SULFUR-mediated synthesis of substituted tetrahydrofurans: Application to the synthesis of goniofufurone

Article abstract of DOI:10.3987/COM-06-10786

An efficient strategy for the synthesis of densely functionalized 2,5-trans-disubstituted-tetrahydrofurans (4), from sulfmyldienols is described. Further transformations of this substrate have resulted in a new synthesis of goniofufurone (1) by means of s

Full text of DOI:10.3987/COM-06-10786

HETEROCYCLES, Vol. 68, No. 8, 2006
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HETEROCYCLES, Vol. 68, No. 8, 2006, pp. 1579 - 1584. © The Japan Institute of Heterocyclic Chemistry
Received, 18th May, 2006, Accepted, 26th June, 2006, Published online, 27th June, 2006. COM-06-10786
SULFUR-MEDIATED SYNTHESIS OF SUBSTITUTED
TETRAHYDROFURANS: APPLICATION TO THE SYNTHESIS OF
GONIOFUFURONE
Roberto Fernández de la Pradilla,*a Jorge Fernández,a Alma Viso,a Javier
Fernández,b and Antonio Gómezb
a Instituto de Química Orgánica, CSIC, Juan de la Cierva, 3; 28006 Madrid, Spain
b
Johnson & Johnson Pharmaceutical Research & Development, Division of
Janssen-Cilag, Medicinal Chemistry Department, Jarama s/n, 45007 Toledo,
Spain E-mail: iqofp19@iqog.csic.es
Abstract – An efficient strategy for the synthesis of densely functionalized
2,5-trans-disubstituted-tetrahydrofurans (4), from sulfinyldienols is described.
Further transformations of this substrate have resulted in a new synthesis of
goniofufurone (1) by means of silylated lactone (11), also readily available from
D-xylose.
INTRODUCTION
Asian trees of the genus Goniothalamus (Annonaceae) have been recognized as a source of therapeutic
agents in folk medicine. In 1972, Geran et al. found that the ethanolic extract of the stem bark of
Goniothalamus giganteus Hook F. & Thomas showed cytotoxic activity during an in vivo antileukemic
screening.1 Subsequent bioactivity-directed studies by McLaughlin’s group on the ethanolic extracts of
these plants led to the discovery of novel styryllactones which were found to possess significant
cytotoxicities against several human tumors.2 Among these styryllactones, (+)-goniofufurone (1),2a and its
stereoisomer, (+)-7-epi-goniofufurone (2),2b (Scheme 1) have attracted much attention from the biological
and synthetic points of view due to their significant activity and selectivity toward several human tumor
cell lines such as human lung carcinoma, and they have become interesting synthetic targets for a number
of groups. Thus, Shing completed the first synthesis of (+)-goniofufurone (1) starting from
D-glycero-D-glyco-heptono-γ-lactone.3a Most of the subsequent syntheses started from different natural
products, particularly carbohydrates. On the other hand, Zhou’s synthesis relied on a Sharpless
asymmetric epoxidation,4a whereas Roberts used a Julia-Colonna asymmetric epoxidation,4b and Hanaoka
used a highly diastereoselective aldol reaction.5 In connection with our involvement in organosulfur

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HETEROCYCLES, Vol. 68, No. 8, 2006
chemistry,6 we report herein substantial extensions of our methodologies to prepare substituted
tetrahydrofurans from α-hydroxysulfinyldienes,7 that have resulted in a synthesis of (+)-goniofufurone
(1) and (+)-7-epi-goniofufurone (2).
HO
HO
H
H
O
H
O H
HO
HO
H
O
H O
O
O
(+)-goniofufurone, (1)
(+)-7-epi-goniofufurone, (2)
Scheme 1
RESULTS AND DISCUSSION
Our retrosynthetic analysis (Scheme 2) was designed with introduction of the aryl ring at the end of the
sequence to facilitate the preparation of analogs at the aryl moiety for preliminary biological testing.
Another key point was to develop a selective route to 2,5-trans-disubstituted-tetrahydrofurans
functionalized at C-3 and C-4 to complement our prior efforts on this field.7 Thus, 1 could derive from
aldehyde (3), similarly to a previous report,3j and 3 should be available from tetrahydrofuran (4) through
an unprecedented sulfonyloxirane cleavage with concurrent lactonization to render a ketolactone,
reduction of the ketone and selective oxidation of the primary alcohol. Sulfonyltetrahydrofuran (4) could
be obtained by stereoselective intramolecular Michael addition of oxiranylenoate (5), that could derive
from α-hydroxysulfinyldiene (6b) by our metal-catalyzed oxidation/epoxidation to produce a vinyl
oxirane, followed by oxidative-cleavage and a Wittig reaction. Diene (6b) could be prepared through a
condensation of the corresponding aldehyde and metalated 1-sulfinylbutadiene, available in a single step
by the protocol of Craig.8
HO
OH
O
O
S
OH
PO
H
H
H
O
PO
SO2p-Tol
PO
O
H
Ph
HO
O H
H
H
O
p-Tol
O
P'O
CO2t-Bu
t-BuO2C
p-TolO2S
H
O
H
O
O
O
(+)-goniofufurone, (1)
5
3
4
6b
P = TBDPS
P' = ?
Scheme 2
To establish the viability and stereoselectivity of the sequence, it was decided to use initially racemic
materials. Thus, lithiation of the racemic mixture of sulfinyldienes (7) (E/Z mixture),8 (Scheme 3), with
concurrent
isomerization
to
the
E
geometry,7
followed
by
reaction
with

HETEROCYCLES, Vol. 68, No. 8, 2006
1581
t-butyldiphenylsilyloxyacetaldehyde,9 yielded the readily separable mixture of diastereoisomers (6a) and
(6b) (66:34) that could be interconverted by a Mitsunobu protocol.10 At this stage, the synthesis was
pursued with the mixture and the treatment of the 6a/6b mixture with t-BuOOH and VO(acac)2 led to
oxidation at sulfur and hydroxyl-directed epoxidation at the more electron deficient double bond with
complete regio- and stereoselectivity.11 Ozonolysis of the labile vinyloxirane intermediate gave lactol (8)
that readily reacted with stabilized ylide Ph3PCHCO2t-Bu to give the desired E-enoate (5). Optimal
conditions to trigger the desired intramolecular Michael addition of 5 entailed the use of Triton B to form
2,5-trans-tetrahydrofuran (4) as a single isomer.12 Finally, we were pleased to find that the treatment of 4
with MgBr2 gave lactone (9), with the fused furano-furone core of (+)-goniofufurone (1), through
epoxysulfone cleavage and lactonization, thus validating our original hypothesis. To our knowledge this
process is unprecedented, with related cyclizations in the literature using more nucleophilic alcohols, thus
generating cyclic ethers, instead of lactones.13
66:34
OH
O
S
O
S
OTBDPS
SO2p-Tol
TBDPSO
p-Tol
p-Tol
O
O
1
2
90:10
HO
7
6a : 6b
8
3
OTBDPS
O
OTBDPS
OH
H
SO2p-Tol
TBDPSO
SO2p-Tol
O
O
O
O
H
O
5
4
H
CO2t-Bu
t-BuO2C
O
9
4
5
Scheme 3. Reagents and conditions: 1. (a) LDA, THF, –78 ºC. (b) TBDPSOCH2CHO, THF, –78 ºC, 30 min, 76%.
2. (a) 5% VO(acac)2, t-BuOOH, C6H6, rt, 5 h 30 min. (b) O3, CH2Cl2-MeOH, 1:1, –78 ºC, 15 min; then, SMe2, –78
to 0 ºC, 2 h, 42% two steps. 3. Ph3PCHCO2t-Bu, C6H6, 0 ºC to rt, 3 h, 30 min, 82%. 4. Triton B, MeOH, rt, 16 h,
72%. 5. MgBr2, Et2O, rt, 72%.
Reduction of ketone (9) under a variety of conditions, afforded the undesired epimer at the carbinol center
as major product.14 After considerable experimentation, lactone opening to afford dimethylamide (10),
followed by hydroxyl-directed ketone reduction15 and acid-catalyzed cyclization led to the desired alcohol
(11) as single isomer (Scheme 4). Seeking additional structural confirmation for 11, furanolactone
(+)-(12) was prepared by the methodology described by Galbis,3j,16 that entails the condensation of
D-xylose and Meldrum’s acid. Selective protection of the primary hydroxyl group as a

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HETEROCYCLES, Vol. 68, No. 8, 2006
t-butyldiphenylsilyl ether gave (+)-11, that had identical spectral features to the racemic material. It was
then decided to continue the synthetic sequence with the optically pure material.
After considerable experimentation with several protecting groups for the secondary alcohol of 11 that
then allowed for selective deprotection of the primary alcohol, protection of the secondary alcohol as a
TBDPS ether was examined. Subsequent selective desilylation of the primary silyl group with
HF-pyridine complex followed by Swern oxidation gave aldehyde (+)-(3). Treatment of this aldehyde
with excess phenylmagnesium bromide led to the separable 95:5 mixture of diastereomeric alcohols
(+)-(13) and (+)-(14) in moderate yield.17 From the major product (+)-(13), (+)-7-epi-goniofufurone (2),
was easily obtained by deprotection of the hydroxyl group. On the other hand, (+)-goniofufurone (1) was
synthesized via a three step sequence, oxidation of the 95:5 mixture followed by reduction and cleavage
of the silyl protecting group. Synthetic 1 and 2 showed all spectroscopic data identical to those reported in
the literature,2a,b including melting points and the sign of the optical rotation.18
95:5
HO
O
H
H
H
O
PO
HO
O H
PO
3
O H
2
H
O H
Ph
1
9
O
PO
PO
CONMe2
H O
H O
(+)-13 (95)/(+)-14 (5)
H O
O
OH
O
O
(+)-3
10
11
4
5
(+)-11
P = TBDPS
HO
Ph
HO
7
H
H
O H
O H
Ph
H
HO
HO
6
O
HO
HO
O H
HO
OH
HO
H O
O
H O
(+)-goniofufurone, (1)
O
(+)-7-epi-goniofufurone, (2)
H O
(+)-12
OH
D-Xylose
O
Scheme 4. Reagents and conditions: 1. (a) Me2NH, EtOH, rt, 2 h; then, Bu4NBH4, CH2Cl2, 0 ºC to rt, 6 h 15 min,
53%. (b) PPTS, toluene, 80 ºC, 3 h, 63%. 2. (a) TBDPSCl, imidazole, DMAP, CH2Cl2, rt, 3 days, 86% and 14%
of 11. (b) HF·Pyr, THF, 0 ºC, 3 h, 67% and 13% of starting material. (c) (COCl)2, DMSO, Et3N, CH2Cl2, –60 ºC,
35 min, 79%. 3. PhMgBr, THF, –20 to 0 ºC, 2 h 45 min, 62%. 4. HF·Py, THF, 0 ºC, 3 h, 30 min, 78%. 5. (a)
PCC, 4 Å MS, CH2Cl2, rt, 70%. (b) LiAlH(O-t-Bu)3, THF, –20 ºC, 2 h, 80%, 56% of (+)-14 and 24% of (+)-13. (c)
HF·Py, THF, 0 ºC, 4 h, 71%. 6. (a) Meldrum’s acid, t-BuNH2, DMF, 40 ºC, 5 days, 61%. 7. TBDPSCl,
imidazole, DMAP, CH2Cl2, rt, 24 h, 90%.
To summarize, we have developed a novel entry to 2,5-trans-disubstituted-tetrahydrofurans
functionalized at C-3 and C-4. This methodology relies on our metal-catalyzed oxidation/epoxidation of
hydroxysulfinyldienes, followed by a stereoselective Michael cyclization of sulfonyloxiranylenoates and
an unprecedented sulfonyloxirane cleavage with concurrent lactonization. These protocols have been

HETEROCYCLES, Vol. 68, No. 8, 2006
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applied to the preparation of goniofufurone (1) and 7-epi-goniofufurone (2) through intermediate (11) that
is also readily available from D-xylose. Further applications of these methodologies, as well as the
preparation of analogs of goniofufurone (1), are being examined in our laboratories.
ACKNOWLEDGEMENTS
This research was supported by DGI MEC (Grants BQU2003-02921 and CTQ2005-04632/BQU). We
thank JANSSEN-CILAG for generous additional support.
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THF, rt; 2. K2CO3, MeOH, rt, 65-80% two steps). For reviews on the Mitsunobu reaction, see: (a) D.
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17. The stereochemical outcome of this addition can be understood by considering the Felkin-Anh
model and/or chelation control of the tetrahydrofuran oxygen; both models lead to the observed
diastereoisomer in this case.
18. (1), mp 154-155 ºC and [α]20D = +8.9 º (c = 0.235 EtOH), lit.,2a mp 152-154 ºC and [α]20D = +9.0 º (c
= 0.5 EtOH). (2), mp 192-193 ºC and [α]20 = +103.1 º (c = 0.32 EtOH), lit.,2b mp 190-192 ºC and
D
[α]20D = +108 º (c = 0.2 EtOH).