Biomimetic Total Syntheses of Amorfrutins A, B, (S)-D and (R)-D and Formal Synthesis of Amorfrutin C

Article abstract of DOI:10.1002/ejoc.202100301

Bibenzyl natural products, such as the amorfrutins, contain a heavily substituted aromatic core and display a diverse range of biological activities (anti-tumor, anti-diabetic, antimicrobial, and antibiotic). In this study, we report unified syntheses of amorfrutin A to D either through total or formal synthesis by employing a dual biomimetic strategy of polyketide aromatization followed by remote terpene functionalization. The key core structures were synthesized from β-keto dioxinone esters through a magnesium(II) mediated regioselective C-acylation, palladium catalyzed decarboxylative allylic rearrangement, and dehydrative cyclization.

Full text of DOI:10.1002/ejoc.202100301

Full Papers
doi.org/10.1002/ejoc.202100301
Biomimetic Total Syntheses of Amorfrutins A, B, (S)-D and
(R)-D and Formal Synthesis of Amorfrutin C
Thomas Mies,[a] Calum Patel,[a] Philip J. Parsons,[a] and Anthony G. M. Barrett*[a]
Bibenzyl natural products, such as the amorfrutins, contain a
heavily substituted aromatic core and display a diverse range of
biological activities (anti-tumor, anti-diabetic, antimicrobial, and
antibiotic). In this study, we report unified syntheses of
amorfrutin A to D either through total or formal synthesis by
employing a dual biomimetic strategy of polyketide aromatiza-
tion followed by remote terpene functionalization. The key core
structures were synthesized from β-keto dioxinone esters
through a magnesium(II) mediated regioselective C-acylation,
palladium catalyzed decarboxylative allylic rearrangement, and
dehydrative cyclization.
Introduction
β-Resorcylate natural products are a structurally diverse class of
secondary metabolites derived from mixed biosynthetic origins,
the polyketide pathway for the aromatic core and the terpene
pathway.[1] These natural products exhibit multiple bioactivities
and are often identified as hits in pharmaceutical studies.[2] In
particular, the amorfrutins, Figure 1, natural products isolated
from edible legumes, Glycyrrhiza foetida and Amorpha
fruticosa,[3] have been shown to be strong peroxisome prolifer-
ator-activated receptor gamma (PPAR-γ) activators.[4] The
nuclear receptor PPAR-γ is highly linked to metabolic diseases
such as obesity and type 2 diabetes.[5] Of particular note, Sauer
and co-workers found that the amorfrutins selectively activate
the PPAR-γ receptor without further downstream side effects, a
promising finding when compared to common PPAR-γ modu-
lating drugs.[2c,4b] In addition, amorfrutin A (1) was found to
exhibit narrow-spectrum antimicrobial and anti-tumor
activities.[3a,6] Liu and Proksch further reported that amorfrutin B
(2) showed micromolar minimum inhibition concentration (MIC)
antibiotic activity against methicillin-resistant strains of Staph-
ylococcus aureus (12.5 μM), vancomycin-resistant strains of
Enterococcus faecium (6.3 μM) and Enterococcus faecalis
(6.3 μM).[3d] However, while isolating and reporting the structure
of amorfrutin D (4S), Liu and Proksch did not report any
biological activities for this novel amorfrutin. Overall, such
findings underscore that the amorfrutins are promising candi-
dates for further pharmaceutical studies and it is thus evident
that a unified method to synthesize amorfrutins 1 to 4 and their
analogs is required.
Figure 1. Amorfrutin natural products 1–4.
Scheme 1. Strategy for the synthesis of the prenyl and geranyl amorfrutin
core.
Derived from the work by Harris and Hyatt,[7] the Barrett
group successfully employed β-keto dioxinone esters such as 7
in the total synthesis of several β-resorcylate natural
products.[8,9] In line with this prior work, our aim was to utilize
the highly electrophilic nature of acyl-ketene 6, which can be
regioselectively generated from dioxane-4,6-dione keto-dioxa-
none 5, in the presence of terpene alcohols such as prenol or
geraniol, to synthesize advanced β-keto dioxinone ester inter-
mediates 7,[9a] Scheme 1.
With this methodology in hand, we now report the
successful total syntheses of amorfrutin A (1), B (2) and both
enantiomers of amorfrutin D (4S and 4R, respectively), as well
as a formal synthesis of amorfrutin C (3), which further opens
up the possibility of SAR studies of C-5 derivatives.[10]
[a] T. Mies, C. Patel, 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/p.parsons
Results and Discussion
www.imperial.ac.uk/people/agm.barrett
Our retrosynthetic analysis therefore followed the aforemen-
tioned methods, with initial synthesis of the terpenoid β-keto
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100301
Eur. J. Org. Chem. 2021, 2540–2548
2540
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100301
Scheme 2. Retrosynthetic analyses for the syntheses of amorfrutins A, B and D (1), (2), (4S) and (4R).
dioxinone esters 7 to prepare the core structure of the
amorfrutins (Scheme 2). In the case of amorfrutin A, core
structure 8 (R1 =Me) should be converted into the natural
product through methylation and saponification according to
literature precedent.[4b,11] For the two enantiomers of amorfrutin
D, the allylic alcohols should be available through Brønsted or
Lewis acid mediated epoxide rearrangement reactions,[12] which
in turn should be available via stereo-, regio- and enantio-
specific epoxidation reactions.[13] This should provide the core
structure of amorfrutin B 8 (R1 =CH2-prenyl) which should be
converted into the natural product through similar manipula-
tions as in the case for amorfrutin A (1).[4c,14] The key core
structure
8 would thus be synthesized from β,δ-di-keto
dioxinone 9 using a biomimetic aromatization reaction.[8]
Dioxinone 9 should be available from β-keto dioxinone esters 7
via regioselective C-acylation followed by a palladium catalyzed
decarboxylative allylic rearrangement reaction.[9,11a,15] In turn,
the β-keto dioxinone esters 7 have already been synthesized
from dioxinone 12 through carboxylation and acyl-ketene
generation and trapping.[9,16]
As previously reported, keto-ester 14 and resorcylate 17
were synthesized according to the following procedure:
dioxinone carboxylic acid 11 was prepared following literature
methods by carboxylation of the enolate derived from
dioxinone 12, generated with lithium bis(trimethylsilyl)
amide.[9a,b] Coupling of acid 11 with 2-phenyl-1,3-dioxane-4,6-
dione (15) using N,N’-dicyclohexyl carbodiimide, followed by
Scheme 3. Synthesis of the dioxinone β-keto ester 14.
moyl chloride (18), followed by a palladium catalyzed Tsuji-
Trost-type decarboxylative allylic rearrangement and base
mediated aromatization (Scheme 4).
Triethylamine, cesium acetate and cesium carbonate were
examined as bases for this aromatization reaction and it was
found that the carbonate worked best on this substrate
providing the intermediate 17 in 49% yield. This was converted
into the natural product amorfrutin A (1) by phenol methylation
(98%) and saponification of the resultant 4H-benzo[d][1,3]
dioxin-4-one 19 (99%) (Scheme 5).[11] The NMR data for
synthetic amorfrutin A (1) were in good agreement with those
reported by Lee et al for the natural product (see Table S1 in
the SI).[6a]
°
regioselective acyl ketene generation at 55 C in the presence of
prenol (13) gave dioxinone ester 14 in excellent yield (99%,
Scheme 3).
Prenyl β-keto dioxinone ester 14 was converted into the key
intermediate 17 through a magnesium(II) chloride and pyridine
mediated regioselective C-acylation reaction with dihydrocinna-
Similarly, heating dioxane-4,6-dione keto-dioxanone 5 in the
presence of geraniol (20) gave β-keto dioxinone ester 21. Again,
Eur. J. Org. Chem. 2021, 2540–2548
www.eurjoc.org
2541
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100301
dium catalyzed Tsuji-Trost-type decarboxylative allylic rear-
rangement and base mediated aromatization gave the amor-
frutin B intermediate 24 (44%) alongside the unsubstituted
resorcylate 25 (8%) (Scheme 6). It is reasonable to suggest that
resorcylate 25 was formed during the palladium catalyzed
rearrangement reaction, according to earlier mechanistic stud-
ies.[15]
After having shown in a previous study that intermediate 17
was converted into amorfrutin C (3) as well as other C-5
substituted amorfrutin analogs,[10] resorcylate 25 is of value as
an intermediate for an alternative route towards the natural
product as well as C-5 analogs via a dihalogenated derivative
according to Wu et al.[17] Thus, iodination of resorcylate 25
(75%)[18] followed by methylation of the resultant diiodide 26
(80%) gave methyl ether 27 (Scheme 7) which should behave
similarly in the cross-coupling reactions Wu et. al. employed in
their total synthesis of amorfurtin C (3) and analogs. This
underlines the potential versatility of the biomimetic strategy
employed in this study to quickly generate amorfrutin natural
products as well as enabling late-stage diversification for the
synthesis of analogs of these natural products.
Scheme 4. Synthesis of the amorfrutin core 17.
To complete the total synthesis of amorfrutin B (2),
resorcylate 24 was methylated (82%) and the resultant 4H-
benzo[d][1,3]dioxin-4-one 28 saponified with aqueous potassi-
um hydroxide in DMSO to give the target natural product 2
(89%) (Scheme 8). Synthetic amorfrutin B exhibited similar NMR
Scheme 5. Completion of the synthesis of amorfrutin A (1).
magnesium(II) chloride and pyridine mediated regioselective
acylation reaction with dihydrocinnamoyl chloride (18), palla-
Scheme 6. Synthesis of the amorfrutin B intermediate 24 and side product 25.
Scheme 7. Formal syntheses of amorfrutin C (3) from intermediate 17[10] or alternatively through diiodo-intermediate 27.[17]
Eur. J. Org. Chem. 2021, 2540–2548
www.eurjoc.org
2542
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100301
Scheme 8. Completion of the synthesis of amorfrutin B (2).
data with those reported by Lee et al for natural amorfrutin B
(see Table S2 in the SI).[6a]
rearrangement to give the allylic alcohol,[12] but also mediated
the hydrolysis of the dioxinone moiety to give the iso-propanol
ester 31 (28% overall). To suppress dioxinone hydrolysis, iso-
propanol was substituted by tert-butanol. Under these con-
ditions, heating (S)-epoxide 30 with aluminum iso-propoxide in
The conversion of the amorfrutin B intermediate 28 into the
two enantiomers of amorfrutin D (4) is shown in Scheme 9. The
route is based on a possible biosynthetic link between
amorfrutin B and D by stereo- and regioselective epoxidation
followed by rearrangement into the two enantiomeric allylic
alcohols.
Asymmetric Sharpless dihydroxylation of diene 28 with AD-
mix-β gave (R)-diol 29 in 47% (enantiomeric ratio determined
as 97:3 through Mosher’s ester analysis).[13c,19] Reaction of diol
29 with methanesulfonyl chloride followed by cesium
carbonate gave the (S)-epoxide 30 in 69% yield.[9c,13e,f] Reaction
of this (S)-epoxide 30 with aluminum iso-propoxide in toluene
°
toluene and tert-butanol at 110 C gave the (S)-allylic alcohol 32
in 36%, while maintaining the dioxinone moiety. Saponification
of 31 and 32 using aqueous potassium hydroxide in DMSO
gave (S)-amorfrutin D (4S) in 97%.[11a,14b] This synthetic (S)-
26:0
amorfrutin D exhibited a different optical rotation value ½a�D
À 4.5 (c 0.40, acetone), compared with the proposed assignment
for the natural “(S)”-amorfrutin D {½a�2D2 +31 (c 0.14, acetone)},[3d]
while exhibiting a similar value to (S)-amorfrutin D synthesized
by Ogura et al {½a�D À 3.5 (c 0.41, acetone)}.[14b] In addition, the
21
°
and iso-propanol at 110 C not only facilitated the epoxide
NMR data for the synthesized (S)-enantiomer of amorfrutin D
Scheme 9. Syntheses of (S)-amorfrutin D (4S) and (R)-amorfrutin D (4R).
Eur. J. Org. Chem. 2021, 2540–2548
www.eurjoc.org
2543
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100301
size 40–63 μm.[21] The progress of reactions was monitored by
was in excellent agreement with that obtained by Ogura (see
Table S3 in the SI).[14b]
analytical thin-layer chromatography (TLC) on silica gel coated
aluminum F254 plates. Components on TLC plates were visualized
under UV light or by spraying with aqueous KMnO4 or acidic vanillin
and warming.
Reaction of diene 28 with AD-mix-α gave (S)-diol 33 in 66%
(enantiomeric ratio determined as 95:5 through Mosher’s ester
analysis).[13c,19] The (S)-diol 33 was converted into the (R)-epoxide
34 in 65% by a similar method as for the (S)-epoxide 30.
Heating (R)-epoxide with aluminum iso-propoxide in toluene
1H-NMR, carbon decoupled 19F-NMR and proton decoupled 13C-NMR
spectra were respectively recorded at 400 MHz and 101 MHz in
deuterated solvents at ambient temperature with chemical shifts
reported in ppm (δ) relative to Me4Si and referenced to the residual
solvent peak (CDCl3: 1H at 7.26 ppm, 13C at 77.16 ppm; CD3OD: 1H at
°
and tert-butanol at 110 C gave the (R)-allylic alcohol 35 in 81%.
Saponification with aqueous potassium hydroxide in DMSO
gave the (R)-enantiomer of amorfurtin D (4R) in 92% yield. The
optical rotation of 4R was found to be ½a�2D5:7 +2.1 (c 0.40,
acetone), which is similar in sign and value to the one reported
by Ogura et al ({½a�D21 +4.0 (c 0.42, acetone)}[14b] and the natural
amorfrutin {½a�2D2 +31 (c 0.14, acetone)}.[3d] The NMR data for the
(R)-enantiomer were consistent to those previously reported by
Liu and Proksch for natural amorfrutin D (see Table S4 in the
SI).[3d]
1
3.31 and 4.87 ppm, 13C at 49.0 ppm). Assignments of the H-NMR
and 13C-NMR spectra were made by the analysis of chemical shift
and coupling constant values, and, as appropriate, using COSY,
DEPT-135, HSQC and HMBC. HRMS spectra were recorded by the
Imperial College Mass Spectrometry Service under conditions of
electrospray ionization (ES), chemical ionization (CI) or electron
ionization (EI). Infra-red spectra of solids and liquids were recorded
as thin films. Melting points were recorded using a hot-stage
microscope apparatus and were reported uncorrected in degrees
°
Celsius ( C).
7-Methoxy-2,2-dimethyl-8-(3-methylbut-2-en-1-yl)-5-phenethyl-
4H-benzo[d][1,3]dioxin-4-one (19): Cs2CO3 (667 mg, 2.05 mmol,
2.93 equiv) and MeI (0.128 mL, 2.05 mmol, 2.93 equiv) were sequen-
tially added dropwise with stirring to resorcylate 17 (256 mg,
0.699 mmol, 1.00 equiv) in dry THF (6 mL). After 18 h, 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 washed with brine (15 mL), dried (MgSO4),
filtered, concentrated in vacuo and chromatographed (pentane:E-
EtOAc, 19:1 to 17:1) to give resorcylate 19 (261 mg, 0.686 mmol,
Conclusion
In this study, we completed the biomimetic total syntheses of
amorfrutin A and B as well as a dual formal synthesis of
amorfrutin C. Amorfrutin A was synthesized in an overall yield
of 42% from dioxinone (12) while amorfrutin B was synthesized
in an overall yield of 24% from 12. The amorfrutin B
intermediate 28 was converted into both enantiomers of the
terminal epoxide (30 and 34) which were separately converted
into natural product (+)-amorfrutin D (4R) and its unnatural
enantiomer (À )-amorfrutin D (4S) through epoxide rearrange-
ment and saponification. Amorfrutin (4S) was synthesized in an
overall yield of 3% from (12), while amorfrutin (4R) was
synthesized in an overall yield of 9% from (12). As in Ogura’s
study we found that the optical rotation value for synthetic (S)-
amorfrutin D did not match the proposed assignment for the
natural amorfrutin D as S. The optical rotation value for the
synthetic (R)-enantiomer matched that reported for natural
amorfrutin D, again in support of Ogura’s observations.
°
98%) as a white solid: m.p. 79–81 C (pentane/CH2Cl2); Rf 0.76
(pentane:Et2O 4:1); 1H NMR (400 MHz, CDCl3) δ=7.27 (d, J=5.3 Hz,
4H), 7.21–7.13 (m, 1H), 6.31 (s, 1H), 5.10 (ddq, J=8.8, 7.3, 1.5 Hz,
1H), 3.79 (s, 3H), 3.37–3.30 (m, 2H), 3.25 (d, J=7.4 Hz, 2H), 2.93–2.86
(m, 2H), 1.75 (d, J=1.4 Hz, 3H), 1.67 (d, J=2.6 Hz, 9H); 13C{1H} NMR
(100 MHz, CDCl3) δ=162.0, 160.7, 155.7, 146.2, 142.0, 131.8, 128.9
(2 C), 128.3 (2 C), 125.9, 121.8, 116.2, 108.2, 105.4, 104.7, 55.8, 37.5,
37.4, 25.9, 25.8 (2 C), 21.9, 17.9; IR νmax (neat) 1720, 1607, 1571,
1386, 1169, 1117 cmÀ 1; HRMS (ES-ToF) m/z: [M+H]+ Calcd for
C24H29O4 381.2060, found 381.2057. Analytical data were in good
agreement with reported values.[11a]
2-Hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)-6-phenethylben-
zoic acid (amorfrutin A) (1): Aqueous KOH (48%; 73.8 μL) was
added with stirring to resorcylate 19 (24.0 mg, 0.0631 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 (3×
15 mL). The combined organic layers were washed with brine
(15 mL), dried (MgSO4), filtered, concentrated in vacuo and
chromatographed (pentane:EtOAc, 1:1) to give amorfrutin A (1)
(24.0 mg, 0.0705 mmol, 99%) as a pale-yellow solid: m.p. 144–
Experimental Section
General Methods: CH2Cl2, THF, Et2O, DMSO, t-BuOH, iso-PrOH, and
PhMe were purified by filtration through activated alumina columns
or purchased as extra dry solvents and stored over 4 Å molecular
sieves. NEt3, (Me3Si)2NH, pyridine and t-BuNH2were purchased as
extra dry reagents and stored over 4 Å molecular sieves. Pentane
146 C (pentane/CH2Cl2); Rf 0.43 (hexane:EtOAc, 1:1); 1H NMR
°
(400 MHz, CDCl3) δ=7.33–7.27 (m, 2H), 7.24–7.15 (m, 3H), 6.22 (s,
1H), 5.24–5.14 (m, 1H), 3.80 (s, 3H), 3.35 (d, J=7.1 Hz, 2H), 3.30–3.21
(m, 2H), 2.96–2.88 (m, 2H), 1.79 (d, J=1.3 Hz, 3H), 1.68 (d, J=1.3 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ=175.7, 163.0, 162.3, 145.9,
142.0, 131.9, 128.7 (2 C), 128.5 (2 C), 126.1, 122.4, 115.5, 106.6,
103.9, 55.7, 39.4, 38.3, 29.8, 22.1, 17.9; IR νmax (neat) 3025, 2960,
2921, 1630, 1607, 1452, 1268 cmÀ 1; HRMS (ES-ToF) m/z: [M+H]+
Calcd for C21H25O4 341.1747, found 341.1746. Analytical data were
in good agreement with reported values.[6a,11a]
°
refers to the petroleum alkane fraction boiling between 40 C and
°
60 C. The concentration of n-BuLi was determined by titration
against diphenylacetic acid according to the procedure by Kofron
and Baclawski.[20] 11, 14 and 17 were synthesized according to
literature procedures.[10]
°
Reactions were carried out in cooled oven-dried (180 C) glassware
under a nitrogen or argon atmosphere using standard Schlenk
techniques and with transfers by cannulas and syringes. Unless
stated to the contrary, reactions were carried out at room temper-
ature, or at reaction temperatures recorded in the external bath.
Unless stated to the contrary, chromatography was carried out
using the flash techniques of Still employing silica gel 60 Å, particle
(E)-3,7-Dimethylocta-2,6-dien-1-yl 4-(2,2-dimethyl-4-oxo-4H-1,3-
dioxin-6-yl)-3-oxobutanoate (21): 2-Phenyl-1,3-dioxane-4,6-dione
(15) (5.51 g, 26.9 mmol, 1.82 equiv), DCC (5.53 g, 27.3 mmol,
1.82 equiv) and DMAP (3.34 g, 27.3 mmol, 1.82 equiv) were dis-
Eur. J. Org. Chem. 2021, 2540–2548
www.eurjoc.org
2544
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100301
solved in CH2Cl2 (230 mL) and, after 5 min, dioxinone acid 11
(5.08 g, 27.3 mmol, 1.82 equiv) was added with stirring. After 18 h,
Resorcylate 25: Rf 0.18 (hexane:EtOAc, 3:1); 1H NMR (400 MHz,
CDCl3) δ=7.33–7.24 (m, 4H), 7.24–7.15 (m, 1H), 6.36 (t, J=2.9 Hz,
1H), 6.30 (t, J=2.0 Hz, 1H), 3.35–3.28 (m, 2H), 2.92–2.85 (m, 2H),
1.68 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ=162.5, 161.2, 159.4,
149.6, 141.8, 128.8 (2 C), 128.4 (2 C), 126.0, 113.7, 105.2, 104.5,
102.1, 37.4, 37.0, 25.7 (2 C); IR νmax (neat) 3235, 1723, 1689, 1609,
°
the mixture was cooled to 0 C, the precipitate was filtered off and
the solid was washed with small portions of CH2Cl2 until the
precipitate appeared colorless. The filtrate was washed with
aqueous HCl (1 M; 2×20 mL) and the organic phase was separated,
dried (MgSO4), filtered and concentrated in vacuo to give crude
dioxane-4,6-dione-keto-dioxinone 5 as a yellow foam, which was
used directly in the next step. The residue was dissolved in PhMe
(115 mL) and geraniol (20) (2.31 g, 2.63 mL, 15.0 mmol, 1.00 equiv)
was added in one portion with stirring. The mixture was heated to
1581, 1446, 1388, 1377, 1355, 1287, 1268, 1204, 1167, 1053 cmÀ 1
;
HRMS (ESI) m/z: [M+H]+ Calcd for C18H19O4 299.1278, found
299.1275. Analytical data were in good agreement with reported
values.[15]
7-Hydroxy-6,8-diiodo-2,2-dimethyl-5-phenethyl-4H-benzo[d][1,3]
dioxin-4-one (26): I2 (54.0 mg, 0.214 mmol, 2.00 equiv) and t-BuNH2
(31.4 mg, 45.1 μL, 0.429 mmol, 4.00 equiv) in PhMe (1.6 mL) were
stirred for 15 min, after which resorcylate 25 (32.0 mg, 0.107 mmol,
1.00 equiv) in CH2Cl2 (0.70 mL) was added dropwise with stirring at
room temperature. After 18 h, the mixture was diluted with CH2Cl2
(10 mL) and quenched with aqueous Na2S2O3 solution (10%;
10 mL). The organic layer was separated, and the aqueous layer
was extracted with CH2Cl2 (3×15 mL). The combined organic layers
were washed with brine (10 mL), dried (MgSO4), filtered, concen-
trated in vacuo and chromatographed (pentane:EtOAc, 4:1) to give
diiodide 26 (44.0 mg, 0.0800 mmol, 75%) as an orange oil which
solidified upon standing: Rf 0.23 (hexane:EtOAc, 7:3); 1H NMR
(400 MHz, CDCl3) δ=7.44–7.39 (m, 2H), 7.35–7.29 (m, 2H,), 7.25–
7.18 (m, 1H), 3.64 (d, J=6.6 Hz, 2H), 2.85 (dd, J=9.3, 7.6 Hz, 2H),
1.73 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ=159.2, 158.5, 158.1,
150.5, 141.3, 128.8 (2 C), 128.6 (2 C), 126.3, 106.8, 105.9, 86.4, 71.0,
41.7, 35.1, 25.8 (2 C); IR νmax (neat) 3423, 1727, 1559, 1451, 1389,
1377, 1275, 1234, 1206, 1047 cmÀ 1; HRMS (APCI) m/z: [M+H]+
Calcd for C18H17I2O4 550.9211, found 550.9203.
°
55 C for 4 h after which the solution was concentrated in vacuo.
Chromatography (pentane:EtOAc, 9:1 to 7:1 to 4:1) gave geraniol
β-keto ester 21 (4.66 g, 12.8 mmol, 85%) as a yellow-orange oil: Rf
1
0.13 (hexane:EtOAc, 4:1); H NMR (400 MHz, CDCl3) δ=5.36 (s, 1H),
5.35–5.30 (m, 1H), 5.06 (tq, J=5.4, 1.5 Hz, 1H), 4.70–4.64 (m, 2H),
3.51 (s, 2H), 3.50 (s, 2H), 2.14–2.07 (m, 2H), 2.06 (s, 2H), 1.71 (s, 9H),
1.67 (d, J=1.3 Hz, 3H), 1.59 (d, J=1.4 Hz, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ=195.8, 166.5, 163.7, 160.6, 143.8, 132.1, 123.7,
117.4, 107.5, 97.3, 62.8, 49.3, 47.1, 39.6, 26.4, 25.8, 25.1 (2 C), 17.8,
16.7; IR νmax (neat) 1718, 1636, 1388, 1375, 1271, 1252, 1201,
1015 cmÀ 1
;
HRMS (ESI) m/z: [M+Na]+ Calcd for C20H28O6Na
387.1778, found 387.1770. Analytical data were in good agreement
with reported values.[9a,9b]
(E)-8-(3,7-Dimethylocta-2,6-dien-1-yl)-7-hydroxy-2,2-dimethyl-5-
phenethyl-4H-benzo[d][1,3]dioxin-4-one (24) and 7-Hydroxy-2,2-
dimethyl-5-phenethyl-4H-benzo[d][1,3]dioxin-4-one (25): MgCl2
(261 mg, 2.74 mmol, 2.00 equiv) and pyridine (293 mg, 0.30 mL,
3.70 mmol, 2.70 equiv) were sequentially added in one portion with
stirring to geraniol β-keto-ester 21 (500 mg, 1.37 mmol, 1.00 equiv)
in CH2Cl2 (7.00 mL) at 0 C. After 15 min, 3-phenylpropanoyl chloride
(18) (278 mg, 0.24 mL, 1.65 mmol, 1.20 equiv) was added dropwise
with stirring and after 1 h at 0 C, reaction was quenched with
saturated aqueous NH4Cl (10 mL) and the pH was adjusted to 1–2
with aqueous HCl (1 M). The two phases were separated, and the
aqueous layer was extracted with EtOAc (3×15 mL). The combined
organic layers were dried (MgSO4), filtered and concentrated in
vacuo to give crude β,δ-diketo ester 22 as a yellow oil, which was
used directly in the next step. The residue was dissolved in dry THF
(7.00 mL) and tri(2-furyl)phosphine (64.0 mg, 0.274 mmol,
0.20 equiv) and tris(dibenzylideneacetone)dipalladium(0) (63.0 mg,
0.0686 mmol, 0.05 equiv) were added sequentially in one portion
with stirring. After 2 h, Cs2CO3 (1.34 g, 4.12 mmol, 3.00 equiv) was
added in one portion and the resulting suspension was stirred for
an additional 1.5 h. Reaction was quenched with aqueous HCl (1 M;
15 mL), the two phases were separated, and the aqueous layer was
extracted with CH2Cl2 (3×15 mL). The combined organic layers
were dried (MgSO4), filtered, concentrated in vacuo and chromato-
graphed (pentane:EtOAc, 19:1 to 15:1 to 10:1) to give geraniol
resorcylate 24 (260 mg, 0.598 mmol, 44% over 2 steps) as an
orange oil and resorcylate 25 (32 mg, 0.107 mmol, 8%) as pale-
orange oil which solidified upon standing:
°
6,8-Diiodo-7-methoxy-2,2-dimethyl-5-phenethyl-4H-benzo[d][1,3]
dioxin-4-one (27): Cs2CO3 (76.0 mg, 0.240 mmol, 3.00 equiv) and
MeI (34.0 mg, 14.9 μL, 0.240 mmol, 3.00 equiv) were sequentially
added dropwise with stirring to resorcylate 26 (44.0 mg,
°
°
0.080 mmol, 1.00 equiv) in dry THF (1.2 mL). After 13 h at 35 C,
reaction was quenched with saturated aqueous NH4Cl (10 mL), the
layers were separated, and the aqueous layer was extracted with
EtOAc (3×10 mL). The combined organic layers were washed with
brine (15 mL), dried (MgSO4), filtered, concentrated in vacuo and
chromatographed (pentane:EtOAc, 9:1) to afford resorcylate 27
(36.0 mg, 0.064 mmol, 80%) as orange oil: Rf 0.64 (hexane:EtOAc
1
4:1); H NMR (400 MHz, CDCl3) δ=7.45–7.41 (m, 2H), 7.35–7.29 (m,
2H), 7.25–7.19 (m, 1H), 3.94 (s, 3H), 3.63 (s, 2H), 2.85 (dd, J=9.3,
7.6 Hz, 2H), 1.73 (s, 7H); 13C{1H} NMR (100 MHz, CDCl3) δ=164.8,
158.6, 158.2, 150.8, 141.5, 128.9 (2 C), 128.5 (2 C), 126.3, 110.2,
106.0, 94.6, 79.7, 60.9, 41.8, 35.2, 25.8 (2 C); IR νmax (neat) 1733, 1555,
1452, 1374, 1273, 1231, 1206, 1053 cmÀ 1; HRMS (APCI) m/z: [M+H]+
Calcd for C19H19I2O4 564.9367, found 564.9391. Major peak found for
m/z: [MÀ (CH3)2CO]+ Calcd for C16H13I2O3 506.8949, found 506.8954.
(E)-8-(3,7-Dimethylocta-2,6-dien-1-yl)-7-methoxy-2,2-dimethyl-5-
phenethyl-4H-benzo[d][1,3]dioxin-4-one (28): Cs2CO3 (1.99 g,
1.79 mmol, 3.00 equiv) and MeI (255 mg, 0.112 mL, 1.79 mmol,
3.00 equiv) were sequentially added dropwise with stirring to
resorcylate 24 (260 mg, 0.598 mmol, 1.00 equiv) in dry THF (8.0 mL).
Geraniol resorcylate 24: Rf 0.43 (hexane:EtOAc, 3:1); 1H NMR
(400 MHz, CDCl3) δ=7.31–7.22 (m, 4H), 7.21–7.12 (m, 1H), 6.89 (s,
1H), 6.47 (s, 1H), 5.26–5.19 (m, 1H), 5.07 (tp, J=6.9, 1.7 Hz, 1H), 3.35
(d, J=7.3 Hz, 2H), 3.32–3.25 (m, 2H), 2.91–2.84 (m, 2H), 2.17–2.08
(m, 2H), 2.08–1.98 (m, 2H), 1.80 (d, J=1.4 Hz, 3H), 1.70 (s, 6H), 1.69–
1.67 (m, 3H), 1.60 (d, J=1.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ=161.3, 160.7, 156.5, 146.3, 142.0, 137.9, 131.9, 128.7 (2 C), 128.4
(2 C), 125.9, 124.0, 121.1, 113.7, 113.4, 104.9, 104.7, 39.8, 37.5, 36.9,
26.6, 25.8 (3 C), 22.0, 17.8, 16.3; IR νmax (neat) 3258, 1689, 1603,
°
After 1.5 h at 40 C, reaction was quenched with saturated aqueous
NH4Cl (15 mL), the layers were separated, and the aqueous layer
was extracted with EtOAc (3×15 mL). The combined organic layers
were washed with brine (20 mL) dried (MgSO4), filtered, concen-
trated in vacuo and chromatographed (pentane:CH2Cl2, 1:1) to
give resorcylate 28 (221 mg, 0.493 mmol, 82%) as a colorless oil: Rf
1
0.57 (hexane:EtOAc 3:1); H NMR (400 MHz, CDCl3) δ=7.27 (d, J=
1591, 1420, 1375, 1295, 1269, 1208, 1165, 1105, 1058, 1048 cmÀ 1
;
6.0 Hz, 4H), 7.18 (ddd, J=8.6, 5.6, 2.6 Hz, 1H), 6.30 (s, 1H), 5.13–5.08
(m, 1H), 5.08–5.03 (m, 1H), 3.79 (s, 3H), 3.37–3.30 (m, 2H), 3.25 (d,
J=7.3 Hz, 2H), 2.93–2.87 (m, 2H), 2.04 (q, J=7.4 Hz, 2H), 1.95 (dd,
J=9.3, 6.0 Hz, 2H), 1.75 (d, J=1.4 Hz, 3H), 1.67 (s, 6H), 1.64 (d, J=
HRMS (APCI) m/z: [M+H]+ Calcd for C28H35O4 435.2530, found
435.2522.
Eur. J. Org. Chem. 2021, 2540–2548
www.eurjoc.org
2545
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100301
1.4 Hz, 3H), 1.57 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ=161.9,
MTBA resorcylate ester, which exhibited the following NMR data:
19F NMR (377 MHz, CDCl3) δ=À 70.71 for the (R)-enantiomer,
À 70.84 for the (S)-enantiomer, corresponding to the α-
trifluoromethyl group of the ester.
160.7, 155.7, 146.1, 141.9, 135.3, 131.4, 128.8 (2 C), 128.3 (2 C),
125.8, 124.2, 121.6, 116.2, 108.1, 105.3, 104.6, 55.7, 39.8, 37.4, 37.4,
26.7, 25.7 (3 C), 21.7, 17.7, 16.1; IR νmax (neat) 1727, 1605, 1575,
1292, 1267, 1209, 1170, 1119 cmÀ 1; HRMS (ES-ToF) m/z: [M+H]+
Calcd for C29H37O4 449.2686, found 449.2697.
(S,E)-8-(5-(3,3-Dimethyloxiran-2-yl)-3-methylpent-2-en-1-yl)-7-
methoxy-2,2-dimethyl-5-phenethyl-4H-benzo[d][1,3]dioxin-4-one
(30): Pyridine (221 mg, 0.230 mL, 2.80 mmol, 15.0 equiv) and
methanesulfonyl chloride (42.5 mg, 28.7 μL, 0.371 mmol,1.99 equiv)
were added sequentially with stirring to (R)-diol 29 (90.0 mg,
0.186 mmol, 1.00 equiv) in CH2Cl2 (3.00 mL). After 12 h, the mixture
was concentrated in vacuo and redissolved in THF (0.8 mL). Cs2CO3
(4.86 g, 14.9 mmol, 80.0 equiv) was added in one portion with
stirring. After 15 h, the mixture was diluted with CH2Cl2 (7.0 mL)
and quenched with H2O (20 mL). The organic layer was separated,
and the aqueous layer was further extracted with CH2Cl2 (3×
15 mL). The combined organic layers were dried (MgSO4), filtered,
concentrated in vacuo and chromatographed (pentane:EtOAc, 9:1)
to give (S)-epoxide 30 (60.0 mg, 0.129 mmol, 69%) as a colorless oil:
(E)-3-(3,7-Dimethylocta-2,6-dien-1-yl)-2-hydroxy-4-methoxy-6-
phenethylbenzoic acid (amorfrutin B) (2): Aqueous KOH (48%;
0.40 mL) was added with stirring to resorcylate 28 (21.0 mg,
°
0.0468 mmol) in dry DMSO (0.40 mL). After 16 h at 80 C, the
mixture was acidified to pH ~1 using aqueous HCl (1 M) and
extracted with EtOAc (3×10 mL). The combined organic layers
were washed with brine (15 mL), dried (MgSO4), filtered, concen-
trated in vacuo and chromatographed (EtOAc:CH2Cl2, 1:15) to give
amorfrutin B (2) (17.0 mg, 0.0416 mmol, 89%) as a yellow solid:
m.p. 79–80 C (pentane/CH2Cl2); Rf 0.35 (hexane:EtOAc, 1:1); 1H
°
NMR (400 MHz, CDCl3) δ=11.59 (s, 1H), 7.36–7.28 (m, 2H), 7.25–7.17
(m, 3H), 6.23 (s, 1H), 5.27–5.19 (m, 1H), 5.09 (dddd, J=8.5, 7.0, 2.8,
1.4 Hz, 1H), 3.80 (s, 3H), 3.37 (d, J=7.1 Hz, 2H), 3.32–3.25 (m, 2H),
2.97–2.91 (m, 2H), 2.07 (t, J=8.1 Hz, 2H), 1.99 (dd, J=9.4, 6.0 Hz,
2H), 1.80 (d, J=1.4 Hz, 3H), 1.66 (d, J=1.5 Hz, 3H), 1.59 (d, J=
1.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ=175.9, 163.1, 162.3,
145.9, 142.0, 135.4, 131.3, 128.7 (2 C), 128.5 (2 C), 126.1, 124.6,
122.2, 115.6, 106.6, 103.8, 55.7, 40.0, 39.4, 38.3, 26.9, 25.8, 22.1, 17.8,
25:2
Rf 0.62 (hexane:EtOAc, 1:1); ½a�D À 1.7 (c 1.00, CHCl3); 1H NMR
(400 MHz, CDCl3) δ=1H NMR (400 MHz, Chloroform-d) δ 7.30–7.25
(m, 4H), 7.18 (ddd, J=8.6, 5.6, 2.4 Hz, 1H), 6.31 (s, 1H), 5.15 (tdd, J=
7.2, 2.5, 1.2 Hz, 1H), 3.79 (s, 3H), 3.38–3.30 (m, 2H), 3.26 (d, J=
7.3 Hz, 2H), 2.94–2.86 (m, 3H), 2.66 (t, J=6.3 Hz, 1H), 2.19–2.01 (m,
2H), 1.77 (d, J=1.3 Hz, 3H), 1.67 (d, J=2.0 Hz, 6H), 1.67–1.55 (m,
2H), 1.24 (s, 3H), 1.23 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ=
162.0, 160.7, 155.7, 146.4, 142.0, 134.4, 128.9 (2 C), 128.4 (2 C),
126.0, 122.4, 116.0, 108.2, 105.4, 104.7, 64.3, 58.5, 55.8, 37.5, 37.4,
36.5, 27.5, 25.9, 25.8, 24.9, 21.9, 18.8, 16.2; IR νmax (neat) 1725, 1604,
1575, 1375, 1334, 1291, 1268, 1208, 1167, 1119, 1051 cmÀ 1; HRMS
(APCI) m/z: [M+H]+ Calcd for C29H37O5 465.2636, found 465.2623;
major peak found for m/z: [MÀ (CH3)2CO]+ Calcd for C26H31O4
407.2217, found 407.2206.
16.3; IR νmax (neat) 2922, 1628, 1607, 1453, 1267, 1225, 1114 cmÀ 1
;
HRMS (ES-ToF) m/z: [MÀ H]À Calcd for C26H31O4 407.2228, found
407.2232. Analytical data were in agreement with reported
values.[6a,14b]
(R,E)-8-(6,7-Dihydroxy-3,7-dimethyloct-2-en-1-yl)-7-methoxy-2,2-
dimethyl-5-phenethyl-4H-benzo[d][1,3]dioxin-4-one (29): Resorcy-
late 28 (196 mg, 0.437 mmol, 1.00 equiv) was dissolved in tert-
°
BuOH (2.20 mL) and H2O (2.20 mL) and cooled to 0 C. Methane-
sulfonamide (42.0 mg, 0.437 mmol, 1.00 equiv) and AD-mix-β
iso-Propyl
(S,E)-2-hydroxy-3-(6-hydroxy-3,7-dimethylocta-2,7-
(612 mg, 0.437 mmol (based on 1.4 g per mmol), 1.00 equiv) were
dien-1-yl)-4-methoxy-6-phenethylbenzoate (31): Aluminium iso-
propoxide (100 mg, 0.490 mmol, 3.80 equiv) was added in one
portion with stirring to (S)-epoxide 30 (60.0 mg, 0.129 mmol,
1.00 equiv) in PhMe (1.70 mL) and iso-PrOH (0.34 mL). After 5 h at
°
sequentially added in one portion with stirring. After 24 h at 0 C,
the mixture was diluted with EtOAc (5.0 mL) and H2O (5.0 mL) and
quenched with solid Na2S2O5 (700 mg). After stirring for 30 min, the
layers were separated, and the aqueous layer was further extracted
with EtOAc (3×15 mL). The combined organic layers were washed
with aqueous KOH (2 M; 20 mL), brine (15 mL), dried (MgSO4),
filtered and concentrated in vacuo. Chromatography (pentane:E-
EtOAc, 9:1 to 7:3) gave (R)-diol 29 (99.0 mg, 0.205 mmol, 47%,
79% corrected for recovered resorcylate 28 as a colorless oil: Rf 0.22
°
110 C, the mixture was diluted with EtOAc (10 mL) and quenched
with aqueous HCl (1 M; 20 mL). The organic layer was separated,
and the aqueous layer was further extracted with EtOAc (3×15 mL).
The combined organic layers were washed with H2O (10 mL), brine
(20 mL), dried (MgSO4), filtered concentrated in vacuo and
chromatographed (pentane:EtOAc, 9:1) to give (S)-allylic alcohol
22:3
(hexane:EtOAc, 1:1); ½a�D +26.4 (c 1.00, CHCl3); 1H NMR (400 MHz,
31 (17.0 mg, 0.0364 mmol, 28%) as a colorless oil: Rf 0.35
25:4 1
CDCl3) δ=7.31–7.24 (m, 4H), 7.18 (ddd, J=8.6, 5.6, 2.4 Hz, 1H), 6.31
(s, 1H), 5.18 (ddt, J=7.3, 6.0, 1.3 Hz, 1H), 3.79 (s, 3H), 3.39–3.29 (m,
3H), 3.27 (d, J=7.3 Hz, 2H), 2.94–2.87 (m, 2H), 2.28–2.17 (m, 1H),
2.11–2.01 (m, 1H), 1.77 (d, J=1.3 Hz, 3H), 1.68 (d, J=1.3 Hz, 6H),
1.57 (dddd, J=13.7, 8.8, 6.6, 1.9 Hz, 1H), 1.47–1.34 (m, 1H), 1.18 (s,
3H), 1.14 (s, 3H);13C{1H} NMR (101 MHz, CDCl3) δ=162.1, 160.7,
155.7, 146.4, 142.0, 135.4, 128.9 (2 C), 128.4 (2 C), 126.0, 122.6,
115.9, 108.3, 105.4, 104.8, 78.5, 73.1, 55.8, 37.5, 37.4, 37.1, 29.7, 26.5,
25.9, 25.9, 23.5, 21.9, 16.1; IR νmax (neat) 3443, 1724, 1605, 1574,
(hexane:EtOAc, 4:1); ½a�D À 39.1 (c 1.00, CHCl3); H NMR (400 MHz,
CDCl3) δ=11.90 (s, 1H), 7.31–7.25 (m, 2H), 7.22–7.15 (m, 3H), 6.11
(d, J=2.5 Hz, 1H), 5.35 (p, J=6.3 Hz, 1H), 5.25 (tp, J=5.6, 1.4 Hz,
1H), 4.89 (dt, J=2.0, 1.0 Hz, 1H), 4.80 (p, J=1.6 Hz, 1H), 4.04–3.98
(m, 1H), 3.73 (d, J=3.1 Hz, 3H), 3.34 (d, J=7.0 Hz, 2H), 3.25 (ddd, J=
8.3, 6.6, 1.5 Hz, 2H), 2.91 (t, J=7.9 Hz, 2H), 2.12–1.90 (m, 2H), 1.78
(dd, J=7.4, 1.3 Hz, 3H), 1.71 (t, J=1.2 Hz, 3H), 1.70–1.52 (m, 2H),
1.39 (s, 3H), 1.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ=171.4,
162.1, 161.1, 147.7, 144.0, 141.9, 134.8, 128.5 (2 C), 128.4 (2 C),
126.0, 123.2, 115.1, 110.9, 106.2, 105.7, 75.9, 69.4, 55.6, 38.4, 38.1,
36.0, 33.2, 22.1 (2 C), 22.1, 17.9, 16.2; IR νmax (neat) 3437, 1642, 1608,
1571, 1453, 1405, 1374, 1277, 1228, 1167, 1103 cmÀ 1; HRMS (APCI)
m/z: [M+H]+ Calcd for C29H39O5 467.2792, found 467.2784; major
peak found for m/z: [MÀ (CH3)2CHOH]+ Calcd for C26H31O4 407.2222,
found 407.2209.
1453, 1410, 1388, 1375, 1335, 1293, 1268, 1210, 1167, 1053 cmÀ 1
;
HRMS (ES-ToF) m/z: [M+H]+ Calcd for C29H39O6 483.2741, found
483.2728. Major peak found for m/z: [M+Na]+ Calcd for C29H38O6Na
505.2561, found 505.2575.
The enantiomeric ratio for resorcylate 29 was determined as 97:3
by Mosher’s ester analysis according to a procedure by Corey and
Zhang:[19]
(S)-(+)-α-Methoxy-α-(trifluoromethyl)phenylacetyl
(S,E)-8-(6-Hydroxy-3,7-dimethylocta-2,7-dien-1-yl)-7-methoxy-2,2-
dimethyl-5-phenethyl-4H-benzo[d][1,3]dioxin-4-one (32): Alumi-
nium iso-propoxide (32.0 mg, 0.155 mmol, 2.00 equiv) was added in
one portion with stirring to (S)-epoxide 30 (36.0 mg, 0.0775 mmol,
1.00 equiv) in PhMe (1.00 mL) and tert-BuOH (0.30 mL). After 23 h at
chloride (9.3 μL, 13 mg, 0.050 mmol, 2.0 equiv) was added to a
mixture of resorcylate 29 (12 mg, 0.025 mmol, 1.0 equiv) and DMAP
(12 mg, 0.099 mmol, 4.0 equiv) in CH2Cl2 (1.0 mL). After 1.5 h, the
reaction mixture was loaded onto a pipette column, and further
eluted with Et2O (15 mL). Concentration in vacuo afforded the (S)-
°
110 C, the mixture was diluted with EtOAc (5.0 mL) and quenched
Eur. J. Org. Chem. 2021, 2540–2548
www.eurjoc.org
2546
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100301
with aqueous HCl (1 M; 15 mL). The organic layer was separated,
δ=162.1, 160.7, 155.7, 146.4, 142.0, 135.4, 128.9 (2 C), 128.3 (2 C),
125.9, 122.5, 116.0, 108.3, 105.4, 104.7, 78.4, 73.0, 55.8, 37.5, 37.3,
37.1, 29.7, 26.5, 25.8, 25.8, 23.4, 21.9, 16.1; IR νmax (neat) 3443, 1718,
1603, 1572, 1452, 1409, 1387, 1375, 1334, 1290, 1266, 1207, 1164,
and the aqueous layer was further extracted with EtOAc (3×10 mL).
The combined organic layers were washed with H2O (10 mL), brine
(20 mL), dried (MgSO4), filtered concentrated in vacuo and
chromatographed (pentane:EtOAc, 85:15) to give (S)-allylic alcohol
1117, 1051 cmÀ 1
;
HRMS (ES-ToF) m/z: [M+Na]+ Calcd for
32 (13.0 mg, 0.0280 mmol, 36%) as
a
colorless oil: Rf 0.17
C29H38O6Na 505.2561, found 505.2575.
26:1
1
(hexane:EtOAc, 4:1); ½a�D À 9.3 (c 1.00, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.30–7.24 (m, 4H), 7.18 (ddd, J=8.6, 5.5, 2.2 Hz, 1H), 6.30
(s, 1H), 5.14 (tq, J=7.5, 1.4 Hz, 1H), 4.89 (dt, J=1.9, 1.0 Hz, 1H), 4.82
(p, J=1.7 Hz, 1H), 4.01 (t, J=6.4 Hz, 1H), 3.79 (s, 3H), 3.38–3.30 (m,
2H), 3.26 (d, J=7.3 Hz, 2H), 2.95–2.86 (m, 2H), 2.09–1.93 (m, 2H),
1.77 (d, J=1.4 Hz, 3H), 1.71 (t, J=1.2 Hz, 3H), 1.67 (s, 6H), 1.66–1.59
(m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ=162.0, 160.7, 155.7, 147.5,
146.4, 142.0, 135.1, 128.9 (2 C), 128.4 (2 C), 126.0, 122.3, 116.0,
111.1, 108.2, 105.4, 104.7, 75.8, 55.8, 37.5, 37.5, 35.9, 33.2, 25.9, 25.9,
21.9, 17.8, 16.2; IR νmax (neat) 3453, 1729, 1604, 1575, 1456, 1411,
1387, 1375, 1334, 1295, 1268, 1208, 1171, 1120, 1051 cmÀ 1; HRMS
(ES-ToF) m/z: [M+H]+ Calcd for C29H37O5 465.2636, found 465.2652;
major peak found for m/z: [M+Na]+ Calcd for C29H36NaO5 487.2455,
found 487.2441.
The enantiomeric ratio for resorcylate 33 was determined as 95:5
by Mosher’s ester analysis according to a procedure by Corey and
Zhang:[19]
(S)-(+)-α-Methoxy-α-(trifluoromethyl)phenylacetyl
chloride (5.4 μL, 7.0 mg, 0.029 mmol, 2.0 equiv) was added to a
mixture of resorcylate 32 (7.0 mg, 0.015 mmol, 1.0 equiv) and
DMAP (7.0 mg, 0.058 mmol, 4.0 equiv) in CH2Cl2 (0.6 mL). After 3 h,
the reaction mixture was loaded onto a pipette column, and further
eluted with Et2O (15 mL). Concentration in vacuo afforded the (S)-
MTBA resorcylate ester, which exhibited the following NMR data:
19F{13C} NMR (400 MHz, CDCl3) δ=À 70.72 for the (R)-enantiomer,
À 70.85 for the (S)-enantiomer, corresponding to the α-
trifluoromethyl group of the ester.
(R,E)-8-(5-(3,3-Dimethyloxiran-2-yl)-3-methylpent-2-en-1-yl)-7-
methoxy-2,2-dimethyl-5-phenethyl-4H-benzo[d][1,3]dioxin-4-one
(34): Pyridine (123 mg, 0.125 mL, 1.55 mmol, 15.0 equiv) and
methanesulfonyl chloride (23.6 mg, 16.0 μL, 0.206 mmol,1.99 equiv)
were added sequentially with stirring to (S)-diol 33 (50.0 mg,
0.104 mmol, 1.00 equiv) in CH2Cl2 (2.00 mL). After 6 h, the mixture
was concentrated in vacuo and redissolved in THF (0.5 mL). Cs2CO3
(2.70 g, 8.29 mmol, 80.0 equiv) was added in one portion with
stirring. After 17 h, the mixture was diluted with CH2Cl2 (4.0 mL)
and quenched with H2O (15 mL). The organic layer was separated,
and the aqueous layer was further extracted with CH2Cl2 (3×
10 mL). The combined organic layers were dried (MgSO4), filtered,
concentrated in vacuo and chromatographed (pentane:EtOAc, 9:1)
to give (R)-epoxide 34 (31.0 mg, 0.0672 mmol, 65%) as a colorless
(S,E)-2-Hydroxy-3-(6-hydroxy-3,7-dimethylocta-2,7-dien-1-yl)-4-
methoxy-6-phenethylbenzoic acid ((S)-amorfrutin D) (4S): Aque-
ous KOH (48%; 0.30 mL) was added with stirring to (S)-iso-propyl
ester 31 (17.0 mg, 0.0364 mmol) in dry DMSO (0.30 mL). After 17 h
°
at 80 C, the mixture was acidified to pH ~1 using aqueous HCl
(1 M) and extracted with EtOAc (3×10 mL). The combined organic
layers were washed with brine (15 mL), dried (MgSO4), filtered,
concentrated in vacuo and chromatographed (EtOAc:CH2Cl2, 1:15)
to give (S)-amorfrutin D (4S) (15.0 mg, 0.0353 mmol, 97%) as a
26:0
white film: Rf 0.03 (hexane:EtOAc, 4:1); ½a�D À 4.5 (c 0.40, acetone);
1H NMR (400 MHz, CDCl3) δ=11.72 (s, 1H), 7.34–7.26 (m, 2H), 7.20
(dt, J=9.3, 3.0 Hz, 3H), 6.20 (s, 1H), 5.31–5.23 (m, 1H), 4.89 (s, 1H),
4.81 (t, J=1.7 Hz, 1H), 4.05 (t, J=6.3 Hz, 1H), 3.78 (d, J=3.4 Hz, 3H),
3.36 (d, J=7.1 Hz, 2H), 3.30–3.22 (m, 2H), 2.91 (dd, J=9.5, 6.3 Hz,
2H), 2.10–1.99 (m, 2H), 1.83–1.79 (m, 3H), 1.71 (s, 3H), 1.70–1.62 (m,
2H); 13C{1H} NMR (101 MHz, CDCl3) δ=175.5, 163.0, 162.1, 147.4,
145.8, 142.1, 135.0, 128.7, 128.5, 126.0, 123.1, 115.2, 111.1, 106.5,
104.0, 76.0, 55.7, 39.4, 38.3, 36.1, 33.1, 22.0, 17.9, 16.2; IR νmax (neat)
1
oil: Rf 0.58 (hexane:EtOAc, 1:1); ½a�25:4 +1.4 (c 1.00, CHCl3); H NMR
(400 MHz, CDCl3) δ=7.32–7.23 (m,D4H), 7.21–7.15 (m, 1H), 6.31 (s,
1H), 5.16 (tq, J=7.3, 1.3 Hz, 1H), 3.79 (s, 3H), 3.39–3.31 (m, 2H), 3.27
(d, J=7.3 Hz, 2H), 2.94–2.87 (m, 2H), 2.67 (t, J=6.3 Hz, 1H), 2.20–
2.01 (m, 2H), 1.78 (d, J=1.3 Hz, 3H), 1.68 (s, 6H), 1.66–1.54 (m, 2H),
1.25 (s, 3H), 1.24 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ=162.0,
160.6, 155.7, 146.4, 142.0, 134.4, 128.9 (2 C), 128.3 (2 C), 125.9,
122.4, 116.0, 108.2, 105.4, 104.7, 64.2, 58.4, 55.8, 37.5, 37.4, 36.5,
27.5, 25.9, 25.8, 24.9, 21.9, 18.8, 16.2; IR νmax (neat) 1724, 1603, 1573,
1410, 1387, 1333, 1290, 1267, 1207, 1166, 1118, 1050 cmÀ 1; HRMS
(APCI) m/z: [M+H]+ Calcd for C29H37O5 465.2636, found 465.2629.
Major peak found for m/z: [MÀ (CH3)2CO]+ Calcd for C26H31O4
407.2217, found 407.2212.
3500, 1649, 1605, 1573, 1453, 1404, 1268, 1226, 1170, 1114 cmÀ 1
;
HRMS (ES-ToF) m/z: [M - H]À Calcd for C26H31O5 423.2177, found
423.2180. Similar yields (93%) were obtained when the (S)-allylic
alcohol 32 was allowed to react in this fashion. Analytical data were
in good agreement with reported values.[14b]
(S,E)-8-(6,7-Dihydroxy-3,7-dimethyloct-2-en-1-yl)-7-methoxy-2,2-
dimethyl-5-phenethyl-4H-benzo[d][1,3]dioxin-4-one (33): Resorcy-
late 28 (80.0 mg, 0.178 mmol, 1.00 equiv) was dissolved in tert-
(R,E)-8-(6-Hydroxy-3,7-dimethylocta-2,7-dien-1-yl)-7-methoxy-2,2-
dimethyl-5-phenethyl-4H-benzo[d][1,3]dioxin-4-one (35): Alumi-
nium iso-propoxide (27.0 mg, 0.133 mmol, 2.00 equiv) was added in
one portion with stirring to (R)-epoxide 34 (31.0 mg, 0.0667 mmol,
1.00 equiv) in PhMe (1.00 mL) and tert-BuOH (0.30 mL). After 23 h at
°
BuOH (1.00 mL) and H2O (1.00 mL) and cooled to 0 C. Methane-
sulfonamide (17.0 mg, 0.178 mmol, 1.00 equiv) and AD-mix-α
(250 mg, 0.178 mmol (based on 1.4 g per mmol), 1.00 equiv) were
°
sequentially added in one portion with stirring. After 24 h at 0 C,
the mixture was diluted with EtOAc (2.0 mL) and H2O (5.0 mL) and
quenched with solid Na2S2O5 (285 mg). After stirring for 30 min, the
layers were separated, and the aqueous layer was further extracted
with EtOAc (3×10 mL). The combined organic layers were washed
with aqueous KOH (2 M; 15 mL), brine (10 mL), dried (MgSO4),
filtered and concentrated in vacuo. Chromatography (pentane:E-
EtOAc, 9:1 to 7:3) gave (S)-diol 33 (57.0 mg, 0.118 mmol, 66%,
87% corrected for recovered resorcylate 28, as a colorless oil: Rf
°
110 C, the mixture was diluted with EtOAc (5.0 mL) and quenched
with aqueous HCl (1 M; 15 mL). The organic layer was separated,
and the aqueous layer was further extracted with EtOAc (3×10 mL).
The combined organic layers were washed with H2O (10 mL), brine
(20 mL), dried (MgSO4), filtered concentrated in vacuo and
chromatographed (pentane:EtOAc, 85:15) to give (R)-allylic alcohol
35 (25.0 mg, 0.0538 mmol, 81%) as
a colorless oil: Rf 0.27
(hexane:EtOAc, 4:1); ½a�D +11.2 (c 1.00, CHCl3); 1H NMR (400 MHz,
CDCl3) δ=7.30–7.24 (m, 4H), 7.18 (pd, J=5.7, 2.5 Hz, 1H), 6.30 (s,
1H), 5.15 (tq, J=7.3, 1.3 Hz, 1H), 4.89 (dq, J=3.1, 2.0, 1.5 Hz, 1H),
4.81 (p, J=1.6 Hz, 1H), 4.01 (t, J=6.4 Hz, 1H), 3.78 (s, 3H), 3.38–3.31
(m, 2H), 3.26 (d, J=7.3 Hz, 2H), 2.94–2.87 (m, 2H), 2.10–1.92 (m, 2H),
1.77 (d, J=1.4 Hz, 3H), 1.71 (t, J=1.2 Hz, 3H), 1.67 (s, 6H), 1.66–1.58
(m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ=162.1, 160.7, 155.8, 147.6,
146.3, 142.0, 135.1, 128.9 (2 C), 128.4 (2 C), 125.9, 122.3, 116.1,
26:1
23:6
0.22 (hexane:EtOAc, 1:1); ½a�D À 24.8 (c 1.00, CHCl3); 1H NMR
(400 MHz, CDCl3) δ=7.30–7.24 (m, 4H), 7.18 (ddd, J=8.7, 5.6,
2.3 Hz, 1H), 6.31 (s, 1H), 5.18 (tq, J=7.3, 1.3 Hz, 1H), 3.79 (s, 3H),
3.39–3.30 (m, 3H), 3.27 (d, J=7.2 Hz, 2H), 2.96–2.86 (m, 2H), 2.35 (s,
1H), 2.29–2.17 (m, 1H), 2.10–2.01 (m, 1H), 1.78 (d, J=1.3 Hz, 3H),
1.72–1.65 (m, 6H), 1.58 (dddd, J=13.8, 8.9, 6.7, 1.9 Hz, 1H), 1.47–
1.38 (m, 1H), 1.19 (s, 3H), 1.15 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
Eur. J. Org. Chem. 2021, 2540–2548
www.eurjoc.org
2547
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100301
K. Siems, L. Muller-Kuhrt, A. Schurmann, R. Schuler, A. F. Pfeiffer, F. C.
111.1, 108.3, 105.4, 104.7, 75.8, 55.8, 37.5, 37.4, 35.9, 33.2, 25.9, 25.9,
21.9, 17.8, 16.2; IR νmax (neat) 3445, 1723, 1603, 1573, 1452, 1410,
1388, 1375, 1334, 1290, 1267, 1208, 1168, 1118, 1051 cmÀ 1; HRMS
(APCI) m/z: [M+H]+ Calcd for C29H37O5 465.2636, found 465.2618;
major peak found for m/z: [MÀ (CH3)2CO]+ Calcd for C26H31O4
407.2217, found 407.2199.
Schroeder, K. Bussow, S. Sauer, Proc. Natl. Acad. Sci. USA 2012, 109,
7257–7262; c) J. C. de Groot, C. Weidner, J. Krausze, K. Kawamoto, F. C.
Schroeder, S. Sauer, K. Büssow, J. Med. Chem. 2013, 56, 1535–1543; d) C.
Weidner, S. J. Wowro, A. Freiwald, K. Kawamoto, A. Witzke, M. Kliem, K.
Siems, L. Müller-Kuhrt, F. C. Schroeder, S. Sauer, Diabetologia 2013, 56,
1802–1812; e) L. Fuhr, M. Rousseau, A. Plauth, F. C. Schroeder, S. Sauer,
J. Nat. Prod. 2015, 78, 1160–1164.
(R,E)-2-Hydroxy-3-(6-hydroxy-3,7-dimethylocta-2,7-dien-1-yl)-4-
methoxy-6-phenethylbenzoic acid ((R)-amorfrutin D) (4R): Aque-
ous KOH (48%; 0.30 mL) was added with stirring to (R)-allylic
alcohol 35 (24.0 mg, 0.0517 mmol) in dry DMSO (0.30 mL). After
[5] a) J. Berger, D. E. Moller, Annu. Rev. Med. 2002, 53, 409–435; b) M.
Lehrke, M. A. Lazar, Cell 2005, 123, 993–999.
[6] a) N. T. Dat, J.-H. Lee, K. Lee, Y.-S. Hong, Y. H. Kim, J. J. Lee, J. Nat. Prod.
2008, 71, 1696–1700; b) C. Mi, J. Ma, K. S. Wang, Z. Wang, M. Y. Li, J. B.
Li, X. Li, L. X. Piao, G. H. Xu, X. Jin, Immunopharmacol. Immunotoxicol.
2017, 39, 338–347.
[7] a) T. M. Harris, C. M. Harris, Tetrahedron 1977, 33, 2159–2185; b) J. A.
Hyatt, P. L. Feldman, R. J. Clemens, J. Org. Chem. 1984, 49, 5105–5108.
[8] R. Cookson, T. N. Barrett, A. G. M. Barrett, Acc. Chem. Res. 2015, 48, 628–
642.
[9] a) D. C. Elliott, T.-K. Ma, A. Selmani, R. Cookson, P. J. Parsons, A. G. M.
Barrett, Org. Lett. 2016, 18, 1800–1803; b) T.-K. Ma, A. J. P. White, A. G. M.
Barrett, Tetrahedron Lett. 2017, 58, 2765–2767; c) T.-K. Ma, D. C. Elliott, S.
Reid, A. J. P. White, P. J. Parsons, A. G. M. Barrett, J. Org. Chem. 2018, 83,
13276–13286; d) T.-K. Ma, P. J. Parsons, A. G. M. Barrett, J. Org. Chem.
2019, 84, 4961–4970.
°
17 h at 80 C, the mixture was acidified to pH~1 using aqueous HCl
(1 M) and extracted with EtOAc (3×10 mL). The combined organic
layers were washed with brine (15 mL), dried (MgSO4), filtered,
concentrated in vacuo and chromatographed (EtOAc:pentane, 3:7)
to give (R)-amorfrutin D (4R) (20.0 mg, 0.0471 mmol, 92%) as a
white film: Rf 0.09 (hexane:EtOAc, 7:3); ½a�2D5:7 +2.1 (c 0.40, acetone);
1H NMR (400 MHz, CDCl3) δ=11.67 (s, 1H), 7.31–7.26 (m, 2H), 7.19
(ddd, J=7.4, 3.7, 2.4 Hz, 3H), 6.20 (s, 1H), 5.26 (tq, J=7.1, 1.4 Hz,
1H), 4.89 (dt, J=1.9, 1.0 Hz, 1H), 4.81 (p, J=1.6 Hz, 1H), 4.08–4.01
(m, 1H), 3.78 (s, 3H), 3.36 (d, J=7.1 Hz, 2H), 3.30–3.21 (m, 2H), 2.97–
2.88 (m, 2H), 2.03 (hept, J=7.0 Hz, 2H), 1.80 (d, J=1.3 Hz, 3H), 1.71
(t, J=1.2 Hz, 3H), 1.67 (dtd, J=8.3, 6.9, 4.6 Hz, 2H); 13C{1H} NMR
(101 MHz, CDCl3) δ=175.5, 163.0, 162.2, 147.4, 145.9, 142.1, 135.0,
128.7 (2 C), 128.5 (2 C), 126.1, 123.1, 115.3, 111.1, 106.5, 104.0, 76.1,
55.7, 39.3, 38.3, 36.1, 33.1, 22.1, 17.9, 16.2; IR νmax (neat) 3488, 1635,
1607, 1571, 1452, 1403, 1265, 1225, 1169, 1113 cmÀ 1; HRMS (ES-
ToF) m/z: [MÀ H]À Calcd for C26H31O5 423.2177, found 423.2186.
Analytical data were in good agreement with reported values.[3d,14b]
[10] C. Patel, T. Mies, A. J. P. White, P. J. Parsons, A. G. M. Barrett, Eur. J. Org.
Chem. 2021, 1258–1265.
[11] a) S. Laclef, K. Anderson, A. J. P. White, A. G. M. Barrett, Tetrahedron Lett.
2012, 53, 225–227; b) Y. Y. Song, H. G. He, Y. Li, Y. Deng, Tetrahedron
Lett. 2013, 54, 2658–2660; c) I. S. Aidhen, R. Mukkamala, C. Weidner, S.
Sauer, Org. Lett. 2015, 17, 194–197; d) X.-Y. Ji, J.-H. Chen, G.-H. Zheng,
M.-H. Huang, L. Zhang, H. Yi, J. Jin, J.-D. Jiang, Z.-G. Peng, Z.-R. Li, J. Med.
Chem. 2016, 59, 10268–10284; e) B. Weber, B. Brandes, D. Powroznik, R.
Kluge, R. Csuk, Tetrahedron Lett. 2019, 60, 1379–1381; f) T. Fujita, S.
Kuwahara, Y. Ogura, Biosci. Biotechnol. Biochem. 2019, 83, 1635–1641;
g) B. J. Curtis, R. J. Micikas, R. N. Burkhardt, R. A. Smith, J. Y. Pan, K.
Jander, F. C. Schroeder, J. Org. Chem. ASAP (DOI: 10.1021/acs.-
joc.0c03043).
[12] D. Eren, E. Keinan, J. Am. Chem. Soc. 1988, 110, 4356–4362.
[13] Common strategies include direct epoxidation with Shi’s catalyst: a) Y.
Tu, Z.-X. Wang, Y. Shi, J. Am. Chem. Soc. 1996, 118, 9806–9807; b) Z.-X.
Wang, Y. Tu, M. Frohn, J.-R. Zhang, Y. Shi, J. Am. Chem. Soc. 1997, 119,
11224–11235. Alternatively, the Sharpless Asymmetric Dihydroxylation
(AD) reaction followed by epoxide formation:; c) K. B. Sharpless, W.
Amberg, Y. L. Bennani, G. A. Crispino, J. Hartung, K. S. Jeong, H. L.
Kwong, K. Morikawa, Z. M. Wang, D. Xu, X.-L. Zhang, J. Org. Chem. 1992,
57, 2768–2771; d) H. C. Kolb, M. S. Van Nieuwenhze, K. B. Sharpless,
Chem. Rev. 1994, 94, 2483–2547; e) K. Imai, S. Marumo, T. Ohtaki,
Tetrahedron Lett. 1976, 17, 1211–1214; f) R. W. Rickards, R. D. Thomas,
Tetrahedron Lett. 1993, 34, 8369–8372.
Acknowledgements
We greatly appreciate the GlaxoSmithKline endowment (to
A.G.M.B.) and extend our thanks to the late Dr. Alfred and Dr.
Isabel Bader for their support. We additionally thank Dr. Lisa
Haigh (Imperial College London) for mass spectrometric analysis.
Conflict of Interest
[14] a) C. Wang, Y. Kong, H. Qiao, Arkivoc 2015, 92–100; b) T. Fujita, S.
Kuwahara, Y. Ogura, Tetrahedron Lett. 2020, 61, 151477.
The authors declare no conflict of interest.
[15] K. Anderson, S. Laclef, A. G. M. Barrett, Tetrahedron 2014, 70, 5569–5579.
[16] The dioxinone β-keto esters (such as 7, 14 and 21), β,δ-diketo-dioxinone
esters (such as 10, 15 and 22) and the β,δ-diketo dioxinone (such as 9,
16 and 23) exist as mixtures of keto and enol tautomers. For brevity,
only the keto form is drawn. This tautomerism is apparent in the 1H and
13C NMR spectra of β,δ-diketo ester 21 (see Supporting Information).
Intermediates 15, 16, 22 and 23 were not isolated due to their
instabilities as shown in previous studies (ref [8, 9a, 11a, 15]).
[17] Q. Miao, Y. Li, J. Xu, A. Lin, G. Tanabe, O. Muraoka, X. Wu, W. Xie, Eur. J.
Org. Chem. 2018, 1443–1448.
[18] a) D. E. Pearson, R. D. Wysong, C. V. Breder, J. Org. Chem. 1967, 32,
2358–2360; b) P. A. Brookes, J. Cordes, A. J. P. White, A. G. M. Barrett,
Eur. J. Org. Chem. 2013, 7313–7319.
[19] E. J. Corey, J. Zhang, Org. Lett. 2001, 3, 3211–3214.
[20] W. G. Kofron, L. M. Baclawski, J. Org. Chem. 1976, 41, 1879–1880.
[21] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923–2925.
Keywords: Amorfrutin · Aromatization · Biomimetic synthesis ·
Ketene · Total synthesis
[1] J. E. Page, J. Nagel in Integrative Plant Biochemistry, (Ed.: J. T. Romeo),
Elsevier, 2006, vol. 40, pp. 179–210.
[2] a) R. Geris, T. J. Simpson, Nat. Prod. Rep. 2009, 26, 1063–1094; b) M.
Zhao, Y. Tang, J. Xie, Z. Zhao, H. Cui, Eur. J. Med. Chem. 2021, 209,
112860; c) S. Sauer, ChemBioChem 2014, 15, 1231–1238.
[3] a) L. A. Mitscher, Y. H. Park, A. Alshamma, P. B. Hudson, T. Haas,
Phytochemistry 1981, 20, 781–785; b) E. L. Ghisalberti, P. R. Jefferies, D.
McAdam, Phytochemistry 1981, 20, 1959–1961; c) C. Weidner, M.
Rousseau, R. J. Micikas, C. Fischer, A. Plauth, S. J. Wowro, K. Siems, G.
Hetterling, M. Kliem, F. C. Schroeder, S. Sauer, J. Nat. Prod. 2016, 79, 2–
12; d) R. Muharini, A. Diaz, W. Ebrahim, A. Mandi, T. Kurtan, N. Rehberg,
R. Kalscheuer, R. Hartmann, R. S. Orfali, W. Lin, Z. Liu, P. Proksch, J. Nat.
Prod. 2017, 80, 169–180.
[4] a) P. Lefebvre, B. Staels, Proc. Natl. Acad. Sci. USA 2012, 109, 7136–7137;
b) C. Weidner, J. C. de Groot, A. Prasad, A. Freiwald, C. Quedenau, M.
Kliem, A. Witzke, V. Kodelja, C. T. Han, S. Giegold, M. Baumann, B. Klebl,
Manuscript received: March 12, 2021
Revised manuscript received: April 5, 2021
Eur. J. Org. Chem. 2021, 2540–2548
www.eurjoc.org
2548
© 2021 Wiley-VCH GmbH