Structural revision of garuganin IV and 1,9′-didesmethylgaruganin III through total synthesis

Article abstract of DOI:10.1021/jo302723n

The chemical structures of garuganin IV and 1,9′-didesmethylgaruganin III were misassigned. The structures were revised on the basis of analysis of the NMR data, and the revisions were verified through total synthesis.

Full text of DOI:10.1021/jo302723n

Note
pubs.acs.org/joc
Structural Revision of Garuganin IV and 1,9′-Didesmethylgaruganin
III through Total Synthesis
Zhi-Qiang Zhu and Christopher M. Beaudry*
Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, Oregon 97331, United States
S
* Supporting Information
ABSTRACT: The chemical structures of garuganin IV and 1,9′-didesmethylgaruganin III were misassigned. The structures were
revised on the basis of analysis of the NMR data, and the revisions were verified through total synthesis.
information was given regarding how the assignments of the
he diarylether heptanoids (DAEHs) are a family of natural
Tproducts characterized by an oxa[1.7]metaparacyclophane individual resonances were made.
We prepared structure 15 and found that the spectral data for
architecture. These natural products display a range of
biological activities1 and have attracted interest from synthetic
chemists.2 Sixteen DAEHs do not possess a stereocenter, but
interestingly, some DAEHs are chiral.3,4 We recently
investigated the relationship between DAEH structure and
chirality.5 Two DAEHs, garuganin IV and 1,9′-didesmethylgar-
uganin III were independently isolated from Garuga pinnata as
optically active compounds,4g,h and we recently published
syntheses of the reported structures.5 However, analysis of the
1H and 13C NMR spectra of these molecules revealed that the
structures had been misassigned. We now report revised
chemical structures for these two natural products. We have
verified our assignments through total synthesis and established
that the molecules are achiral.
The original assignment of garuganin IV (1) was based on
chemical shift calculations and comparison with garugamblin I
(2). The chemical shifts assigned to H2 and H4 were reported
to be nearly the same (see Figure 1 for DAEH numbering6)
and exhibited broadening at 250 and 500 MHz. As a result,
values of the coupling constants were not reported. No
the synthetic material did not match the data for the natural
substance. In an attempt to deduce the true structure of
garuganin IV, we considered the NMR data reported for the
compound. Proton H6 was present as evidenced by its
diagnostic anisotropic upfield shift (δ 5.30 ppm) resulting
from the ring current of the adjacent phenyl ring. The 1H NMR
data also showed the existence of a para-substituted phenyl
ring, four methylenes, and a vinylogous methyl ester.
Furthermore, the geminal methylene protons were chemical
shift inequivalent, which only occurs for E-configured vinyl-
ogous esters with the C9 carbonyl regioisomer.5 Natural
garguanin IV was hydrolyzed to the corresponding vinylogous
acid and assigned as 3,4g which established the presence of the
vinylogous ester functional group. Since we determined
experimentally that the structure of garuganin IV was not
structure 1, and since Sabata and co-workers reported that the
structure was different than garugamblin I,4g we considered the
only other isomeric possibility (5, Figure 1). We surmised that
in the event that H2 and H3 were accidentally chemical shift
equivalent, they would not experience J coupling, and this
would explain the observed shifts and coupling patters
reported. Synthetically, vinylogous ester 5 was envisioned to
arise from vinylogous acid 6, which would allow us to prepare
regio- and stereoisomers of 5 and compare the spectral data of
6 with the data reported for the hydrolysis product of natural
garuganin IV (and assigned as structure 3).
To test this hypothesis, we prepared structure 5. The
synthesis begins with known benzaldehyde 7 (Scheme 1).7 A
standard three-step sequence gave hydrocinnamaldehyde 9.
Aldol addition of 9 to the lithium enolate derived from ketone
Received: December 18, 2012
Published: March 12, 2013
Figure 1. Reported structure of garuganin IV and congeners.
© 2013 American Chemical Society
3336
dx.doi.org/10.1021/jo302723n | J. Org. Chem. 2013, 78, 3336−3341

The Journal of Organic Chemistry
Note
Scheme 1. Synthesis of 5
1
Table 1. H NMR Chemical Shifts for Garuganin IV and Congeners
a
b
b
b
reported
1
2
5
7.36 d (8 Hz, 1 H)
7.05 d (8 Hz, 1 H)
6.84 s (2 H)
7.35 dd (8.3, 1.3 Hz, 1 H)
7.01 dd (8.3, 1.8 Hz, 1 H)
6.84 dd (8.2, 1.4 Hz, 1 H)
6.83 dd (8.2, 1.9 Hz, 1 H)
6.53 t (2.2 Hz, 1 H)
7.37 d (8.2 Hz, 1 H)
7.33 dd (8.3, 2.0 Hz, 1 H)
6.94−6.90 m (2 H)
6.87 dd (8.1, 2.3 Hz, 1 H)
6.84 dd (8.1, 2.0 Hz, 1 H)
6.71 d (8.8 Hz, 1 H)
5.32 s (1 H)
7.06 d (8.1 Hz, 1 H)
6.85 br s (2 H)
6.72 d (8 Hz, 1 H)
6.58 d (8 Hz, 1 H)
5.30 s (1 H)
6.73 d (8.1 Hz, 1 H)
6.60 dd (8.1, 2.1 Hz, 1 H)
5.31 s (1 H)
6.25 br s (1 H)
5.27 s (1 H)
5.30 s (1 H)
5.26 d (2.0 Hz, 1 H)
5.27 d (3.1 Hz, 1 H)
3.97 td (12.9, 3.4 Hz, 1 H)
3.75 s (3 H)
4.02/2.44 m (2 H)
3.94 s (3 H)
4.83 br s (1 H)
4.02 td (12.9, 3.4 Hz, 1 H)
3.93 s (3 H)
4.01 td (12.9, 3.4 Hz, 1 H)
3.78 s (3 H)
3.67 s (3 H)
3.68 s (3 H)
3.69 s (3 H)
3.19/2.91 m (2 H)
3.19/2.26 m (2H)
2.91/2.26 m (2 H)
3.68 s (3 H)
3.20 dd (14.8, 11.6 Hz, 1 H)
2.97 dt (12.8, 4.0 Hz, 1 H)
2.89 td (12.9, 3.1 Hz, 1 H)
2.53 ddd (17.8, 7.3, 1.2 Hz, 1 H)
2.42 ddd (17.9, 11.4, 0.8 Hz, 1 H)
2.31 ddd (12.8, 4.4, 3.4 Hz, 1 H)
2.27 dd (15.2, 7.0 Hz, 1 H)
2.96 dt (12.7, 4.0 Hz, 1 H)
2.86 td (13.0, 2.9 Hz, 2 H)
3.26 dd (14.5, 11.7 Hz, 1 H)
2.96 dt (12.6, 3.9 Hz, 1 H)
2.90 td (12.9, 3.0 Hz, 1 H)
2.50 ddd (17.8, 7.3, 1.5 Hz, 1 H)
2.44 dd (17.6, 11.3 Hz, 1 H)
2.32 dt (12.9, 3.8 Hz, 1 H)
2.27 dd (15.2, 7.0 Hz, 1 H)
2.72 ddd (16.4, 7.1, 1.0 Hz, 1 H)
2.55 ddd (18.2, 7.0, 1.4 Hz, 1 H)
2.42 ddd (18.2, 11.5, 1.1 Hz, 1 H)
2.30 ddd (12.8, 4.4, 3.4 Hz, 1 H)
a
b
CDCl3, 500 MHz. CDCl3, 700 MHz.
10 produced adduct 11. IBX-mediated oxidation8 and removal
of the benzyl ether9 gives bromophenol 12. Ullmann
cyclization10 of 12 gives 6, which did not match the data
reported for the hydrolysis product of the natural substance
(assigned as 3). Furthermore, an unselective kinetic methyl-
ation of 6 gave 13 and 14.2a−c,5 Neither Z-configured
vinylogous ester 13 nor 14 matched the data reported for
garuganin IV. Isomerization of 13 and 14 gave E-configured
regioisomers 5 and 15, respectively. Neither of these structures
had NMR data that matched the reported data for garuganin
IV.
decreasing chemical shift order) reported for garuganin IV,
along with the data for synthetic compounds 1, 2, and 5. The
aromatic region of the spectra (5.0−8.0 ppm) was most useful
in the analysis because many of the signals upfield of 5.0 ppm
were reported as overlapping multiplets. Inspection of the
chemical shift values reveals that the compound isolated and
1
named garuganin IV and garugamblin I (2) have H chemical
shifts that are nearly identical. Isomeric structures 1 and 5 do
not match the reported data. Moreover, the 13C NMR chemical
shifts reported for garuganin IV match the shifts of 2, and the
reported data for 9′-desmethylgaruganin IV (originally assigned
as 3) matches that of 4. We believe that the material isolated
and reported as garuganin IV is garugamblin I (2). Although
We then revisited the NMR data for garuganin IV. Table 1
shows the 1H NMR chemical shifts and multiplicities (in
3337
dx.doi.org/10.1021/jo302723n | J. Org. Chem. 2013, 78, 3336−3341

The Journal of Organic Chemistry
Note
the natural sample was reported to be optically active, we have
previously shown that this molecule is achiral.5
Scheme 2. Synthesis of 18
The assignment of 1,9′-didesmethylgaruganin III as structure
16 (Figure 2) was based on analysis of the 2D NMR data and
1
Table 2. H NMR Chemical Shifts for 1,9′-
Didesmethylgaruganin III, 16, and 18
a
b
b
reported
16
18
7.18 d (8 Hz, 2 H)
6.98 d (8 Hz, 2 H)
6.36 d (1.2 Hz,1 H)
5.15 d (1.2 Hz,1 H)
4.93 s (1 H)
15.17 br s (1 H)
7.17 d (8.3 Hz, 2 H)
6.99 d (8.3 Hz, 2 H)
6.31 br s (1 H)
5.51 br s (1 H)
5.25 d (1.7 Hz, 1 H)
4.94 s (1 H)
15.17 br s (1 H)
7.18 d (8.5 Hz, 2 H)
6.98 d (8.5 Hz, 2 H)
6.37 m (1 H)
Figure 2. Reported structure of 1,9′-didesmethylgaruganin III and
1
congeners. CDCl3, 700 MHz; H NMR chemical shifts for selected
methyl groups; 13C NMR chemical shifts in parentheses.
5.78 s (1 H)
on comparison with garuganin III (17).4h Specifically, the
methyl ether was assigned on the basis of the HMBC
correlation of the methyl protons to C3. We previously
prepared structure 16 and found the data for the synthetic
material did not match the natural product.
4.05 s (3 H)
5.15 d (2.0 Hz, 1 H)
4.93 s (1 H)
3.04 t (6.6 Hz, 2 H)
2.87 m (2 H)
3.87 s (3 H)
4.05 s (3 H)
2.46 t (6.6 Hz, 2 H)
2.34 m (2 H)
3.03 t (6.8 Hz, 2 H)
2.90 m (2 H)
3.04 t (6.8 Hz, 2 H)
2.87 m (2 H)
During the course of our synthesis of the garuganin and
garugamblin DAEHs, we prepared a variety of closely related
chemical structures and acquired their 1H and 13C NMR
spectra. Selected structures are shown in Figure 2 along with
some of their chemical shift data. As evidenced by the
2.45 t (6.8 Hz, 2 H)
2.35 m (2 H)
2.46 t (6.8 Hz, 2 H)
2.33 m (2 H)
a
b
CDCl3, 600 MHz. CDCl3, 700 MHz.
1
tablulated data, the H and 13C chemical shift ranges of all C3-
bound methoxy groups are 3.81−3.88 and 56.0−56.3 ppm,
respectively. Furthermore, the 1H and 13C chemical shifts of the
C2-bound methoxy groups are 3.97 and 61.2 ppm, respectively.
The reported 1H and 13C chemical shifts of the methoxy group
for the natural product assigned as 1,9′-didesmethylgaruganin
III are 4.05 and 61.3 ppm, respectively. These data suggest that
the true structure of the natural substance has the methoxy
group at C2, and the structure of the natural product is 18. We
decided to synthesize structure 18 to verify our prediction.
The synthesis of 18 begins with known gallic acid derivative
19 (Scheme 2).11 Protection of the phenol and subsequent
oxidation state change produced aldehyde 20. Intermediate 20
underwent Horner−Wadsworth−Emmons reaction and reduc-
tion to yield hydrocinnamate 21. Reduction, aldol addition,
oxidation, and debenzylation gave bromophenol 22. Cyclization
of 22 and removal of the isopropyl group leads to structure 18.
Gratifyingly, the spectral data for 18 matches the reported
data for the natural product (Table 2).12 The chemical shifts of
the protons associated with the tetrasubstituted ring are the
most diagnostic. Specifically, the two aryl protons (δ 6.37, 5.15
ppm) match the data of 18 nearly exactly. Furthermore, the
chemical shift of the methyl group (δ 4.05 ppm) in 18 is a
perfect match to the reported data. Finally, the reported 13C
NMR chemical shifts also match compound 18 and do not
match the chemical shifts for 16.
heptanoid numbering schemes, we propose the name garuganin
VII for this natural product to avoid confusion. Additionally,
despite reported optical activity, the molecule displays
enantiotopic geminal methylene protons, which indicates that
it is an achiral molecule.
In conclusion, we have determined that the natural product
assigned as garuganin IV is garugamblin I. The natural product
assigned as 1,9′-didesmethylgaruganin III has structure 18, and
we propose the name garuganin VII for structure 18. Finally,
we previously showed that garugamblin I is achiral, and since
garuganin VII has enantiotopic geminal methylene protons, we
conclude that this structure is also achiral, despite the optical
activities reported for the natural substances.
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.
All combined organic extracts were dried over MgSO4. Column
chromatography was carried out with SiliaFlash P60 silica gel. Thin
layer chromatography was performed using Silica Gel 60 plates.
Tetrahydrofuran (THF), methylene chloride (CH2Cl2) and acetoni-
trile (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 CaH2. 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
Since the natural product is not appropriately named 1,9′-
didesmethylgaruganin III with any of the various diarylether
3338
dx.doi.org/10.1021/jo302723n | J. Org. Chem. 2013, 78, 3336−3341

The Journal of Organic Chemistry
Note
NMR) were recorded in deuterated chloroform (CDCl3) at 700 or
400 MHz as indicated. Melting points are uncorrected.
1-(4-Bromophenyl)-7-(5-hydroxy-2-methoxyphenyl)-
heptane-3,5-dione (12). To a solution of 11 (763 mg, 1.48 mmol)
in EtOAc (15 mL, 0.1 M) at rt was added IBX (1.243 g, 4.44 mmol).
The reaction mixture was heated to reflux for 4 h. The reaction
mixture was cooled to rt, filtered through a pad of silica gel, and
concentrated to give 1-(5-(benzyloxy)-2-methoxyphenyl)-7-(4-
bromophenyl)heptane-3,5-dione, which was used directly without
further purification.
3-(5-(Benzyloxy)-2-methoxyphenyl)propanal (9). To a slurry
of NaH (216 mg, 5.4 mmol) in THF (10 mL, 0.2 M) at 0 °C was
slowly added methyl 2-(diethoxyphosphoryl)acetate (991 μL, 5.4
mmol) over a period of 10 min. After stirring at 0 °C for 30 min, a
solution of 5-(benzyloxy)-2-methoxybenzaldehyde13 (872 mg, 3.6
mmol) in THF (8 mL) was added. The mixture was warmed to rt and
stirred at rt for 30 min. To the above reaction mixture were added
H2O (18 mL), NaOAc (1.181 g, 14.4 mmol) and a solution of
TsNHNH2 (2.011 g, 10.8 mmol) in THF (18 mL) over a period of 30
min at 80 °C. The mixture was stirred for 24 h and then allowed to
cool to rt. The organic phase was separated, and the aqueous phase
was extracted with EtOAc. Purification by flash column chromatog-
raphy (hexanes:EtOAc = 10:1 to 8:1) gave methyl 3-(5-(benzyloxy)-2-
methoxyphenyl)propanoate (S1, 1.07 g, 3.56 mmol, 99% yield, 2
steps) as a light yellow solid. Data for S1: Rf 0.54 (3:1
hexanes:EtOAc); mp = 41−43 °C, IR (thin film) 2949, 1737, 1501,
1223, 1042 cm−1; 1H NMR (700 MHz, CDCl3) δ 7.44 (d, J = 7.6 Hz,
2 H), 7.39 (t, J = 7.6 Hz, 2 H), 7.33 (t, J = 7.3 Hz, 1 H), 6.85 (d, J =
2.9 Hz, 1 H), 6.80 (dd, J = 8.8, 2.9 Hz, 1 H), 6.76 (d, J = 8.8 Hz, 1 H),
5.01 (s, 2 H), 3.79 (s, 3 H), 3.68 (s, 3 H), 2.93 (t, J = 7.9 Hz, 2 H),
2.62 (t, J = 7.9 Hz, 2 H); 13C NMR (176 MHz, CDCl3, HSQC,
DEPT) δ C 173.7, 152.5, 151.9, 137.3, 129.9; CH 128.5, 127.8, 127.4,
117.3, 112.6, 110.9; CH2 70.5, 33.9, 26.2; CH3 55.7, 51.5; HRMS
(TOF MS ES+) calcd for C18H20O4Na [M + Na] 323.1259, found
323.1260.
To a solution of methyl 3-(5-(benzyloxy)-2-methoxyphenyl)-
propanoate (901 mg, 3 mmol) in CH2Cl2 (30 mL, 0.1 M) at −78
°C was added DIBAL-H (3 mL, 3.6 mmol, 1.2 M in toluene) over a
period of 60 min. The reaction was quenched with saturated aqueous
Rochelle’s salt at −78 °C. The mixture was warmed to rt. The organic
phase was separated, and the inorganic phase was extracted with
EtOAc. Purification by flash column chromatography (hexanes:EtOAc
= 5:1) gave 9 (730 mg, 2.7 mmol, 90% yield) as light yellow oil. Data
for 9: Rf 0.46 (3:1 hexanes:EtOAc); IR (thin film) 2834, 1723, 1500,
1222, 1038 cm−1; 1H NMR (700 MHz, CDCl3) δ 9.80 (t, J = 1.6 Hz, 1
H), 7.43 (d, J = 7.5 Hz, 2 H), 7.38 (t, J = 7.6 Hz, 2 H), 7.32 (t, J = 7.3
Hz, 1 H), 6.82 (d, J = 2.9 Hz, 1 H), 6.79 (dd, J = 8.8, 2.9 Hz, 1 H),
6.76 (d, J = 8.8 Hz, 1 H), 5.00 (s, 2 H), 3.78 (s, 3 H), 2.92 (t, J = 7.5
Hz, 2 H), 2.71 (td, J = 7.5, 1.6 Hz, 2 H); 13C NMR (176 MHz, CDCl3,
HSQC, DEPT) δ C 152.6, 151.8, 137.2, 129.8; CH 202.4, 128.5, 127.9,
127.5, 117.4, 112.6, 111.0; CH2 70.6, 43.8, 23.6; CH3 55.6; HRMS
(TOF MS ES+) calcd for C17H19O3 [M + H] 271.1334, found
271.1324.
To a stirred solution of 1-(5-(benzyloxy)-2-methoxyphenyl)-7-(4-
bromophenyl)heptane-3,5-dione (approximately 1.48 mmol) in
CH2Cl2 (15 mL, 0.1 M) were added pentamethylbenzene (658 mg,
4.44 mmol) and BCl3 (5.9 mL, 5.92 mmol, 1 M in DCM) at −78 °C
over a period of 10 min. The reaction was quenched with MeOH at
−78 °C. The mixture was warmed to rt. Diluted aqueous NaHCO3
was added until the aqueous phase had pH 6. The organic phase was
separated, and the aqueous phase was extracted with EtOAc.
Purification by flash column chromatography (hexanes:EtOAc = 5:1
to 3:1) gave 12 (413 mg, 1.02 mmol, 69% yield, 2 steps) as a light
yellow solid. Data for 12: Rf 0.46 (2:1 hexanes:EtOAc); mp = 58−60
°C, IR (thin film) 3380 (br), 1609, 1504, 1439, 1286, 1221, 1033,
1011 cm−1; 1H NMR (700 MHz, CDCl3, enol tautomer) δ 15.42 (br s,
1 H), 7.42 (d, J = 8.2 Hz, 2 H), 7.07 (d, J = 8.3 Hz, 2 H), 6.75−6.63
(m, 3 H), 5.46 (s, 1 H), 5.31 (br s, 1 H), 3.78 (s, 3 H), 2.92−2.76 (m,
4 H), 2.60−2.54 (m, 4 H); 13C NMR (176 MHz, CDCl3, HSQC,
DEPT, enol tautomer) δ C 193.8, 192.7, 151.5, 149.2, 139.6, 119.9;
CH 131.5, 130.0, 117.1, 113.3, 111.4, 99.6; CH2 39.7, 38.1, 30.8, 26.5;
CH3 55.8; HRMS (TOF MS ES+) calcd for C20H22BrO4 [M + H]
405.0701, found 405.0688.
6-Methoxy-2-oxatricyclo[13.2.2.13,7]icosa-1(17),3,5,7-
(20),15,18-hexaene-10,12-dione (6). To a sealed tube were added
12 (20.3 mg, 0.05 mmol), CuBr·Me2S (25.7 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 for 48 h. The mixture was
cooled 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. Purification by flash column chromatography (hexanes:EtOAc
= 8:1 to 6:1) gave 6 (7.6 mg, 0.0234 mmol, 47% yield) as a light
yellow solid. Data for 6: Rf 0.66 (2:1 hexanes:EtOAc); IR (thin film)
1
2930, 1598, 1495, 1215 cm−1; H NMR (700 MHz, CDCl3) δ 15.06
(br s, 1 H), 7.14 (d, J = 8.5 Hz, 2 H), 6.97 (dd, J = 8.8, 3.0 Hz, 1 H),
6.94 (d, J = 8.5 Hz, 2 H), 6.74 (d, J = 8.8 Hz, 1 H), 5.65 (d, J = 3.0 Hz,
1 H), 4.96 (s, 1 H), 3.78 (s, 3 H), 3.01 (t, J = 6.8 Hz, 2 H), 2.91 (m, 2
H), 2.44 (t, J = 6.8 Hz, 2 H), 2.39 (m, 2 H); 13C NMR (176 MHz,
CDCl3, HSQC, DEPT) δ C 197.2, 188.2, 155.8, 155.4, 151.8, 136.1,
130.0; CH 130.5, 122.8, 114.8, 114.5, 110.6, 103.0; CH2 39.5, 36.4,
32.2, 21.6; CH3 55.8; HRMS (TOF MS ES+) calcd for C20H21O4 [M
+ H] 325.1440, found 325.1437.
7-(5-(Benzyloxy)-2-methoxyphenyl)-1-(4-bromophenyl)-5-
hydroxyheptan-3-one (11). To a solution of diisopropylamine (316
mg, 3.12 mmol) in THF (13 mL, 0.1 M) at 0 °C was added n-BuLi
(1.95 mL, 3.12 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 4-(4-bromophenyl)butan-2-one14 (681 mg, 3 mmol) in
THF (6 mL) was added over a period of 30 min. After stirring at −78
°C for 30 min, a solution of aldehyde 9 (676 mg, 2.5 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. The organic
phase was separated, and the inorganic phase was extracted with
EtOAc. Purification by flash column chromatography (hexanes:EtOAc
= 5:1 to 5:2) gave 11 (946 mg, 1.9 mmol, 76% yield) as a white solid.
Data for 11: Rf 0.43 (2:1 hexanes:EtOAc); mp = 62−64 °C, IR (thin
E-6,12-Dimethyl-2-oxatricyclo[13.2.2.13,7]icosa-1(17),3,5,7-
(20),11,15,18-heptaen-10-one (5). To a solution of 6 (16.2 mg,
0.05 mmol) in a mixed solvent of CH3CN and MeOH (5 mL, 0.01 M,
10:1 v/v) was added TMSCHN2 (0.25 mL, 0.5 mmol, 2 M in
hexanes). After 4 h, the solvent was removed under reduced pressure.
Purification by flash column chromatography (hexanes:EtOAc = 5:1 to
3:1) gave 13 (8.1 mg, 0.0239 mmol, 48% yield, white solid, more
polar) and 14 (8.0 mg, 0.0236 mmol, 47% yield, white solid, less
polar). Treating 13 and 14 with dry acidic CDCl3 (“old” CDCl3 dried
by 3 Å MS) at rt (about 5 min) gave 5 and 15, respectively, in >99%
yield. Data for 5: white solid, Rf 0.63 (2:1 hexanes:EtOAc); IR (thin
film) 2934, 1683, 1587, 1496, 1212, 1097 cm−1; 1H NMR (700 MHz,
CDCl3) δ 7.33 (dd, J = 8.3, 2.0 Hz, 1 H), 6.94−6.90 (m, 2 H), 6.87
(dd, J = 8.1, 2.3 Hz, 1 H), 6.84 (dd, J = 8.1, 2.0 Hz, 1 H), 6.71 (d, J =
8.8 Hz, 1 H), 5.32 (s, 1 H), 5.27 (d, J = 3.1 Hz, 1 H), 3.97 (td, J =
12.9, 3.4 Hz, 1 H), 3.75 (s, 3 H), 3.69 (s, 3 H), 2.96 (dt, J = 12.7, 4.0
Hz, 1 H), 2.86 (td, J = 13.0, 2.9 Hz, 2 H), 2.72 (ddd, J = 16.4, 7.1, 1.0
Hz, 1 H), 2.55 (ddd, J = 18.2, 7.0, 1.4 Hz, 1 H), 2.42 (ddd, J = 18.2,
11.5, 1.1 Hz, 1 H), 2.30 (ddd, J = 12.8, 4.4, 3.4 Hz, 1 H); 13C NMR
(176 MHz, CDCl3, HSQC, DEPT) δ C 196.9, 172.8, 156.3, 156.2,
151.3, 137.6, 130.8; CH 131.2, 129.9, 124.2, 122.1, 116.8, 113.8, 110.9,
101.0; CH2 43.9, 33.9, 33.0, 19.9; CH3 56.1, 55.2; HRMS (TOF MS
1
film) 3500 (br), 2928, 1709, 1499, 1222, 1042 cm−1; H NMR (700
MHz, CDCl3) δ 7.44−7.36 (m, 6 H), 7.32 (t, J = 7.3 Hz, 1 H), 7.04 (d,
J = 8.4 Hz, 2 H), 6.82 (d, J = 2.5 Hz, 1 H), 6.77 (dd, J = 8.8, 2.6 Hz, 1
H), 6.76 (d, J = 8.8 Hz, 1 H), 5.00 (s, 2 H), 3.99 (m, 1 H), 3.77 (s, 3
H), 3.09 (br s, 1 H), 2.84 (t, J = 7.3 Hz, 2 H), 2.76−2.67 (m, 4 H),
2.57−2.49 (m, 2 H), 1.78−1.71 (m, 1 H), 1.69−1.63 (m, 1 H); 13C
NMR (176 MHz, CDCl3, HSQC, DEPT) δ C 210.2, 152.8, 151.7,
139.8, 137.2, 131.1, 119.9; CH 131.5, 130.1, 128.5, 127.8, 127.5, 117.4,
112.3, 111.2, 66.9; CH2 70.5, 49.3, 44.8, 36.7, 28.7, 26.0; CH3 55.9;
HRMS (TOF MS ES+) calcd for C27H30BrO4 [M + H] 497.1327,
found 497.1321.
3339
dx.doi.org/10.1021/jo302723n | J. Org. Chem. 2013, 78, 3336−3341

The Journal of Organic Chemistry
Note
ES+) calcd for C21H23O4 [M + H] 339.1596, found 339.1581. Data for
13C NMR (176 MHz, CDCl3, HSQC, DEPT) δ C 173.3, 152.6, 151.7,
15: white solid, Rf 0.37 (2:1 hexanes:EtOAc); IR (thin film) 2935,
138.9, 137.3, 135.8; CH 128.5, 127.7, 127.2, 109.8, 107.9, 71.6; CH2
71.2, 35.8, 31.1; CH3 60.7, 51.6, 22.2; HRMS (EI+) calcd for
C21H26O5 [M] 358.1780, found 358.1789.
1
1668, 1564, 1496, 1214 cm−1; H NMR (700 MHz, CDCl3) δ 7.30−
7.25 (m, 2 H), 6.95−6.89 (m, 3 H), 6.71 (d, J = 8.8 Hz, 1 H), 5.23 (d,
J = 3.0 Hz, 1 H), 5.18 (s, 1 H), 3.77 (s, 3 H), 3.43 (s, 3 H), 3.08 (t, J =
7.0 Hz, 2 H), 3.06−2.40 (m, 6 H); 13C NMR (176 MHz, CDCl3,
HSQC, DEPT) δ C 198.8 174.1, 155.9, 154.6, 151.6, 137.2, 130.1; CH
131.3, 123.4, 112.9, 112.7, 110.2, 101.9; CH2 44.3, 31.2, 28.1, 21.6;
CH3 55.7, 55.6; HRMS (TOF MS ES+) calcd for C21H23O4 [M + H]
339.1596, found 339.1583.
3-(Benzyloxy)-5-isopropoxy-4-methoxybenzaldehyde (20).
To a solution of methyl 3-(benzyloxy)-5-hydroxy-4-methoxyben-
zoate15 (577 mg, 2 mmol) in DMF (20 mL, 0.1 M) was added
K2CO3 (415 mg, 3 mmol) and 2-bromopropane (284 μL, 3 mmol).
The mixture was heated to 80 °C for 6 h. The mixture was cooled to rt
and poured into 50 mL of H2O. The resultant mixture was extracted
with Et2O. Purification by flash column chromatography (hexanes:E-
tOAc = 8:1) gave methyl 3-(benzyloxy)-5-isopropoxy-4-methoxyben-
zoate (S2, 648 mg, 1.96 mmol, 98% yield) as a white solid. Data for
S2: Rf 0.64 (2:1 hexanes:EtOAc); mp = 76−78 °C, IR (thin film)
2978, 1721, 1588, 1500, 1428, 1327, 1117, 1009 cm−1; 1H NMR (700
MHz, CDCl3) δ 7.48−7.29 (m, 7 H), 5.15 (s, 2 H), 4.61 (sept, J = 6.1
Hz, 1 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 1.37 (d, J = 6.1 Hz, 6 H); 13C
NMR (176 MHz, CDCl3, HSQC, DEPT) δ C 166.7, 152.3, 151.4,
144.3, 136.7, 124.9; CH 128.5, 128.0, 127.4, 110.7, 108.6, 71.6; CH2
71.0; CH3 60.8, 52.2, 22.1; HRMS (EI+) calcd for C19H22O5 [M]
330.1467, found 330.1464.
1-(4-Bromophenyl)-7-(3-hydroxy-5-isopropoxy-4-methoxy-
phenyl)heptane-3,5-dione (22). To a solution of 21 (1.326 g, 3.7
mmol) in CH2Cl2 (37 mL, 0.1 M) at −78 °C was added DIBAL-H
(3.7 mL, 4.44 mmol, 1.2 M in toluene) over a period of 60 min. The
reaction was quenched with saturated aqueous Rochelle’s salt at −78
°C and warmed to rt. The organic phase was separated, and the
inorganic phase was extracted with EtOAc. Purification by flash
column chromatography (hexanes:EtOAc = 5:1) gave 3-(3-(benzyl-
oxy)-5-isopropoxy-4-methoxyphenyl)propanal (S3, 1.022 g, 3.11
mmol, 84% yield) as a light yellow oil. Data for S3: Rf 0.61 (2:1
hexanes:EtOAc); IR (thin film) 2976, 1723, 1588, 1503, 1435, 1237,
1117, 1010 cm−1; 1H NMR (700 MHz, CDCl3) δ 9.78 (t, J = 1.4 Hz, 1
H), 7.46−7.29 (m, 5 H), 6.43 (s, 2 H), 5.10 (s, 2 H), 4.52 (sept, J =
6.1 Hz, 1 H), 3.84 (s, 3 H), 2.84 (t, J = 7.5 Hz, 2 H), 2.71 (td, J = 7.5,
1.1 Hz, 2 H), 1.35 (d, J = 6.1 Hz, 6 H); 13C NMR (176 MHz, CDCl3,
HSQC, DEPT) δ C 152.6, 151.7, 138.9, 137.2, 135.6; CH 201.4, 128.4,
127.7, 127.2, 109.9, 108.0, 71.6; CH2 71.2, 45.2, 28.2; CH3 60.6, 22.2;
HRMS (EI+) calcd for C20H24O4 [M] 328.1675, found 328.1672.
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 4-(4-bromophenyl)-
butan-2-one (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 3-
(3-(benzyloxy)-5-isopropoxy-4-methoxyphenyl)propanal (657 mg, 2
mmol) in THF (6 mL) was added over a period of 30 min. After 2 h,
the reaction was quenched with saturated aqueous NH4Cl. The
organic phase was separated, and the inorganic phase was extracted
with EtOAc. Purification by flash column chromatography (hexane-
s:EtOAc = 5:1 to 3:1) gave 7-(3-(benzyloxy)-5-isopropoxy-4-
methoxyphenyl)-1-(4-bromophenyl)-5-hydroxyheptan-3-one (S4, 808
mg, 1.45 mmol, 73% yield) as a colorless oil. Data for S4: Rf 0.29 (2:1
hexanes:EtOAc); IR (thin film) 3501 (br), 2975, 2931, 1709, 1587,
1501, 1489, 1434, 1237, 1116, 1011 cm−1; 1H NMR (700 MHz,
CDCl3) δ 7.44 (d, J = 7.4 Hz, 2 H), 7.41−7.34 (m, 4 H), 7.30 (t, J =
7.4 Hz, 1 H), 7.04 (d, J = 8.3 Hz, 2 H), 6.43 (s, 2 H), 5.10 (s, 2 H),
4.52 (sept, J = 6.1 Hz, 1 H), 4.00 (m, 1 H), 3.84 (s, 3 H), 3.02 (br s, 1
H), 2.84 (t, J = 7.5 Hz, 2 H), 2.75−2.65 (m, 3 H), 2.58−2.46 (m, 3
H), 1.77−1.70 (m, 1 H), 1.63−1.56 (m, 1 H), 1.35 (dd, J = 6.1, 1.4
Hz, 6 H); 13C NMR (176 MHz, CDCl3, HSQC, DEPT) δ C 210.6,
152.5, 151.5, 139.6, 138.4, 137.3, 137.0, 119.9; CH 131.5, 130.0, 128.4,
127.7, 127.2, 109.8, 107.8, 71.4, 66.7; CH2 71.0, 49.2, 44.6, 37.9, 31.8,
28.7; CH3 60.7, 22.2; HRMS (TOF MS ES+) calcd for C30H36BrO5
[M + H] 555.1746, found 555.1730.
To a solution of 7-(3-(benzyloxy)-5-isopropoxy-4-methoxyphenyl)-
1-(4-bromophenyl)-5-hydroxyheptan-3-one (389 mg, 0.7 mmol) in
EtOAc (7 mL, 0.1 M) at rt was added IBX (588 mg, 2.1 mmol). The
reaction mixture was heated to reflux for 4 h. The mixture was cooled
to rt, filtered through a pad of silica gel, and concentrated to give 1-(3-
(benzyloxy)-5-isopropoxy-4-methoxyphenyl)-7-(4-bromophenyl)-
heptane-3,5-dione, which was used without further purification.
To a stirred solution of 1-(3-(benzyloxy)-5-isopropoxy-4-methox-
yphenyl)-7-(4-bromophenyl)heptane-3,5-dione (from above, approx-
imately 0.7 mmol) in CH2Cl2 (14 mL, 0.05 M) were added
pentamethylbenzene (311 mg, 2.1 mmol) and BCl3 (2.8 mL, 2.8
mmol, 1 M in DCM) at −78 °C over a period of 10 min. The reaction
was quenched with MeOH at −78 °C. The mixture was warmed to rt.
Diluted aqueous NaHCO3 was added until the aqueous phase had pH
6. The organic phase was separated, and the aqueous phase was
extracted with EtOAc. Purification by flash column chromatography
(hexanes:EtOAc = 5:1 to 3:1) gave 22 (227 mg, 0.49 mmol, 70% yield,
2 steps) as a light yellow oil. Data for 22: Rf 0.56 (2:1
Hexanes:EtOAc); IR (thin film) 3432 (br), 2976, 2932, 1592, 1507,
1489, 1368, 1330, 1195, 1115, 1073, 1011 cm−1; 1H NMR (700 MHz,
CDCl3, enol tautomer) δ 15.41 (br s, 1 H), 7.39 (d, J = 8.3 Hz, 2 H),
7.05 (d, J = 8.3 Hz, 2 H), 6.40 (d, J = 1.9 Hz, 1 H), 6.28 (d, J = 1.9 Hz,
To a solution of methyl 3-(benzyloxy)-5-isopropoxy-4-methox-
ybenzoate (661 mg, 2 mmol) in CH2Cl2 (20 mL, 0.1 M) at −78 °C
was added DIBAL-H (4 mL, 4.8 mmol, 1.2 M in toluene) over a
period of 10 min. The mixture was warmed to rt and quenched with
saturated aqueous Rochelle’s salt. The organic phase was separated,
and the inorganic phase was extracted with EtOAc. Concentration
gave (3-(benzyloxy)-5-isopropoxy-4-methoxyphenyl)methanol, which
was used without further purification.
To a solution of (3-(benzyloxy)-5-isopropoxy-4-methoxyphenyl)-
methanol (from above, about 2 mmol) in CH2Cl2 (10 mL, 0.2 M) at 0
°C was added DMP (1.272 g, 3 mmol). After stirring at 0 °C for 30
min, the reaction was quenched with diluted aqueous NaHCO3 (20
mL, to pH 7). The organic phase was separated. The aqueous phase
was extracted with EtOAc. Purification by flash column chromatog-
raphy (hexanes:EtOAc = 8:1) gave 20 (560 mg, 1.86 mmol, 93% yield,
2 steps) as a light yellow oil. Data for 20: Rf 0.69 (2:1 hexanes:EtOAc);
IR (thin film) 2978, 1694, 1583, 1496, 1440, 1385, 1323, 1235, 1116,
1
1006 cm−1; H NMR (700 MHz, CDCl3) δ 9.80 (s, 1 H), 7.47−7.31
(m, 5 H), 7.14 (d, J = 1.8 Hz, 1 H), 7.13 (d, J = 1.8 Hz, 1 H), 5.18 (s, 2
H), 4.63 (sept, J = 6.1 Hz, 1 H), 3.94 (s, 3 H), 1.39 (d, J = 6.1 Hz, 6
H); 13C NMR (176 MHz, CDCl3, HSQC, DEPT) δ C 153.0, 152.2,
145.8, 136.6, 131.6; CH 191.0, 128.6, 128.1, 127.3, 110.6, 108.6, 71.8;
CH2 71.2; CH3 60.8, 22.1; HRMS (EI+) calcd for C18H20O4 [M]
300.1362, found 300.1372.
Methyl 3-(3-(benzyloxy)-5-isopropoxy-4-methoxyphenyl)-
propanoate (21). To a slurry of NaH (180 mg, 4.5 mmol, 60% oil
dispersion) in THF (8 mL, 0.2 M) at 0 °C was slowly added methyl 2-
(diethoxyphosphoryl)acetate (826 μL, 4.5 mmol) over a period of 10
min. After stirring at 0 °C for 30 min, a solution of 20 (901 mg, 3
mmol) in THF (7 mL) was added. The mixture was warmed to rt and
stirred for 30 min. The reaction was quenched with H2O (15 mL).
To the above mixture were added NaOAc (984 mg, 12 mmol) and a
solution of TsNHNH2 (1.676 g, 9 mmol) in THF (15 mL) over a
period of 30 min. The mixture was heated to 80 °C for 24 h. The
mixture was cooled to rt. The organic phase was then separated, and
the inorganic phase was extracted with EtOAc. Purification by flash
column chromatography (hexanes:EtOAc = 10:1 to 8:1) gave 21 (1.07
g, 2.99 mmol, >99% yield, 2 steps) as a colorless oil. Data for 21: Rf
0.69 (2:1 hexanes:EtOAc); IR (thin film) 2976, 1738, 1588, 1503,
1
1435, 1237, 1117, 1010 cm−1; H NMR (700 MHz, CDCl3) δ 7.46−
7.28 (m, 5 H), 6.44 (d, J = 1.9 Hz, 1 H), 6.43 (d, J = 1.9 Hz, 1 H), 5.10
(s, 2 H), 4.51 (sept, J = 6.1 Hz, 1 H), 3.84 (s, 3 H), 3.66 (s, 3 H), 2.83
(t, J = 7.8 Hz, 2 H), 2.57 (t, J = 7.8 Hz, 2 H), 1.35 (d, J = 6.1 Hz, 3 H);
3340
dx.doi.org/10.1021/jo302723n | J. Org. Chem. 2013, 78, 3336−3341

The Journal of Organic Chemistry
Note
1 H), 5.80 (br s, 1 H), 5.42 (s, 1 H), 4.57−4.49 (m, 1 H), 3.87 (s, 3
H), 2.89−2.73 (m, 4 H), 2.58−2.51 (m, 4 H); 13C NMR (176 MHz,
CDCl3, HSQC, DEPT, enol tautomer) δ C 192.9, 192.7, 150.2, 149.3,
139.5, 136.5, 134.8, 119.9; CH 131.5, 130.0, 107.3, 107.1, 99.7, 70.7;
CH2 39.8, 39.7, 31.5, 30.8; CH3 60.7, 22.1; HRMS (TOF MS ES+)
calcd for C23H26BrO4 [M + H − H2O] 445.1014, found 445.1020.
Garuganin VII (18). To a sealed tube were added 22 (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 at 130 °C for 48 h. The mixture was cooled 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. Purification
by flash column chromatography (hexanes:EtOAc = 8:1 to 6:1) gave
isopropylgaruganin VII (S5, 8.6 mg, 0.0225 mmol, 45% yield) as a
light yellow solid. Data for S5: Rf 0.64 (2:1 Hexanes:EtOAc); IR (thin
film) 2974, 2931, 1587, 1504, 1436, 1215, 1113, 1064 cm−1; 1H NMR
(700 MHz, CDCl3) δ 15.15 (s, 1 H), 7.16 (d, J = 8.4 Hz, 2 H), 6.98 (d,
J = 8.4 Hz, 2 H), 6.32 (d, J = 1.7 Hz, 1 H), 5.23 (d, J = 2.0 Hz, 1 H),
4.94 (s, 1 H), 4.52 (sept, J = 6.1 Hz, 1 H), 3.95 (s, 3 H), 3.03 (t, J = 6.8
Hz, 2 H), 2.89 (m, 2 H), 2.45 (t, J = 6.8 Hz, 2 H), 2.35 (m, 2 H), 1.36
(d, J = 6.1 Hz, 6 H); 13C NMR (176 MHz, CDCl3, HSQC, DEPT) δ
C 196.9, 188.7, 155.2, 154.8, 151.4, 137.4, 136.5, 136.2; CH 130.5,
123.1, 109.3, 107.0, 103.1, 71.5; CH2 39.4, 37.6, 32.2, 28.0; CH3 61.0,
22.2; HRMS (TOF MS ES+) calcd for C23H27O5 [M + H] 383.1858,
found 383.1866.
To a solution of isopropylgaruganin VII (8.4 mg, 0.022 mmol) in
DCM (2 mL, 0.011 M) was added BCl3 (33 μL, 0.033 mmol) at 0 °C.
The mixture was allowed to warm to rt. The reaction was then
quenched with MeOH and stirred for 10 min. The solvent was
evaporated under reduced pressure. Purification by flash column
chromatography (hexanes:EtOAc = 6:1 to 4:1) gave garuganin VII
(6.5 mg, 0.0191 mmol, 87% yield) as a white solid. Data for garuganin
VII: Rf 0.51 (2:1 hexanes:EtOAc); IR (thin film) 3346 (br), 2932,
1587, 1504, 1347, 1215, 1044, 995 cm−1; 1H NMR (700 MHz,
CDCl3) δ 15.17 (br s, 1 H), 7.18 (d, J = 8.5 Hz, 2 H), 6.98 (d, J = 8.5
Hz, 2 H), 6.37 (m, 1 H), 5.78 (s, 1 H), 5.15 (d, J = 2.0 Hz, 1 H), 4.93
(s, 1 H), 4.05 (s, 3 H), 3.04 (t, J = 6.8 Hz, 2 H), 2.87 (m, 2 H), 2.46 (t,
J = 6.8 Hz, 2 H), 2.33 (m, 2 H); 13C NMR (176 MHz, CDCl3, HSQC,
DEPT) δ C 196.9, 188.7, 154.2, 153.8, 149.0, 137.1, 136.8, 133.6; CH
130.6, 123.0, 108.2, 106.2, 103.1; CH2 39.4, 37.7, 32.2, 27.8; CH3 61.3;
HRMS (TOF MS ES+) calcd for C20H21O5 [M + H] 341.1389, found
341.1390.
(2) (a) Keseru, G. M.; Dienes, Z.; Nog
́
rad
́
i, M.; Kajtar
́
-Peredy, M. J.
̈
Org. Chem. 1993, 58, 6725−6728. (b) Kumar, G. D. K.; Natarajan, A.
Tetrahedron Lett. 2008, 49, 2103−2105. (c) Vermes, B.; Keseru, G. M.;
̂
́ ́ ́ ́
Mezey-Vandor, G.; Nogradi, M.; Toth, G. Tetrahedron 1993, 49,
4893−4900. (d) Islas Gonzalez, G.; Zhu, J. J. Org. Chem. 1999, 64,
914−924. (e) Jeong, B.-S.; Wang, Q.; Son, J.-K.; Jahng, Y. Eur. J. Org.
Chem. 2007, 1338−1344.
(3) For review of the diarylether heptanoids, see: Zhu, J.; Islas-
Gonzalez, G.; Bois-Choussy, M. Org. Prep. Proced. Int. 2000, 32, 505−
546.
(4) (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,
̊
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.
(5) Zhu, Z.-Q.; Salih, M. Q.; Fynn, E.; Bain, A. D.; Beaudry, C. M. J.
Org. Chem. 2013, DOI: 10.1021/jo400157d.
(6) Of the multiple numbering systems for the DAEHs, we choose to
use the system adopted by Nagai. See ref 4c.
(7) Chan, D. C. M.; Fu, H.; Forsch, R. A.; Queener, S. F.; Rosowsky,
A. J. Med. Chem. 2005, 48, 4420−4431.
(8) (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.
(9) Okano, K.; Okuyama, K.-i.; Fukuyama, T.; Tokuyama, H. Synlett
2008, 13, 1977−1980.
(10) Ullmann, F.; Sponagel, P. Ber. Dtsch. Chem. Ges. 1905, 38,
2211−2212.
ASSOCIATED CONTENT
■
(11) Alam, A.; Takaguchi, Y.; Ito, H.; Yoshida, T.; Tsuboi, S.
Tetrahedron 2005, 61, 1909−1918.
S
* Supporting Information
1
Depiction of H and 13C NMR spectra of all new compounds.
1
(12) The H NMR spectrum of synthetic 18 displays two hydroxyl
This material is available free of charge via the Internet at
http://pubs.acs.org.
resonances that did not appear in the spectrum of the natural material.
(13) Chan, D. C. M.; Fu, H.; Forsch, R. A.; Queener, S. F.;
Rosowsky, A. J. Med. Chem. 2005, 48, 4420−4431.
(14) 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.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: christopher.beaudry@oregonstate.edu.
(15) Alam, A.; Takaguchi, Y.; Ito, H.; Yoshida, T.; Tsuboi, S.
Notes
Tetrahedron 2005, 61, 1909−1918.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support from Oregon State
University.
REFERENCES
■
(1) (a) Ishida, J.; Kozuka, M.; Tokuda, H.; Nishino, H.; Nagumo, S.;
Lee, K.-H.; Nagai, M. Bioorg. Med. Chem. 2002, 10, 3361−3365.
(b) Bryant, V. C.; Kumar, G. D. K.; Nyong, A. M.; Natarajan, A.
Bioorg. Med. Chem. Lett. 2012, 22, 245−248. (c) Takahashi, M.;
Fuchino, H.; Sekita, S.; Satake, M. Phytother. Res. 2004, 18, 573−578.
3341
dx.doi.org/10.1021/jo302723n | J. Org. Chem. 2013, 78, 3336−3341