The garuganin and garugamblin diarylether heptanoids: Total synthesis and determination of chiral properties using dynamic NMR

Article

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The Garuganin and Garugamblin Diarylether Heptanoids: Total

Synthesis and Determination of Chiral Properties Using Dynamic

NMR

Zhi-Qiang Zhu,^†M. Quamar Salih,^†Edward Fynn,^†Alex D. Bain,*^,‡and Christopher M. Beaudry*^,†

^†Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, Oregon 97331, United States

^‡Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario L8S 4M1, Canada

S

* Supporting Information

ABSTRACT: The synthesis of the garuganin and garugamblin diarylether heptanoids using an intramolecular Ullmann coupling

is reported. Alkene stereoisomers, vinylogous ester regioisomers, and β-diketone congeners are also synthesized. The chiral

properties and free energies of activation for racemization of the garuganin and garugamblin diarylether heptanoids and

congeners are determined using dynamic NMR methods. A combination of techniques including coalescence measurements, line

shape analysis, and selective inversion experiments are used to measure racemization barriers. None of the garuganin or

garugamblin diarylether heptanoids are chiral, despite their reported speciﬁc rotation values.

racemization, and absolute stereochemistry of the DAEHs

that display a heptanone ansa bridge, speciﬁcally 1−6.⁶

Myricatomentogenin, jugcathanin, galeon, and pterocarine are

chiral molecules that undergo racemization at temperatures in

excess of 200 °C with half-lives of several hours. However,

acerogenin C and acerogenin L undergo rapid racemization at

temperatures above −60 °C.⁶

The garuganin and garugamblin DAEHs (7−14) share a

highly conserved molecular architecture. These compounds

diﬀer only in the substitution pattern at C2−C4 and the

methylation pattern of the 1,3-diketone.⁷As shown in Figure 1,

ﬁve of these compounds were reported to be optically active,

suggesting that they are chiral nonracemic compounds. Three

of these compounds were isolated without mention of optical

activity or chirality, and it is unclear if they are achiral, racemic,

or chiral nonracemic molecules. Nogradi and co-workers

synthesized garuganin III, garugamblin I, and garugamblin II

using a Wittig macrocyclization approach.^4a−c

INTRODUCTION

■

Chirality is of paramount importance to medicine, biology, and

chemistry.¹When molecules contain sp³hybridized stereogenic

centers, chirality can be readily identiﬁed. In molecules without

stereogenic centers, the presence of chirality is not as easily

recognized. Experimental determination of the presence or

absence of chirality is not trivial, particularly when attempting

to distinguish between racemic and achiral materials. It is our

contention that the chiral properties of many cyclophane

natural products are not well understood. Herein, we describe

the use of dynamic NMR methods to experimentally determine

the chiral properties of the garuganin and garugamblin

diarylether heptanoid (DAEH) natural products.

Diarylether heptanoids (DAEHs) represent a class of natural

products isolated from terrestrial woody plants.²DAEHs share

a highly conserved oxa[1.7]metaparacyclophane architecture.

These natural products display a range of biological activities³

and have attracted interest from synthetic chemists.⁴Figure 1

shows the 16 natural DAEHs that do not possess a stereocenter

and their speciﬁc rotation values. Interestingly, despite their

highly conserved structures, some (though not all) DAEHs

were isolated as optically active compounds.⁵We recently

reported the synthesis, free energies of activation for

Received: January 23, 2013

Published: March 5, 2013

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Figure 1. Diarylether heptanoid natural products that lack stereogenic centers.

vinylogous acids from hot methanolic extraction, and that

they were the thermodynamically favored isomer or “sta-

bilomer” (vide infra).

RESULTS AND DISCUSSION

■

Synthesis of the Garuganin and Garugamblin Diary-

lether Heptanoids. We decided to prepare 7−14 to

investigate their chiral properties. We envisioned the vinylogous

ester DAEHs, exempliﬁed by general structures 17 or 18,

arising from the corresponding vinylogous acid 19 (Scheme 1).

Simpliﬁcation of the macrocycle by way of an intramolecular

Ullmann coupling⁸leads to bromophenols 20. Positioning the

phenolic functional group on the more electron rich phenyl

ring was anticipated to give a smoother cyclization than an

alternative approach with an electron-rich bromoarene. The β-

diketone functional group present in 20 suggested that it could

be prepared via an aldol addition with subsequent oxidation,

thus beginning with aldehyde 21 and methyl ketone 22.⁹

The synthesis of garuganin I (7) began with hydro-

cinnamaldehyde derivative 23 (Scheme 2). Addition of 23 to

the lithium enolate derived from 22 resulted in formation of

aldol product 24. Oxidation of the β-hydroxy ketone using IBX

gave β-diketone 25.¹⁰Debenzylation gave the Ullmann

coupling substrate 26 in good yield.¹¹

Scheme 1. Retrosynthetic Analysis of the Garuganin and

Garugamblin DAEHs

Compounds 27−31 were prepared using an analogous 3-step

sequence. Note that Ullmann substrate 31 has the position of

the bromide and the phenol reversed relative to its congeners.

With the Ullmann substrates in hand, we then investigated the

key macrocyclization (Table 1). Cyclization occurred using

stoichiometric CuO in pyridine at elevated temperatures. The

yields for the Ullmann reaction were good and quite suﬃcient

for material throughput. Previously, this type of cyclization was

predicted to be problematic.^4a

Although this strategy would require regio- and stereoselective

vinylogous ester formation, it would allow a uniﬁed strategy for

the formation of all the garuganins and garugamblins, and it

could provide access to isomeric DAEH structures for

investigation. Moreover, we considered the possibility that

the vinylogous esters had formed upon isolation of the

The formation of 12 represents the synthesis of 9′-

desmethylgarugamblin I. Spectral data for this compound

Scheme 2. Synthesis of the Ullmann Substrates

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Table 1. Ullmann Cyclizations

Table 2. Synthesis of the Garuganin and Garugamblin

DAEHs

matched those reported in the literature.^5gCleavage of the

isopropyl ether of 34 gave the structure reported for 1,9′-

didesmethylgaruganin III (10), which does not have spectral

data consistent with that published for the natural compound,

and we believe the structure of the natural product has been

misassigned.^5hThe correct structure of the natural product and

its veriﬁcation through synthesis will be described in a

forthcoming paper.¹²

We next investigated the methylation of the vinylogous acids

12, 32, 33, 35, and 36. Methylation with (trimethylsilyl)-

diazomethane was quantitative, giving a 1:1 mixture of

vinylogous ester regioisomers with Z-conﬁguration (see general

structures 37 and 38, Table 2).^4a−cThese conditions trap the

dominant thermodynamic Z conformation of the vinylogous

acid tautomer, leading to the Z-vinylogous esters. If desired, the

regioisomeric Z-vinylogous esters can be separated by column

chromatography, isolated, and observed by NMR in anhydrous

base-treated CDCl₃. In practice, the Z-vinylogous esters were

typically not isolated because quantitative isomerization to the

E-conﬁgured esters (general structures 39 and 40) is induced

by treatment with weak acid (e.g., CSA, acetic acid, proline).

A convenient method for inducing quantitative and rapid

isomerization involves dissolving the Z-conﬁgured ester in dry

CDCl₃that has not been treated with base. If desired, any of

the E- and Z-conﬁgured esters can be recycled by hydrolysis to

the corresponding diketones by treatment with aqueous acid.

Note that natural products 7, 8, 11, and 13 are exempliﬁed by

generic structure 39, and garuganin III (9) is exempliﬁed by

generic structure 40. All of the spectral data for the DAEHs

matched those data reported for the natural samples, except for

garuganin IV (8),¹³and we believe the structure of garuganin

IV has been misassigned. The correct structure of the natural

product and its veriﬁcation through synthesis will be described

in a forthcoming paper.¹²

DAEHs are commonly isolated by Soxhlet extraction with

methanol, and we wondered if the vinylogous ester DAEHs

were isolation artifacts arising from the corresponding diketone.

To this end, we subjected 12 to hot acidic methanolic

conditions (Table 3). After 72 h, the reaction mixture

contained a 1:1 ratio of 12 and garugamblin I (11) as a single

regio- and stereoisomer. These reaction conditions also gave a

single regio- and stereoisomer of garuganin I (7), the reported

structure of garuganin IV (8), and garugamblin II (13) in

chemical yields of 17, 14, and 12%, respectively. The mass

balance contained only unreacted starting material. Interest-

ingly, treatment of 35 with acidic methanol led to the

regioisomer of garuganin III (44) in 16% yield. Garuganin III

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Table 3. Alternative Synthesis of the Garuganin and

Garugamblin DAEHs

Figure 2. Garuganin and garugamblin structure types.

1

The 1D H NMR spectra of 7−14 and congeners can be

used to obtain qualitative information regarding the rate of

interconversion of enantiomeric conformations. Figure 3 shows

1

the room temperature H NMR spectra of the garuganin I

series of compounds (i.e., 32, 7, 41, and 14).¹⁴Only the

spectrum of garuganin I (7), which displays the E-conﬁgured

C₉-oxo structure⁷(structure type B) shows chemical shift

inequivalent geminal methylene protons. Furthermore, sym-

metry-related protons H₁₅/H₁₉and H₁₆/H₁₈show chemical

shift inequivalence in 7 only. The vinylogous acid 32 (structure

type A), isomer 41 (strucuture type C), and garuganin VI (14)

exhibit chemical shift equivalent geminal methylene (and

symmetry-related phenyl) protons. This observation holds in

the other garuganin and garugamblin series as well: only

DAEHs of structure type B have chemical shift inequivalent

geminal methylene and phenyl protons.¹⁵The chemical shift

equivalence in structure types A and C−E suggests that

enantiomeric conformations are interconverting rapidly at rt.¹⁶

Variable temperature (VT) NMR was next used to

investigate the rate of interconversion of enantiomeric forms.

Low temperature NMR spectra of molecules with structure

type A (i.e., 12, 32, 33, 35, and 36), structure type C (41−43,

9, and 45), and garuganin VI (14) were used to determine

approximate rates of interconversion of enantiomeric con-

formations at cryogenic temperatures (see data for 32, Figure

4). At low temperatures, racemization becomes slow relative to

the NMR time scale, and decoalescence occurs.¹⁷

a

1

Yield determined by H NMR of the crude reaction mixture.

(9) was not observed in the reaction mixture. This suggests that

garuganin III is not an artifact of the isolation process.

Garuganin VI (14) displays geminal methyl groups, and it

was prepared from 32 by methylation with MeI in hot basic

THF (eq 1). Using the strategy discussed above, 10−100 mg

quantities of the garuganins and garugamblins (7−14) were

prepared for further study of their chiral properties.

In two-site equally populated cases, the relationship k_C= 2.22

× Δv gives the rate constant for coalescence (k_C), where Δv is

the separation in Hz of the coalescing peaks at temperatures

below coalescence.¹⁸We used this relationship to estimate the

rate of conformational exchange in DAEHs that have

coalescence temperatures below rt. For 32, our estimated Δv

= 106 Hz gave k_C= 236 s⁻¹, an approximate ΔG^‡_rac= 9.0 kcal/

mol at −80 °C, and a half-life (t_1/2) of 0.003 s at −80 °C. All

molecules with structure type A had nearly identical values

(Table 4).

Conformational Dynamics of the Garuganin and

Garugamblin Diarylether Heptanoids. With 7−14 and

regiosiomers 41−45 in hand, we attempted to determine which

have stable isolable enantiomeric conformations. Note that all

of the cyclophane molecules discussed in this study can be

grouped into one of six structure types (type A through E, and

garuganin VI; Figure 2). Analytical HPLC of 7−14 and 41−45

using chiral stationary phases showed a single peak regardless of

chiral columns (OD, ODH, AY, OZ, IC), solvents, ﬂow rate, or

temperature (0 °C to rt). Of course, a single peak is consistent

with a compound with enantiomeric conformations that

interconvert rapidly on the HPLC time scale, or a compound

with two stable enantiomers that have coincident retention

times.

For structure 41, we observed T_C= −10 °C and Δv = 76 Hz

giving k_C= 169 s⁻¹, an approximate ΔG^‡= 12.7 kcal/mol,

rac

and a half-life of 0.0041 s at −10 °C. All molecules with

structure type C had nearly identical values (Table 4).

Garuganin VI (14) showed T_C= −50 °C and Δv = 31 Hz

giving k_C= 68 s⁻¹, an approximate ΔG^‡_rac= 11.1 kcal/mol, and

a half-life of 0.0102 s at −50 °C. Thus, DAEHs with structure

types A, C, and garuganin VI (7) are achiral molecules, despite

any reported nonzero speciﬁc rotation values at room

temperature.

Chemical shift inequivalence in structure type B indicates

that the interconversion of enantiomeric conformations is slow

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1

Figure 3. H NMR spectra of 32, 7, 41, and 14 (CDCl₃, 400 MHz).

Figure 4. Low temperature NMR spectra of 32 (toluene-d₉, 400 MHz). *Indicates resonance used to determine T_C.

does not demonstrate that enantiomeric conformations of

Table 4. Half-Lives of Molecules with Structure Types A, C,

and Garuganin VI (14) at Cryogenic Temperatures

structure type B could be resolved at rt.

1

The H NMR spectra of compounds with structure type B

structure-

type

Δv

T_C

(K)

ΔG

(i.e., 7, 11, 13, 44, 8) were recorded at elevated temperatures

(see data for 7, Figure 5; Table 5). Coalescence of the geminal

methylene protons and of the symmetry-related phenyl protons

occurs at 90 °C. The coalescence temperature (T_C) and the

separation between coalescing peaks below T_Ccan be used to

determine k_C.¹⁷For 7, Δv = 180 Hz, giving a value of k_C= 400

s⁻¹. This results in an approximate free energy of activation for

racemization (ΔG^‡_rac) of 17 kcal/mol at 90 °C. Of course, the

free energy of activation for racemization at elevated temper-

atures does not give the half-life of an enantiomeric

conformation at rt.

Line shape analysis using simulated spectra gives the rate of

interconversion of enantiomers at temperatures below

coalescence and is more accurate than using coalescence

measurements.¹⁹Figure 6 shows experimental and simulated

spectra for garuganin I (7). Analysis of these spectra give values

of k = 5, 25, 60, and 110 s⁻¹at 35, 45, 55, and 65 °C,

compound

(Hz)

k_C

(kcal/mol)

t_1/2(s)

10

12

32

33

35

36

9

A

C

115

94

193

263

223

256

208

236

324

290

285

154

169

157

155

152

68

9.0

9.1

0.0027

0.0033

0.0029

0.0021

0.0024

0.0045

0.0041

0.0044

0.0045

0.0046

0.0102

106

146

131

128

69

9.0

8.9

9.0

12.7

12.6

12.7

11.1

41

42

43

45

14

76

71

70

68

31

on the NMR time scale at rt. However, since the NMR time

scale is faster than the laboratory time scale, this observation

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Figure 5. High temperature NMR spectra of 7 (DMSO-d₆, 400 MHz). *Indicates resonance used to determine T_C.

noninverted site. The noninverted site shows a characteristic

negative transient. These relaxations can be analyzed exactly,

and the analysis results in accurate values of the interconversion

rate. Use of SIR in combination with line shape analysis gives a

very accurate measurement of rate.

SIR experiments were performed on the molecules with

structure type B. In these spectra, the signal for H₁₅was

suﬃciently well resolved to enable selective inversion using a

soft pulse. The delay between pulses was varied between 0.001

and 10 s, and magnetization transfer to H₁₉was observed (see

data for 7, Figure 7). Mathematical analysis of the delay-

Table 5. Half-Lives of Molecules with Structure Types B at

Elevated Temperatures

structure-

type

Δv

T_C

(K)

ΔG

compound

(Hz)

k_C

(kcal/mol)

t_1/2(s)

7

B

180

189

190

192

150

363

400

419

423

426

333

17.1

17.0

17.2

0.0017

0.0016

0.0021

8

11

13

44

1

Figure 6. Experimental and simulated H NMR spectra of 7.

●

Figure 7. Selective inversion recovery experiments using 7. = data

for H₁₅; × = data for H₁₉.

respectively. Extrapolation of the data using Eyring analysis²⁰

gives a value of k = 2.4 s⁻¹at 25 °C, which corresponds to an

approximate half-life of 0.29 s for each enantiomeric

conformation. The calculated half-lives based on line shape

analysis of compounds with structure type B were all quite

similar (see Table 6, below).

Selective inversion recovery (SIR) describes a two-pulse

NMR technique that can be used to obtain rates of processes

that occur slowly on the NMR time scale.²¹Using this

technique, selectively inverting one site leads to relaxation to

equilibrium by normal T1 mechanisms and exchange with the

dependent integration of H₁₅and H₁₉was used to obtain the

rate of exchange at rt. Using SIR, we found that the rate of

interconversion of enantiomeric conformations of 7 is k_rac= 3.5

s⁻¹, giving a half-life of 0.20 s at 25 °C. This value corresponds

well to the value obtained using line shape analysis (0.29 s).

Moreover, we found that half-lives for enantiomeric con-

formations of compounds with structure type B at rt as

determined from SIR experiments were quite similar and

agreed well with the values obtained from line shape analysis

(Table 6).

CONCLUSION

■

Table 6. Room Temperature Half-Lives of Enantiomeric

Conformations of Molecules with Structure Type B

Garuganin and garugamblin DAEHs were synthesized using a

key Ullmann bond-forming reaction to build the cyclophane

molecular architecture of the natural products. Selective

methylation of the vinylogous acid DAEHs (e.g., 9′-

desmethylgarugamblin I, 12) occurred in hot acidic methanol

and produced a single isomer of the vinylogous ester DAEHs

(e.g., garugamblin I, 11). An unselective methylation using

(trimethylsilyl)diazomethane, followed by acid-catalyzed iso-

merization, also gave access to the natural products along with

compound t_1/2(s) from line shape analysis t_1/2(s) from SIR experiments

7

0.29

0.38

0.51

0.54

0.23

0.20

0.18

0.30

0.63

0.30

8

11

13

44

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MHz as indicated. Multiplicities are abbreviated as follows: s = singlet,

d = doublet, t = triplet, q = quartet, sept = septet, br = broad, m =

multiplet. Melting points are uncorrected.

their corresponding regio- and stereoisomers. The overall

synthesis proceeded with yields of 8−12% and conveniently

produced 10−100 mg quantities of the natural products for

study.

The line shapes were simulated using the MEXICO suite of

programs (available from ADB). The program simulates the line

shape, given spectral parameters and a rate, and this simulated shape is

compared to the experimental one using Bruker’s TopSpin program.

Chemical shifts and coupling constants were estimated by simulating

the low-temperature spectrum with a very slow rate. At higher

temperatures, the rate and the chemical shifts (which depend on

temperature) were adjusted until a good ﬁt of the spectrum was

obtained. The estimated error of the rates is about 10%.

Selective inversion recovery (SIR) data were analyzed using the

CIFIT program (available from ADB). Intensities of the lines as a

function of delay time were measured in Bruker’s TopSpin program.

Their time dependence is a sum of exponentials, so CIFIT does a ﬁt to

this functional form, using a Levenberg−Marquardt nonlinear least-

squares algorithm. For data of the quality collected here, errors in rates

are estimated to be less than 5%.

3-(5-(Benzyloxy)-2,4-dimethoxyphenyl)propanal (23). To a

solution of ethyl 3-(2,4-dimethoxyphenyl)propanoate²²(1.191 g, 5

mmol) in CH₂Cl₂(20 mL, 0.25 M) at 0 °C were added acetyl chloride

(535 μL, 7.5 mmol) and AlC1₃(2 × 500 mg, 7.5 mmol).¹After

stirring for 2 h at 0 °C, the reaction mixture was poured into a mixture

of ice (50 g) and aqueous HCl (10 mL, 1 M). The organic phase was

separated. The aqueous phase was extracted with EtOAc (3 × 30 mL).

The combined organic phases were dried with MgSO₄. Evaporation of

the solvent gave ethyl 3-(5-acetyl-2,4-dimethoxyphenyl)propanoate

(S1, 1.334 g, 4.76 mmol, 95% yield) as a white solid. Data for S1: R_f

0.41 (3:2 hexanes:EtOAc); mp = 90−92 °C; IR (thin ﬁlm) 1723,

1656, 1605, 1570, 1262, 1234, 1208, 1171, 1020 cm⁻¹; ¹H NMR (400

MHz, CDCl₃) δ 7.68 (s, 1 H), 6.42 (s, 1 H), 4.13 (q, J = 7.1 Hz, 2 H),

3.93 (s, 3 H), 3.90 (s, 3 H), 2.88 (t, J = 7.8 Hz, 2 H), 2.57 (s, 3 H),

2.56 (t, J = 7.8 Hz, 2 H), 1.26 (t, J = 7.1 Hz, 3 H); ¹³C NMR (101

MHz, CDCl₃, HSQC, DEPT) δ C 197.6, 173.1, 162.2, 160.2, 121.1,

119.9; CH 132.1, 94.5, CH₂60.3, 34.3, 25.2; CH₃55.6, 55.5, 31.9, 14.2;

HRMS (TOF MS ES+) calcd for C₁₅H₂₀O₅Na [M + Na] 303.1208,

found 303.1211.

The racemization barriers of the garuganin and garugamblin

DAEH natural products and congeners were measured. DAEHs

that belong to the same structural class (A−E, see Figure 2)

have nearly identical racemization barriers. Compounds with

structure types A and C (e.g., 9′-desmethylgarugamblin I,

garuganin III, and 1,9′-didesmethylgaruganin III) undergo

racemization at cryogenic temperatures with half-lives on the

order of milliseconds. Enantiomeric conformations of garuga-

nin VI (14) have an approximate half-life of 0.01 s at −50 °C

and cannot be resolved at rt. DAEHs with structure type B

(e.g., garugamblin I, garugamblin II, garuganin I, and the

reported structure of garuganin IV) have relatively higher

barriers of racemization; however, resolution of enantiomeric

conformations is not possible at rt. Line shape analysis and

selective inversion recovery experiments indicate that the half-

life of enantiomeric conformations of DAEHs with structure

type B are less than 1 s at rt. Thus, all garuganin and

garugamblin DAEHs are achiral, and they are not optically

active.

Scheme 3 depicts the two enantiomeric conformations of

garuganin I (7), which has structure type B. Racemization of

Scheme 3. Racemization of Garuganin I

To a solution of S1 (1.682 g, 6 mmol) in CH₂Cl₂(14 mL, 0.25 M)

at 0 °C were added TsOH (52 mg, 0.3 mmol) and a solution of

mCPBA (70%, 2.071 g, 8.4 mmol) in CH₂Cl₂(10 mL) over a period

of 30 min. The reaction mixture was stirred for 30 min at 0 °C and 4 h

at rt. Subsequently, aqueous Na₂S₂O₃(5 mL, 1 M) was added, and the

suspension was stirred for 15 min at rt. Aqueous saturated NaHCO₃

was added until aqueous phase had pH 7. The organic phase was

separated, and the aqueous phase was extracted with CH₂Cl₂(3 × 30

mL). The combined organic phases were dried with MgSO₄.

Puriﬁcation by ﬂash column chromatography (hexanes:EtOAc = 5:1)

gave ethyl 3-(5-acetoxy-2,4-dimethoxyphenyl)propanoate (S2, 1.25 g,

4.22 mmol, 70% yield) as a light yellow solid. Data for S2: R_f0.42 (2:1

hexanes:EtOAc); mp = 33−35 °C; IR (thin ﬁlm) 2939, 1764, 1732,

this molecule requires conformational “ﬂipping” of the seven

carbon ansa loop over the para-substituted arene. Interestingly,

molecules with structure type B, which display the C9 carbonyl,

have a higher barrier than other garuganin and garugamblin

structure types (i.e., A and C−E). Thus, both the geometry of

the alkene and the location of the methyl group aﬀect the rate

of this conformational exchange. The racemization process may

involve the rotation of the C7−C8 and C12−C13 sigma bonds,

but whether this is a concerted movement or a stepwise process

is currently unknown. We have initiated a DFT-based

computational study of the precise mechanism of this process

in all the DAEH natural products, and our results will be

published in a forthcoming manuscript.

1

1619, 1515, 1371, 1319, 1197, 1034, 913 cm⁻¹; H NMR (400 MHz,

CDCl₃) δ 6.83 (s, 1 H), 6.51 (s, 1 H), 4.12 (q, J = 7.1 Hz, 2 H), 3.82

(s, 6 H), 2.85 (t, J = 7.7 Hz, 2 H), 2.56 (t, J = 7.7 Hz, 2 H), 2.28 (s, 3

H), 1.24 (t, J = 7.1 Hz, 3 H); ¹³C NMR (101 MHz, CDCl₃, HSQC,

DEPT) δ C 173.2, 169.4, 155.8, 150.0, 132.6, 120.8; CH 123.8, 96.8,

CH₂60.2, 34.2, 25.2; CH₃56.1, 55.7, 20.6, 14.2; HRMS (TOF MS ES

+) calcd for C₁₅H₂₀O₆Na [M + Na] 319.1158, found 319.1151.

To a solution of S2 (296 mg, 1 mmol) in EtOH (10 mL, 0.1 M)

was added K₂CO₃(415 mg, 3 mmol) at rt. The mixture was heated to

70 °C. After 2 h, BnBr (178 μL, 1.5 mmol) was added. The mixture

was maintained at 70 °C for another 2 h. The mixture was cooled to rt

and quenched by the addition of saturated aqueous NH₄Cl (20 mL).

The resultant mixture was extracted with EtOAc (4 × 20 mL). The

combined organic phases were dried with MgSO₄. Puriﬁcation by ﬂash

column chromatography (hexanes:EtOAc = 6:1) gave ethyl 3-(5-

(benzyloxy)-2,4-dimethoxyphenyl)propanoate (S3, 323 mg, 0.94

mmol, 94% yield) as a light yellow solid. Data for S3: R_f0.57 (2:1

hexanes:EtOAc); mp = 41−43 °C; IR (thin ﬁlm) 2937, 1731, 1614,

1513, 1455, 1374, 1208, 1034, 865 cm⁻¹; ¹H NMR (400 MHz,

EXPERIMENTAL SECTION

■

General Experimental Details. All reactions were carried out

under an inert Ar atmosphere in oven-dried glassware. External bath

temperatures were used to record all reaction mixture temperatures.

Flash column chromatography was carried out with SiliaFlash P60

silica gel. Tetrahydrofuran (THF), methylene chloride (CH₂Cl₂) and

acetonitrile (MeCN) were dried by passage through activated alumina

columns. DMF and DMSO were stored over 3 Å molecular sieves.

Pyridine (C₆H₅N) and diisopropylamine were distilled from CaH. All

other reagents and solvents were used without further puriﬁcation

from commercial sources.

FT-IR spectra were obtained as thin ﬁlms on NaCl plates. Proton

and carbon NMR spectra (¹H NMR and ¹³C NMR) were recorded in

deuterated chloroform (CDCl₃) unless otherwise noted at 700 or 400

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CDCl₃) δ 7.51−7.29 (m, 5 H), 6.79 (s, 1 H), 6.54 (s, 1 H), 5.08 (s, 2

H), 4.13 (q, J = 7.1 Hz, 2 H), 3.90 (s, 3 H), 3.83 (s, 3 H), 2.85 (t, J =

7.8 Hz, 2 H), 2.55 (t, J = 7.8 Hz, 2 H), 1.26 (t, J = 7.1 Hz, 3 H); ¹³C

NMR (101 MHz, CDCl₃, HSQC, DEPT) δ C 173.4, 152.4, 149.2,

141.8, 137.6, 120.6; CH 128.4, 127.8, 127.6, 118.1, 98.0, CH₂72.5,

60.2, 34.6, 25.5; CH₃56.5, 56.0, 14.3; HRMS (TOF MS ES+) calcd for

C₂₀H₂₅O₅[M + H] 345.1702, found 345.1686.

(2:1 hexanes:EtOAc); mp = 69−71 °C; IR (thin ﬁlm) 3455 (br),

2939, 1612, 1513, 1201, 1034 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, enol

tautomer) δ 15.44 (br s, 1 H), 7.41 (d, J = 8.1 Hz, 2 H), 7.08 (d, J =

8.1 Hz, 2 H), 6.73 (s, 1 H), 6.49 (s, 1 H), 5.45 (s, 1 H), 5.24 (br s, 1

H), 3.90 (s, 3 H), 3.80 (s, 3 H), 2.95−2.71 (m, 4 H), 2.63−2.46 (m, 4

H); ¹³C NMR (101 MHz, CDCl₃, HSQC, DEPT, enol tautomer) δ C

193.5, 192.8, 150.9, 145.1, 139.7, 139.2, 121.4, 120.0; CH 131.5, 130.1,

115.8, 99.5, 96.7; CH₂39.8, 38.6, 30.8, 25.8; CH₃56.3, 56.2; HRMS

(TOF MS ES+) calcd for C₂₁H₂₄BrO₅[M + H] 435.0807, found

435.0816.

To a solution of S3 (482 mg, 1.4 mmol) in CH₂Cl₂(14 mL, 0.1 M)

at −78 °C was added DIBAL-H (1.4 mL, 1.68 mmol, 1.2 M in

toluene) over a period of 30 min. After the addition was complete,

TLC indicated complete consumption of the starting material. The

reaction was quenched with saturated aqueous Rochelle’s salt (30 mL)

at −78 °C. The mixture was warmed to rt. The organic phase was

separated, and the inorganic phase was extracted with EtOAc (3 × 30

mL). The combined organic phases were dried with MgSO₄.

Puriﬁcation by ﬂash column chromatography (hexanes:EtOAc = 5:1)

gave 23 (366 mg, 1.22 mmol, 87% yield) as white solid. Data for 23: R_f

0.33 (5:2 hexanes:EtOAc); mp = 80−82 °C; IR (thin ﬁlm) 2936,

1713, 1607, 1519, 1462, 1402, 1310, 1219, 1027 cm⁻¹; ¹H NMR (400

MHz, CDCl₃) δ 9.77 (s, 1 H), 7.51−7.29 (m, 5 H), 6.75 (s, 1 H), 6.54

(s, 1 H), 5.08 (s, 2 H), 3.91 (s, 3 H), 3.82 (s, 3 H), 2.85 (t, J = 7.2 Hz,

2 H), 2.66 (t, J = 7.2 r4 Hz, 2 H); ¹³C NMR (101 MHz, CDCl₃,

HSQC, DEPT) δ C 152.2, 149.4, 141.8, 137.6, 120.1; CH 202.5, 128.5,

127.8, 127.6, 118.2, 98.0; CH₂72.6, 44.2, 22.9; CH₃56.5, 55.9; HRMS

(TOF MS ES+) calcd for C₁₈H₂₀O₄Na [M + Na] 323.1259, found

323.1263.

7-(5-(Benzyloxy)-2,4-dimethoxyphenyl)-1-(4-bromophenyl)-

5-hydroxyheptan-3-one (24). To a solution of diisopropylamine

(363 mg, 3.59 mmol) in THF (12 mL, 0.1 M) at 0 °C was added n-

BuLi (2.24 mL, 3.59 mmol, 1.6 M in hexane) over a period of 10 min.

After stirring at 0 °C for 30 min, the mixture was cooled to −78 °C. A

solution of 22⁹(782 mg, 3.44 mmol) in THF (8 mL) was added over

a period of 1 h. After stirring at −78 °C for 30 min, a solution of 23

(862 mg, 2.87 mmol) in THF (9 mL) was added over a period of 1 h.

After stirring for 2 h, the reaction was quenched with saturated

aqueous NH₄Cl (30 mL). The organic phase was separated, and the

aqueous phase was extracted with EtOAc (3 × 30 mL). The combined

organic phases were dried with MgSO₄. Puriﬁcation by ﬂash column

chromatography (hexanes:EtOAc = 5:1 to 5:2) gave 24 (1.146 g, 2.17

mmol, 76% yield) as a white solid. Data for 24: R_f0.20 (2:1

hexanes:EtOAc); mp = 75−78 °C; IR (thin ﬁlm) 3512 (br), 2933,

1708, 1511, 1454, 1404, 1315, 1203, 1072, 1035 cm⁻¹; ¹H NMR (400

MHz, CDCl₃) δ 7.49−7.28 (m, 7 H), 7.06 (d, J = 8.3 Hz, 2 H), 6.74

(s, 1 H), 6.53 (s, 1 H), 5.08 (s, 2 H), 3.94 (m, 1 H), 3.90 (s, 3 H), 3.81

(s, 3 H), 3.00 (br s, 1 H), 2.86 (t, J = 7.3 Hz, 2 H), 2.78−2.44 (m, 6

H), 1.75−1.53 (m, 2 H); ¹³C NMR (101 MHz, CDCl₃, HSQC,

DEPT) δ C 210.2, 152.1, 149.0, 142.1, 139.9, 137.6, 121.5, 119.9; CH

131.6, 130.2, 128.5, 127.8, 127.6, 118.1, 98.2, 66.9; CH₂72.4, 49.4,

44.8, 37.1, 28.8, 25.4; CH₃56.5, 56.3; HRMS (TOF MS ES+) calcd for

C₂₈H₃₂BrO₅[M + H] 527.1433, found 527.1442.

1-(5-(Benzyloxy)-2,4-dimethoxyphenyl)-7-(4-bromophenyl)-

heptane-3,5-dione (26). To a solution of 24 (106 mg, 0.2 mmol) in

EtOAc (2 mL, 0.1 M) at rt was added IBX (168 mg, 0.6 mmol). The

reaction mixture was heated to reﬂux until complete consumption of

the starting material was observed (TLC, approximately 4 h). The

reaction mixture was allowed to cool to rt, ﬁltered through a short pad

of silica gel, and concentrated to give the crude β-diketone 25, which

was used directly without further puriﬁcation.

To a stirred solution of 25 (0.2 mmol, from previous step) in

CH₂Cl₂(4 mL, 0.05 M) were added pentamethylbenzene (89 mg, 0.6

mmol) and BCl₃(0.8 mL, 0.8 mmol, 1 M in DCM) at −78 °C over a

period of 10 min. After the addition was complete, TLC indicated

complete consumption of the starting material. The reaction was

quenched with MeOH (1 mL) at −78 °C. The resultant mixture was

allowed to warm to rt. Diluted aqueous NaHCO₃was added until the

aqueous phase had pH 6. The organic phase was separated, and the

aqueous phase was extracted with EtOAc (3 × 10 mL). The combined

organic phases were dried with MgSO₄. Puriﬁcation by ﬂash column

chromatography (hexanes:EtOAc = 5:1 to 3:1) gave 26 (59 mg, 0.136

mmol, 68% yield, 2 steps) as a light yellow solid. Data for 26: R_f0.40

4,6-Dimethoxy-2-oxatricyclo[13.2.2.1]^3,7[icosa-1(17),3,5,7-

(20),15,18-hexene-10−12-dione (32). To a sealed tube were added

26 (21.8 mg, 0.05 mmol), CuO (9.9 mg, 0.125 mmol) and K₂CO₃

(13.8 mg, 0.1 mmol). The tube was evacuated and backﬁlled with Ar,

followed by the addition of pyridine (10 mL, 0.005 M). The tube was

then sealed and heated to 120 °C. After 36 h, TLC indicated the

complete consumption of the starting material. The reaction mixture

was allowed to cool to rt. After evaporation of the solvent, aqueous

HCl (1 mL, 1 M) and H₂O (5 mL) were added. The mixture was

extracted with EtOAc (4 × 10 mL). The combined organic phases

were dried with MgSO₄. Puriﬁcation by ﬂash column chromatography

(hexanes:EtOAc = 8:1 to 6:1) gave 32 (7.9 mg, 0.0223 mmol, 45%

yield) as a light yellow solid. Data for 32: R_f0.52 (2:1

hexanes:EtOAc); IR (thin ﬁlm) 2933, 1604, 1520, 1504, 1392, 1318,

1

1209, 1030, 868 cm⁻¹; H NMR (700 MHz, CDCl₃) δ 15.13 (br s, 1

H), 7.17 (d, J = 8.4 Hz, 2 H), 6.99 (d, J = 8.4 Hz, 2 H), 6.53 (s, 1 H),

5.67 (s, 1 H), 4.98 (s, 1 H), 3.99 (s, 3 H), 3.82 (s, 3 H), 3.04 (t, J = 6.8

Hz, 2 H), 2.89 (m, 2 H), 2.46 (t, J = 6.8 Hz, 2 H), 2.39 (m, 2 H); ¹³C

NMR (176 MHz, CDCl₃, HSQC, DEPT) δ C 197.3, 188.5, 155.6,

151.7, 146.8, 144.8, 136.2, 121.1; CH 130.6, 123.0, 115.2, 103.0, 97.3;

CH₂39.5, 36.8, 32.3, 20.8; CH₃56.6, 56.2; HRMS (TOF MS ES+)

calcd for C₂₁H₂₃O₅[M + H] 355.1545, found 355.1555.

Garuganin I (7) and (10E)-4,6,12-Trimethoxy-2-oxatricyclo-

[13.2.2.1^3,7]icosa-1(17),3,5,7(20),10,15,18-heptaen-12-one (41).

To a solution of 32 (28.4 mg, 0.08 mmol) in CH₃CN and MeOH (8

mL, 0.01 M, 10:1 v/v) was added TMSCHN₂(0.4 mL, 0.8 mmol, 2 M

in hexanes). After stirring at rt for 4 h, the solvent was removed under

reduced pressure. Puriﬁcation by ﬂash column chromatography

(hexanes:EtOAc = 5:1 to 3:1) gave 37a (14.1 mg, 0.0383 mmol,

48% yield, white solid, more polar) and 38a (13.9 mg, 0.0377 mmol,

47% yield, white solid, less polar) in 1:1 regioselectivity. Treating 37a

and 38a with dry acidic CDCl₃(“old” CDCl₃dried by 3 Å MS) at rt

(approximately 5 min) gave garuganin I (7) and 41, respectively in

>95% yield. Data for garuganin I (7): white solid, R_f0.46 (2:1

hexanes:EtOAc); IR (thin ﬁlm) 2928, 1684, 1587, 1512, 1204, 1097,

1035 cm⁻¹; ¹H NMR (700 MHz, CDCl₃) δ 7.37 (dd, J = 8.3, 1.8 Hz, 1

H), 7.01 (dd, J = 8.3, 2.3 Hz, 1 H), 6.91 (dd, J = 8.1, 2.3 Hz, 1 H), 6.86

(dd, J = 8.1, 1.8 Hz, 1 H), 6.48 (s, 1 H), 5.34 (s, 1 H), 5.28 (s, 1 H),

4.01 (td, J = 12.9, 3.3 Hz, 1 H), 3.98 (s, 3 H), 3.79 (s, 3 H), 3.71 (s, 3

H), 2.99 (dt, J = 12.9, 3.8 Hz, 1 H), 2.88 (td, J = 12.9, 2.9 Hz, 1 H),

2.83 (dd, J = 15.9, 11.6 Hz, 1 H), 2.70 (dd, J = 16.0, 6.8 Hz, 1 H), 2.57

(dd, J = 17.8, 6.8 Hz, 1 H), 2.41 (dd, J = 18.2, 11.5 Hz, 1 H), 2.32 (dt,

J = 12.8, 3.8 Hz, 1 H); ¹³C NMR (176 MHz, CDCl₃, HSQC, DEPT) δ

C 197.2, 172.8, 156.0, 151.2, 146.3, 145.7, 137.8, 122.0; CH 131.1,

130.0, 124.4, 122.3, 117.1, 101.0, 97.5; CH₂44.4, 33.9, 33.0, 19.1; CH₃

56.6, 56.5, 55.2; HRMS (TOF MS ES+) calcd for C₂₂H₂₅O₅[M + H]

369.1702, found 369.1693.

Data for 41: white solid, R_f0.25 (2:1 hexanes:EtOAc); IR (thin

ﬁlm) 2928, 1664, 1562, 1515, 1504, 1441, 1394, 1203, 1034 cm⁻¹; ¹H

NMR (700 MHz, CDCl₃) δ 7.32−7.27 (m, 2 H), 6.98 (d, J = 8.5 Hz, 2

H), 6.51 (s, 1 H), 5.26 (s, 1 H), 5.20 (s, 1 H), 3.99 (s, 3 H), 3.81 (s, 3

H), 3.45 (s, 3 H), 3.10 (t, J = 7.0 Hz, 2 H), 3.08−2.40 (m, 6 H); ¹³C

NMR (176 MHz, CDCl₃, HSQC, DEPT) δ C 198.9, 174.2, 154.5,

151.4, 145.7, 145.2, 137.2, 121.1; CH 131.3, 123.5, 113.3, 102.0, 97.0;

CH₂44.3, 31.3, 28.3, 20.9; CH₃56.6, 56.0, 55.6; HRMS (TOF MS ES

+) calcd for C₂₂H₂₅O₅[M + H] 369.1702, found 369.1697.

Garuganin VI (14). To a solution of 32 (8 mg, 0.0226 mmol) in

THF (2 mL, 0.0113 M) was added K₂CO₃(31.2 mg, 0.226 mmol).

After stirring at rt for 30 min, CH₃I (42 μL, 0.678 mmol) was added.

The mixture was heated to reﬂux. After 24 h, another 42 μL of CH₃I

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was added. After reﬂuxing for another 24 h, TLC indicated the

complete consumption of the starting material. The mixture was

allowed to cool to rt and ﬁltered through a short pad of Celite.

Puriﬁcation by ﬂash column chromatography (hexanes:EtOAc = 10:1

to 6:1) gave 14 (5 mg, 0.0131 mmol, 58% yield) as a light yellow solid.

Data for 14: R_f0.31 (3:1 hexanes:EtOAc); IR (thin ﬁlm) 2925, 1691,

9′-Desmethylgarugamblin I (12). To a sealed tube were added

27 (20.3 mg, 0.05 mmol), CuO (9.9 mg, 0.125 mmol) and K₂CO₃

(13.8 mg, 0.1 mmol). The tube was evacuated and backﬁlled with Ar,

followed by the addition of pyridine (10 mL, 0.005 M). The tube was

then sealed and heated to 120 °C. After 24 h, TLC indicated the

complete consumption of the starting material. The reaction mixture

was allowed to cool to rt. After evaporation of the solvent, aqueous

HCl (1 mL, 1 M) and H₂O (5 mL) were added. The mixture was

extracted with EtOAc (4 × 10 mL). The combined organic phases

were dried with MgSO₄. Puriﬁcation by ﬂash column chromatography

(hexanes:EtOAc = 8:1 to 5:1) gave 12 (8.3 mg, 0.0256 mmol, 51%

yield) as a light yellow solid. Data for 12: R_f0.54 (2:1

hexanes:EtOAc); IR (thin ﬁlm) 2922, 2850, 1589, 1515, 1505, 1440,

1262, 1228, 1128 cm⁻¹; ¹H NMR (700 MHz, CDCl₃) δ 15.27 (br s, 1

H), 7.21 (d, J = 8.5 Hz, 2 H), 7.03 (d, J = 8.5 Hz, 2 H), 6.84 (d, J = 8.3

Hz, 1 H), 6.72−6.68 (m, 1 H), 5.63 (d, J = 2.2 Hz, 1 H), 4.98 (s, 1 H),

3.97 (s, 3 H), 3.07 (t, J = 6.8 Hz, 2 H), 2.95 (m, 2 H), 2.49 (t, J = 6.8

Hz, 2 H), 2.38 (m, 2 H); ¹³C NMR (176 MHz, CDCl₃, HSQC,

DEPT) δ C 196.9, 189.2, 154.3, 151.0, 146.6, 136.8, 133.8; CH 130.7,

123.3, 121.3, 113.5, 111.6, 103.1; CH₂39.5, 38.1, 32.3, 27.5; CH₃56.2;

HRMS (TOF MS ES+) calcd for C₂₀H₂₁O₄[M + H] 325.1440, found

325.1454.

Garugamblin I (11) and (10E)-4,10-Dimethoxy-2-oxatricyclo-

[13.2.2.1]^3,7icosa-1(17),3,5,7(20),10,15,18-heptaen-12-one (42).

To a solution of 12 (13 mg, 0.04 mmol) in a mixed solvent of CH₃CN

and MeOH (4 mL, 0.01 M, 10:1 v/v) was added TMSCHN₂(0.2 mL,

0.4 mmol, 2 M in hexanes). After stirring at rt for 4 h, the solvent was

removed under reduced pressure. Puriﬁcation by ﬂash column

chromatography (hexanes:EtOAc = 5:1 to 3:1) gave 37b (6.5 mg,

0.0192 mmol, 48% yield, more polar) and 38b (6.4 mg, 0.0189 mmol,

47% yield, less polar) in 1:1 ratio. Treating 37b and 38b with dry

acidic CDCl₃(“old” CDCl₃dried by 3 Å MS) at rt (approximately 5

min) gave garugamblin I (11) and 42, respectively in >99% yield. Data

for garugamblin I (11): R_f0.50 (2:1 hexanes:EtOAc); IR (thin ﬁlm)

2933, 1681, 1589, 1515, 1432, 1259, 1210, 1128, 1097 cm⁻¹; ¹H NMR

(700 MHz, CDCl₃) δ 7.40 (d, J = 8.5 Hz, 1 H), 7.11−7.06 (m, 1 H),

6.90−6.86 (m, 2 H), 6.76 (d, J = 8.1 Hz, 1 H), 6.63 (dd, J = 8.1, 2.1

Hz, 1 H), 5.34 (s, 1 H), 5.29 (d, J = 2.1 Hz, 1 H), 4.05 (td, J = 12.9,

3.4 Hz, 1 H), 3.95 (s, 3 H), 3.71 (s, 3 H), 3.23 (dd, J = 14.8, 11.6 Hz, 1

H), 3.00 (dt, J = 12.8, 4.0 Hz, 1 H), 2.92 (td, J = 12.9, 3.1 Hz, 1 H),

2.59−2.52 (m, 1 H), 2.49−2.42 (m, 1 H), 2.37−2.32 (m, 1 H), 2.30

(dd, J = 15.1, 7.0 Hz, 1 H); ¹³C NMR (176 MHz, CDCl₃, HSQC,

DEPT) δ C 197.2, 173.1, 155.1, 151.6, 146.3, 138.2, 135.0; CH 130.8,

130.5, 124.5, 122.3, 120.6, 115.4, 111.0, 101.2; CH₂45.4, 33.9, 33.0,

26.7; CH₃56.1, 55.2; HRMS (EI+) calcd for C₂₁H₂₂O₄[M] 338.1518,

found 338.1520.

Data for 42: R_f0.26 (2:1 hexanes:EtOAc); IR (thin ﬁlm) 2929,

1668, 1566, 1515, 1504, 1442, 1266, 1226, 1127 cm⁻¹; ¹H NMR (700

MHz, CDCl₃) δ 7.33−7.27 (m, 2 H), 6.99 (d, J = 8.6 Hz, 2 H), 6.84

(d, J = 8.2 Hz, 1 H), 6.68 (dd, J = 8.2, 2.1 Hz, 1 H), 5.29 (d, J = 2.1

Hz, 1 H), 5.22 (s, 1 H), 3.96 (s, 3 H), 3.46 (s, 3 H), 3.11 (t, J = 7.0 Hz,

2 H), 3.08−2.40 (m, 6 H); ¹³C NMR (176 MHz, CDCl₃, HSQC,

DEPT) δ C 198.9, 174.0, 154.3, 151.1, 145.7, 137.5, 133.3; CH 131.3,

123.6, 121.0, 112.6, 111.7, 102.1; CH₂44.3, 31.2, 28.6, 26.0; CH₃56.2,

55.7; HRMS (TOF MS ES+) calcd for C₂₁H₂₃O₄[M + H] 339.1596,

found 339.1582.

1-(4-Bromophenyl)-7-(7-hydroxybenzo[d][1,3]dioxol-5-yl)-

heptane-3,5-dione (28). To a slurry of NaH (312 mg, 7.8 mmol) in

THF (10 mL, 0.195 M) at 0 °C was slowly added ethyl 2-

(diethoxyphosphoryl)acetate (1.55 mL, 7.8 mmol) over a period of 10

min. After stirring at 0 °C for 30 min, a solution of 7-

(benzyloxy)benzo[d][1,3]dioxole-5-carbaldehyde²⁴(1.0 g, 3.9 mmol)

in THF (10 mL) was added. The mixture was warmed to rt and stirred

at rt for 30 min. The reaction was quenched with saturated NH₄Cl

solution (30 mL). The organic phase was then separated, and the

aqueous phase was extracted with EtOAc (3 × 30 mL). The combined

organic phases were dried with MgSO₄. Puriﬁcation by ﬂash column

chromatography (hexanes:EtOAc = 10:1 to 5:1) gave (E)-ethyl 3-(7-

(benzyloxy)benzo[d][1,3]dioxol-5-yl)acrylate (S6, 1.27 g, 3.89 mmol,

>99% yield) as a white solid. Data for S6: R_f0.51 (4:1

1

1606, 1453, 1318, cm⁻¹; H NMR (700 MHz, CDCl₃) δ 7.27 (d, J =

8.5 Hz, 2 H), 6.97 (d, J = 8.5 Hz, 2 H), 6.47 (s, 1 H), 4.92 (s, 1 H),

3.98 (s, 3 H), 3.78 (s, 3 H), 3.04−2.92 (m, 4 H), 2.63 (t, J = 5.4 Hz, 2

H), 2.54 (br s, 2 H), 1.40 (s, 6 H); ¹³C NMR (176 MHz, CDCl₃,

HSQC, DEPT) δ C 207.6, 207.4 155.5, 151.2, 146.2, 145.9, 138.4,

121.1, 62.7; CH 131.1, 123.4, 115.7, 97.3; CH₂41.4, 37.3, 28.8, 19.2;

CH₃56.6, 56.4, 22.8; HRMS (TOF MS ES+) calcd for C₂₃H₂₆O₅Na

[M + Na] 405.1678, found 405.1691.

1-(3-(Benzyloxy)-4-methoxyphenyl)-7-(4-bromophenyl)-

heptane-3,5-dione (27). To a solution of diisopropylamine (468

mg, 4.62 mmol) in THF (15 mL, 0.1 M) at 0 °C was added n-BuLi

(2.89 mL, 4.62 mmol, 1.6 M in hexane) over a period of 10 min. After

stirring at 0 °C for 30 min, the mixture was cooled to −78 °C. A

solution of 22 (1.01 g, 4.44 mmol) in THF (11 mL) was added over a

period of 30 min. After stirring at −78 °C for 30 min, a solution of 3-

(3-(benzyloxy)-4-methoxyphenyl)propanal²³(1 g, 3.7 mmol) in THF

(11 mL) was added over a period of 30 min. After stirring for 2 h, the

reaction was quenched with saturated aqueous NH₄Cl (40 mL). The

organic phase was separated, and the aqueous phase was extracted with

EtOAc (3 × 40 mL). The combined organic phases were dried with

MgSO₄. Puriﬁcation by ﬂash column chromatography (hexanes:EtOAc

= 5:1 to 3:1) gave 7-(3-(Benzyloxy)-4-methoxyphenyl)-1-(4-bromo-

phenyl)-5-hydroxyheptan-3-one (S4, 1.325 g, 2.66 mmol, 72% yield)

as white solid. Data for S4: R_f0.29 (2:1 hexanes:EtOAc); mp = 96−98

°C; IR (thin ﬁlm) 3504 (br), 2931, 1707, 1514, 1258, 1138, 1011

1

cm⁻¹; H NMR (400 MHz, CDCl₃) δ 7.50−7.28 (m, 7 H), 7.06 (d, J

= 8.4 Hz, 2 H), 6.84 (d, J = 8.0 Hz, 1 H), 6.79−6.71 (m, 2 H), 5.15 (s,

2 H), 3.99 (m, 1 H), 3.88 (s, 3 H), 2.91 (d, J = 3.4 Hz, 1 H), 2.86 (t, J

= 7.4 Hz, 2 H), 2.77−2.47 (m, 6 H), 1.81−1.54 (m, 2 H); ¹³C NMR

(101 MHz, CDCl₃, HSQC, DEPT) δ C 210.5, 148.1, 148.0, 139.7,

137.3, 134.3, 120.0; CH 131.6, 130.1, 128.5, 127.8, 127.4, 121.0, 114.9,

112.1, 66.8; CH₂71.1, 49.3, 44.7, 38.1, 31.2, 28.8; CH₃56.2; HRMS

(TOF MS ES+) calcd for C₂₇H₃₀BrO₄[M + H] 497.1327, found

497.1327.

To a solution of S4 (199 mg, 0.4 mmol) in EtOAc (4 mL, 0.1 M) at

rt was added IBX (336 mg, 1.2 mmol). The reaction mixture was

heated to reﬂux until complete consumption of the starting material

was observed (TLC, approximately 6 h). The reaction mixture was

allowed to cool to rt, ﬁltered through a short pad of silica gel, and

concentrated to give the crude S5, which was used directly without

further puriﬁcation.

To a solution of S5 (0.4 mmol, from previous step) in CH₂Cl₂(8

mL, 0.05 M) were added pentamethylbenzene (178 mg, 1.2 mmol)

and BCl₃(1.6 mL, 1.6 mmol, 1 M in DCM) over a period of 10 min at

−78 °C. After the addition was complete, TLC indicated complete

consumption of the starting material. The reaction was quenched with

MeOH (1 mL) at −78 °C. The resultant mixture was allowed to warm

to rt. Diluted aqueous NaHCO₃was added until aqueous phase had

pH 6. The organic phase was separated, and the aqueous phase was

extracted with EtOAc (3 × 20 mL). The combined organic phases

were dried with MgSO₄. Puriﬁcation by ﬂash column chromatography

(hexanes:EtOAc = 6:1 to 4:1) gave 27 (105 mg, 0.26 mmol, 65% yield,

2 steps) as a light yellow solid. Data for 27: R_f0.41 (2:1

hexanes:EtOAc); mp = 54−56 °C; IR (thin ﬁlm) 3445 (br), 2933,

1592, 1513, 1489, 1442, 1273, 1129, 1011 cm⁻¹; ¹H NMR (700 MHz,

CDCl₃, enol tautomer) δ 15.42 (br s, 1 H), 7.42 (d, J = 8.4 Hz, 2 H),

7.08 (d, J = 8.4 Hz, 2 H), 6.81−6.75 (m, 2 H), 6.68 (dd, J = 8.2, 2.1

Hz, 1 H), 5.61 (br s, 1 H), 5.44 (s, 1 H), 3.89 (s, 3 H), 2.90 (t, J = 7.8

Hz, 2 H), 2.85 (t, J = 7.8 Hz, 2 H), 2.60−2.54 (m, 4 H); ¹³C NMR

(176 MHz, CDCl₃, HSQC, DEPT, enol tautomer) δ C 193.0, 192.8,

145.5, 145.0, 139.6, 133.9, 120.0; CH 131.6, 130.1, 119.7, 114.4, 110.6,

99.7; CH₂40.0, 39.8, 30.9, 30.8; CH₃56.0; HRMS (EI+) calcd for

C₂₀H₂₁BrO₄[M] 404.0623, found 404.0610.

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hexanes:EtOAc); mp = 115−118 °C; IR (thin ﬁlm) 1698, 1511, 1434,

131.6, 130.1, 128.6, 128.0, 127.6, 109.9, 102.8, 66.6; CH₂101.2, 71.5,

49.3, 44.7, 38.1, 31.7, 28.8; HRMS (TOF MS ES+) calcd for

C₂₇H₂₈BrO₅[M + H] 511.1120, found 511.1125.

To a solution of S9 (199 mg, 0.39 mmol) in EtOAc (4 mL, 0.1 M)

at rt was added IBX (328 mg, 1.17 mmol). The reaction mixture was

heated to reﬂux until complete consumption of the starting material

was observed (TLC, approximately 6 h). The reaction mixture was

allowed to cool to rt, ﬁltered through a short pad of silica gel, and

concentrated to give the crude S10, which was used directly without

further puriﬁcation.

1

1279, 1235, 1130, 1090, 1034 cm⁻¹; H NMR (400 MHz, CDCl₃) δ

7.54 (d, J = 15.9 Hz, 1 H), 7.49−7.30 (m, 5 H), 6.76 (s, 2 H), 6.26 (d,

J = 15.9 Hz, 1 H), 6.02 (s, 2 H), 5.20 (s, 2 H), 4.27 (q, J = 7.1 Hz, 2

H), 1.35 (t, J = 7.1 Hz, 3 H); ¹³C NMR (101 MHz, CDCl₃, HSQC,

DEPT) δ C 167.1, 149.6, 142.6, 137.8, 136.4, 129.2; CH 144.3, 128.7,

128.2, 127.6, 116.8, 111.6, 101.4; CH₂101.9, 71.6, 60.4; CH₃14.4;

HRMS (TOF MS ES+) calcd for C₁₉H₁₉O₅[M + H] 327.1232, found

327.1229.

To a solution of S6 (1.7 g, 5.21 mmol) in THF (40 mL, 0.065 M)

were added 40 mL of H₂O, NaOAc (1.71 g, 20.84 mmol) and a

solution of TsNHNH₂(4.85 g, 26.05 mmol) in THF (40 mL) over a

period of 30 min at 80 °C. After 24 h, TLC indicated the complete

consumption of the starting material. The mixture was allowed to cool

to rt. The organic phase was then separated, and the aqueous phase

was extracted with EtOAc (3 × 40 mL). The combined organic phases

were dried with MgSO₄. Puriﬁcation by ﬂash column chromatography

(hexanes:EtOAc = 10:1 to 6:1) gave ethyl 3-(7-(benzyloxy)benzo[d]-

[1,3]dioxol-5-yl)propanoate (S7, 1.7 g, 5.18 mmol, >99% yield) as a

colorless solid. Data for S7: R_f0.55 (4:1 hexanes:EtOAc); mp = 51−53

°C; IR (thin ﬁlm) 2933, 1731, 1632, 1509, 1437, 1373, 1190, 1126,

1086, 1043 cm⁻¹; ¹H NMR (700 MHz, CDCl₃) δ 7.48−7.32 (m, 5 H),

6.45 (d, J = 1.4 Hz, 1 H), 6.42 (d, J = 1.4 Hz, 1 H), 5.96 (s, 2 H), 5.19

(s, 2 H), 4.15 (q, J = 7.1 Hz, 2 H), 2.86 (t, J = 7.8 Hz, 2 H), 2.58 (t, J =

7.8 Hz, 2 H), 1.27 (t, J = 7.1 Hz, 3 H); ¹³C NMR (176 MHz, CDCl₃,

HSQC, DEPT) δ C 172.8, 149.1, 142.5, 136.8, 135.1, 134.0; CH 128.6,

128.1, 127.6, 109.7, 102.7; CH₂101.2, 71.5, 60.5, 36.2, 31.0; CH₃14.3;

HRMS (TOF MS ES+) calcd for C₁₉H₂₁O₅[M + H] 329.1389, found

329.1405.

To a solution of S7 (328 mg, 1 mmol) in CH₂Cl₂(10 mL, 0.1 M) at

−78 °C was added DIBAL-H (1 mL, 1.2 mmol, 1.2 M in toluene) over

a period of 15 min. After the addition was complete, TLC indicated

complete consumption of the starting material. The reaction was

quenched with saturated aqueous Rochelle’s salt (20 mL) at −78 °C.

The mixture was allowed to warm to rt. The organic phase was

separated, and the inorganic phase was extracted with EtOAc (3 × 20

mL). The combined organic phases were dried with MgSO₄.

Puriﬁcation by ﬂash column chromatography (hexanes:EtOAc = 5:1)

gave 3-(7-(benzyloxy)benzo[d][1,3]dioxol-5-yl)propanal (S8, 261 mg,

0.92 mmol, 92% yield) as a light yellow oil. Data for S8: R_f0.58 (2:1

hexanes:EtOAc); IR (thin ﬁlm) 2925, 1722, 1632, 1509, 1436, 1192,

1127, 1087, 1043 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 9.80 (t, J = 1.3

Hz, 1 H), 7.48−7.31 (m, 5 H), 6.42 (d, J = 1.3 Hz, 1 H), 6.40 (d, J =

1.3 Hz, 1 H), 5.96 (s, 2 H), 5.19 (s, 2 H), 2.86 (t, J = 7.4 Hz, 2 H),

2.72 (t, J = 7.4 Hz, 2 H); ¹³C NMR (101 MHz, CDCl₃, HSQC,

DEPT) δ C 149.2, 142.5, 136.8, 134.8, 134.1; CH 201.4, 128.6, 128.1,

127.6, 109.9, 102.7; CH₂101.2, 71.6, 45.4, 28.1; HRMS (TOF MS ES

+) calcd for C₁₇H₁₇O₄[M + H] 285.1127, found 285.1124.

To a solution of diisopropylamine (223 mg, 2.2 mmol) in THF (8

mL, 0.1 M) was added n-BuLi (1.38 mL, 2.2 mmol, 1.6 M in hexane)

over a period of 10 min at 0 °C. After stirring at 0 °C for 30 min, the

mixture was cooled to −78 °C. A solution of 22 (479 mg, 2.11 mmol)

in THF (5 mL) was added over a period of 30 min. After stirring at

−78 °C for 30 min, a solution of S8 (500 mg, 1.76 mmol) in THF (5

mL) was added over a period of 30 min. After stirring for 2 h, the

reaction was quenched with saturated aqueous NH₄Cl (20 mL). The

organic phase was separated, and the aqueous phase was extracted with

EtOAc (3 × 20 mL). The combined organic phases were dried with

MgSO₄. Puriﬁcation by ﬂash column chromatography (hexanes:EtOAc

= 5:1 to 3:1) gave 7-(7-(benzyloxy)benzo[d][1,3]dioxol-5-yl)-1-(4-

bromophenyl)-5-hydroxyheptan-3-one (S9, 511 mg, 1 mmol, 57%

yield) as a white solid. Data for S9: R_f0.26 (3:1 hexanes:EtOAc); mp

= 113−115 °C; IR (thin ﬁlm) 3468 (br), 2928, 1707, 1631, 1508,

1489, 1436, 1191, 1125, 1073, 1042 cm⁻¹; ¹H NMR (700 MHz,

CDCl₃) δ 7.48−7.32 (m, 7 H), 7.07 (d, J = 8.4 Hz, 2 H), 6.43 (d, J =

1.2 Hz, 1 H), 6.41 (d, J = 1.2 Hz, 1 H), 5.95 (s, 2 H), 5.19 (s, 2 H),

4.02 (m, 1 H), 2.95 (br s, 1 H), 2.87 (t, J = 7.5 Hz, 2 H), 2.74 (t, J =

7.5 Hz, 2 H), 2.73−2.67 (m, 1 H), 2.62−2.49 (m, 3 H), 1.79−1.72 (m,

1 H), 1.65−1.58 (m, 1 H); ¹³C NMR (176 MHz, CDCl₃, HSQC,

DEPT) δ C 210.5, 149.0, 142.4, 139.7, 136.9, 136.2, 133.8, 120.0; CH

To a solution of S10 (approximately 0.39 mmol, from previous

step) in CH₂Cl₂(8 mL, 0.05 M) were added pentamethylbenzene

(173 mg, 1.17 mmol) and BCl₃(0.78 mL, 0.78 mmol, 1 M in DCM)

over a period of 10 min at −78 °C. After addition is completed, TLC

indicated complete consumption of the starting material. The reaction

was quenched with MeOH (2 mL) at −78 °C. The resultant mixture

was allowed to warm to rt. Diluted aqueous NaHCO₃was added until

the aqueous phase had pH 6. The organic phase was separated, and the

aqueous phase was extracted with EtOAc (3 × 20 mL). The combined

organic phases were dried with MgSO₄. Puriﬁcation by ﬂash column

chromatography (hexanes:EtOAc = 6:1 to 4:1) gave 1-(4-bromo-

phenyl)-7-(7-hydroxybenzo[d][1,3]dioxol-5-yl)heptane-3,5-dione (28,

125 mg, 0.3 mmol, 76% yield, 2 steps) as a light yellow solid. Data for

28: R_f0.38 (2:1 hexanes:EtOAc); mp = 89−91 °C; IR (thin ﬁlm) 3400

1

(br), 2925, 1621, 1505, 1488, 1446, 1070 cm⁻¹; H NMR (400 MHz,

CDCl₃, enol tautomer) δ 15.37 (s, 1 H), 7.42 (d, J = 8.1 Hz, 2 H), 7.07

(d, J = 8.1 Hz, 2 H), 6.33 (s, 2 H), 5.94 (s, 2 H), 5.43 (s, 1 H), 5.22

(br s, 1 H), 2.94−2.74 (m, 4 H), 2.62−2.50 (m, 4 H); ¹³C NMR (101

MHz, CDCl₃, HSQC, DEPT, enol tautomer) δ C 193.0, 192.8, 148.8,

139.6, 139.1, 135.3, 132.5, 120.0; CH 131.6, 130.1, 110.6, 101.9, 99.8;

CH₂101.3, 40.0, 39.7, 31.3, 30.9; HRMS (TOF MS ES+) calcd for

C₂₀H₂₀BrO₅[M + H] 419.0494, found 419.0486.

2,5,7-Trioxatetracyclo[16.2.2.1^3,10.0^4,8]tricosa-1(20),3,8,10-

(23)18,21-hexaene-3,15-dione (33). To a sealed tube were added

28 (21.8 mg, 0.05 mmol), CuO (9.9 mg, 0.125 mmol) and K₂CO₃

(13.8 mg, 0.1 mmol). The tube was evacuated and backﬁlled with Ar,

followed by the addition of pyridine (10 mL, 0.005 M). The tube was

then sealed and heated to 130 °C. After 24 h, TLC indicated the

complete consumption of the starting material. The reaction mixture

was allowed to cool to rt. After evaporation of the solvent, aqueous

HCl (1 mL, 1 M) and H₂O (5 mL) were added. The mixture was

extracted with EtOAc (4 × 10 mL). The combined organic phases

were dried with MgSO₄. Puriﬁcation by ﬂash column chromatography

(hexanes:EtOAc = 8:1 to 6:1) gave 33 (6.4 mg, 0.0189 mmol, 38%

yield) as a light yellow solid. Data for 33: R_f0.63 (2:1

hexanes:EtOAc); IR (thin ﬁlm) 1635, 1600, 1504, 1435, 1210, 1192,

1064 cm⁻¹; ¹H NMR (700 MHz, CDCl₃) δ 15.19 (br s, 1 H), 7.21 (d,

J = 8.5 Hz, 2 H), 7.04 (d, J = 8.5 Hz, 2 H), 6.33 (m, 1 H), 6.03 (s, 2

H), 5.21 (m, 1 H), 4.96 (s, 1 H), 3.06 (t, J = 6.8 Hz, 2 H), 2.91 (m, 2

H), 2.48 (t, J = 6.8 Hz, 2 H), 2.37 (m, 2 H); ¹³C NMR (176 MHz,

CDCl₃, HSQC, DEPT) δ C 197.0, 188.7, 154.1, 148.9, 144.8, 137.0,

135.4, 133.1; CH 130.6, 123.0, 107.7, 103.1, 102.8; CH₂101.6, 39.4,

38.0, 32.2, 28.0; HRMS (EI+) calcd for C₂₀H₁₈O₅[M] 338.1154,

found 338.1138.

Garugamblin II (13) and (13E)-13-Methoxy-2,5,7-

trioxatetracyclo[16.2.2.1^3,10.0^4,8]tricosa-1(20),3,8,10-

(23),13,18,21-heptaen-15-one (43). To a solution of 33 (13.5 mg,

0.04 mmol) in a mixed solvent of CH₃CN and MeOH (4 mL, 0.01 M,

10:1 v/v) was added TMSCHN₂(0.2 mL, 0.4 mmol, 2 M in hexanes).

After stirring at rt for 4 h, the solvent was removed under reduced

pressure. Puriﬁcation by ﬂash column chromatography (hexanes:E-

tOAc = 5:1 to 3:1) gave 37c (6.7 mg, 0.019 mmol, 48% yield, white

solid, more polar) and 38c (6.8 mg, 0.0193 mmol, 48% yield, white

solid, less polar) in 1:1 ratio. Treating 37c and 38c with dry acidic

CDCl₃(“old” CDCl₃dried by 3 Å MS) at rt (approximately 5 min)

gave garugamblin II (13) and 43, respectively in >99% yield. Data for

garugamblin II (13): R_f0.58 (2:1 hexanes:EtOAc); IR (thin ﬁlm)

2932, 1681, 1634, 1587, 1505, 1438, 1192, 1097, 1061 cm⁻¹; ¹H NMR

(700 MHz, CDCl₃) δ 7.39 (dd, J = 8.3, 2.0 Hz, 1 H), 7.08 (dd, J = 8.3,

2.3 Hz, 1 H), 6.90 (dd, J = 8.1, 2.3 Hz, 1 H), 6.87 (dd, J = 8.1, 2.0 Hz,

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1 H), 6.27 (m, 1 H), 6.02−5.99 (m, 2 H), 5.33 (s, 1 H), 4.90 (br s, 1

H), 4.03 (td, J = 12.9, 3.5 Hz, 1 H), 3.72 (s, 3 H), 3.21 (dd, J = 15.1,

11.3 Hz, 1 H), 3.00 (dt, J = 12.8, 4.0 Hz, 1 H), 2.91 (td, J = 12.9, 3.1

Hz, 1 H), 2.57−2.51 (m, 1 H), 2.49−2.42 (m, 1 H), 2.36−2.32 (m, 1

H), 2.25 (dd, J = 15.4, 6.9 Hz, 1 H); ¹³C NMR (176 MHz, CDCl₃,

HSQC, DEPT) δ C 197.0, 173.1, 154.8, 148.4, 145.6, 138.5, 136.4,

132.5; CH 130.8, 130.3, 124.3, 122.1, 109.7, 102.6, 101.2; CH₂101.4,

45.4, 33.9, 33.0, 27.2; CH₃55.3; HRMS (TOF MS ES+) calcd for

C₂₁H₂₁O₅[M + H] 353.1389, found 353.1373.

Data for 43: R_f0.33 (2:1 hexanes:EtOAc); IR (thin ﬁlm) 2919,

1667, 1636, 1567, 1504, 1440, 1190, 1064 cm⁻¹; ¹H NMR (700 MHz,

CDCl₃) δ 7.33−7.27 (m, 2 H), 7.00 (d, J = 8.6 Hz, 2 H), 6.29 (d, J =

1.2 Hz, 1 H), 6.01 (s, 2 H), 5.21 (s, 1 H), 4.87 (br s, 1 H), 3.46 (s, 3

H), 3.11 (t, J = 6.9 Hz, 2 H), 3.08−2.40 (m, 6 H); ¹³C NMR (176

MHz, CDCl₃, HSQC, DEPT) δ C 198.8, 173.9, 153.8, 148.9, 145.0,

137.8, 134.9, 132.2; CH 131.2, 123.4, 106.5, 102.2, 102.1; CH₂101.4,

44.3, 31.2, 28.6, 26.8; CH₃55.7; HRMS (TOF MS ES+) calcd for

C₂₁H₂₁O₅[M + H] 353.1389, found 353.1374.

1-(4-Bromophenyl)-7-(3-hydroxy-4-isopropoxy-5-

methoxyphenyl)heptane-3,5-dione (29). To a solution of 3-

(benzyloxy)-4-hydroxy-5-methoxybenzaldehyde²⁵(1.162 g, 4.5 mmol)

in DMF (45 mL, 0.1 M) was added K₂CO₃(933 mg, 6.75 mmol) and

2-bromopropane (634 μL, 6.75 mmol) at 80 °C. After 1 h, TLC

indicated complete consumption of the starting material. The reaction

mixture was allowed to cool to rt and poured into 100 mL of H₂O.

The resultant mixture was extracted with Et₂O (4 × 50 mL). The

combined organic phases were dried with MgSO₄. Puriﬁcation by ﬂash

column chromatography (hexanes:EtOAc = 6:1) gave 3-(benzyloxy)-

4-isopropoxy-5-methoxybenzaldehyde (S11, 1.334 g, 4.44 mmol, 99%

yield) as a white solid. Data for S11: R_f0.43 (3:1 hexanes:EtOAc); mp

= 57−59 °C; IR (thin ﬁlm) 2976, 1693, 1585, 1493, 1429, 1383, 1326,

1233, 1119 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 9.85 (s, 1 H), 7.50−

7.31 (m, 5 H), 7.20 (d, J = 1.7 Hz, 1 H), 7.16 (d, J = 1.7 Hz, 1 H), 5.18

(s, 2 H), 4.60 (sept, J = 6.2 Hz, 1 H), 3.92 (s, 3 H), 1.34 (d, J = 6.2 Hz,

6 H); ¹³C NMR (101 MHz, CDCl₃, HSQC, DEPT) δ C 154.6, 153.3,

142.7, 136.6, 131.5; CH 191.1, 128.6, 128.0, 127.3, 109.1, 106.6, 76.1;

CH₂71.2; CH₃56.2, 22.6; HRMS (TOF MS ES+) calcd for C₁₈H₂₁O₄

[M + H] 301.1440, found 301.1441.

hexanes:EtOAc); IR (thin ﬁlm) 2976, 1732, 1588, 1502, 1454, 1428,

1

1375, 1236, 1117, 936 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 7.50−

7.29 (m, 5 H), 6.50 (d, J = 1.3 Hz, 1 H), 6.46 (d, J = 1.3 Hz, 1 H), 5.10

(s, 2 H), 4.39 (sept, J = 6.2 Hz, 1 H), 4.15 (q, J = 7.1 Hz, 2 H), 3.84 (s,

3 H), 2.89 (t, J = 7.8 Hz, 1 H), 2.61 (t, J = 7.8 Hz, 1 H), 1.31 (d, J =

6.2 Hz, 6 H), 1.26 (t, J = 7.1 Hz, 3 H); ¹³C NMR (101 MHz, CDCl₃,

HSQC, DEPT) δ C 172.9, 154.0, 152.9, 137.4, 135.8, 135.4; CH 128.4,

127.7, 127.3, 107.7, 105.9, 75.3; CH₂71.2, 60.4, 36.0, 31.3; CH₃56.1,

22.6, 14.2; HRMS (TOF MS ES+) calcd for C₂₂H₂₉O₅[M + H]

373.2015, found 373.2025.

To a solution of S13 (1.594 g, 4.28 mmol) in CH₂Cl₂(43 mL, 0.1

M) at −78 °C was added DIBAL-H (4.28 mL, 5.14 mmol, 1.2 M in

toluene) over a period of 1 h. After the addition was complete, TLC

indicated complete consumption of the starting material. The reaction

was quenched with saturated aqueous Rochelle’s salt (100 mL) at −78

°C. The mixture was allowed to warm to rt. The organic phase was

separated, and the inorganic phase was extracted with EtOAc (3 × 100

mL). The combined organic phases were dried with MgSO₄.

Puriﬁcation by ﬂash column chromatography (hexanes:EtOAc = 5:1)

gave 3-(3-(benzyloxy)-4-isopropoxy-5-methoxyphenyl)propanal (S14,

1.14 g, 3.47 mmol, 81% yield) as a white solid. Data for S14: R_f0.50

(2:1 hexanes:EtOAc); mp = 60−62 °C; IR (thin ﬁlm) 2974, 1723,

1

1587, 1503, 1454, 1428, 1235, 1117, 933 cm⁻¹; H NMR (400 MHz,

CDCl₃) δ 9.81 (m, 1 H), 7.50−7.29 (m, 5 H), 6.47 (d, J = 1.8 Hz, 1

H), 6.44 (d, J = 1.8 Hz, 1 H), 5.10 (s, 2 H), 4.39 (sept, J = 6.2 Hz, 1

H), 3.84 (s, 3 H), 2.89 (t, J = 7.4 Hz, 2 H), 2.76 (t, J = 7.4 Hz, 2 H),

1.31 (d, J = 6.2 Hz, 6 H); ¹³C NMR (101 MHz, CDCl₃, HSQC,

DEPT) δ C 154.1, 153.0, 137.4, 135.6, 135.4; CH 201.6, 128.4, 127.8,

127.3, 107.8, 105.9, 75.4; CH₂71.2, 45.3, 28.4; CH₃56.1, 22.6; HRMS

(TOF MS ES+) calcd for C₂₀H₂₅O₄[M + H] 329.1753, found

329.1755.

To a solution of diisopropylamine (253 mg, 2.5 mmol) in THF (8

mL, 0.1 M) was added n-BuLi (1.56 mL, 2.5 mmol, 1.6 M in hexane)

over a period of 10 min at 0 °C. After stirring at 0 °C for 30 min, the

mixture was cooled to −78 °C. A solution of 22 (545 mg, 2.4 mmol)

in THF (6 mL) was added over a period of 30 min. After stirring at

−78 °C for 30 min, a solution of S14 (657 mg, 2 mmol) in THF (6

mL) was added over a period of 30 min. After stirring for 2 h, the

reaction was quenched with saturated aqueous NH₄Cl (30 mL). The

organic phase was separated, and the aqueous phase was extracted with

EtOAc (3 × 30 mL). The combined organic phases were dried with

MgSO₄. Puriﬁcation by ﬂash column chromatography (hexanes:EtOAc

= 5:1 to 3:1) gave 7-(3-(benzyloxy)-4-isopropoxy-5-methoxyphenyl)-

1-(4-bromophenyl)-5-hydroxyheptan-3-one (S15, 891 mg, 1.6 mmol,

80% yield) as a colorless oil. Data for S15: R_f0.26 (2:1

hexanes:EtOAc); IR (thin ﬁlm) 3490 (br), 2932, 1708, 1588, 1503,

To a slurry of NaH (276 mg, 6.9 mmol) in THF (10 mL, 0.3 M) at

0 °C was added ethyl 2-(diethoxyphosphoryl)acetate (1.37 mL, 6.9

mmol) over a period of 10 min. After stirring at 0 °C for 30 min, a

solution of S11 (1.382 g, 4.6 mmol) in THF (5 mL) was added. The

mixture was warmed to rt and stirred at rt for 30 min. The reaction

was quenched with saturated aqueous NH₄Cl (30 mL). The organic

phase was then separated, and the aqueous phase was extracted with

EtOAc (3 × 30 mL). The combined organic phases were dried with

MgSO₄. Puriﬁcation by ﬂash column chromatography (hexanes:EtOAc

= 10:1 to 5:1) gave (E)-ethyl 3-(3-(benzyloxy)-4-isopropoxy-5-

methoxyphenyl)acrylate (S12, 1.7 g, 4.59 mmol, >99% yield) as a

colorless solid. Data for S12: R_f0.47 (3:1 hexanes:EtOAc); mp = 66−

68 °C; IR (thin ﬁlm) 2977, 1710, 1636, 1579, 1500, 1425, 1274, 1246,

1

1454, 1431, 1236, 1115, 935 cm⁻¹; H NMR (400 MHz, CDCl₃) δ

7.50−7.29 (m, 7 H), 7.06 (d, J = 8.3 Hz, 2 H), 6.48 (d, J = 1.5 Hz, 1

H), 6.44 (d, J = 1.5 Hz, 1 H), 5.10 (s, 2 H), 4.39 (sept, J = 6.2 Hz, 1

H), 4.05 (m, 1 H), 3.83 (s, 3 H), 3.02 (br s, 1 H), 2.87 (t, J = 7.4 Hz, 2

H), 2.80−2.47 (m, 6 H), 1.86−1.58 (m, 2 H), 1.31 (d, J = 6.2 Hz, 6

H); ¹³C NMR (101 MHz, CDCl₃, HSQC, DEPT) δ C 210.5, 154.0,

152.8, 139.7, 137.5, 137.0, 135.1, 120.0; CH 131.6, 130.1, 128.4, 127.7,

127.3, 107.9, 106.0, 75.3, 66.9; CH₂71.2, 49.4, 44.7, 38.1, 32.1, 28.8;

CH₃56.1, 22.6; HRMS (TOF MS ES+) calcd for C₃₀H₃₆BrO₅[M +

H] 555.1746, found 555.1749.

To a solution of S15 (805 mg, 1.45 mmol) in EtOAc (14.5 mL, 0.1

M) at rt was added IBX (1.218 g, 4.35 mmol). The reaction mixture

was heated to reﬂux until complete consumption of the starting

material was observed (TLC, approximately 4−8 h). The reaction

mixture was allowed to cool to rt, ﬁltered through a short pad of silica

gel and concentrated. Puriﬁcation by ﬂash column chromatography

(hexanes:EtOAc = 5:1) gave 1-(3-(benzyloxy)-4-isopropoxy-5-me-

thoxyphenyl)-7-(4-bromophenyl)heptane-3,5-dione (S16, 640 mg,

1.16 mmol, 80% yield) as a light yellow oil. Data for S16: R_f0.67

(2:1 hexanes:EtOAc); IR (thin ﬁlm) 2973, 1590, 1503, 1489, 1453,

1232, 1117, 1011, 931 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, enol

tautomer) δ 15.44 (br s, 1 H), 7.50−7.30 (m, 7 H), 7.07 (d, J = 8.3 Hz,

2 H), 6.48 (d, J = 1.6 Hz, 1 H), 6.43 (d, J = 1.6 Hz, 1 H), 5.41 (s, 1 H),

5.10 (s, 2 H), 4.40 (sept, J = 6.2 Hz, 1 H), 3.83 (s, 3 H), 2.94−2.75

1

1175, 1156, 1116 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 7.60 (d, J =

15.9 Hz, 1 H), 7.51−7.30 (m, 5 H), 6.82 (d, J = 1.5 Hz, 1 H), 6.79 (d,

J = 1.5 Hz, 1 H), 6.33 (d, J = 15.9 Hz, 1 H), 5.14 (s, 2 H), 4.50 (sept, J

= 6.2 Hz, 1 H), 4.28 (q, J = 7.1 Hz, 2 H), 3.88 (s, 3 H), 1.39−1.30 (m,

9 H); ¹³C NMR (101 MHz, CDCl₃, HSQC, DEPT) δ C 167.0, 154.3,

153.1, 139.1, 136.9, 129.6; CH 144.7, 128.5, 127.9, 127.3, 117.2, 107.8,

105.5, 75.8; CH₂71.2, 60.5; CH₃56.1, 22.6, 14.4; HRMS (TOF MS

ES+) calcd for C₂₂H₂₇O₅[M + H] 371.1858, found 371.1842.

To a solution of S12 (1.482 g, 4 mmol) in THF (20 mL, 0.1 M)

were added H₂O (20 mL), NaOAc (1.312 g, 16 mmol) and a solution

of TsNHNH₂(2.235 g, 12 mmol) in THF (20 mL) over a period of

40 min at 80 °C. After 18 h, TLC indicated the complete consumption

of the starting material. The mixture was allowed to cool to rt. The

organic phase was then separated, and the aqueous phase was

extracted with EtOAc (3 × 30 mL). The combined organic phases

were dried with MgSO₄. Puriﬁcation by ﬂash column chromatography

(hexanes:EtOAc = 10:1 to 6:1) gave ethyl 3-(3-(benzyloxy)-4-

isopropoxy-5-methoxyphenyl)propanoate (S13, 1.49 g, 4 mmol,

>99% yield) as a colorless oil. Data for S13: R_f0.40 (5:1

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(m, 4 H), 2.62−2.51 (m, 4 H), 1.32 (d, J = 6.2 Hz, 6 H); ¹³C NMR

(101 MHz, CDCl₃, HSQC, DEPT, enol tautomer) δ C 192.9, 192.8,

154.0, 152.9, 139.6, 137.4, 135.8, 135.4, 120.0; CH 131.6, 130.1, 128.4,

127.8, 127.3, 107.8, 105.9, 99.8, 75.3; CH₂71.2, 40.0, 39.7, 31.9, 30.8;

CH₃56.1, 22.6; HRMS (TOF MS ES+) calcd for C₃₀H₃₃BrO₅Na [M +

Na] 575.1409, found 575.1415.

°C for 30 min, a solution of 3-(benzyloxy)-4,5-dimethoxybenzalde-

hyde⁵(1.634 g, 6 mmol) in THF (10 mL) was added. The mixture

was warmed to rt and stirred at rt for 30 min. The reaction was

quenched with saturated aqueous NH₄Cl (30 mL). The organic phase

was then separated, and the aqueous phase was extracted with EtOAc

(3 × 30 mL). The combined organic phases were dried with MgSO₄.

Puriﬁcation by ﬂash column chromatography (hexanes:EtOAc = 10:1

to 5:1) gave (E)-ethyl 3-(3-(benzyloxy)-4,5-dimethoxyphenyl)acrylate

(S17, 2.038 g, 5.95 mmol, >99% yield) as a white solid. Data for S17:

R_f0.51 (3:1 hexanes:EtOAc); mp = 67−69 °C; IR (thin ﬁlm) 2940,

1709, 1636, 1581, 1504, 1425, 1275, 1176, 1152, 1120, 1005 cm⁻¹; ¹H

NMR (400 MHz, CDCl₃) δ 7.58 (d, J = 15.9 Hz, 1 H), 7.49−7.31 (m,

5 H), 6.81 (d, J = 1.8 Hz, 1 H), 6.78 (d, J = 1.8 Hz, 1 H), 6.32 (d, J =

15.9 Hz, 1 H), 5.15 (s, 2 H), 4.27 (q, J = 7.1 Hz, 2 H), 3.92 (s, 3 H),

3.89 (s, 3 H), 1.35 (t, J = 7.1 Hz, 3 H); ¹³C NMR (101 MHz, CDCl₃,

HSQC, DEPT) δ C 166.9, 153.6, 152.5, 140.8, 136.8, 129.9; CH 144.5,

128.6, 128.0, 127.3, 117.5, 107.7, 105.4; CH₂71.2, 60.5; CH₃61.0,

56.2, 14.4; HRMS (TOF MS ES+) calcd for C₂₀H₂₃O₅[M + H]

343.1545, found 343.1528.

To a solution of S17 (1.883 g, 5.5 mmol) in THF (28 mL, 0.1 M)

were added H₂O (28 mL), NaOAc (1.805 g, 22 mmol) and a solution

of TsNHNH₂(3.072 g, 16.5 mmol) in THF (27 mL) over a period of

1 h at 80 °C. After 24 h, TLC indicated the complete consumption of

the starting material. The mixture was allowed to cool to rt. The

organic phase was then separated, and the aqueous phase was

extracted with EtOAc (3 × 30 mL). The combined organic phases

were dried with MgSO₄. Puriﬁcation by ﬂash column chromatography

(hexanes:EtOAc = 10:1 to 6:1) gave ethyl 3-(3-(benzyloxy)-4,5-

dimethoxyphenyl)propanoate (S18, 1.88 g, 5.46 mmol, >99% yield) as

a colorless oil. Data for S18: R_f0.39 (4:1 hexanes:EtOAc); IR (thin

ﬁlm) 2940, 1732, 1590, 1508, 1454, 1429, 1239, 1120, 1011 cm⁻¹; ¹H

NMR (700 MHz, CDCl₃) δ 7.49−7.31 (m, 5 H), 6.50 (d, J = 1.8 Hz, 1

H), 6.46 (d, J = 1.8 Hz, 1 H), 5.14 (s, 2 H), 4.15 (q, J = 7.1 Hz, 2 H),

3.88 (s, 3 H), 3.87 (s, 3 H), 2.89 (t, J = 7.8 Hz, 2 H), 2.60 (t, J = 7.8

Hz, 2 H), 1.27 (t, J = 7.1 Hz, 3 H); ¹³C NMR (176 MHz, CDCl₃,

HSQC, DEPT) δ C 172.9, 153.3, 152.3, 137.2, 137.1, 136.3; CH 128.5,

127.9, 127.3, 107.5, 105.6; CH₂71.1, 60.5, 36.0, 31.3; CH₃60.9, 56.1,

14.3; HRMS (TOF MS ES+) calcd for C₂₀H₂₅O₅[M + H] 345.1702,

found 345.1699.

To a solution of S18 (344 mg, 1 mmol) in CH₂Cl₂(10 mL, 0.1 M)

at −78 °C was added DIBAL-H (1 mL, 1.2 mmol, 1.2 M in toluene)

over a period of 15 min. After the addition was complete, TLC

indicated complete consumption of the starting material. The reaction

was quenched with saturated aqueous Rochelle’s salt (20 mL) at −78

°C. The mixture was warmed to rt. The organic phase was separated,

and the inorganic phase was extracted with EtOAc (3 × 30 mL). The

combined organic phases were dried with MgSO₄. Puriﬁcation by ﬂash

column chromatography (hexanes:EtOAc = 5:1) gave 3-(3-(benzyl-

oxy)-4,5-dimethoxyphenyl)propanal (S19, 246 mg, 0.82 mmol, 82%

yield) as a colorless oil. Data for S19: R_f0.49 (2:1 hexanes:EtOAc); IR

(thin ﬁlm) 2937, 1722, 1589, 1507, 1453, 1429, 1239, 1119, 1008

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 9.80 (br s, 1 H), 7.49−7.29 (m,

5 H), 6.47 (d, J = 1.6 Hz, 1 H), 6.44 (d, J = 1.6 Hz, 1 H), 5.13 (s, 2 H),

3.87 (s, 3 H), 3.86 (s, 3 H), 2.88 (t, J = 7.4 Hz, 2 H), 2.74 (t, J = 7.4

Hz, 2 H); ¹³C NMR (101 MHz, CDCl₃, HSQC, DEPT) δ C 153.4,

152.4, 137.3, 137.2, 136.0; CH 201.5, 128.5, 127.9, 127.3, 107.7, 105.8;

CH₂71.2, 45.3, 28.4; CH₃60.9, 56.1; HRMS (TOF MS ES+) calcd for

C₁₈H₂₁O₄[M + H] 301.1440, found 301.1449.

To a solution of diisopropylamine (190 mg, 1.88 mmol) in THF (6

mL, 0.1 M) was added n-BuLi (1.17 mL, 1.88 mmol, 1.6 M in hexane)

over a period of 10 min at 0 °C. After stirring at 0 °C for 30 min, the

mixture was cooled to −78 °C. A solution of 22 (409 mg, 1.8 mmol)

in THF (4 mL) was added over a period of 30 min. After stirring at

−78 °C for 30 min, a solution of S19 (451 mg, 1.5 mmol) in THF (5

mL) was added over a period of 30 min. After stirring for 2 h, the

reaction was quenched with saturated aqueous NH₄Cl (20 mL). The

organic phase was separated, and the aqueous phase was extracted with

EtOAc (3 × 20 mL). The combined organic phases were dried with

MgSO₄. Puriﬁcation by ﬂash column chromatography (hexanes:EtOAc

= 5:1 to 3:1) gave 7-(3-(benzyloxy)-4,5-dimethoxyphenyl)-1-(4-

To a solution of S16 (166 mg, 0.3 mmol) in EtOAc (15 mL, 0.02

M) was added 20% Pd/C (16.6 mg, 10% w/w). Hydrogen gas was

applied (balloon), and the mixture was stirred at rt until complete

consumption of the starting material (carefully monitored by TLC,

approximately 30 min−2 h). The reaction was quenched by ﬁltering

through a short pad of silica gel. Puriﬁcation by ﬂash column

chromatography (hexanes:EtOAc = 10:1 to 8:1) gave 1-(4-

bromophenyl)-7-(3-hydroxy-4-isopropoxy-5-methoxyphenyl)heptane-

3,5-dione (29, 95 mg, 0.205 mmol, 68% yield) as a yellow oil. Data for

29: R_f0.39 (3:1 hexanes:EtOAc); IR (thin ﬁlm) 3445 (br), 2974,

1

1704, 1602, 1508, 1489, 1459, 1357, 1197, 1107, 1011, 929 cm⁻¹; H

NMR (400 MHz, CDCl₃, enol tautomer) δ 15.42 (br s, 1 H), 7.41 (d,

J = 8.2 Hz, 2 H), 7.07 (d, J = 8.2 Hz, 2 H), 6.45 (d, J = 1.6 Hz, 1 H),

6.30 (d, J = 1.6 Hz, 1 H), 5.82 (br s, 1 H), 5.43 (s, 1 H), 4.53 (sept, J =

6.2 Hz, 1 H), 3.82 (s, 3 H), 2.93−2.75 (m, 4 H), 2.62−2.51 (m, 4 H),

1.31 (d, J = 6.2 Hz, 6 H); ¹³C NMR (101 MHz, CDCl₃, HSQC,

DEPT, enol tautomer) δ C 192.9, 192.8, 152.3, 150.0, 139.6, 136.5,

120.0; CH 131.6, 130.1, 107.4, 104.2, 99.7, 75.1; CH₂39.9, 39.7, 31.6,

30.8; CH₃55.8, 22.6; HRMS (TOF MS ES+) calcd for C₂₃H₂₆BrO₄

[M + H − H₂O] 445.1014, found 445.1006.

5-Methoxy-4-(propan-2yloxy)-2-oxatricyclo[13.2.2.1^3,7]-

icosa-1(17),3,5,7(20),15,18-hexaene-10,12-dione (34). To a

sealed tube were added 29 (23.2 mg, 0.05 mmol), CuO (9.9 mg,

0.125 mmol) and K₂CO₃(13.8 mg, 0.1 mmol). The tube was

evacuated and backﬁlled with Ar, followed by the addition of pyridine

(10 mL, 0.005 M). The tube was then sealed and heated to 130 °C.

After 72 h, the reaction mixture was allowed to cool to rt. After

evaporation of the solvent, aqueous HCl (1 mL, 1 M) and H₂O (5

mL) were added. The mixture was extracted with EtOAc (4 × 10 mL).

The combined organic phase was dried with MgSO₄. Puriﬁcation by

ﬂash column chromatography (hexanes:EtOAc = 8:1 to 6:1) gave 34

(7.1 mg, 0.0186 mmol, 37% yield) as a light yellow solid. Data for 34:

R_f0.41 (3:1 hexanes:EtOAc); IR (thin ﬁlm) 3450 (br), 2973, 1590,

1

1505, 1433, 1216, 1092, 934 cm⁻¹; H NMR (700 MHz, CDCl₃) δ

15.17 (br s, 1 H), 7.18 (d, J = 8.5 Hz, 2 H), 6.99 (d, J = 8.5 Hz, 2 H),

6.33 (d, J = 1.9 Hz, 1 H), 5.26 (d, J = 1.9 Hz, 1 H), 4.98 (s, 1 H), 4.50

(sept, J = 6.2 Hz, 1 H), 3.84 (s, 3 H), 3.05 (t, J = 6.8 Hz, 2 H), 2.95

(m, 2 H), 2.48 (t, J = 6.8 Hz, 2 H), 2.39 (m, 2 H), 1.41 (d, J = 6.2 Hz,

6 H); ¹³C NMR (176 MHz, CDCl₃, HSQC, DEPT) δ C 197.2, 188.6,

155.5, 155.0, 153.7, 136.4, 136.0, 134.0; CH 130.5, 123.2, 106.9, 105.5,

103.2, 75.6; CH₂39.4, 37.6, 32.3, 28.1; CH₃56.1, 22.6; HRMS (TOF

MS ES+) calcd for C₂₃H₂₇O₅[M + H] 383.1858, found 383.1865.

Reported Structure of 1,9′-Didesmethylgaruganin III (10).

To a solution of 34 (5 mg, 0.013 mmol) in DCM (1 mL, 0.013 M)

was added BCl₃(39 uL, 0.039 mmol) at 0 °C. The mixture was

allowed to warm to rt. After 5 min, TLC indicated consumption of

starting material. The reaction was then quenched with MeOH (1 mL)

and stirred for 10 min. The solvent was evaporated under reduced

pressure. Puriﬁcation by ﬂash column chromatography (hexanes:E-

tOAc = 6:1 to 4:1) gave 10 (3.2 mg, 0.0097 mmol, 74% yield) as a

light yellow solid. Data for 10: R_f0.20 (3:1 hexanes:EtOAc); IR (thin

ﬁlm) 3441 (br), 2939, 1603, 1518, 1454, 1436, 1213, 1083, 860 cm⁻¹;

¹H NMR (700 MHz, CDCl₃) δ 15.19 (br s, 1 H), 7.20 (d, J = 8.4 Hz,

2 H), 7.02 (d, J = 8.4 Hz, 2 H), 6.34 (br s, 1 H), 5.53 (s, 1 H), 5.28 (d,

J = 1.7 Hz, 1 H), 4.97 (s, 1 H), 3.90 (s, 3 H), 3.06 (t, J = 6.8 Hz, 2 H),

2.93 (m, 2 H), 2.48 (t, J = 6.8 Hz, 2 H), 2.38 (m, 2 H); ¹³C NMR (176

MHz, CDCl₃, HSQC, DEPT) δ C 197.0, 188.8, 154.7, 148.9, 147.2,

136.8, 132.6, 132.0; CH 130.6, 123.2, 106.7, 105.0, 103.2; CH₂39.5,

37.9, 32.2, 28.0; CH₃56.3; HRMS (TOF MS ES+) calcd for C₂₀H₂₁O₅

[M + H] 341.1389, found 341.1380.

1-(4-Bromophenyl)-7-(3-hydroxy-4,5-dimethoxyphenyl)-

heptane-3,5-dione (30). To a slurry of NaH (360 mg, 9 mmol) in

THF (10 mL, 0.3 M) was added ethyl 2-(diethoxyphosphoryl)acetate

(1.79 mL, 9 mmol) over a period of 10 min at 0 °C. After stirring at 0

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bromophenyl)-5-hydroxyheptan-3-one (S20, 554 mg, 1.05 mmol, 70%

yield) as a colorless oil. Data for S20: R_f0.21 (2:1 hexanes:EtOAc); IR

(thin ﬁlm) 3500 (br), 2934, 1707, 1590, 1505, 1489, 1330, 1239, 1118,

1010 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.50−7.29 (m, 7 H), 7.06

(d, J = 8.3 Hz, 2 H), 6.48 (br s, 1 H), 6.45 (br s, 1 H), 5.13 (s, 2 H),

4.04 (m, 1 H), 3.88 (s, 3 H), 3.86 (s, 3 H), 3.06 (brs, 1 H), 2.86 (t, J =

7.3 Hz, 2 H), 2.80−2.47 (m, 6 H), 1.84−1.57 (m, 2 H); ¹³C NMR

(101 MHz, CDCl₃, HSQC, DEPT) δ C 210.5, 153.3, 152.3, 139.7,

137.4, 137.3, 137.0, 120.0; CH 131.6, 130.1, 128.5, 127.8, 127.3, 107.8,

105.9, 66.8; CH₂71.1, 49.4, 44.7, 38.1, 32.0, 28.8; CH₃60.9, 56.1;

HRMS (TOF MS ES+) calcd for C₂₈H₃₂BrO₅[M + H] 527.1433,

found 527.1429.

To a solution of S20 (448 mg, 0.85 mmol) in EtOAc (8.5 mL, 0.1

M) at rt was added IBX (714 mg, 2.55 mmol). The reaction mixture

was heated to reﬂux until complete consumption of the starting

material was observed (TLC, approximately 4−8 h). The reaction

mixture was allowed to cool to rt, ﬁltered through a short pad of silica

gel, and concentrated to give the crude S21, which was used directly

without further puriﬁcation.

(0.3 mL, 0.6 mmol, 2 M in hexanes). After stirring at rt for 4 h, the

solvent was removed under reduced pressure. Puriﬁcation by ﬂash

column chromatography (hexanes:EtOAc = 5:1 to 3:1) gave 37d (10.6

mg, 0.0288 mmol, 48% yield, white solid, more polar) and 38d (10.6

mg, 0.0288 mmol, 48% yield, white solid, less polar) in 1:1 ratio.

Treating 37d and 38d with dry acidic CDCl₃(“old” CDCl₃dried by 3

Å MS) at rt (approximately 5 min) gave 44 and garuganin III (9),

respectively in >99% yield. Data for garuganin III (9): R_f0.25 (2:1

hexanes:EtOAc); IR (thin ﬁlm) 2925, 1667, 1589, 1568, 1506, 1451,

1271, 1214, 1093 cm⁻¹; ¹H NMR (700 MHz, CDCl₃) δ 7.32−7.26 (m,

2 H), 6.97 (d, J = 8.6 Hz, 2 H), 6.30 (d, J = 1.7 Hz, 1 H), 5.22 (s, 1 H),

4.92 (d, J = 1.7 Hz, 1 H), 4.00 (s, 3 H), 3.86 (s, 3 H), 3.47 (s, 3 H),

3.11 (t, J = 7.0 Hz, 2 H), 3.08−2.40 (m, 6 H); ¹³C NMR (176 MHz,

CDCl₃, HSQC, DEPT) δ C 198.8, 173.8, 155.2, 154.5, 153.1, 137.4,

136.1, 135.3; CH 131.2, 123.4, 106.0, 105.0, 102.1; CH₂44.3, 31.1,

28.5, 26.9; CH₃61.2, 56.0, 55.7; HRMS (TOF MS ES+) calcd for

C₂₂H₂₅O₅[M + H] 369.1702, found 369.1686.

Data for 44: R_f0.41 (2:1 hexanes:EtOAc); IR (thin ﬁlm) 2935,

1682, 1589, 1506, 1432, 1261, 1210, 1147, 1096, 1007 cm⁻¹; ¹H NMR

(700 MHz, CDCl₃) δ 7.38 (dd, J = 8.2, 1.4 Hz, 1 H), 7.04 (dd, J = 8.2,

1.9 Hz, 1 H), 6.90−6.84 (m, 2 H), 6.30 (d, J = 1.8 Hz, 1 H), 5.33 (s, 1

H), 4.94 (d, J = 1.8 Hz, 1 H), 4.02 (td, J = 12.9, 3.4 Hz, 1 H), 4.00 (s,

3 H), 3.86 (s, 3 H), 3.71 (s, 3 H), 3.24 (dd, J = 14.7, 11.4 Hz, 1 H),

2.99 (dt, J = 12.8, 4.0 Hz, 1 H), 2.91 (td, J = 12.9, 3.1 Hz, 1 H), 2.57−

2.51 (m, 1 H), 2.48 (dd, J = 17.5, 11.0 Hz, 1 H), 2.34 (dt, J = 12.8, 3.8

Hz, 1 H), 2.28 (dd, J = 15.6, 6.7 Hz, 1 H); ¹³C NMR (176 MHz,

CDCl₃, HSQC, DEPT) δ C 196.8, 173.0, 155.6, 155.5, 152.8, 138.1,

137.4, 135.7; CH 130.8, 130.2, 124.4, 122.2, 108.9, 105.5, 101.2; CH₂

45.0, 33.9, 33.0, 27.5; CH₃61.2, 56.2, 55.2; HRMS (TOF MS ES+)

calcd for C₂₂H₂₅O₅[M + H] 369.1702, found 369.1692.

1-(3-Bromo-5-methoxyphenyl)-7-(4-hydroxyphenyl)-

heptane-3,5-dione (31). To a slurry of NaH (540 mg, 13.5 mmol)

in THF (15 mL, 0.3 M) was added ethyl 2-(diethoxyphosphoryl)-

acetate (2.68 mL, 13.5 mmol) over a period of 10 min at 0 °C. After

stirring at 0 °C for 30 min, a solution of 3-bromo-5-methoxybenzal-

dehyde²⁶(1.935 g, 9 mmol) in THF (15 mL) was added. The mixture

was warmed to rt and stirred at rt for 30 min. The reaction was

quenched with saturated aqueous NH₄Cl (50 mL). The organic phase

was then separated, and the aqueous phase was extracted with EtOAc

(3 × 50 mL). The combined organic phases were dried with MgSO₄.

Puriﬁcation by ﬂash column chromatography (hexanes:EtOAc = 10:1

to 5:1) gave (E)-ethyl 3-(3-bromo-5-methoxyphenyl)acrylate (S22,

2.541 g, 8.91 mmol, 99% yield) as a colorless solid. Data for S22: R_f

0.41 (5:1 hexanes:EtOAc); mp = 43−45 °C; IR (thin ﬁlm) 2981,

1713, 1641, 1565, 1456, 1422, 1270, 1178, 1050 cm⁻¹; ¹H NMR (700

MHz, CDCl₃) δ 7.56 (d, J = 16.0 Hz, 1 H), 7.27 (t, J = 1.3 Hz, 1 H),

7.07 (t, J = 2.0 Hz, 1 H), 6.96 (t, J = 1.7 Hz, 1 H), 6.42 (d, J = 16.0 Hz,

1 H), 4.28 (q, J = 7.1 Hz, 2 H), 3.83 (s, 3 H), 1.35 (t, J = 7.1 Hz, 3 H);

¹³C NMR (176 MHz, CDCl₃, HSQC) δ C 166.5, 160.5, 137.2; CH

To a solution of S21 (approximately 0.85 mmol, from previous

step) in CH₂Cl₂(17 mL, 0.05 M) were added pentamethylbenzene

(378 mg, 2.55 mmol) and BCl₃(3.4 mL, 3.4 mmol, 1 M in DCM)

over a period of 10 min at −78 °C. After the addition was complete,

TLC indicated complete consumption of the starting material. The

reaction was quenched with MeOH (2 mL) at −78 °C. The resultant

mixture was allowed to warm to rt. Diluted aqueous NaHCO₃was

added until the aqueous phase had pH 6. The organic phase was

separated, and the aqueous phase was extracted with EtOAc (3 × 20

mL). The combined organic phases were dried with MgSO₄.

Puriﬁcation by ﬂash column chromatography (hexanes:EtOAc = 6:1

to 4:1) gave 1-(4-bromophenyl)-7-(3-hydroxy-4,5-dimethoxyphenyl)-

heptane-3,5-dione (30, 263 mg, 0.604 mmol, 71% yield, 2 steps) as a

light yellow solid. Data for 30: R_f0.39 (2:1 hexanes:EtOAc); mp =

60−63 °C; IR (thin ﬁlm) 3432 (br), 2934, 1594, 1511, 1489, 1356,

1

1202, 1106, 1010 cm⁻¹; H NMR (400 MHz, CDCl₃, enol tautomer)

δ 15.41 (br s, 1 H), 7.42 (d, J = 8.2 Hz, 2 H), 7.08 (d, J = 8.2 Hz, 2 H),

6.45 (d, J = 1.7 Hz, 1 H), 6.31 (d, J = 1.7 Hz, 1 H), 5.74 (br s, 1 H),

5.44 (s, 1 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 2.94−2.76 (m, 4 H), 2.63−

2.53 (m, 4 H); ¹³C NMR (101 MHz, CDCl₃, HSQC, DEPT, enol

tautomer) δ C 192.9, 192.7, 152.3, 149.2, 139.6, 136.9, 133.9, 120.0;

CH 131.6, 130.1, 107.7, 104.3, 99.7; CH₂39.9, 39.7, 31.6, 30.8; CH₃

61.0, 55.8; HRMS (TOF MS ES+) calcd for C₂₁H₂₄BrO₅[M + H]

435.0807, found 435.0791.

4,5-Dimethoxy-2-oxatricyclo[13.2.2.1^3,7]icosa-1(17),3,5,7-

(20),15,18-henaene-10,12-dione (35). To a sealed tube were

added 30 (21.8 mg, 0.05 mmol), CuO (9.9 mg, 0.125 mmol) and

K₂CO₃(13.8 mg, 0.1 mmol). The tube was evacuated and backﬁlled

with Ar, followed by the addition of pyridine (10 mL, 0.005 M). The

tube was then sealed and heated to 130 °C. After 48 h, TLC indicated

the complete consumption of the starting material. The reaction

mixture was allowed to cool to rt. After evaporation of the solvent,

aqueous HCl (1 mL, 1 M) and H₂O (5 mL) were added. The mixture

was extracted with EtOAc (4 × 10 mL). The combined organic phases

were dried with MgSO₄. Puriﬁcation by ﬂash column chromatography

(hexanes:EtOAc = 8:1 to 5:1) gave 35 (9 mg, 0.0254 mmol, 51%

yield) as a light yellow solid. Data for 35: R_f0.53 (2:1

hexanes:EtOAc); IR (thin ﬁlm) 2932, 1589, 1507, 1454, 1432, 1215,

142.9, 123.3, 120.0, 118.7, 112.5; CH₂60.7; CH₃55.6, 14.3; HRMS

(TOF MS ES+) calcd for C₁₂H₁₄BrO₃[M + H] 285.0126, found

285.0138.

To a solution of S22 (2.024 g, 7.1 mmol) in THF (36 mL, 0.1 M)

were added H₂O (36 mL), NaOAc (2.33 g, 28.4 mmol) and a solution

of TsNHNH₂(3.967 g, 21.3 mmol) in THF (35 mL) over a period of

1 h at 80 °C. After 24 h, TLC indicated the complete consumption of

the starting material. The mixture was allowed to cool to rt. The

organic phase was then separated, and the aqueous phase was

extracted with EtOAc (3 × 50 mL). The combined organic phases

were dried with MgSO₄. Puriﬁcation by ﬂash column chromatography

(hexanes:EtOAc = 10:1 to 8:1) gave ethyl 3-(3-bromo-5-

methoxyphenyl)propanoate (S23, 2.04 g, 7.1 mmol, >99% yield) as

a colorless oil. Data for S23: R_f0.55 (3:1 hexanes:EtOAc); IR (thin

ﬁlm) 2939, 1724, 1598, 1568, 1459, 1430, 1153, 1055 cm⁻¹; ¹H NMR

(700 MHz, CDCl₃) δ 6.97 (t, J = 1.5 Hz, 1 H), 6.92 (d, J = 2.0 Hz, 1

H), 6.70 (m, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 3.80 (s, 3 H), 2.91 (t, J =

7.7 Hz, 2 H), 2.62 (t, J = 7.7 Hz, 2 H), 1.27 (t, J = 7.1 Hz, 3 H); ¹³C

NMR (176 MHz, CDCl₃, HSQC, DEPT) δ C 172.6, 160.4, 143.8,

122.7; CH 123.8, 114.9, 113.4; CH₂60.6, 35.5, 30.7; CH₃55.4, 14.2;

HRMS (EI+) calcd for C₁₂H₁₅BrO₃[M] 286.0205, found 286.0201.

1

1096, 1003 cm⁻¹; H NMR (700 MHz, CDCl₃) δ 15.16 (br s, 1 H),

7.19 (d, J = 8.4 Hz, 2 H), 7.01 (d, J = 8.4 Hz, 2 H), 6.35 (d, J = 1.8 Hz,

1 H), 5.29 (d, J = 1.8 Hz, 1 H), 4.97 (s, 1 H), 4.00 (s, 3 H), 3.88 (s, 3

H), 3.06 (t, J = 6.8 Hz, 2 H), 2.95 (m, 2 H), 2.48 (t, J = 6.8 Hz, 2 H),

2.39 (m, 2 H); ¹³C NMR (176 MHz, CDCl₃, HSQC, DEPT) δ C

196.9, 188.7, 154.9, 154.8, 153.1, 136.6, 136.5, 136.1; CH 130.6, 123.1,

107.0, 105.6, 103.2; CH₂39.4, 37.6, 32.2, 28.1; CH₃61.2, 56.1; HRMS

(TOF MS ES+) calcd for C₂₁H₂₃O₅[M + H] 355.1545, found

355.1539.

(11E)-4,15,12-Trimethoxy-2-oxatricyclo[13.2.2.1^3,7]icosa-1-

(17),3,5,7(20),11,15,18-heptaen-10-one (44) and Garuganin III

(9). To a solution of 35 (21.3 mg, 0.06 mmol in a mixed solvent of

CH₃CN and MeOH (6 mL, 0.01 M, 10:1 v/v) was added TMSCHN₂

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To a solution of S23 (2.01 g, 7 mmol) in CH₂Cl₂(70 mL, 0.1 M) at

−78 °C was added DIBAL-H (7 mL, 8.4 mmol, 1.2 M in toluene) over

a period of 1 h. After the addition was complete, TLC indicated

complete consumption of the starting material. The reaction was

quenched with saturated aqueous Rochelle’s salt (100 mL) at −78 °C.

The mixture was warmed to rt. The organic phase was separated, and

the inorganic phase was extracted with EtOAc (3 × 10 mL). The

combined organic phases were dried with MgSO₄. Puriﬁcation by ﬂash

column chromatography (hexanes:EtOAc = 5:1) gave 3-(3-bromo-5-

methoxyphenyl)propanal (S24, 1.38 g, 5.68 mmol, 81% yield) as a

light yellow oil. Data for S24: R_f0.41 (3:1 hexanes:EtOAc); IR (thin

ﬁlm) 2981, 1713, 1641, 1565, 1456, 1422, 1270, 1178, 1050 cm⁻¹; ¹H

NMR (700 MHz, CDCl₃) δ 9.83 (t, J = 1.2 Hz, 1 H), 6.95 (t, J = 1.5

Hz, 1 H), 6.92 (t, J = 2.0 Hz, 1 H), 6.69 (m, 1 H), 3.79 (s, 3 H), 2.91

(t, J = 7.5 Hz, 2 H), 2.81−2.77 (m, 2 H); ¹³C NMR (176 MHz,

CDCl₃, HSQC, DEPT) δ C 160.4, 143.6, 122.9; CH 200.9, 123.7,

114.8, 113.5; CH₂44.9, 27.8; CH₃55.5; HRMS (EI+) calcd for

C₁₀H₁₁BrO₂[M] 241.9942, found 241.9940.

To a solution of diisopropylamine (481 mg, 4.75 mmol) in THF

(20 mL, 0.1 M) was slowly added n-BuLi (2.97 mL, 4.75 mmol, 1.6 M

in hexane) over a period of 10 min at 0 °C. After stirring at 0 °C for 30

min, the mixture was cooled to −78 °C. A solution of 4-(4-

(benzyloxy)phenyl)butan-2-one²⁷(1.16 g, 4.56 mmol) in THF (9

mL) was added over a period of 1 h. After stirring at −78 °C for 30

min, a solution of S24 (924 mg, 3.8 mmol) in THF (9 mL) was added

over a period of 1 h. After stirring for 2 h, the reaction was quenched

with saturated aqueous NH₄Cl (30 mL). The organic phase was

separated, and the aqueous phase was extracted with EtOAc (3 × 30

mL). The combined organic phases were dried with MgSO₄.

Puriﬁcation by ﬂash column chromatography (hexanes:EtOAc = 5:1

to 3:1) gave 1-(4-(benzyloxy)phenyl)-7-(3-bromo-5-methoxyphenyl)-

5-hydroxyheptan-3-one (S25, 1.377 g, 2.77 mmol, 73% yield) as a light

yellow solid. Data for S25: R_f0.25 (2:1 hexanes:EtOAc); mp = 80−82

°C; IR (thin ﬁlm) 3371 (br), 2929, 1705, 1605, 1566, 1512, 1454,

1237, 1154, 817 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.49−7.30 (m,

5 H), 7.10 (d, J = 8.6 Hz, 2 H), 6.95 (br s, 1 H), 6.94−6.87 (m, 3 H),

6.69 (br s, 1 H), 5.06 (s, 2 H), 4.03 (m, 1 H), 3.79 (s, 3 H), 3.09 (d, J

= 3.1 Hz, 1 H), 2.92−2.46 (m, 8 H), 1.84−1.59 (m, 2 H); ¹³C NMR

(101 MHz, CDCl₃, HSQC, DEPT) δ C 211.2, 160.4, 157.3, 145.1,

137.1, 132.9, 122.7; CH 129.2, 128.6, 127.9, 127.4, 123.9, 115.0, 114.5,

113.5, 66.6; CH₂70.1, 49.2, 45.2, 37.6, 31.5, 28.7; CH₃55.4; HRMS

(TOF MS ES+) calcd for C₂₇H₃₀BrO₄[M + H] 497.1327, found

497.1310.

154.1, 143.8, 132.6, 122.8; CH 129.4, 123.8, 115.4, 114.9, 113.4, 99.8;

CH₂40.2, 39.6, 31.1, 30.8; CH₃55.5; HRMS (TOF MS ES+) calcd for

C₂₀H₂₂BrO₄[M + H] 405.0701, found 405.0709.

5-Methoxy-2-oxatricyclo[13.2.2.1^3,7]isoca-1(17),3,5,7-

(20),15,18-hexaene-10,12-dione (36). To a sealed tube were

added 31 (40.5 mg, 0.1 mmol), CuO (19.9 mg, 0.25 mmol) and

K₂CO₃(27.6 mg, 0.2 mmol). The tube was evacuated and backﬁlled

with Ar, followed by the addition of pyridine (20 mL, 0.005 M). The

tube was then sealed and heated to 130 °C. After 72 h, the reaction

mixture was allowed to cool to rt. After evaporation of the solvent,

aqueous HCl (2 mL, 1 M) and H₂O (10 mL) were added. The

mixture was extracted with EtOAc (4 × 20 mL). The combined

organic phases were dried with MgSO₄. Puriﬁcation by ﬂash column

chromatography (hexanes:EtOAc = 8:1 to 6:1) gave 36 (13 mg, 0.04

mmol, 40% yield) as a light yellow solid. Data for 36: R_f0.63 (2:1

hexanes:EtOAc); IR (thin ﬁlm) 2939, 1599, 1505, 1461, 1434, 1342,

1

1294, 1218, 1137, 1059 cm⁻¹; H NMR (700 MHz, CDCl₃) δ 15.20

(br s, 1 H), 7.20 (d, J = 8.4 Hz, 2 H), 6.99 (d, J = 8.4 Hz, 2 H), 6.60 (t,

J = 2.2 Hz, 1 H), 6.34 (m, 1 H), 5.21 (m, 1 H), 4.97 (s, 1 H), 3.82 (s, 3

H), 3.06 (t, J = 6.8 Hz, 2 H), 2.96 (m, 2 H), 2.48 (t, J = 6.8 Hz, 2 H),

2.38 (m, 2 H); ¹³C NMR (176 MHz, CDCl₃, HSQC) δ C 197.0,

188.8, 162.9, 160.6, 154.6, 143.3, 136.7; CH 130.6, 123.1, 107.8, 105.7,

103.2, 100.3; CH₂39.4, 37.7, 32.2, 28.4; CH₃55.4; HRMS (TOF MS

ES+) calcd for C₂₀H₂₁O₄[M + H] 325.1440, found 325.1456.

Reported Structure of Garuganin IV (8) and (10E)-5,10-

Dimethoxy-2-oxatricyclo[13.2.2.1^3,7]isoca-1(17),3,5,7-

(20),10,15,18-heptaen-12-one (45). To a solution of 36 (26 mg,

0.08 mmol) in a mixed solvent of CH₃CN and MeOH (8 mL, 0.01 M

10:1 v/v) was added TMSCHN₂(0.4 mL, 0.8 mmol, 2 M in hexanes).

After stirring at rt for 4 h, the solvent was removed under reduced

pressure. Puriﬁcation by ﬂash column chromatography (hexanes:E-

tOAc = 5:1 to 3:1) gave 37e (13.3 mg, 0.0393 mmol, 49% yield, white

solid, more polar) and 38e (13 mg, 0.0384 mmol, 48% yield, white

solid, less polar) in 1:1 ratio. Treating 37e and 38e with dry acidic

CDCl₃(“old” CDCl₃dried by 3 Å MS) at rt (approximately 5 min)

gave garuganin IV (8) and 45, respectively in >99% yield. Data for

garuganin IV (8): white solid, R_f0.57 (2:1 hexanes:EtOAc); IR (thin

ﬁlm) 2932, 1682, 1591, 1503, 1462, 1434, 1212, 1136, 1098 cm⁻¹; ¹H

NMR (700 MHz, CDCl₃) δ 7.38 (d, J = 8.3 Hz, 1 H), 7.04 (dd, J =

8.3, 1.8 Hz, 1 H), 6.90−6.83 (m, 2 H), 6.56 (t, J = 2.2 Hz, 1 H), 6.28

(br s, 1 H), 5.33 (s, 1 H), 4.86 (br s, 1 H), 4.03 (td, J = 12.9, 3.4 Hz, 1

H), 3.80 (s, 3 H), 3.71 (s, 3 H), 3.26 (dd, J = 14.5, 11.7 Hz, 1 H), 2.99

(dt, J = 12.6, 3.9 Hz, 1 H), 2.92 (td, J = 12.9, 3.0 Hz, 1 H), 2.57−2.50

(m, 1 H), 2.47 (dd, J = 17.8, 11.2 Hz, 1 H), 2.34 (dt, J = 12.9, 3.8 Hz,

1 H), 2.30 (dd, J = 15.2, 7.0 Hz, 1 H); ¹³C NMR (176 MHz, CDCl₃,

HSQC, DEPT) δ C 196.9, 173.0, 163.6, 160.4, 155.4, 144.2, 138.2; CH

130.7, 130.3, 124.4, 122.2, 107.6, 107.4, 101.3, 99.5; CH₂45.0, 33.9,

32.9, 27.6; CH₃55.4, 55.2; HRMS (TOF MS ES+) calcd for C₂₁H₂₃O₄

[M + H] 339.1596, found 339.1584.

Data for 45: white solid, R_f0.31 (2:1 hexanes:EtOAc); IR (thin

ﬁlm) 2917, 1668, 1589, 1567, 1505, 1458, 1440, 1267, 1215, 1133

cm⁻¹; ¹H NMR (700 MHz, CDCl₃) δ 7.32−7.26 (m, 2 H), 6.96 (d, J

= 8.6 Hz, 2 H), 6.55 (t, J = 2.3 Hz, 1 H), 6.30 (m, 1 H), 5.21 (s, 1 H),

4.87 (m, 1 H), 3.80 (s, 3 H), 3.46 (s, 3 H), 3.11 (t, J = 7.0 Hz, 2 H),

3.08−2.40 (m, 6 H); ¹³C NMR (176 MHz, CDCl₃, HSQC, DEPT) δ

C 198.7, 173.9, 163.2, 160.4, 154.4, 142.8, 137.5; CH 131.1, 123.5,

107.1, 104.7, 102.0, 99.6; CH₂44.3, 31.2, 28.3, 27.1; CH₃55.6, 55.3;

HRMS (TOF MS ES+) calcd for C₂₁H₂₃O₄[M + H] 339.1596, found

339.1601.

Garugamblin I (11). To a solution of 12 (1.5 mg, 4.63 μmole) in

dry MeOH (0.46 mL, 0.01 M) was added TsOH (0.1 mg, 0.58 μmole)

in a conical vial and heated to 60 °C. After 3 d, the reaction was

quenched with pH = 7 buﬀer (1 mL), extracted with DCM (3 × 2

mL) and concentrated. Analysis of the crude material by NMR

indicated that it was a mixture of unreacted starting material and

garugamblin I (11) (50% yield).

To a solution of S25 (497 mg, 1 mmol) in EtOAc (10 mL, 0.1 M)

at rt was added IBX (840 mg, 3 mmol). The reaction mixture was

heated to reﬂux until complete consumption of the starting material

was observed (TLC, approximately 4−8 h). The reaction mixture was

allowed to cool to rt, ﬁltered through a short pad of silica gel, and

concentrated to give crude S26, which was used directly without

further puriﬁcation.

To a stirred solution of S26 (approximately 1 mmol, from previous

step) in CH₂Cl₂(20 mL, 0.05 M) were added pentamethylbenzene

(445 mg, 3 mmol) and BCl₃(4 mL, 4 mmol, 1 M in DCM) over a

period of 10 min at −78 °C. After the addition was complete, TLC

indicated complete consumption of the starting material. The reaction

was quenched with MeOH (2 mL) at −78 °C. The resultant mixture

was allowed to warm to rt. Diluted aqueous NaHCO₃was added until

the aqueous phase had pH 6. The organic phase was separated, and the

aqueous phase was extracted with EtOAc (3 × 20 mL). The combined

organic phases were dried with MgSO₄. Puriﬁcation by ﬂash column

chromatography (hexanes:EtOAc = 6:1 to 4:1) gave 1-(3-Bromo-5-

methoxyphenyl)-7-(4-hydroxyphenyl)heptane-3,5-dione (31, 291 mg,

0.72 mmol, 72% yield, 2 steps) as a light yellow solid. Data for 31: R_f

0.49 (2:1 hexanes:EtOAc); mp = 54−57 °C; IR (thin ﬁlm) 3402 (br),

1

2936, 1724, 1699, 1600, 1569, 1515, 1456, 1266, 1054, 828 cm⁻¹; H

NMR (400 MHz, CDCl₃, enol tautomer) δ 15.39 (br s, 1 H), 7.05 (d,

J = 8.3 Hz, 2 H), 6.95 (br s, 1 H), 6.92 (t, J = 1.9 Hz, 1 H), 6.77 (d, J =

8.3 Hz, 2 H), 6.67 (br s, 1 H), 5.44 (s, 1 H), 5.26 (br s, 1 H), 3.79 (s, 3

H), 2.92−2.72 (m, 4 H), 2.62−2.51 (m, 4 H); ¹³C NMR (101 MHz,

CDCl₃, HSQC, DEPT, enol tautomer) δ C 193.02, 193.0, 160.4,

Garuganin I (7). To a solution of 32 (2.0 mg, 5.65 μmole) in dry

MeOH (0.57 mL, 0.01 M) was added TsOH (0.1 mg, 0.58 μmole) in

a conical vial and heated to 60 °C. After 3 d, the reaction was

quenched with pH = 7 buﬀer (1 mL), extracted with DCM (3 × 2

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mL) and concentrated. Analysis of the crude material by NMR

indicated that it was a mixture of unreacted starting material and

garuganin I (7) (17% yield).

(5) (a) Costantino, V.; Fattorusso, E.; Mangoni, A.; Perinu, C.; Teta,

R.; Panza, E.; Ianaro, A. J. Org. Chem. 2012, 77, 6377−6383.

(b) Malterud, K. E.; Anthonsen, T.; Hjortas, J. Tetrahedron Lett. 1976,

̊

Reported Structure of Garuganin IV (8). To a solution of 37

(1.8 mg, 5.55 μmole) in dry MeOH (0.56 mL, 0.01 M) was added

TsOH (0.1 mg, 0.58 μmole) in a conical vial and heated to 60 °C.

After 3 d, the reaction was quenched with pH = 7 buﬀer (1 mL),

extracted with DCM (3 × 2 mL) and concentrated. Analysis of the

crude material by NMR indicated that it was a mixture of unreacted

starting material and reported structure of garuganin IV (8) (14%

yield).

Garugamblin II (13). To a solution of 34 (1.5 mg, 4.44 μmole) in

dry MeOH (0.44 mL, 0.01 M) was added TsOH (0.1 mg, 0.58 μmole)

in a conical vial and heated to 60 °C. After 3 d, the reaction was

quenched with pH = 7 buﬀer (1 mL), extracted with DCM (3 × 2

mL) and concentrated. Analysis of the crude material by NMR

indicated that it was a mixture of unreacted starting material and

garugamblin II (13) (12% yield).

17, 3069−3072. (c) Morihara, M.; Sakurai, N.; Inoue, T.; Kawai, K.-i.;

Nagai, M. Chem. Pharm Bull. 1997, 45, 820−823. (d) Li, Y.-X.; Ruan,

H.-L.; Zhou, X.-F.; Zhang, Y.-H.; Pi, H.-F.; Wu, J.-Z. Chem. Res. Chin.

Univ. 2008, 24, 427−429. (e) Liu, J.-X.; Di, D.-L.; Wei, X.-N.; Han, Y.

Planta Med. 2008, 74, 754−759. (f) Liu, H. B.; Cui, C. B.; Cai, B.; Gu,

Q. Q.; Zhang, D. Y.; Zhao, Q. C.; Guan, H. S. Chin. Chem. Lett. 2005,

16, 215−218. (g) Venkatraman, G.; Mishra, A. K.; Thombare, P. S.;

Sabata, B. K. Phytochemistry 1993, 33, 1221−1225. (h) Ara, K.;

Rahman, A. H. M. M.; Hasan, C. M.; Iskander, M. N.; Asakawa, Y.;

Quang, D. N.; Rashid, M. A. Phytochemistry 2006, 67, 2659−2662.

(i) Kalchhauser, H.; Krishnamurty, H. G.; Talukdar, A. C.; Schmid, W.

Monatsh. Chem. 1988, 119, 1047−1050. (j) Nagumo, S.; Ishizawa, S.;

Nagai, M.; Inoue, T. Chem. Pharm. Bull. 1996, 44, 1086−1089.

(k) Reddy, V. L. N.; Ravinder, K.; Srinivasulu, M.; Goud, T. V.; Reddy,

S. M.; Srujankumar, D.; Rao, T. P.; Murty, U. S.; Venkateswarlu, Y.

Chem. Pharm. Bull. 2003, 51, 1081−1084. (l) Kubo, M.; Nagai, M.;

Inoue, T. Chem. Pharm. Bull. 1983, 31, 1917−1922. (m) Haribal, M.

M.; Mishra, A. K.; Sabata, B. K. Tetrahedron 1985, 41, 4949−4951.

(n) Mishra, A. K.; Haribal, M. M.; Sabata, B. K. Phytochemistry 1985,

24, 2463−2465.

(11E)-4,15,12-Trimethoxy-2-oxatricyclo[13.2.2.1^3,7]icosa-1-

(17),3,5,7(20),11,15,18-heptaen-10-one (44). To a solution of 30

(2.2 mg, 6.21 μmole) in dry MeOH (0.62 mL, 0.01 M) was added

TsOH (0.1 mg, 0.58 μmole) in a conical vial and heated to 60 °C.

After 3 d, the reaction was quenched with pH = 7 buﬀer (1 mL),

extracted with DCM (3 × 2 mL) and concentrated. Analysis of the

crude material by NMR indicated that it was a mixture of unreacted

starting material and (11E)-4,15,12-trimethoxy-2-oxatricyclo-

[13.2.2.13,7]icosa-1(17),3,5,7(20),11,15,18-heptaen-10-one (44)

(16% yield).

(6) Salih, M. Q.; Beaudry, C. M. Org. Lett. 2012, 14, 4026−4029.

(7) Of the multiple numbering systems for the DAEHs, we choose to

use the system adopted by Nagai. See Scheme 1 and ref 5c.

(8) Ullmann, F.; Sponagel, P. Ber. Dtsch. Chem. Ges. 1905, 38, 2211−

2212.

(9) Roman, G.; Riley, J. G.; Vlahakis, J. Z.; Kinobe, R. T.; Brien, J. F.;

Nakatsub, K.; Szarek, W. A. Bioorg. Med. Chem. 2007, 15, 3225−3234.

(10) (a) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001−3003.

(b) Bartlett, S. L.; Beaudry, C. M. J. Org. Chem. 2011, 76, 9852−9855.

(11) Okano, K.; Okuyama, K.-I.; Fukuyama, T.; Tokuyama, H. Synlett

2008, 13, 1977−1980.

ASSOCIATED CONTENT

■

S

* Supporting Information

1

Depiction of H and ¹³C NMR spectra of all new compounds,

VT NMR spectra, simulated spectra for line shape analysis, and

SIR data. This material is available free of charge via the

Internet at http://pubs.acs.org.

(12) Zhu, Z.-Q.; Beaudry, C. M. J. Org. Chem. 2013, DOI: 10.1021/

jo302723n.

(13) Furthermore, natural garuganin IV was hydrolyzed to the

corresponding diketone, which does not have the same NMR shifts as

synthetic 37 prepared in this report. See ref 5g.

(14) Molecules of structure type D and E were prepared from

structure type A as described above and in the Experimental Section.

They showed chemical shift equivalent geminal methylene protons in

their ¹H NMR. However, they were converted to structure types B and

C, respectively, without full characterization.

AUTHOR INFORMATION

Corresponding Author

*E-mail: bain@mcmaster.ca; christopher.beaudry@oregonstate.

■

edu.

Notes

The authors declare no competing ﬁnancial interest.

(15) Some line broadening of the geminal methylene protons can be

seen in 41 and 14. This is the result of a coalescence temperature near

rt. See the Supporting Information for collated VT NMR spectra at

multiple temperatures.

(16) Note that the chemical shift equivalence could, in principle, be

the unlikely result of accidental equivalence of all geminal methylene

and symmetry-related phenyl protons.

(17) For all garuganin and garugamblin molecules, symmetry related

phenyl protons (i.e., H₁₅and H₁₉) were used to determine the

coalescence temperature (T_C) as indicated by * in Figure 3. See also

the spectra in the Supporting Information.

(18) Friebolin, H. Basic One- and Two-Dimensional NMR Spectros-

copy, 4th ed.; Wiley-VCH: Weinheim, 2005; pp 305−333.

(19) Bain, A. D. Prog. Nucl. Magn. Reson. Spectrosc. 2003, 43, 63−103.

(20) Moore, J. W.; Pearson, R. G. Kinetics and Mechanism; Wiley:

New York, 1981; pp 284−333.

(21) Bain, A. D.; Fletcher, D. A. Mol. Phys. 1998, 95, 1091−1098.

(22) Bang, H. B.; Han, S. Y.; Choi, D. H.; Hwang, J. W.; Jun, J.-G.

ARKIVOC 2009, ii, 112−125.

(23) De Capua, A.; Goodman, M.; Amino, Y.; Saviano, M.; Benedetti,

E. ChemBioChem 2006, 7, 377−387.

(24) Jinno, S.; Okita, T. Heterocycles 1999, 51, 303−314.

(25) Planchenault, D.; Dhal, R. Tetrahedron 1995, 51, 1395−1404.

(26) Bolstad, D. B.; Bolstad, E. S. D.; Frey, K. M.; Wright, D. L.;

Anderson, A. C. J. Med. Chem. 2008, 51, 6839−6852.

ACKNOWLEDGMENTS

■

The authors acknowledge ﬁnancial support from Oregon State

University.

REFERENCES

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dx.doi.org/10.1021/jo400157d | J. Org. Chem. 2013, 78, 2881−2896

Article Doi

The garuganin and garugamblin diarylether heptanoids: Total synthesis and determination of chiral properties using dynamic NMR

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