Formal synthesis of englerin A utilizing regio- and diastereoselective [4+3] cycloaddition

Article abstract of DOI:10.1038/ja.2017.91

Englerin A, a guaiane sesquiterpene isolated from Phyllanthus engleri, showed highly potent and selective growth inhibitory activities against renal cancer cell lines. We synthesized the key tricyclic intermediate from commercially available 2,2-dimethyl-1,3-dioxan-5-one via regio- and diastereoselective [4+3] cycloaddition between the formyl enol silyl ether and the disubstituted furan, in 4.8% total yield over 10 steps.

Full text of DOI:10.1038/ja.2017.91

The Journal of Antibiotics (2017), 1–6
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ORIGINAL ARTICLE
Formal synthesis of englerin A utilizing regio- and
diastereoselective [4+3] cycloaddition
Shuichi Hagihara, Kengo Hanaya, Takeshi Sugai and Mitsuru Shoji1
Englerin A, a guaiane sesquiterpene isolated from Phyllanthus engleri, showed highly potent and selective growth
inhibitory activities against renal cancer cell lines. We synthesized the key tricyclic intermediate from commercially available
2,2-dimethyl-1,3-dioxan-5-one via regio- and diastereoselective [4+3] cycloaddition between the formyl enol silyl ether and the
disubstituted furan, in 4.8% total yield over 10 steps.
The Journal of Antibiotics advance online publication, 2 August 2017; doi:10.1038/ja.2017.91
INTRODUCTION
skeleton in the synthesis of 1, they required oxidation and
carbon–carbon bond-formation steps after the cycloaddition. For this
reason, we employed the formyl enol silyl ether 4, which had
oxygen function at 6-position and full skeletal carbons for the
methylcyclopentane ring, and 2-isopropyl-5-methylfuran (5)16 as
the substrates for the [4+3] cycloaddition. The biggest problem
that should be overcome in the cycloaddition was regio- and
diastereoselectivities in the reaction because eight isomers could
possibly be produced.
In 2009, Beutler and co-workers isolated englerin A (1, Figure 1)
from the bark of Phyllanthus engleri, a plant of the Euphorbiacea
family found in East Africa, particularly Tanzania and Zimbabwe,
and
activities against renal cancer cell lines (GI50 1–87 nM).1 The guaiane
sesquiterpene has the unique tricyclic structure including
1 showed highly potent and selective growth inhibitory
1
8-oxabicyclo[3.2.1]octane core. The characteristic structure and
interesting biological properties of 1 attracted the attention of the
synthetic chemistry community. Christmann and co-workers reported
the first synthesis of 1 and determined its absolute configuration.2 RESULTS AND DISCUSSION
Two research groups of Ma3 and Echavarren4 individually constructed
the tricyclic skeleton of 1 from linear precursor via Au-catalyzed
cycloisomerization. Nicolaou, Chen, and co-workers elegantly
synthesized 1 utilizing [5+2] cycloaddition of oxopyrilium species
and acrylate in the formation of 8-oxabicyclo[3.2.1]octane
framework.5 On the other hand, the 8-oxabicyclo[3.2.1]octane
skeleton was also prepared via [4+3] cycloaddition between furans
and enol silyl ethers.6,7 Moreover, several other research groups
achieved total or formal synthesis of 1.8–15 Although many synthetic
The preparation of formyl enol silyl ether 4a was commenced from
commercially available 2,2-dimethyl-1,3-dioxan-5-one (6) as shown in
Scheme 2. In order to avoid the self-dimerization under the basic
conditions applied for the side-chain elongation, ketone 6 was
converted to less electrophilic cyclohexylimine. Monoalkylation of
the resulting imine with homoallylic iodide under the basic conditions
followed by acidic treatment provided monoalkylketone 7. Formation
of enol silyl ether using sodium bis(trimethylsilyl)amide and
tert-butyldimethylsilyl (TBS) chloride and the subsequent thermal
approaches have been reported, more efficient strategies are treatment successfully afforded the formyl enol silyl ether 4a.17
As the desired formyl enol silyl ether 4a was in hand, the regio-
and diastereoselective [4+3] cycloaddition between 4a and 5 was
investigated. Lewis acid-mediated [4+3] cycloadditions using Me2
AlCl,17 Sc(OTf)3,18 and TiCl4 in dichloromethane resulted in complex
demanded. Herein, we report a formal synthesis of ( )-englerin A
(1) via regio- and diastereoselective [4+3] cycloaddition between the
2,5-disubstituted furan and formyl enol silyl ethers, which possesses all
skeletal carbon atoms enabling the short-step preparation of 1.
Our retrosynthesis of ( )-englerin A (1) is illustrated in Scheme 1. mixture, probably due to the coordination of the furan to the Lewis
We envisaged that ( )- 1 should be prepared from the tricyclic diol 2 acids to deactivate them. On the other hand, Brønsted acid such as
according to Sun’s synthesis.7 The methylcyclopentane moiety in 2 trifluoromethanesulfonic acid successfully promoted the [4+3]
would be constructed via Wacker oxidation of the terminal alkene in cycloaddition to afford the desired 8-oxabicyclo[3.2.1]octane
ketoalkene
3 followed by intramolecular McMurry coupling framework whereas the regioselectivity was low (3a+3e:8a+8e= 1:1).
and hydrogenation. A few research groups have utilized [4+3] Interestingly, two out of the eight isomers were selectively obtained
cycloaddition for the formation of the 8-oxabicyclo[3.2.1]octane probably due to the formation of cis-oxyallyl cation intermediate with
Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Tokyo, Japan
1Current address: Faculty of Pharmacy, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama 245-0066, Japan
Correspondence: Professor M Shoji, Faculty of Pharmacy, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama 245-0066, Japan.
E-mail: mitsu.shoji@hamayaku.ac.jp
Dedicated to Professor K.C. Nicolaou and his Outstanding Contributions to Complex Natural Product Total Synthesis and Chemical Biology.
Received 11 May 2017; revised 21 June 2017; accepted 23 June 2017

Synthesis of englerin A
S Hagihara et al
2
O
the subsequent silyl group migration onto the terminal oxygen atom
in dichloromethane might proceed faster than that in toluene, which
might cause the steric repulsion between the silyl and isopropyl
groups. On the other hand, protonation on the formyl group followed
by the formation of the oxyallyl cation and the [4+3] cycloaddition
avoiding the steric repulsion between the alkenyl chain and
the isopropyl group to form the bicycle compound 3 might be
predominant in toluene. To prevent the cleavage of the silyl ether in
the reaction mixture, bulkier triisopropylsilyl (TIPS) group was
employed. As a result, the yield of 3b increased but the regioselectivity
deteriorated instead (entry 3). In the case of triethylsilyl (TES) group,
the regioselectivity was almost the same with tert-butyldimethylsily
group (entry 4). Finally, the formyl enol silyl ether 4d possessing
diethylisopropylsilyl group furnished the desired bicycloketone 3d and
3e in high yield with excellent regioselectivity (3d+3e:8d+8e = 11:1,
entry 5). The stereochemistry of the two bicycloketones 3e and 8e was
determined by nuclear overhauser effect (NOE) experiment as shown
in Figure 2.
H
O
6
1
H
Ph
O
O
9
O
HO
(–)-englerin A (1)
guaiane
Figure 1 Structures of (−)-englerin A (1) and guaiane.
H
OH
1
6
H
ref. 7
O
( )-englerin A (1)
9
HO
As the bicycloketone framework was successfully constructed, the
formation of the methylcyclopentane moiety was investigated next.
Though Wacker oxidation on the terminal alkenes of 3c and 3e
smoothly proceeded, the following intramolecular McMurry coupling
under acidic conditions resulted in low yield. In these reactions, the
major side reactions were cleavage of the silyl ether bond for 3c
and reduction of the hydroxy group into hydrogen atom
for hydroxyketone 3e, respectively. Therefore, the hydroxy group on
3e was protected as acid-stable benzyl ether. Benzylation using
benzyltrichloroimidate, TriBOT19 and Dudly reagent20 resulted in
low yield or complex mixture. On the other hand, treatment of
alcohol 3e with excess amounts of benzyl bromide in the presence of
silver (I) oxide and tetrabutylammonium iodide afforded the benzyl
ether in 90% yield (Scheme 3). The subsequent Wacker oxidation of
the resulting alkene followed by intramolecular McMurry coupling
successfully provided the cyclopentene 9 in good yield. Hydroboration
of the disubstituted alkene 9 using 9-borabicyclo[3.3.1]nonane
required harsh conditions, whereas the desired alcohol 10 was
exclusively produced in moderate yield after oxidative treatment of
the corresponding alkyl borane as reported.6,7 Finally, reductive
removal of the benzyl ether concomitant with hydrogenation of the
tetrasubstituted alkene on tricyclic compound 10 furnished tricyclic
diol 2, which was the key synthetic intermediate for the total synthesis
of englerin A (1). The 1H NMR spectral data of 2 were in good
accordance with those reported by Sun and co-workers.7
2
O
H
H
[4 + 3]
OR
1
6
O
3
OR
O
O
+
1
6
515)
4
Scheme 1 Retrosynthesis of ( )-englerin A (1) via [4+3] cycloaddition.
1) cyclohexylamine
MS 4Å, benzene, rt
O
2) LiNEt2,
THF, –78 °C to rt
then NH4Cl, rt
79% (2 steps)
I
O
O
6
1) NaHMDS
TBSCl,THF
–78 to –50 °C
O
In conclusion, we accomplished the formal synthesis of englerin A
(1) from commercially available 2,2-dimethyl-1,3-dioxan-5-one (6)
into the key intermediate 2 in 4.8% total yield over 10 steps. The key
step was the regio- and diastereoselective [4+3] cycloaddition between
the 2,5-disubstituted furan and the formyl enol silyl ether, and the
product possessed all skeletal carbon atoms of the key intermediate for
the synthesis of 1.
O
O
2) toluene
110 °C
7
OTBS
O
78% (2 steps)
4a
EXPERIMENTAL PROCEDURES
General
Scheme 2 Preparation of formyl enol silyl ether 4a.
Merck silica gel 60 F254 thin-layer plates (1.05715.0001) was used for analytical
TLC. Merck silica gel 60 F254 thin-layer plates (1.057440001, 0.5 mm thickness)
and silica gel 60 (spherical and neutral; 63–210 μm, 37565-84) from Kanto
Chemical Co. (Tokyo, Japan) were used for preparative TLC and column
chromatography, respectively. IR spectra were measured as ATR on a JEOL FT-
IR SPX60 spectrometer or IRTracer-100. 1H NMR spectra were measured at
400 or 500 MHz on VARIAN 400-MR or 500-MR spectrometers and 13C NMR
less steric repulsion, followed by endo selective [4+3] cycloaddition
with some removal of the tert-butyldimethylsily group under acidic
conditions (Table 1, entry 1). When toluene was used as the solvent,
the regioselectivity between 3 and 8 considerably improved (3a+3e:8a
+8e= 8.3:1) to afford the desired bicycloketone 3a and 3e in 50% yield
(entry 2). From these results, protonation on the silyl enol ether and spectra were measured at 100 or 125 MHz on VARIAN 400-MR or 500-MR
The Journal of Antibiotics

Synthesis of englerin A
S Hagihara et al
3
Table 1 [4+3] cycloadditions between 4a-d and 5
OR
O
2
O
O
O
H
H
H
H
TfOH
(1.8–2.2 eq.)
RO
6
OR
4a-d
+
1
6
1
+
O
7
10
7
10
solvent
–78 °C
9
O
3a: R = TBS
8a: R = TBS
8b: R = TIPS
8c: R = TES
8d: R = i-PrEt2Si
8e: R = H
3b: R = TIPS
3c: R = TES
3d: R = i-PrEt2Si
3e: R = H
5
(3.0 eq.)
Yielda
Ratio
Entry
R
Solvent
3
8
3:8
1
2
3
4
5
TBS (4a)
CH2Cl2
Toluene
Toluene
Toluene
Toluene
32% (3a: 23%; 3e: 9%)
50% (3a: 20%; 3e: 30%)
64% (3b only)
33% (8a: 25%; 8e: 8%)
6% (8a: 2%; 8e: 4%)
17% (8b only)
1:1
TBS (4a)
8.3:1
3.8:1
8.3:1
11:1
TIPS (4b)
TES (4c)
58% (3c: 37%; 3e: 21%)
76% (3d: 11%; 3e: 65%)
7% (8c only)
i-PrEt2Si (4d)
7% (8d: 5%; 8e: 2%)
aCalculated by 1H NMR.
1) BnBr, Ag2O
TBAI, 90%
2) PdCl2, CuCl, O2
DMF, H2O, rt, 92%
0.7%
O
H
OH
CH3
H
6
0.8%
O
O
7
HO
O
3) TiCl4, Zn, pyridine
DME, reflux, 71%
3e
H
10
1
9
2
1.5%
3e
CH3
9-BBN, THF, 120 °C
OBn
H
H
H
O
then
1.2%
2.6%
NaOH, H2O2
H2O, rt, 53%
: nOe
9
OBn
Pd(OH)2, H2
CH3
H
1
H
O
O
10
1.5%
EtOH, rt, 38%
O
HO
H
7
10
6
8e
OH
CH3
2.0%
H
OH
ref. 7
( )-englerin A (1)
H
Figure 2 nOe correlations of bicycloketones 3e and 8e.
O
HO
spectrometers, respectively. High-resolution mass spectra were recorded on a
JEOL JMS-700 MStation spectrometer or a JEOL JMS-T100LP Accu TOF
spectrometer.
2
Scheme 3 Formal synthesis of ( )-englerin A (1).
4-(3-Butenyl)-2,2-dimethyl-1,3-dioxan-5-one (7)
To a solution of 2,2-dimethyl-1,3-dioxan-5-one (6, 200 mg, 1.54 mmol) in dry −35 °C under argon atmosphere, was added a solution of the above imine in
benzene (5.0 ml) was added cyclohexylamine (352 μl, 3.1 mmol) and molecular dry THF (1.6 ml) at − 78 °C over 10 min. The mixture was warmed to − 35 °C
sieves (4 Å, 400 mg). The mixture was stirred for 15 h at room temperature over 2 h and re-cooled to − 78 °C. To the solution was added 4-iodobutene
and filtered. The filtrate was concentrated in vacuo to give the crude imine. (279 mg, 1.54 mmol) and warmed to room temperature over 2 h. To the
To a solution of lithium diethylamide, which was prepared by the addition of reaction mixture was added saturated NH4Cl aq. solution and the resultant
n-butyllithium (1.56 M in hexane, 1.0 ml, 1.54 mmol) to a solution of mixture was stirred for 12 h at that temperature. The mixture was diluted with
diethylamine (0.158 ml, 1.54 mmol) in dry tetrahydrofuran (THF) (1.6 ml) at Et2O and the organic layer was washed with brine. The solution was dried over
The Journal of Antibiotics

Synthesis of englerin A
S Hagihara et al
4
anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the
1H), 5.06 (tdd, J = 1.6, 1.7, 17.0 Hz, 1H), 5.70 (t, J = 7.2 Hz, 1H), 5.82
residue was purified by silica gel column chromatography with hexane-EtOAc (tdd, J = 6.6, 10.2, 17.0 Hz, 1H), 9.14 (s, 1H). The enhancement of signal
(20:1) to afford ketone 7 (225 mg, 79%) as a colorless oil. The NMR spectrum (1.0%) for H-3 was observed by a NOE, when H-1 was irradiated.; 13C NMR
was identical with that reported previously.21
(100 MHz, CDCl3) δ 4.7, 7.0, 13.8, 17.2, 25.2, 32.4, 115.4, 134.7, 137.4, 151.8,
189.0; FT-IR (neat) ν 3077, 2952, 2875, 1693, 1633, 1462, 1398, 1371, 1319,
1242, 1182, 1119, 1012, 991, 912, 881, 721 cm− 1. HRMS (DART) [M+H]+
calculated for C14H27O2Si: 255.1780, found: 255.1791.
(Z)-2-(tert-Butyldimethylsiloxy)hepta-2,6-dienal (4a)
To a solution of NaHMDS (1.9 M in THF, 0.42 ml, 0.81 mmol) in dry THF
(2.8 ml) was added a solution of ketone 7 (100 mg, 0.54 mmol) in THF
(5.0 ml) over 10 min at − 78 °C under argon atmosphere. To the solution was
added TBSCl (105 mg, 0.70 mmol) and the solution was warmed to − 50 °C
over 2 h. The reaction was quenched with saturated NaHCO3 aq. solution and
the mixture was diluted with hexane. The organic layer was washed with brine
and dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in
vacuo and the residue was purified by silica gel column chromatography with
hexane-EtOAc (20:1) to afford the dioxin (148 mg, 92%) as a yellow oil. 1H
NMR (500 MHz, CDCl3) δ 0.13 (s, 3H), 0.14 (s, 3H), 0.92 (s, 9H), 1.43 (s, 3H),
1.45 (s, 3H), 1.63–1.69 (m, 1H), 1.81–1.88 (m, 1H), 2.09–2.23 (m, 2H), 4.13
(ddd, J = 1.3, 3.0, 6.9 Hz, 1H), 4.94 (dd, J = 2.0, 10.0 Hz, 1H), 5.02
(dd, J = 16.9, 2.0 Hz, 1H), 5.84 (tdd, J = 5.8, 10.0, 16.9 Hz, 1H), 6.12 (s, 1H);
13C NMR (125 MHz, CDCl3) δ − 4.6, − 4.4, 17.9, 20.9, 25.6, 27.8, 28.5, 30.3,
69.2, 93.3, 114.4, 126.4, 134.4, 138.7; FT-IR (neat) ν 3081, 2954, 2914, 2877,
(1R*,2S*,4R*,5S*)-2-(3-Butenyl)-4-hydroxy-5-isopropyl-1-methyl-8-
oxabicyclo[3.2.1]oct-6-en-3-one (3e)
To a solution of enal 4d (168 mg, 0.66 mmol) and furan 5 (236 mg, 1.9 mmol)
in toluene (0.5 ml) was added TfOH (112 μl, 1.3 mmol) in toluene (5.5 ml)
over 1.5 h at −78 °C by syringe pump under argon atmosphere. The reaction
was quenched with pyridine. To the mixture was added MeOH (3.3 ml) and
the solution was warmed to room temperature and stirred for 12 h at that
temperature. The reaction mixture was concentrated and diluted with CH2Cl2.
The solution was washed with saturated NaHCO3 aq. solution and the organic
materials were extracted with CH2Cl2. The combined organic layers were
washed with brine and dried over anhydrous Na2SO4 and filtered. The filtrate
was concentrated in vacuo and the residue was purified by silica gel column
chromatography with hexane-EtOAc (100:1) to afford 3e (108 mg, 65%), a
mixture of 3d and 8d (40 mg, total 16%), and 8e (3.0 mg, 2%) as colorless oil.
Other [4+3] cycloadditions in Table 1 were carried out in similar manners as
described above.
2858, 1641, 1460, 1369, 1265, 1203, 1174, 1140, 1003, 910, 860, 727 cm− 1
HRMS (FAB) calculated for C16H29O3Si: 297.1886, Found: 297.1887.
;
A solution of the above dioxin (50 mg, 0.16 mmol) in dry toluene (1.7 ml)
was stirred for 2 h at 110 °C under argon atmosphere and cooled to room
temperature. The solution was concentrated in vacuo and the residue
(4a, 36 mg, 78% over two steps) was used for the next reaction without
3e: 1H NMR (500 MHz, CDCl3)
δ 0.95 (d, J = 6.9 Hz, 3H), 1.09
(d, J = 6.9 Hz, 3H), 1.33 (dddd, J = 2.7, 6.8, 9.8, 16.1 Hz, 1H), 1.51 (s, 3H),
1.79 (dtd, J = 5.6, 8.8, 14.4 Hz, 1H), 2.04–2.11 (m, 1H), 2.20–2.34 (m, 1H),
2.26 (sept, J = 6.8 Hz, 1H), 2.59 (dd, J = 2.9, 9.0 Hz, 1H), 3.61 (d, J = 3.1 Hz,
1H), 4.22 (d, J = 2.9 Hz, 1H), 5.00 (tdd, J = 1.2, 2.2, 10.3 Hz, 1H), 5.02
(tdd, J = 1.5, 1.7, 17.1 Hz, 1H), 5.78 (dddd, J = 6.1, 7.1, 10.3, 17.1 Hz, 1H), 5.89
(d, J = 5.8 Hz, 1H), 5.95 (d, J =5.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
16.4, 17.0, 21.7, 24.2, 29.3, 32.7, 58.7, 77.9, 88.6, 92.6, 115.4, 135.0, 135.5,
138.0, 209.9; FT-IR (neat) ν 3475, 2966, 2933, 2875, 2157, 1704, 1641, 1450,
1380, 1334, 1259, 1114, 1072, 991, 908, 836, 761, 688 cm− 1; HRMS (DART)
[M+H]+ calculated for C15H23O3: 251.1647, found: 251.1656.
1
further purification. H NMR (500 MHz, CDCl3) δ 0.17 (s, 6H), 0.95 (s, 9H),
2.23 (q, J = 7.3 Hz, 2H), 2.44 (q, J = 7.3 Hz, 2H), 5.01 (dd, J = 1.4, 10.0 Hz,
1H), 5.06 (dd, J = 1.4, 17.1 Hz, 1H), 5.71 (t, J = 7.3 Hz, 1H), 5.82 (tdd, J = 6.6,
10.2, 17.1 Hz, 1H), 9.16 (s, 1H). The enhancement of signal (2.3%) for H-3 was
observed by a NOE, when H-1 was irradiated.; 13C NMR (125 MHz, CDCl3) δ
− 4.1, 18.6, 25.3, 25.8, 32.4, 115.5, 135.1, 137.2, 151.5, 188.9; FT-IR (neat) ν
3081, 2954, 2925, 2898, 2366, 2341, 1641, 1471, 1369, 1251, 1205, 1172, 1139,
877, 838, 777, 688 cm− 1; HRMS (DART) [M+H]+ calculated for C13H25O2Si:
241.1624, found: 241.1640.
3d and 8d: 1H NMR (500 MHz, CDCl3) δ 0.59–0.77 (m, 4H), 0.90–1.03
(m, 19H), 1.20–1.30 (m, 1H), 1.47 (s, 33/16H), 1.48 (s, 15/16H), 1.66
(dtd, J = 5.3, 9.0, 14.1 Hz, 5/16H), 1.82 (dtd, J = 5.3, 8.6, 13.9 Hz, 11/16H),
2.10–2.02 (m, 1.5H), 2.24–2.31 (m, 1.5H), 2.43 (dd, J =3.0, 8.3 Hz, 11/16H),
2.63 (dd, J = 2.4, 9.2 Hz, 5/16H), 4.05 (s, 5/16H), 4.28 (s, 11/16H), 4.95–5.02
(m, 2H), 5.74–5.83 (m, 1H), 5.85 (d, J = 5.8 Hz, 5/16H), 5.87 (d, J = 6.1 Hz,
11/16H), 5.93 (d, J = 5.9 Hz, 5/16H), 5.95 (d, J = 5.8 Hz, 11/16H); 13C NMR
(125 MHz, CDCl3) δ 3.7, 4.0, 4.1, 4.4, 7.1, 7.2, 7.3, 13.2, 13.4, 15.9, 16.1, 17.1,
17.3, 17.35, 17.41, 17.48, 20.6, 21.8, 23.5, 24.2, 28.1, 29.2, 32.9, 33.0, 55.8, 59.3,
79.6, 83.1, 87.6, 87.9, 92.8, 93.1, 115.1 (2C), 134.9, 135.6, 138.3, 138.4, 207.5,
207.8; FT-IR (neat) ν 3078, 2958, 2935, 2875, 2329, 2198, 1724, 1641, 1458,
(Z)-2-(Triisopropylsiloxy)hepta-2,6-dienal (4b)
The reaction was carried out in a similar manner for preparation of 4a. 1H
NMR (500 MHz, CDCl3) δ 1.05 (d, J = 7.5 Hz, 18H), 1.27 (sept, J = 7.5 Hz,
3H), 2.23 (q, J = 7.3 Hz, 2H), 2.48 (q, J = 7.3 Hz, 2H), 5.01 (dd, J = 1.4,
10.3 Hz, 1H), 5.06 (tdd, J =1.4, 1.7, 17.1 Hz, 1H), 5.67 (t, J = 7.3 Hz, 1H), 5.83
(tdd, J =6.6, 10.3, 17.1 Hz, 1H), 9.14 (s, 1H). The enhancement of signal
(2.8%) for H-3 was observed by a NOE, when H-1 was irradiated.; 13C NMR
(125 MHz, CDCl3) δ 13.7, 18.1, 25.3, 32.4, 115.4, 134.4, 137.4, 152.1, 188.9;
FT-IR (neat) ν 3080, 2945, 2866, 1693, 1630, 1464, 1398, 1371, 1321, 1248,
1182, 1122, 1016, 993, 914, 881, 816, 737, 679, 645 cm− 1. HRMS (DART) [M
+H]+ calculated for C16H31O2Si: 283.2093, found: 283.2111.
1381, 1336, 1286, 1240, 1190, 1132, 1072, 1007, 910, 881, 818, 719 cm−1
;
HRMS (ESI) [M+Na]+ calculated for C22H38NaO3Si: 401.2512, found:
401.2506.
8e: 1H NMR (500 MHz, CDCl3)
δ 0.92 (d, J = 6.6 Hz, 3H), 1.02
(Z)-2-(Triethylsiloxy)hepta-2,6-dienal (4c)
The reaction was carried out in a similar manner for preparation of 4a. 1H
NMR (500 MHz, CDCl3) δ 0.72 (q, J = 8.1 Hz, 6H), 0.96 (t, J = 8.1 Hz, 9H),
2.22 (q, J = 7.1 Hz, 2H), 2.44 (q, J =7.3 Hz, 2H), 5.02 (tdd, J = 1.7, 1.7, 10.7 Hz,
1H), 5.06 (tdd, J =1.7, 1.7, 17.1 Hz, 1H), 5.71 (t, J = 7.3 Hz, 1H), 5.82 (tdd,
J = 6.6, 10.2, 16.8 Hz, 1H), 9.15 (s, 1H). The enhancement of signal (2.8%) for
H-3 was observed by a NOE, when H-1 was irradiated.; 13C NMR (125 MHz,
CDCl3) δ 5.7, 6.8, 25.2, 32.4, 115.5, 134.9, 137.4, 151.7, 189.1; FT-IR (neat) ν
3084, 2956, 2912, 1691, 1633, 1458, 1398, 1369, 1321, 1240, 1182, 1117, 1001,
912, 733 cm− 1. HRMS (DART) [M+H]+ calculated for C13H25O2Si: 241.1624,
found: 241.1607.
(d, J = 6.9 Hz, 3H), 1.35 (dddd, J = 2.2, 7.3, 9.3, 16.1 Hz, 1H), 1.54 (s, 3H),
1.66 (dtd, J = 5.3, 9.3, 13.9 Hz, 1H), 2.02–2.15 (m, 1H), 2.11 (sept, J = 6.8 Hz,
1H), 2.23–2.35 (m, 1H), 2.78 (dd, J = 2.2, 10.0 Hz, 1H), 3.64 (d, J = 3.4 Hz,
1H), 3.99 (d, J = 3.2 Hz, 1H), 4.99 (brd, J = 10.8 Hz, 1H), 5.02
(brd, J = 17.3 Hz, 1H), 5.79 (dddd, J = 7.3, 7.3, 10.2, 17.1 Hz, 1H), 5.86
(d, J = 5.8 Hz, 1H), 5.92 (d, J =5.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
15.9, 17.4, 20.2, 23.5, 29.2, 32.5, 55.2, 81.3, 87.4, 93.7, 115.5, 134.7, 136.0,
138.0, 210.0; FT-IR (neat) ν 3482, 2964, 2916, 2875, 2848, 1707, 1641, 1448,
1377, 1369, 1339, 1260, 1190, 1169, 1111, 1072, 1024, 978, 912, 799, 760 cm-1;
HRMS (ESI) [M+Na]+ calculated for C15H22NaO3: 273.1467, found: 273.1625.
(3aR*,4R*,7S*,8S*)-8-(Benzyloxy)-7-isopropyl-1,4-dimethyl-
2,3,3a,4,7,8-hexahydro-4,7-epoxyazulene (9)
To a solution of alcohol 3e (98 mg, 0.39 mmol) in BnBr (0.5 ml, 4.2 mmol)
(Z)-2-(Diethylisopropylsiloxy)hepta-2,6-dienal (4d)
The reaction was carried out in a similar manner for preparation of 4a. 1H
NMR (400 MHz, CDCl3) δ 0.73 (q, J = 8.2 Hz, 4H), 0.96 (d, J = 7.7 Hz, 3H),
0.99 (t, J = 8.2 Hz, 6H), 1.01 (d, J =6.6 Hz, 3H), 1.06–1.19 (m, 1H), 2.18 were added Ag2O (362 mg, 1.6 mmol) and TBAI (15 mg, 0.039 mmol) and
(q, J = 6.7 Hz, 2H), 2.45 (q, J = 7.4 Hz, 2H), 5.01 (tdd, J = 1.4, 1.8, 10.1 Hz, stirred for 22 h at room temperature. To the reaction mixture was added 2 M
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Synthesis of englerin A
S Hagihara et al
5
NaOH aq. solution. The reaction mixture was filtered and washed with Et2O was vacuumed under reduced pressure to 80 μl to ensure the concentration
and the organic layer was washed with brine. The solution was dried over based on benzyl ether 9 was 0.7 mol/l. The solution was heated for 22 h at 120 °
anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the
C and cooled down to 0 °C. Then 3 M NaOH aq. solution (0.25 ml) and H2O2
residue was purified by silica gel column chromatography with hexane-EtOAc (0.25 ml, 30% aq.) was added in sequentially and the resulting solution was
(200:1) to afford the corresponding benzyl ether (136 mg, 90%) as a colorless stirred for 1 h at room temperature. The organic layer was washed with brine
oil. 1H NMR (500 MHz, CDCl3) δ 0.86 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, twice, and the organic materials were extracted with CH2Cl2. The combined
3H), 1.24–1.30 (m, 1H), 1.48 (s, 3H), 1.83 (dtd, J = 5.6, 8.5, 13.9 Hz, 1H), organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was
2.05–2.13 (m, 1H), 2.26 (sept, J = 6.8 Hz, 1H), 2.22–2.37 (m, 1H), 2.47 concentrated in vacuo. The residue was purified by silica gel column
(dd, J = 2.9, 8.3 Hz, 1H), 4.00 (s, 1H), 4.51 (d, J = 11.2 Hz, 1H), 4.98–5.06 chromatography with hexane-EtOAc (50:1) to afford alcohol 10 (10 mg,
(m, 3H), 5.81 (tdd, J = 7.0, 10.1, 16.7 Hz, 1H), 5.90 (d, J = 5.9 Hz, 1H), 6.00 53%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.01 (d, J = 7.1 Hz,
(d, J = 6.1 Hz, 1H), 7.26–7.32 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 16.1, 3H), 1.03 (d, J = 6.8 Hz, 3H), 1.20 (s, 3H), 1.35–1.43 (m, 1H), 1.79 (s, 3H),
17.0, 21.8, 24.3, 28.4, 33.0, 59.7, 73.9, 84.1, 88.0, 92.1, 115.2, 127.8, 128.32, 1.91 (dtd, J = 3.9, 10.0, 13.9 Hz, 1H), 2.06 (sept, J = 6.9 Hz, 1H), 2.24–2.45
128.33, 135.16, 135.22, 137.9, 138.3, 208.6; FT-IR (neat) ν 3342, 2970, 2929, (m, 3H), 2.73 (br, 1H), 3.84 (dd, J = 1.7, 7.6 Hz, 1H), 4.07 (br, 1H), 4.54
2837, 2339, 1718, 1653, 1454, 1381, 1334, 1119, 1070, 1024, 906 cm− 1; HRMS (d, J = 11.2 Hz, 1H), 4.74 (d, J = 11.5 Hz, 1H), 7.28–7.38 (m, 5H); 13C NMR
(ESI) [M+Na]+ calculated for C22H28NaO3: 363.1936, found: 363.1969.
To
dimethylformamide (10 ml) and water (1 ml) were added PdCl2 (6.0 mg, 3315, 2947, 2837, 2341, 1653, 1452, 1417, 1109, 1016 cm− 1; HRMS (ESI)
0.033 mmol) and CuCl (13 mg, 0.13 mmol) at room temperature. The solution [M+Na]+ calculated for C22H30NaO3: 365.2093, found: 365.2116.
was stirred for 12 h at that temperature under O2 atmosphere. The reaction
(125 MHz, CDCl3) δ 14.1, 17.5, 17.9, 18.4, 22.5, 31.3, 39.7, 42.0, 57.1, 72.9,
solution of the above benzyl ether (224 mg, 0.66 mmol) in 74.1, 82.1, 86.6, 87.6, 127.4, 127.5, 128.3, 130.8, 132.2, 138.2; FT-IR (neat) ν
a
mixture was filtered and washed with Et2O and saturated NaHCO3 aq. solution.
(1R*,3aR*,4S*,5R*,7R*,8S*,8aR*)-7-Isopropyl-1,4-
The organic materials in the filtrate were extracted with Et2O three times and
the combined organic layers were washed with brine. The solution was
dimethyldecahydro-4,7-epoxyazulene-5,8-diol (2)
To a solution of allylic alcohol 10 (1.4 mg, 4.0 μmol) in EtOH (1.0 ml) was
dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in
added Pd(OH)2 (20% on carbon, 5.0 mg, 7.0 μmol) and stirred for 15 h at
vacuo and the residue was purified by silica gel column chromatography with
room temperature under H2 atmosphere. After filtration through a pad of
hexane-EtOAc (10:1-3:1) to afford the corresponding diketone (230 mg, 92%)
celite, the filtrate was concentrated in vacuo. The residue was purified by silica
1
as a colorless oil. H NMR (500 MHz, CDCl3) δ 0.84 (d, J = 6.8 Hz, 3H), 0.87
gel column chromatography with hexane-EtOAc (30:1–10:1) to afford diol 2
(0.4 mg, 38%) as a colorless oil. The 1H NMR spectrum was identical with that
reported previously.7
(d, J = 7.1 Hz, 3H), 1.51 (s, 3H), 1.67 (dt, J = 6.6, 7.3 Hz, 2H), 2.14 (s, 3H),
2.25 (sept, J = 7.1 Hz, 1H), 2.48 (t, J = 6.4 Hz, 1H), 2.49 (dt, J = 7.5, 18.4 Hz,
1H), 2.84 (dt, J = 7.1, 17.8 Hz, 1H), 4.00 (s, 1H), 4.49 (d, J = 11.2 Hz, 1H),
5.01 (d, J = 11.3 Hz, 1H), 5.91 (d, J =6.1 Hz, 1H), 6.00 (d, J = 6.1 Hz, 1H),
7.27–7.33 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 16.1, 17.0, 19.5, 21.6, 28.4,
29.9, 42.5, 59.8, 73.9, 84.3, 88.0, 92.1, 127.8, 128.25, 128.31, 135.1, 135.3, 137.8,
208.6, 209.0; FT-IR (neat) ν 2967, 2934, 2876, 1714, 1497, 1454, 1410, 1383,
1366, 1337, 1236, 1209, 1182, 1169, 1121, 1072, 1040, 1028, 989, 903, 766, 739,
700 cm−1; HRMS (ESI) [M+Na]+ calculated for C22H28NaO4: 379.1885,
found: 379.1899.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
This work was supported by Platform for Drug Discovery, Informatics and
Structural Life Science (No. 12759017) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
To a stirred suspension of activated zinc powder (72 mg, 1.1 mmol) in
dry dimethoxyethane (2.3 ml) were added titanium (IV) chloride (60 μl,
0.56 mmol) and pyridine (45 μl, 0.56 mmol) at −78 °C under argon
atmosphere. The suspension was warmed to room temperature and then
refluxed for 2 h. Then the suspension was cooled to room temperature and to
the suspension of titanium reagent were added the above diketone (20 mg,
0.056 mmol) in dimethoxyethane (0.56 ml). The mixture was refluxed for 20 h
and cooled to room temperature. The reaction was quenched with 10% K2CO3
aq. solution at 0 °C and the mixture was filtered and washed with Et2O. The
organic materials in the filtrate were extracted with Et2O. The precipitates on
the celite were washed with 2 M HCl aq. solution and organic materials were
extracted with Et2O. The combined organic layers were washed with brine and
dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in
vacuo and the residue was purified by silica gel column chromatography with
hexane-EtOAc (50:1-20:1) to afford cyclopentene 9 (13 mg, 71%) as a colorless
oil. 1H NMR (500 MHz, CDCl3) δ 0.92 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.9 Hz,
3H), 1.05–1.14 (m, 1H), 1.31 (s, 3H), 1.75 (s, 3H), 1.84 (tdd, J = 1.3,
7.8, 12.3 Hz, 1H), 2.07 (dd, J =9.5, 15.6 Hz, 1H), 2.27 (sept, J = 6.9 Hz, 1H),
2.23–2.35 (m, 1H), 2.66 (dt, J = 1.4, 8.1 Hz, 1H), 4.24 (d, J = 1.5 Hz, 1H), 4.67
(d, J =11.2 Hz, 1H), 4.77 (d, J = 11.2 Hz, 1H), 5.84 (d, J = 5.9 Hz, 1H), 6.01
(d, J = 5.9 Hz, 1H), 7.26–7.32 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 14.6,
16.8, 17.8, 21.2, 25.1, 27.9, 38.9, 55.1, 73.6, 79.8, 87.5, 91.6, 127.36, 127.44,
128.3, 133.3, 133.6, 134.3, 134.5, 138.4; FT-IR (neat) ν 3329, 2943, 2835, 2337,
2044, 1653, 1448, 1404, 1111, 1020 cm− 1; HRMS (ESI) [M+Na]+ calculated for
C22H28NaO2: 347.1987, found: 347.1973.
1
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