Synthetic studies on the cornexistins: Synthesis of (±)-5-epi- hydroxycornexistin

Article abstract of DOI:10.1039/b811245b

The synthesis of 5-epi-hydroxycornexistin (44), a diastereoisomer of the herbicidal natural product hydroxycornexistin (2) has been completed. Palladium mediated sp²-sp³ coupling of the stannane 25 and the chloride 31 and ring-closing metathesis of the resulting diene 32 has been used to construct the tricyclic lactone 34a, which possesses the nine-membered carbocyclic core found in the natural product, in good yield. The synthesis of 5-epi-hydroxycornexistin (44) has established the feasibility of using a furan as precursor for the cyclic anhydride unit present in the natural product and has demonstrated the viability of other late-stage transformations that will be used to prepare hydroxycornexistin (2). The 2008 Royal Society of Chemistry.

Full text of DOI:10.1039/b811245b

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Synthetic studies on the cornexistins: synthesis of
( )-5-epi-hydroxycornexistin†‡
J. Stephen Clark,*a John M. Northall,b Fre´de´ric Marlin,b Bastien Nay,b Claire Wilson,b Alexander J. Blakeb
and Michael J. Waringc
Received 2nd July 2008, Accepted 31st July 2008
First published as an Advance Article on the web 8th September 2008
DOI: 10.1039/b811245b
The synthesis of 5-epi-hydroxycornexistin (44), a diastereoisomer of the herbicidal natural product
hydroxycornexistin (2) has been completed. Palladium mediated sp2–sp3 coupling of the stannane 25
and the chloride 31 and ring-closing metathesis of the resulting diene 32 has been used to construct the
tricyclic lactone 34a, which possesses the nine-membered carbocyclic core found in the natural product,
in good yield. The synthesis of 5-epi-hydroxycornexistin (44) has established the feasibility of using a
furan as precursor for the cyclic anhydride unit present in the natural product and has demonstrated
the viability of other late-stage transformations that will be used to prepare hydroxycornexistin (2).
well tolerated by some crop plants such as maize (Zea mays);3
hydroxycornexistin is a particularly potent herbicidal agent and
exhibits good activity against many very aggressive varieties of
Introduction
Cornexistin (1) and hydroxycornexistin (2) are unusual members of
broadleaf weed.2,3 It has been suggested that the cornexisitins
might exert their herbicidal activity by interfering with aspartate
amino transferase isozymes,3 but their precise mode of action
is still unclear. As a consequence of their selective and potent
herbicidal activity combined with their apparent novel mode of
action, the cornexistins have significant potential as novel lead
compounds in the search for new post-emergence weed control
agents in crop production.1–3
The term “nonadride” was introduced by Barton and
Sutherland4 to refer to the bisanhydrides glauconic acid (3),
glaucanic acid (4) and byssochlamic acid (5) because these
natural products appeared to be biosynthesised from two C9-
units (Fig. 2). The term has since been extended to cover a
range of related natural products that possess core structures in
which a nine-membered carbocycle is fused to one or more maleic
anhydride units.
the nonadride family of natural products (Fig. 1). Cornexistin was
originally isolated from a culture of the fungus Paecilomyces vari-
otii Bainier (strain SANK 21086) in 1987 by researchers at Sankyo
Co. who were searching for new microbial products possessing
herbicidal activity.1 The structure of cornexistin was determined
using NMR spectroscopy and by X-ray crystallography, but the
absolute configuration was not established. Hydroxycornexistin
was later obtained from the same strain of P. variotii by workers
at DowElanco and its structure was determined by NMR analysis
and a comparison of spectroscopic data to those of cornexistin.2
The cornexistins are rather unusual members of the nonadride
family because they possess just a single anhydride unit, while
most of the others possess two (Fig. 2). The first of the nonadrides
to be discovered—glauconic acid (3) and glaucanic acid (4)—were
both isolated from the fungus Penicillium glaucum (now known
as Penicillium purpurogenum) in 1931.4 This was followed by the
isolation of byssochlamic acid (5) from the fungus Byssochlamys
fulva in 1933.5 In each compound, the nine-membered carbocycle
is substituted with simple alkyl side chains and in the case of
glauconic acid there is an addition hydroxyl group. Subsequently,
rubratoxins A (6) and B (7)—toxic metabolites of the fungus
Penicillium rubrum—were isolated and found to possess more
elaborate side chains appended to the nine-membered ring.6
Interestingly, rubratoxin B does have some phytotoxic activity,
but it is a much weaker herbicide than either of the cornexistins.1–3
Finally, the nonadrides heveadride (8), homoheveadride (9),7
dihydroepiheveadride (10)8 and deoxoepiheveadride (11)9 were
isolated. Heveadride (8) has weak anti-fungal activity whereas
dihydroepiheveadride has activity against a range of fungi,
Fig. 1 The cornexistins.
Both cornexistin (1) and hydroxycornexistin (2) display potent
herbicidal activity against grasses and broadleaf weeds but are
aWestCHEM, Department of Chemistry, Joseph Black Building, University
of Glasgow, University Avenue, Glasgow, G12 8QQ, UK. E-mail: stephenc@
chem.gla.ac.uk
bSchool of Chemistry, University of Nottingham, University Park,
Nottingham, NG7 2RD, UK
cAstraZeneca, Mereside, Alderley Park, Cheshire, SK10 4TF, UK
† Dedicated to Professor Andrew B. Holmes FRS on the occasion of his
65th birthday with much gratitude for his friendship and support over the
past two decades.
‡ Electronic supplementary information (ESI) available: Experimental
procedures for the preparation of compounds 21–25 and 27–32. CCDC
reference numbers 693628 (34a), 196700 (34b) and 693627 (36). For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b811245b
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compounds the nine-membered carbocyclic core is embedded
within a bicyclo[4.3.1]deca-1,6-diene framework. The compounds
are the most widely studied of all the nonadrides and have aroused
considerable interest in the pharmaceutical industry because they
inhibit squalene synthase and Ras farnesyl transferase; inhibitors
of these enzymes have been found to possess cholesterol-lowering
and anti-cancer properties respectively.14,15
In spite of the significant potential they have as novel lead
compounds in the search for new post-emergence weed control
agents, the cornexistins have been the subject of relatively few
synthetic studies and little has been published concerning their
total synthesis. Aside from our own preliminary studies,16 the
only attempt to synthesise one of the cornexistins has been that
recently reported by Taylor and co-workers.17 In this work, the
bicyclic compound 17, prepared by intermolecular Diels–Alder
cycloaddition of the diene 16 with dimethyl acetylenedicarboxy-
late, was subjected to ozonolytic ring opening and methylenation
to give the cyclononenone 18 (Scheme 1). Further elaboration
by inversion of configuration of one of the hydroxyl-bearing
stereogenic centres and installation of the exocyclic trisubstituted
alkene using a silicon-tethered diene ring-closing metathesis and
Fleming–Tamao oxidation sequence gave the diol 19. Elaboration
of the diol 19 to give hydroxycornexistin was not reported by
Taylor and co-workers.17
Fig. 2 Nonadride natural products related to the cornexistins.
including some human pathogens. Other nonadride natural prod-
ucts, such as scytalidin (12)10 and deoxyscytalidin (13),11 have also
been shown to possess significant anti-fungal activity.12
The most structurally complex nonadrides to have been isolated
to date are the fungal metabolites CP-225,917 (14) and CP-
263,114 (15) (Fig. 3)—also known as phomoidrides A and B—
which were discovered by workers at Pfizer in 1997.13,14 In both
Scheme 1 Taylor’s synthesis of an advanced intermediate for the synthesis
∫
of hydroxycornexistin. Regents and conditions: (a) MeO2CC CCO2Me,
hydroquinone, PhMe, reflux [50%]; (b) O3, CH2Cl2, -78 ◦C; (c) Tebbe
reagent, THF, PhMe, -78 ◦C [45% over 2 steps].
Results and discussion
Our interest in cornexistin and hydroxycornexistin as synthetic
targets was aroused by the synthetic challenges these compounds
present coupled with their potent bioactivity. Both compounds
possess a nine-membered carbocycle fused to a highly reac-
tive cyclic anhydride, a combination of structural features that
constitutes a significant obstacle to conventional methods of
ring construction. In addition, the cornexistins present several
potential problems concerning stereocontrol, with control of the
exocyclic alkene configuration being especially challenging.
Fig. 3 The phomoidride natural products.
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The retrosynthetic analysis of hydroxycornexistin that we de-
vised begins with simple functional group interconversion (FGI) to
mask the anhydride and give the furan i (Scheme 2). Connection of
two of the hydroxyl groups in the form of a lactone and conversion
of the ketone carbonyl group into a hydroxyl group then affords
the diol ii. Conversion of the diol into an alkene then leads to
the tricyclic lactone iii and disconnection of the ring through
the alkene produces the diene iv. Disconnection of one of the
bonds between the butenolide and the furan then delivers the
simple lactone v and a 3,4-disubstituted furan vi bearing suitable
substituents (X and Y) for a metal-mediated sp2–sp3 coupling
reaction.
Scheme 3 Synthesis of the butenolide fragment 25. Reagents and
conditions: (a) pyrrolidine, heat [97%]; (b) t-BuLi, CH2CHCH2Br, THF,
-78 ◦C → rt [76%]; (c) HCl aq., 60 ◦C [89%]; (d) Tf2O, i-Pr2NEt, CH2Cl2,
-78 ◦C [89%]; (e) (Bu3Sn)2, LiCl, Pd(PPh3)4, THF, reflux [54%].
The synthesis of the second coupling partner commenced from
commercially available furan dicarboxylate bisester 26 (Scheme 4).
Reduction of the diester 26 with lithium aluminium hydride
followed by selective mono-oxidation of the resulting diol with
manganese dioxide afforded the aldehyde 27.22 Protection of the
free hydroxyl group as a TBS ether followed by Wittig reaction
of the aldehyde with methyl (triphenylphosphoranylidene)acetate
Scheme 2 Retrosynthetic analysis of hydroxycornexistin.
The key strategic transformation implied in our retrosynthetic
analysis is construction of the nine-membered ring using a ring-
closing metathesis (RCM) reaction. At the outset, we already had
considerable experience in the preparation of medium-sized cyclic
ethers using diene RCM reactions and other workers had used
RCM to prepare other medium-ring carbocycles.18,19 However,
there were no literature examples involving direct construction
of nine-membered carbocycles using RCM when we commenced
our synthetic studies and so it was not clear whether a diene RCM
reaction would deliver the nonadride core in good yield.
The first objective was the synthesis of the fragments (corre-
sponding to synthons v and vi in Scheme 2) required for imple-
mentation of the synthetic plan suggested by our retrosynthetic
analysis. In the case of synthon v, the corresponding stannane 25
was prepared as shown in Scheme 3. The readily available starting
material tetronic acid (20) was first converted into the vinylogous
carbamate 21 by condensation with pyrrolidine. Deprotonation
of the compound 21 with tert-butyllithium and treatment of the
resulting anion with allyl bromide then afforded the alkylated
product 22.20 Acid-catalysed hydrolysis then delivered the tetronic
acid derivative 23 and this was then converted into the triflate
24. The stannane 25 required for the sp2–sp3 fragment coupling
reaction was obtained in reasonable yield by the palladium-
catalysed reaction of the triflate 24 with hexabutylditin.21
Scheme 4 Synthesis of the furan fragment 31. Reagents and conditions: (a)
LiAlH4, THF, -78 ◦C → rt; (b) MnO2, CH2Cl2, rt; (c) TBSCl, imidazole,
=
DMAP, CH2Cl2, rt [73% over 3 steps]; (d) Ph3P CHCO2Et, THF, rt [89%];
(e) LiAlH4, THF, -78 ◦C → rt [84%]; (f) P(O)(OEt)2Cl, pyridine, DMAP,
CH2Cl2, rt; (g) n-PrMgCl, CuCN (10 mol%), LiCl (30 mol%), THF, -78 ◦C
[64% over 2 steps]; (h) TBAF, THF, rt [96%]; (i) MeSO2Cl, LiCl, collidine,
DMF, 0 ◦C, [77%].
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delivered the a,b-unsaturated ester 28 in high yield. The ester was
then reduced with lithium aluminium hydride and the resulting
allylic alcohol was treated with diethyl chlorophosphate to give
the allylic phosphate 29. The propyl side chain was then installed
by copper-catalysed SN2¢ displacement of the allylic phosphate
with n-propylmagnesium chloride following a procedure described
by Yamamoto and co-workers, to give the alkene 30.23 Cleavage
of the TBS ether and conversion of the resulting primary alcohol
into the corresponding chloride via the mesylate, using a procedure
described by Tanis for the synthesis of related chlorides,24 afforded
the chloride 31 which was to serve as the coupling partner.
The precursor required for the key diene RCM reaction was
prepared by sp2–sp3 coupling of the vinylic stannane 25 and the
chloride 31.25 The coupled product 32 was obtained in 87% yield
(1 : 1 mixture of diastereoisomers) upon treatment of a mixture
of the racemic stannane 25 and the racemic chloride 31 with
Pd2(dba)3 and triphenylarsine in THF at reflux (Scheme 5). Ring
closure was effected by subjecting the diastereomeric mixture
of the dienes 32 to diene RCM using the ruthenium complex
33 in dichloromethane at reflux. The reaction was complete
in 18 hours and the diastereomeric tricyclic products 34a and
34b were obtained as a separable mixture of diastereoisomers
(2 : 3 ratio) in a combined yield of 77%.
Fig. 4 X-Ray crystal structure of the RCM product 34a (displacement
ellipsoid plots drawn at 50% probability level).
Scheme 5 Construction of the nine-membered ring by fragment coupling
and diene ring-closing metathesis. Reagents and conditions: (a) Pd2(dba)3
(3 mol%), AsPh3 (8 mol%), THF, 60 ◦C [87%, 1 : 1]; (b) complex 33
(20 mol%), CH2Cl2, reflux [30% 34a, 47% 34b].
Both of the diastereoisomeric alkenes 34a and 34b were obtained
as a crystalline solids. The compound 34b crystallised readily to
give crystals of suitable quality for X-ray analysis whereas the
isomeric compound 34a was obtained as an oil that subsequently
crystallised to give a low-melting solid. X-ray analysis of both
isomers revealed that the less polar compound was the tricyclic
lactone 34a possessing the relative stereochemistry required for
the synthesis of the cornexistins (Fig. 4).‡
Dihydroxylation of the alkene 34a using Upjohn conditions
was sluggish,26 but consistent yields of 50–55% could be obtained
(~70% based on recovered alkene 34a) (Scheme 6). The modest
yields obtained from the dihydroxylation reaction suggest that
decomposition of the alkene 34a and/or the diol 35 occurs on
Scheme
6 Conversion of RCM product 34a into the advanced
hydroxycornexistin precursors 40 and 41. Reagents and conditions:
(a) OsO4 (10 mol%), NMO, Me2CO, H2O, rt [50–55% (55–70% based
on recovered starting material)]; (b) p-O2NC6H4COCl, DMAP, pyridine,
CH2Cl2, 0 C → rt [66%]; (c) p-MeOC6H4CH(OMe)2, CSA, 4 A sieves,
CH2Cl2, 0 ◦C → rt [93%, ~1 : 1]; (d) LiAlH4, TMEDA, Et2O, 0 ◦C;
(e) NaH, MeOC6H4CH2Cl, n-Bu4NI, DMF, 0 ◦C → rt [49%, 2 steps];
(f) DiBAl-H, CH2Cl2, PhMe, -78 ◦C → rt [29% 40, 33% 41 (81% based on
recovered starting material)].
◦
˚
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prolonged exposure to the reaction conditions. The stereochemical
outcome of the dihydroxylation reaction was determined by X-ray
analysis of the crystalline mono-p-nitrobenzoate 36 prepared
by mono-esterification the diol 35 using p-nitrobenzoyl chloride
(Scheme 6).‡ The relative configuration in the ester 36 meant
that the dihydroxylation reaction had delivered the diol 35
with C-5 configuration that was opposite to that found in
hydroxycornexistin (2) (Fig. 5).
Scheme 7 Completion of the synthesis of 5-epi-hydroxycornexistin.
˚
Reagents and conditions: (a) TPAP, 4 A sieves, CH2Cl2, rt [80%]; (b) O2,
hn, rose Bengal, i-Pr2NEt, -78 ◦C → rt; (c) TPAP, 4 A sieves, CH2Cl2, rt;
˚
(d) DDQ, CH2Cl2, H2O, rt [10% over 3 steps].
TPAP oxidation of the crude product.29 The reaction with singlet
oxygen delivered a complex mixture of products from which a
5-hydroxy-2(5H)-furanone could be isolated (39% yield) as the
major component. The mixture of products resulting from singlet
oxygen reaction was unstable, as was the cyclic anhydride 43,
and so removal of the PMB groups using DDQ was performed
as quickly as possible after partial purification of the anhydride
43. The resulting ( )-5-epi-hydroxycornexistin (44) was relatively
unstable but could be purified by reverse phase HPLC giving
an overall yield of 10% for the final three steps. The instability
of the cyclic anhydride to silica gel and the extensive work-up
required after deprotection account for the modest yield obtained
for the three-step conversion of the bicyclic furan 42 into ( )-5-
epi-hydroxycornexistin (44).
Fig. 5 X-Ray crystal structure of the p-nitrobenzoate 36 (displacement
ellipsoid plots drawn at 50% probability level).
The X-ray crystal structure of the ester 34a (Fig. 4) was
remarkable because it clearly showed that dihydroxylation of the
most accessible face of the alkene (i.e. that facing out from the ring)
should deliver the required diastereomeric syn 1,2-diol product
rather thanthediol 35 (assuming free rotation of the propyl group).
This finding illustrates the pitfalls of relying on X-ray crystal data
to predict the reactive conformation of a conformationally mobile
medium-ring system, such as the alkene 34a, in solution.
Even though the dihydroxylation reaction had not delivered
the diastereoisomer required for the total synthesis of hydroxy-
cornexistin, further elaboration of the diol 35 was explored in
order to complete the synthesis of 5-epi-hydroxycornexistin and
thereby establish the viability of the steps late in the synthesis.
It was also expected that it would be possible to complete the
synthesis of hydroxycornexistin by inverting the stereochemistry
at the hydroxyl-bearing stereogenic centre later in the synthesis.
The 1,2-diol 35 was converted into a diastereomeric mixture
of the acetals 37 (1.3 : 1 ratio) by acid-catalysed transacetalation
(Scheme 6). Lactone reduction using LiAlH4 in the presence of
TMEDA27 and then double PMB protection of the resulting diols
38 afforded the acetals 39. Reductive opening of this mixture of
cyclic acetals with DiBAl-H produced the alcohols 40 and 41
(1 : 1.1 mixture) in 62% yield (81% based on recovered starting
material).
Comparison of the 1H and 13C NMR data for the natural
product 2 with that of the synthetic C-5 diastereoisomer 44
revealed some interesting similarities and differences between the
compounds (Table 1).2b Most of the 13C NMR chemical shifts
differed by less than 2 ppm and in some cases there was an
excellent match even though the NMR samples did not have the
same concentration and the NMR instruments differed. There was
also some agreement with between the 1H NMR data for the two
compounds but in this case considerable differences in chemical
shifts and coupling constants were obvious for some of the signals.
The completion of the synthesis of ( )-5-epi-hydroxycornexistin
(44) demonstrated that the late-stage chemical transformations
should be chemically viable for the total synthesis of hydroxy-
cornexistin (2). Several attempts were then made to access the
natural product by inversion of the C-5 stereocentre. In the first
approach, Misunobu esterification with inversion of configuration
was attempted using p-nitrobenzoic acid (Scheme 8).30 Selective
protection of the diol 35 by acetylation delivered a mixture of the
diacetate 45 (20% yield) and the required monoacetate 46 (64%
yield). Attempted Misunobu esterification of the free hydroxyl
group of the monoacetate 46 with inversion of configuration using
p-nitrobenzoic acid failed to deliver the required p-nitrobenzoate
ester 47. As an alternative, oxidation of the C-5 hydroxyl group
followed by ketone reduction was explored. However, reduction
The synthesis of ( )-5-epi-hydroxycornexistin (44) was com-
pleted as shown in Scheme 7. The alcohol 41 was converted
into the ketone 42 in 80% yield by TPAP oxidation.28 The final
major transformation—conversion of the furan into the cyclic
anhydride—was then performed by reaction of the furan 42
with singlet oxygen in the presence of Hu¨nig’s base followed by
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Table 1 Comparison of the 1H and 13C NMR data for natural hydroxycornexistin (2) and the synthetic ( )-5-epi-hydroxycornexistin (44)
1H NMR data (CD3CN)
2 dH (300 MHz): 5.80 (1H, t, J = 6.4 Hz), 4.75 (1H, dd, J = 8.8, 4.9 Hz), 4.23–4.04 (2H, m), 3.81 (1H, d, J = 9.5 Hz), 3.44–3.34 (3H, m), 3.10 (1H, d),
2.58 (3H, br), 2.44 (1H, dd), 1.45–1.20 (2H, m), 0.89 (3H, t, J = 7.3 Hz) (2 ¥ H missing due to overlap of solvent peak at ~2 ppm)
44 dH (500 MHz): 5.86 (1H, dd, J = 6.5, 5.9 Hz), 4.99 (1H, dd, J = 10.3, 6.2 Hz), 4.43–4.41 (1H, m), 4.16–4.14 (2H, m), 3.71 (1H, ddd, J = 8.9, 6.2,
2.5 Hz), 3.50 (1H, d, J = 4.9 Hz), 3.38 (1H, dd, J = 16.5, 10.3 Hz), 3.34 (1H, br s), 3.22 (1H, d, J = 14.3 Hz), 3.12 (1H, dd, J = 14.3, 1.1 Hz), 2.85 (1H,
br s), 2.71 (1H, dd, J = 16.5, 6.2 Hz), 2.30–2.21 (1H, m), 1.92–1.86 (1H, m), 1.41–1.27 (2H, m), 0.95 (3H, t, J = 7.4 Hz)
13C NMR data (CD3CN)
2 dC (100 MHz): 212.5, 167.0, 166.3, 146.8, 142.6, 137.4, 135.6, 80.8, 68.3, 58.4, 44.7, 41.1, 30.6, 28.1, 21.7, 14.1
44 dC (125 MHz): 210.2, 166.8, 165.1, 147.4, 141.2, 137.6, 136.4, 79.4, 66.5, 58.4, 42.9, 41.0, 31.2, 25.2, 21.6, 14.3
Scheme 8 Attempted inversion of configuration at the C-5 stereocentre.
Reagents and conditions: (a) Ac2O, DMAP, Et3N, CH2Cl2, 0 ◦C → rt [20%
45, 64% 46]; (b) p-O2NC6H4CO2H, EtO2CNNCO2Et, PPh3, THF, 0 ◦C →
rt; (c) Dess–Martin periodinane, CH2Cl2, rt [95%]; (d) NaBH4, THF, 0 ◦C
Scheme 9 Attempted inversion of configuration at the C-5 hydroxy-bear-
ing stereogenic centre after opening of the lactone. Reagents and conditions:
(a) Me2C(OMe)2, PPTS, CH2Cl2, rt [98%]; (b) DiBAl-H, CH2Cl2, PhMe,
-78 ◦C then LiAlH4, THF, -78 → 0 ◦C [74%]; (c) NaH, MeOC6H4CH2Cl,
n-Bu4NI, DMF, 0 ◦C → rt [74%]; (d) p-TSA, MeOH, rt [54% (67% based
on recovered starting material)]; (e) Ac2O, DMAP, Et3N, CH2Cl2, 0 ◦C →
rt [65%]; (f) Dess–Martin periodinane, CH2Cl2, rt; (g) NaBH4, THF, 0 ◦C
[recovered 53].
[recovered 46].
of the ketone 48 with NaBH4 merely returned the original alcohol
46 (Scheme 8).
Further attempts to correct the configuration at the C-5 stere-
ocentre were also made using intermediates lacking the lactone
(Scheme 9). It was expected that lactone opening would result in a
significant change in the conformation of the nine-membered ring
and that this might lead to a reversal of facial selectivity during
ketone reduction.
Prior to opening of the lactone, the diol 35 was converted
into the acetonide 49 (Scheme 9). Initial attempts to reduce the
lactone 49 with LiAlH4 resulted in decomposition and the use
of alternative reducing agents such as LiBH4 and NaBH4 was
also unsuccessful. Transformation of the lactone 49 into the
diol 50 was eventually accomplished in 74% yield by sequential
one-pot reduction with DiBAl-H and then LiAlH4. The diol
50 was protected as the bis-PMB ether 51 and removal of the
acetonide under acidic conditions then afforded the diol 52.
Selective acetylation of the C-6 hydroxyl group and oxidation
of the resulting alcohol 53 using the Dess–Martin periodinane
provided the corresponding ketone. Reduction of this ketone with
NaBH4 did not deliver the required alcohol 54; the only compound
isolated was the original alcohol 53.
Two further attempts were made to obtain hydroxycornexistin
(Scheme 10). In the first case, epimerisation at the C-5 position
of the ketone 42 was attempted using a variety of reagents,31
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34a (309 mg, 30%) and 34b (484 mg, 47%) as colourless solids.
Recrystallisation of the alkene 34a from hexane and ethyl acetate
and recrystallisation of the alkene 34b from petroleum ether and
dichloromethane gave crystals suitable for X-ray crystallography.
34a. Mp 77–79 ◦C (Found: C, 74.10; H, 6.95; C16H18O3
requires: C, 74.40; H, 7.02%); Rf: = 0.18 (petroleum ether–diethyl
ether, 1 : 1); nmax (CHCl3)/cm-1 2958, 2930, 2873, 1796, 1748,
1634, 901, 871; dH (500 MHz, CDCl3) 7.34 (1H, s, Fur-H), 7.21
(1H, dd, J = 1.6, 1.3 Hz, Fur-H), 5.87 (1H, s, COCH=C), 5.78
(1H, ddd, J = 10.2, 10.0, 6.8 Hz, CH2CH=CH), 5.42 (1H, dd,
=
J = 10.2, 10.2 Hz, CH CHCH), 4.92 (1H, dd, J = 10.2, 5.5 Hz,
=
=
CH CCHO), 3.55 (1H, d, J = 15.4 Hz, CH2C CH), 3.50 (1H, d,
=
J = 15.4 Hz, CH2C CH), 3.41 (1H, ddd, J = 10.2, 9.6, 4.0 Hz,
=
=
CHCH CH), 2.88 (1H, ddd, J = 13.0, 6.8, 5.5 Hz, CH2CH CH),
Scheme 10 Further attempts to correct the C-5 stereochem-
istry by epimerisation and oxidation/reduction in order to obtain
hydroxycornexistin.
=
2.54 (1H, ddd, J = 13.0, 10.2, 10.0 Hz, CH2CH CH), 1.86–1.78
(1H, m, CHCH2CH2), 1.59–1.50 (1H, m, CHCH2CH2), 1.49–1.38
(1H, m, CH2CH3), 1.34–1.23 (1H, m, CH2CH3), 0.93 (3H, t, J =
7.4 Hz, CH3); dC (100 MHz, CDCl3) 172.8 (C), 172.6 (C), 140.8
(CH), 139.5 (CH), 136.8 (CH), 125.3 (C), 120.7 (C), 122.1 (CH),
119.0 (CH), 81.6 (CH), 34.4 (CH2), 33.5 (CH), 33.3 (CH2), 23.1
(CH2), 20.3 (CH2), 14.1 (CH3); m/z (EI) 258.1248 [M]+, C16H18O3
requires 258.1256.
but unfortunately these reactions failed to deliver any of the
required isomeric compound 55. The second approach involved
reduction of the ketone 56, obtained by oxidation of the alcohol
40 (Scheme 6), using a variety of reducing agents.32 Some of these
reagents are known to give the thermodynamically rather than
kinetically favoured product, but in all cases either the ketone 56
did not react or the alcohol 40 was obtained instead of the required
alcohol 57.
34b. Mp 92–95 ◦C (Found: C, 74.17; H, 7.05; C16H18O3
requires C, 74.40; H, 7.02%); Rf: = 0.10 (petroleum ether–diethyl
ether, 1 : 1); nmax (CHCl3)/cm-1 2958, 2932, 2873, 1748, 1641, 975,
938, 910, 885; dH (500 MHz, CDCl3) 7.38 (1H, d, J = 1.1 Hz,
Fur-H), 7.17 (1H, s, Fur-H), 5.74 (1H, s, COCH=C), 5.29 (1H,
Conclusions
In summary, 5-epi-hydroxycornexistin (44) has beenprepared from
the tricyclic alkene 34a in nine steps. The tricyclic alkene 34a
can be accessed by RCM of the diene produced by palladium-
mediated coupling of the chloride 31 and the stannane 25 and
these fragments can be prepared from readily available starting
materials in nine and five steps respectively.
Our synthesis of 5-epi-hydroxycornexistin (44) has demon-
strated the feasibility of the late-stage transformations that will
be used to prepare hydroxycornexistin (2). Preliminary attempts
to access the natural product by inversion of configuration at
the C-5 stereogenic centre have not been successful, but work is
continuing in an effort to synthesise both cornexistins using the
strategy described herein.
=
ddd, J = 10.8, 10.6, 5.3 Hz, CH2CH CH), 5.25 (1H, dd, J = 10.8,
=
=
9.7 Hz, CH CHCH), 5.24 (1H, dd, J = 4.4, 2.1 Hz, CH CCHO),
=
3.57 (1H, dd, J = 15.3, 1.4 Hz, CH2C CH), 3.39 (1H, ddd, J = 9.7,
=
=
9.3, 5.5 Hz, CHCH CH), 3.17 (1H, d, J = 15.3 Hz, CH2C CH),
=
3.14–3.05 (1H, m, CH2CH CH), 2.76 (1H, ddd, J = 14.4, 5.3,
=
4.4 Hz, CH2CH CH), 1.70–1.63 (2H, m, CHCH2CH2), 1.43–1.39
(1H, m, CH2CH3), 1.33–1.27 (1H, m, CH2CH3), 0.93 (3H, t, J =
7.4 Hz, CH3); dC (100 MHz, CDCl3) 172.8 (C), 170.7 (C), 140.0
(CH), 139.2 (CH), 139.0 (CH), 128.1 (C), 121.3 (C), 119.9 (CH),
119.8 (CH), 84.5 (CH), 35.2 (CH2), 32.8 (CH), 28.0 (CH2), 21.1
(CH2), 20.8 (CH2), 13.9 (CH3); m/z (EI) 258.1256 [M]+, C16H18O3
requires 258.1256.
X-Ray crystal structure data for alkene 34a. C16H18O3, M =
258.30, monoclinic, a = 10.3476(7), b = 12.7195(9), c =
Experimental
◦
3
˚
˚
(4R*,5Z,7aR*)-4-Propyl-7,7a-dihydro-4H,11H-2,8-
dioxadicyclopenta[a,d]cyclononen-9-one 34a and
(4R*,5Z,7aS*)-4-propyl-7,7a-dihydro-4H,11H-2,8-
dioxadicyclopenta[a,d]cyclononen-9-one 34b
11.1244(8) A, b = 114.035(2) , U = 1337.21(16) A T = 150(2) K,
,
space group P21/n, Z = 4, Dc = 1.283 g cm-3, m(Mo-Ka) =
0.088 mm-1, 12219 reflections collected, 3087 unique (Rint = 0.096).
Final R1 [2629 F > 4s(F)] = 0.0436, wR2 [all F2] = 0.122. CCDC
number 693628.‡
The ruthenium catalyst 33 (654 mg, 0.798 mmol) was added
to a stirred solution of a mixture (1 : 1) of the diastereomeric
dienes 32 (1.14 g, 4.01 mmol) in dichloromethane (1.0 L) at room
temperature. The resulting red solution was heated at reflux for
18 h and then cooled to room temperature. The brown solution
was stirred under an air atmosphere for 1 h then concentrated
to afford the crude mixture of alkenes 34a and 34b as a brown
oil. Purification by flash column chromatography on silica gel
(petroleum ether–diethyl ether, 7 : 3 → 1 : 1) yielded the alkenes
X-Ray crystal structure data for alkene 34b. C16H18O3, M =
258.30, monoclinic, a = 16.9137(13), b = 8.9021(7), c =
◦
3
˚
˚
9.1712(7) A, b = 102.642(1) , U = 1347.4(2) A T = 150(2) K,
,
space group P21/c, Z = 4, Dc = 1.273 g cm-3, m(Mo-Ka) =
0.087 mm-1, 11825 reflections collected, 3390 unique (Rint = 0.066).
Final R1 [2766 F > 4s(F)] = 0.0395, wR2 [all F2]= 0.120. CCDC
number 196700.‡
4018 | Org. Biomol. Chem., 2008, 6, 4012–4025
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(4S*,5S*,6R*,7aR*)-5,6-Dihydroxy-4-propyl-5,6,7,7a-tetrahydro-
4H,11H-2,8-dioxadicyclopenta[a,d]cyclononen-9-one 35
CDCl3) 8.27 (2H, ddd, J = 9.0, 2.1, 2.1 Hz, 2 ¥ Ar-H), 8.18 (2H,
ddd, J = 9.0, 2.1, 2.1 Hz, 2 ¥ Ar-H), 7.39 (1H, dd, J = 1.6,
1.1 Hz, Fur-H), 7.37 (1H, d, J = 1.6 Hz, Fur-H), 6.24 (1H, s,
The alkene 34a (218 mg, 0.844 mmol) was dissolved in a mixture
of acetone (9 mL) and water (1 mL). N-Methylmorphine-N-oxide
(119 mg, 1.01 mmol) and osmium tetroxide (0.52 mL of a 4 mol%
solution in water, 0.084 mmol) were then added and the mixture
was stirred for 12 h at room temperature. The dihydroxylation
reaction was then quenched by the addition of a saturated aqueous
solution of sodium metabisulfite (15 mL) and the resulting mixture
stirred at room temperature for 1 h. The mixture was diluted
with water (15 mL) and ethyl acetate (30 mL) and the aqueous
phase was separated and washed with further ethyl acetate (2 ¥
20 mL). The organic extracts were dried (MgSO4) and the solvent
removed under reduced pressure. The residue was purified by
flash column chromatography on silica gel (petroleum ether–ethyl
acetate, 1 : 1) to give the diol 35 as a colourless oil which solidified
on standing (123 mg, 50%): mp 75–78 ◦C; Rf: = 0.16 (petroleum
ether–ethyl acetate, 2 : 1); nmax (CHCl3)/cm-1 3604, 2959, 2991,
1754, 1630, 1602, 979, 909, 872; dH (400 MHz, CDCl3) 7.32 (1H,
d, J = 1.5 Hz, Fur-H), 7.30 (1H, dd, J = 1.5, 1.4 Hz, Fur-H),
=
COCH=C), 5.03 (1H, br s, CH CCHO), 4.84 (1H, ddd, J =
4.2, 2.5, 2.4 Hz, CHO2CAr), 4.04 (1H, br s, CHOH), 3.90 (1H,
=
dd, J = 18.4, 1.1 Hz, CH2C CH), 3.79 (1H, br d, J = 18.4 Hz,
=
CH2C CH), 2.56 (1H, dd, J = 9.3, 6.2 Hz, CHCH2CH2), 2.12–
1.99 (3H, m, CHCH2CH, OH), 1.81–1.60 (2H, m, CHCH2CH2),
1.36–1.24 (2H, m, CH2CH3), 0.88 (3H, t, J = 7.4 Hz, CH3); dC
(100 MHz, CDCl3) 171.6 (C), 167.8 (C), 163.4 (C), 150.7 (C),
142.6 (CH), 140.7 (CH), 135.4 (C), 131.0 (CH), 123.6 (CH), 122.4
(C), 120.4 (CH), 118.7 (C), 81.6 (CH), 72.6 (CH), 72.6 (CH), 37.1
(CH2), 37.0 (CH), 30.5 (CH2), 23.9 (CH2), 20.5 (CH2), 13.8 (CH3);
m/z (EI) 464.1303 [M + Na]+, C23H23NaNO8 requires 464.1321.
X-Ray crystal structure data for alkene 36. C23H23NO8,
M = 441.42, monoclinic, a = 7.2351(7), b = 25.532(2), c =
◦
3
˚
˚
12.0626(12) A, b = 104.539(2) , U = 2156.9(3) A T = 150(2) K,
,
space group P21/c, Z = 4, Dc = 1.359 g cm-3, m(Mo-Ka) =
0.104 mm-1, 18983 reflections collected, 4848 unique (Rint = 0.067).
C Final R1 [3821 F > 4s(F)] = 0.0406, wR2 [all F2]= 0.121. CDCC
number 693627.‡
=
6.11 (1H, s, COCH=C), 5.01 (1H, br s, CH CCHO), 3.87 (1H,
=
br s, CHCHOH), 3.81 (1H, d, J = 18.4 Hz, CH2C CH), 3.68
(4S*,5S*,6R*,7aR*)-5,6-[(4-Methoxyphenyl)methylenedioxy]-
4-propyl-5,6,7,7a-tetrahydro-4H,11H-2,8-
dioxadicyclopenta[a,d]cyclononene-9-one 37
=
(1H, dd, J = 18.4, 1.4 Hz, CH2C CH), 3.23 (1H, br d, J =
5.3 Hz, CH2CHOH), 2.91 (2H, br s, 2 ¥ OH), 2.33 (1H, dd, J =
9.5, 6.0 Hz, CHCH2CH2), 1.91 (1H, ddd, J = 16.5, 5.3, 2.7 Hz,
CHCH2CH), 1.80–1.70 (2H, m, CHCH2CH, CHCH2CH2), 1.68–
1.61 (1H, m, CHCH2CH2), 1.29–1.23 (2H, m, CH2CH3), 0.85
(3H, t, J = 7.4 Hz, CH3); dC (100 MHz, CDCl3) 172.8 (C), 169.5
(C), 142.7 (CH), 139.8 (CH), 122.8 (C), 119.4 (CH), 118.6 (C),
82.8 (CH), 74.7 (CH), 68.1 (CH), 37.8 (CH2), 36.4 (CH), 33.4
(CH2), 24.2 (CH2), 20.6 (CH2), 13.9 (CH3); m/z (EI) 292.1316
[M]+, C16H20O5 requires 292.1311.
The diol 35 (127 mg, 0.434 mmol) was dissolved in
˚
dichloromethane (4.5 mL) and powdered 3 A molecular sieves
(20 mg) was added followed by camphorsulfonic acid (20 mg,
0.086 mmol). The mixture was cooled to 0 ◦C and p-anisaldehyde
dimethyl acetal (0.11 mL, 0.65 mmol) was added. The mixture was
stirred at 0 ◦C for 15 min and then warmed to room temperature
and allowed to stir at this temperature for a further 2 h. The
reaction mixture was diluted with dichloromethane (5 mL), filtered
and then concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (petroleum
ether–ethyl acetate, 4 : 1 then 1 : 1) to give an inseparable mixture
(1.3 : 1) of the acetals 37 (166 mg, 93%) as a colourless solid: mp
4-Nitrobenzoic acid (4S*,5S*,6R*,7aR*)-5-hydroxy-9-oxo-4-
propyl-5,6,7,7a,9,11-hexahydro-4H-2,8-
dioxadicyclopenta[a,d]cyclononen-6-yl ester 36
◦
Pyridine (47 mL, 0.58 mmol), DMAP (1.5 mg, 0.012 mmol)
and p-nitrobenzoyl chloride (21.5 mg, 0.116 mmol) were added
to a stirred solution of the diol 35 (34.0 mg, 0.116 mmol) in
dichloromethane (1.5 mL) at 0 ◦C under argon. The reaction
mixture was allowed to warm to room temperature and stirred for
1 h. Additional p-nitrobenzoyl chloride (64.5 mg, 0.348 mmol) was
added and stirring was continued for a further 1 h. The reaction
mixture was poured into water (5 mL) and the phases were sep-
arated. The aqueous phase was extracted with dichloromethane
(3 ¥ 5 mL) and the combined organic extracts were washed with
a saturated aqueous solution of copper sulfate (3 ¥ 5 mL) and
brine (5 mL) then dried (MgSO4). The solvent was removed under
reduced pressure to afford the crude product as a pale yellow
solid. Purification by flash column chromatography on silica gel
(0 → 10% ethyl acetate in dichloromethane) yielded the ester
36 as a colourless solid (34.1 mg, 66%). Recrystallisation from
dichloromethane and hexane gave colourless crystals suitable for
X-ray crystallography: mp 172–175 ◦C (Found: C, 62.51; H, 5.17;
N, 3.20; C23H23NO8 requires: C, 62.58; H, 5.25; N, 3.17%); Rf: =
0.51 (ethyl acetate–petroleum ether, 2 : 1); nmax (CHCl3)/cm-1 3622,
2959, 2932, 1759, 1724, 1631, 1608, 970, 909, 872; dH (400 MHz,
58–60 C (Found: C, 69.84; H, 6.28; C24H26O6 requires C, 70.23;
H, 6.38%); Rf: = 0.28 (petroleum ether–ethyl acetate, 1 : 1); nmax
(CHCl3)/cm-1 2958, 2933, 1751, 1614, 964; dH (400 MHz, CDCl3)
major isomer 7.38 (1H, s, Fur-H), 7.35–7.25 (3H, m, Fur-H, 2 ¥
Ar-H), 6.91–6.86 (2H, m, 2 ¥ Ar-H), 6.09 (1H, s, COCH=C),
=
5.68 (1H, s, OCHO), 4.93 (1H, d, J = 4.5 Hz, CH CCHO),
4.13–4.02 (2H, m, CHOCHArOCH), 3.92 (1H, d, J = 17.5 Hz,
=
=
CH2C CH), 3.81 (3H, s, OCH3), 3.68–3.64 (1H, m, CH2C CH),
2.77 (1H, ddd, J = 10.1, 5.2, 1.4 Hz, CHCH2CH2), 2.13–2.02 (1H,
m, CHCH2CH), 1.95–1.60 (3H, m, CHCH2CH, CHCH2CH2),
1.36–1.20 (2H, m, CH2CH3), 0.89 (3H, t, J = 7.3 Hz, CH3); minor
isomer 7.41 (1H, s, Fur-H), 7.35–7.25 (3H, m, Fur-H, 2 ¥ Ar-H),
6.91–6.86 (2H, m, 2 ¥ Ar-H), 6.09 (1H, s, COCH=C), 5.84 (1H, s,
=
OCHO), 4.99 (1H, d, J = 4.9 Hz, CH CCHO), 4.13–4.02 (2H,
=
m, CHOCHArOCH), 3.89 (1H, d, J = 16.8 Hz, CH2C CH),
=
3.81 (3H, s, OCH3), 3.68–3.64 (1H, m, CH2C CH), 2.65 (1H, dd,
J = 10.2, 5.1 Hz, CHCH2CH2), 2.13–2.02 (1H, m, CHCH2CH),
1.95–1.60 (3H, m, CHCH2CH, CHCH2CH2), 1.36–1.20 (2H, m,
CH2CH3), 0.86 (3H, t, J = 7.3 Hz, CH3); dC (100 MHz, CDCl3)
major isomer 172.1 (C), 169.5 (C), 160.5 (C), 142.6 (CH), 139.1
(CH), 131.6 (C), 128.3 (CH), 123.7 (C), 123.6 (C), 118.6 (CH),
This journal is
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113.8 (CH), 102.6 (CH), 82.0 (CH), 80.3 (CH), 73.1 (CH), 55.4
(CH3), 38.8 (CH2), 34.3 (CH2), 33.0 (CH), 24.9 (CH2), 20.7 (CH2),
13.8 (CH3); minor isomer 172.1 (C), 169.5 (C), 160.2 (C), 142.5
(CH), 139.1 (CH), 130.1 (C), 127.6 (CH), 123.7 (C), 123.6 (C),
118.9 (CH), 113.8 (CH), 102.0 (CH), 81.7 (CH), 78.2 (CH), 72.1
(CH), 55.4 (CH3), 38.8 (CH2), 33.3 (CH), 32.6 (CH2), 24.8 (CH2),
20.7 (CH2), 13.8 (CH3); m/z (EI) 411.1788 [M + H]+, C24H27O6
requires 411.1802.
CH2OCH2Ar), 3.54–3.52 (1H, m, CHCH2CH2), 3.39–3.36 (1H,
=
m, CH2C CH), 3.38 (3H, s, OCH3), 3.37 (3H, s, OCH3), 3.35
=
(3H, s, OCH3), 3.09 (1H, d, J = 14.7 Hz, CH2C CH), 2.18–1.98
(2H, m, CHCH2CH), 1.90–1.65 (2H, m, CHCH2CH2), 1.36–1.22
(2H, m, CH2CH3), 0.80 (3H, t, J = 7.4 Hz, CH3); dC (125 MHz,
C6D6, 343 K) major isomer 161.1 (C), 160.1 (C), 160.1 (C), 142.7
(CH), 141.8 (C), 138.8 (CH), 131.7 (C), 131.5 (C), 131.1 (C), 129.6
(CH), 129.5 (CH), 128.9 (CH), 127.5 (CH), 125.5 (C), 124.5 (C),
114.5 (CH), 114.4 (CH), 114.2 (CH), 102.8 (CH), 81.9 (CH), 76.2
(CH), 75.1 (CH), 72.6 (CH2), 70.9 (CH2), 66.6 (CH2), 55.0 (CH3),
55.0 (CH3), 55.0 (CH3), 39.7 (CH2), 36.1 (CH2), 34.0 (CH), 31.0
(CH2), 21.1 (CH2), 14.0 (CH3); minor isomer 160.8 (C), 160.1 (C),
160.1 (C), 142.6 (CH), 140.9 (C), 138.8 (CH), 133.5 (C), 131.0 (C),
128.4 (CH), 128.1 (CH), 127.9 (CH), 125.5 (C), 124.0 (C), 114.5
(CH), 114.4 (CH), 114.2 (CH), 102.3 (CH), 80.2 (CH), 76.7 (CH),
75.8 (CH), 72.7 (CH2), 70.9 (CH2), 66.9 (CH2), 55.0 (CH3), 39.6
(CH2), 35.3 (CH2), 34.3 (CH), 32.0 (CH2), 21.1 (CH2), 14.0 (CH3);
m/z (EI) 654.3188 [M]+, C40H46O8 requires 654.3193.
(3aR*,5R*,6Z,11S*,11aS*)-5-[(4-Methoxybenzyl)oxy]-6-{2-[(4-
methoxybenzyl)oxy]ethylidene}-2-(4-methoxyphenyl)-11-propyl-
4,5,6,7,11,11a-hexahydro-3aH-furo[3¢,4¢:4,5]cyclonona[1,2-
d][1,3]dioxole 39
Lithium aluminium hydride (42.3 mg, 1.11 mmol) was added to a
stirred solution of TMEDA (135 mL, 0.900 mmol) in diethyl ether
(5 mL) at room temperature under argon. The reaction mixture
◦
was stirred at room temperature for 10 min, cooled to 0 C and
then stirred for a further 20 min. To this suspension was added
the lactone 37 (183 mg, 0.446 mmol) and stirring was continued
for 1 h. The reaction was quenched by careful addition of water
(0.5 mL) and the mixture was warmed to room temperature. The
mixture was diluted with diethyl ether (5 mL) and the organic layer
was separated, dried (MgSO4) and concentrated to give the crude
diol 38 as a colourless solid.
(4S*,5S*,6R*,8R*,9Z)-6,8-Bis[(4-methoxybenzyl)oxy]-9-{2-[(4-
methoxybenzyl)oxy]ethylidene}-4-propyl-5,6,7,8,9,10-hexahydro-
4H-cyclonona[c]furan-5-ol 40 and (4S*,5S*,6R*,8R*,9Z)-5,8-
bis[(4-methoxybenzyl)oxy]-9-{2-[(4-methoxybenzyl)oxy]-
ethylidene}-4-propyl-5,6,7,8,9,10-hexahydro-4H-
cyclonona[c]furan-6-ol 41
The diol was dissolved in dry DMF (5 mL) at 0 ◦C under argon.
Tetra-n-butylammonium iodide (16.3 mg, 0.0441 mmol) was
added along with p-methoxybenzyl chloride (141 mL, 1.12 mmol)
and sodium hydride (89.2 mg of a 60% dispersion in mineral oil,
2.23 mmol). The reaction mixture was stirred at 0 ◦C for 2 h then
quenched by addition of water (5 mL). The mixture was diluted
with diethyl ether (10 mL) and the aqueous phase was extracted
with diethyl ether (3 ¥ 10 mL). The organic layers were combined,
washed with a saturated aqueous solution of copper sulfate (3 ¥
10 mL) and brine (10 mL), then dried (MgSO4) and concentrated
to afford the crude product as a pale yellow oil. Purification
by flash column chromatography on silica gel (0 → 30% ethyl
acetate in hexane with 1% triethylamine) yielded a diastereomeric
mixture (~2 : 1) of the acetals 39 (142 mg, 49% over 2 steps) as a
colourless oil: Rf: = 0.28 (petroleum ether–ethyl acetate, 4 : 1); nmax
(CHCl3)/cm-1 2957, 2934, 2862, 2838, 1682, 1614, 1587, 1508; dH
(500 MHz, C6D6, 343 K) major isomer 7.41 (2H, d, J = 8.7 Hz,
2 ¥ Ar-H), 7.37 (1H, d, J = 1.6 Hz, Fur-H), 7.25–7.17 (4H, m,
4 ¥ Ar-H), 7.03 (1H, dd, J = 1.3, 1.1 Hz, Fur-H), 6.84–6.75
A solution of diisobutylaluminium hydride (260 mL of a 1.0 M
solution in toluene, 0.260 mmol) was added to a stirred solution of
the acetals 39 (85.3 mg, 0.130 mmol) in dichloromethane at -78 ◦C
◦
under argon. The reaction mixture was stirred at -78 C for 2 h
then three further portions of a solution of diisobutylaluminium
hydride (260 mL of a 1.0 M solution in toluene, 0.260 mmol) were
added at 2 h intervals. The reaction mixture was then quenched
with methanol (1 mL), warmed to room temperature, then poured
into a saturated aqueous solution of potassium sodium tartrate
(10 mL). The aqueous phase was extracted with dichloromethane
(5 ¥ 10 mL) and the organic layers were combined, dried (MgSO4)
and concentrated to afford the crude product mixture as a pale
yellow oil. Purification by flash column chromatography on silica
gel (30 → 40% diethyl ether in hexane) yielded the alcohols 40
(25.0 mg, 29%) and 41 (28.0 mg, 33%) and the original mixture of
acetals 39 (20.1 mg, 24%) as colourless oils.
40. Rf: = 0.40 (60% diethyl ether in petroleum ether); nmax
(CHCl3)/cm-1 3569, 2957, 2935, 2863, 2838, 1613, 1586, 870;
dH (400 MHz, CDCl3) 7.26–7.13 (8H, m, 6 ¥ Ar-H, 2 ¥ Fur-
H), 6.89–6.79 (6H, m, 6 ¥ Ar-H), 5.80 (1H, dd, J = 6.1,
=
(6H, m, 6 ¥ Ar-H), 5.81–5.78 (1H, m, C CHCH2O), 5.78 (1H, s,
OCHO), 4.66 (1H, ddd, J = 11.0, 6.7, 2.5 Hz, CH2CHOCHArO),
4.38–4.12 (7H, m, 2 ¥ CH2Ar, CHOCH2Ar, OCHArOCHCH,
CH2OCH2Ar), 4.03 (1H, dd, J = 12.7, 5.4 Hz, CH2OCH2Ar),
3.72 (1H, ddd, J = 9.6, 6.0, 1.6 Hz, CHCH2CH2), 3.39–3.36 (1H,
=
4.4 Hz, C CHCH2O), 4.53 (1H, d, J = 11.9 Hz, OCH2Ar),
4.44 (1H, d, J = 11.4 Hz, OCH2Ar), 4.34 (1H, d, J = 11.9 Hz,
OCH2Ar), 4.32 (1H, d, J = 11.4 Hz, OCH2Ar), 4.29–4.25 (1H,
m, CH2OCH2Ar), 4.25 (2H, s, CH2OCH2Ar), 4.09 (1H, dd, J =
=
m, CH2C CH), 3.39 (3H, s, OCH3), 3.37 (3H, s, OCH3), 3.32
=
=
(3H, s, OCH3), 3.07 (1H, d, J = 14.5 Hz, CH2C CH), 2.18–1.98
13.3, 6.1 Hz, OCH2Ar), 3.95–3.92 (2H, m, CHOH, CH CCHO),
(2H, m, CHCH2CH), 1.90–1.65 (2H, m, CHCH2CH2), 1.36–1.22
(2H, m, CH2CH3), 0.83 (3H, t, J = 7.4 Hz, CH3); minor isomer
7.49 (2H, d, J = 8.4 Hz, 2 ¥ Ar-H), 7.43 (1H, d, J = 1.5 Hz, Fur-
H), 7.25–7.17 (4H, m, 4 ¥ Ar-H), 7.01 (1H, dd, J = 1.4, 1.3 Hz,
Fur-H), 6.84–6.75 (6H, m, 6 ¥ Ar-H), 5.99 (1H, s, OCHO), 5.84–
3.82 (3H, s, OCH3), 3.77 (6H, 2 ¥ OCH3), 3.54 (1H, d, J = 5.4 Hz,
=
CHCHOCH2Ar), 3.36 (1H, d, J = 15.5 Hz, CH2C CH), 3.24
=
(1H, d, J = 15.5 Hz, CH2C CH), 2.83 (1H, dd, J = 9.7, 5.9 Hz,
CHCH2CH2), 2.17 (1H, d, J = 4.0 Hz, OH), 1.91–1.57 (4H, m,
CHCH2CH, CHCH2CH2), 1.33–1.25 (2H, m, CH2CH3), 0.87 (3H,
t, J = 7.3 Hz, CH3); dC (100 MHz, CDCl3) 159.2 (C), 159.1 (C),
159.0 (C), 142.0 (CH), 139.1 (CH), 137.4 (C), 130.9 (C), 130.5 (C),
=
5.81 (1H, m, C CHCH2O), 4.83–4.79 (1H, m, CH2CHOCHArO),
4.38–4.12 (8H, m, 2 ¥ CH2Ar, CHOCH2Ar, OCHArOCHCH,
4020 | Org. Biomol. Chem., 2008, 6, 4012–4025
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130.5 (C), 129.4 (CH), 129.1 (CH), 128.8 (CH), 123.5 (C), 122.1
(C), 113.8 (CH), 113.8 (CH), 78.2 (CH), 77.7 (CH), 73.8 (CH),
72.2, 70.5 (CH), 69.3 (CH2), 67.4 (CH2), 55.4 (CH3), 55.3 (CH3),
37.8 (CH2), 35.8 (CH), 34.0 (CH2), 33.8 (CH2), 20.7 (CH2), 13.9
(CH3); m/z (ES) 657.3407 [M + H]+, C40H49O8 requires 657.3427.
66.2 (CH2), 55.3 (CH3), 42.7 (CH2), 36.6 (CH), 34.6 (CH2), 24.5
(CH2), 20.7 (CH2), 14.0 (CH3); m/z (ES) 677.3070 [M + Na]+,
C40H46NaO8 requires 677.3090.
(4S*,5S*,8R*,9Z)-5,8-Dihydroxy-9-(2-hydroxyethylidene)-4-
propyl-4,5,7,8,9,10-hexahydro-1H-cyclonona[c]furan-1,3,6-trione
(5-epi-hydroxycornexistin) 44
41. Rf: = 0.32 (60% diethyl ether in petroleum ether); nmax
(CHCl3)/cm-1 3695, 3556, 2957, 2934, 2871, 2839, 1612, 1585,
872. dH (400 MHz, CDCl3) 7.28–7.16 (8H, m, 6 ¥ Ar-H, 2 ¥
Fur-H), 6.90–6.84 (6H, m, 6 ¥ Ar-H), 5.85 (1H, dd, J = 6.4,
Rose Bengal (0.4 mg, 0.3 mmol) and diisopropylethylamine (11 mL,
0.063 mmol) were added to a stirred solution of the furan
42 in dichloromethane (1 mL) and the solution was cooled to
-78 ◦C. Oxygen was bubbled through the pink solution for 5 min
=
6.1 Hz, C CHCH2O), 4.72 (1H, d, J = 11.4 Hz, OCH2Ar), 4.60
(1H, d, J = 11.4 Hz, OCH2Ar), 4.47–4.38 (3H, m, OCH2Ar,
CH2OCH2Ar) 4.31 (1H, br s, CHOH), 4.30–4.15 (4H, m,
◦
=
OCH2Ar, OCH2Ar, CH CCHO), 3.82 (3H, s, OCH3), 3.82 (3H, s,
at -78 C. The solution was stirred for a further 5 min and then
OCH3), 3.81 (3H, s, OCH3), 3.63 (1H, s, CHCHOCH2Ar), 3.33
sealed. The solution was then irradiated with a 500 W tungsten
incandescent lamp for 30 min. Further diisopropylethylamine
(11 mL, 0.063 mmol) was added to the reaction mixture and it
was allowed to warm slowly to room temperature over 2 h. The
reaction mixture was poured into a saturated aqueous solution
of ammonium chloride (5 mL) and the aqueous phase was
extracted with dichloromethane (3 ¥ 5 mL). The organic layers
were combined, dried (MgSO4) and concentrated to afford the
crude product mixture as a pale yellow oil. The compound was
sufficiently pure to use without further purification.
=
(1H, d, J = 15.6 Hz, CH2C CH), 3.25 (1H, d, J = 15.6 Hz,
=
CH2C CH), 2.82 (1H, dd, J = 7.2, 7.2 Hz, CHCH2CH2), 2.15
(1H, ddd, J = 15.8, 5.3, 2.1 Hz, CHCH2CH), 2.06 (1H, d, J =
4.2 Hz, CHOH), 1.80 (1H, ddd, J = 15.8, 6.8, 3.2 Hz, CHCH2CH),
1.70–1.57 (2H, m, CHCH2CH2), 1.27–1.19 (2H, m, CH2CH3), 0.84
(3H, t, J = 7.3 Hz, CH3); dC (100 MHz, CDCl3) 159.3 (C), 159.1
(C), 141.3 (CH), 141.1 (C), 139.7 (CH), 131.2 (C), 130.7 (C), 130.4
(C), 129.5 (CH), 129.2 (CH), 129.1 (CH), 128.9 (CH), 124.4 (C),
123.3 (C), 113.9 (CH), 113.8 (CH), 113.8 (CH), 82.3 (CH), 73.6
(CH), 73.0 (CH2), 72.3 (CH2), 71.3 (CH), 69.8 (CH2), 66.6 (CH2),
55.4 (CH3), 37.3 (CH2), 37.2 (CH), 36.9 (CH2), 31.4 (CH2), 20.7
(CH2), 14.1 (CH3); m/z (ES) 679.3227 [M + Na]+, C40H48NaO8
requires 679.3247.
˚
4 A Molecular sieves (10 mg) and TPAP (16.0 mg, 0.0455 mmol)
were added to a stirred solution of the crude oxidation product
(~0.03 mmol) in dichloromethane (1 mL) at room temperature
under argon. Thereaction mixture was stirred at room temperature
for 2 h then filtered through a short plug of silica gel eluting with
ethyl acetate to afford a pale yellow oil. To a solution of this
oil in dichloromethane (1 mL), were added water (200 mL) and
DDQ (20.6 mg, 0.0909 mmol). The deprotection reaction was
monitored by analysis of reaction aliquots by mass spectrometry
and the mixture was poured into a saturated aqueous solution of
sodium hydrogen carbonate (5 mL) when analysis indicated that
all three of the PMB protecting groups had been removed (~4 h).
The phases were separated and the aqueous phase was washed with
dichloromethane (3 ¥ 5 mL), acidified to pH 2 with a 1 M HCl
solution and extracted with ethyl acetate (3 ¥ 5 mL). The organic
layers were combined, dried (MgSO4) and concentrated to afford
the crude product as a pale yellow oil. Purification of the product
by reverse phase preparative HPLC (0 → 100% acetonitrile in
water) yielded the pure triol 44 as a colourless solid (1.0 mg, 10%
over 3 steps): mp 62–65 ◦C; nmax (film)/cm-1 3385, 2959, 2926, 2873,
2855, 1832, 1766, 1714, 1643, 1574, 924, 780, 752; dH (500 MHz,
(4S*,5S*,8R*,9Z)-5,8-Bis[(4-methoxybenzyl)oxy]-9-{2-[(4-
methoxybenzyl)oxy]ethylidene}-4-propyl-4,5,7,8,9,10-hexahydro-
6H-cyclonona[c]furan-6-one 42
˚
4 A Molecular sieves (20 mg), TPAP (3.0 mg, 0.0085 mmol) and
NMO (15.0 mg, 0.128 mmol) were added to a stirred solution of
the alcohol 41 (56.0 mg, 85.4 mmol) in dichloromethane (2 mL) at
room temperature under argon. The reaction mixture was stirred
at room temperature for 16 h then concentrated to afford the
crude ketone product as a black residue. Purification by flash
column chromatography on silica gel (30 → 40% diethyl ether
in hexane) yielded the pure ketone 42 as a colourless oil (44.5 mg,
80%): Rf: = 0.32 (60% diethyl ether in petroleum ether); nmax
(CHCl3)/cm-1 2957, 2935, 2863, 2838, 1720, 1613, 1586, 908, 870,
834; dH (400 MHz, CDCl3) 7.30–7.19 (8H, m, 6 ¥ Ar-H, 2 ¥ Fur-
H), 6.91–6.85 (6H, m, 6 ¥ Ar-H), 5.81 (1H, dd, J = 8.0, 4.4 Hz,
=
=
C CHCH2O), 4.71 (1H, d, J = 11.7 Hz, OCH2Ar), 4.59 (1H, dd,
CD3CN) 5.86 (1H, dd, J = 6.5, 5.9 Hz, C CH), 4.99 (1H, dd,
J = 9.5, 6.7 Hz, CH2CHOCH2Ar), 4.49–4.43 (3H, m, OCH2Ar,
OCH2Ar), 4.26 (1H, dd, J = 12.5, 8.0 Hz, CH2OCH2Ar), 4.20 (1H,
d, J = 11.7 Hz, OCH2Ar), 4.19 (1H, d, J = 11.3 Hz, OCH2Ar),
4.01 (1H, dd, J = 12.5, 4.4 Hz, CH2OCH2Ar), 3.95 (1H, d, J =
2.7 Hz, OCCHOCH2Ar), 3.82 (6H, s, 2 ¥ OCH3), 3.81 (3H, s,
OCH3), 3.37–3.29 (1H, m, CHCH2CH2), 3.23 (1H, br s, OCCH2),
J = 10.3, 6.2 Hz, CH2CHOH), 4.43–4.41 (1H, m, CHCHOH),
4.16–4.14 (2H, m, CH2OH), 3.71 (1H, ddd, J = 8.9, 6.2, 2.5 Hz,
CHCH2CH2), 3.50 (1H, d, J = 4.9 Hz, OH), 3.38 (1H, dd, J =
16.5, 10.3 Hz, CH2CO), 3.34 (1H, br s, OH), 3.22 (1H, d, J =
14.3 Hz, CH2OH), 3.12 (1H, dd, J = 14.3, 1.1 Hz, CH2OH),
2.85 (1H, br s, OH), 2.71 (1H, dd, J = 16.5, 6.2 Hz, CH2CO),
2.30–2.21 (1H, m, CHCH2CH2), 1.92–1.86 (1H, m, CHCH2CH2),
1.41–1.27 (2H, m, CH2CH3), 0.95 (3H, t, J = 7.4 Hz, CH3); dC
(125 MHz, CD3CN) 210.2 (C), 166.8 (C), 165.1 (C), 147.4 (C),
141.2 (C), 137.6 (C), 136.4 (CH), 79.4 (CH), 66.5 (CH), 58.4
(CH2), 42.9 (CH2), 41.0 (CH), 31.2 (CH2), 25.2 (CH2), 21.6 (CH2),
14.3 (CH3); m/z (ES) 347.1095 [M + Na]+, C16H20NaO7 requires
347.1107.
=
3.17–3.01 (2H, m, CH CCH2), 2.68–2.58 (1H, m, OCCH2), 1.74–
1.62 (2H, m, CHCH2CH2), 1.28–1.08 (2H, m, CH2CH3), 0.86 (3H,
t, J = 7.3 Hz, CH3); dC (125 MHz, CDCl3) 207.7 (C), 159.4 (C),
159.3 (C), 159.3 (C), 141.9 (CH), 139.5 (CH), 137.5 (C), 132.6
(CH), 130.5 (C), 130.3 (C), 129.9 (C), 129.7 (CH), 129.5 (CH),
129.5 (CH), 129.4 (CH), 124.0 (C), 122.1 (C), 113.9 (CH), 113.8
(CH), 84.5 (CH), 72.6 (CH2), 72.2 (CH), 71.8 (CH2), 69.5 (CH2),
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Acetic acid (4S*,5S*,6R*,7aR*)-5-acetoxy-9-oxo-4-propyl-
5,6,7,7a,9,11-hexahydro-4H-2,8-dioxadicyclopenta[a,d]cyclo-
nonen-6-yl ester 45 and acetic acid (4S*,5S*,6R*,7aR*)-5-
hydroxy-9-oxo-4-propyl-5,6,7,7a,9,11-hexahydro-4H-2,8-
dioxadicyclopenta[a,d]cyclononen-6-yl ester 46
in dichloromethane (1 mL) at room temperature under argon.
The resultant suspension was stirred at room temperature for
5 h before addition of more Dess–Martin periodinane (20 mg,
0.048 mmol). Stirring was continued for 16 h and a saturated
aqueous solution of sodium thiosulfate (1 mL) was then added.
After the mixture had been stirred for 1 h, the aqueous phase was
extracted with dichloromethane (2 ¥ 2 mL). The organic layers
were combined, dried (MgSO4) and concentrated to afford the
crude product as a pale yellow solid. Purification by flash column
chromatography on silica gel (10 → 35% ethyl acetate in hexane)
yielded the pure ketone 48 as a colourless oil (7.6 mg, 95%): Rf: =
0.27 (petroleum ether–ethyl acetate, 2 : 1); nmax (CHCl3)/cm-1
2960, 2874, 1757, 1634, 953, 909, 872; dH (400 MHz, CDCl3)
7.40 (1H, d, J = 1.6 Hz, Fur-H), 7.32 (1H, m, Fur-H), 5.98
A solution of triethylamine (100 mL of a 0.77 M solution in
dichloromethane, 0.077 mmol), DMAP (0.9 mg, 8 mmol) and a
solution of freshly distilled acetic anhydride (100 mL of a 0.64 M
solution in dichloromethane, 0.064 mmol) were added to a stirred
solution of the diol 35 (18.7 mg, 0.0640 mmol) in dichloromethane
(1 mL) at 0 ◦C under argon. The reaction was allowed to warm to
room temperature and the mixture was stirred for 3 h. The reaction
mixture was poured into water (5 mL) and the aqueous phase was
extracted with dichloromethane (2 ¥ 5 mL). The organic layers
were combined, dried (MgSO4) and concentrated to afford the
crude product mixture as a pale yellow oil. Purification by flash
column chromatography on silica gel (20 → 45% ethyl acetate in
hexane) yielded the diacetate 45 (4.2 mg, 20%) as a colourless solid
and the acetate 46 as a colourless oil (14.0 mg, 64%).
=
(1H, s, COCH=C), 5.10 (1H, d, J = 7.5 Hz, CH CCHO), 5.02
(1H, dd, J = 4.2, 3.6 Hz, CHOAc), 3.80 (1H, d, J = 15.7 Hz,
=
CH2C CH), 3.74 (1H, dd, J = 7.3, 7.3 Hz, CHCH2CH2), 3.36
=
(1H, d, J = 15.7 Hz, CH2C CH), 2.27 (1H, ddd, J = 16.1, 4.2,
1.7 Hz, CHCH2CH), 2.15 (3H, s), 2.19–1.98 (2H, m, CHCH2CH,
CHCH2CH2), 1.60–1.51 (1H, m, CHCH2CH2), 1.33–1.23 (2H, m,
CH2CH3), 0.92 (3H, t, J = 7.3 Hz, CH3); dC (100 MHz, CDCl3)
205.0 (C), 171.8 (C), 170.6 (C), 169.4 (C), 142.3 (CH), 142.1
(CH), 121.0 (C), 118.8 (C), 117.7 (CH), 79.2 (CH), 74.4 (CH),
45.9 (CH), 34.1 (CH2), 33.1 (CH2), 23.0 (CH2), 20.5 (CH3), 20.3
(CH2), 13.9 (CH3); m/z (ES) 333.1328 [M + H]+, C18H21O6 requires
333.1338.
45. Mp 157–159 ◦C; Rf: = 0.52 (ethyl acetate–petroleum ether,
2 : 1); nmax (CHCl3)/cm-1 2959, 2930, 2873, 1747, 1631, 1602,
950, 917, 897, 870; dH (400 MHz, CDCl3) 7.35 (1H, s, Fur-
H), 7.23 (1H, d, J = 1.3 Hz, Fur-H), 6.20 (1H, s, COCH=C),
=
5.34 (1H, s, CHCHOAc), 4.96 (1H, s, CH CCHO), 4.60–4.56
=
(1H, m, CH2CHOAc), 3.85 (1H, d, J = 18.7 Hz, CH2C CH),
=
3.76 (1H, d, J = 18.7 Hz, CH2C CH), 2.55 (1H, dd, J =
(4S*,5S*,6R*,7aR*)-(5,6-Methylenedioxy)-4-propyl-5,6,7,7a-
tetrahydro-4H,11H,-2,8-dioxadicyclopenta[a,d]cyclononene-
9-one 49
9.0, 6.4 Hz, CHCH2CH2), 2.13 (3H, s, COCH3), 1.99–1.94
(2H, m, CHCH2CH), 1.96 (3H, s, COCH3), 1.59–1.46 (2H, m,
CHCH2CH2), 1.33–1.24 (2H, m, CH2CH3), 0.84 (3H, t, J =
7.3 Hz, CH3); dC (100 MHz, CDCl3) 171.5 (C), 170.4 (C), 169.8
(C), 167.7 (C), 142.4 (CH), 140.2 (CH), 122.8 (C), 120.3 (CH),
118.8 (C), 81.7 (CH), 72.8 (CH), 68.8 (CH), 36.8 (CH2), 35.6 (CH),
30.9 (CH2), 23.8 (CH2), 21.0 (CH3), 20.9 (CH3), 20.3 (CH2), 13.8
(CH3); m/z (ES) 377.1588 [M + H]+, C20H25O7 requires 377.1600.
p-Toluenesulfonic acid monohydrate (20.7 mg, 0.109 mmol)
and 2,2-dimethoxypropane (402 mL, 3.30 mmol) were added
to a stirred solution of the diol 35 (319 mg, 1.09 mmol) in
dichloromethane (11 mL) at room temperature under argon. The
reaction mixture was stirred at room temperature for 1.5 h, then
poured into water (10 mL). The aqueous layer was extracted
with dichloromethane (2 ¥ 10 mL) and the organic extracts were
combined, washed with brine (10 mL), dried (MgSO4), filtered and
concentrated to afford the crude product as a pale yellow solid.
Purification by flash column chromatography on silica gel (10 →
40% ethyl acetate in petroleum ether) yielded the pur◦e acetonide
49 as a colourless solid (356 mg, 98%): mp 158–160 C (Found:
C, 68.42; H, 7.34; C19H24O5 requires: C, 68.66; H, 7.28%); Rf: =
0.34 (petroleum ether-ethyl acetate, 2 : 1); nmax (CHCl3)/cm-1 2958,
2934, 2872, 1750, 1632, 981, 961, 890, 872; dH (400 MHz, CDCl3)
7.35 (1H, d, J = 1.5 Hz, Fur-H), 7.30 (1H, dd, J = 1.5, 1.5 Hz, Fur-
46. Rf: = 0.36 (ethyl acetate–petroleum ether, 2 : 1); nmax
(CHCl3)/cm-1 3615, 2958, 2873, 1758, 1631, 975, 945, 908, 870;
dH (400 MHz, CDCl3) 7.35 (1H, dd, J = 1.6, 1.1 Hz, Fur-H),
7.33 (1H, d, J = 1.6 Hz, Fur-H), 6.19 (1H, s, COCH=C), 4.98–
=
4.94 (1H, m, CH CCHO), 4.58 (1H, ddd, J = 3.6, 3.6, 1.9 Hz,
CHOAc), 3.89 (1H, br s, CHOH), 3.84 (1H, ddd, J = 18.5, 1.6,
=
=
1.1 Hz, CH2C CH), 3.74 (1H, br d, J = 18.5 Hz, CH2C CH),
2.48 (1H, dd, J = 9.5, 6.0 Hz, CHCH2CH2), 2.06 (3H, s, COCH3),
1.89 (1H, d, J = 3.6 Hz, CHCH2CH), 1.88 (1H, d, J = 3.6 Hz,
CHCH2CH), 1.78–1.58 (3H, m, CHCH2CH2, OH), 1.34–1.20
(2H, m, CH2CH3), 0.87 (3H, t, J = 7.3 Hz, CH3); dC (100 MHz,
CDCl3) 171.7 (C), 169.5 (C), 167.9 (C), 142.6 (CH), 140.5 (CH),
122.5 (C), 120.2 (CH), 118.8 (C), 81.8 (CH), 72.9 (CH), 70.8
(CH), 37.1 (CH2), 36.9 (CH), 30.5 (CH2), 23.8 (CH2), 21.3 (CH3),
20.5 (CH2), 13.9 (CH3); m/z (CI, NH3) 334.1414 [M]+, C18H22O6
requires 334.1416.
=
H), 6.06 (1H, s, COCH=C), 4.89 (1H, d, J = 4.5 Hz, CH CCHO),
=
4.08 (1H, d, J = 4.8 Hz, CHCHO), 3.91–3.84 (2H, m, CH2C CH,
=
CH2CHO), 3.62 (1H, d, J = 17.6 Hz, CH2C CH), 2.63 (1H, ddd,
J = 10.1, 5.3, 1.5 Hz, CHCH2CH2), 1.95 (1H, dd, J = 15.5, 5.2 Hz,
CHCH2CH), 1.82–1.59 (3H, m, CHCH2CH, CHCH2CH2), 1.32
(3H, s, CCH3), 1.32–1.21 (2H, m, CH2CH3), 1.28 (3H, s, CCH3),
0.88 (3H, t, J = 7.3 Hz, CH2CH3); dC (100 MHz, CDCl3) 172.1
(C), 169.3 (C), 142.5 (CH), 138.9 (CH), 123.7 (C), 118.9 (CH),
118.6 (C), 107.4 (C), 82.0 (CH), 78.0 (CH), 72.4 (CH), 38.8 (CH2),
34.1 (CH2), 33.0 (CH), 28.2 (CH3), 26.1 (CH3), 24.8 (CH2), 20.7
(CH2), 13.9 (CH3); m/z (EI) 332.1639 [M]+, C19H24O5 requires
332.1624.
Acetic acid (4S*,6R*,7aR*)-5,9-dioxo-4-propyl-5,6,7,7a,9,11-
hexahydro-4H-2,8-dioxadicyclopenta[a,d]cyclononen-6-yl ester 48
Dess–Martin periodinane (10 mg, 0.024 mmol) was added in one
portion to a stirred solution of the alcohol 46 (8.0 mg, 0.024 mmol)
4022 | Org. Biomol. Chem., 2008, 6, 4012–4025
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(3aR*,5R*,6Z,11S*,11aS*)-6-(2-Hydroxyethylidene)-2,2-
dimethyl-11-propyl-4,5,6,7,11,11a-hexahydro-3aH-
furo[3¢,4¢:4,5]cyclonona[1,2-d][1,3]dioxol-5-ol 50
(1H, s, Fur-H), 6.88 (2H, d, J = 8.6 Hz, 2 ¥ Ar-H), 6.86 (2H, d, J =
=
8.7 Hz, 2 ¥ Ar-H), 5.77 (1H, dd, J = 6.3, 6.2 Hz, C CHCH2), 4.44–
4.40 (3H, m, CH2Ar, CH2Ar), 4.34 (1H, ddd, J = 9.8, 5.7, 3.0 Hz,
CH2CHO), 4.25–4.15 (4H, m, CHCHO, CH2OCH2Ar, CH2Ar),
4.05 (1H, br s, CHOCH2Ar), 3.82 (3H, s, OCH3), 3.81 (3H, s,
OCH3), 3.37 (1H, dd, J = 9.4, 5.4 Hz, CHCH2CH2), 3.29 (1H d,
A solution of diisobutylaluminium hydride (1.2 mL of a 1.5 M
solution in toluene, 1.8 mmol) was added dropwise to a stirred
solution of the lactone 49 (296 mg, 0.891 mmol) in THF (10 mL)
at -78 ◦C under argon. The reaction mixture was stirred at -78 ◦C
for 2 h before dropwise addition of a solution of lithium aluminium
hydride (1.8 mL of 1.0 M solution in THF, 1.8 mmol). The reaction
mixture was allowed to warm slowly to room temperature then
stirred for 16 h. The reaction was quenched by careful addition of
methanol (2 mL), the mixture was then poured into a saturated
aqueous solution of potassium sodium tartrate (10 mL) and the
aqueous phase was extracted with ethyl acetate (3 ¥ 10 mL).
The organic layers were combined, washed with brine (10 mL),
dried (MgSO4) and concentrated to afford the crude product as
a pale yellow oil. Purification by flash column chromatography
on silica gel (30 → 70% ethyl acetate in petroleum ether) yielded
the pure diol 50 as a colourless foam (221 mg, 74%): mp 122–
124 ◦C; Rf: = 0.36 (ethyl acetate–petroleum ether, 2 : 1); nmax
(CHCl3)/cm-1 3611, 3488, 2958, 2933, 2872, 1715, 908, 872; dH
(500 MHz, CDCl3) 7.22 (1H, s, Fur-H), 7.15 (1H, s, Fur-H), 5.78
=
=
J = 14.6 Hz, CH2C CH), 3.21 (1H, d, J = 14.6 Hz, CH2C CH),
1.76–1.55 (4H, m, CHCH2CH, CHCH2CH2), 1.34 (3H, s, CCH3),
1.32–1.18 (2H, m, CH2CH3), 1.28 (3H, s, CCH3), 0.83 (3H, t,
J = 7.3 Hz, CH2CH3); dC (100 MHz, CDCl3) 159.3 (C), 159.1
(C), 141.8 (CH), 138.1 (CH), 130.5 (C), 130.4 (C), 129.5 (CH),
129.0 (CH), 127.1 (CH), 124.6 (C), 123.4 (C), 113.9 (CH), 113.8
(CH), 106.5 (C), 79.2 (CH), 77.3 (CH), 75.5 (CH), 72.4 (CH2),
70.1 (CH2), 66.5 (CH2), 55.3 (CH3), 39.0 (CH2), 36.2 (CH2), 33.2
(CH), 31.7 (CH2), 27.9 (CH3), 25.7 (CH3), 20.7 (CH2), 13.9 (CH3);
m/z (EI) 576.3091 [M]+, C35H44O7 requires 576.3087.
(4S*,5S*,6R*,8R*,9Z)-8-[(4-Methoxybenzyl)oxy]-9-{2-[(4-
methoxybenzyl)oxy]ethylidene}-4-propyl-5,6,7,8,9,10-hexahydro-
4H-cyclonona[c]furan-5,6-diol 52
p-Toluenesulfonic acid monohydrate (4.2 mg, 22 mmol) was added
to a stirred solution of the acetonide 51 (128 mg, 0.222 mmol)
in methanol (15 mL) at room temperature under argon. The
reaction mixture was stirred at room temperature for 16 h, then
poured into a saturated aqueous solution of sodium hydrogen
carbonate (10 mL). The mixture was diluted with water (10 mL)
and the aqueous phase was extracted with dichloromethane (5 ¥
50 mL). The organic layers were combined, dried (MgSO4), filtered
and concentrated to afford the crude diol as a pale yellow oil.
Purification by flash column chromatography on silica gel (20 →
60% ethyl acetate in petroleum ether) yielded the pure diol 52
(64.8 mg, 54%) and the original acetonide 51 (24.0 mg, 19%) as
colourless oils: Rf: = 0.24 (petroleum ether–ethyl acetate, 1 : 1);
nmax (CHCl3)/cm-1 3563, 2957, 2933, 2862, 2838, 1613, 1586, 870;
dH (400 MHz, CDCl3) 7.27 (1H, s, Fur-H), 7.24 (1H, s, Fur-
H), 7.23–7.18 (4H, m, 4 ¥ Ar-H), 6.88 (2H, d, J = 8.0 Hz, 4 ¥
Ar-H), 6.86 (2H, d, J = 8.5 Hz, 4 ¥ Ar-H), 5.86 (1H, dd, J =
=
(1H, dd, J = 6.8, 6.0 Hz, C CHCH2), 4.48 (1H, dd, J = 11.9,
6.8 Hz, CH2OH), 4.37 (1H, dd, J = 10.3, 5.4 Hz, CHOH), 4.28
(1H, s, CH2CHO), 4.19–4.12 (2H, m, CH2OH, CHCHO), 3.48
=
(2H, br s, 2 ¥ OH), 3.34 (1H d, J = 15.4 Hz, CH2C CH), 3.22
=
(1H, d, J = 15.4 Hz, CH2C CH), 3.10 (1H, br s, CHCH2CH2),
1.84–1.52 (4H, m, CHCH2CH, CHCH2CH2), 1.33 (3H, s, CCH3),
1.31–1.21 (2H, m, CH2CH3), 1.25 (3H, s, CCH3), 0.86 (3H, t, J =
7.3 Hz, CH2CH3); dC (125 MHz, CDCl3) 142.0 (C), 142.0 (CH),
138.4 (CH), 127.7 (CH), 124.1 (C), 122.2 (C), 107.0 (C), 79.2 (CH),
75.1 (CH), 71.3 (CH), 58.9 (CH2), 39.6 (CH2), 38.6 (CH2), 33.1
(CH), 33.1 (CH2), 27.9 (CH3), 26.0 (CH3), 20.8 (CH2), 13.9 (CH3);
m/z (ES) 359.1812 [M + Na]+, C19H28NaO5 requires 359.1834.
(3aR*,5R*,6Z,11S*,11a*S)-5-[(4-Methoxybenzyl)oxy]-6-{2-[(4-
methoxybenzyl)oxy]ethylidene}-2,2-dimethyl-11-propyl-
4,5,6,7,11,11a-hexahydro-3aH-furo[3¢,4¢:4,5]cyclonona[1,2d][1,3]-
dioxole 51
=
6.0, 5.9 Hz, C CHCH2), 4.46–4.41 (2H, m, CH2Ar), 4.44 (1H,
d, J = 11.5 Hz, CH2Ar), 4.32–4.29 (2H, m, CH2OCH2Ar), 4.28
(1H, d, J = 11.5 Hz, CH2Ar), 4.03 (1H, dd, J = 4.4, 4.3 Hz,
CHOCH2Ar), 3.98 (1H, dd, J = 6.0, 1.9 Hz, CH2CHOH), 3.82–
3.81 (1H, m, CHCHOH), 3.82 (3H, s, OCH3), 3.81 (3H, s, OCH3),
Tetra-n-butylammonium iodide (11.0 mg, 0.298 mmol), p-
methoxybenzyl chloride (95 mL, 0.70 mmol) and sodium hydride
(60% dispersion in mineral oil, 60 mg, 1.4 mmol) were added
to a stirred solution of the diol 50 (101 mg, 0.300 mmol) in
DMF (4 mL) at 0 ◦C under argon. The reaction mixture was
stirred at 0 ◦C for 30 min then warmed to room temperature and
stirred for a further 3 h. The reaction was quenched by dropwise
addition of water (10 mL) and the mixture was then diluted with
diethyl ether (10 mL). The aqueous phase was separated and
extracted with diethyl ether (3 ¥ 10 mL). The organic layers were
combined, washed with a saturated aqueous solution of copper
sulfate (3 ¥ 10 mL), dried (MgSO4), filtered and concentrated
to afford the crude product as a yellow oil. Purification by flash
column chromatography on silica gel (0 → 30% ethyl acetate in
hexane) yielded the pure acetonide 51 as a colourless oil (128 mg,
74%) (Found: C, 72.87; H, 7.83; C35H44O7 requires C, 72.89; H,
7.69%); Rf: = 0.34 (petroleum ether–ethyl acetate, 4 : 1); nmax
(CHCl3)/cm-1 2934, 2862, 2838, 1731, 1613, 1586, 907, 872; dH
(400 MHz, CDCl3) 7.26–7.20 (5H, m, Fur-H, 4 ¥ Ar-H), 7.15
=
3.30 (1H, d, J = 15.5 Hz, CH2C CH), 3.23 (1H, d, J = 15.5 Hz,
=
CH2C CH), 2.95 (1H, dd, J = 7.8, 7.7 Hz, CHCH2CH2), 1.84–
1.61 (6H, m, CHCH2CH, CHCH2CH2, 2 ¥ OH), 1.35–1.26 (2H,
m, CH2CH3), 0.88 (3H, t, J = 7.3 Hz, CH3); dC (100 MHz, CDCl3)
159.3 (C), 159.2 (C), 141.2 (CH), 140.2 (CH), 138.6 (C), 130.4 (C),
129.5 (CH), 129.4 (CH), 129.1 (CH), 123.5 (C), 122.9 (C), 113.9
(CH), 113.9 (CH), 76.2 (CH), 75.4 (CH), 72.4 (CH2), 71.3 (CH),
70.1 (CH2), 66.9 (CH2), 55.4 (CH3), 37.0 (CH2), 36.3 (CH), 36.3
(CH2), 32.0 (CH2), 20.6 (CH2), 13.9 (CH3); m/z (EI) 536.2792
[M]+, C32H40O7 requires 536.2774.
(4S*,5S*,6R*,8R*,9Z)-5-Hydroxy-8-[(4-methoxybenzyl)oxy]-9-
{2-[(4-methoxybenzyl)oxy]ethylidene}-4-propyl-5,6,7,8,9,10-
hexahydro-4H-cyclonona[c]furan-6-yl acetate 53
Triethylamine (22 mL, 0.16 mmol), DMAP (0.5 mg, 5 mmol) and
freshly distilled acetic anhydride (5.2 mL, 0.055 mmol) were added
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to a stirred solution of the diol 52 (27.9 mg, 0.519 mmol) in
dichloromethane (1 mL) at 0 ◦C under argon. The reaction mixture
was stirred at 0 ◦C for 30 min, then warmed to room temperature
and stirred for a further 2 h. The reaction mixture was poured
into a saturated aqueous solution of ammonium chloride (5 mL)
and the aqueous phase was extracted with dichloromethane (3 ¥
5 mL). The organic layers were combined, dried (MgSO4), filtered
and concentrated to afford the crude product as a pale yellow oil.
Purification by flash column chromatography on silica gel (0 →
30% ethyl acetate in hexane) yielded the acetate 53 as a colourless
oil (19.7 mg, 65%): Rf: = 0.38 (petroleum ether–ethyl acetate, 1 : 1);
Acknowledgements
We thank the University of Nottingham, AstraZeneca and EPSRC
(Grant no. GR/N63666/01) for funding this work and EPSRC
for the funding of X-ray diffractometers. Financial support by
Novartis through the Novartis European Young Investigator
Award in Chemistry to JSC is also gratefully acknowledged.
We thank Dr John Clough (Syngenta, Jealott’s Hill Research
Station, Brackell, Berkshire, UK) for helpful discussions regarding
this work and Dr Stephen Fields (Discovery Research, Dow
Agrosciences, Inc., Indianapolis, USA) for providing the original
NMR spectra for hydroxyconexistin (2).
n
max (CHCl3)/cm-1 3541, 2958, 2934, 2863, 2838, 1730, 1613, 1586,
908, 870; dH (400 MHz, CDCl3) 7.26 (2H, d, J = 8.3 Hz), 7.21
(2H, m), 7.26 (2H, d, J = 8.6 Hz), 6.87 (2H, d, J = 8.3 Hz), 6.85
(2H, d, J = 8.6 Hz), 5.90 (1H, dd, J = 5.9, 5.9 Hz), 5.29–5.25 (1H,
m), 4.49–4.23 (6H, m), 3.98 (1H, dd, J = 4.3, 4.2 Hz), 3.88 (1H, d,
J = 6.7 Hz), 3.81 (6H, s), 3.34–3.21 (2H, m), 2.99 (1H, dd, J = 8.0,
7.6 Hz), 2.02 (3H, s), 1.79–1.60 (4H, m), 1.36–1.26 (2H, m), 0.87
(3H, t, J = 7.3 Hz); dC (100 MHz, CDCl3) 170.2 (C), 159.2 (C),
159.1 (C), 141.3 (CH), 140.4 (CH), 137.9 (C), 130.6 (C), 130.4 (C),
130.0 (CH), 129.6 (CH), 128.9 (CH), 123.1 (C), 122.9 (C), 113.8
(CH), 113.8 (CH), 75.4 (CH), 74.4 (CH), 73.6 (CH), 72.4 (CH2),
69.9 (CH2), 67.0 (CH2), 55.3 (CH3), 36.8 (CH), 36.7 (CH2), 32.2
(CH2), 31.6 (CH2), 21.4 (CH3), 20.6 (CH2), 13.9 (CH3); m/z (ES)
601.2757 [M + Na]+, C34H42NaO8 requires 601.2777.
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˚
4 A Molecular sieves (20 mg), TPAP (2.6 mg, 7.3 mmol) and
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=
5.49 (1H, m, C CHCH2), 4.71 (1H, d, J = 11.1 Hz, CH2Ar), 4.53
=
(1H, dd, J = 11.3, 4.6 Hz, CH CCHO), 4.39–4.29 (4H, m, 2 ¥
CH2Ar), 4.16–4.11 (2H, m, CH2Ar, CH2OCH2Ar), 3.98 (1H, dd,
J = 5.9, 2.0 Hz, COCHCHO), 3.82 (3H, s, OCH3), 3.81 (3H, s,
OCH3), 3.79 (3H, s, OCH3), 3.78–3.73 (1H, m, CH2OCH2Ar),
3.69 (1H, dd, J = 7.7, 6.4 Hz, CHCH2CH2), 3.14 (1H, d, J =
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=
=
16.1 Hz, CH CCH2), 3.01 (1H, d, J = 16.1 Hz, CH CCH2), 2.68
(1H, ddd, J = 14.5, 11.3, 2.0 Hz, CHCH2CH), 2.39 (1H, ddd, J =
14.5, 5.9, 4.6 Hz, CHCH2CH), 1.82–1.69 (2H, m, CHCH2CH2),
1.35–1.21 (2H, m, CH2CH3), 0.92 (3H, t, J = 7.3 Hz, CH2CH3);
dC (125 MHz, CDCl3) 209.3 (C), 159.4 (C), 159.3 (C), 159.2 (C),
141.3 (CH), 140.5 (CH), 136.0 (CH), 135.0 (C), 130.7 (C), 130.5
(C), 130.2 (C), 129.7 (CH), 129.6 (CH), 129.5 (CH), 123.4 (C),
123.2 (C), 113.9 (CH), 113.9 (CH), 113.8 (CH), 82.4 (CH), 72.6
(CH2), 72.0 (CH2), 71.9 (CH), 69.7 (CH2), 66.5 (CH2), 55.4 (CH3),
55.3 (CH3), 42.7 (CH), 34.0 (CH2), 33.0 (CH2), 22.1 (CH2), 21.2
(CH2), 14.2 (CH3); m/z (ES) 677.3061 [M + Na]+, C40H46NaO8
requires 677.3090.
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rt; p-MeC6H4SO3H, C6D6, rt → 50 ◦C; 2M HCl, MeOD, → 50 ◦C.
32 Reduction conditions: NaBH4, MeOH, rt; i-Bu2AlH, PhMe, THF,
-78 ◦C → rt; (i-PrO)3Al, i-PrOH, rt → reflux; i-Bu2Al(Oi-Pr), PhMe,
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The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 4012–4025 | 4025
©