Synthesis of (-)-Chamobtusin A from (+)-Dehydroabietylamine

Article abstract of DOI:10.1021/acs.joc.6b02328

Chamobtusin A, a unique diterpene alkaloid isolated from Chamaecyparis obtusa cv. tetragon, is considered to be biosynthesized from an abietane diterpenoid. On the basis of this biosynthetic hypothesis, ferruginol (15) was synthesized from (+)-dehydroabietylamine and then biomimetically transformed into (a?)-chamobtusin A in 6 steps (12 steps from (+)-dehydroabietylamine).

Full text of DOI:10.1021/acs.joc.6b02328

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Article
Synthesis of (–)-Chamobtusin A from (+)-Dehydroabietylamine
Naoki Mori, Kazuma Kuzuya, and Hidenori Watanabe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02328 • Publication Date (Web): 21 Oct 2016
Downloaded from http://pubs.acs.org on October 21, 2016
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Synthesis of (–)-Chamobtusin A from (+)-Dehydroabietylamine
Naoki Mori, Kazuma Kuzuya, Hidenori Watanabe*
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Department of Applied Biological Chemistry, Graduate School of
Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi,
Bunkyo-ku, Tokyo 113-8657, Japan
Corresponding Author: ashuten@mail.ecc.u-tokyo.ac.jp
Table of Contents Graphic
Abstract
Chamobtusin A,
a
unique diterpene alkaloid isolated from
Chamaecyparis obtusa cv. tetragon, is considered to be biosynthesized from
an abietane diterpenoid. On the basis of this biosynthetic hypothesis,
ferruginol (15) was synthesized from (+)-dehydroabietylamine, and then
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biomimetically transformed into (–)-chamobtusin A in 6 steps (12 steps from
(+)-dehydroabietylamine).
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Introduction
The family Cupressaceae, which has a worldwide distribution, is
abundant in natural products such as terpenes, flavones and lignans. During
the search for new bioactive compounds in this family, Tan and co-workers
isolated a novel diterpene alkaloid chamobtusin A (1) from Chamaecyparis
obtusa cv. tetragon.1 Although no remarkable biological activity of 1 has been
reported to date, its unique structure having a 2H-pyrrole ring intrigues
synthetic chemists. In 2010, we achieved the first total synthesis of (±)-1 by
using a presumed biomimetic aza-cyclization.2 Following our synthesis,
Aoyagi et al. accomplished the asymmetric3a as well as racemic3b synthesis of
1.
Our proposed biosynthetic pathway of 1 is shown in Scheme 1. Oxidative
cleavage of benzene ring of C4 with a well-known abietane skeleton would
generate keto aldehyde B. In the presence of ammonia, B would be converted
into imine A and subsequent aza-Michael addition to C8 would produce 1.
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Scheme 1. Presumed Biosynthesis of 1
Based on this hypothesis, the biomimetic aza-cyclization was employed
as a key reaction in our synthesis of (±)-1 as outlined in Scheme 2.2 Our
racemic synthesis commenced with the transformation of known alchohol 25
into 3 through a four-step sequence. Compound 4, a precursor for
intramolecular aza-cyclization, could be obtained from 3 through epoxidation
of the double bond followed by side chain elongations at C11 and C13
(chamobtusin A numbering). Imine formation, as shown in 5, and subsequent
intramolecular aza-Michael addition smoothly proceeded from both
Scheme 2. Our Racemic Synthesis of 12
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geometrical isomers of 4 by treatment with ammonia in the presence of
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acetic acid to afford 6 (65% from
E isomer, 60% from Z isomer). Finally, TBS
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group was removed with TBAF to give (±)-1.
Thus, the remaining task for us is to synthesize optically active 1 from
an abietane diterpenoid through a biomimetic pathway. In this article, we
describe
the
synthesis
of
(–)-chamobtusin
A
starting
from
(+)-dehydroabietylamine.
Results and Discussion
Scheme 3 illustrates our retrosynthetic analysis for the synthesis of an
optically active form of 1. The 2 -pyrrole ring of 1 would be elaborated from
H
keto aldehyde D in the same manner as that was used in our racemic
synthesis. Keto aldehyde D would be accessed from E by selective cleavage of
the C12-C13 bond. Commercially available (+)-dehydroabietylamine (F) was
considered to be suitable for a starting material, which would be converted
Scheme 3. Retrosynthetic Analysis
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into E in a straightforward manner. Key points in this strategy are when to
introduce a hydroxy group at C15 and how to cleave the C12-C13 bond
selectively.
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The synthesis started with deamination6 of (+)-dehydroabietylamine (7
= F) (Scheme 4). Amine 7 was converted to formamide 8 by treatment with
acetic-formic anhydride in 86% yield. Dehydration of formamide proceeded
under Appel’s conditions7 (PPh3, CCl4, Et3N) to give 9 in 93% yield. The
resulting isocyano group was removed by treatment with potassium and
dicyclohexano-18-crown-6 in toluene8 to afford dehydroabietane 10. With 10
in hand, we then investigated the feasibility of introduction of a C15 hydroxy
group at an earlier stage. Benzylic oxidation9 (at C7 and C15) of 10 followed
Scheme 4. Preparation of 10 and Attempt to Introduce a TBSoxy Group at
C15
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by modified Wolff-Kishner reduction10 of a ketone at C7 successfully
introduced a hydroxy group at C15 to afford the alcohol 11. Disappointingly,
the hydroxy group of 11 was prone to dehydration, and even the TBS ether
12 could not be obtained under various conditions. This result suggested that
a hydroxy group at C15 should be installed at a later stage.
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Having faced the instability of the oxygen functionality at C15, we next
turned our attention to the oxidative cleavage of the C12-C13 bond. At first,
we attempted the 1,2-glycol cleavage (17 → 18) as shown in Scheme 5.
Friedel-Crafts acylation of 10 gave 13, which was then converted to the
acetate 14 by Baeyer-Villiger oxidation in 77% yield over two steps.11 The
hydrolysis of 14 smoothly proceeded to give the phenol 15 (= ferruginol)12 in
99% yield. After extensive experimentation, the acetate 16 could be obtained
by using a Wessely oxidation (Pb(OAc)4).13 On the other hand, a hydroxy
Scheme 5. First Attempt to Cleave the C12-C13 Double Bond
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group couldn’t be introduced at C13 by using other oxidants ((PhSeO)2O,14
hypervalent iodine(III) reagent,15 MoO5•Py•HMPA16). Reduction of 16 to the
glycol 17 was then examined, but disappointingly, treatment with DIBAL or
LAH resulted in regenaration of 15.
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Next, we focused on ozonolysis17 for the selective cleavage of the
C12-C13 bond (Scheme 6). The phenol 15 was converted to the methyl ether
19 by treatment with dimethyl sulfate and sodium hydride in DMF.
Standard ozonolysis of 19 in dichlorometane at –78ºC afforded a trace
amount of the desired product 20, in which reaction the addition of boron
trifluoride18 suppressed the overoxidation to raise the yield of 20 (E/Z = 1.9:1)
up to 38%. E/Z mixtures of 20 were subjected to DIBAL reduction to give the
corresponding diol. The crude product was then oxidized with Dess-Martin
periodinane to afford (E)-21 as a single isomer in a moderate yield. On the
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Scheme 6. Completion of the Synthesis
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other hand, a Swern oxidation as well as a TPAP oxidation provided E/Z
mixtures of 21 (Swern: 38%, TPAP: 21%), but the reproducibility of these
reactions was poor. Imine formation and subsequent intramolecular
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aza-Michael addition of (E)-21 proceeded under the same condition as that
was used in our racemic synthesis to afford 22 in 74% yield. Finally, a
hydroxy group was successfully introduced at C15 by aerobic oxidation19 to
yield (–)-1 in 53% yield, whose spectroscopic data and optical rotation agreed
with those of natural chamobtusin A.
In conclusion, we have succeeded in the biomimetic transformation of
ferruginol (15), which was synthesized from (+)-dehydroabietylamine, into
(–)-chamobtusin A in 6 steps. Key steps of the synthesis include a boron
trifluoride assisted selective ozonolysis of the C12-C13 bond and a late stage
installation of a hydroxy group at C15.
Experimental Section
General Procedures. Dry tetrahydrofuran (THF) and toluene were distilled
from sodium-benzophenone ketyl before use. Anhydrous methylene chloride
(CH2Cl2) was distilled from phosphorus pentoxide (P2O5) and stored under
an argon atmosphere. IR spectra were measured with an FT-IR
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spectrophotometer. H-NMR and 13C-NMR spectra were recorded at room
temperature. Chemical shifts ( ) were referenced to the residual solvent
peak as the internal standard (CDCl3: H = 7.26, C = 77.0; C6D6: H = 7.15,
δ
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δ
δ
δ
δC = 128.4; CD3OD: δH = 3.30, δC = 49.0). Column chromatography was
performed using 0.060-0.200mm silica gel. TLC was carried out using 0.25
mm plate. Preparative TLC was carried out using 0.5 mm plate.
(+)-(1R,4aS,10aR)-1-(Formamidomethyl)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4
a,9,10,10a-octahydrophenanthrene (8). An equimolar mixture of formic acid
(4.10 ml, 95.5 mmol) and acetic anhydride (9.00 ml, 95.5 mmol) was heated
at 65 °C for 10 minutes. After cooling to 0 °C, this solution was added to
(+)-dehydroabietylamine (18.2 g, 63.7 mmol) in THF (200 ml). After stirring
at room temperature for 20 minutes, the reaction mixture was poured into
water and extracted with EtOAc. The organic layer was successively washed
with saturated aqueous NaHCO3, water and brine, dried over anhydrous
magnesium sulfate and concentrated in vacuo. The residue was
chromatographed over silica gel. Elution with hexane-ethyl acetate (1:1)
gave 8 (17.2 g, white solid, 86%): [α]D19 = +36.7 (
IR νmax (nujol) cm-1: 3291, 2241, 1663, 1544, 1497, 1456, 1384, 1231, 1039,
909, 822, 771, 732. 1H NMR
(300 MHz, CDCl3) ppm: 0.96 (3H, s), 1.22 (3H,
c 1.05, CHCl3). Mp 43-46 °C.
δ
s), 1.22 (6H, d,
J
= 6.9 Hz), 1.33-2.04 (8H, m), 2.30 (1H, m), 2.82 (1H, sep, J =
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6.9 Hz), 2.78-2.91 (2H, m), 3.13 (1H, dd, 14.1, 6.9 Hz), 3.29 (1H, dd,
J = 14.1,
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6.9 Hz), 5.55 (1H, br), 6.90 (1H, brs), 7.00 (1H, dd, = 8.1, 1.5 Hz), 7.16 (1H,
J
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d, = 8.1 Hz), 8.19 (1H, d, δ (125 MHz, CDCl3) ppm:
J
J
= 1.5 Hz).13C NMR
18.8, 18.9, 19.1, 24.2, 25.4, 30.2, 33.6, 36.4, 37.5, 37.6, 38.5, 45.3, 48.5, 124.1,
124.3, 127.1, 134.9, 145.9, 147.3, 161.5. ESI-TOFMS m/z calcd. for
C21H31NNaO [M+Na]+ 336.2298, found 336.2331.
(+)-(1R,4aS,10aR)-1-Isocyanomethyl-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,1
0,10a-octahydrophenanthrene (9). To a solution of 8 (26.8 mg, 85.0 mmol) in
CH2Cl2 (1.0 ml) were added triphenylphospine (63.0 mg, 0.239 mmol),
triethylamine (83.0 ml, 0.595 mmol) and carbon tetrabromide (85.0 mg,
0.255 mmol), and stirring was continued under argon at 0 °C for 10 minutes.
The reaction mixture was poured into saturated aqueous NH4Cl and
extracted with Et2O. The organic layer was washed with brine, dried over
sodium sulfate and concentrated in vacuo
chromatographed over silica gel. Elution with hexane-ethyl acetate (1:1)
gave 9 (23.3 mg, orange oil, 93%): [α]D20 = +10.3 (
1.02, CHCl3). IR νmax
(nujol) cm-1: 2143, 1497, 1456, 1387, 822. 1H NMR
(300 MHz, CDCl3) ppm:
0.99 (3H, s), 1.23 (3H, s), 1.23 (6H, d, = 6.9 Hz), 1.40-1.88 (8H, m), 2.32 (1H,
dt, = 12.9, 3.3 Hz), 2.83 (1H, sep, = 6.9 Hz), 2.92 (2H, dd, = 8.1, 4.8 Hz),
3.17 (1H, d, = 14.7 Hz), 3.33 (1H, d, = 14.7 Hz), 6.90 (1H, d, = 1.2 Hz),
.
The residue was
c
δ
J
J
J
J
J
J
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7.01 (1H. dd.
J = 8.1, 1.2 Hz), 7.18 (1H, d, J δ (125 MHz,
= 8.1 Hz). 13C NMR
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9
CDCl3) ppm: 18.3, 18.7, 19.2, 24.2, 25.3, 30.2, 33.7, 36.1, 37.1, 37.7, 38.3, 45.2,
53.9, 124.2, 124.5, 127.0, 134.5, 146.0, 146.7, 157.1. ESI-TOFMS m/z calcd.
for C21H29NNa [M+Na]+ 318.2192, found 318.2211.
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(+)-(4aS,10aS)-7-Isopropyl-1,1,4a-trimethyl-1,2,3,4,4a,9,10,10a-octahydroph
enanthrene (10). To a solution of 9 (14.1 mg, 48.0 mmol) in toluene (1.0 ml)
were added dicyclohexano-18-c-6-ether (35.0 mg, 95.0 mmol) and potassium
(56.0 mg, 1.43 mmol), and stirring was continued under argon at room
temperature for 80 minutes. The reaction mixture was quenched by the
addition of isopropyl alcohol. After stirring for 2 hours, the reaction mixture
was poured into water and extracted with Et2O. The organic layer was
successively washed with water and brine, dried over anhydrous magnesium
sulfate and concentrated in vacuo. The residue was chromatographed over
20
silica gel. Elution with hexane gave 10 (11.1 mg, white crystal, 96%): [α]D
=
+48.3 (
c
1.00, CHCl3). Mp 34-35 °C. IR νmax (nujol) cm-1: 1497, 1457, 1374,
1038, 888, 821. 1H NMR
1.18 (3H, s), 1.23 (6H, d,
δ
S(300 MHz, CDCl3) ppm: 0.93 (3H, s), 0.94 (3H, s),
J
= 6.9 Hz), 1.32-2.17 (8H, m), 2.27 (1H, m), 2.83 (1H,
sep,
J
= 6.9 Hz), 2.78-2.97 (2H, m), 6.89 (1H, s), 6.99 (1H, d,
J = 8.4 Hz). 7.18
(1H, d,
J
= 8.4 Hz). 13C NMR
δ
(125 MHz, CDCl3) ppm: 19.3, 19.6, 21.8, 24.2
(2C), 25.1, 30.7, 33.6, 33.7, 37.7, 39.1, 41.9, 50.6, 124.0, 124.5, 127.0, 135.1,
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145.6, 147.8. ESI-TOFMS m/z calcd. for C20H30Na [M+Na]+ 293.2240, found
293.2264.
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(+)-(4aS,10aS)-6-Acetyl-7-isopropyl-1,1,4a-trimethyl-1,2,3,4,4a,9,10,10a-octa
hydrophenanthrene (13). To a solution of 10 (406 mg, 1.50 mmol) and AcCl
(373 ml, 5.25 mmol) in CH2Cl2 (7.5 ml) was added AlCl3 (125 mg, 4.50 mmol)
at 0 °C under argon. After stirring for 3 minutes at room temperature, the
reaction mixture was poured into ice-cold 3N HCl and extracted with Et2O.
The organic layer was successively washed with saturated aqueous NaHCO3,
water and brine, dried over anhydrous magnesium sulfate and concentrated
in vacuo. The residue was chromatographed over silica gel. Elution with
hexane-ethyl acetate (20:1) gave 13 (337 mg, white solid, 88%): [α]D20 = +62.5
(
c
1.01, CHCl3). Mp 95-98 °C. IR νmax (nujol) cm-1: 1683, 1557, 1457, 1353,
1262, 1218, 771. 1H NMR
(300 MHz, CDCl3) ppm: 0.78 (3H, s), 0.80 (3H, s),
1.03 (3H, s), 1.04 (3H, d, = 6.9 Hz), 1.97 (3H, d, = 6.9 Hz), 1.10-1.79 (8H,
m), 2.13 (1H, m), 2.40 (3H, s), 2.61-2.84 (2H, m), 3.33 (1H, sep, = 6.9 Hz),
6.89 (1H, s), 7.11 (1H, s). 13C NMR
(125 MHz, CDCl3) ppm: 19.1, 19.4, 21.8,
δ
J
J
J
δ
24.3, 24.5, 25.1, 28.8, 30.6, 30.7, 33.5, 33.7, 37.7, 39.0, 41.8, 50.5, 124.7, 127.1,
136.4, 139.3, 144.9, 147.4, 203.6. ESI-TOFMS m/z calcd. for C22H32NaO
[M+Na]+ 335.2345, found 335.2332.
(+)-(4aS,10aS)-6-Acetoxy-7-isopropyl-1,1,4a-trimethyl-1,2,3,4,4a,9,10,10a-oct
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ahydrophenanthrene
(14).
13
(63.8
mg,
0.204
mmol)
and
8
9
meta-chloroperbenzoic acid (ca. 65%, 63.8 mg 1.22 mmol) were dissolved in
CH2Cl2 (1.5 ml). At 0 °C, trifluorocetic acid (15.0 ml, 0.204 mmol) was added
dropwise to the mixture. After stirring overnight at room temperature, the
reaction mixture was diluted with CH2Cl2, poured into 5% aqueous Na2SO3
and extracted with CH2Cl2. The organic layer was successively washed with
saturated aqueous NaHCO3, water and brine, dried over anhydrous
magnesium sulfate and concentrated in vacuo. The residue was
chromatographed over silica gel. Elution with hexane-ethyl acetate (50:1)
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14
15
16
17
18
19
20
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gave 14 (58.0 mg, yellow oil, 87%): [α]D21 = +54.6 (
c
0.96, CHCl3). IR νmax
1
(nujol) cm-1: 1760, 1496, 1457, 1366, 1205, 1164, 1015, 913, 772. H NMR
δ
(300 MHz, CDCl3) ppm: 0.92 (3H, s), 0.94 (3H, s), 1.16 (3H, d,
1.18 (3H, s), 1.19 (3H, d, = 7.2 Hz), 1.24-1.88 (8H, m), 2.16 (1H, m), 2.30 (3H,
s), 2.76-2.94 (3H, m), 6.83 (1H, s), 6.94 (1H, s). 13C NMR
(125 MHz, CDCl3)
J = 7.2 Hz),
J
δ
ppm: 19.3, 19.4, 21.2, 21.8, 23.2, 23.3, 25.0, 27.3, 30.2, 33.5, 33.6, 37.8, 39.0,
41.9, 50.2, 118.1, 127.1, 133.3, 136.8, 146.3, 149.0, 170.2. ESI-TOFMS m/z
calcd. for C22H32NaO2 [M+Na]+ 351.2295, found 351.2274.
(+)-(4aS,10aS)-6-Hydroxy-7-isopropyl-1,1,4a-trimethyl-1,2,3,4,4a,9,10,10a-oc
tahydrophenanthrene (15). To a solution of 14 (6.65 g, 20.2 mmol) in MeOH
(70 ml) was added 4N NaOH (150 ml), and stirring was continued at room
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temperature for 2 hours. The reaction mixture was poured into 3N HCl and
extracted with Et2O. The organic layer was successively washed with
saturated aqueous NaHCO3, water and brine, dried over anhydrous
magnesium sulfate and concentrated in vacuo. The residue was
chromatographed over silica gel. Elution with hexane-ethyl acetate (10:1)
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11
12
13
14
15
16
17
18
19
20
21
22
23
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gave 15 (5.74 g, white amorphous, 99%): [α]D22 = +55.7 ( 0.91, CHCl3) {lit.12a
c
[α]D20 = +45.6 (
c
2.5, CHCl3)}. IR νmax (nujol) cm-1: 3336, 1507, 1458, 1417,
1
1374, 1323, 1221, 1164, 1001, 908, 891, 771, 734. H NMR
δ
(300 MHz,
= 6.9 Hz),
= 6.9 Hz), 1.28-1.90 (8H, m), 2.16 (1H, m), 2.72-2.91 (2H, m),
= 6.9 Hz), 4.59 (1H, br), 6.64 (1H, s), 6.85 (1H, s). 13C NMR
CDCl3) ppm: 0.93 (3H, s), 0.95 (3H, s), 1.18 (3H, s), 1.24 (3H, d,
1.25 (3H, d,
3,12 (1H, sep,
J
J
J
δ
(125 MHz, CDCl3) ppm: 19.4, 19.5, 21.8, 22.7, 23.0, 25.0, 27.0, 30.0, 33.5, 33.6,
37.7, 39.1, 41.9, 50.6, 111.2, 126.8, 127.5, 131.6, 148.9, 150.9. ESI-TOFMS
m/z calcd. for C20H30NaO [M+Na]+ 309.2189, found 309.2190.
(+)-(4aS,10aS)-7-Isopropyl-6-methoxy-1,1,4a-trimethyl-1,2,3,4,4a,9,10,10a-o
ctahydrophenanthrene (19). To a solution of sodium hydride (530 mg, 12.2
mmol) in DMF (30 ml) was added a solution of 15 (2.32 g, 8.10 mmol) in DMF
(30 ml) at 0 °C. After stirring for 30 minutes, dimethyl sulfate (3.84 ml, 40.5
mmol) was added to the mixture and stirring was continued for 10 minutes.
The reaction mixture was poured into water and extracted with EtOAc. The
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organic layer was successively washed with 3N HCl, saturated aqueous
NaHCO3, water and brine, dried over anhydrous magnesium sulfate and
concentrated in vacuo. The residue was chromatographed over silica gel.
Elution with hexane-ethyl acetate (20:1) gave 19 (2.28 g, colorless oil, 94%):
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13
14
15
16
17
18
19
20
21
22
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c
[α]D22 = +61.9 ( 0.81, CHCl3). IR νmax (nujol) cm-1: 1613, 1573, 1499, 1463,
1404, 1374, 1323, 1249, 1207, 1165, 1104, 969, 909, 892, 735. 1H NMR
δ
(300
= 6.6
= 6.6
MHz, CDCl3) ppm: 0.95 (3H, s), 0.97 (3H, s), 1.22 (3H, s), 1.23 (6H, d,
Hz), 1.20-1.92 (8H, m), 2.28 (1H, m), 2.75-2.91 (2H, m), 3.25 (1H, sep,
J
J
Hz), 3.82, (3H, s), 6.75 (1H, s), 6.87 (1H, s). 13C NMR
δ (125 MHz, CDCl3)
ppm: 19.4, 19.6, 21.8, 22.9, 23.1, 25.0, 26.6, 30.0, 33.6, 33.7, 38.1, 39.1, 41.9,
50.7, 55.8, 106.7, 126.6, 127.1, 134.3, 148.3, 155.2. ESI-TOFMS m/z calcd. for
C21H32NaO [M+Na]+ 323.2345, found 323.2326.
Methyl
2-[(4aS,8aS)-5,5,8a-trimethyl-2-(3-methyl-2-oxobutylidene)-3,4,4a,5,6,7,8,8a-
octahydronaphthalen-1-ylidene]acetate (20). At –78 °C, a stream of ozone
was bubbled through a solution of 19 (17.0 mg, 56.6 mmol) and BF3•OEt2
(8.00 ml, 62.3 mmol) in CH2Cl2 (2.0 ml) for 15 minutes. The organic layer
was washed with water, dried over anhydrous magnesium sulfate and
concentrated in vacuo. The residue was chromatographed over silica gel.
Elution with hexane-ethyl acetate (7:1) gave 20 (7.2 mg, yellow oil, 38%,
E:Z
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= 1.9:1). Two isomers were separated by preparative TLC for instrumental
8
9
analyses: (
1685, 1612, 1462, 1371, 1173, 1055, 487, 473, 454, 436, 415. 1H NMR
MHz, C6D6) ppm: 0.65 (6H, s), 0.82 (3H, s), 1.05 (6H, d, = 7.2 Hz), 0.54-1.55
(9H, m), 1.99 (1H, ddt, = 5.7, 1.8, 13.2 Hz), 2.35 (1H, sep, = 7.2 Hz), 3.42
(3H, s), 4.40 (1H, m), 5.51 (1H, s), 5.97 (1H, d,
E
)-20; [α]D21 = –43.8 (
c
1.02, CHCl3). IR νmax (nujol) cm-1: 1728,
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16
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19
20
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22
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50
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53
54
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56
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59
60
δ
(300
J
J
J
13
J
= 1.8 Hz). C NMR δ (125
MHz, C6D6) ppm: 18.5, 18.7, 19.7, 20.0, 22.3, 23.8, 31.2, 33.7, 34.5, 37.5, 42.5,
43.9, 51.3, 53.8, 111.5, 123.6, 155.9, 167.8, 168.0, 203.9. ESI-TOFMS m/z
25
calcd. for C21H32NaO3 [M+Na]+ 355.2244, found 355.2253: (
+36.5 (
1178, 1048, 855, 668. 1H NMR
s), 1.08 (3H, d, = 7.2 Hz), 1.11 (3H, d,
m), 2.19-2.27 (2H, m), 2.47 (1H, sep,
6.04 (1H, s). 13C NMR
Z)-20; [α]D
=
c
1.11, CHCl3). IR νmax (nujol) cm-1: 1727, 1644, 1612, 1458, 1389,
(300 MHz, C6D6) ppm: 0.70 (3H, s), 0.71 (3H,
δ
J
J
= 7.2 Hz), 1.12 (3H, s), 0.84-1.58 (9H,
= 7.2 Hz), 3.41 (3H, s), 5.72 (1H, s),
J
δ
(125 MHz, C6D6) ppm: 17.8, 18.9, 19.7, 22.4, 25.2,
33.9, 34.8, 37.1, 40.2, 41.3, 42.7, 45.1, 51.0, 55.7, 110.8, 122.8, 153.3, 165.4,
167.0, 201.8. ESI-TOFMS m/z calcd. for C21H32NaO3 [M+Na]+ 355.2244,
found 355.2253.
(–)-(2E)-2-[(4aS,8aS)-5,5,8a-trimethyl-2-(3-methyl-2-oxobutylidene)-3,4,4a,5,
6,7,8,8a-octahydronaphthalen-1-ylidene]acetaldehyde (21). To a solution of
20 (19.6 mg, 59.0 mmol) in THF (0.5 ml) was added 1.03 M DIBAL in hexane
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(286 ml, 0.295 mmol) at –10 °C. After stirring for 5 minutes, the reaction
mixture was quenched with MeOH and a saturated aqueous Rochell’s salt
solution, and extracted with EtOAc. The organic layer was washed with
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brine, dried over anhydrous magnesium sulfate and concentrated in vacuo
.
The crude product was used for the next step without purification. To a
solution of the crude alcohol in CH2Cl2 (1.0 ml) were added Dess-Martin
periodinane (75.0 mg, 0.177 mmol) and NaHCO3 (25.0 mg, 0.295 mmol) at
room temperature, and stirring was continued for 4 h. The reaction mixture
was diluted with Et2O, poured into 5% aqueous Na2S2O3 solution and
extracted with Et2O. The organic layer was washed with brine, dried over
sodium sulfate and concentrated in vacuo
chromatographed over silica gel. Elution with hexane-ethyl acetate (10:1)
gave ( 0.98, CHCl3).
)-21 (6.7 mg, yellow oil, 38% in 2 steps): [α]D19 = –87.4 (
IR νmax (nujol) cm-1: 1674, 1604, 1462, 1378, 1117, 1051, 861. 1H NMR
(300
MHz, C6D6) ppm: 0.63 (3H, s), 0.67 (3H, s), 0.73 (3H, s), 0.92 (3H, d, = 6.6
Hz), 0.93 (3H, d, = 6.6 Hz), 0.69-1.50 (9H, m), 1.62 (1H, ddt, = 6.0, 2.1,
13.8 Hz), 2.15 (1H, sep, = 6.6 Hz), 4.16 (1H, ddd, = 13.8, 4.2, 2.1 Hz), 5.73
(1H, d, = 2.1 Hz), 5.77 (1H, d, = 7.2 Hz), 9.85 (1H, d,
= 7.2 Hz). 13C NMR
(125 MHz, C6D6) ppm: 18.3, 18.5, 19.5, 20.2, 22.3, 23.4, 31.4, 33.6, 34.6, 37.2,
.
The residue was
E
c
δ
J
J
J
J
J
J
J
J
δ
42.2, 42.3, 43.6, 53.0, 123.4, 127.3, 153.4, 174.3, 192.3, 203.3. ESI-TOFMS
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m/z calcd. for C20H30NaO2 [M+Na]+ 325.2138, found 325.2129.
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9
(–)-3-Methyl-1-[(3aS,5aS,9aS)-6,6,9a-trimethyl-4,5,5a,6,7,8,9,9a-octahydro-3
aH-benzo[e]indol-3a-yl]butan-2-one (22). At room temperature, a stream of
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ammonia gas was bubbled through a solution of (
E)-21 (42.1 mg, 0.139 mmol)
and AcOH (3.0 ml) in -BuOH (5.0 ml) for 5 minutes, and stirring was
t
continued for 2 hours. The reaction mixture was concentrated in vacuo, and
the residue was chromatographed over silica gel. Elution with ethyl acetate
gave 22 (31.0 mg, yellow oil, 74%): [α]D20 = –221 (
(nujol) cm-1: 1709, 1604, 1517, 1465, 1381, 1235, 1138, 835, 455, 432, 413. 1H
NMR (300 MHz, C6D6) ppm: 0.70 (3H, s), 0.77 (3H, s), 0.95 (3H, d, = 6.9
Hz), 1.04 (3H, s), 1.08 (3H, d, = 6.9 Hz), 0.49-1.65 (10H, m), 2.41 (1H, d,
13.2 Hz), 2.67 (1H, sep, = 6.9 Hz), 2.79 (1H, dt,
= 13.2 Hz), 5.61 (1H, s), 7.78 (1H, s). 13C NMR
c 1.02 , CHCl3). IR νmax
δ
J
J
J =
J
J
= 12.6, 3.0 Hz), 2.99 (1H, d,
J
δ (125 MHz, C6D6) ppm: 18.0,
18.5, 18.6, 19.2, 19.9, 22.1, 34.2, 34.2, 38.3, 39.1, 40.4, 42.1, 42.6, 45.9, 58.1,
81.8, 117.3, 162.6, 183.1, 210.8. ESI-TOFMS m/z calcd. for C20H31NNaO
[M+Na]+ 324.2298, found 324.2308.
(–)-3-Hydroxy-3-methyl-1-[(3aS,5aS,9aS)-6,6,9a-trimethyl-4,5,5a,6,7,8,9,9a-
octahydro-3aH-benzo[e]indol-3a-yl]butan-2-one (Chamobtusin A, 1). To a
solution of 22 (43.2 mg, 0.143 mmol) in
t-BuOH/DMF (1:2, 1.5 ml) were
added triethyl phosphite (48.0 ml, 0.286 mmol) and
t
-BuOK (18.0 mg, 0.157
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mmol) at 0 °C, and stirring was continued under oxygen for 1 hour. The
reaction mixture was diluted with EtOAc, washed with water and brine,
dried over anhydrous magnesium sulfate and concentrated in vacuo. The
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residue was chromatographed over silica gel. Elution with ethyl acetate gave
20
1 (24.0 mg, yellow crystal, 53%): [α]D = –297 (
c 0.22, CH3OH). Mp
139-144 °C. IR νmax (KBr) cm-1: 3154, 2925, 1723, 1607, 1521, 1476, 1390,
1
1242, 1182, 1054, 969, 831, 707. H NMR
δ (500 MHz, CD3OD) ppm:
0.65-0.76 (2H, m), 0.89 (3H, s), 0.98 (3H, s), 1.16 (3H, s), 1.20 (3H, s), 1.21
(3H, s), 1.08-1.87 (8H, m), 2.62 (1H, dt, = 13.0, 3.0 Hz), 3.39 (1H, d, = 17.5
Hz), 3.53 (1H, d, (125 MHz,
= 17.5 Hz), 6.10 (1H, s), 7.96 (1H, s). 13C NMR
J
J
J
δ
CD3OD) ppm: 17.5, 19.7, 20.5, 22.3, 26.9, 34.4, 35.0, 38.9, 41.6, 42.3, 42.7,
43.4, 59.8, 78.1, 80.9, 118.2, 165.9, 184.7, 213.7. ESI-TOFMS m/z calcd. for
C20H31NNaO2 [M+Na]+ 340.2247, found 340.2249.
Acknowledgments
This work was supported by Grant-in-Aid for Young Scientists (B) (No.
21780108) to N.M. from JSPS.
Supporting Information
1H and 13C NMR Spectra of Compounds 8-10, 13-15, 19-22 and 1.
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References
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(10) Minlon, H. J. Am. Chem. Soc. 1946, 68, 2487-2488.
(11) Malkowsky, I. M.; Nieger, M.; Kataeva, O.; Waldvogel, S. R. Synthesis
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(12) Other methods for preparing 15 have been reported. See: (a) González,
M. A.; Pérez-Guaita, D. Tetrahedron 2012, 68, 9612-9615. (b) González, M.
A.; Clark, J.; Connelly, M.; Rivas, F. Bioorg. Med. Chem. Lett. 2014, 24
,
5234-5237. (c) Roa-Linares, V. C.; Brand, Y. M.; Agudelo-Gomez, L. S.;
Tangarife-Castaño, V.; Betancur-Galvis, L. A.; Gallego-Gomez, J. C.;
González, M. A. Eur. J. Med. Chem. 2016, 108, 79-88.
(13) (a) Wessely, F.; Lauterbach-Kiel, G.; Sinwel, F. Monatsch. Chem.
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Chem. Int. Ed. 2009, 48, 4605-4609.
(16) Vedejs, E.; Larsen, S. Org. Synth. 1986, 64, 127-137.
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reported. Akita, H.; Oishi, T. Tetrahedron Lett. 1978, 19, 3733-3736.
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(18) Isobe, K.; Mohri, K.; Tokoro, K.; Fukushima, C.; Higuchi, F.; Taga, J.;
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