Access to 12-Membered Cyclic ortho, meta-Diarylheptanoids: Total Synthesis of Actinidione via Isomyricanone

Synthesis of Actinidione via Isomyricanone

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Access to 12-Membered Cyclic ortho,meta-Diarylheptanoids: Total

Paul Masse, Sabine Choppin,* Lucia Chiummiento, Franc o ̧ ise Colobert, and Gilles Hanquet*

Cite This: J. Org. Chem. 2021, 86, 3033 −3040

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sı Supporting Information

ABSTRACT: We describe herein the ﬁrst access to 12-membered cyclic[7,0]ortho,meta-diarylheptanoids. The key features of the

synthesis include both a Suzuki−Miyaura coupling and a ring closing metathesis. Actinidione, a promising natural product, along

with a bioactive tetracyclic derivative were obtained in 14 steps for the ﬁrst time from cheap commercially available substrates with

an overall yield of 18−21%. Our modus operandi complies with the principles of the synthesis ideality by using notably strategic

reactions.

ince the discovery of curcumin in 1815 by Vogel and

Pelletier, diarylheptanoids have been thoroughly inves-

ortho position to release the ring strain was inferred (Scheme

1A, structure A). Nonetheless, Nagai et al. reported in 1991

the revision of the structure based on further NMR studies

(see Supporting Information for the proposed mechanism).

Furthermore, actinidione 5 was isolated in 2006 by Zhang et

tigated due to their unique architectural features as well as their

broad range of biological activities. Indeed, many approaches

have been explored for the synthesis of the appealing family of

cyclic 13-membered meta,meta-bridged biphenyls. However,

al. from leaves and twigs of Actinidiaceae, endemic to China

to the best of our knowledge, no route scouting has been

described to prepare 12-membered ortho,meta-bridged biphen-

yls.

The tetracyclic diarylheptanoid 1 represents an interesting

compound of this family. A structure−activity relationship

study revealed that 1, synthesized by Dickey et al. and resulting

from an acid-catalyzed cyclodehydration of myricanol 2

(

Scheme 1C). These species are employed as traditional

medicine for hernia, hepatitis, hematemesis, and rheumatic

diseases. As far as we are aware, it is the ﬁrst natural cyclic

diarylheptanoid bearing both a [7,0]ortho,meta-cyclophane

scaﬀold and a 1,4-benzoquinone. Its cytotoxicity has been

shown to be promising against human breast cancer (Bre-04,

GI = 26.67 μM), lung cancer (Lu-06, GI = 31.82 μM), and

(

Scheme 1A), exhibits a robust protein tau reduction activity,

neuroma (Neu-04, GI₅₀= 15.02 μM) cell lines. This

compound was then isolated from the bark of Myrica nana,

hence an anti-Alzheimer’s disease eﬀect, on a par with

(

−)-aS,11R-myricanol (EC₅₀= 35 μM). This rearranged

Myrica Rubra, and Myrica adenophora. As might be expected

molecule is unexpected due to its isomyricanone-type biaryl

axis but also by the presence of the tetralin moiety. The two

enantiomers have been studied separately and have commen-

surate activity.

from the 1,4-benzoquinone motif, actinidione demonstrates a

strong antioxidant activity (IC = 7.93 μM) against superoxide

10b

dismutase as well.

Additionally, isomyricanone 3 was the ﬁrst 12-membered

7,0]ortho,meta-cyclophane, prepared by Whiting et al. by

Received: October 20, 2020

Published: January 21, 2021

[

isomerization of natural myricanone 4 with boron triﬂuoride

etherate. 3 unveils a potent inhibitory activity (IC = 350 mol

ratio/TPA) against the Epstein−Barr virus early antigens,

which induces lymphomas and carcinomas. Initially, only a

migration of the alkyl chain on the aromatic cycle from meta to

2021 American Chemical Society

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Scheme 1. Previous Work in the Literature and Our Retrosynthetic Approach

This paper details a versatile access to a large range of

ortho,meta-bridged diarylheptanoids via a key intermediate,

isomyricanone 3, and exempliﬁes the preparation of 1 and 5.

This total synthesis was performed keeping in mind the

highlight that no cyclic diarylheptanoid has ever been prepared

by RCM.

Our synthesis of isomyricanone 3, the key precursor, begins

with the preparation of the ﬁrst coupling partner 7, as depicted

in Scheme 2. Thereupon, cheap 3,4,5-trimethoxybromoben-

zene 10 undergoes a Rieche formylation. Subsequently,

outlines of the ideality to prepare a natural product.₁The

latter has been numerically expressed by Baran et al. and

successive AlCl -promoted regioselective demethylation in

graphically crafted by Christmann et al.

Hence, we

ortho position of the aldehyde, addition of the allyl Grignard

reagent to build the alkyl chain, and reduction of the resulting

carbinol by triethylsilane were performed to aﬀord 11

smoothly. Since a lithium−bromine exchange followed by

envisaged a new retrosynthetic approach of 3 involving two

evident disconnections and therefore two key reactions: a

Suzuki−Miyaura coupling (SM coupling) along with a ring

closing metathesis (RCM) between a type I and type II oleﬁn

for the macrocyclization step (Scheme 1C). Indeed, in the

literature, only two examples for the formation of 12-

membered macrocycles featuring a (hetero)biaryl scaﬀold

insertion of a boron-containing electrophile (B(OMe) or

B(OiPr) ) did not allow us to aﬀord the required boronic acid

as pure product, we ended up using a one-pot procedure to

isolate triﬂuoroborate salt 7 on exposure to potassium

hydrogen biﬂuoride, in 81% yield.

Concurrently, the second building block 8 was quantitatively

obtained in one step through iodination of the commercially

have been described. The ﬁrst one was illustrated by Ku

ndig et

al., who synthesized vertine, an alkaloid commonly known as

cryogenine, by means of a RCM. Macrocyclization was

enabled by the Hoveyda-Grubbs second-generation catalyst on

the preconformationally prone to cyclize seco-precursor, which

allowed to isolate vertine in 37% yield (Scheme 1B). In the

second instance, Bristol-Myers Squibb has described the

synthesis of a 12-membered macrocyclic compound containing

a heterocycle via RCM using Grubbs second-generation

available 9 with I and silver sulfate. Notwithstanding, during

scale up, we observed predominantly the formation of a

byproduct resulting from the rearrangement of the benzylic

ether into the ortho-benzyl alkylated phenol. In the aftermath

of this displacement, we eventually had to tweak the conditions

by using NIS in acidic medium, which aﬀorded 8 in

quantitative yield, regardless of the scale.

catalyst in 71% yield (Scheme 1B). It is important to

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Scheme 2. Synthesis of Isomyricanone 3 and Isomyricanol 13 with Its Molecular Structure Showing 50% Ellipsoids

Procedures: (a) Dichloromethyl methyl ether, TiCl , CH Cl , 0 °C to r.t.; (b) AlCl , CH Cl , 15 °C; (c) allylmagnesium bromide, THF, 0 °C;

(

d) Et SiH, TFAA, CH Cl , 0 °C then TBAF, THF; (e) BnBr, NaH, NaI, DMF, 0 °C; (f) t-BuLi, THF, −78 °C then i-PrOBpin, −78 to 40 °C

then KHF , H O, MeOH, r.t.; (g) NIS, TFA, MeCN, r.t.; (h) Pd(PPh ) , K CO , dioxane/H O (8/2), 100 °C; (i) CH NHOCH ·HCl, AlMe ,

PhMe, 0 °C to r.t.; (j) vinylmagnesium bromide, THF, 0 °C; (k) Grubbs II, CH Cl , 40 °C; (l) H (55 psi), Pd/C, AcOEt, r.t.; (m) NaBH ,

MeOH, r.t.

With both coupling partners 7 and 8 in hand, obtained

without column chromatography on multigram scale, the SM

coupling proceeded in 35% yield in the presence of Pd(PPh₃)₄

and K CO in water. We observed the formation of the

Stemming from 13, challenging tetracyclic diarylheptanoid 1

was obtained by acid-dehydration on the heptylene chain

followed by electrophilic aromatic substitution as a pair of

enantiomers (presumably aR,R and aS,S) in 79% yield after

puriﬁcation via semipreparative HPLC (Scheme 3).

corresponding carboxylic acid due to in situ saponiﬁcation. To

overcome this problem, we tuned the solvent ratio to dioxane/

H O (8/2) in order to get the coupled product in 67% yield.

Scheme 3. Synthesis of 1 and 5 from 13

Adding a ligand such as Xphos or SPhos led to the

isomerization of the terminal oleﬁn. The preparation of the

Weinreb amide at 0 °C ensued, pending treatment with vinyl

Grignard to give rise to the terminal α,β-unsaturated ketone 6,

the seco-precursor of the RCM. RCM of 6 was performed

using Grubbs second-generation catalyst at reﬂux in DCM in

high-dilution conditions. Pleasingly, the conversion of starting

material was complete and only one addition of catalyst was

required to reach expected macrocyclized synthon 12 in 85%

yield. This implies that the ring strain is fully released in an

ortho,meta-diarylheptanoid compared to a meta,meta-diary-

lheptanoid. Subsequently, an hydrogenation was achieved in

order to saturate the heptylene chain and to deprotect the

benzyl groups, giving prominence to pressure to ensure

reproducibility. Finally, isomyricanone 3, the 12-membered

key intermediate was furnished in 12 steps with an overall yield

of 33%.

Procedures: (a) PTSA, PhCH , 90 °C; (b) salcomin, O , DMF, r.t.

At this stage, we envisaged the postderivation of 3 to access

other derivatives of interest. The ﬁrst one to be supplied was

isomyricanol 13, obtained as a pair of enantiomers, by

reduction of 3 using sodium borohydride. The latter was

recrystallized out of a mixture of ethyl acetate and chloroform

at room temperature to aﬀord a single crystal, giving rise to an

X-ray structure.

The last envisaged postderivation delivered the natural

bioactive actinidione 5. Indeed, this ortho,meta-diarylheptanoid

was obtained by a regioselective phenol oxidation of 13 in a

satisfying yield of 68%, by engaging salcomin under oxygen

atmosphere in DMF (Scheme 3). To the best of our

knowledge, no precedent synthesis was described in the

literature. By using Frem

y’s catalyst, we observed several

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products including one stemming from a dehydrogenation

followed by an ipso-hydroxylation in ortho of the phenol on the

southern aromatic ring.

decent overall yield of 18% for the ﬁrst synthesis of natural

actinidione 5.

In the attempt to optimize our synthesis of 3, we tackled the

step-economy by avoiding protecting groups at most, in order

to attain a suﬃcient ideality, still having in mind the complexity

of our targeted molecule. Our tactic focused likewise on

optimizing each step to get a high overall yield, even on

scalability. Furthermore, we set out to develop a modular

approach to gain access to diverse ortho,meta-diarylheptanoids

through a common intermediate, 3. To that extent, we decided

to follow the model of Christmann et al., who recently

promoted a color-coded ﬂowchart to apprehend the ideality of

EXPERIMENTAL SECTION

■

General Information. All reactions were conducted under argon

atmosphere unless otherwise noted and THF was distilled by standard

technique prior to use. Commercially available reagents were used

without additional puriﬁcation, unless otherwise stated. 9 was bought

from Fluorochem and 10 from TCI Chemicals. Hydrogenation

reactions were performed using a QianCapQ-Tube-Purging-12-SS

system pressure reactor. NMR analyses were recorded in CDCl or

CD CN. H and proton-decoupled C NMR spectra were either

recorded on Bruker AV 400 or Bruker AV 500. Chemical shifts are

reported in parts per million (ppm) and are referenced to the residual

11d

a synthesis (Scheme 4). Concerning our synthesis of 5, out

solvent resonance as the internal standard (CDCl : δ [ H] = 7.267

and accordingly δ [ C] = 77.16 ppm). Coupling constants (J) are

given in Hz. IR spectra were recorded on PerkinElmer Spectrum

UATR two equipped with a diamond detector and an ATR unit.

HRMS (Q-TOF) analysis were performed by the analytical facility at

the University of Strasbourg. Crystal X-ray diﬀraction analyses were

carried out by the Radiocrystallography Service of the University of

Strasbourg by using a Bruker PHOTON III pixel detector

diﬀractometer equipped with two microsources IμS Mo and IμS

Diamond Cu. Chiral HPLC measurements were performed on a

Shimadzu system with a quaternary low-pressure LC-20AD pump, an

automatic SIL-20A HT injector, a CTO-10 AS oven and a SPD-M20

A diode array detector (DAD). The injection volume was 1 μL, the

temperature of the oven set to 25 °C and the concentration of the

sample 1 g/L. Semipreparative HPLC was performed with a Varian

Prostar 210PDA apparatus equipped with a semipreparative Daicel

column (Chiralpak IA 20 mm × 250 mm, 5 μm) at 215 nm.

Scheme 4. Flowchart Representation of the Synthesis of 5

Preparation of 3-(Benzyloxy)-1-bromo-2-(but-3-en-1-yl)-

,5-dimethoxybenzene (11) Starting from (10). 6-Bromo-

,3,4-trimethoxybenzaldehyde (14). A magnetically stirred solution

of dichloromethyl methyl ether (2.05 equiv, 15 mL, 165.75 mmol)

and TiCl (2.25 equiv, 20 mL, 182.4 mmol) in CH Cl (300 mL) was

treated with a solution of commercially available 10 (1 equiv, 20 g,

0.94 mmol) in anhydrous CH Cl (100 mL) at 0 °C. The red

mixture was stirred at room temperature for 5 h. HCl (10%, 40 mL)

was added at 0 °C, the stirring was continued for 15 min. The organic

layer was then separated, and the aqueous phase extracted with

CH Cl (3× 200 mL). The combined extracts were washed with a

saturated solution of NaHCO (50 mL), brine, dried over MgSO ,

ﬁltered oﬀ and concentrated under reduced pressure to aﬀord 14 as a

yellow solid. (22 g, 80.13 mmol, 99% yield) without further

puriﬁcation. Analytical data are consistent with those reported in

the literature.

-Bromo-2-hydroxy-3,4-dimethoxybenzaldehyde (15). To a

solution of 14 (1 equiv, 10 g, 36.35 mmol) in dry CH Cl (300

mL) was added AlCl (1 equiv, 4.85 g, 36.35 mmol) portionwise at 0

C under inert atmosphere. After 1 h, another equivalent of AlCl was

added. The mixture was stirred for another 3 h below 15 °C. The ﬂask

was dived in an ice bath at 0 °C. The reaction mixture was then

poured carefully into a mixture of ice and HCl (10%) over a few

minutes, also dived in an ice bath. The mixture was stirred for 1 h.

Aqueous phase was extracted with CH Cl (3× 200 mL). The

of 14 steps and an overall yield of 18%, it is unequivocal that

most of the steps are green, to wit strategic. We exclusively

account for three functional group interconversions (iodina-

tion, boronation, Weinreb amide preparation) and one

required benzyl-protecting step. Accordingly, we have a high

degree of ideality of 71%, which is calculated by the strategic

combined organic layer were washed successively with a saturated

solution of NaHCO (100 mL), brine, dried over anhydrous Na SO ,

11a

steps out of the total number of steps.

ﬁltered oﬀ through a pad of silica gel and concentrated under reduced

pressure to aﬀord 15 as a yellow oil (8.26 g, 31.62 mmol, 87% yield)

without further puriﬁcation. Analytical data are consistent with those

In conclusion, we undertook a novel, rapid, eﬃcient, and

modular approach to the appealing family of 12-membered

ortho,meta-diarylheptanoids via two key metal-mediated

reactions (RCM and SM coupling). Attempts to prepare

reported in the literature.

-Bromo-2-(1-hydroxybut-3-en-1-yl)-5,6-dimethoxyphenol (16).

Allylmagnesium bromide (2.09 equiv, 1 M in Et O, 72 mL, 72 mmol)

cyclic diarylheptanoids by RCM beforehand had failed. It is

worth noting that the key precursor 3 was obtained in 12 steps

in 33% overall yield, and late-stage diversiﬁcation thereof gives

access to promising compounds 1, 5, and 13. As an outcome,

we have reached a high degree of ideality combined with a

was added dropwise over 5 min to a stirred solution of 15 (1 equiv, 9

g, 34.47 mmol) in THF (170 mL) at 0 °C. The mixture was stirred at

°C for 30 min. The reaction mixture was quenched at 0 °C by

addition of a saturated solution of NH Cl (150 mL). The aqueous

phase was extracted with EtOAc (3× 200 mL). The combined organic

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Note

layers were washed with brine (50 mL), dried over Na SO , ﬁltered

14.5 mL H O, 65.25 mmol) was added at room temperature. The

oﬀ and evaporated under reduced pressure. Crude was ﬁltered

through a pad of silica/Celite/activated charcoal to aﬀord 16 as a

yellow oil (10.44 g, 34.45 mmol, 99% yield) without further

reaction was stirred for 1.5 h minutes at room temperature. PhCH₃

(3× 50 mL) was added, and the mixture was concentrated under

reduced pressure to eliminate water and to aﬀord a yellowish solid.

Acetone was added and the mixture was ﬁltered oﬀ to eliminate

inorganic salts. The ﬁltrate was evaporated to aﬀord a yellowish solid.

Hexane (3× 20 mL) was then added and supernatant was removed.

puriﬁcation; R 0.41 (SiO , Hex/EtOAc 7:3); H NMR (500

MHz, CDCl ) δ 8.33 (s, 1H), 6.58 (s, 1H), 5.88 (ddt, J = 17.2, 10.2,

.1 Hz, 1H), 5.19−5.06 (m, 3H), 3.84 (s, 3H), 3.81 (s, 3H), 2.62−

.50 (m, 2H); ¹³C{ H} NMR (125 MHz, CDCl ) δ 152.3, 149.9,

White powder was washed thrice with Et O to aﬀord 7 as a white

36.0, 134.3, 120.3, 118.3, 115.8, 108.0, 74.7, 60.9, 56.1, 40.7; IR

solid (3.84 g, 9.49 mmol, 81% yield) without any further puriﬁcation.

−

(

cm ) ν 3389, 3078, 2935, 2841, 1603, 1571, 1493, 1444, 1417,

301, 1244, 1123, 1045, 919, 811; HRMS (ESI+) m/z [M + Na]

H NMR (500 MHz, CD CN) δ 7.52 (d, J = 6.9 Hz, 2H), 7.43−7.30

(m, 3H), 6.95 (s, 1H), 5.91 (ddt, J = 16.9, 10.2, 6.5 Hz, 1H), 4.98 (s,

2H), 4.98−4.93 (m, 1H, 20), 4.88 (ddt, J = 10.2, 2.4, 1.3 Hz, 1H),

3.80 (s, 3H), 3.78 (s, 3H), 2.81−2.76 (m, 2H), 2.26−2.19 (m, 2H);

calcd for C H BrO Na325.0046, found 325.0068.

-Bromo-2-(but-3-en-1-yl)-5,6-dimethoxyphenol (17). Under

inert atmosphere, 16 (1 equiv, 5.3 g, 17.52 mmol) was dissolved in

CH Cl (85 mL) and the mixture was cooled to 0 °C. Triethylsilane

C{ H} NMR (125 MHz, CD CN) δ 151.2, 151.0, 141.4, 139.9,

132.0, 129.3, 128.7, 128.5, 113.7, 112.8, 75.4, 60.9, 56.3, 36.8, 29.4;

(

1.13 equiv, 3.2 mL, 19.81 mmol) and triﬂuoroacetic anhydride (1.31

equiv, 3.2 mL, 23.0 mmol) were added. The reaction was stirred for

.5 h at 0 °C. The reaction mixture was quenched with H O (10 mL)

B NMR (160 MHz, CD CN) δ 3.31; F NMR (470 MHz,

−1

CD CN) δ −138.35; IR (cm ) ν 3622, 3564, 3034, 3001, 2967,

2938, 2878, 2838, 1648, 1413, 1372, 1318, 1121, 1069, 980, 920, 859,

796, 752, 697; HRMS (ESI−) m/z [M − K] calcd for

C H BF O 365.1545, found 365.1530.

at 0 °C and the aqueous phase was extracted with CH Cl (3× 100

mL). The combined organic layers were dried over Na SO , ﬁltered

oﬀ and evaporated under reduced pressure. The residue was dissolved

in THF (105 mL) and TBAF (1.02 equiv, 1 M in THF, 18 mL, 18

mmol) was added. The mixture was stirred for 30 min at room

Methyl 3-(4-(benzyloxy)-3-iodophenyl)propanoate (8). To a

solution of 9 (1 equiv, 10 g, 36.99 mmol) in CH CN (150 mL)

and TFA (0.3 equiv, 0.82 mL, 11.10 mmol) was added NIS (1.5

equiv, 12.5 g, 55.56 mmol) at 0 °C. The mixture was stirred at room

temperature for 5 h. EtOAc (300 mL) was added and the organic

phase was washed with a saturated aqueous solution of Na S O (70

temperature. HCl (10%, 50 mL) was added at 0 °C. Et O was added

and the organic phase was washed with HCl (3× 80 mL). Organic

layer was washed with brine (50 mL), dried over Na SO , ﬁltered oﬀ

and the solvent was concentrated under reduced pressure to aﬀord 17

mL) then NaOH (6 N, 200 mL), dried over Na SO , ﬁltered oﬀ and

as a yellow oil (4.63 g, 16.12 mmol, 92% yield) without any further

concentrated under reduced pressure to aﬀord 8 as a yellow oil (14.7

puriﬁcation. R 0.36 (SiO , Hex/EtOAc 9:1). H NMR (500 MHz,

g, 36.97 mmol, 99% yield) without any further puriﬁcation. R 0.33

CDCl ) δ 6.69 (s, 1H), 5.97−5.84 (m, 2H), 5.11−4.91 (m, 2H), 3.89

(SiO₂, Hex/EtOAc 9:1). The analytical data are consistent with

(

s, 3H), 3.84 (s, 3H), 2.88−2.77 (m, 2H), 2.32−2.27 (m, 2H).

those reported in the literature.

C{ H} NMR (125 MHz, CDCl ) δ 150.6, 148.0, 138.4, 134.7,

Preparation of 5-(3′,6-Bis(benzyloxy)-2′-(but-3-en-1-yl)-

4′,5′-dimethoxy-[1,1′-biphenyl]-3-yl)pent-1-en-3-one (6)

Starting from (7) and (8). Methyl 3-(3′,6-bis(benzyloxy)-2′-(but-

−

21.2, 118.8, 114.7, 108.0, 61.1, 56.1, 33.0, 29.3. IR (cm ) ν 3495,

071, 2998, 2935, 2853, 1639, 1576, 1607, 1493, 1454, 1421, 1315,

-en-1-yl)-4′,5′-dimethoxy-[1,1′-biphenyl]-3-yl)propanoate (18).

237, 1197, 1123, 1043, 911, 797. HRMS (ESI−) m/z [M − H]

To a round-bottomed ﬂask was added 7 (1.5 equiv, 1.91 g, 4.71

calcd for C H BrO 285.0132, found 285.0130.

mmol) and 8 (1 equiv, 1.27 g, 3.21 mmol). Then, H O (10 mL) and

-(Benzyloxy)-1-bromo-2-(but-3-en-1-yl)-4,5-dimethoxybenzene

11). To a solution of 17 (1 equiv, 4.25 g, 14.8 mmol) in DMF (60

mL) was added NaH (1.2 equiv, 710 mg, 17.82 mmol) at 0 °C. After

0 min of stirring, benzyl bromide (1.01 equiv, 1.77 mL, 14.8 mmol)

(

dioxane (40 mL) were added, followed by tetrakis-

(triphenylphosphine)palladium(0) (11 mol %, 414 mg, 0.358

mmol) and dry K

mixture was stirred at 100 °C using an aluminum heating block for 16

h. Once the reaction mixture was back at room temperature, H O (30

mL) was added. The aqueous phase was extracted with CH Cl (3×

100 mL). The combined organic layers were dried over Na SO

2 3

CO (5 equiv, 2.22 g, 16.06 mmol). The reaction

and NaI (9 mol %, 200 mg, 1.32 mmol) were added. The reaction

mixture was stirred at room temperature for 1.5 h. A saturated

solution of NH Cl (25 mL) was added slowly to quench the reaction

at 0 °C. The aqueous phase was extracted with Et O (3× 100 mL).

Combined organic layers were washed with cold water (3× 250 mL),

ﬁltered oﬀ and evaporated under reduced pressure. Crude was

puriﬁed by ﬂash chromatography on silica gel (gradient was

performed from 100/0, v/v cyclohexane/ethyl acetate to 8/2, v/v)

dried over Na SO , ﬁltered oﬀ and concentrated under reduced

pressure. Crude was puriﬁed by ﬂash chromatography on silica gel

gradient was performed from 100/0, v/v cyclohexane/ethyl acetate

to 8/2, v/v) to aﬀord 11 (5.02 g, 13.32 mmol, 90% yield) as a yellow

(

to aﬀord 18 (1.2 g, 2.15 mmol, 67% yield) as a colorless oil. R

0.23

(SiO , Hex/EtOAc 9:1); H NMR (400 MHz, CDCl ) δ 7.56−7.45

2 3

oil. R 0.56 (SiO , Hex/EtOAc 9:1). H NMR (400 MHz, CDCl ) δ

(m, 2H), 7.41−7.27 (m, 3H), 7.27−7.17 (m, 5H), 7.12 (dd, J = 8.4,

2.4 Hz, 1H), 7.03 (d, J = 2.3 Hz, 1H, 16), 6.92 (d, J = 8.4 Hz, 1H),

6.55 (s, 1H, 3), 5.59 (ddt, J = 17.0, 10.4, 6.7 Hz, 1H), 5.09 (AB, J =

10.8 Hz, ΔνAB = 36.5 Hz, 2H), 5.00 (s, 2H), 4.79−4.71 (m, 2H), 3.94

(s, 3H), 3.82 (s, 3H), 3.66 (s, 3H), 2.92 (t, J = 7.8, 7.8 Hz, 2H),

2.69−2.56 (m, 3H), 2.43−2.30 (m, 1H), 2.16−1.91 (m, 2H);

.49−7.44 (m, 2H), 7.43−7.32 (m, 3H), 6.90 (s, 1H), 5.87 (ddt, J =

6.9, 10.2, 6.7 Hz, 1H), 5.07 (s, 2H), 5.05−4.93 (m, 2H), 3.86 (s,

H), 2.82−2.73 (m, 2H), 2.28−2.19 (m, 2H); C{ H} NMR (125

MHz, CDCl ) δ 152.2, 151.5, 142.1, 138.3, 137.7, 128.6, 128.4, 128.1,

−1

28.1, 118.3, 114.8, 112.1, 75.5, 61.0, 56.3, 33.7, 29.9; IR (cm ) ν

065, 3031, 2964, 2934, 2841, 1639, 1589, 1481, 1444, 1429, 1412,

367, 1284, 1231, 1212, 1120, 1091, 1045, 996, 909, 795, 734, 696;

C{ H} NMR (125 MHz, CDCl ) δ 173.4, 154.2, 151.0, 150.9,

141.6, 138.9, 138.2, 137.5, 134.1, 132.8, 131.4, 131.2, 128.5, 128.4,

128.3, 128.0, 127.8, 127.6, 127.3, 126.6, 114.1, 113.2, 109.9, 75.2,

HRMS (ESI+) m/z [M + K] calcd for C H BrO K 415.0306,

−

found 415.0305.

70.3, 61.0, 56.0, 51.7, 36.0, 34.7, 30.2, 27.6; IR (cm ) ν 3065, 3031,

2929, 2856, 1737, 1636, 1599, 1487, 1453, 1414, 1341, 1251, 1126,

1045, 1024, 736, 697; HRMS (ESI+) m/z [M + Na]⁺calcd for

C H O Na 589.2561, found 589.2533.

Potassium (3-(benzyloxy)-2-(but-3-en-1-yl)-4, 5-

dimethoxyphenyl)triﬂuoroborate (7). To a solution of 11 (1 equiv,

.42 g, 11.72 mmol) in THF (200 mL) was added t-BuLi (2.02 equiv,

.7 M in pentane, 13.7 mL, 23.37 mmol) dropwise at −78 °C under

3-(3′,6-Bis(benzyloxy)-2′-(but-3-en-1-yl)-4′,5′-dimethoxy-[1,1′-

argon. It was stirred for 30 min at −78 °C. Then, distilled 2-

isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5 equiv, 0.25 mL,

biphenyl]-3-yl)-N-methoxy-N-methylpropanamide (19). To a slurry

mixture of N,O-dimethylhydroxylamine hydrochloride (5 equiv, 1.04

g, 10.66 mmol) in dry PhCH₃(6 mL) was added dropwise

.23 mmol) was added quickly at −78 °C. Dry ice bath was removed,

and the reaction medium was stirred at room temperature for 4 h.

Solvent was evaporated under reduced pressure. The residue was

trimethylaluminum (5 equiv, 2 M in PhCH , 5.3 mL, 10.6 mmol)

over 10 min at 0 °C under argon atmosphere (vigorous bubbling was

observed). Then, the solution was allowed to warm to room

temperature for 1 h. The mixture was recooled at 0 °C and a

taken up in CH OH (120 mL) and a sonicated aqueous solution of

potassium hydrogen ﬂuoride (5.57 equiv, 5 g KHF , 4.5 M in H O,

037

J. Org. Chem. 2021, 86, 3033−3040

The Journal of Organic Chemistry

https://pubs.acs.org/doi/10.1021/acs.joc.0c02489.

Note

sonicated solution of 18 (1 equiv, 1.2 g, 2.12 mmol) in PhCH (6

130.3, 128.6, 128.5, 128.4, 127.9, 127.9, 127.7, 126.7, 125.7, 112.8,

−

mL) was added. The yellow mixture was vigorously stirred at room

temperature for 4 h. The reaction was hydrolyzed slowly at 0 °C with

HCl (10%, 20 mL, vigorous bubbling was observed). An aqueous

saturated solution of Rochelle’s salt (potassium sodium tartrate, 30

mL) was added and it was stirred for 10 min. The aqueous layer was

extracted with EtOAc (3× 150 mL). The combined organic layers

107.9, 75.1, 70.5, 61.0, 56.0, 40.8, 33.8, 33.5, 27.6; IR (cm ) ν 3031,

2924, 2854, 1685, 1654, 1596, 1486, 1415, 1374, 1344, 1249, 1126,

1104, 1023, 736, 697; HRMS (ESI+) m/z [M + K]⁺calcd for

C H O K 573.2038, found: 573.2048.

1,2-Dihydroxy-14,15-dimethoxy-1(1,2),2(1,3)-dibenzenacyclono-

naphan-5-one (Isomyricanone, 3). To a solution of 12 (1 equiv, 50

mg, 0.094 mmol) in EtOAc (1 mL) was added palladium on activated

charcoal (1 equiv, 10 mg, 0.103 mmol) and stirred for 16 h under a

were washed with an aqueous saturated solution of NaHCO (100

mL), dried over Na SO , ﬁltered oﬀ and evaporated under reduced

H atmosphere (55 psi). The reaction mixture was ﬁltered through a

pressure to aﬀord 19 (1.25 g, 2.10 mmol, 99%) without any further

pad of Celite and solvent was evaporated under reduced pressure to

puriﬁcation as a colorless oil. R 0.22 (SiO , Hex/EtOAc 7:3); H

aﬀord isomyricanone 3 (33 mg, 0.093 mmol, 99% yield) without any

NMR (500 MHz, CDCl ) δ 7.55−7.46 (m, 2H), 7.43−7.29 (m, 3H),

further puriﬁcation as a colorless oil. R 0.15 (SiO , Hex/EtOAc

.29−7.19 (m, 5H), 7.17 (dd, J = 8.3, 2.4 Hz, 1H), 7.07 (d, J = 2.4

Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.57 (s, 1H), 5.61 (ddt, J = 17.0,

0.4, 6.7 Hz, 1H), 5.10 (AB, J = 12.0 Hz, Δν = 46.0 Hz, 2H), 5.00

:3); Analytical data are consistent with those reported in the

literature.

,1-Dimethoxy-1(1,2),2(1,3)-dibenzenacyclononaphane-1,2,5-

(

s, 2H), 4.83−4.65 (m, 2H), 3.94 (s, 3H), 3.83 (s, 3H), 3.61 (s, 2H),

triol, (Isomyricanol, 13). To a solution of isomyricanone 3 (1 equiv,

.18 (s, 3H), 2.97−2.91 (m, 2H), 2.77−2.71 (m, 2H), 2.66−2.57 (m,

13 1

200 mg, 0.56 mmol) in CH OH (7 mL) was added sodium

H), 2.44−2.33 (m, 1H), 2.20−1.96 (m, 2H); C{ H} NMR (125

borohydride (6 equiv, 126 mg, 3.34 mmol) at 0 °C under inert

MHz, CDCl ) δ 173.8, 154.1, 151.0, 150.9, 141.6, 139.0, 138.2, 137.5,

atmosphere and was stirred for 1 h at room temperature. H O (5 mL)

34.2, 133.6, 131.3, 131.3, 128.5, 128.4, 128.0, 127.8, 127.6, 127.3,

and EtOAc (25 mL) were added. The aqueous phase was extracted

with EtOAc (3× 30 mL). Combined organic layers were dried over

Na SO , ﬁltered oﬀ and concentrated under reduced pressure to

26.7, 114.0, 113.2, 109.9, 75.2, 70.3, 61.3, 61.0, 56.0, 34.7, 34.0, 32.3,

−1

9.9, 27.6; IR (cm ) ν 3065, 3028, 2933, 2853, 1664, 1596, 1571,

487, 1453, 1414, 1374, 1341, 1251, 1125, 1024, 908, 736, 697;

aﬀord isomyricanol 13 (168 mg, 0.47 mmol, 84%) without any further

puriﬁcation as a white solid. Analytical data are consistent with those

HRMS (ESI+) m/z [M + H] calcd for C H NO 596.3007, found

96.2994.

reported in the literature. This compound is present as a 50:50 ratio

-(3′,6-Bis(benzyloxy)-2′-(but-3-en-1-yl)-4′,5′-dimethoxy-[1,1′-

of two enantiomers and chiral HPLC are available in the SI.

biphenyl]-3-yl)pent-1-en-3-one (6). To a sonicated solution of 19 (1

equiv, 1.45 g, 2.10 mmol) in dry THF (6 mL) was added

vinylmagnesium bromide (2.4 equiv, 1 M in THF, 6 mL, 5.0

mmol) at 0 °C. The yellow mixture was then stirred at 0 °C for 1 h.

The reaction mixture was quickly quenched at 0 °C with HCl (10%,

,7-Dihydroxy-2 ,2 -dimethoxy-1(1,3)-benzena-2(1,2)-cyclohex-

1 4 3 6

anacyclononaphane-2 ,2 -diene-2 ,2 -dione (Actinidione, 5). Iso-

myricanol 13 (1 equiv, 50 mg, 0.14 mmol) and salcomine (0.4 equiv,

8 mg, 0.054 mmol) were charged and DMF (2.5 mL) was added.

Oxygen gas was continuously bubbled through the stirring mixture for

h. Afterward, an additional 18 mg of catalyst was added. The

reaction was complete after 16 h under oxygen atmosphere. EtOAc

30 mL) was added. The organic phase was washed with cold H O

0 mL). The aqueous phase was extracted with EtOAc (3× 150 mL)

and the combined organic layers were washed with brine (50 mL),

dried over Na SO , ﬁltered oﬀ and concentrated under reduced

(

pressure to aﬀord 6 (1.37 g, 2.10 mmol, 99%) without any further

(5× 10 mL), dried over anhydrous MgSO , ﬁltered oﬀ and

puriﬁcation as an orange oil. R 0.21 (SiO , Hex/EtOAc 9:1); H

concentrated under reduced pressure to aﬀord actinidione 5 (35

mg, 0.093 mmol, 68%) without any further puriﬁcation as an orange

NMR (500 MHz, CDCl ) δ 7.52−7.47 (m, 2H), 7.40−7.29 (m, 3H),

.28−7.17 (m, 5H), 7.13 (dd, J = 8.4, 2.4 Hz, 1H), 7.03 (d, J = 2.3

oil. R 0.40 (SiO , Hex/EtOAc 3:7); H NMR (500 MHz, CDCl ) δ

Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.56 (s, 1H), 6.35 (X(AMX), J =

.07 (dd, J = 8.2, 2.2 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.81 (d, J =

.2 Hz, 1H), 5.36 (s, 1H), 4.06 (s, 3H), 4.02 (s, 3H), 3.73 (t, J = 9.3,

.3 Hz, 1H), 2.83 (dt, J = 13.8, 4.2, 4.2 Hz, 1H), 2.67 (td, J = 12.9,

2.3, 3.7 Hz, 1H), 2.41 (ddd, J = 12.1, 10.4, 7.6 Hz, 1H), 1.96 (dt, J =

7.7, 10.5 Hz, 1H), 6.02 (AM(AMX), J = 17.7, 10.5, 0.9 Hz, Δν

56.5 Hz, 2H), 5.60 (ddt, J = 17.0, 10.4, 6.7 Hz, 1H), 5.14 (AB, J =

0.7 Hz, Δν = 36.3 Hz, 1H), 5.00 (s, 2H), 4.79−4.72 (m, 2H), 3.94

(

s, 3H), 3.82 (s, 3H), 2.95−2.87 (m, 4H), 2.66−2.56 (m, 1H), 2.43−

13 1

13.7, 4.3, 4.3 Hz, 1H), 1.93−1.84 (m, 0H), 1.73−1.55 (m, 1H),

.32 (m, 1H), 2.19−1.94 (m, 2H); C{ H} NMR (125 MHz,

.25−1.12 (m, 1H), 1.06−0.96 (m, 1H), 0.79 (t, J = 14.5 Hz, 1H).

CDCl ) δ 199.9, 154.2, 151.1, 150.9, 141.6, 139.0, 138.2, 137.5, 136.6,

C{ H} NMR (125 MHz, CDCl ) δ 184.3, 184.2, 151.0, 146.6,

34.1, 133.3, 131.4, 131.3, 128.5, 128.4, 128.3, 128.0, 127.9, 127.6,

45.0, 144.5, 141.1, 133.7, 131.2, 130.6, 120.8, 117.6, 72.2, 61.4, 61.3,

27.3, 126.7, 114.0, 113.2, 109.9, 75.2, 70.3, 61.0, 56.1, 41.5, 34.7,

−

39.9, 34.8, 33.7, 26.9, 26.4, 24.2; IR (cm ) ν 3391, 3013, 2925, 2854,

651, 1613, 1599, 1507, 1454, 1287, 1202, 1144, 1130, 1070, 1016,

9.1, 27.6. IR (cm ) ν 3062, 3034, 2930, 2859, 1702, 1679, 1638,

596, 1571, 1486, 1453, 1412, 1372, 1340, 1284, 1250, 1123, 1044,

822, 758; HRMS (ESI+) m/z [M + Na] calcd for C21

95.1465, found 395.1450.

H O Na

24 6

022, 908, 842, 811, 735, 696; HRMS (ESI+) m/z [M + H] calcd for

C H O 563.2792, found 563.2804.

(

S)-8,9-Dimethoxy-2,3,3a,4,5,6-hexahydro-1H-benzo[4,5]-

(

E)-13,26-Bis(benzyloxy)-14,15-dimethoxy-1(1,2),2(1,3)-dibenze-

nacyclononaphan-6-en-5-one (12). A solution of 6 (1 equiv, 97 mg,

.170 mmol) in CH Cl (165 mL) was degassed for 30 min under a

cycloocta[1,2,3-de]naphthalene-7,11-diol (1). To a solution of

isomyricanol 13 (1 equiv, 50 mg, 0.139 mmol) in PhCH (10 mL)

was added para-toluenesulfonic acid (3.3 equiv, 79 mg, 0.459 mmol).

The solution was heated at 90 °C with an aluminum heating block for

ﬂow of argon. The reaction mixture was heated at reﬂux by using a

glycerol bath. Then, Grubbs-II catalyst (20 mol %, 30 mg, 0.035

mmol) was added in one portion. The reaction mixture was stirred at

reﬂux for 16 h. The reaction mixture was ﬁltered through a pad of

both activated charcoal and silica gel and solvent was evaporated

under reduced pressure to 12 (78 mg, 0.15 mmol, 85%) without any

h under air atmosphere. After cooling, Et O (15 mL) was added.

The organic phase was washed with a saturated solution of

NaHCO (5 mL), dried over MgSO , ﬁltered oﬀ and evaporated

under reduced pressure. Crude was puriﬁed by semipreparative HPLC

to aﬀord 1 (37.4 mg, 0.110 mmol) as a pair of enantiomers. R 0.69

(SiO , Hex/EtOAc 6:4). Analytical data are consistent with those

further puriﬁcation as a colorless oil. R 0.21 (SiO , Hex/EtOAc

:1); H NMR (400 MHz, CDCl ) δ 7.44−7.36 (m, 2H), 7.32−7.21

reported in the literature. This compound is present as a 50:50 ratio

of two enantiomers and chiral HPLC are available in the SI.

(

m, 3H), 7.21−7.09 (m, 5H), 6.95 (dd, J = 8.2, 2.3 Hz, 1H), 6.78 (d,

J = 8.3 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), 6.53 (s, 1H), 5.83 (dt, J =

5.8, 7.8 Hz, 1H), 5.56 (d, J = 16.0 Hz, 1H), 5.07 (AB, J = 11.3 Hz,

Δν = 63.9 Hz, 2H), 4.93 (AB, J = 12.2 Hz, Δν_A_B= 16.5 Hz, 2H),

ASSOCIATED CONTENT

■

.86 (s, 3H), 3.78 (s, 3H), 2.95−2.83 (m, 2H), 2.83−2.72 (m, 1H),

sı Supporting Information

The Supporting Information is available free of charge at

.69−2.58 (m, 1H), 2.51−2.41 (m, 1H), 2.29−2.08 (m, 2H), 1.88−

.76 (m, 1H); ¹³C{ H} NMR (100 MHz, CDCl ) δ 203.8, 154.3,

51.8, 151.2, 151.1, 141.4, 138.1, 137.4, 135.7, 134.9, 133.9, 131.9,

038

J. Org. Chem. 2021, 86, 3033−3040

The Journal of Organic Chemistry

Proposed mechanism, detailed synthetic schemes, H,

Smith, G. R.; Reitz, A. B.; Baker, B. J.; Dickey, C. A. Synthesis,

Note

(

4) Martin, M. D.; Calcul, L.; Smith, C.; Jinwal, U. K.; Fontaine, S.

N.; Darling, A.; Seeley, K.; Wojtas, L.; Narayan, M.; Gestwicki, J. E.;

Stereochemical Analysis, and Derivatization of Myricanol Provide

New Probes That Promote Autophagic Tau Clearance. ACS Chem.

Biol. 2015, 10, 1099−1109.

C{ H}, F and B NMR spectra of all compounds

and X-ray molecular structure for compound 13 (PDF)

Accession Codes

CCDC 2012419 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge

via www.ccdc.cam.ac.uk/data_request/cif, or by emailing

data_request@ccdc.cam.ac.uk, or by contacting The Cam-

bridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

(

5) Begley, M. J.; Campbell, R. V. M.; Crombie, L.; Tuck, B.;

Whiting, D. A. Constitution and Absolute Configuration of

Meta,Meta-Bridged, Strained Biphenyls from Myrica Nagi; X-Ray

Analysis of 16-Bromomyricanol. J. Chem. Soc. C 1971, 3634−3642.

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6) Ishida, J.; Kozuka, M.; Tokuda, H.; Nishino, H.; Nagumo, S.;

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Diarylheptanoids. Bioorg. Med. Chem. 2002, 10, 3361−3365.

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Myricanol Glycosides from Myrica Rubra and Revision of the

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and a Diaryl-Heptanoid from Clematoclethra Actinidioides. Planta

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(9) Zhang, H.; Zhang, Z. Handbook of Chinese Traditional Medicine

Resources; Academic Press: Beijing, 1994.

AUTHOR INFORMATION

Corresponding Authors

■

Sabine Choppin − Laboratoire d’Innovation Moléculaire et

Applications (UMR CNRS 7042), Université de Strasbourg,

Université de Haute Alsace, 67087 Strasbourg, France;

orcid.org/0000-0002-9642-7396;

Zhang, L.; Cheng, Y. Cyclic Diarylheptanoids from Myrica Nana

Email: sabine.choppin@unistra.fr

Gilles Hanquet − Laboratoire d’Innovation Moléculaire et

Applications (UMR CNRS 7042), Université de Strasbourg,

Université de Haute Alsace, 67087 Strasbourg, France;

Email: ghanquet@unistra.fr

(10) (a) Wang, J.; Dong, S.; Wang, Y.; Lu, Q.; Zhong, H.; Du, G.;

Inhibiting Nitric Oxide Release. Bioorg. Med. Chem. 2008, 16, 8510−

8515. (b) Yoshimura, M.; Yamakami, S.; Amakura, Y.; Yoshida, T.

Diarylheptanoid Sulfates and Related Compounds from Myrica Rubra

Bark. J. Nat. Prod. 2012, 75, 1798−1802. (c) Ting, Y. C.; Ko, H. H.;

Wang, H. C.; Peng, C. F.; Chang, H. S.; Hsieh, P. C.; Chen, I. S.

Biological Evaluation of Secondary Metabolites from the Roots of

Myrica Adenophora. Phytochemistry 2014 , 103 , 89 −98.

Authors

Paul Masse − Laboratoire d’Innovation Moléculaire et

Applications (UMR CNRS 7042), Université de Strasbourg,

Université de Haute Alsace, 67087 Strasbourg, France

Lucia Chiummiento − Department of Science, University of

Basilicata, 85100 Potenza, Italy

(11) (a) Gaich, T.; Baran, P. S. Aiming for the Ideal Synthesis. J. Org.

Chem. 2010, 75 , 4657 −4673. (b) Newhouse, T.; Baran, P. S.;

Hoffmann, R. W. The Economies of Synthesis. Chem. Soc. Rev. 2009,

Franc o̧ ise Colobert − Laboratoire d’Innovation Moléculaire et

8 , 3010 −3021. (c) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W.

Applications (UMR CNRS 7042), Université de Strasbourg,

Université de Haute Alsace, 67087 Strasbourg, France;

orcid.org/0000-0003-4730-9868

Redox Economy in Organic Synthesis. Angew. Chem., Int. Ed. 2009 ,

48 , 2854 −2867. (d) Schwan, J.; Christmann, M. Enabling Strategies

for Step Efficient Syntheses. Chem. Soc. Rev. 2018, 47, 7985−7995.

(

12) Chausset-Boissarie, L.; Arvai, R.; Cumming, G. R.; Besnard, C.;

ndig, E. P. Total Synthesis of (±)-Vertine with Z-Selective RCM as

a Key Step. Chem. Commun. 2010, 46, 6264−6266.

13) Corte, J. R.; Pinto, D. J. P.; Fang, T.; Osuna, H.; Yang, W.;

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02489

(

Notes

Wang, Y.; Lai, A.; Clark, C. G.; Sun, J. H.; Rampulla, R.; Mathur, A.;

Kaspady, M.; Neithnadka, P. R.; Li, Y. X. C.; Rossi, K. A.; Myers, J. E.;

Sheriff, S.; Lou, Z.; Harper, T. W.; Huang, C.; Zheng, J. J.; Bozarth, J.

M.; Wu, Y.; Wong, P. C.; Crain, E. J.; Seiffert, D. A.; Luettgen, J. M.;

Lam, P. Y. S.; Wexler, R. R.; Ewing, W. R. Potent, Orally Bioavailable,

and Efficacious Macrocyclic Inhibitors of Factor XIa. Discovery of

Pyridine-Based Macrocycles Possessing Phenylazole Carboxamide P1

Groups. J. Med. Chem. 2020, 63, 784−803.

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

We would like to thank Matthieu Chesse

tetracyclic 1 via semipreparative HPLC and the French

■

for the puriﬁcation of

government for Paul Masse’s Ph.D. fellowship.

(14) Du, Z.; Lu, J.; Yu, H.; Xu, Y.; Li, A. A Facile Demethylation of

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