Syntheses of Amorfrutins and Derivatives via Tandem Diels-Alder and Anionic Cascade Approaches

Article abstract of DOI:10.1021/acs.joc.0c03043

We describe two complementary approaches based on a convergent [4+2] logic toward the synthesis of amorfrutins, cannabinoids, and related plant metabolites. An anionic cascade cyclization employing β-methoxycrotonates and β-chloro-α,β-unsaturated esters yielded amorfrutins in four linear steps and demonstrated utility of β-alkoxycrotonate-derived nucleophiles as functional equivalents of β-ketoester-derived dianions. Analogously, tandem Diels-Alder/retro-Diels-Alder cycloaddition of dimedone-derived bis(trimethylsiloxy)-dienes and α,β-alkynyl ester dienophiles provided facile access to resorcinol precursors of amorfrutins and cannabinoids, avoiding late-stage installation of prenyl or geranyl moieties as in previous approaches.

Full text of DOI:10.1021/acs.joc.0c03043

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Syntheses of Amorfrutins and Derivatives via Tandem Diels−Alder
and Anionic Cascade Approaches
Brian J. Curtis, Robert J. Micikas, Russell N. Burkhardt, Rubin A. Smith, Judy Y. Pan, Katrina Jander,
and Frank C. Schroeder*
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ABSTRACT: We describe two complementary approaches based
on a convergent [4+2] logic toward the synthesis of amorfrutins,
cannabinoids, and related plant metabolites. An anionic cascade
cyclization employing β-methoxycrotonates and β-chloro-α,β-
unsaturated esters yielded amorfrutins in four linear steps and
demonstrated utility of β-alkoxycrotonate-derived nucleophiles as
functional equivalents of β-ketoester-derived dianions. Analo-
gously, tandem Diels−Alder/retro-Diels−Alder cycloaddition of
dimedone-derived bis(trimethylsiloxy)-dienes and α,β-alkynyl ester
dienophiles provided facile access to resorcinol precursors of
amorfrutins and cannabinoids, avoiding late-stage installation of
prenyl or geranyl moieties as in previous approaches.
morfrutins are plant-derived natural products based on an
isoprenoid-substituted β-resorcylic acid core, with a wide
B).13 Notably, the majority of previous amorfrutin syntheses
include a problematic late-stage installation of prenyl or
geranyl (R1) substituents, requiring potassium phenolates/
hydrophobic solvents to favor C- vs O-alkylation.3,4,13,14
Subsequent iterations of this approach employed a Claisen
rearrangement of dimethylallyl ether precursors15 or a
decarboxylative prenyl migration−aromatization sequence.16
We envisioned developing shorter and more broadly
applicable routes that would minimize the use of activation
steps and avoid late-stage installation of the R1 moiety, while
increasing the scope to include cannabinoid derivatives such as
CBGA (6). Whereas most previous approaches employ
aromatic precursors and proceed in a linear fashion, we here
describe two routes to amorfrutins and related cannabinoids
that both utilize a convergent [4+2] assembly strategy for the
aromatic core. Approach C is based on a novel tandem anionic
cascade addition sequence using enolates of β-methoxycroto-
nate methyl esters (10) and β-chloro-α,β-unsaturated Michael
acceptors (11). Approach D is based on a Diels−Alder/retro-
Diels−Alder step employing dimedone-derived 1,3-bis-
(trimethylsiloxy)-dienes (12) and α,β-alkynyl esters (13).23−25
Approach C was inspired by a tandem Michael−Aldol
sequence recently described for the synthesis of amorfrutin C
A
range of biological activities.1,2 Amorfrutin A (1) and B (2)
(Figure 1a), isolated from Amorpha fruticosa and Glycyrrhiza
foetida, increase insulin production in mice by targeting the
peroxisome proliferator-activated receptor gamma (PPARγ), a
key regulator of fat and glucose metabolism, and further
decrease inflammation.3−5 A structural variant, amorfrutin 2
(3), also demonstrates high affinity to PPARγ despite bearing a
pentyl group instead of the phenethyl moiety. Amorfrutin C
(4), isolated from the plant Glycyrrhiza foetida, reduces colon
cancer progression by disrupting mitochondrial function via an
unknown mechanism.6,7 Corresponding resorcinol derivatives
of amorfrutin A and B have been isolated from R. complanata
and H. umbraculigerum,8−11 and similar resorcinol-based
natural products have been described, such as grifolic acid
(5) first identified from the fungus Albatrellus confluens.12
Amorfrutins are closely related to cannabinoids, such as CBGA
(6), with identical substitution positions of geranyl and pentyl
groups about the resorcinol.11
Given their potential pharmaceutical significance, numerous
approaches to amorfrutins and related derivatives have been
reported over the past decade.3,4,13−22 Earlier syntheses were
based on extensive derivatization of phloroglucinol carboxylic
acid (7) via Mitsunobu, Sonogashira coupling, and ortho-
alkylation steps (Figure 1b, approach A).3,4 In application to
amorfrutin A (1), an elegant tandem Michael−Claisen
condensation approach using ethyl acetoacetate (8) and
Michael acceptor (9) provided a 1,3-cyclohexadione adduct,
which was converted to the corresponding resorcinol by
oxidative aromatization using mercury(II) acetate (approach
Special Issue: Natural Products: An Era of Discovery
in Organic Chemistry
Received: December 28, 2020
https://dx.doi.org/10.1021/acs.joc.0c03043
© XXXX American Chemical Society
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provide amorfrutin esters and derivatives (17) could result
from a Dieckmann cyclization of an intermediate (18) derived
from Michael addition of deprotonated β-methoxy-α-alkylcrot-
onate derivatives (10) to (Z)-β-chloro-α,β-unsaturated ester
Michael acceptors (11) (Scheme 1b), analogous to a
previously described method for the preparation of p-
hydroxybenzoates.27
α-Alkylation of methyl β-methoxycrotonate (20)28 derived
from commercially available methyl acetoacetate (19)
provided facile access to mixtures of α,β- and β,γ-unsaturated
enol ethers 10a and 10b (Scheme 2a).29 (Z)-β-Chloro-α,β-
Scheme 2. Synthesis of Amorfrutin Derivatives via the
Anionic Cascade Approach
Figure 1. (a) Examples of amorfrutin and cannabinoid derivatives. (b)
Representative previous approaches to amorfrutins (left) and this
work (right).
(4), which furnished the resorcinol precursor (14) in 56%
yield from treatment of the β-chloro-α,β-unsaturated malonate
derivative (15) with approximately two equivalents of lithiated
1,3-diprenylacetone (16) (Scheme 1a).7 However, when
unsaturated esters 11a and 11b were prepared in a high yield
in one step from terminal alkynes, e.g., 21a and 21b, using a
rhodium-catalyzed chloroesterification approach using ethyl
chloroformate (22).30
Scheme 1. Retrosynthetic Analyses for Tandem Anionic
Cascade Addition Approaches
Provided that initial Michael addition to β-chloroester
Michael acceptors consumes one equivalent of base, it
appeared that at least two equivalents of base were required
to allow further deprotonation of the Michael adduct for
subsequent Dieckmann cyclization, such as for the Michael−
Aldol annulation (Scheme 1a). Varying equivalents of LDA
and enol ether 10a/b, we found that use of three equivalents of
base and enol ether was necessary for complete consumption
of β-chloroesters 11, affording the desired amorfrutin ethyl
esters 17a−c as well as byproducts (i.e., 23 and 24) derived
from alternative cyclization via C3 and the ethyl ester moiety
(see Figure S1), which could be easily separated. Byproduct
formation could be partially suppressed by addition of a
stoichiometric amount of HMPA. The excess of enol ethers
10a/b was recoverable and recyclable. Although modest
yielding, this annulation sequence provided two carbon−
carbon bonds in one pot, furnishing esters of amorfrutins A, B,
and 2 (17a−c) in three linear steps starting from methyl
acetoacetate (19).
applied to unsymmetrically substituted ketones, this reaction
produced mixtures of difficult-to-separate regioisomers. Next,
we considered applicability of a tandem Michael-addition−
Dieckmann condensation/annulation sequence as previously
employed for the synthesis of mycophenolic acid,26 suggesting
a retrosynthetic cut in the ring formation step between C1−C2
(Scheme 1b) as opposed to C2−C3 for the Michael−Aldol
approach (Scheme 1a). We envisioned that ring formation to
Next, we examined a related retrosynthetic approach based
on the formation of the same carbon−carbon bonds as in the
Michael−Dieckmann cascade approach, but instead using a
B
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Diels−Alder reaction. Tandem Diels−Alder/retro-Diels−Alder
approaches using 1,3-bis(trimethylsiloxy)-dienes derived from
dimedone (i.e., 12a) have been reported as highly
regioselective for ene-ynes24 as well as α,β-alkynyl esters
(13), e.g., in application to the syntheses of psymberin (25)25
and 1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
(26) (Scheme 3a).23 We reasoned that the application of
Scheme 4. Synthesis of Amorfrutin Derivatives via the
Diels−Alder/Retro-Diels−Alder Approach
Scheme 3. Utility of Tandem Diels−Alder/Retro-Diels−
Alder Approaches to Resorcinol Derivatives
this methodology to 2-alkyldimedone derivatives should
provide access to diverse amorfrutin and cannabinoid
derivatives through their resorcinol precursors (27) (Scheme
3b).
diones 29a and 29b could be recovered almost quantitatively
by crystallization and/or chromatography from the mixture
following desilylation.
Methylation of resorcinols 27a and 27b afforded amorfrutin
ethyl esters 17a (66%, 77% BRSM) and 17b (60%, 67%
BRSM) (Scheme 4b). Although regioselective, we did observe
formation of up to 20% of bis-methylated derivatives, even
when methylation was terminated prior to complete
consumption of starting material. Subsequent alkaline hydrol-
ysis14,15 afforded amorfrutins A (1) and B (2) in four linear
steps from methyl acetoacetate (19) and five linear steps from
dimedone (28). Further, resorcinol 27d was hydrolyzed and
decarboxylated to afford pure cannabigerol (CBG, 30) in 81%
yield. Alternatively, careful treatment of 27d with concentrated
aqueous sodium sulfide has been reported to allow hydrolysis
to CBGA (5), providing access to CBG and CBGA in four
steps from dimedone.33 While short synthetic approaches to
CBG have been described from the condensation of geraniol
and olivetol, additional undesired regioisomers and bis-
geranylated products have been reported.34,35
In summary, we here present two complementary
convergent approaches to amorfrutins and related resorcinol
derivatives, starting from simple, acyclic precursors. The
tandem anionic cascade cyclization approach provides access
to amorfrutins in only four linear steps from inexpensive
precursors. Although yields of the anionic cyclization step are
modest, the approach is scalable and products can be isolated
easily in high purity. Further, this cyclization reaction
demonstrates novel reactivity for a carbonyl-conjugated enol
ether, which following deprotonation serves as a functional
equivalent to a β-keto ester-derived dianion. In the context of
amorfrutin synthesis, the use of the enol ether in this step
The requisite 1,3-bis(trimethylsiloxy)-dienes were prepared
in two steps from dimedone (28) (Scheme 4a). Alkylation of
dimedone (28) with prenyl and geranyl bromides furnished 2-
substituted derivatives 29a and 29b, in addition to O-alkylation
and bis-alkylation byproducts,31 which could be removed easily
by crystallization of the product from the reaction mixture. The
corresponding bis(trimethylsiloxy)-dienes 12b and 12c were
prepared analogous to known procedures.23 Silylation
proceeds quantitatively, and products require no purification
for use in the subsequent Diels−Alder reaction. Dienophile
(13a), targeting amorfrutin A and B, was prepared via acylation
of 4-phenyl-1-butyne (21a) using nBuLi and ethyl chlor-
oformate (22),32 whereas methyl-2-octynoate (13b), used for
the preparation of amorfrutin 2 and cannabinoids, was
commercially available.
The Diels−Alder/retro-cycloaddition step was performed
neat using dienes 12b or 12c and alkynoates 13a or 13b
(Scheme 4b). Complete consumption of dienophiles required
high temperatures (∼170 °C) and use of up to 4.3 equivalents
1
of dienes 12b and 12c. Gratifyingly, H NMR spectra of the
crude reaction mixtures revealed formation of a single aromatic
product, indicating near 100% regioselectivity (Figure S2).
Following desilylation of the reaction crudes using SiO2/
MeOH,25 pure resorcinols were obtained in excellent yields,
including amorfrutin A and B precursors, 27a (89%, based on
dienophile) and 27b (84%), respectively, from dienophile 13a
as well as amorfrutin 2 precursor 27c (85%), and cannabinoid
precursor 27d (80%) from methyl-2-octynoate (13b). Excess
C
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removed the need for late-stage monomethylation of a
resorcinol intermediate; however, substitution of β-alkoxycrot-
onate-derived nucleophiles for β-keto ester-derived dianions
may have more widespread utility. The tandem Diels−Alder/
retro-Diels−Alder cycloaddition provided resorcinol deriva-
tives with complete regiospecificity and higher yields than the
anionic cascade cyclization approach; however, the preparation
of the diene from dimedone is somewhat inefficient. Both
routes presented here avoid the use of protection/deprotection
steps, accommodate a wide range of substituents R1 and R2,
and are shorter than previous approaches to amorfrutins A, B,
and 2, demonstrating the advantages of convergent [4+2]
strategies for this class of natural products. The methods are
applicable to a wide range of amorfrutins and cannabinoids as
well as non-natural derivatives and probes, which will facilitate
exploration of their biological activities and modes of action.
Methyl 2-Geranyl-3-methoxy-2- and 3-butenoate (10b).
This reagent was prepared according to a previously published
procedure.29 To a freshly prepared solution of LDA from
nBuLi (4.30 mL, 10.75 mmol, 2.5 M in hexanes, 1.16 equiv)
and DIPA (1.40 mL, 10.0 mmol, 1.08 equiv) in 10 mL of THF
was added enol ether 20 (1.20 g, 9.23 mmol, 1.00 equiv)28 in 2
mL of THF at −78 °C dropwise under Ar. The resulting
solution was stirred up to 0 °C (formation of a white
precipitate was observed). HMPA (1.70 mL, 9.78 mmol, 1.06
equiv) was added; then, the solution was cooled down to −78
°C to which geranyl bromide (3.00 g, 13.8 mmol, 1.49 equiv)
was added dropwise in 3 mL THF. The reaction mixture was
stirred up to room temperature over a 1 h period and then
stirred at that temperature for 42 h. The solution was poured
into cold sat. aqueous NaHCO3 and extracted with EtOAc
(3×). Combined organics were washed with brine, dried with
MgSO4, filtered, and concentrated in vacuo. Flash column
chromatography on alumina using 3% EtOAc in hexanes
afforded 10b (1.40 g, 55%, primarily β,γ isomer) as a colorless
EXPERIMENTAL SECTION
■
General Procedures, Materials, and Instrumentation.
All oxygen- and moisture-sensitive reactions were carried out
under an argon (Ar) atmosphere in flame-dried glassware.
Solutions and solvents sensitive to moisture and oxygen were
transferred via standard syringe and cannula techniques.
Reaction mixtures were cooled using dry ice−acetone or
ice−water baths and heated using a mineral oil bath. Unless
stated otherwise, all chemicals and reagents used for synthetic
compound preparation were purchased from Sigma-Aldrich
and used without further purification. Tetrahydrofuran (THF),
toluene, dichloromethane (DCM), and hexamethylphosphor-
amide (HMPA) were dried and stored over 3 or 4 Å molecular
sieves prior to use. Diisopropylamine (DIPA) was passed
through a plug of silica and dried over 4 Å molecular sieves. 4-
Phenyl-1-butyne and bis(triphenylphosphine)rhodium(I) car-
bonyl chloride were purchased from BeanTown Chemical.
Ethyl chloroformate was purchased from Alfa Aesar. Chloro-
form (CHCl3), DCM, diethyl ether (Et2O), ethyl acetate
(EtOAc), ethanol (EtOH), hexanes, and toluene were
purchased from Fisher Scientific. Thin-layer chromatography
(TLC) was performed using J. T. Baker Silica Gel IB2F plates.
Flash chromatography was performed using Teledyne Isco
CombiFlash systems with Teledyne Isco RediSep Rf silica or
manually using aluminum oxide, activated, neutral, Brockmann
grade 1, 58 Å (Alfa Aesar). All deuterated solvents were
purchased from Cambridge Isotopes. Nuclear magnetic
resonance (NMR) spectra were recorded on Varian INOVA
600 (600 MHz), Varian INOVA 400 (400 MHz), and Bruker
AV500 spectrometers at Cornell University’s NMR facility. 1H
NMR chemical shifts are reported in ppm (δ) relative to
residual solvent peaks (7.26 ppm for chloroform-d, 7.16 ppm
for benzene-d6, 2.05 for acetone-d6). NMR spectroscopic data
are reported as follows: chemical shift, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br = broad),
coupling constants (Hz), and integrals. 13C NMR chemical
shifts are reported in ppm (δ) relative to residual solvent peaks
(77.16 ppm for chloroform-d, 128.06 ppm for benzene-d6, and
29.84 for acetone-d6). All NMR data processing was done
using MNOVA 12.0.1 (https://mestrelab.com/). All high-
resolution mass spectrometry data were acquired using a
Thermo Scientific Q Exactive HF hybrid quadrupole-orbitrap
mass spectrometer and reported to four decimal places.
1
oil, with up to ∼9% (mol/mol) bis-alkyl impurity. H NMR
(500 MHz, benzene-d6): δ 5.27 (t, J = 7.1 Hz, 1H), 5.19 (t, J =
7.0 Hz, 1H), 4.14 (d, J = 2.4 Hz, 1H), 3.92 (d, J = 2.4 Hz, 1H),
3.37 (s, 3H), 3.24 (t, J = 7.7 Hz, 1H), 3.14 (s, 3H), 2.82 (ddd,
J = 14.6, 7.4 Hz, 1H), 2.66 (ddd, J = 14.6, 7.4 Hz, 1H), 2.12
(q, J = 7.6 Hz, 2H), 2.03 (t, J = 7.3 Hz, 2H), 1.67 (br s, 3H),
1.58 (s, 3H), 1.54 (s, 3H). 13C{1H} NMR (126 MHz,
benzene-d6): δ 172.3, 161.4, 137.3, 131.1, 124.8, 121.8, 83.0,
54.8, 51.9, 51.5, 40.2, 29.2, 27.1, 25.9, 17.8, 16.1. HRMS (ESI)
m/z: [M + H]+ calcd for C16H27O3, 267.1955; found,
267.1951.
(Z)-Ethyl-3-chloro-5-phenylpent-2-enoate (11a). Chlor-
oester 11a was prepared according to a previously reported
procedure.30 Ethyl chloroformate (22, 5.74 mL, 60.3 mmol,
3.00 equiv), 4-phenyl-1-butyne (21a, 2.80 mL, 20.1 mmol,
1.00 equiv), and bis(triphenylphosphine)rhodium(I) carbonyl
chloride (139 mg, 0.20 mmol, 0.01 equiv) were dissolved in 16
mL of dry toluene in a sealed container and heated to 110 °C
for 18 h. The reaction mixture was cooled to room
temperature, quenched with the addition of sat. aqueous
NaHCO3, and extracted 3× with EtOAc. Organics were dried
with MgSO4, filtered, and concentrated in vacuo. Flash column
chromatography on silica using a gradient of 0−20% EtOAc in
hexanes was performed, affording 11a (4.40 g, 92%) as a
yellow oil. 1H NMR (500 MHz, benzene-d6): δ 7.13−7.05 (m,
2H), 7.06−6.99 (m, 1H), 6.90−6.84 (m, 2H), 5.71 (t, J = 0.9
Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H), 2.59−2.51 (m, 2H), 2.28−
2.20 (m, 2H), 0.94 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (126
MHz, benzene-d6): δ 163.3, 148.7, 140.0, 128.7, 128.6, 126.6,
117.5, 60.2, 43.0, 33.6, 14.2. HRMS (ESI) m/z: [M + H]+
calcd for C13H16ClO2, 239.0833; found, 239.0830.
(Z)-Ethyl-3-chlorooct-2-enoate (11b). Chloroester 11b was
prepared according to a previously reported procedure.30 Ethyl
chloroformate (22, 2.86 mL, 30.0 mmol, 3.00 equiv), 1-
heptyne (21b, 1.31 mL, 10.0 mmol, 1.00 equiv, Sigma-
Aldrich), and bis(triphenylphosphine)rhodium(I) carbonyl
chloride (69.0 mg, 0.10 mmol, 0.01 equiv) were dissolved in
6 mL of dry toluene in a sealed container and heated to 110 °C
for 24 h. The reaction mixture was cooled to room
temperature, quenched by the addition of sat. aqueous
NaHCO3, and extracted 3× with EtOAc. Organics were
dried with Na2SO4, filtered, and concentrated in vacuo. Flash
column chromatography on silica using a gradient of 0−20%
EtOAc in hexanes afforded 11b (1.93 g, 94%) as a light yellow
Methyl 2-Prenyl-3-methoxy-2- and 3-butenoate (10a).
This reagent was prepared according to a previously published
procedure using enol ether 2028 and prenyl bromide.29
D
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1
oil. H NMR (500 MHz, benzene-d6): δ 5.85 (t, J = 1.0 Hz,
on silica using a gradient of 0−50% DCM in hexanes afforded
1
1H), 4.01 (q, J = 7.1 Hz, 2H), 1.97 (t, J = 7.6 Hz, 2H), 1.29 (p,
J = 7.6 Hz, 2H), 1.13−1.02 (m, 2H), 1.00−0.92 (m, 2H), 0.98
(t, J = 7.1 Hz, 3H), 0.76 (t, J = 7.3 Hz, 3H). 13C{1H} NMR
(126 MHz, benzene-d6): δ 163.5, 150.2, 116.9, 60.2, 41.2, 30.8,
27.0, 22.6, 14.3, 14.0. HRMS (ESI) m/z: [M + H]+ calcd for
C10H18ClO2, 205.0990; found, 205.0987.
17c (44.0 mg, 31%). H NMR (500 MHz, benzene-d6): δ
12.57 (s, 1H), 6.16 (s, 1H), 5.71 (t, J = 7.0 Hz, 1H), 3.97 (q, J
= 7.1 Hz, 2H), 3.82 (d, J = 7.2 Hz, 2H), 3.32 (s, 3H), 2.91−
2.87 (m, 2H), 1.91 (s, 3H), 1.69 (s, 3H), 1.62−1.52 (m, 2H),
1.38−1.30 (m, 4H), 0.93 (m, 6H). 13C{1H} NMR (126 MHz,
benzene-d6): δ 172.2, 163.1, 161.6, 145.6, 131.1, 123.5, 115.7,
105.9, 105.8, 61.1, 55.0, 38.0, 32.6, 32.5, 26.0, 23.1, 22.8, 18.1,
14.4, 14.0. HRMS (ESI) m/z: [M + H]+ calcd for C20H31O4,
335.2217; found, 335.2209.
General Procedure for the Anionic Cascade Ap-
proach. To a freshly prepared solution of LDA from nBuLi
(0.53 mL, 1.32 mmol, 2.5 M in hexanes, 3.15 equiv) and DIPA
(0.18 mL, 1.32 mmol, 3.15 equiv) in 20 mL of THF was added
enol ether 10a or 10b (1.26 mmol, 3.00 equiv) at −30 °C
dropwise under Ar. The resulting solution was stirred up to
approximately 0−5 °C (total time roughly 1 h) and then
cooled to −20 °C after which HMPA (0.22 mL, 1.26 mmol,
3.00 equiv) was added, followed by dropwise addition of
chloroester 11a or 11b (0.42 mmol, 1.00 equiv) in 2 mL of
THF up to approximately −10 to 0 °C. The resulting solution
was stirred up to room temperature over a 4 h period. The
reaction was quenched at 0 °C with the addition of cold sat.
aqueous NaHCO3 solution, and the organics were extracted
three times with EtOAc (3×). Combined organics were
washed with brine, dried with MgSO4, filtered, and
concentrated in vacuo.
Amorfrutin A Ethyl Ester (17a). According to the general
procedure, enol ether 10a (250 mg, 1.26 mmol, 3.00 equiv),
chloride 11a (100 mg, 0.42 mmol, 1.00 equiv), and 22 mL of
THF were used. Purification by flash column chromatography
on silica using a gradient of 0−10% EtOAc in hexanes (w/0.3%
TEA) was performed (to recover clean enol ether 10a),
followed by additional purification with 0−50% DCM in
hexanes, affording 17a (59 mg, 38%) as a colorless oil, and
recovered 10a (150 mg). 1H NMR (500 MHz, benzene-d6): δ
12.55 (s, 1H), 7.20−7.17 (m, 2H), 7.12−7.06 (m, 3H), 6.00
(s, 1H), 5.70 (t, J = 7.3 Hz, 1H), 3.97 (q, J = 7.1 Hz, 2H), 3.80
(d, J = 7.1 Hz, 2H), 3.26 (s, 3H), 3.22−3.17 (m, 2H), 2.86−
2.81 (m, 2H), 1.90 (br s, 3H), 1.69 (br s, 3H), 0.89 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (126 MHz, benzene-d6): δ 172.1,
163.1, 161.6, 144.3, 142.3, 131.2, 128.7, 126.3, 123.5, 116.0,
106.2, 105.9, 61.3, 55.0, 39.0, 38.5, 26.0, 22.8, 18.1, 14.0.
HRMS (ESI) m/z: [M + H]+ calcd for C23H29O4, 369.2060;
found, 369.2051. See Tables S1 and S2 for NMR spectroscopic
data of byproducts 23 and 24.
2-Prenyldimedone (29a). To a mixture of dimedone (28,
6.00 g, 42.8 mmol, 1.00 equiv, Sigma-Aldrich) in 170 mL of
CHCl3 was added K2CO3 (11.00 g, 79.6 mmol, 1.86 equiv),
followed by prenyl bromide (5.60 mL, 48.5 mmol, 1.13 equiv).
The reaction mixture was stirred at room temperature for 60 h
and was then diluted with 50 mL of CHCl3 and 50 mL of H2O
followed by acidification to pH ∼ 5 using aqueous 1 M HCl.
The organic layer was separated, and the aqueous layer was
extracted with three 100 mL portions of CHCl3. Combined
organics were washed with brine, dried with MgSO4, filtered,
and concentrated in vacuo. The residue was stirred with
hexanes to remove O-alkyl and bis-alkyl products along with
excess 3,3-dimethylallyl bromide resulting in the formation of a
precipitate, which was collected via vacuum filtration, affording
29a (3.77 g, 42%), as a white solid containing ∼1% of
1
unreacted dimedone as an impurity. H NMR (400 MHz,
chloroform-d, enol): δ 6.78 (br s, 1H), 5.20 (t, J = 7.3 Hz, 1H),
3.08 (d, J = 7.4 Hz, 2H), 2.27 (s, 4H), 1.79−1.71 (m, 6H),
1.06 (s, 6H). 1H NMR (400 MHz, chloroform-d, keto): δ 5.06
(t, J = 7.2 Hz, 1H), 3.28 (t, J = 6.1 Hz, 1H), 2.63 (d, J = 13.7
Hz, 2H), 2.54−2.44 (m, 2H), 2.48 (d, J = 13.7 Hz, 2H), 1.66
(s, 3H), 1.64 (s, 3H), 1.14 (s, 3H), 0.87 (s, 3H). 13C{1H}
NMR (151 MHz, chloroform-d, keto−enol): δ 204.7, 136.3,
133.9, 122.0, 121.1, 112.6, 67.0, 54.3, 31.9, 31.1, 30.1, 28.5,
28.4, 26.8, 25.9, 22.6, 21.3, 18.0, 17.9. HRMS (ESI) m/z: [M +
H]+ calcd for C13H21O2, 209.1536; found, 209.1538.
2-Geranyldimedone (29b). To a mixture of dimedone (28,
2.80 g, 20.0 mmol, 1.00 equiv) in 75 mL of CHCl3 was added
K2CO3 (5.50 g, 39.8 mmol, 1.99 equiv), followed by geranyl
bromide (4.40 mL, 22.1 mmol, 1.10 equiv). The reaction
mixture was stirred at room temperature for 70 h and was then
diluted with 50 mL of CHCl3 and 10 mL of H2O, followed by
acidification to pH ∼ 6 using aqueous 1 M HCl. The organic
layer was separated, and the aqueous layer was extracted with
two 50 mL portions of CHCl3. Combined organics were
washed with brine, dried with MgSO4, filtered, and
concentrated in vacuo. The crude oil was stored at −20 °C
for 24 h, and the resulting solid was separated from the
remaining yellow oil (O-alkyl and bis-alkyl products along with
any excess geranyl bromide) by washing with hexanes via
vacuum filtration, affording 29b (2.52 g, 45%) as a white solid.
NMR spectroscopic data were identical to those reported
previously.36
Amorfrutin B Ethyl Ester (17b). According to the general
procedure, enol ether 10b (335 mg, 1.26 mmol, 3.00 equiv),
chloride 11a (100 mg, 0.42 mmol, 1.00 equiv), and 22 mL of
THF were used. Purification by flash column chromatography
on silica using a gradient of 0−10% Et2O in hexanes afforded
1
17b (57.0 mg, 31%). H NMR (400 MHz, benzene-d6): δ
12.58 (s, 1H), 7.26−7.17 (m, 2H), 7.15−7.00 (m, 3H), 6.00
(s, 1H), 5.75 (t, J = 7.0 Hz, 1H), 5.20 (t, J = 7.1 Hz, 1H), 3.96
(q, J = 7.4 Hz, 2H), 3.84 (d, J = 7.3 Hz, 2H), 3.26 (s, 3H),
3.24−3.15 (m, 2H), 2.87−2.79 (m, 2H), 2.23−2.08 (m, 4H),
1.96 (br s, 3H), 1.61 (br s, 3H), 1.49 (br s, 3H), 0.87 (t, J = 7.2
Hz, 3H). 13C{1H} NMR (126 MHz, benzene-d6): δ 172.0,
163.1, 161.6, 144.3, 142.3, 135.0, 130.9, 128.7, 126.3, 125.1,
123.3, 116.0, 106.2, 105.9, 61.3, 55.0, 40.4, 39.0, 38.5, 27.3,
25.8, 22.7, 17.7, 16.5, 14.0. HRMS (ESI) m/z: [M + H]+ calcd
for C28H37O4, 437.2686; found, 437.2679.
Amorfrutin 2 Ethyl Ester (17c). According to the general
procedure, enol ether 10a (250 mg, 1.26 mmol, 3.00 equiv),
chloride 11b (86.0 mg, 0.42 mmol, 1.00 equiv), and 22 mL of
THF were used. Purification by flash column chromatography
Diene (12b).23 To a suspension of 29a (2.00 g, 9.60 mmol,
1.00 equiv) in 14 mL of DCM was added hexamethyldisilazane
(HMDS) (2.60 mL, 12.4 mmol, 1.29 equiv). The resulting
solution was concentrated in vacuo after 12 h and added in 5
mL of THF to a freshly prepared solution of LDA from nBuLi
(4.21 mL, 10.5 mmol, 2.5 M in hexanes, 1.09 equiv) and DIPA
(1.47 mL, 10.5 mmol, 1.09 equiv) in 25 mL of THF at −78 °C
over a 10 min period under Ar. After stirring up to −40 °C
over a 1 h period, the solution was cooled to −78 °C, TMSCl
(1.40 mL, 11.0 mmol, 1.14 equiv) was added dropwise, and
E
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Note
the resulting solution was stirred up to room temperature over
a 2 h period. The reaction mixture was concentrated in vacuo,
diluted in hexanes, filtered, and concentrated in vacuo,
affording bis-TMS diene 12b (3.37 g, 100%) as a yellow oil.
1H NMR (400 MHz, benzene-d6): δ 5.49 (t, J = 6.9 Hz, 1H),
4.60 (s, 1H), 3.22 (d, J = 6.7 Hz, 2H), 2.20 (s, 2H), 1.77 (br s,
3H), 1.69 (br s, 3H), 1.08 (s, 6H), 0.24 (s, 9H), 0.16 (s, 9H).
13C{1H} NMR (151 MHz, benzene-d6): δ 149.6, 147.7, 129.9,
125.0, 115.0, 107.9, 45.0, 32.2, 29.2, 25.9, 23.7, 18.2, 1.06, 0.37.
Diene (12c).23 To a suspension of 29b (1.05 g, 3.80 mmol,
1.00 equiv) in 6 mL of DCM was added HMDS (1.00 mL,
4.78 mmol, 1.26 equiv). The resulting solution was
concentrated in vacuo after 24 h and added in 3 mL of THF
to a freshly prepared solution of LDA from nBuLi (1.74 mL,
4.35 mmol, 2.5 M in hexanes, 1.14 equiv) and DIPA (0.61 mL,
4.35 mmol, 1.14 equiv) in 10 mL of THF at −78 °C over a 10
min period under Ar. After stirring up to −10 °C over a 1 h
period, the solution was cooled to −78 °C, TMSCl (0.70 mL,
5.51 mmol, 1.45 equiv) was added dropwise, and the resulting
solution was stirred up to room temperature over a 1 h period.
The reaction mixture was concentrated in vacuo, diluted in
hexanes, filtered, and concentrated in vacuo, affording bis-TMS
diene 12c (1.60 g, 100%) as a yellow oil. 1H NMR (400 MHz,
benzene-d6): δ 5.53 (t, J = 6.9 Hz, 1H), 5.24 (t, J = 7.0 Hz,
1H), 4.60 (s, 1H), 3.24 (d, J = 6.7 Hz, 2H), 2.24−2.09 (m,
4H), 2.21 (s, 2H), 1.81 (br s, 3H), 1.67 (br s, 3H), 1.55 (br s,
3H), 1.08 (s, 6H), 0.25 (s, 9H), 0.17 (s, 9H). 13C{1H} NMR
(151 MHz, benzene-d6): 149.6, 147.7, 133.8, 130.9, 125.1,
124.8, 115.0, 107.8, 45.0, 40.3, 32.3, 29.2, 27.3, 25.9, 23.6, 17.8,
16.6, 1.07, 0.40.
Ethyl 5-Phenylpent-2-ynoate (13a). This reagent was
prepared according to a previously published procedure
starting from 4-phenyl-1-butyne (21a) and ethyl chloroformate
(22) using nBuLi.32
General Procedure for Diels−Alder Approach. Excess
diene (12b or 12c) and alkyne (13a or 13b) were combined
and heated in a sealed tube at 170 °C for the indicated time
period, allowing for complete consumption of alkyne. The
reaction was then diluted with a mixture of MeOH/DCM,
SiO2 was added, and the resulting mixture was refluxed for
several hours, until all TMS−ethers had been deprotected, as
determined by TLC. The reaction mixture was then filtered
and concentrated in vacuo.
128.6, 126.3, 122.5, 113.1, 111.2, 105.2, 61.3, 38.6, 38.5, 25.8,
22.7, 17.8, 14.0. HRMS (ESI) m/z: [M − H]− calcd for
C22H25O4, 353.1758; found, 353.1753.
Resorcinol (27b). According to the general procedure, diene
(12c, 1.03 g, 2.45 mmol, 4.30 equiv) and alkyne (13a, 115 mg,
0.57 mmol, 1.00 equiv) were heated for 23 h. TMS
deprotection was performed for 4.5 h with 15 mL of
MeOH/2 mL of DCM and 1.7 g of SiO2. The reaction
mixture was filtered and concentrated in vacuo. Flash column
chromatography on silica using a gradient of 0−30% EtOAc in
hexanes afforded 27b (203 mg, 84%) as a yellow solid, along
with recovered 2-geranyldimedone (29b, 380 mg, 1.38 mmol,
73% of expected recovery). 1H NMR (500 MHz, benzene-d6):
δ 12.84 (s, 1H), 7.22−7.18 (m, 2H), 7.13−7.08 (m, 3H), 5.99
(s, 1H), 5.49 (t of septets, J = 7.3, 1.4 Hz, 1H), 5.32 (s, 1H),
5.13 (t of septets, J = 7.1, 1.4 Hz, 1H), 3.95 (q, J = 7.1 Hz,
2H), 3.66 (d, J = 7.2 Hz, 2H), 3.16−3.08 (m, 2H), 2.83−2.76
(m, 2H), 2.09 (q, J = 7.5 Hz, 2H), 2.00 (t, J = 7.5 Hz, 2H),
1.72 (br s, 3H), 1.66 (br s, 3H), 1.50 (d, J = 1.3 Hz, 3H), 0.86
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz, benzene-d6): δ
172.2, 163.9, 159.8, 144.6, 142.4, 137.8, 131.5, 128.7, 128.6,
126.3, 124.6, 122.4, 113.0, 111.3, 105.2, 61.3, 40.1, 38.6, 38.5,
26.9, 25.9, 22.7, 17.7, 16.2, 14.0. HRMS (ESI) m/z: [M − H]−
calcd for C27H33O4, 421.2384; found, 421.2376.
Resorcinol (27c). According to the general procedure, diene
(12b, 1.70 g, 4.81 mmol, 4.15 equiv) and alkyne (13b, 176 mg,
1.16 mmol, 1.00 equiv) were heated for 36 h. TMS
deprotection was performed for 4 h with 30 mL of MeOH/3
mL of DCM and 2.7 g of SiO2. The reaction mixture was
filtered and concentrated in vacuo. Flash column chromatog-
raphy on silica using a gradient of 0−20% EtOAc in hexanes
1
afforded 27c (279 mg, 85%) as an off-white solid. H NMR
(500 MHz, benzene-d6): δ 12.67 (s, 1H), 6.04 (s, 1H), 5.42 (t
of septets, J = 7.3, 1.4 Hz, 1H), 5.27 (s, 1H), 3.62 (d, J = 7.3
Hz, 2H), 3.33 (s, 3H), 2.80−2.74 (m, 2H), 1.67 (br s, 3H),
1.55 (d, J = 1.0 Hz, 3H), 1.54−1.46 (m, 2H), 1.33−1.46 (m,
2H), 0.92−0.86 (m, 3H). 13C{1H} NMR (126 MHz, benzene-
d6): δ 172.7, 163.8, 159.7, 145.7, 133.7, 122.6, 112.7, 111.0,
105.0, 51.3, 37.1, 32.5, 32.0, 25.8, 22.9, 22.7, 17.8, 14.3. HRMS
(ESI) m/z: [M − H]− calcd for C18H25O4, 305.1758; found,
305.1750.
Resorcinol (27d). According to the general procedure, diene
(12c, 0.93 g, 2.21 mmol, 4.25 equiv) and alkyne (13b, 79.0
mg, 0.52 mmol, 1.00 equiv) were heated for 36 h. TMS
deprotection was performed for 4 h with 15 mL of MeOH/2
mL of DCM and 1.6 g of SiO2. The reaction mixture was
filtered and concentrated in vacuo. Flash column chromatog-
raphy on silica using a gradient of 0−10% EtOAc in hexanes
Resorcinol (27a). According to the general procedure, diene
(12b, 3.30 g, 9.35 mmol, 4.08 equiv) and alkyne (13a, 465 mg,
2.29 mmol, 1.00 equiv) were heated for 42 h. TMS
deprotection was performed for 5 h with 60 mL of MeOH/6
mL of DCM and 5.6 g of SiO2. The reaction mixture was
filtered and concentrated in vacuo. To precipitate excess 2-
prenyldimedone (29a), a 1:1 mixture of hexanes/DCM (100
mL) was added to the crude, and the mixture was then vacuum
filtered. The collected solid was washed with hexanes, affording
pure recovered 2-prenyldimedone (29a, 1.34 g, 6.44 mmol,
91% of expected recovery). The filtrate was concentrated in
vacuo, and flash column chromatography on silica using a
gradient of 0−20% EtOAc in hexanes afforded 27a (721 mg,
1
afforded 27d (155 mg, 80%) as a yellow solid. H NMR (500
MHz, benzene-d6): δ 12.70 (s, 1H), 6.10 (s, 1H), 5.46 (t of
septets, J = 7.3, 1.4 Hz, 1H), 5.39 (s, 1H), 5.12 (t of septets, J
= 7.0, 1.4 Hz, 1H), 3.65 (d, J = 7.2 Hz, 2H), 3.33 (s, 3H),
2.80−2.74 (m, 2H), 2.08 (q, J = 7.4 Hz, 2H), 1.98 (t, J = 7.5
Hz, 2H), 1.70 (br s, 3H), 1.66 (br s, 3H), 1.54−1.47 (m, 2H),
1.49 (br s, 3H), 1.32−1.25 (m, 4H), 0.91−0.87 (m, 3H).
13C{1H} NMR (126 MHz, benzene-d6): δ 172.7, 163.7, 159.9,
145.8, 137.9, 131.6, 124.6, 122.4, 112.6, 111.1, 105.0, 51.3,
40.1, 37.1, 32.5, 32.0, 26.8, 25.9, 22.9, 22.6, 17.7, 16.2, 14.3.
HRMS (ESI) m/z: [M − H]− calcd for C23H33O4, 373.2384;
found, 373.2381.
1
89%) as an off-white solid. H NMR (500 MHz, benzene-d6):
δ 12.81 (s, 1H), 7.22−7.17 (m, 2H), 7.14−7.07 (m, 3H), 5.93
(s, 1H), 5.45 (t of septets, J = 7.1, 1.4 Hz, 1H), 5.21 (s, 1H),
3.95 (q, J = 7.1 Hz, 2H), 3.64 (d, J = 7.3 Hz, 2H), 3.14−3.09
(m, 2H), 2.82−2.77 (m, 2H), 1.69 (br s, 3H), 1.57 (d, J = 1.0
Hz, 3H), 0.87 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz,
benzene-d6): δ 172.2, 163.9, 159.5, 144.5, 142.4, 133.7, 128.7,
Amorfrutin A Ethyl Ester (17a). To a solution of resorcinol
27a (100 mg, 0.28 mmol, 1.00 equiv) in acetone (4.8 mL) was
added K2CO3 (0.73 g, 5.29 mmol, 18.9 equiv) followed by MeI
F
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Note
(26.0 μL, 0.42 mmol, 1.50 equiv). The resulting mixture was
vigorously stirred at room temperature for 3 h, neutralized with
1 M aqueous HCl, and extracted with EtOAc (3 × 15 mL).
The combined organics were washed with brine, dried with
MgSO4, filtered, and concentrated in vacuo. Flash column
chromatography on silica using a gradient of 0−10% EtOAc in
hexanes afforded 17a (68.0 mg, 66%) as a colorless oil, along
with recovered 27a (11.0 mg, 11%). NMR spectroscopic data
were identical to those reported previously.
AUTHOR INFORMATION
Corresponding Author
■
Frank C. Schroeder − Boyce Thompson Institute and
Department of Chemistry and Chemical Biology, Cornell
University, Ithaca, New York 14853, United States;
orcid.org/0000-0002-4420-0237; Email: fs31@
cornell.edu
Authors
Amorfrutin B Ethyl Ester (17b). To a solution of resorcinol
27b (100 mg, 0.23 mmol, 1.00 equiv) in acetone (4 mL) was
added K2CO3 (0.62 g, 4.49 mmol, 19.5 equiv) followed by MeI
(20.0 μL, 0.35 mmol, 1.52 equiv). The resulting mixture was
vigorously stirred at room temp for 3.5 h, acidified with 1 M
aqueous HCl, and extracted with EtOAc (3×). The organics
were washed with brine, dried with MgSO4, filtered, and
concentrated in vacuo. Flash column chromatography on silica
using a gradient of 0−10% EtOAc in hexanes was performed,
affording 17b (62.0 mg, 60%) as a colorless oil, along with
recovered 27b (7.0 mg, 7%). NMR spectroscopic data were
identical to those reported previously.
Cannabigerol (CBG, 30). Resorcinol 27d (57.0 mg, 0.15
mmol, 1.00 equiv) was combined with KOH (408 mg, 7.28
mmol, 48.5 equiv) in a 1:1 mixture of EtOH/H2O (5 mL) and
was refluxed for 8 h. The resulting solution was concentrated in
vacuo, acidified with 1 M aqueous HCl to pH ∼ 5, and then
extracted with EtOAc (3×). The combined organic layers were
dried with MgSO4, filtered, and concentrated in vacuo. Flash
column chromatography on silica using a gradient of 0−30%
EtOAc in hexanes afforded 30 (39.0 mg, 81%) as an off-white
solid. NMR spectroscopic data were identical to those reported
previously.34
Amorfrutin A (1). A mixture of 17a (71 mg, 0.19 mmol,
1.00 equiv) and KOH (101 mg, 1.80 mmol, 9.47 equiv) in 3
mL of EtOH and 2 mL of H2O was refluxed for 2.5 h. The
resulting solution was concentrated in vacuo, acidified with 1 M
aqueous HCl to pH ∼ 2, and then extracted with EtOAc (4×).
The combined organic extracts were dried with MgSO4,
filtered, and concentrated in vacuo. Flash column chromatog-
raphy on silica using a gradient of 0−60% EtOAc in hexanes
afforded 1 (62 mg, 95%) as a white solid. NMR spectroscopic
data were identical to those reported previously.3
Amorfrutin B (2). A mixture of 17b (70 mg, 0.16 mmol,
1.00 equiv) and KOH (100 mg, 1.78 mmol, 11.12 equiv) in 3
mL of EtOH and 2 mL of H2O was refluxed for 1.75 h. The
resulting solution was concentrated in vacuo, acidified with 1 M
aqueous HCl to pH ∼ 1, and then extracted with EtOAc (4×).
The combined organic extracts were dried with MgSO4,
filtered, and concentrated in vacuo. Flash column chromatog-
raphy on silica using a gradient of 0−60% EtOAc in hexanes
afforded 2 (61 mg, 94%) as a white solid. NMR spectroscopic
data were identical to those reported previously.4
Brian J. Curtis − Boyce Thompson Institute and Department
of Chemistry and Chemical Biology, Cornell University,
Ithaca, New York 14853, United States
Robert J. Micikas − Boyce Thompson Institute and
Department of Chemistry and Chemical Biology, Cornell
University, Ithaca, New York 14853, United States
Russell N. Burkhardt − Boyce Thompson Institute and
Department of Chemistry and Chemical Biology, Cornell
University, Ithaca, New York 14853, United States
Rubin A. Smith − Boyce Thompson Institute and Department
of Chemistry and Chemical Biology, Cornell University,
Ithaca, New York 14853, United States
Judy Y. Pan − Boyce Thompson Institute and Department of
Chemistry and Chemical Biology, Cornell University, Ithaca,
New York 14853, United States
Katrina Jander − Boyce Thompson Institute and Department
of Chemistry and Chemical Biology, Cornell University,
Ithaca, New York 14853, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c03043
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare the following competing financial
interest(s): F.C.S. is a founder of Ascribe Bioscience, a
company that develops plant treatments based on natural small
molecules.
ACKNOWLEDGMENTS
■
We thank Tae Hyung Won for assistance with mass
spectrometry and Ryan A. Woltornist and David B. Collum
for helpful discussions. This work was partly supported by the
NIH (P41GM79571 and R35GM131877 to F.C.S. and
T32GM008500 to B.J.C.) and the Howard Hughes Medical
Institute.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c03043.
Suppression of by-product formation in the anionic
cascade reaction, regioselectivity of Diels−Alder/retro-
Diels−Alder reaction, and NMR spectroscopic data
(PDF)
Schroeder, F. C.; Sauer, S.; Bu
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G
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