98.4 mg, 0.929 mmol) were stirred
together in CH2Cl2 (4 mL) at ꢀ78 ꢁC under N2. A solution of 60%
m-CPBA (53.4 mg, 0.186 mmol) in CH2Cl2 (1 mL) was added drop
wise over 5 min. After stirring an additional 15 min at ꢀ78 ꢁC,
aqueous saturated Na2CO3 solution (1 mL) was added. The organic
layer was decanted from the solids and washed with 0.5 N aqueous
NaOH solution (5ꢂ5 mL). The organic layer was then dried over
anhydrous Na2CO3, filtered and concentrated to yield the crude
sulfoxides as colorless oil (80.0 mg, 96%). Purification on silica (3:1,
hexane/ethyl acetate) provided a 2:1:1 mixture of three di-
3.5. (3aS,8aS)-4-(tert-Butyldimethylsilyloxy)-
2,3,3a,8a,tetrahydro-2-hydroxy-6-methoxyfuro[2,3-b]
benzofuran
astereomers. Major diastereomer: 1H NMR (CDCl3)
d 0.10 (3H, s),
0.16 (3H, s), 0.89 (9H, s), 1.99 (1H, ddd, J¼1.76, 5.99, 13.2), 2.80 (1H,
dt, J¼8.90,13.2), 3.69 (3H, s), 4.03 (1H, ddd, J¼1.66, 5.58, 9.04), 4.69
(1H, dd, J¼6.00, 8.23), 5.88 (1H, d, J¼2.00), 6.06 (1H, d, J¼1.99) 6.38
The silyl protected furanone (223 mg, 0.663 mmol) was dis-
solved in CH2Cl2 (15 mL) and cooled to ꢀ78 ꢁC. DIBAL (0.723 mL,
0.723 mmol, c 1 M in CH2Cl2) was added drop wise over 5 min. After
stirring 30 min at ꢀ78 ꢁC, the reaction was quenched with aqueous
saturated ammonium chloride solution (10 mL), the organic layer
was removed, and the aqueous layer was washed with CH2Cl2
(4ꢂ20 mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated. Chromatography (hexane/ethyl acetate,
2:1) yielded the lactol as a colorless oil containing a 1:1 mixture of
diastereomers (179 mg, 80%).
(2H, d, J¼5.57), 7.48 (3H, m), 7.54 (2H, m) 13C NMR (CDCl3)
d 8e4.33,
ꢀ4.28, 17.94, 25.51, 27.05, 44.20, 55.50, 89.62, 89.53, 97.53, 99.12,
109.43, 112.84, 124.11, 129.21, 131.20, 140.07, 152.82, 140.07, 152.82,
160.33, 161.91; IR (film) 2930 (m), 1630 (s), 1624 (s), 1558 (s), 1497
(m), 1436 (m), 1256 (w), 1196 (m), 1140 (s), 1081(s). Anal. Calcd for
C23H30O5SSi: C, 61.86; H, 6.77. Found: C, 61.57; H, 6.87. Minor di-
astereomer A 1H NMR (CDCl3)
d 50.21 (3H, s), 0.24 (3H, s), 0.98 (6H,
s), 2.48 (1H, ddd, J¼3.04, 6.86, 13.6), 2.76 (1H, ddd, J¼7.07, 9.18,
13.5), 3.69 (3H, s), 3.87 (1H, ddd, J¼2.89, 5.56, 9.11), 4.60 (1H, d,
J¼7.18), 5.94 (1H, d, J¼2.05), 6.03 (1H, d, J¼1.97), 6.32 (1H, d,
3.6. (3aS,8aS)-4-(tert-Butyldimethylsilyloxy)-6-methoxy-2-
(phenylthio)-2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran (8)
J¼5.66), 7.51 (3H, m), 7.62 (2H, m); 13C NMR (CDCl3)
d 5e4.34,
ꢀ4.10, 18.13, 25.64, 32.10, 44.47, 55.54, 89.73, 95.65, 99.29, 109.81,
112.97,125.19,129.11,131.45,140.13,152.80,160.24,162.01; IR (film)
2930 (m), 1630 (s), 1624 (s), 1558 (s), 1497 (m), 1436 (m), 1256 (w),
1196 (m), 1140 (s), 1081(s). Anal. Calcd for C23H30O5SSi: C, 61.86;
1e1, 6.77. Found: C, 61.57; H, 6.87. Minor diastereomer B 1H NMR
Tri-n-butylphosphine (88.3
ml, 0.354 mmol) was added to
a solution of N-phenylthiosuccinimide (73.5 mg, 0.354 mmol) in
benzene (2 mL) at 25 ꢁC under N2. After stirring for 15 min,
a solution of the lactols (100 mg, 0.295 mmol) in benzene
(0.5 mL) was added rapidly. The resulting solution was allowed to
stir at 25 ꢁC for 15 min, at which time water (2 mL) was added.
The organic layer was removed, dried over Na2SO4, filtered, and
concentrated. The resulting crude oil yielded the desired com-
pound (8) upon elution with hexane/ethyl acetate (6:1) as col-
orless oil containing a 2:1 mixture of diastereomers (99.2 mg,
(CDCl3)
d
50.27 (3H,s), 0.34 (3H, s),1.03 (6H, s), 2.63 (1H, ddd, J¼7.27,
8.95, 14.5), 3.12 (1H, d, J¼14.8), 3.76 (3H, s), 4.05 (1H, dd, J¼6.00,
8.58), 4.89 (1H, t, J¼6.85), 6.35 (1H, d, J¼5.89), 7.51 (3H, m), 7.63
(2H, m); 13C NMR (CDCl3)
d
5e4.03, ꢀ4.00,18.04, 25.71, 33.14, 43.88,
55.54, 89.86, 99.27, 99.66, 109.45, 113.19, 125.31, 128.76, 131.18,
139.98, 153.20, 159.13, 162.41; IR (film) 2930 (m), 1630 (s), 1624 (s),
1558 (s), 1497 (m), 1436 (m), 1256 (w), 1196 (m), 1140 (s), 1081 (s).
Anal. Calcd for C23H30O5SSi: C, 61.86; H, 6.77. Found: C, 61.57;
H, 6.87.
78%). Major isomer: 1H NMR (CDCl3)
d 0.22 (3H, s), 0.26 (3H, s),
2.18 (1H, ddd, J¼8.66, 10.7, 12.8), 2.61 (1H, dd, J¼4.7, 12.5), 3.72
(3H, s), 3.96 (1H, dd, J¼6.00,8.61), 5.30 (1H, dd, J¼4.90, 10.6), 5.36
(1H, d, J¼5.80), 5.94 (1H, d, J¼2.04), 6.07 (1H, d, J¼1.95), 7.26 (3H,
3.8. (3aS,8aS)-4-(tert-Butyldimethylsilyloxy)-3a,8a-dihydro-6-
methoxyfuro[2,3-b]benzofuran
m), 7.51 (2H, m); 13C NMR (CDCl3)
d
ꢀ4.42, ꢀ4.11, 17.97, 25.57,
37.46, 44.44, 55.41, 85.85, 89.27, 98.85, 109.10, 111.55, 127.28,
128.90, 131.26, 134.06, 152.76, 161.00, 161.73; IR (film) 3059 (w),
2954 (s), 2360 (s), 1734 (s), 1616 (m), 1496 (m), 1369 (m), 1254
(m), 1195 (m), 1147(m), 1082 (m) cmꢀ1; MS (El, 70 eV) 430 (Mþ),
401, 321 (100%), 293, 263, 73; HRMS calcd for C23H30O4SSi
430.1634, found 430.1632. Anal. Calcd for C23H30O4SSi: C, 64.16;
H, 7.02. Found: C, 64.23; H, 7.04.
A solution of the crude sulfoxides (80.0 mg, 0.179 mmol) in
toluene (4 mL) and dry pyridine (28.9
ml, 0.358 mmol) were
heated at 110 ꢁC for 40 min. Aqueous saturated Na2CO3 solution
(2 mL) was added. The organic layer was removed and the
aqueous layer was washed with ethyl acetate (1ꢂ2 mL). The
combined organic layers were dried over Na2SO4, filtered and
concentrated. Chromatography (6:1, hexane/ethyl acetate) of the
resulting oil provided the vinyl ether as a colorless oil (55.4 mg,
Minor isomer: 1H NMR (CDCl3)
d 0.25 (3H, s), 0.30 (3H, s), 1.00
(9H, s), 2.52 (1H, dd, J¼1.18, 13.2), 2.68 (1H, ddd J¼7.80, 9.00, 13.6),
3.57 (3H, s), 4.00 (1H, dd, J¼6.16, 8.70), 5.37(1H, d, J¼6.00), 5.72 (1H,
dd, 1.18, 7.80), 5.98 (1H, d, J¼2.01), 6.13 (1H, d, J¼1.98), 7.26 (3H, m),
97%); [
a
]
25 ꢀ155ꢁ (c 0.40, CHCl3); 1H NMR (CDCl3)
d 60.25 (3H, s),
D
0.26 (3H, s), 1.01 (9H, s), 3.72 (3H, s), 4.50 (1H, dt, J¼7.18, 2.18),
5.29 (1H, dd, J¼2.35, 2.80), 5.94 (1H, d, J¼2.00), 6.14 (1H, d,
J¼2.00), 6.42 (1H, dd, J¼2.16, 2.82), 6.64 (1H, d, J¼7.16); 13C NMR
7.50 (2H, m); 13C NMR (CDCl3)
44.50, 55.36, 88.31, 89.62, 98.62, 110.24, 112.90, 126.96, 128.63,
d
5e4.28, ꢀ4.07, 18.01, 25.62, 38.27,

J.P. Marino et al. / Tetrahedron 67 (2011) 837e841
841
(CDCl3)
d
ꢀ4.32, ꢀ4.18, 18.06, 25.60, 48.42, 55.50, 89.77, 98.82,
422.0987. Anal. Calcd for C21H17O6F3: C, 59.72; H, 4.06. Found: C,
59.73; H, 4.15.
103.06,110.50, 112.11, 144.67, 152.22, 159.86, 161.37; IR (film) 2955
(s), 2845 (s), 1683 (br s), 1622 (s), 1496 (m), 1471 (m), 1471 (m),
1435 (m), 1333 (w), 1254 (m), 1202 (s), 1142, 1087 (s), 966 (s); MS
(El, 70 eV) 320 (Mþ), 291 (100%), 263, 235, 189, 73; HRMS calcd
for C17H24O4Si 320.1444, found 320.1438. Anal. Calcd for
C17H24O4Si: C, 63.81; H, 7.56. Found: C, 63.89; H, 7.59.
Acknowledgements
Support for this research from NIH Grant CA 22237 is grate-
fully acknowledged. K.A.K. acknowledges the partial support for
this work from the NIH pharmacological sciences Training Grant
T32-GM07767.
3.9. (3aS,8aS)-4-Hydroxy-6-methoxy-3a(S),8a(R)-dihydrofuro
[2,3-b]benzofuran (9)
Supplementary data
The silyl protected vinyl ether (50.0 mg, 0.156 mmole) was
dissolved in dry CH3CN (4 mL) at 0 ꢁC under N2. Anhydrous
cesium fluoride (28.4 mg, 0.187 mmol) was added and the mix-
ture stirred for 3 h at 0 ꢁC. Aqueous saturated sodium bicarbonate
solution (2 mL) was added and the organic layer was removed.
The aqueous layer was then washed with ethyl acetate (1ꢂ5 mL).
The combined organic layers were dried over Na2SO4, filtered and
concentrated to yield the crude vinyl ether. Column chromatog-
raphy (2:1, hexane/ethyl acetate) provided the pure compound
(32.0 mg, 100%): mp 153e155 ꢁC An analytical sample was
Supplementary data associated with this article, includes copy
of 1H and 13C NMR. Supplementary data associated with this article
can be found in the online version at doi:10.1016/j.tet.2010.10.003.
References and notes
1. (a) Baertschi, S. W.; Raney, K. D.;Stone, M. P.; Harris, T. M. J. Am. Chem. Soc.1988,110,
7229; (b) Gopalakrishnan, S.; Stone, M. P.; Harris, T. M. J. Am. Chem. Soc. 1989, 111,
7232;(c) Gopalakrishnan, S.; Stone, M. P.;Harris, T. M. Biochemistry 1990, 29,10438.
€
2. Buchi, G.; Foulkes, D. M.; Kurono, M.; Mitchell, G. F.; Scheider, R. S. J. Am. Chem.
Soc. 1967, 89, 6745.
obtained after crystallization: mp 156e157 ꢁC (CH2Cl2/hexane);
€
3. Buchi, G.; Weinreb, S. M. J. Am. Chem. Soc. 1971, 93, 746.
25
ꢀ194ꢁ (c 0.67, CHCl3); 1H NMR (CDCl3)
d 3.72 (3H, s), 4.56
€
4. (a) Buchi, G.; Francisco, M. A.; Liesch, J. M.; Schuda, P. F. J. Am. Chem. Soc. 1981,
[
a
]
D
103, 3497; (b) Castellino, A. J.; Rapoport, H. J. Org. Chem. 1986, 51, 1006; (c)
Weeratunga, G.; Horne, S.; Rodrigo, R. J. Chem. Soc., Chem. Commun. 1988, 721;
(d) Horne, S.; Weeratunga, G.; Rodrigo, R. J. Chem. Soc., Chem. Commun. 1990,
39; (e) Kraus, G. A.; Johnston, B. E.; Applegate, J. M. J. Org. Chem. 1991, 56, 5688;
(g) Hoffman, H. M. R.; Schmidt, B.; Wolff, S. Tetrahedron 1989, 6113; (h) Hoff-
man, H. M. R.; Wolff, S. Synthesis 1988, 760; (i) Sloan, C. P.; Cuevas, J. C.;
Quesnelle, C.; Snieckus, V. Tetrahedron Lett. 1988, 4685; (j) Kraus, G. A.; Thomas,
P. J.; Schwinden, M. D. Tetrahedron Lett. 1990, 1819.
(1H, dd, J¼7.16, 2.04), 5.34 (1H, t, J¼2.56), 5.37 (1H, br s), 5.93 (1H,
d, J¼1.95),6.11 (1H,d,J¼1.86), 6.44(1H,t,J¼2.40), 6.68(1H,d,J¼7.18);
13C NMR (CDCl3)
d 647.89, 55.60, 89.50, 95.30, 102.89, 106.49,
112.35, 144.75, 152.25, 160.19, 161.59; IR (KBr) 3391 (br s), 1645
(s), 1614 (s), 1508 (m), 1442 (m), 1370 (w), 1212 (m), 1192 (m),
1147 (m), 1062 (5), 966 (s); MS (El, 70 eV) 206 (Mþ), 191, 177
(100%), 149, 69; HRMS calcd for C11H10O4 206.0579, found
206.0573. Anal. Calcd for C11H10O4: C, 64.07; H, 4.88. Found: C,
63.14; H, 4.78.
5. Marino, J. P.; Neisser, M. J. Am. Chem. Soc. 1981, 103, 7687.
ꢀ
6. (a) Marino, J. P.; Fernandez de la Pradilla, R.; Laborde, E. Synthesis 1987, 1088; (c)
Burke, S. D.; Shankaran, K.; Jones Helber, M. Tetrahedron Lett. 1991, 4655; (d)
Marino, J. P.; Bogdan, S.; Kimura, K. J. Am. Chem. Soc. 1992, 114, 5566.
7. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
8. Deering, C.F. Ph.D. Thesis, The University of Michigan, Ann Arbor, 1988.
9. Compound 3 was synthesized in two steps from 5-methoxyresorcinol18 together
with the regioisomer, 2,4-diacetoxy-6-methoxyiodobenzene. First, acetylation
(AcCl, pyr, THF) gave the bis protected phenol in 75% yield. Iodination (AgO2CCF3,
I2, CH2Cl2) provided a 1:1 mixture of regioisomer 3 in 44% yield.
3.10. (3aS,8aS)-6-Methoxy-4-[2(R)-methoxy-2-
(trifluoromethyl)phenylacetoxy]-3a(S),8a(S)-dihydrofuro[2,3-
b]benzofuran 10
10. For a leading reference see: Farina, V.; Krishnan, B. J. Am. Chem. Soc.1991,113, 9585.
11. Analysis of lactone 6 by HPLC on a Chiracel-OD column indicated that 6 was 98%
The dihydrofuran (9) (12 mg, 0.058 mmol) was dissolved in
dry pyridine (0.5 mL) and cooled to 0 ꢁC. Excess R (þ) MPTA
chloride17 (0.10 mL) was added drop wise. The reaction was
allowed to warm to room temperature and stir for 3 h. Pyridine
was then removed in vacuo, benzene (2 mL) was added and the
organic layer was washed with aqueous saturated NaHCO3 so-
lution (1ꢂ2 mL). The organic layer was dried over Na2SO4, filtered
and concentrated. 1H NMR (benzene-d6) of Mosher’s ester 10
indicated an 8.1:1 ratio of diastereomers (80% ee), as determined
by integration of the vinyl proton signals at 4.21 and 5.91, and the
acetal proton at 6.43. Column chromatography (4:1, hexane/ethyl
ee: HPLC conditionsd(95:5 hexanes/isopropanol 0.6 mL/min), tR (ꢀ)
25
lactone¼24.8 min; tR (þ)lactone¼28 min. [
a
]
ꢀ72ꢁ (c 2.0, chloroform)
D
12. The enantiomeric purity of the final dihydrofuran 9 was determined via its
Mosher’s ester 10 (Ref. 17). Integration of signals for the two vinyl ether protons
at 4.71 and 5.91 and the acetal proton at 6.43 indicate a ratio of 8.1:1 of the two
distereomers of the ester, corresponding to an ee of 80%.
O
OH
Ph
F3C
(R)-(+)MTPA
Pyridine 3h
O
MeO
O
O
CH3O
O
O
CH3O
acetate) provided an analytical sample of the Mosher’s ester
9
10
25
(22 mg, 90%); [
d
a
]
ꢀ82ꢁ (c 0.44, CHCl3); 1H NMR (benzene-d6)
D
3.06 (3H, s), 3.43 (3H, d, J¼1.11), 3.97 (1H, dt, J¼2.19, 7.23), 4.71
13. Zaugg, H. E. J. Org. Chem. 1976, 41, 3419.
14. Kunesch, N.; Miet, C.; Poisson, J. Tetrahedron Lett. 1987, 3569.
15. Walker, K. A. M. Tetrahedron Lett. 1977, 4475.
16. (a) Cava, M. P.; Appa Rao, J. J. Org. Chem. 1989, 54, 2751; (b) Graybill, T. L.; Pal, K.;
McGuire, S. M.; Brobst, S. W.; Townsend, C. A. J. Am. Chem. Soc. 1989, 111, 8306.
17. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
18. Weidel, H.; Pollack, J. Monatsh. Chem. 1900, 21, 22.
(1H, t, J¼2.58), 5.91 (1H, t, J¼2.47), 6.22 (2H, d, 7.18), 6.32 (2H, d,
J¼2.03), 6.39 92H, d, J¼2.05), 7.07 (3H, m), 7.75 (2H, m; IR (film)
2942 (w), 1771 (s), 1635 (s), 1496 (s), 1472 (m), 1456 (m), 1182 (br
s), 1128 (s) cmꢀ1; MS (El, 70 eV) 423,422 (Mþ), 394, 393, 220, 190,
189(100%), 105; HRMS calcd for C21H17O6F3 422.0977, found