Total syntheses of (+)-7-epi-goniofufurone, (+)-goniopypyrone and (+)-goniofufurone from a common precursor

Article abstract of DOI:10.1039/b713070h

Total syntheses of (+)-7-epi-goniofufurone, (+)-goniopypyrone and (+)-goniofufurone have been achieved from an advanced common precursor formed from d-(+)-mannitol by changing the carbinol protection profile. The Royal Society of Chemistry.

Full text of DOI:10.1039/b713070h

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Total syntheses of (+)-7-epi-goniofufurone, (+)-goniopypyrone and
(+)-goniofufurone from a common precursor{
Veejendra K. Yadav* and Divya Agrawal
Received (in Cambridge, UK) 24th August 2007, Accepted 1st October 2007
First published as an Advance Article on the web 10th October 2007
DOI: 10.1039/b713070h
The combination of the fascinating structures and the broad
spectrum biological activity has prompted comprehensive efforts
for the syntheses of these styryllactones.10 As a part of our
continuing goal of the fabrication of the heavily oxygenated
styryllactones, we have recently modified our previous poor
yielding racemic strategy11 and achieved formal total syntheses of
Hagen’s gland lactones and trans-kumausynes through an
enantiospecific route that involves ring-closing metathesis and
base-assisted single-step rearrangement of a 7-substituted-4,5-
epoxy-2-oxepanone to the requisite 2,6-dioxabicyclo[3.3.0]octan-
3-one skeleton as the two key steps.12 In this communication, we
disclose the syntheses of (+)-7-epi-goniofufurone 2, (+)-gonio-
pypyrone 3 and (+)-goniofufurone 1 from a single D-(+)-mannitol-
derived precursor by employing the above rearrangement protocol,
though in differential manners.
Total syntheses of (+)-7-epi-goniofufurone, (+)-goniopypyrone
and (+)-goniofufurone have been achieved from an advanced
common precursor formed from D-(+)-mannitol by changing
the carbinol protection profile.
The plant family Annonaceae has, for a long time, aroused
considerable interest from the pharmacological point of view, due
mainly to its polyketide constituents.1 The genus Goniothalamus
comprises several species of shrubs and trees growing in Asia and
has long been recognized as a potential source of chemotherapeutic
agents.2 The extracts and leaves from these plants have tradi-
tionally been used for the treatment of edema and rheumatism,3 as
a pain killer and mosquito repellent,4 and also as an abortifacient.5
Bioactivity-directed studies by McLaughlin on the ethanolic
extracts of the stem bark of Goniothalamus giganteus Hook f.
Thomas have resulted in the isolation and characterization of a
series of novel styryllactones that possess pesticidal, ratogenic and
embryotoxic activity, and marginal to significant cytotoxic activity
against several human tumor cell lines.2a,6
Retrosynthetic analysis of the styryllactones comprising c- and
d-lactone motifs envisions the a,b-unsaturated lactone
A
(Scheme 1) as a key intermediate for its further transformation
into the bicyclic species. Lactone A was traced to B that comprises
three contiguous asymmetric centers and an alkene tether. Further
disconnection of B shows it to be derivable from the known styryl
alcohol C13 via sequential protection of the hydroxyl group,
acetonide cleavage, selective protection of the allyl alcohol, and
esterification of the remaining alcohol. The alcohol C is readily
accessible from tri-O-isopropylidene-D-(+)-mannitol 4,14 the
terminal acetonides acting as surrogates to the generation of the
styryl alcohol and the olefin.
Related to the size of the lactone ring, these styryllactones can be
classified into two main groups (Fig. 1). In the group comprising
c-lactones, (+)-goniofufurone 1 shows significant cytotoxic activity
to several human tumor cell lines and moderate toxicity to brine
shrimp (BS). In contrast, the isomeric (+)-7-epi-goniofufurone 2 is
only weakly bioactive.2a,6b–d,h,7 The absolute configurations were
established independently by Shing and Ja¨ger from the syntheses
of ent-(2)-goniofufurone and (2)-epi-goniofufurone respectively.8
(+)-Goniopypyrone 3, a d-lactone, is the most bioactive con-
stituent and shows non-selective cytotoxicity to several human
tumor cell lines such as lung carcinoma A-549, breast adenocarci-
noma MCF-7, and colon adenocarcinoma HT-29. It also exhibits
high toxicity to BS and causes significant inhibition of the forma-
tion of crown gall tumors on potato discs (PD).6b,c Shing et al.
have confirmed its absolute configuration by total synthesis from
D-glycero-D-gulo-heptono-c-lactone.9
The synthetic sequence commenced with the formation of the
terminal diol 5 (Scheme 2) from the triacetonide 4 by a slight
Fig. 1 Selected bioactive styryllactones from Goniothalamus species.
Department of Chemistry, Indian Institute of Technology, Kanpur,
208016, India. E-mail: vijendra@iitk.ac.in
{ Electronic supplementary information (ESI) available: Experimental
details and spectroscopic data of all new compounds. See DOI: 10.1039/
b713070h
Scheme 1 Retrosynthetic analysis of selected styryllactones.
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Scheme 2 Reagents and conditions: (a) (i) H2SO4, acetone, 25 uC, 6 h; (ii)
aq. NaOH, 85%; (b) (i) EtOH, H2O, HCl, 45 uC, 1 h; (ii) K2CO3, 99%; (c)
(i) PPh3–imidazole–iodine, toluene, 110 uC, 3 h; (ii) aq. Na2S2O3, aq.
NaHCO3, 81%; (d) CuCl2?2H2O, CH3CN, 0 uC, 40 min, 99.9%; (e)
Pb(OAc)4, CH2Cl2, 0 uC, 3 h, 99%; (f) PhMgBr, THF, 0–25 uC, 8 h, 78%.
Scheme 3 Reagents and conditions: (a) p-methoxybenzyl bromide, NaH,
THF, 0–25 uC, 6 h, 93%; (b) 5 : 2 AcOH–H2O, 50 uC, 4 h, 99%; (c)
TBDPSCl, imidazole, CH2Cl2, 0–25 uC, 12 h, 95%; (d) vinylacetic acid,
DCC, DMAP, CH3CN, 0–25 uC, 10 h, 77%; (e) 5 mol% Grubbs’ 2nd
generation catalyst, C6H6, 80 uC, 10 h, 82%; (f) m-CPBA, NaHCO3, 45 uC,
48 h, 78%; (g) 5% HF in CH3CN, 25 uC, 24 h, 78%; (h) (i) DBU, CHCl3,
25 uC, 24 h, 70%; (ii) TBAF, AcOH, THF, 0 uC, 5 min, 98%.
modification of a literature method.14 Pb(OAc)4-cleavage of 5
followed by Wittig reaction provided the terminal olefin 6 in poor
yield along with an unidentifiable mixture of products. Ph3P–
imidazole–iodine in toluene, however, led to a smooth one-step
conversion of 5 into 6 in 81% yield.15 The diacetonide 6 underwent
selective hydrolysis of the terminal acetonide using an equivalent
amount of CuCl2?2H2O at 0 uC to generate the diol 7 in
quantitative yield.16 Pb(OAc)4-cleavage of 7 furnished 8 which,
without purification, was reacted with an excess of PhMgBr at
0 uC to provide the diastereomeric alcohols 9 and 10 in 1.5 : 1
ratio.13 While the carbinol stereochemistry present in 9 is suitable
for the syntheses of (+)-7-epi-goniofufurone 2 and (+)-goniopy-
pyrone 3, that in 10 is suitable for the synthesis of (+)-
goniofufurone 1. The key building blocks 9 and 10 were thus
synthesized in a facile manner from D-(+)-mannitol in a combined
52% overall yield.
Ru-catalyst was noted to cause isomerization of the isolated
olefin in 14 in conjugation with the carbonyl function under the
reaction conditions, necessitating arrest of the reaction before
completion.
Oxidation of 15 by m-CPBA and NaHCO3 in CH2Cl2 by the
Immediate Solvent Evaporation Method (ISEM)18 furnished the
c-hydroxy-a,b-unsaturated-7-membered ring lactone 16 in 78%
yield based on 60% of the starting material having been recovered.
Cleavage of the PMB group with 5% HF in CH3CN furnished the
diol 17 in 78% yield which rearranged, on exposure to DBU, to the
required bicyclo[3.3.0] skeleton through a two-step protocol
involving (a) transformation of the seven-membered ring lactone
into a five-membered ring lactone, and (b) a second ring closure
through an intramolecular Michael addition. Finally, desilylation
using TBAF afforded (+)-7-epi-goniofufurone 2. The spectral and
physical properties of the synthetic (+)-7-epi-goniofufurone 2 were
identical to those reported in the literature.6d
The results of the initial studies for the regioselective protection
of the two terminal hydroxyl groups leaving the middle one free
for esterification were frustrating. The reaction of the triol
obtained from acetonide cleavage of 9 as a 3,5-benzylidene
derivative using p-methoxybenzaldehyde dimethyl acetal and
PPTS gave a complex mixture. The three-step conversion involving
sequential PMB protection of the free carbinol in 9, acetonide
cleavage, and DDQ-promoted transformation to the 3,5-benzyl-
idene derivative17 was also unsuccessful as it generated only
the 4,5-benzylidene compound. We therefore investigated several
combinations of protecting groups for the sequential protection of
the styryl alcohol and the allylic alcohol formed from acetonide
cleavage. PMB and TBDPS used for the protection of the styryl
alcohol and the allyl alcohol, respectively, offered excellent
yields and selectivity. Thus, PMB protection of the styryl alcohol
in 9 and acetonide cleavage by aqueous AcOH produced the diol
12 (Scheme 3). Reaction of 12 with 1.0 equiv. of TBDPSCl and
3.0 equiv. of imidazole furnished a 1 : 8 mixture of the bis-
protected and the requisite mono-protected products that were
separated easily by radial chromatography.
The long reaction time required for the epoxidation and
moderate yields of PMB-cleavage using HF and DBU-promoted
rearrangement prompted us to remove all the protecting groups
before the oxidation of the double bond in the RCM product. We
wished to generate triol 20 (Scheme 4) and study its rearrangement,
hoping to generate both (+)-7-epi-goniofufurone through c-lactone
formation from the engagement of the C5-alcohol and (+)-
goniopypyrone through d-lactone formation from the engagement
of the C6-alcohol in the first step of the rearrangement. Cleavage
of PMB in 15 using Ph3CBF4, according to a literature pro-
cedure,19 proceeded smoothly to generate the alcohol 18 in 95%
yield. Reflux of 18 with CBr4 in MeOH generated 19 in 85%
yield.20 Oxidation of the double bond using t-BuOOH–VO(acac)2
afforded a 5 : 1 mixture of the c-hydroxy-a,b-unsaturated lactones
20 and 21. DBU treatment of 20 led to the formation of only
(+)-goniopypyrone 3 in excellent yield. The spectral and physical
properties of the synthetic (+)-goniopypyrone 3 were identical to
those reported in the literature.6c The failure to form (+)-7-epi-
goniofufurone is in accord with Vate`le’s observation21a that
dismisses Shing’s hypothesis21b of (+)-7-epi-goniotriol being a
biogenetic precursor of (+)-7-epi-goniofufurone.
Esterification of 13 with vinylacetic acid led to the formation of
14 in 77% yield along with the isolation of the starting material
which was separated easily by radial chromatography. To avoid
isomerization of the double bond by prolonged exposure to the
reaction conditions, the reaction was arrested before complete
disappearance of the starting material. Grubbs’ ring-closing
metathesis of 14 proceeded well under dilute conditions and the
seven-membered ring lactone 15 was isolated in 82% yield. The
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Notes and references
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Scheme 4 Reagents and conditions: (a) Ph3CBF4, CH2Cl2, 25 uC, 30 s,
95%; (b) CBr4, MeOH, 65 uC, 12 h, 85%; (c) t-BuOOH–VO(acac)2, C6H6,
0–25 uC, 10 h, 80%; (d) DBU, CHCl3, 25 uC, 0.5 h, 84%.
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Scheme 5 Reagents and conditions: (a) p-methoxybenzyl bromide, NaH,
THF, 0–25 uC, 6 h, 91%; (b) 5 : 2 AcOH–H2O, 50 uC, 4 h, 99%; (c)
TBDPSCl, imidazole, CH2Cl2, 0–25 uC, 12 h, 73%; (d) vinylacetic acid,
DCC, DMAP, CH3CN, 0–25 uC, 8 h, 78%; (e) 5 mol% Grubbs’ 2nd
generation catalyst, C6H6, 80 uC, 10 h, 85%; (f) Ph3CBF4, CH2Cl2, 25 uC,
5 min, 94.5%; (g) m-CPBA, CH2Cl2, 45 uC, 24 h, 96%; (h) (i) DBU,
CHCl3, 25 uC, 24 h, 82%; (ii) TBAF, AcOH, THF, 0 uC, 5 min, 99%.
The synthesis of (+)-goniofufurone 1 from 10 by following
the steps outlined in Scheme 3 was problematic for achieving
epoxidation of the species equivalent to 15. However, PMB-
cleavage before epoxidation worked well as shown in Scheme 5.
The key intermediate 28 rearranged to (+)-goniofufurone 1 after
DBU-treatment and desilylation, in that order. The spectral and
physical properties of synthetic (+)-goniofufurone 1 were identical
to those reported in the literature.6c
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In summary, we have achieved the total syntheses of (+)-7-epi-
goniofufurone, (+)-goniopypyrone and (+)-goniofufurone from a
common precursor simply by changing the sequence of carbinol
protection and thus allowing the formation of either a c-lactone
or a d-lactone in the first step of the rearrangement that
leads to further ring closure to generate, respectively, the
bicyclo[3.3.0] skeleton of goniofufurones or the [3.3.1] skeleton of
goniopypyrone.
V.K.Y. thanks the Department of Science & Technology for a
Ramanna Fellowship and D.A. thanks the Council of Scientific &
Industrial Research for a Senior Research Fellowship.
5234 | Chem. Commun., 2007, 5232–5234
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