Biomimetic Syntheses of Amorfrutin C and C-5 Substituted Amorfrutin Analogues

Article abstract of DOI:10.1002/ejoc.202001487

Amorfrutin C, a C-5 prenyl amorfrutin, its allyl analog and an amorfrutin C-5 aldehyde have been synthesized using a biomimetic strategy from non-aromatic precursors. In this approach, a dioxinone derived β,δ-diketo ester underwent a decarboxylative Pd(0)

Full text of DOI:10.1002/ejoc.202001487

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Biomimetic Syntheses of Amorfrutin C and C-5 Substituted
Amorfrutin Analogues
Calum Patel,[a] Thomas Mies,[a] Andrew J. P. White,[a] Philip J. Parsons,[a] and
Anthony G. M. Barrett*[a]
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Amorfrutin C, a C-5 prenyl amorfrutin, its allyl analog and an
amorfrutin C-5 aldehyde have been synthesized using a
biomimetic strategy from non-aromatic precursors. In this
approach, a dioxinone derived β,δ-diketo ester underwent a
decarboxylative Pd(0) catalyzed prenyl migration to give a β,δ-
diketo dioxinone, which readily aromatized giving the amor-
frutin core. The introduction of prenyl and allyl moieties at the
C-5 position of the scaffold was accomplished using a Claisen
rearrangement. Alternatively, iodination, lithium-iodine ex-
change and trapping with DMF gave the amorfrutin aldehyde
and an amorfrutin alcohol when excess n-BuLi was used.
Introduction
The amorfrutins are a family of meroterpenoid β-resorcylates
that continue to attract attention on account of their anti-
inflammatory, anti-diabetic and anti-cancer activities.[1-3] These
secondary metabolites, biosynthesized via a mixed polyketide-
terpenoid pathway, comprise a characteristic planar 6-alkyl-2,4-
dihydroxybenzoic acid (resorcylic acid) unit typically substituted
with prenyl, geranyl, phenethyl or alkyl residues and a methoxy
group at the C-4 position (Figure 1).[4] The dried fruits and leaves
of Amorpha fruticosa, an American shrub, provided the first
extracts of amorfrutin A (1) and amorfrutin B (2), however,
amorfrutin A (1) has also been isolated from the liquorice roots
of Glycyrrhiza acanthocarpa.[5,6] Biological studies on this class of
meroterpenoid β-resorcylates showed promising activities, with
narrow spectrum anti-microbial activity exhibited by amorfrutin
A (1).[5] Following investigations revealed the PPAR-γ (perox-
isome proliferator-activated receptor gamma) modulating prop-
erties of both amorfrutins 1 and 2, resulting in potent anti-
diabetic effects in mouse models.[2] Recently, two new members
of the amorfrutin family were reported. Amorfrutin C (3) was
isolated in 2016 from the dried roots of Glycyrrhiza foetida
(22 mg per 1 kg) and amorfrutin D (4) was isolated from
Amorpha fruticosa.[7,8] Weidner et al subsequently reported that
amorfrutin C (3) induced apoptosis at greater micromolar mean
IC50 concentrations than cis-platin in human colon (HT-29 and
T84), prostate (PC-3) and breast (MCF7) cancer cell lines.
Figure 1. Amorfrutin natural products 1–4.
being a promising hit structure for targeted cancer therapeutics.
In addition, amorfrutin C (3) was found to be a weak PPAR-γ
agonist compared to amorfrutins 1 and 2, flagging the bio-
logical significance of the C-5 prenyl substituent on the
activities of the amorfrutins. Structure-activity relationship (SAR)
studies revealed that the carboxylic acid and hydroxy moieties
of amorfrutin C (3) are essential for the induction of apoptosis
observed in colon cancer cells, however, the role of the C-5
substituent is yet to be fully defined.[8] To date, there have been
no synthetic efforts made to install a substituent, other than a
prenyl, at the C-5 position of the amorfrutin core.[9]
Notably, amorfrutin C (3) exhibited weaker antiproliferative
activity in primary colon cells (IC50 ~49 μM) compared to colon
cancer cells (HT-29 IC50 8 μM), consistent with the compound
In light of the scarcity of C-5 substituted amorfrutin natural
products and amorfrutin C serving as a promising candidate for
[a] C. Patel, T. Mies, Dr. A. J. P. White, Prof. Dr. P. J. Parsons,
Prof. Dr. A. G. M. Barrett
Department of Chemistry,
Molecular Sciences Research Hub,
Imperial College London, White City Campus,
Wood Lane, London, W12 0BZ, England
E-mail: agm.barrett@imperial.ac.uk
www.imperial.ac.uk/people/agm.barrett
novel anti-cancer therapeutics, we sought to develop
a
methodology for the synthesis of analogues for biological
evaluation. We considered that our biomimetic aromatization
approach to synthesize dioxinone β-ketoesters and derived
meroterpenoid β-resorcylates should serve as a blueprint to
prepare diverse amorfrutins, which can be further derivatized at
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the C-5 substituent to prepare amorfrutin C (3) and analogues
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for SAR studies (Figure 2).[10]
Our methodology, inspired by the research of Harris and
Hyatt, was previously used to synthesize amorfrutin A (1) and
has since been developed for the synthesis of a broad range of
biologically
active
meroterpenoid
β-resorcylates
and
analogues.[11–13] Herein, we report the synthesis of the resorcy-
late 5, in five steps from commercially available dioxinone 16.
We successfully demonstrate that resorcylate 5 can be derivat-
ized via a Claisen rearrangement to furnish both amorfrutin C
(3) and the C-5 allyl substituted amorfrutin 6 in 14% and 10%
overall yields, respectively. Finally, as part of our studies towards
the synthesis of novel C-5 substituted amorfrutins, we disclose a
method to formylate resorcylate 5, via a copper-mediated
lithium-iodine exchange of diiodide 7, to access C-5 amorfrutin
aldehyde 8.
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Our strategy for the synthesis of C-5 substituted amorfrutins
delayed the introduction of the C-5 substituent to a later stage
for reasons of parallel synthetic efficiency and utilization of our
prior methodology (Scheme 1). Amorfrutin C (3) possesses a
prenyl group ortho to a hydroxy group, the structural prereq-
uisite for an aromatic Claisen rearrangement (Scheme 1A).
Analogously, this approach could be used to insert an allyl
group at the C-5 position. Alternatively, retrosynthetic scission
of the C-5 CÀ C bond in intermediate 15 reveals halide 13, which
could be readily derivatized using an organometallic coupling
reaction to access a range of C-5 substituted amorfrutins
(Scheme 1B). This disconnection is significantly simplified by
involving intermediate 14 directly, which we speculated could
be achieved via direct deprotonation-magnesiation and subse-
quent trapping with an electrophilic reagent.[14] The retrosyn-
thetic disassembly of resorcylate 5 involves the biomimetic
aromatization of β,δ-diketo dioxinone 20, which would, in turn,
be prepared through a regioselective C-acylation of dioxinone
β-ketoester 18, followed by palladium(0)-catalyzed decarboxyla-
tive prenyl rearrangement (Scheme 1C).[12,13a] Our regioselective
acyl-ketene generation would be key for the preparation of 18
from dioxinone acid 17, derived from dioxinone 16.[13a,b]
Scheme 1. A) Retrosynthetic analysis of resorcylates 11 and 12 via a Claisen
rearrangement.[15] B) Retrosynthetic analysis of 15 via an organometallic
coupling or magnesiation. C) Retrosynthetic analysis of resorcylate scaffold
5.
Results and Discussion
The synthesis of resorcylate 5 commenced with the carboxyla-
tion of dioxinone 16, via its corresponding lithium enolate
generated using lithium hexamethyldisilazide, to give dioxinone
Figure 2. Structures of the key amorfrutin intermediate 5, C-5 allyl
substituted amorfrutin 6, diiodide 7 and an amorfrutin C-5 aldehyde 8.
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acid 17 (Scheme 2). DCC-mediated coupling between acid 17
and malonate 21 gave dioxane-4,6-dione-keto dioxinone 22,
which was immediately used in the next step. Heating of
a decarboxylative palladium(0) catalyzed prenyl migration to
give β,δ-diketodioxinone 20 as an intermediate, which readily
cyclized and aromatized under basic conditions to give
resorcylate 5 in modest yield (49% over two steps).
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intermediate 22 at 55 C selectively generated the highly
electrophilic dioxinone acyl-ketene 23 via a retro-Diels-Alder
reaction, which was subsequently trapped with prenol 24 to
give dioxinone β-keto ester 18 (98%). There is precedent for
the observed regioselectivity exhibited during this selective
ketene generation, which is attributed to phenyl ring π-
delocalization into the OÀ CO σ* orbital of the dioxane-4,6-dione
moiety.[13a,16]
It is noteworthy that this five-step biomimetic aromatization
sequence easily gave over half a gram of resorcylate 5,
providing rapid entry for our studies of CÀ C bond formation at
the C-5 position. We first decided to explore the Claisen
rearrangement strategy to access amorfrutin C (3). Accordingly,
the reaction of resorcylate 5 with carbonate 26 under palladium
catalysis induced a Tsuji-Trost O-alkylation to produce aryl ether
9 (66%) (Scheme 4). A Claisen rearrangement proceeded in
toluene solution under microwave heating to afford C-5 prenyl
substituted resorcylate 11 (63%). Subsequent methylation and
saponification gave amorfrutin C (3) in an overall yield of 14%.
The NMR data for synthetic amorfrutin C and its precursor 27
were in excellent agreement with those previously reported by
Wu et al (see Table S1 and Table S2 in the SI).
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Dioxinone β-keto ester 18 underwent a highly regioselective
C-acylation with hydrocinnamoyl chloride (25), in the presence
of magnesium chloride, to give β,δ-diketo ester 19 (Scheme 3).
Addition of a catalytic amount of Pd2(dba)3 to ester 19 triggered
The reaction of resorcylate 5 with allyl bromide 28 gave aryl
°
ether 10 (83%). Subsequent heating in DMF at 200 C resulted
in a Claisen rearrangement to give C-5 allyl resorcylate 12 in
60% yield, despite the product’s tendency to undergo further
hydrolytic decarboxylation at this temperature. Careful control
of reaction time was key to obtaining resorcylate 12 in
reasonable yield. The difference in temperature required for the
Claisen rearrangement of 10 compared to 9 was particularly
noteworthy. We believe that the Claisen rearrangement of 9 is
facilitated by the Thorpe-Ingold effect, where strain between
the gem-dimethyl group and the adjacent alkene CÀ H bond is
relieved through the transformation, allowing the reaction to
proceed at a lower temperature. Finally, O-methylation and
saponification gave C-5 allyl amorfrutin 6 in an overall yield of
10%.
Methylation of resorcylate 5 provided ether 14, which was a
convenient compound for further C-5 derivatization studies
(Scheme 3). Deprotonation of ether 14 using 2,2,6,6-tetrameth-
ylpiperidinylmagnesium chloride lithium chloride complex
(TMPMgCl·LiCl) was systematically investigated, with the em-
ployment of copper(I) bromide dimethyl sulfur complex.
However, this proved unsatisfactory for our system. Employ-
ment of alternative known, ortho-directing groups (OBoc) also
proved ineffective,[14] however halogenation reactions proved to
be more useful. Although halogenation of ether 14 gave
intractable mixtures, the reaction of resorcylate 5 with iodine
and t-butylamine gave iodo-ether 30 (9%) and diiodide 7 (83%)
(Scheme 5). Since arene iodination most likely proceeded via a
phenyl-hypoiodite intermediate, reactions using excess iodine,
elevated temperatures or with increased reaction times did not
convert the iodo-ether 30 into diiodide 7.[17,18] However, with
diiodide 7 as the major product, further derivatization was
examined with this compound. Attempted alkylation using a
palladium-catalyzed Suzuki-Molander-Miyaura cross-coupling
gave only intractable mixtures.[19] However, diiodide 7 was
derivatized via a copper-mediated lithium-iodine exchange
(Scheme 5).
Scheme 2. Synthesis of dioxinone β-keto ester 18.
The reaction of diiodide 7 with n-butyllithium (n-BuLi) not
only allowed for derivatization at the C-5 position but also
Scheme 3. Synthesis of resorcylate 5 and methylated amorfrutin 14.
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Scheme 4. Syntheses of amorfrutin C (3) and C-5 allyl amorfrutin 6 from resorcylate 5.
Scheme 6. Copper mediated lithium-iodine exchange of diiodide 7 using 4
equivalents of n-BuLi.
BuLi gave amorfrutin alcohol 31 (36%) and resorcylate 5 (38%)
(Scheme 6). As trace amounts of amorfrutin aldehyde 8 were
isolated from this reaction, we suspect that alcohol 31 is formed
via the reduction of 8 by excess n-BuLi, proposedly promoted
by TMEDA co-ordination, via an ortho-quinone methide inter-
mediate.
Oxidation of alcohol 31 using Dess-Martin Periodinane
(DMP) regenerated amorfrutin aldehyde 8. Both alcohol 31 and
aldehyde 8 should serve as synthetically useful intermediates
for the synthesis of other novel C-5 substituted amorfrutins.
Scheme 5. Iodination of resorcylate 5 and copper-mediated lithium-iodine
exchange of diiodide 7 using 2 equivalents of n-BuLi, with X-ray crystal
structures of 7 and aldehyde 8.
Conclusion
This study demonstrates the value of our biomimetic aromatiza-
tion sequence to synthesize amorfrutins. A Claisen rearrange-
ment was employed to prepare both amorfrutin C (3) and its C-
5 allyl analog 6, in a linear sequence of seven steps overall.
Furthermore, iodination of resorcylate 5 in the presence of t-
butylamine, followed by subsequent copper-mediated lithium-
iodine exchange using 2 equivalents of n-BuLi gave amorfrutin
aldehyde 8. Alternatively, the addition of 4 equivalents of n-
BuLi gave amorfrutin alcohol 31, which underwent oxidation
using DMP to regenerate aldehyde 8. Such methodology is
opened the cyclic iodo-ether to restore the prenyl group
exclusively, affording amorfrutin aldehyde 8 (24%) along with
°
resorcylate 5 (25%). Carrying out this reaction at – 100 C in a
mixed solvent system of toluene/THF in the presence of an
organometallic stabilizer N,N,N’,N’-tetramethylethylenediamine
(TMEDA) was found to be key for this transformation.[9a]
Changing the solvent to diethyl ether, THF or toluene was not
tolerated. Alternatively, treatment of 7 with 4 equivalents of n-
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dioxinone 22 as a yellow foam, which was used directly in the next
step. Crude dioxane-4,6-dione-keto-dioxinone 22 and prenol 24
(1.50 mL, 15.0 mmol) were dissolved in PhMe (120 mL) and stirred
relevant for the parallel synthesis of further amorfrutins, such as
1, 2 and 4, and analogs for bioassay SAR studies.
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°
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at 55 C for 4 h. Concentration in vacuo and chromatography
(pentane/EtOAc, 9:1 to 4:1) provided dioxinone β-keto ester 18
(4.33 g, 14.6 mmol, 98%) as a yellow oil: Rf 0.30 (hexane/Et2O, 1:2);
1H NMR (400 MHz, CDCl3) δ=5.36 (s, 1H), 5.36–5.31 (m, 1H), 4.65 (d,
J=7.3 Hz, 2H), 3.51 (s, 2H), 3.50 (s, 2H), 1.77 (s, 3H), 1.71
(overlapping s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ=195.6, 166.4,
163.6, 160.5, 140.4, 117.6, 107. 4, 97.1, 62.6, 49.1, 47.0, 25.8 (2 C),
Experimental Section
General Methods: All reagents and solvents were used directly
without further purification unless otherwise specified. The syn-
thesis of malonate 21 was carried out according to Barrett et al and
the synthesis of carbonate 26 was carried out according to Trost
et al.[13b,20] All solvents were purified and dried by solvent
purification systems. All air- and moisture-sensitive reactions were
carried out under an atmosphere of N2 using standard Schlenk
techniques in oven-dried glassware equipped with a magnetic
stirring bar. Reactions were performed at room temperature (23–
25.0, 18.1; IR νmax (neat) 1721, 1636, 1390, 1271, 1202, 1014 cmÀ 1
;
HRMS (ESI) m/z: [M - H]À Calcd for C15H19O6 295.1182, found
295.1194. Analytical data were in good agreement with literature
values.[21]
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7-Hydroxy-2,2-dimethyl-8-(3-methylbut-2-en-1-yl)-5-phenethyl-
4H-benzo[d][1,3]dioxin-4-one (5): MgCl2 (0.643 g, 6.72 mmol) and
pyridine (0.734 mL, 9.11 mmol) were added with stirring to
dioxinone β-keto-ester 18 (1.00 g, 3.37 mmol) in dry CH2Cl2 (70 mL)
at 0 C. After 10 min, 3-phenylpropanoyl chloride 25 (0.602 mL,
4.05 mmol) was added dropwise with stirring at 0 C. After 1 h, the
°
25 C) unless otherwise stated. Reaction temperatures above room
temperature were measured externally from the DrySyn. Microwave
reactions were carried out in a Biotage® Initatior+ microwave
synthesizer. The progress of reactions was monitored by analytical
thin-layer chromatography (TLC) on silica gel coated aluminum
oxide F254 plates. Developed TLC were visualized under UV light and
stained with an acidic vanillin solution. Flash column chromatog-
raphy was performed employing silica gel 60 Å, particle size 40–
63 μm. All 1H and proton-decoupled 13C NMR spectra were recorded
at 400 MHz and 101 MHz, respectively, at ambient temperature in
deuterated solvents (CDCl3 and CD3OD). NMR spectra were
referenced to residual solvent peaks (CDCl3: δ=7.26 for 1H NMR
°
°
reaction was quenched with saturated aqueous NH4Cl (10 mL) and
the pH was adjusted to ~2 with aqueous HCl (1 M). The two phases
were separated and the aqueous layer was extracted with EtOAc
(3×25 mL). The combined organic layers were dried (MgSO4),
filtered and concentrated in vacuo to give crude β,δ-diketo ester 19
as a light-yellow residue. Pd2(dba)3 (0.155 g, 0.169 mmol) and P(2-
furyl)3 (0.157 g, 0.675 mmol) were added with stirring to crude β,δ-
diketo ester 19 in dry THF (20 mL). After 2 h, Cs2CO3 (3.30 g,
10.1 mmol) was added and the resulting suspension was stirred for
an additional 1.5 h. The reaction was quenched with aqueous HCl
(1 M, 15 mL), the two phases were separated and the aqueous layer
was extracted with CH2Cl2 (3×25 mL). The combined organic layers
were dried (MgSO4), filtered, concentrated in vacuo and chromato-
graphed (pentane/EtOAc, 19:1 to 10:1) to give resorcylate 5
(612 mg, 1.67 mmol, 49% over 2 steps) as a pale-yellow solid: Rf
and δ=77.0 for 13C NMR, CD3OD: δ=3.31 and 4.87 for H NMR and
1
δ=49.0 for 13C NMR) and chemical shifts were reported in ppm. IR
spectra were recorded on an Agilent Cart 630 FTIR spectrometer
and recorded in cmÀ 1. Mass spectra were obtained from the
Imperial College Mass Spectrometry Service under conditions of
electrospray ionization (ESI), electron ionization (EI) or chemical
ionization (CI). Melting points were recorded using Leica Galen III
hot-stage microscope apparatus and were reported uncorrected in
0.37 (pentane/EtOAc, 4:1); m.p. 118–120 C; 1H NMR (400 MHz,
°
degrees Celsius ( C).
°
CDCl3) δ=7.30–7.26 (m, 4H), 7.22–7.14 (m, 1H), 6.36 (s, 1H), 5.76 (s,
1H), 5.23–5.14 (m, 1H), 3.32 (d, J=7.3 Hz, 2H), 3.30–3.25 (m, 2H),
2.90–2.83 (m, 2H), 1.80 (s, 3H), 1.74 (d, J=1.4 Hz, 3H), 1.68 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3) δ=160.6, 160.0, 156.2, 146.4, 141.9,
134.8, 128.7 (2 C), 128.3 (2 C), 125.8, 120.9, 113.2, 113.1, 105.0,
104.7, 37.3, 36.8, 25.8, 25.7 (2 C), 22.0, 17.9; IR νmax (neat) 3308, 1689,
1591, 1419, 1389 cmÀ 1; HRMS (ESI) m/z: [M+H]+ Calcd for C23H27O4
367.1904, found 367.1907. Analytical data were in good agreement
with literature values.[12]
2-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)acetic acid (17): n-BuLi in
cyclohexane (2 M; 39.0 mL, 77.4 mmol) was added dropwise with
stirring to (Me3Si)2NH (16.0 mL, 77.4 mmol) in THF (70 mL) at
°
°
À 78 C. The resulting mixture was warmed to 0 C and, after 30 min,
°
recooled back to À 78 C. Dioxinone 16 (9.35 mL, 70.3 mmol) was
°
added dropwise with stirring at À 78 C. After 1 h, CO2 gas was
bubbled through the solution for 20 min and the resulting mixture
was gradually warmed to room temperature and stirred for 18 h.
The pH was adjusted to ~1 with aqueous HCl (4 M) and the mixture
was diluted with EtOAc (100 mL). The two phases were separated
and the aqueous layer was extracted with EtOAc (5×50 mL). The
combined organic layers were dried (MgSO4), filtered, concentrated
in vacuo and recrystallized from EtOH to provide dioxinone acid 17
2,2-Dimethyl-8-(3-methylbut-2-en-1-yl)-7-((2-methylbut-3-en-2-yl)
oxy)-5-phenethyl-4H-benzo[d][1,3]dioxin-4-one (9): Resorcylate 5
(150 mg, 0.410 mmol) and carbonate 26 (267 mg, 1.44 mmol) were
dissolved in degassed THF (0.8 mL). 3 Å molecular sieves (500 mg)
were added with stirring to the reaction mixture which was cooled
(11.5 g, 61.7 mmol, 88%) as white crystals: Rf 0.15 (pentane/EtOAc,
1
°
1:1); m.p. 104–105 C; H NMR (400 MHz, CDCl3) δ=10.32 (br s, 1H),
°
to À 20 C. Pd(PPh3)4 (23.7 mg, 0.0205 mmol) was added in one
5.45 (s, 1H), 3.32 (s, 2H), 1.71 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3)
δ=171.3, 162.8, 160.6, 107.3, 96.6, 38.7, 24.7; IR νmax (neat) 3107,
1701, 1644 cmÀ 1; HRMS (ESI) m/z: [M+H]+ Calcd for C8H10O5
187.0606, found 187.0607. Analytical data were in good agreement
with literature values.[13b]
°
portion with stirring. After 18 h at À 20 C, the mixture was filtered
through Celite® and the solids rinsed with EtOAc (30 mL). The
filtrate was concentrated in vacuo and chromatographed (pentane/
EtOAc, 19:1 to 15:1) to afford ether 9 (118 mg, 0.271 mmol, 66%)
as a viscous colorless oil: Rf 0.45 (pentane/EtOAc, 4:1); 1H NMR
(400 MHz, CDCl3) δ=7.27–7.22 (m, 2H), 7.21–7.13 (m, 3H), 6.53 (s,
1H), 6.06 (dd, J = 17.0, 10.9 Hz, 1H), 5.15 (dd, J = 17.0, 0.8 Hz, 1H,),
5.12 (dd, J=10.9, 0.8 Hz, 1H,), 5.13–5.07 (m, 1H), 3.29–3.20 (m, 4H),
2.90–2.82 (m, 2H), 1.75 (d, J=1.3 Hz, 3H), 1.67 (d, J=1.3 Hz, 3H),
1.67 (s, 6H), 1.43 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ=160.7,
159.7, 155.9, 144.5, 144.1, 141.9, 131.3, 128.7 (2 C), 128.2 (2 C),
125.7, 122.1, 118.4, 114.6, 113.6, 105.1, 104.5, 80.6, 37.0, 36.8, 27.4
(2 C), 25.8, 25.8 (2 C), 22.4, 17.9; IR νmax (neat) 1724, 1601, 1567,
3-Methylbut-2-en-1-yl 4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-
3-oxobutanoate (18): Malonate 21 (5.51 g, 26.9 mmol), DCC (5.55 g,
26.9 mmol) and DMAP (3.30 g, 26.9 mmol) were dissolved in CH2Cl2
(50 mL) and, after 5 min, dioxinone acid 17 (5.00 g, 26.9 mmol) was
°
added with stirring. After 18 h, the mixture was cooled to 0 C and
the precipitate was filtered off and washed with CH2Cl2 (50 mL). The
filtrate was washed with aqueous HCl (1 M, 2×30 mL) and the
organic phase was separated, dried (MgSO4), re-filtered and
concentrated in vacuo to give crude dioxane-4,6-dione-keto-
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1411, 1375, 1106 cmÀ 1; HRMS (ESI) m/z: [M+H]+ Calcd for C28H35O4
435.2535, found 435.2534.
(MgSO4), filtered, concentrated in vacuo and chromatographed
(pentane/EtOAc, 19:1 to 15:1) to afford a colorless oil, which
solidified upon standing to give ether 10 (138 mg, 0.340 mmol,
1
2
3
4
5
6
7
8
9
7-Hydroxy-2,2-dimethyl-6,8-bis(3-methylbut-2-en-1-yl)-5-phe-
83%) as a colorless crystalline solid: Rf 0.68 (pentane/EtOAc, 4:1);
nethyl-4H-benzo[d][1,3]dioxin-4-one (11): Ether
9
(115 mg,
1
°
m.p. 38–41 C; H NMR (400 MHz, CDCl3) δ=7.34–7.21 (m, 4H), 7.21–
0.265 mmol) was dissolved in dry PhMe (3 mL) in a microwave
reaction vessel. The mixture was heated in a microwave reactor
7.12 (m, 1H), 6.29 (s, 1H), 6.00 (ddt, J=17.2, 10.5, 5.1 Hz, 1H), 5.44–
5.35 (m, 1H), 5.35–5.23 (m, 1H,), 5.16–5.07 (m, 1H), 4.52–4.48 (m,
2H), 3.35–3.29 (m, 2H), 3.28 (d, J=7.4 Hz, 2H), 2.92–2.85 (m, 2H),
1.75 (d, J=1.3 Hz, 3H), 1.67 (s, 6H), 1.66 (d, J=1.3 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ=160.9, 160.6, 155.7, 146.0, 141.9, 132.6,
131.7, 128.8 (2 C), 128.3 (2 C), 125.8, 121.7, 117.7, 116.4, 109.1,
105.3, 104.6, 69.0, 37.4, 37.3, 25.8, 25.7 (2 C), 22.0, 17.9; IR νmax (neat)
1722, 1602, 1571, 1412, 1375, 1266, 1167 cmÀ 1; HRMS (ESI) m/z: [M
+H]+ Calcd for C26H31O4 407.2222, found 407.2220.
°
(400 W) at 160 C for 1 h 40 min. Concentration in vacuo and
chromatography (pentane/EtOAc, 19:1 to 18:1) gave resorcylate 11
(73.0 mg, 0.168 mmol, 63%) as a viscous colorless oil: Rf 0.53
(pentane/Et2O, 4:1); 1H NMR (400 MHz, CDCl3) δ=7.36–7.32 (m, 2H),
7.32–7.27 (m, 2H), 7.22–7.16 (m, 1H), 6.09 (s, 1H), 5.22–5.15 (m, 1H),
5.12–5.03 (m, 1H), 3.43–3.36 (overlapping d and m, J=6.6 Hz, 4H),
3.34 (d, J=7.4 Hz, 2H), 2.85–2.77 (m, 2H), 1.81 (s, 6H), 1.74 (s, 6H),
1.67 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ=160.7, 159.1, 154.3,
143.5, 142.2, 134.6, 134.4, 128.6 (2 C), 128.3 (2 C), 125.8, 122.1,
122.0, 121.1, 113.5, 105.5, 104.2, 36.9, 32.8, 25.8, 25.8, 25.7 (2 C),
25.0, 22.3, 18.1, 17.8; IR νmax (neat) 3405, 1724, 1696, 1598, 1577,
1308, 1280, 1211 cmÀ 1, HRMS (ESI) m/z: [M+H]+ Calcd for C28H35O4
435.2535, found 435.2520.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
6-Allyl-7-hydroxy-2,2-dimethyl-8-(3-methylbut-2-en-1-yl)-5-phe-
nethyl-4H-benzo[d][1,3]dioxin-4-one (12): Ether 10 (35.0 mg,
0.0861 mmol) was dissolved in dry DMF (800 μL). After 8 h at
°
200 C, the reaction mixture was washed with aqueous LiCl (10%,
5 mL) and extracted with EtOAc (2×10 mL). The combined organic
layers were washed with H2O (3×1 mL), dried (MgSO4), filtered,
concentrated in vacuo and chromatographed (pentane/EtOAc, 20:1
to 18:1) to give resorcylate 12 (21.0 mg, 0.0517 mmol, 60%) as a
viscous colorless oil: Rf 0.58 (pentane/EtOAc, 9:1); 1H NMR
(400 MHz, CDCl3) δ=7.39–7.27 (m, 4H), 7.24–7.17 (m, 1H), 5.96 (ddt,
J=17.2, 10.1, 5.7 Hz, 1H), 5.22–5.15 (m, 1H), 5.13–5.08 (m, 1H), 5.08–
5.01 (m, 1H), 3.48–3.42 (m, 2H), 3.41–3.31 (overlapping m and d, J=
7.3 Hz, 4H), 2.84–2.78 (m, 2H), 1.82 (d, J=1.3 Hz, 3H), 1.76 (d, J=
1.3 Hz, 3H), 1.68 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ=160.6,
159.1, 154.5, 144.3, 142.2, 136.0, 135.6, 128.6 (2 C), 128.3 (2 C),
125.9, 120.8, 120.2, 116.0, 113.0, 105.5, 104.3, 36.8, 32.4, 29.9, 25.8,
25.7 (2 C), 22.3, 17.9; IR νmax (neat) 3396, 1724, 1696, 1576, 1454,
1280, 1210 cmÀ 1; HRMS (ESI) m/z: [M+H]+ Calcd for C26H31O4
407.2222, found 407.2221.
7-Methoxy-2,2-dimethyl-6,8-bis(3-methylbut-2-en-1-yl)-5-phe-
nethyl-4H-benzo[d][1,3]dioxin-4-one (27): Cs2CO3 (157 mg,
0.449 mmol) and MeI (27.9 μL, 0.449 mmol) were sequentially
added dropwise with stirring to resorcylate 11 (65.0 mg,
°
0.150 mmol) in dry THF (2 mL). After 2 h at 40 C, reaction was
quenched with H2O (1 mL) and the organic layer was separated.
The aqueous layer was extracted with EtOAc (2×2 mL) and the
combined organic layers were dried (MgSO4), filtered, concentrated
in vacuo and chromatographed (pentane/EtOAc, 20:1 to 18:1) to
give resorcylate 27 (56.0 mg, 0.125 mmol, 84%) as a viscous pale-
yellow oil: Rf 0.82 (pentane/Et2O, 4:1); 1H NMR (400 MHz, CDCl3) δ=
7.36–7.26 (m, 4H), 7.25–7.16 (m, 1H), 5.17–5.09 (m, 1H), 5.09–4.99
(m, 1H), 3.75 (s, 3H), 3.43–3.25 (overlapping m, 6H), 2.85–2.74 (m,
2H), 1.77 (d, J=1.4 Hz, 3H), 1.75 (d, J=1.4 Hz, 3H), 1.69 (s, 6H) 1.68
(s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ=162.5, 160.6, 155.1, 144.6,
142.5, 132.0, 129.8, 128.8 (2 C), 128.4 (2 C), 126.0, 123.8, 122.4,
122.0, 109.2, 104.6, 61.9, 37.1, 32.6, 25.8 (3 C), 25.8, 25.3, 23.3, 18.3,
6-Allyl-7-methoxy-2,2-dimethyl-8-(3-methylbut-2-en-1-yl)-5-phe-
nethyl-4H-benzo[d][1,3]dioxin-4-one (29): Cs2CO3 (45.7 mg,
0.140 mmol) and MeI (7.89 μL, 0.140 mmol) were sequentially
added dropwise with stirring to resorcylate 12 (19.0 mg,
18.1; IR νmax (neat) 1728, 1571, 1437, 1375, 1278, 1207, 1116 cmÀ 1
;
HRMS (ESI) m/z: [M+H]+ Calcd for C29H37O4 449.2692, found
0.0467 mmol) in dry THF (1 mL). After 2 h at 40 C, reaction was
°
449.2691.
quenched with H2O (1 mL), the layers were separated and the
aqueous layer was extracted with EtOAc (2×2 mL). The combined
organic layers were dried (MgSO4), filtered, concentrated in vacuo
and chromatographed (pentane/CH2Cl2, 1:1) to afford resorcylate
29 (13.0 mg, 0.0309 mmol, 66%) as a viscous colorless oil: Rf 0.64
(pentane/EtOAc, 4:1); 1H NMR (400 MHz, CDCl3) δ=7.35–7.27 (m,
4H), 7.23–7.15 (m, 1H), 5.98 (ddt, J=17.2, 10.2, 5.5 Hz, 1H), 5.16–
5.08 (m, 1H), 5.07–5.01 (m, 1H), 4.93–4.85 (m, 1H), 3.75 (s, 3H), 3.47–
3.42 (m, 2H), 3.39–3.33 (m, 2H), 3.31 (d, J=7.0 Hz, 2H), 2.84–2.76 (m,
2H), 1.77 (d, J=1.4 Hz, 3H), 1.69 (d, J=1.4 Hz, 3H), 1.68 (s, 6H); 13C
{1H} NMR (101 MHz, CDCl3) δ=162.7, 160.6, 155.5, 144.8, 142.4,
137.3, 132.1, 128.7 (2 C), 128.5 (2 C), 127.3, 126.0, 122.3, 122.1,
115.6, 109.2, 104.7, 62.1, 37.1, 32.5, 30.2, 25.9, 25.8 (2 C), 23.3, 18.1;
IR νmax (neat) 1730, 1573, 1375, 1208, 1209, 1120 cmÀ 1; HRMS (ESI)
m/z: [M+H]+ Calcd for C27H33O4 421.2373, found 421.2359.
2-Hydroxy-4-methoxy-3,5-bis(3-methylbut-2-en-1-yl)-6-phene-
thylbenzoic acid (amorfrutin C) (3): Aqueous KOH (48%, 65.1 μL,
0.557 mmol) was added with stirring to resorcylate 27 (25.0 mg,
°
0.0557 mmol) in dry DMSO (100 μL). After 18 h at 80 C, the mixture
was acidified to pH~1 using aqueous HCl (1 M) and extracted with
EtOAc (15 mL). The combined organic layers were dried (MgSO4),
filtered, concentrated in vacuo and chromatographed (pentane/
EtOAc, 1:1) to afford amorfrutin C (3) (21.0 mg, 0.0514 mmol, 92%)
°
as a pale-yellow solid: Rf 0.07 (pentane:EtOAc, 1:4); m.p. 112–114 C;
1H NMR (400 MHz, CD3OD) δ=7.29–7.22 (m, 2H), 7.22–7.13 (m, 3H),
5.27–5.18 (m, 1H), 5.05–4.97 (m, 1H), 3.69 (s, 3H), 3.38–3.34 (m, 4H),
3.24–3.16 (m, 2H), 2.83–2.74 (m, 2H), 1.78 (d, J=1.3 Hz, 3H), 1.73 (d,
J=1.3 Hz, 3H), 1.68 (s, 6H); 13C{1H} NMR (101 MHz, CD3OD) δ=175.1,
162.5, 161.8, 143.8, 143.4, 132.1, 131.9, 129.3 (2 C), 129.3 (2 C),
126.9, 126.8, 125.8, 124.4, 122.0, 111.0, 61.9, 38.7, 34.4, 26.2, 25.9,
25.8, 24.3, 18.2, 18.0; IR νmax (neat) 2957, 1635, 1597, 1448, 1261,
1216, 1092 cmÀ 1; HRMS (ESI) m/z: [M+H]+ Calcd for C26H33O4
409.2379, found 409.2379.
3-Allyl-6-hydroxy-4-methoxy-5-(3-methylbut-2-en-1-yl)-2-phene-
thylbenzoic acid (6): Aqueous KOH (48%, 36.1 μL, 0.309 mmol) was
added with stirring to resorcylate 29 (13.0 mg, 0.0309 mmol) in dry
°
DMSO (90 μL). After 18 h at 80 C, the mixture was acidified to pH~
1 using aqueous HCl (1 M) and extracted with EtOAc (10 mL). The
combined organic layers were dried (MgSO4), filtered, concentrated
in vacuo and chromatographed (pentane/EtOAc, 7:1) to afford
resorcylate 6 (7.00 mg, 0.0184 mmol, 60%) as a pale-yellow solid: Rf
7-(Allyloxy)-2,2-dimethyl-8-(3-methylbut-2-en-1-yl)-5-phenethyl-
4H-benzo[d][1,3]dioxin-4-one (10): Cs2CO3 (401 mg, 1.23 mmol)
and allyl bromide (0.106 mL, 1.23 mmol) were sequentially added
dropwise with stirring to resorcylate 5 (150 mg, 0.410 mmol) in dry
THF (5 mL). After 18 h, reaction was quenched with H2O (5 mL), the
layers were separated and the aqueous layer was extracted with
EtOAc (2×10 mL). The combined organic layers were dried
1
0.02 (pentane/EtOAc, 9:1); H NMR (400 MHz, CDCl3) δ=7.32–7.26
(m, 2H), 7.25–7.17 (m, 3H), 5.99 (ddt, J=17.2, 10.4, 5.3 Hz, 1H), 5.31–
5.20 (m, 1H), 5.06–4.99 (m, 1H), 4.93–4.83 (m, 1H), 3.75 (s, 3H), 3.50–
3.43 (m, 2H), 3.41 (d, J=6.7 Hz, 2H), 3.30–3.21 (m, 2H), 2.90–2.80 (m,
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2H), 1.80 (d, J=1.3 Hz, 3H), 1.71 (d, J=1.3 Hz, 3H); 13C{1H} NMR
7-Hydroxy-2,2-dimethyl-8-(3-methylbut-2-en-1-yl)-4-oxo-5-phe-
nethyl-4H-benzo[d][1,3]dioxine-6-carbaldehyde (8): (�)-Diiodide 7
(20.0 mg, 0.0323 mmol) was dissolved in dry THF (300 μL) and dry
1
2
3
4
5
6
7
8
9
(101 MHz, CDCl3) δ=175.4, 162.3, 161.7, 143.4, 142.3, 137.6, 132.2,
128.6 (2 C), 128.3 (2 C), 126.0, 124.0, 122.8, 121.4, 115.2, 108.7, 61.9,
37.6, 33.1, 30.4, 25.8, 23.7, 18.1; IR νmax (neat) 2921, 2851, 1734,
1701, 1653, 1593, 1453, 1197 cmÀ 1; HRMS (ESI) m/z: [M – H]À Calcd
for C24H27O4 379.1909, found 379.1914. Elemental analysis calcd for
C24H28O4: C 75.76, H 7.42, found: C: 75.90, H 7.52.
°
PhMe (180 μL). After cooling to À 100 C, n-BuLi (2 M in
cyclohexane, 32.0 μL, 0.0645 mmol) was added to the solution with
stirring. After 10 min, a solution of CuBr·Me2S (2.00 mg, 9.70 μmol)
and TMEDA (24.2 μL, 0.162 mmol) in dry THF (60.0 μL) were added
°
in one portion at À 100 C. After 1 min of stirring, dry DMF (13 μL,
7-Methoxy-2,2-dimethyl-8-(3-methylbut-2-en-1-yl)-5-phenethyl-
4H-benzo[d][1,3]dioxin-4-one (14): Cs2CO3 (667 mg, 2.05 mmol)
and MeI (0.128 mL, 2.05 mmol) were sequentially added dropwise
with stirring to resorcylate 5 (256 mg, 0.699 mmol) in dry THF
(6 mL). After 18 h, the reaction was quenched with H2O (15 mL), the
layers were separated and the aqueous layer was extracted with
EtOAc (3×20 mL). The combined organic layers were dried
(MgSO4), filtered, concentrated in vacuo and chromatographed
(pentane/EtOAc, 19:1 to 17:1) to afford resorcylate 14 (261 mg,
0.162 mmol) was added to the reaction mixture which was
subsequently warmed to room temperature and stirred for 18 h.
The reaction mixture was quenched with saturated aqueous NH4Cl
(1 mL) and the aqueous layer was extracted twice with Et2O (2×
3 mL). Combined organic layers were dried (MgSO4), filtered and
concentrated in vacuo to afford a pale-yellow residue. The product
was purified by preparative TLC (pentane/Et2O 4:1) to provide
aldehyde 8 (3.00 mg, 0.00761 mmol, 24%) as a white solid and
resorcylate 5 (3.00 mg, 0.00819 mmol, 25%) as a pale-yellow solid.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
0.686 mmol, 98%) as a white solid: Rf 0.76 (pentane/Et2O 4:1); m.p.
1
1
°
79–81 C; H NMR (400 MHz, CDCl3) δ=7.32–7.23 (m, 4H), 7.23–7.13
Analytical data for aldehyde 8: Rf 0.30 (pentane/Et2O 4:1); H NMR
(m, 1H), 6.30 (s, 1H), 5.14–5.05 (m, 1H), 3.79 (s, 3H), 3.37–3.29 (m,
2H), 3.24 (d, J=7.4 Hz, 2H), 2.96–2.83 (m, 2H), 1.75 (d, J=1.4 Hz,
3H), 1.67 (s, 6H), 1.66 (d, J=1.4 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ=161.9, 160.6, 155.6, 146.1, 141.9, 131.7, 128.8 (2 C), 128.2
(2 C), 125.8, 121.7, 116.1, 108.1, 105.3, 104.6, 55.7, 37.4 (2 C), 25.8,
25.7 (2 C), 21.8, 17.8; IR νmax (neat) 1720, 1607, 1571, 1386, 1169,
1117 cm À 1; HRMS (ESI) m/z: [M+H]+ Calcd for C24H29O4 381.2060,
found 381.2057. Analytical data were in good agreement with
literature values.[12]
(400 MHz, CDCl3): δ=13.16 (s, 1H), 10.14 (s, 1H), 7.34–7.26 (m, 2H),
7.26–7.18 (m, 3H), 5.16–5.09 (m, 1H), 3.79–3.68 (m, 2H), 3.30 (d, J=
7.4 Hz, 2H), 2.99–2.92 (m, 2H), 1.77 (d, J=1.3 Hz, 3H), 1.70 (s, 6H),
1.68 (d, J=1.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ=205.9,
194.4, 166.8, 159.5, 151.9, 140.7, 132.9, 128.9 (2 C), 128.8 (2 C),
126.6, 120.7, 116.6, 114.9, 105.3, 105.0, 38.5, 29.9, 29.8, 26.1, 25.9,
21.4, 18.0; IR νmax (neat) 2922, 2851, 1733, 1634, 1583, 1264,
1208 cm-1 HRMS (ESI) m/z [M - H]À Calcd for C24H25O5 393.1702,
found 393.1710. Elemental analysis calcd for C24H26O5: C 73.08, H
6.64, found: C 73.08, H 7.11.
8-(2-Iodopropan-2-yl)-2,2-dimethyl-5-phenethyl-8,9-dihydro-4H-[1,3]
dioxino[4,5 e]benzofuran-4-one (30) and 6-Iodo-8-(2-iodopropan-2-
yl)-2,2-dimethyl-5-phenethyl-8,9-dihydro-4H-[1,3]dioxino[4,5-e]
benzofuran-4-one (7): I2 (230 mg, 0.906 mmol) and t-BuNH2 (142 μL,
1.36 mmol) in PhMe (3.5 mL) were stirred for 15 min, after which 5
(83 mg, 0.226 mmol) in CH2Cl2 (1.5 mL) was added dropwise with
stirring at room temperature. After 15 h, CH2Cl2 (20 mL), aqueous
Na2S2O3 solution (10%, 15 mL) and H2O (10 mL) were added
successively. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (3×20 mL). The combined organic
layers were washed in brine (15 mL), dried (MgSO4), filtered,
concentrated in vacuo and chromatographed (pentane/CH2Cl2, 1:1
to 1:4) to afford (�)-iodo-ether 30 (10 mg, 0.0203 mmol, 9%) as a
colorless oil and (�)-diiodide 7 (116 mg, 0.188 mmol, 83%) as a
white foam.
7-hydroxy-6-(hydroxymethyl)-2,2-dimethyl-8-(3-methylbut-2-en-
1-yl)-5-phenethyl-4H-benzo[d][1,3]dioxin-4-one (31): (�)-Diiodide
7 (80.0 mg, 0.129 mmol) was dissolved in dry THF (1.4 mL) and dry
°
PhMe (0.7 mL). After cooling to À 100 C, n-BuLi (2 M in cyclohexane,
0.26 mL, 0.518 mmol) was added to the solution with stirring. After
10 min, CuBr・Me2S (8.00 mg, 0.0388 mmol) and TMEDA (0.10 mL,
°
0.647 mmol) were added sequentially in one portion at À 100 C.
After 2 min of stirring, dry DMF (47.3 mg, 0.05 mL, 0.647 mmol) was
added to the reaction mixture, which was subsequently warmed to
room temperature and stirred for 18 h. The reaction mixture was
quenched with saturated aqueous NH4Cl (4 mL) and the aqueous
layer was extracted with EtOAc (3×10 mL). The combined organic
layers were washed with an aqueous HCl solution (10 mL) and a
saturated aqueous sodium chloride solution (15 mL). The washed
solution was dried (MgSO4), the dried solution was filtered and the
filtrate was concentrated under reduced pressure. Flash column
chromatography (pentane/EtOAc 15:1 to 10:1) gave amorfrutin
Analytical data for (�)-iodo-ether 30: Rf 0.56 (pentane/EtOAc 9:1);
1H NMR (400 MHz, CDCl3) δ=7.30–7.22 (m, 4H), 7.21–7.11 (m, 1H),
6.37 (s, 1H), 4.43 (dd, J=8.4, 7.3 Hz, 1H), 3.41–3.25 (overlapping m,
3H), 3.10 (dd, J=16.2, 7.3 Hz, 1H), 2.91 – 2.85 (m, 2H), 2.00 (s, 3H),
1.93 (s, 3H), 1.71 (s, 3H), 1.70 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3)
δ=165.6, 160.0, 153.9, 149.9, 141.8, 128.7 (2 C), 128.3 (2 C), 125.9,
111.0, 107.0, 105.0 (2 C), 92.6, 49.7, 37.4 (2 C), 33.7, 32.2, 31.7, 25.9,
25.8; IR νmax (neat) 1726, 1626, 1593, 1350, 1286, 1103 cmÀ 1; HRMS
(ESI) m/z [M+H]+ Calcd for C23H26IO4 493.0876, found 493.0887.
alcohol 31 (18 mg, 0.0454 mmol, 36%) as
a yellow oil and
resorcylate 5 (18 mg, 0.0491 mmol, 38%) as a yellow-white solid.
1
Analytical data for alcohol 31: Rf 0.05 (hexane/EtOAc 9:1); H NMR
(400 MHz, CDCl3) δ=8.68 (s, 1H), 7.30–7.25 (m, 2H), 7.23–7.18 (m,
1H), 7.16 (dd, J=8.1, 1.4 Hz, 2H), 5.15 (tdt, J=5.7, 2.8, 1.5 Hz, 1H),
4.66 (s, 2H), 3.51–3.33 (m, 1H), 3.30 (d, J=7.3 Hz, 2H), 2.84 (t, J=
7.5 Hz, 2H), 1.78 (d, J=1.4 Hz, 3H) 1.69 (d, J=1.4 Hz, 3H), 1.66 (s,
6H); 13C{1H} NMR (101 MHz, CDCl3) δ=161.3, 161.0, 156.3, 141.9,
141.8, 132.6, 129.2 (2 C), 128.5 (2 C), 126.2, 121.6, 119.7, 115.7,
104.7, 104.5, 60.3, 37.2, 31.2, 25.9, 22.0, 18.0; IR νmax (neat) 3339,
2924, 1722, 1691, 1588, 1453, 1305, 1211, 1130 cmÀ 1; HRMS (APCI)
m/z [M+H]+ Calcd for C24H29O5 397.2010, found 397.2002. Peak
found for m/z [MÀ H2O]+ Calcd for C24H27O4 379.1904, found
379.1889.
1
Analytical data for (�)-diiodide 7: Rf 0.44 (pentane/EtOAc 9:1); H
NMR (400 MHz, CDCl3) δ=7.44–7.40 (m, 2H), 7.35–7.28 (m, 2H),
7.25–7.16 (m, 1H), 4.58 (dd, J=9.2, 6.8 Hz, 1H), 3.72–3.54 (m, 2H),
3.50 (dd, J=16.4, 9.2 Hz, 1H), 3.29 (dd, J=16.4, 6.8 Hz, 1H), 2.87–
2.74 (m, 2H), 2.07 (s, 3H), 1.95 (s, 3H), 1.70 (s, 6H); 13C{1H} NMR
(101 MHz, CDCl3) δ 165.8, 159.1, 153.9, 150.4, 141.7, 128.8 (2 C),
128.3 (2 C), 126.0, 110.6, 106.7, 105.1, 91.7, 76.1, 49.0, 40.6, 35.3,
33.9, 33.8, 31.4, 25.8, 25.7; IR νmax (neat) 2922, 2852, 1733, 1454,
1283, 1205 cmÀ 1; HRMS (ESI) m/z [M+H]+ Calcd for C23H25I2O4
618.9842, found 618.9831. Elemental analysis calcd for C23H24I2O4: C
44.68, H 3.91, found: C 44.66, H 3.87.
Oxidation procedure of alcohol 31: Dess-Martin periodinane
(22 mg, 0.053 mmol) was added with stirring in one portion to
alcohol 31 (14 mg, 0.035 mmol) in CH2Cl2 (0.8 mL). After 2 h, the
mixture was concentrated and loaded onto a column with a Celite®
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Full Papers
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Deposition Numbers 2027209 (for 7), and 2027210 (for 8) contain
the supplementary crystallographic data for this paper. These data
are provided free of charge by the joint Cambridge Crystallographic
Data Centre and Fachinformationszentrum Karlsruhe Access Struc-
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Acknowledgements
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We greatly appreciate the GlaxoSmithKline endowment (to
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and mass spectrometric analysis, respectively. We also extend our
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elemental microanalysis.
Conflict of Interest
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Keywords: Aromatization · Biomimetic synthesis · Cyclization ·
Ketenes · Natural products
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Manuscript received: November 12, 2020
Revised manuscript received: January 25, 2021
Accepted manuscript online: January 27, 2021
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© 2021 Wiley-VCH GmbH