Total Syntheses of Urgineanins A, B, D, and Their Analogues

Article abstract of DOI:10.1055/s-0036-1588105

The first asymmetric total syntheses of urgineanins A, B, and D - potent antiproliferative homoisoflavonoids - were achieved by utilizing Pd-catalyzed allylic substitution of the allylic acetate with arylboronic acids for introduction of the C rings of ho

Full text of DOI:10.1055/s-0036-1588105

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
D. K. Singh et al.
Paper
Synthesis
Total Syntheses of Urgineanins A, B, D, and Their Analogues
Dileep Kumar Singh
Youngeun Jung
Ikyon Kim*
OMe
O
OMe
OH
MeO
MeO
MeO
MeO
O
OMe
OH
College of Pharmacy and Yonsei Institute of
Pharmaceutical Sciences, Yonsei University,
85 Songdogwahak-ro, Yeonsu-gu, Incheon
21983, Republic of Korea
(+)-urgineanin A
8 steps in 32% overall yield
Pd-catalyzed allylic arylation
ikyonkim@yonsei.ac.kr
Received: 10.09.2016
Accepted after revision: 01.11.2016
Published online: 28.11.2016
synthetic approach to a tetracyclic homoisoflavanoid, bra-
zilin, by employing Pd-catalyzed allylic arylation (1 to 2) as
a key step (Scheme 1, a).5 As oxidation of the olefinic bond
in 2 or 3 would lead to homoisoflavonoids, we decided to
embark on the total syntheses of urgineanins via 3 (Scheme
1, b). Introduction of the C ring in 3 via allylic substitution
required allylic acetate 4, which would be readily available
from 3,4,5-trimethoxyphenol. Here we wish to describe our
results.
DOI: 10.1055/s-0036-1588105; Art ID: ss-2016-h0625-op
Abstract The first asymmetric total syntheses of urgineanins A, B, and
D – potent antiproliferative homoisoflavonoids – were achieved by uti-
lizing Pd-catalyzed allylic substitution of the allylic acetate with arylbo-
ronic acids for introduction of the C rings of homoisoflavonoid skeleton.
Several unnatural urgineanin analogues were also prepared in this man-
ner.
Keywords homoisoflavonoid, natural product, Pd catalysis, allylic ary-
lation, anticancer agent
OMe
OMe
MeO
MeO
OAc
Pd-catalyzed
allylic arylation
(a)
H
Homoisoflavonoids, an important subset of flavonoid
natural products, have been reported to exhibit various bio-
logical functions including antioxidant, antiviral, and anti-
angiogenic activities.1,2 Not surprisingly, they have been
one of the main resources for structure–activity relation-
ship (SAR) studies to discover new therapeutic agents. Syn-
theses of homoisoflavonoids mainly rely on Claisen–
Schmidt condensation to install various benzyl side chains.3
Since it is employed at an early stage of the synthesis, the
remaining synthetic steps have to be carried out separately
for each homoisoflavonoid, which may hamper rapid gen-
eration of homoisoflavonoid-based chemical library. Thus,
more efficient route is required to allow for a late-stage di-
versification.
MeO
O
O
OH
MeO
O
1
MeO
O
2
trimethyl ether
of brazilin
OMe
OMe
oxidation
OH
MeO
MeO
R2
MeO
MeO
R2
(b)
A
B
C
O
R1
O
R1
Pd-catalyzed
urgineanin A (R1 = OMe, R2 = H)
urgineanin B (R1 = R2 = H)
urgineanin D (R1, R2 = OCH2O)
3
allylic arylation
OMe
OAc
OMe
MeO
MeO
MeO
MeO
O
OH
4
In 2013, Kingston and co-workers reported the isolation
of six new bioactive homoisoflavonoids, urgineanins A–F,
from the South African plant Urginea depressa Baker (As-
paragaceae Juss.).4 Biological evaluation revealed that five
of them had good antiproliferative activity against several
cancer cell lines. Particularly, urgineanin A exhibits the
most potent anticancer activity with submicromolar IC50
values. Recently, we have communicated on the concise
Scheme 1 Retrosynthetic plan for urgineanins A, B, and D
We began our study by preparing the allylic acetate 4.
As shown in Scheme 2, propargylation of 3,4,5-trimethoxy-
phenol and thermal cycloisomerization6 provided
chromene 67 in 72% overall yield. Subsequent Vilsmeier–
Haack formylation allowed for regioselective installation of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
D. K. Singh et al.
Paper
Synthesis
OMe
OMe
OMe
PhNEt2
K2CO3
250 °C, 3 h
propargyl bromide
MeO
MeO
MeO
MeO
MeO
MeO
75%
95%
O
O
OH
5
6
OMe
OMe
OAc
POCl3
DMF
1) NaBH4
MeO
MeO
CHO
MeO
0 °C
95%
2) Ac2O
Et3N
O
MeO
O
7
4
95% (two steps)
Scheme 2 Synthesis of allylic acetate 4
a formyl group at the C3 position of the chromene 6 to fur-
nish 7. Reduction and acetylation led to the allylic acetate 4
in 95% yield.
Coupling of 4 with 4-methoxyphenylboronic acid in the
presence of Pd(PPh3)4 and K3PO4 in THF at 100 °C delivered
the desired product 3a in good yield (Scheme 3).8 No
branched regiosiomer was observed. Only linear isomer 3a
was isolated in 79% yield. Anhydrous K3PO4 was crucial in
obtaining a good yield. For the syntheses of other urginean-
ins and their analogues, several boronic acids were allowed
to react with 4 under the same conditions to afford the cor-
responding adducts. Electron-rich arylboronic acids as well
as electron-deficient arylboronic acids were well tolerated.
Alkene 3a was converted into (+)-urgineanin A through
dihydroxylation and IBX oxidation9 (Scheme 4).
At this point, asymmetric dihydroxylation10 of 3 was at-
tempted in order to make an optically active urgineanin A.
While (+)-8a was obtained in 19:81 er with (DHQ)2PHAL li-
gand, use of (DHQD)2PHAL led to (–)-8a in 89:11 er.11 Sub-
sequent oxidation of each diol with IBX provided (+)-urgin-
eanin A and its enantiomer in good yields. Similarly, urgine-
anins B and D as well as several analogues were prepared12
(Scheme 5).
OMe
OMe
OAc
ArB(OH)2
MeO
MeO
MeO
MeO
Ar
cat. Pd(PPh3)4
K3PO4
O
O
THF, 100 °C
In summary, we have established a highly efficient syn-
thetic route to urgineanins – highly potent anticancer ho-
moisoflavonoid natural products – by utilizing Pd-cata-
lyzed allylic substitution with arylboronic acids as a means
to incorporate the diverse C ring moieties. The requisite
coupling precursor, allylic acetate 4, was rapidly derived
4
3a (Ar = 4-MeOC6H4): 79%
3b (Ar = Ph): 79%
3c (Ar = 3,4-(OCH2O)C6H3): 89%
3d (Ar = 3,5-(MeO)2C6H3): 81%
3e (Ar = 4-ClC6H4): 76%
3f (Ar = 4-NO2C6H4): 92%
Scheme 3 Pd-catalyzed allylic arylation of 4
OMe
O
OMe OH
OMe
MeO
cat. OsO4
NMO
OH
OH
IBX
MeO
MeO
MeO
MeO
68%
0 °C
78%
O
OMe
O
OMe
MeO
O
OMe
3a
8a
( )-urgineanin A
Scheme 4 Synthesis of (+)-urgineanin A
OMe
O
O
OMe OH
OH
OMe
MeO
cat. OsO4
(DHQ)2PHAL
OH
IBX
MeO
MeO
MeO
Ar
Ar
Ar
K3Fe(CN)6
K2CO3
MeO
O
MeO
O
MeSO2NH2
0 °C
(+)-urgineanin A (76%)
(+)-urgineanin B (72%)
(+)-urgineanin D (68%)
9 (84%)
10 (78%)
11 (80%)
(+)-8a (82%)
(+)-8b (72%)
(+)-8c (82%)
(+)-8d (53%)
(+)-8e (64%)
(+)-8f (80%)
3a–f
OMe
O
O
OMe OH
OMe
cat. OsO4
(DHQD)2PHAL
OH
OH
IBX
MeO
MeO
MeO
MeO
MeO
MeO
Ar
Ar
Ar
K3Fe(CN)6
K2CO3
O
O
MeSO2NH2
0 °C
(–)-urgineanin A (72%)
(–)-8a (85%)
3a
Scheme 5 Asymmetric approaches to urgineanins and their analogues
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
D. K. Singh et al.
Paper
Synthesis
from 3,4,5-trimethoxyphenol through a series of high-
yielding steps. The route described herein should be gener-
al enough for ready access to a wide variety of homoisofla-
vonoid compounds. Further studies to apply this sequence
to other carbo- and heterocycle synthesis are ongoing in
our laboratory.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C12H14O4Na: 245.0784;
found: 245.0784.
5,6,7-Trimethoxy-2H-chromene-3-carbaldehyde (7)
To a stirred solution of 6 (450 mg, 2.0 mmol) in DMF (2 mL) was add-
ed dropwise a mixture of POCl3 (1.9 mL, 20 mmol, 10 equiv) and DMF
(1.6 mL, 20 mmol, 10 equiv) at 0 °C. After stirring for 3 h, the reaction
mixture was quenched by adding H2O (5 mL) dropwise at 0 °C. The
mixture was basified with aq NaOH (pH ~8) and extracted with EtOAc
(10 mL). The aqueous layer was extracted with EtOAc (2 × 10 mL). The
combined organic layers were dried (MgSO4) and concentrated in
vacuo and the residue thus obtained was purified by silica gel column
chromatography (hexanes–EtOAc = 9:1) to give 7 (483 mg, 95%) as a
yellow solid; mp 94.1–95.2 °C.
Unless specified, all reagents and starting materials were purchased
from commercial sources and used as received without purification.
‘Concentrated’ refers to the removal of volatile solvents via distillation
using a rotary evaporator. ‘Dried’ refers to pouring onto, or passing
through, anhyd MgSO4 followed by filtration. Flash chromatography
was performed using silica gel (230–400 mesh) with hexanes, EtOAc,
and CH2Cl2 as eluent. All reactions were monitored by TLC on 0.25
mm silica gel plates (F-254) visualizing with UV light. Melting points
IR (ATR): 2935, 1656, 1567, 1463, 1092, 836 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.52 (s, 1 H), 7.49 (s, 1 H), 6.21 (s, 1 H),
4.93 (s, 2 H), 3.99 (s, 3 H), 3.85 (s, 3 H), 3.79 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 189.4, 157.8, 153.3, 151.0, 137.3,
136.1, 128.1, 108.0, 95.7, 63.2, 61.7, 61.1, 56.1.
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C13H15O5: 251.0914; found:
251.0916.
were measured using a capillary melting point apparatus. 1H and 13
C
NMR spectra were recorded on 400 MHz NMR spectrometer and were
described as chemical shifts, multiplicity (standard abbreviations),
coupling constant in hertz (Hz), and number of protons. IR spectra
were recorded on FT-IR using diamond ATR technique and are de-
scribed as wavenumbers (cm–1). HRMS were measured with electro-
spray ionization (ESI) and Q-TOF mass analyzer.
5,6,7-Trimethoxy-2H-chromen-3-yl)methyl Acetate (4)
To a stirred solution of 7 (600 mg, 2.39 mmol) in a mixture of anhyd
MeOH:CH2Cl2 (3:1, 20 mL) was added NaBH4 (108.5 mg, 2.87 mmol,
1.2 equiv) at 0 °C. After stirring for 5 min, the reaction mixture was
quenched with H2O (5 mL) and the solvent was evaporated. The resi-
due was diluted with EtOAc (10 mL) and washed with aq 1 N HCl (2
× 10 mL) and H2O (10 mL). The organic layer was dried (MgSO4) and
concentrated in vacuo. The residue thus obtained was purified by sili-
ca gel column chromatography (hexanes–EtOAc = 4:1) to give the in-
termediate allylic alcohol (576 mg, 95%) as a light yellow liquid.
1,2,3-Trimethoxy-5-prop-2-ynyloxybenzene (5)
To a stirred solution of 3,4,5-trimethoxyphenol (1.0 g, 5.43 mmol) in
acetone (10 mL) were added K2CO3 (0.9 g, 6.52 mmol, 1.2 equiv) and
propargyl bromide (0.49 mL, 6.52 mmol, 1.2 equiv) and the reaction
mixture was heated at 50 °C. After stirring at 50 °C for 5 h, the mix-
ture was cooled down to r.t. and filtered through a pad of Celite. The
filtrate was concentrated under reduced pressure, diluted with CH2Cl2
(10 mL), and washed with H2O (10 mL). The aqueous layer was ex-
tracted with CH2Cl2 (2 × 5 mL). The combined organic layers were
dried (MgSO4) and concentrated in vacuo. The residue was purified by
silica gel column chromatography (hexanes–EtOAc = 9:1) to give 5
(1.15 g, 95%) as a white solid; mp 55.4–56.6 °C.
IR (ATR): 3266, 2943, 2129, 1592, 1502, 1122, 993 cm–1
1H NMR (400 MHz, CDCl3): δ = 6.23 (s, 2 H), 4.65 (d, J = 2.3 Hz, 2 H),
3.83 (s, 6 H), 3.78 (s, 3 H), 2.54 (t, J = 2.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 154.1, 153.6, 132.9, 92.8, 78.5, 75.6,
60.9, 56.2, 56.1.
IR (ATR): 3397, 2937, 1607, 1487, 1092, 1024 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.56 (s, 1 H), 6.21 (s, 1 H), 4.70 (s, 2 H),
4.21 (d, J = 5.9 Hz, 2 H), 3.87 (s, 1 H), 3.80 (s, 1 H), 3.78 (s, 1 H), 1.88 (t,
J = 5.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 153.7, 149.9, 149.4, 136.2, 130.2,
115.2, 108.9, 95.9, 66.2, 63.8, 61.5, 61.1, 55.9.
.
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C13H17O5: 253.1071; found:
253.1070.
To a stirred solution of the above allylic alcohol (570 mg, 2.26 mmol)
in CH2Cl2 (5 mL) at 0 °C were added DMAP (27.5 mg, 0.23 mmol, 0.1
equiv), Et3N (0.47 mL, 3.39 mmol, 1.5 equiv), and Ac2O (0.32 mL, 3.39
mmol, 1.5 equiv). After stirring at r.t. for 30 min, the reaction mixture
was diluted with CH2Cl2 (10 mL) and washed with 5% aq HCl and aq
NaHCO3, successively. The aqueous layer was extracted with CH2Cl2 (2
× 10 mL). The combined organic layers were dried (MgSO4) and con-
centrated in vacuo to give 4 (665 mg, 100%) as a white solid; mp 49.5–
50.6 °C.
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C12H15O4: 223.0965; found:
223.0966.
5,6,7-Trimethoxy-2H-chromene (6)
A mixture of 5 (600 mg, 2.69 mmol) in N,N-diethylaniline (6 mL) was
heated at 250 °C for 3 h. After cooling down to r.t., the reaction mix-
ture was diluted with Et2O (10 mL) and washed with 5% aq HCl and
brine. The organic layer was dried (MgSO4) and concentrated in vac-
uo. The residue was purified by silica gel column chromatography
(hexanes–EtOAc = 19:1) to give 6 (451 mg, 75%) as a colorless liquid.
IR (ATR): 2939, 1732, 1608, 1460, 1089, 1020, 878 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.65 (s, 1 H), 6.21 (s, 1 H), 4.67 (s, 2 H),
4.64 (s, 2 H), 3.88 (s, 3 H), 3.80 (s, 3 H), 3.78 (s, 3 H), 2.08 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.8, 154.1, 150.0, 149.6, 136.2,
124.8, 118.8, 108.6, 95.8, 66.3, 65.0, 61.5, 61.0, 55.9, 20.8.
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C15H19O6: 295.1176; found:
295.1179.
IR (ATR): 2936, 1607, 1488, 1106, 1036 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.62 (d, J = 9.8 Hz, 1 H), 6.20 (s, 1 H),
5.67–5.62 (m, 1 H), 4.71–4.70 (m, 2 H), 3.88 (s, 3 H), 3.81 (s, 3 H), 3.79
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 153.6, 150.6, 149.4, 136.2, 119.5,
118.3, 109.3, 96.1, 65.3, 61.5, 61.1, 55.9.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
D. K. Singh et al.
Paper
Synthesis
5,6,7-Trimethoxy-3-(4-methoxybenzyl)-2H-chromene (3a)
IR (ATR): 2935, 1595, 1459, 1131, 1090, 1037, 816 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.47 (s, 1 H), 6.38 (s, 2 H), 6.34 (s, 1 H),
6.20 (s, 1 H), 4.53 (s, 2 H), 3.89 (s, 3 H), 3.80 (s, 6 H), 3.77 (s, 6 H), 3.40
(s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 160.9, 153.1, 149.4, 149.0, 140.3,
136.2, 130.0, 115.3, 109.4, 106.8, 98.4, 95.9, 67.7, 61.5, 61.1, 55.9,
55.3, 55.2, 40.5.
To a stirred solution of 4 (200 mg, 0.68 mmol) in THF (10 mL) were
added 4-methoxyphenylboronic acid (310 mg, 2.04 mmol, 3 equiv),
Pd(PPh3)4 (39.2 mg, 0.034 mmol, 0.05 equiv), and K3PO4 (288.5 mg,
1.36 mmol, 2 equiv) at r.t. After stirring at 100 °C for 3 h, the reaction
mixture was filtered through a pad of Celite and the filtrate thus ob-
tained was concentrated under reduced pressure to give a residue,
which was purified by silica gel column chromatography (hexanes–
EtOAc = 19:1) to afford 3a (184 mg, 79%) as a colorless gum.
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C21H25O6: 373.1646; found:
373.1649.
IR (ATR): 2935, 1606, 1486, 1130, 1089, 1021, 814 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.14 (d, J = 8.5 Hz, 2 H), 6.84 (d, J = 8.5
Hz, 2 H), 6.42 (s, 1 H), 6.20 (s, 1 H), 4.52 (s, 2 H), 3.88 (s, 3 H), 3.79 (s, 9
H), 3.40 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 158.3, 153.0, 149.3, 149.0, 136.2,
130.9, 129.7, 128.4, 114.8, 113.9, 109.5, 95.9, 67.8, 61.4, 61.1, 55.9,
55.3, 39.3.
3-(4-Chlorobenzyl)-5,6,7-trimethoxy-2H-chromene (3e)
Prepared from compound 4 (100 mg, 0.34 mmol), 4-chlorophenylbo-
ronic acid (159 mg, 1.02 mmol, 3 equiv), Pd(PPh3)4 (19.6 mg, 0.017
mmol, 0.05 equiv), and K3PO4 (143.9 mg, 0.68 mmol, 2 equiv) by using
the procedure for the synthesis of 3a; yield: 90 mg (76%); yellow gum.
IR (ATR): 2936, 1607, 1487, 1132, 1089, 1036, 819 cm–1
.
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C20H23O5: 343.1540; found:
343.1537.
1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 8.28 Hz, 2 H), 7.15 (d,
J = 8.28 Hz, 2 H), 6.41 (s, 1 H), 6.18 (s, 1 H), 4.48 (s, 2 H), 3.86 (s, 3 H),
3.78 (s, 6 H), 3.40 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 153.3, 149.3, 149.1, 136.4, 136.3,
132.3, 130.1, 129.8, 128.7, 115.6, 109.3, 95.8, 67.6, 61.5, 61.1, 55.9,
39.5.
3-Benzyl-5,6,7-trimethoxy-2H-chromene (3b)
Prepared from compound 4 (100 mg, 0.34 mmol), phenylboronic acid
(124 mg, 1.02 mmol, 3 equiv), Pd(PPh3)4 (19.6 mg, 0.017 mmol, 0.05
equiv), and K3PO4 (143.9 mg, 0.68 mmol, 2 equiv) by using the proce-
dure for the synthesis of 3a; yield: 84 mg (79%); white solid; mp
55.3–56.6 °C.
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C19H20ClO4: 347.1045;
found: 347.1044.
IR (ATR): 2936, 1605, 1487, 1130, 1090, 1022, 815 cm–1
.
5,6,7-Trimethoxy-3-(4-nitrobenzyl)-2H-chromene (3f)
1H NMR (400 MHz, CDCl3): δ = 7.33–7.29 (m, 2 H), 7.24–7.22 (m, 3 H),
6.45 (s, 1 H), 6.20 (s, 1 H), 4.53 (s, 2 H), 3.88 (s, 3 H), 3.80 (s, 6 H), 3.47
(s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 153.1, 149.3, 149.0, 137.9, 136.3,
130.4, 128.8, 128.5, 126.5, 115.2, 109.5, 95.9, 67.7, 61.5, 61.1, 55.9,
40.2.
Prepared from compound 4 (100 mg, 0.34 mmol), 4-nitrophenylbo-
ronic acid (169.8 mg, 1.02 mmol, 3 equiv), Pd(PPh3)4 (19.6 mg, 0.017
mmol, 0.05 equiv), and K3PO4 (143.9 mg, 0.68 mmol, 2 equiv) by using
the procedure for the synthesis of 3a; yield: 112 mg (92%); yellow sol-
id; mp 91.7–92.5 °C.
IR (ATR): 2935, 1598, 1515, 1340, 1133, 1085, 1019, 828 cm–1
.
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C19H21O4: 313.1434; found:
313.1432.
1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 8.56 Hz, 2 H), 7.41 (d,
J = 8.56 Hz, 2 H), 6.46 (s, 1 H), 6.20 (s, 1 H), 4.51 (s, 2 H), 3.89 (s, 3 H),
3.80–3.79 (m, 6 H), 3.56 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 153.6, 149.3, 149.1, 146.9, 145.8,
136.3, 129.6, 128.3, 123.8, 116.7, 109.0, 95.8, 67.4, 61.5, 61.1, 55.9,
39.8.
3-Benzo[1,3]dioxol-5-ylmethyl-5,6,7-trimethoxy-2H-chromene
(3c)
Prepared from compound 4 (100 mg, 0.34 mmol), 3,4-(methylenedi-
oxy)phenylboronic acid (168.8 mg, 1.02 mmol, 3 equiv), Pd(PPh3)4
(19.6 mg, 0.017 mmol, 0.05 equiv), and K3PO4 (143.9 mg, 0.68 mmol,
2 equiv) by using the procedure for the synthesis of 3a; yield: 108 mg
(89%); pale yellow solid; mp 67.4–68.5 °C.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C19H19NO6Na: 380.1105;
found: 380.1115.
5,6,7-Trimethoxy-3-(4-methoxybenzyl)chroman-3,4-diol (8a)
IR (ATR): 2934, 1606, 1484, 1131, 1035, 807 cm–1
.
To a stirred solution of 3a (50 mg, 0.146 mmol) in a mixture of ace-
tone:H2O (3:1, 4 mL) were added OsO4 (2.5 wt% in t-BuOH, 0.073 mL,
0.006 mmol, 0.04 equiv) and NMO (51.3 mg, 0.438 mmol, 3 equiv) at
0 °C. After stirring at 0 °C for 5 h, the reaction mixture was quenched
with aq Na2SO3 and concentrated under reduced pressure. The resi-
due was diluted with CH2Cl2 (10 mL) and washed with H2O (10 mL).
The aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The com-
bined organic layers were dried (MgSO4) and concentrated in vacuo to
give a crude residue, which was purified by silica gel column chroma-
tography (hexanes–EtOAc = 7:3) to afford 8a (43 mg, 78%) as a color-
less gum.
1H NMR (400 MHz, CDCl3): δ = 6.75–6.66 (m, 5 H), 6.44 (s, 1 H), 6.20
(s, 1 H), 5.93 (s, 2 H), 4.51 (s, 2 H), 3.89 (s, 3 H), 3.80 (s, 6 H), 3.37 (s, 2
H).
13C NMR (100 MHz, CDCl3): δ = 153.1, 149.3, 149.0, 147.8, 146.2,
136.3, 131.6, 130.5, 121.7, 115.1, 109.4, 109.1, 108.2, 100.9, 95.8, 67.6,
61.5, 61.1, 55.9, 39.9.
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C20H21O6: 357.1333; found:
357.1335.
3-(3,5-Dimethoxybenzyl)-5,6,7-trimethoxy-2H-chromene (3d)
IR (ATR): 3478, 2935, 1610, 1511, 1112, 1099, 1025, 811 cm–1
.
Prepared from compound 4 (100 mg, 0.34 mmol), 3,5-dimethoxy-
phenylboronic acid (185.1 mg, 1.02 mmol, 3 equiv), Pd(PPh3)4 (19.6
mg, 0.017 mmol, 0.05 equiv), and K3PO4 (143.9 mg, 0.68 mmol, 2
equiv) by using the procedure for the synthesis of 3a; yield: 102 mg
(81%); pale yellow gum.
1H NMR (400 MHz, CDCl3): δ = 7.15 (d, J = 8.5 Hz, 2 H), 6.84 (d, J = 8.5
Hz, 2 H), 6.24 (s, 1 H), 4.50 (s, 1 H), 3.96 (s, 3 H), 3.83–3.79 (m, 10 H),
3.69 (d, J = 11.4 Hz, 1 H), 3.01 (br s, 1 H), 2.86 (br s, 1 H), 2.79 (d,
J = 14.2 Hz, 1 H), 2.68 (d, J = 14.2 Hz, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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D. K. Singh et al.
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13C NMR (100 MHz, CDCl3): δ = 158.4, 154.8, 152.4, 149.9, 135.8,
131.6, 127.9, 113.6, 108.5, 95.8, 69.3, 66.8, 64.7, 61.3, 60.9, 55.9, 55.2,
39.4.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C20H24O7Na: 399.1414;
found: 399.1412.
3-Benzyl-5,6,7-trimethoxychroman-3,4-diol [(+)-8b]
Prepared from olefin 3b (40 mg, 0.128 mmol), K3Fe(CN)6 (126.5 mg,
0.38 mmol, 3.0 equiv), K2CO3 (53.1 mg, 0.38 mmol, 3.0 equiv),
MeSO2NH2 (36.5 mg, 0.38 mmol, 3.0 equiv), (DHQ)2PHAL (4.98 mg,
0.006 mmol, 0.05 equiv), and OsO4 (0.016 mL, 0.001 mmol, 0.01
equiv) in t-BuOH:H2O (1:1, 4 mL) by using the procedure for the
asymmetric dihydroxylation of 3a; colorless gum (32 mg, 72%, 13:87
er); [α]D21 +56.69 (c 0.12, MeOH).
(±)-Urgineanin A
To a stirred solution of 8a (25 mg, 0.066 mmol) in EtOAc (2 mL) was
added IBX (55.8 mg, 0.199 mmol, 3 equiv). After refluxing for 3 h, the
reaction mixture was filtered through a pad of Celite and the filterate
thus obtained was washed with aq NaHCO3 (2 ×). The combined or-
ganic layers were dried (MgSO4) and concentrated in vacuo. The resi-
due was purified by silica gel column chromatography (hexanes–
EtOAc = 17:3) to afford (±)-urgineanin A (17 mg, 68%) as a pale yellow
gum.
IR (ATR): 3435, 2934, 1610, 1488, 1104, 1026, 815 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.22 (m, 5 H), 6.25 (s, 1 H), 4.50
(s, 1 H), 3.96 (s, 3 H), 3.86–3.84 (m, 4 H), 3.81 (s, 3 H), 3.71 (d, J = 10.6
Hz, 1 H), 3.02 (br s, 1 H), 2.86 (d, J = 14 Hz, 1 H), 2.80 (br s, 1 H), 2.77
(d, J = 14 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 154.8, 152.4, 149.9, 135.9, 135.8,
130.7, 128.1, 126.7, 108.5, 95.8, 69.3, 66.8, 64.6, 61.3, 61.0, 55.8, 40.3.
IR (ATR): 3451, 2936, 1676, 1598, 1244, 1119, 1024, 822 cm–1
.
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C19H23O6: 347.1489; found:
347.1488.
1H NMR (400 MHz, CDCl3): δ = 7.14 (d, J = 8.5 Hz, 2 H), 6.83 (d, J = 8.5
Hz, 2 H), 6.30 (s, 1 H), 4.20 (d, J = 11.2 Hz, 1 H), 3.99 (d, J = 11.2 Hz, 1
H), 3.92–390 (m, 7 H), 3.83 (s, 3 H), 3.78 (s, 3 H), 2.95 (d, J = 14 Hz, 1
H), 2.87 (d, J = 14 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 193.5, 160.1, 159.4, 158.6, 154.1,
137.7, 131.5, 126.7, 113.6, 106.2, 96.2, 72.3, 71.8, 61.7, 61.3, 56.2,
55.2, 40.3.
3-Benzo[1,3]dioxol-5-ylmethyl-5,6,7-trimethoxychroman-3,4-diol
[(+)-8c]
Prepared from olefin 3c (40 mg, 0.112 mmol), K3Fe(CN)6 (110.9 mg,
0.34 mmol, 3.0 equiv), K2CO3 (46.5 mg, 0.34 mmol, 3.0 equiv),
MeSO2NH2 (32 mg, 0.34 mmol, 3.0 equiv), (DHQ)2PHAL (4.37 mg,
0.006 mmol, 0.05 equiv), and OsO4 (0.009 mL, 0.001 mmol, 0.01
equiv) in t-BuOH–H2O (1:1, 4 mL) by using the procedure for the
asymmetric dihydroxylation of 3a; colorless gum (36 mg, 82%, 15:85
er); [α]D21 +63.75 (c 0.12, MeOH).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C20H23O7: 375.1438; found:
375.1443.
Asymmetric Dihydroxylation of 3a
IR (ATR): 3480, 2937, 1609, 1487, 1103, 1028, 811 cm–1
.
With (DHQ)2PHAL: After a mixture of K3Fe(CN)6 (86.5 mg, 0.26 mmol,
3.0 equiv), K2CO3 (36.3 mg, 0.26 mmol, 3.0 equiv), MeSO2NH2 (25.1
mg, 0.26 mmol, 3.0 equiv), and (DHQ)2PHAL (3.4 mg, 0.004 mmol,
0.05 equiv) was stirred in t-BuOH–H2O (1:1, 4 mL) at 0 °C for 5 min,
OsO4 (2.5 wt% in t-BuOH, 0.011 mL, 0.0009 mmol, 0.01 equiv) was
added. Then, the olefin 3a (30 mg, 0.088 mmol) was added to the re-
action mixture at 0 °C. After stirring at 0 °C for overnight, the mixture
was quenched at 0 °C by aq Na2SO3, diluted with EtOAc (10 mL), and
washed with H2O (2 × 10 mL). The combined organic layers were
dried (MgSO4) and concentrated in vacuo The residue was purified by
silica gel column chromatography (hexanes–EtOAc = 7:3) to give (+)-
1H NMR (400 MHz, CDCl3): δ = 6.78 (s, 1 H), 6.71 (d, J = 7.80 Hz, 1 H),
6.62 (d, J = 7.32 Hz, 1 H), 6.23 (s, 1 H), 5.91 (s, 2 H), 4.46 (s, 1 H), 3.94
(s, 3 H), 3.82–3.79 (m, 7 H), 3.68 (d, J = 10.48 Hz, 1 H), 3.10 (s, 1 H),
2.99 (br s, 1 H), 2.74 (d, J = 14 Hz, 1 H), 2.65 (d, J = 14 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 154.8, 152.4, 149.9, 147.4, 146.3,
135.8, 129.6, 123.5, 111.1, 108.5, 107.8, 100.8, 95.8, 69.4, 66.6, 64.6,
61.3, 60.9, 55.8, 39.9.
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C20H23O8: 391.1387; found:
391.1383.
21
8a (27 mg, 82%, 19:81 er) as a colorless gum; [α]D +50.61 (c 0.12,
3-(3,5-Dimethoxybenzyl)-5,6,7-trimethoxychroman-3,4-diol
[(+)-8d]
MeOH).
With (DHQD)2PHAL: Asymmetric dihydroxylation of 3a (30 mg, 0.088
mmol) with (DHQD)2PHAL ligand furnished (–)-8a (28 mg, 85%, 89:11
er) as a colorless gum; [α]D21 –45.73 (c 0.12, MeOH).
Prepared from olefin 3d (40 mg, 0.107 mmol), K3Fe(CN)6 (106.1 mg,
0.32 mmol, 3.0 equiv), K2CO3 (44.5 mg, 0.32 mmol, 3.0 equiv),
MeSO2NH2 (30.6 mg, 0.32 mmol, 3.0 equiv), (DHQ)2PHAL (4.18 mg,
0.005 mmol, 0.05 equiv), and OsO4 (0.014 mL, 0.001 mmol, 0.01
equiv) in t-BuOH–H2O (1:1, 4 mL) by using the procedure for the
asymmetric dihydroxylation of 3a; colorless gum (23 mg, 53%, 20:80
er); [α] D21 +53.48 (c 0.12, MeOH);
Spectral data of (+)-8a and (–)-8a are the same as those of 8a except
for the optical rotation.
(+)-Urgineanin A
Prepared from (+)-8a (25 mg, 0.066 mmol) by using the procedure for
IR (ATR): 3489, 2935, 1592, 1458, 1200, 1134, 1105, 1026, 823 cm–1
.
21
IBX oxidation of 8a; pale yellow gum (19 mg, 76%); [α]D +38.96 (c
1H NMR (400 MHz, CDCl3): δ = 6.38 (s, 2 H), 6.36 (s, 1 H), 6.24 (s, 1 H),
4.50 (s, 1 H), 3.94 (s, 3 H), 3.88–3.80 (m, 7 H), 3.76–3.72 (m, 7 H), 3.03
(s, 1 H), 2.88 (br s, 1 H), 2.78 (d, J = 13.84 Hz, 1 H), 2.69 (d, J = 13.84
Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 160.5, 154.7, 152.4, 149.9, 138.1,
135.8, 108.7, 108.5, 98.6, 95.8, 69.3, 66.9, 64.6, 61.3, 60.9, 55.9, 55.2,
40.5.
0.00153, CHCl3); [α]D21 +54.88 (c 0.12, MeOH) {Lit.4 [α]D21 +26 (c 0.12,
MeOH)}.
(–)-Urgineanin A
Prepared from (–)-8a (25 mg, 0.066 mmol) by using the procedure for
21
IBX oxidation of 8a; pale yellow gum (18 mg, 72%); [α]D –60.27 (c
0.12, MeOH).
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C21H26O8Na: 429.1520;
found: 429.1521.
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F
D. K. Singh et al.
Paper
Synthesis
21
3-(4-Chlorobenzyl)-5,6,7-trimethoxychroman-3,4-diol [(+)-8e]
(±)-urgineanin A; colorless gum (17 mg, 68%); [α]D +49.79 (c 0.12,
MeOH).
Prepared from olefin 3e (40 mg, 0.115 mmol), K3Fe(CN)6 (113.9 mg,
0.35 mmol, 3.0 equiv), K2CO3 (47.8 mg, 0.35 mmol, 3.0 equiv),
MeSO2NH2 (32.9 mg, 0.35 mmol, 3.0 equiv), (DHQ)2PHAL (4.49 mg,
0.006 mmol, 0.05 equiv), and OsO4 (0.014 mL, 0.001 mmol, 0.01
equiv) in t-BuOH–H2O (1:1, 4 mL) by using the procedure for the
asymmetric dihydroxylation of 3a; pale yellow gum (28 mg, 64%,
20:80 er); [α]D21 +53.15 (c 0.12, MeOH).
IR (ATR): 3449, 2937, 1676, 1598, 1484, 1247, 1116, 1080, 1035, 924
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.74–6.71 9 (m, 2 H), 6.64 (d, J = 7.88
Hz, 1 H), 6.29 (s, 1 H), 5.92 (s, 2 H), 4.21 (d, J = 11.2 Hz, 1 H), 3.99 (d,
J = 11.2 Hz, 1 H), 3.94 (s, 1 H), 3.91–3.90 (m, 6 H), 3.82 (s, 3 H), 2.92 (d,
J = 14 Hz, 1 H), 2.84 (d, J = 14 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 193.3, 160.2, 159.4, 154.1, 147.4,
146.6, 137.6, 128.3, 123.5, 110.9, 107.9, 106.2, 100.9, 96.2, 72.3, 71.7,
61.6, 61.3, 56.2, 40.8.
IR (ATR): 3478, 2935, 1610, 1488, 1111, 1014, 818 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.26 (d, J = 8.2 Hz, 2 H), 7.17 (d, J = 8.2
Hz, 2 H), 6.24 (s, 1 H), 4.46 (s, 1 H), 3.97 (s, 3 H), 3.84 (s, 3 H), 3.81–
3.80 (m, 4 H), 3.67 (d, J = 10.6 Hz, 1 H), 3.09 (s, 1 H), 2.82–2.72 (m, 3
H).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C20H21O8: 389.1231; found:
389.1230.
13C NMR (100 MHz, CDCl3): δ = 154.9, 152.3, 149.9, 135.8, 134.5,
132.6, 132.0, 128.5, 108.3, 95.8, 69.2, 66.7, 64.7, 61.3, 60.9, 55.9, 39.6.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C19H21ClO6Na: 403.0919;
3-(3,5-Dimethoxybenzyl)-3-hydroxy-5,6,7-trimethoxychroman-4-
one (9)
found: 403.0921.
Prepared from compound (+)-8d (18 mg, 0.044 mmol) and IBX (37
mg, 0.13 mmol, 3.0 equiv) by using the procedure for the synthesis of
21
5,6,7-Trimethoxy-3-(4-nitrobenzyl)chroman-3,4-diol [(+)-8f]
(±)-urgineanin A; colorless gum (15 mg, 84%); [α]D +49.90 (c 0.12,
MeOH).
Prepared from olefin 3f (40 mg, 0.112 mmol), K3Fe(CN)6 (110.6 mg,
0.34 mmol, 3.0 equiv), K2CO3 (46.4 mg, 0.34 mmol, 3.0 equiv),
MeSO2NH2 (31.9 mg, 0.34 mmol, 3.0 equiv), (DHQ)2PHAL (4.36 mg,
0.006 mmol, 0.05 equiv), and OsO4 (0.014 mL, 0.001 mmol, 0.01
equiv) in t-BuOH–H2O (1:1, 4 mL) by using the procedure for the
asymmetric dihydroxylation of 3a; white solid; mp 150.1–151.3 °C
(35 mg, 80%, 42:58 er); [α]D21 +22.89 (c 0.12, MeOH).
IR (ATR): 3447, 2937, 1678, 1595, 1456, 1200, 1148, 1117, 1084, 1024
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.36–6.35 (m, 3 H), 6.30 (s, 1 H), 4.25
(d, J = 11.2 Hz, 1 H), 4.01 (d, J = 11.2 Hz, 1 H), 3.96 (s, 1 H), 3.92–3.89
(m, 6 H), 3.82 (s, 3 H), 3.76 (s, 6 H), 2.94 (d, J = 13.6 Hz, 1 H), 2.88 (d,
J = 13.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 193.1, 160.4, 160.1, 159.3, 154.1,
137.7, 136.9, 108.6, 106.2, 98.9, 96.2, 72.3, 72.0, 61.6, 61.3, 56.2, 55.2,
41.5.
IR (ATR): 3485, 2934, 1608, 1517, 1488, 1343, 1111, 1027, 824 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 8.4 Hz, 2 H), 7.41 (d, J = 8.4
Hz, 2 H), 6.24 (s, 1 H), 4.43 (s, 1 H), 3.96 (s, 3 H), 3.83 (s, 3 H), 3.79–
3.75 (m, 4 H), 3.61 (d, J = 10.68 Hz, 1 H), 3.28 (s, 1 H), 2.91 (br s, 1 H),
2.87–2.82 (m, 2 H).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C21H25O8: 405.1544; found:
405.1552.
13C NMR (100 MHz, CDCl3): δ = 155.0, 152.2, 149.8, 146.9, 144.1,
135.8, 131.6, 123.1, 108.0, 95.8, 69.4, 66.4, 64.7, 61.3, 60.9, 55.9, 39.9.
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C19H22NO8: 392.1340;
3-(4-Chlorobenzyl)-3-hydroxy-5,6,7-trimethoxychroman-4-one
(10)
found: 392.1342.
Prepared from compound (+)-8e (18 mg, 0.047 mmol) and IBX (40
mg, 0.14 mmol, 3.0 equiv) by using the procedure for the synthesis of
21
3-Benzyl-3-hydroxy-5,6,7-trimethoxychroman-4-one (Urgineanin
B)
(±)-urgineanin A; yellow gum (14 mg, 78%); [α]D +52.14 (c 0.12,
MeOH).
IR (ATR): 3447, 2936, 1676, 1597, 1262, 1200, 1119, 1025, 823 cm–1
.
Prepared from compound (+)-8b (25 mg, 0.072 mmol), IBX (61 mg,
0.22 mmol, 3.0 equiv) by using the procedure for the synthesis of (±)-
urgineanin A; colorless gum (18 mg, 72%); [α]D +65.21 (c 0.12,
MeOH).
1H NMR (400 MHz, CDCl3): δ = 7.26 (d, J = 8.3 Hz, 2 H), 7.15 (d, J = 8.3
Hz, 2 H), 6.30 (s, 1 H), 4.17 (d, J = 11.2 Hz, 1 H), 3.99 (d, J = 11.2 Hz, 1
H), 3.94 (s, 1 H), 3.92–3.91 (m, 6 H), 3.83 (s, 3 H), 2.98 (d, J = 13.8 Hz, 1
H), 2.89 (d, J = 13.8 Hz, 1 H).
21
IR (ATR): 3445, 2936, 1677, 1597, 1262, 1117, 1085, 1024 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.31–7.21 (m, 5 H), 6.31 (s, 1 H), 4.21
(d, J = 11.2 Hz, 1 H), 4.00 (d, J = 11.2 Hz, 1 H), 3.95 (s, 1 H), 3.92 (s, 3
H), 3.90 (s, 3 H), 3.83 (s, 3 H), 3.00 (d, J = 13.6 Hz, 1 H), 2.93 (d, J = 13.6
Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 193.3, 160.2, 159.4, 154.1, 137.7,
134.8, 130.5, 128.1, 126.9, 106.2, 96.2, 72.2, 71.8, 61.6, 61.3, 56.2,
41.1.
13C NMR (100 MHz, CDCl3): δ = 193.1, 160.3, 159.4, 154.1, 137.7,
133.2, 132.9, 131.8, 128.3, 106.1, 96.2, 72.1, 71.7, 61.7, 61.3, 56.2,
40.5.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C19H19ClO6Na: 401.0762;
found: 401.0763.
3-Hydroxy-5,6,7-trimethoxy-3-(4-nitrobenzyl)chroman-4-one
(11)
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C19H21O6: 345.1333; found:
345.1342.
Prepared from compound (+)-8f (25 mg, 0.064 mmol) and IBX (54 mg,
0.19 mmol, 3.0 equiv) by using the procedure for the synthesis of (±)-
urgineanin A; pale yellow solid (20 mg, 80%); mp 141.7–142.8 °C;
[α]D21 +14.85 (c 0.12, MeOH).
3-Benzo[1,3]dioxol-5-ylmethyl-3-hydroxy-5,6,7-trimethoxychro-
man-4-one (Urgineanin D)
Prepared from compound (+)-8c (25 mg, 0.064 mmol) and IBX (54
mg, 0.19 mmol, 3.0 equiv) by using the procedure for the synthesis of
IR (ATR): 3438, 2937, 1676, 1597, 1343, 1263, 1201, 1120, 1080, 1024
cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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D. K. Singh et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 8.56 Hz, 2 H), 7.39 (d,
J = 8.56 Hz, 2 H), 6.32 (s, 1 H), 4.15 (d, J = 11.4 Hz, 1 H), 4.03–4.01 (m,
2 H), 3.93–3.92 (m, 6 H), 3.83 (s, 3 H), 3.10 (d, J = 13.6 Hz, 1 H), 3.01 (d,
J = 13.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 192.5, 160.6, 159.3, 154.2, 147.1,
142.7, 137.8, 131.4, 123.2, 105.9, 96.3, 71.9, 71.7, 61.7, 61.3, 56.3,
40.9.
Lee, B.; Lee, H.; Sulaiman, R. S.; An, H.; Magana, C.; Shadmand,
M.; Vayl, A.; Rajashekhar, G.; Kim, E.-Y.; Suh, Y.-G.; Lee, K.; Seo,
S.-Y.; Corson, T. W. J. Med. Chem. 2015, 58, 5015.
(3) (a) Siddaiah, V.; Rao, C. V.; Venkateswarlu, S.; Subbaraju, G. V.
Tetrahedron 2006, 62, 841. (b) Gan, C.; Zhao, Z.; Nan, D.-D.; Yin,
B.; Hu, J. Eur. J. Med. Chem. 2014, 76, 125. (c) Javed, U.; Karim,
M.; Jahng, K. C.; Park, J.-G.; Jahng, Y. Tetrahedron: Asymmetry
2014, 25, 1270. (d) Das, U.; Lorand, T.; Dimmock, S. G.; Perjesi,
P.; Dimmock, J. R. J. Enzyme Inhib. Med. Chem. 2015, 30, 259.
(e) Hou, C.; Chen, H.; Xu, X.; Zhu, F.; Guo, L.; Jiang, M.; Yang, C.;
Deng, L. Eur. J. Org. Chem. 2015, 3040.
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C19H20NO8: 390.1183;
found: 390.1184.
(4) Dai, Y.; Harinantenaina, L.; Brodie, P. J.; Goetz, M.; Shen, Y.;
TenDyke, K.; Kingston, D. G. I. J. Nat. Prod. 2013, 76, 865.
(5) Jung, Y.; Kim, I. Org. Biomol. Chem. 2015, 13, 4331.
(6) (a) Venugopalan, B.; Balasubramanian, K. K. Heterocycles 1985,
23, 81. (b) Kenny, R. S.; Mashelkar, U. C.; Rane, D. M.; Bezawada,
D. K. Tetrahedron 2006, 62, 9280.
(7) Synthesis of 6 was initially attempted by using the similar pro-
cedures as those reported in ref. 5. But the yield was low.
(8) (a) Pd-catalyzed allylic substitution of allylic alcohol was also
conducted under base-free conditions but resulted in very low
yield of 3a. (b) See: Tsukamoto, H.; Sato, M.; Kondo, Y. Chem.
Commun. 2004, 1200. (c) See also: Tsukamoto, H.; Uchiyama, T.;
Suzuki, T.; Kondo, Y. Org. Biomol. Chem. 2008, 6, 3005.
(9) For reviews on IBX, see: (a) Tohma, H.; Kita, Y. Adv. Synth. Catal.
2004, 346, 111. (b) Duschek, A.; Kirsch, S. F. Angew. Chem. Int.
Ed. 2011, 50, 1524. For the oxidation of alcohols with IBX in
EtOAc, see: (c) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
(d) Bartlett, S. L.; Beaudry, C. M. J. Org. Chem. 2011, 76, 9852.
(10) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
(11) The ers of 8a and 8b were determined by chiral HPLC analysis
(CHIRALPAK IA column; flow, 0.5 mL min–1; H2O–MeCN =
50:50; λ = 254 nm). See Supporting Infromation for details.
(12) The er of 8e was determined by chiral HPLC analysis (CHIRAL-
PAK IA column; flow, 0.5 mL min–1; H2O–MeCN = 50:50; λ = 254
nm). The ers of 8c and 8d were determined by chiral HPLC anal-
ysis (CHIRALPAK IC column; flow, 1 mL min–1; hexane–EtOH =
80:20; λ = 210 nm). The er of 8f was determined by chiral HPLC
analysis (CHIRALPAK IA column; flow, 0.5 mL min–1; H2O–
MeCN = 60:40; λ = 254 nm). See Supporting Information for
details.
Acknowledgment
This work was supported by the National Research Foundation of
Korea (NRF) grant funded by the Korea government (MSIP)
(2014R1A2A1A11050491). This work was supported in part by the
Yonsei Research Fund of 2015 (project no.: 2015-12-0215).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588105. 1H and 13C NMR spectra
of 3–11, synthetic urgineanins A, B, D, and chiral chromatographic
data of (+)-8a, (–)-8a, (+)-8b, (+)-8c, (+)-8d, (+)-8e, (+)-8f are includ-
ed.
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References
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