Total synthesis and structural revision of hericerin

Article abstract of DOI:10.1021/jo300719m

The total synthesis of hericerin, a pollen growth inhibitor from Hericium erinaceum, was achieved. We found that the reported structure of hericerin should be revised to be the carbonyl regioisomer.

Full text of DOI:10.1021/jo300719m

Note
pubs.acs.org/joc
Total Synthesis and Structural Revision of Hericerin
Shoji Kobayashi,*,† Tomoharu Inoue,† Ami Ando,‡ Hidetsugu Tamanoi,† Ilhyong Ryu,‡
and Araki Masuyama†
†Department of Applied Chemistry, Faculty of Engineering, Osaka Institute of Technology, 5-16-1 Ohmiya, Asahi-ku, Osaka
535-8585, Japan
‡Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai 599-8531, Japan
S
* Supporting Information
ABSTRACT: The total synthesis of hericerin, a pollen growth
inhibitor from Hericium erinaceum, was achieved. We found
that the reported structure of hericerin should be revised to be
the carbonyl regioisomer.
ericerin is one of the members of the geranyl resorcylate
family of natural products, isolated from the mushroom
170 °C for 15−22 h provided lactam 1 in 12−23% yield
(Scheme 1).5
H
Hericium erinaceum.1 The structure was determined by Tsuneda
and co-workers in 1991 as 1 (Figure 1).2 Hericerin shows
Scheme 1. Direct Lactamization of 2
Figure 1. Proposed structure of hericerin.2
inhibitory activity against pine pollen germination and tea
pollen growth and, therefore, is expected to be useful as a
research tool for agrochemical discovery.
Recently, in the course of our studies on development of
one-pot multifunctionalization reactions for an assembly of
bioactive molecules, we discovered an efficient route to 6-
bromo-5,7-dihydroxyphthalide 5-methyl ether, a key synthetic
intermediate of the geranyl resorcylates, employing a CuBr2-
mediated multistep reaction.3 This development was extended
to the total synthesis of hericenone J and hericene A, both of
which are members of the hericerin family.3 Since our synthetic
method was designed to cover a broad range of structures of
geranylated resorcinols, we expanded the strategy to lactam-
containing natural products. In this paper, we report the first
total synthesis of hericerin, which revealed that the structure
reported in 1991 was incorrect and should be revised to be the
carbonyl regioisomer.
Unexpectedly, the NMR data of synthetic 1 were not the
same as those of the natural product. Among the chemical shifts
observed, the signals assigned to the benzolactam moiety (C1−
C7a), C1′, and C1′′ were considerably different, whereas the
signals assigned to the geranyl side chain (C2′−C10′) and the
phenylethyl group (C2′′−C6′′) were nearly identical. This
observation indicates that the major difference is ascribed to the
structure of the benzolactam moiety. To determine the actual
structure of the natural product, the H4 chemical shift of
known compounds was surveyed. Figure 2 shows the structures
of related compounds along with chemical shifts of the
aromatic protons. These data clearly suggest that the chemical
shift of the aromatic proton is largely dependent on the
location of the carbonyl group. While the aromatic signal of
hericenone J (3)3,4,6 and Rama Rao’s intermediate (4)7 appears
at 6.4−6.7 ppm, the corresponding signals of erinacerin A (5)8
and hericenone A (6)7 appear around 6.9 ppm. These analyses
indicate that our synthetic compound with its aromatic proton
at δ 6.40 possesses a structure related to the former compounds
3 and 4, while the structure of the natural product is analogous
The geranylated lactone 23,4 was subjected to direct
lactamization in the presence of excess 2-phenylethylamine
(20 equiv) under thermal conditions. The reaction, however,
resulted in partial cleavage of the methoxymethyl (MOM)
ether without forming the lactam, even after prolonged heating.
When the reaction was carried out in the presence of i-Pr2NEt
at 135 °C, the acyclic amide intermediate was produced as the
major product, together with a trace amount of lactam 1. This
indicated that higher temperature would be necessary to trigger
lactamization. Eventually, heating with n-Bu3N (bp 216 °C) at
Received: April 9, 2012
Published: June 6, 2012
© 2012 American Chemical Society
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Note
lactam 11 in 83% yield. Finally, acid-catalyzed cleavage of the
MOM ether provided our desired product 12.
1
As expected, H and 13C NMR data of synthetic 12 were in
accordance with those of the natural product, even though the
original raw data were not available (Table S1, Supporting
Information).15 Nuclear Overhauser effect spectroscopy
(NOESY) analysis of synthetic 12 revealed a correlation
between H7 (δ 6.96) and C6-OMe (δ 3.84). In contrast, a cross
peak between H7 (δ 6.96) and H3 (δ 4.15) was not observed.
In the original paper, the authors reported that NOE effects
were observed between the signals at δ 6.95 (H7) and δ 3.84
(OMe) and at δ 6.95 (H7) and δ 4.16 (H3). However, the
supplemental spectra to support this observation were not
provided.2 It is possible that the authors’ latter correlation could
be attributed to noise signals. Very recently, Miyazawa and co-
workers isolated compound 12 from the fruiting bodies of
Hericium erinaceum and named it isohericerin.16 The two sets of
spectra are in good agreement. Accordingly, it is speculated that
the two natural products isolated independently are the same.
In conclusion, we have achieved the first total synthesis of
hericerin starting from the key synthetic intermediate 2
prepared in our previous paper. Our findings reveal that the
actual structure of hericerin is 12, which is the carbonyl
regioisomer of 1. From a biosynthetic standpoint, it is
interesting that both series of carbonyl regioisomers are
distributed in the same organism. We believe that the present
investigation will be informative for researchers who are
interested in the biosynthetic pathway of hericerin and its
family.
1
Figure 2. Structures and H NMR data of related compounds.
to that of the latter molecules 5 and 6 based on the aromatic
proton signal at δ 6.95. In the preceding research, Rama Rao
pointed out the same regiochemical issues with respect to
hericenone A and B.7 They suggested that the structures of
natural products should be revised as the carbonyl regioisomers
on the basis of IR and PMR spectra. A part of their assertion
was confirmed by the unambiguous total synthesis of
hericenone A (6), whereas structure elucidation of hericenone
B, which was the 5′-oxo analogue of hericerin, was left
untouched. Of special interest is that their work ensures
occurrence of both regioisomeric phthalides in nature. On the
basis of the above information, we speculated that the actual
structure of hericerin was the carbonyl regioisomer and
undertook its synthesis to verify the hypothesis.
Thus, lactone 2 was reduced with LiAlH4 to provide the 1,3-
diol, which was selectively oxidized upon exposure to Ag2CO3
on Celite9 to produce the desired lactone 8 accompanied by
isomeric lactone 2 in 72% and 21% yields, respectively, for two
steps (Scheme 2). This selectivity is explained by oxidation
taking place more facilely at the less hindered lower alcohol
rather than the upper one, which is then followed by rapid
lactol formation and the second oxidation to afford 8. Since
direct lactamization of 8 under extreme thermal conditions
resulted in a very poor yield of the lactam, we resorted to a
stepwise method including amide formation and N-cyclization.
Thus, lactone 8 was treated with 2-phenylethylamine in the
presence of Me3Al10 to afford acyclic amide 9 in 87% yield.11
Because direct intramolecular N-alkylation of 9 with i-PrMgCl
EXPERIMENTAL SECTION
■
General Techniques. All reactions utilizing air- or moisture-
sensitive reagents were performed under an atmosphere of argon.
Commercially available dry solvents were used for DMF, CH2Cl2,
THF, and MeOH. Triethylamine and 1,2-dichloroethane were distilled
from CaH2. Reactions were monitored by thin-layer chromatography
(TLC) carried out on 0.25 mm silica gel plates (60-F254) that were
analyzed by fluorescence upon 254 nm irradiation or by staining with
p-anisaldeyde/AcOH/H2SO4/EtOH, 12MoO3·H3PO4/EtOH, or
(NH4)6Mo7O24·4H2O/H2SO4. The products were purified by flash
chromatography on silica gel (spherical, neutral, 40−50 μm) and, if
necessary, HPLC equipped with prepacked column using hexane/
EtOAc as eluent. NMR spectra were recorded with a 500 MHz (1H:
500 MHz, 13C: 125 MHz), a 400 MHz (1H: 400 MHz, 13C: 100
MHz), or a 300 MHz (1H: 300 MHz, 13C: 75 MHz) spectrometer and
referenced to the solvent peak at 7.26 ppm (1H) and 77.16 ppm (13C)
for CDCl3. Splitting patterns are indicated as follows: br, broad; s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet. Infrared spectra
were recorded with a FT/IR spectrometer and reported as
wavenumber (cm−1). Low- and high-resolution FAB mass spectra
12
and ClP(O)(OEt)2 resulted in a low yield of 11 (27%
yield),13 we again employed a two-step method. Alcohol 9 was
treated with excess MsCl and Et3N to provide chloride 10,
which possibly arises from SN2 displacement onto the mesylate
or the O-cyclized imine intermediate.14 Subsequent treatment
with NaH in DMF induced rapid N-cyclization to provide
Scheme 2. Total Synthesis of Hericerin
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Note
were recorded with a double-focusing magnetic sector mass
spectrometer in positive ion mode.
(s, 3H, MOM), 3.34 (d, 2H, J = 6.6 Hz, H1′), 2.97 (t, 2H, J = 7.2 Hz,
H2′′), 2.08−2.00 (m, 2H, H5′), 1.98−1.93 (m, 2H, H4′), 1.74 (br s,
3H, H9′), 1.64 (br s, 3H, H8′), 1.57 (s, 3H, H10′); 13C NMR (75
MHz, CDCl3) δ 168.8, 158.3, 156.1, 139.1, 136.5, 135.7, 131.5, 128.9,
128.6, 126.5, 126.3, 124.5, 124.3, 122.0, 107.7, 100.4, 57.6, 56.8, 55.9,
41.5, 39.7, 35.7, 26.7, 25.8, 23.8, 17.8, 16.3; FT-IR (ZnSe) 3290, 3062,
3027, 2933, 1634, 1597, 1553, 1498, 1455, 1397, 1331, 1304, 1223,
1202, 1158, 1111, 1065 cm−1; HRMS (FAB) m/z calcd for
C29H39NO5Na [M + Na]+ 504.2726, found 504.2688.
(E)-6-(3,7-Dimethylocta-2,6-dienyl)-7-hydroxy-5-methoxy-2-
phenethylisoindolin-1-one (1). A mixture of phthalide 2 (59.0 mg,
0.164 mmol), phenylethylamine (413 μL, 3.28 mmol), and n-Bu3N
(1.39 mL, 5.84 mmol) was heated in a screw-capped test tube at 170
°C. After being stirred for 22 h, the reaction mixture was diluted with
EtOAc, washed with 1 M aqueous HCl and brine, and dried over
anhydrous MgSO4. After concentration, the residue was purified by
flash chromatography (n-hexane/EtOAc = 5) to give the title
compound 1 (15.7 mg, 0.0374 mmol, 23%) as a pale yellow solid:
(E)-2-(Chloromethyl)-4-(3,7-dimethylocta-2,6-dienyl)-5-me-
thoxy-3-(methoxymethoxy)-N-phenethylbenzamide (10). To a
solution of alcohol 9 (4.0 mg, 8.3 μmol) in CH2Cl2 (1.0 mL) were
added Et3N (13.9 μL, 99.7 μmol) and MsCl (3.3 μL, 41 μmol) at 0
°C. The mixture was stirred at 0 °C for 2 h and quenched by the
addition of saturated aqueous NaHCO3 solution. The resulting
mixture was extracted with EtOAc (2×), and the combined organic
layer was washed with saturated aqueous NH4Cl solution, brine, dried
over anhydrous MgSO4, and concentrated. The residue was purified by
flash column chromatography (n-hexane/EtOAc = 3) to give chloride
1
mp 69−71 °C; H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H, OH),
7.34−7.20 (m, 5H, Ph), 6.40 (s, 1H, H4), 5.20 (br t, 1H, J = 7.2 Hz,
H2′), 5.06 (br t, 1H, J = 7.2 Hz, H6′), 4.12 (s, 2H, H3), 3.83 (s, 3H,
OMe), 3.78 (t, 2H, J = 7.6 Hz, H1′′), 3.34 (d, 2H, J = 6.8 Hz, H1′),
2.95 (t, 2H, J = 7.6 Hz, H2′′), 2.05 (m, 2H, H5′), 1.95 (br t, 2H, J = 7.6
Hz, H4′), 1.77 (s, 3H, H9′), 1.64 (br s, 3H, H8′), 1.57 (s, 3H, H10′);
13C NMR (100 MHz, CDCl3) δ 170.5 (C1), 162.4 (C5), 153.9 (C7),
140.2 (C3a), 138.9 (C3′′), 135.5 (C3′), 131.3 (C7′), 128.8 (C4′′, C5′′),
126.7 (C6′′), 124.6 (C6′), 122.0 (C2′), 116.0 (C6), 110.7 (C7a), 97.1
(C4), 56.1 (OMe), 51.4 (C3), 43.7 (C1′′), 39.9 (C4′), 35.3 (C2′′), 26.9
(C5′), 25.8 (C8′), 21.7 (C1′), 17.8 (C10′), 16.2 (C9′); FT-IR (ZnSe)
3326, 3062, 3028, 2963, 2938, 2856, 1666, 1498, 1456, 1438, 1417,
1375, 1336, 1250, 1236, 1198, 1170 cm−1; HRMS (FAB) m/z calcd
for C27H34NO3 [M + H]+ 420.2539, found 420.2539.
(E)-5-(3,7-Dimethylocta-2,6-dienyl)-6-methoxy-4-
(methoxymethoxy)isobenzofuran-1(3H)-one (8). To a solution
of phthalide 2 (264 mg, 0.731 mmol) in THF (7.3 mL) was added
LiAlH4 (83.5 mg, 2.20 mmol) at 0 °C. The mixture was stirred at 0 °C
for 1 h and quenched with water. Et2O and saturated aqueous Rochelle
salt solution were added, and the resulting mixture was stirred at room
temperature for 1 h. The mixture was extracted with Et2O (3×), and
the combined organic layer was washed with brine, dried over
anhydrous MgSO4, and concentrated to give the corresponding diol3
(269 mg), which was used for the next reaction without further
purification.
To a solution of diol (266 mg) in toluene was added 50 wt % of
Ag2CO3 on Celite (1.01 g, 1.83 mmol). The mixture was heated at
reflux and stirred for 1 h. The precipitate was removed by filtration,
and the filtrate was concentrated. The residue was purified by flash
chromatography (n-hexane/EtOAc = 5 → 3) to give phthalide 8 (189
mg, 0.525 mmol, 72%) as a pale yellow viscous oil and phthalide 2
(56.0 mg, 0.155 mmol, 21%) as a colorless solid. Data for 8: mp 36−
39 °C; 1H NMR (300 MHz, CDCl3) δ 7.14 (s, 1H, H7), 5.37 (s, 2H,
MOM), 5.11 (br t, J = 5.7 Hz, H2′), 5.06 (s, 2H, H3), 5.04 (m, 1H,
H6′), 3.89 (s, 3H, OMe), 3.53 (s, 3H, MOM), 3.44 (d, 2H, J = 6.9 Hz,
H1′), 2.07−2.01 (m, 2H, H5′), 1.98−1.93 (m, 2H, H4′), 1.77 (br s,
3H, H9′), 1.63 (br s, 3H, H8′), 1.56 (br s, 3H, H10′); 13C NMR (75
MHz, CDCl3) δ 171.5, 159.7, 150.3, 136.1, 131.5, 129.2, 129.1, 125.3,
124.2, 121.3, 101.7, 97.2, 69.2, 56.8, 56.2, 39.8, 26.7, 25.8, 23.7, 17.8,
16.3; FT-IR (ZnSe) 2973, 2914, 2848, 1766, 1736, 1475, 1434, 1409,
1373, 1332, 1230, 1213, 1155, 1100, 1066, 1023 cm−1; HRMS (FAB)
m/z calcd for C21H29O5 [M + H]+ 361.2015, found 361.1993. Anal.
Calcd for C21H28O5: C, 69.98; H, 7.83. Found: C, 69.81; H, 7.72.
(E)-4-(3,7-Dimethylocta-2,6-dienyl)-2-(hydroxymethyl)-5-
methoxy-3-(methoxymethoxy)-N-phenethylbenzamide (9). To
a solution of 2-phenylethylamine (70.5 μL, 0.560 mmol) in (CH2Cl)2
(1.0 mL) was added Me3Al (1.4 M solution in hexane, 104 μL, 0.146
mmol). The mixture was stirred at room temperature for 0.5 h
followed by the addition of phthalide 8 (40.4 mg, 0.112 mmol) in
(CH2Cl)2 (1.3 mL). The resulting mixture was stirred at 40 °C for 7.5
h and quenched by the addition of water at 0 °C. The resulting
mixture was extracted with EtOAc (2×) and the combined organic
layer was washed with 1 M aqueous HCl, brine, dried over anhydrous
MgSO4, and concentrated. The residue was purified by flash
chromatography (n-hexane/EtOAc = 2) to give amide 9 (47.0 mg,
0.0976 mmol, 87%) as a pale yellow viscous oil: 1H NMR (300 MHz,
CDCl3) δ 7.50 (br t, J = 5.4 Hz, NH), 7.34−7.20 (m, 5H, Ph), 7.03 (s,
1H, H7), 5.10−5.00 (m, 2H, H2′, H6′), 4.96 (s, 2H, MOM), 4.53 (s,
2H, H3), 3.84 (s, 3H, OMe), 3.74 (dt, 2H, J = 7.2, 5.4 Hz, H1′′), 3.62
1
10 (2.5 mg, 5.0 μmol, 60%) as a colorless solid: mp 98−100 °C; H
NMR (300 MHz, CDCl3) δ 7.35−7.19 (m, 5H, Ph), 6.72 (s, 1H, H6),
6.22 (br t, 1H, J = 6.0 Hz, NH), 5.10−5.01 (m, 2H, H2′, H6′), 5.02 (s,
2H, MOM), 4.82 (s, 2H, H7), 3.80 (s, 3H, OMe), 3.77 (td, 2H, J =
6.9, 6.0 Hz, H1′′), 3.62 (s, 3H, MOM), 3.35 (d, 2H, J = 6.3 Hz, H1′),
2.98 (t, 2H, J = 6.9 Hz, H2′′), 2.07−2.00 (m, 2H, H5′), 1.98−1.92 (m,
2H, H4′), 1.73 (br s, 3H, H9′), 1.63 (br s, 3H, H8′), 1.57 (br s, 3H,
H10′); 13C NMR (75 MHz, CDCl3) δ 168.8, 159.2, 155.8, 138.8,
136.6, 135.9, 131.5, 128.9, 128.8, 126.7, 126.6, 124.3, 122.1, 121.1,
106.7, 100.8, 57.8, 55.9, 41.2, 39.8, 39.7, 35.5, 26.7, 25.8, 23.9, 17.8,
16.3; FT-IR (ZnSe) 3287, 3064, 3028, 2965, 2927, 2856, 1629, 1595,
1576, 1540, 1462, 1434, 1395, 1340, 1261, 1219, 1186, 1168, 1112
cm−1; HRMS (FAB) m/z calcd for C29H39ClNO4 [M + H]+ 500.2568,
found 500.2548.
(E)-5-(3,7-Dimethylocta-2,6-dienyl)-6-methoxy-4-(methoxy-
methoxy)-2-phenethylisoindolin-1-one (11). To a solution of
chloride 10 (4.4 mg, 8.8 μmol) in DMF (1.0 mL) was added NaH
(60% dispersion in mineral oil, 8.0 mg, 0.20 mmol) at 0 °C. The
mixture was stirred at 0 °C for 20 min and quenched by the addition
of water. The resulting mixture was extracted with Et2O (2×), and the
combined organic layer was washed with brine, dried over anhydrous
MgSO4, and concentrated. The residue was purified by flash column
chromatography (n-hexane/EtOAc = 1) to give lactam 11 (3.4 mg, 7.3
1
μmol, 83%) as a colorless oil: H NMR (300 MHz, CDCl3) δ 7.33−
7.19 (m, 5H, Ph), 7.15 (s, 1H, H7), 5.12 (br t, 1H, J = 7.2 Hz, H2′),
5.04 (m, 1H, H6′), 4.99 (s, 2H, MOM), 4.24 (s, 2H, H3), 3.88 (s, 3H,
OMe), 3.85 (t, 2H, J = 7.5 Hz, H1′′), 3.47 (s, 3H, MOM), 3.40 (d, 2H,
J = 6.9 Hz, H1′), 2.98 (t, 2H, J = 7.5 Hz, H2′′), 2.07−2.00 (m, 2H,
H4′), 1.98−1.92 (m, 2H, H5′), 1.76 (br s, 3H, H9′), 1.63 (br s, 3H,
H8′), 1.56 (s, 3H, H10′); 13C NMR (75 MHz, CDCl3) δ 168.4, 159.1,
150.9, 139.0, 135.5, 132.6, 131.5, 128.9, 128.7, 126.6, 126.5, 124.44,
124.36, 122.2, 101.1, 98.0, 56.9, 56.2, 49.5, 44.3, 39.8, 35.1, 26.8, 25.8,
23.6, 17.8, 16.3; FT-IR (ZnSe) 3086, 3061, 3027, 2914, 2852, 1687,
1620, 1602, 1497, 1468, 1436, 1416, 1375, 1317, 1247, 1153, 1117
cm−1; HRMS (FAB) m/z calcd for C29H38NO4 [M + H]+ 464.2801,
found 464.2823.
(E)-5-(3,7-Dimethylocta-2,6-dienyl)-4-hydroxy-6-methoxy-2-
phenethylisoindolin-1-one (Hericerin, 12). To a solution of
lactam 11 (4.3 mg, 9.3 μmol) in MeOH (1 mL) was added CSA (5.0
mg, 0.022 mmol). The mixture was stirred at room temperature for 70
h and quenched by the addition of Et3N (1 mL). The reaction mixture
was concentrated and the residue was purified by flash column
chromatography (n-hexane/EtOAc = 2) to give the title compound 12
1
(3.3 mg, 7.9 μmol, 85%) as a colorless solid: mp 143−146 °C; H
NMR (300 MHz, CDCl3) δ 7.29−7.19 (m, 5H, Ph), 6.96 (s, 1H, H7),
6.13 (br s, 1H, OH), 5.23 (br t, 1H, J = 6.9 Hz, H2′), 5.02 (m, 1H,
H6′), 4.15 (s, 2H, H3), 3.85 (br t, 2H, J = 7.3 Hz, H1′′), 3.84 (s, 3H,
OMe), 3.49 (d, 2H, J = 6.9 Hz, H1′), 2.97 (t, 2H, J = 7.3 Hz, H2′′),
2.09 (br s, 2H, H4′, H5′), 1.80 (s, 3H, H9′), 1.66 (s, 3H, H8′), 1.58 (s,
3H, H10′); 13C NMR (75 MHz, CDCl3) δ 169.1 (C1), 158.6 (C6),
150.7 (C4), 139.5 (C3′), 138.9 (C3′′), 132.4 (C7′), 132.3 (C7a), 128.8
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Note
(C4′′), 128.7 (C5′′), 126.6 (C6′′), 123.8 (C6′), 121.34 (C2′ or C3a),
121.26 (C2′ or C3a), 118.6 (C5), 97.7 (C7), 56.2 (OMe), 48.3 (C3),
44.4 (C1′′), 39.8 (C4′), 35.0 (C2′′), 26.4 (C5′), 25.8 (C8′), 22.9 (C1′),
17.8 (C10′), 16.3 (C9′); FT-IR (ZnSe) 3146, 3029, 2966, 2927, 2856,
1647, 1589, 1471, 1455, 1436, 1422, 1368, 1336, 1310, 1264, 1229,
1193, 1165, 1119, 1089, 1066 cm−1; HRMS (FAB) m/z calcd for
C27H34NO3 [M + H]+ 420.2539, found 420.2535. Anal. Calcd for
C27H33NO3: C, 77.29; H, 7.93; N, 3.34. Found: C, 77.26; H, 7.81; N,
3.40.
(15) We observed that the chemical shift of the phenolic OH varied
according to the concentration of 12 in CDCl3. For instance, when the
1H NMR spectrum was recorded at 7 μM, the OH signal appeared at δ
5.84, whereas it shifted to δ 6.13 at 24 μM and δ 6.36 at 48 μM.
(16) (a) Miyazawa, M.; Takahashi, T.; Horibe, I.; Ishikawa, R.
Tetrahedron 2012, 68, 2007−2010. (b) Miyazawa, M.; Takahashi, T.;
Horibe, I.; Ishikawa, R. Tetrahedron 2012, 68, 3786.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all new synthetic
compounds as well as HMQC, HMBC, and NOESY spectra for
1 and 12. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: koba@chem.oit.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported in part by a Grant-in-Aid for Scientific
Research (C) (Nos. 22550115 and 24550124) from the JSPS.
■
REFERENCES
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(5) Although the mechanism for the spontaneous cleavage of the
MOM ether bond is unclear, it appears that the harsh reaction
conditions induced degradation of its functionality. In fact, the
deprotected lactone (hericenone J) was obtained in 35% yield under
these conditions and did not undergo further lactamization.
(6) Ueda, K.; Tsujimori, M.; Kodani, S.; Chiba, A.; Kubo, M.;
Masuno, K.; Sekiya, A.; Nagai, K.; Kawagishi, H. Bioorg. Med. Chem.
Lett. 2008, 16, 9467−9470.
(7) Rao, A. V. R.; Reddy, R. G. Tetrahedron Lett. 1992, 33, 4061−
4064.
(8) Yaoita, Y.; Danbara, K.; Kikuchi, M. Chem. Pharm. Bull. 2005, 53,
1202−1203.
(9) (a) Fetizon, M.; Golfier, M. C. R. Acad. Sci., Ser. C 1968, 267, 900.
(b) McKillop, A.; Young, D. W. Synthesis 1979, 401−422.
(10) (a) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett.
1977, 18, 4171−4172. (b) Lemire, A.; Grenon, M.; Pourashraf, M.;
Charette, A. B. Org. Lett. 2004, 6, 3517−3520.
(11) The corresponding MOM-deprotected amide was obtained in
7% yield.
(12) (a) Tsuritani, T.; Kii, S.; Akao, A.; Sano, K.; Nonoyama, N.;
Mase, T.; Yasuda, N. Synlett 2006, 801−803. (b) Tsuritani, T.;
Mizuno, H.; Nonoyama, N.; Kii, S.; Akao, A.; Sato, K.; Yasuda, N.;
Mase, T. Org. Process Res. Dev. 2009, 13, 1407−1412.
(13) It is likely that phosphorylation was disturbed by the presence of
the chelating MOM group. Addition of a cosolvent such as HMPA did
not affect the result.
(14) When an equimolar amount of MsCl was employed, alcohol 9
was not fully consumed, likely due to hydrolysis of the O-cyclized
imine intermediate after workup.
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dx.doi.org/10.1021/jo300719m | J. Org. Chem. 2012, 77, 5819−5822