Total synthesis of aphadilactones A-D

Article abstract of DOI:10.1021/jo501117k

The first total synthesis of aphadilactones A-D, diastereomeric natural products recently isolated from the Meliaceae plant Aphanamixis grandifolia by Yue and co-workers, which possess an unprecedented carbon skeleton, has been achieved. The synthesis features a catalytic asymmetric hetero-Diels-Alder reaction to form the dihydropyran ring, concurrent installation of the lactone and furan moieties via a tandem acid-catalyzed acetal cleavage, oxidation, and cyclization process, and an intermolecular Diels-Alder reaction to forge the target products.

Full text of DOI:10.1021/jo501117k

Article
pubs.acs.org/joc
Total Synthesis of Aphadilactones A−D
Jian-Peng Yin,† Min Gu,‡ Ying Li,*,† and Fa-Jun Nan*,‡
†State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou
730000, PR China
‡The National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, Shanghai 201203, PR China
S
* Supporting Information
ABSTRACT: The first total synthesis of aphadilactones A−D, diastereomeric natural products recently isolated from the
Meliaceae plant Aphanamixis grandifolia by Yue and co-workers, which possess an unprecedented carbon skeleton, has been
achieved. The synthesis features a catalytic asymmetric hetero-Diels−Alder reaction to form the dihydropyran ring, concurrent
installation of the lactone and furan moieties via a tandem acid-catalyzed acetal cleavage, oxidation, and cyclization process, and
an intermolecular Diels−Alder reaction to forge the target products.
The diastereomeric aphadilactones A−D were obtained in
similar amount from their natural source, which strongly
suggests that the final dimeric reaction is a nonenzymatically
catalyzed process. Following these considerations, our synthetic
design (Scheme 1) hinged upon the use of this bioinspired [4 +
2] dimerization of S-dienelactone 12, and as such, it follows in
the footsteps of other successful biomimetic syntheses. Further
disconnection of monomer 12 was envisioned via Suzuki and
aldol couplings to introduce the two termini, and a tandem
acid-catalyzed acetal cleavage, oxidation, and cyclization
reaction. An asymmetric catalytic hetero-Diels−Alder reaction
would provide a highly efficient route to the required chiral
lactone.
INTRODUCTION
■
Aphadilactones A−D (1−4), a novel class of diterpenoid
dimers, were first isolated from the leaves of Aphanamixis
grandifolia, an arbor tree that grows mainly in the tropical and
subtropical areas of Asia, by Yue and co-workers.1 Yue et al.
have proposed that the aphadilactones are formed via a
biosynthetic [4 + 2] dimerization of monomer. Aphanamenes A
and B (5, 6), which may originate from dimerization of a
similar monomer, have been isolated from the same plant by
Kong and co-workers.2 Monomer derivatives nemoralisins (7−
10) have also been reported by Yue3 and Kong4 (Figure 1).
Aphadilactone C has exhibited significant inhibitory activity
against diacylglycerol O-acyltransferase 1 (DGAT-1) with an
With this in mind, our investigation began with synthesis of
oxidation/cyclization precursor 13, as shown in Scheme 2. In
seeking an efficient, enantioselective method for the prepara-
tion of alkynyl acetal 15, we were particularly intrigued by the
possibility of applying the recently developed Cr-catalyzed
hetero-Diels−Alder (HDA) reaction to this task. In earlier
studies, cycloadditions between 1-methoxybutadiene and
simple aldehydes catalyzed by complex S3 or its enantiomer
(developed by Jacobsen and co-workers9−12) proceeded with
high enantioselectivity; this approach has also successfully been
applied in other natural product total syntheses.13,14 Upon
investigation of the reaction of alkoxybutadiene derivatives with
2-butynal 17, we were pleased to find that 17 was indeed an
effective partner in the asymmetric HDA reaction, affording
cycloadducts in good yield (84%) and enantioselectivity (98%
IC50 of 0.46
0.09 μM and high selectivity for DGAT-2
(selectivity index >217).1 DGAT-1 and DGAT-2 have been
reported to play important roles in triglyceride synthesis and
metabolism; the accumulation of triglycerides in adipocytes is
associated with a number of human diseases such as obesity,
diabetes, and steatohepatitis.5−8 In this paper, we report a full
account of the first total synthesis of aphadilactones A−D.
RESULTS AND DISCUSSION
■
The isolation team proposed a reasonable biosynthetic pathway
for the assembly of aphadilactones A−D, with a [4 + 2]
dimerization of monomer 12 at its heart (Scheme 1).1
A
concerted Diels−Alder cycloaddition of the starting diene 12
would be expected to afford the key intermediate 11. Although
a stepwise Diels−Alder reaction cannot be excluded, we believe
that a concerted Diels−Alder reaction might followed by a fast,
thermodynamically favorable 1,3-hydrogen migration, leading
to the formation of the aphadilactones (Scheme 1).
Received: May 20, 2014
© XXXX American Chemical Society
A
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a
Figure 1. Diterpenoids and diterpenoids dimers from Aphanamixis grandifolia. The absolute configuration of 7 is not known.
Scheme 1. Retrosynthetic Analysis of Aphadilactones A−D
Scheme 2. Synthesis of the Oxidation/Cyclization Precursor Diene 13
ee). Acetal 15 was transformed to the thermodynamically more
stable 18 in the presence of acid in i-PrOH, and was isolated as
a single diastereomer.13,14 Conversion of 18 to the desired E-
vinyl iodide 14 was achieved by stannylation with in situ
generated Bu3Sn(Bu)CuCNLi2 followed by Sn−I exchange
with NIS.15 Alternative methods for the formation of the
metalated vinyl intermediate required for this transformation,
such as Pd mediated hydrostannylation or the use of Schwartz
reagent, afforded the desired product in low yields and as
mixtures of regioisomers (E/Z ratios between 5:1 and 1:1).
Subsequent Suzuki cross-coupling with readily available
organoborane reagent S1 gave the trisubstituted E-20.16
Deprotection and oxidation with TPAP/NMO gave aldehyde
22;17 other oxidation methods, including Swern oxidation,
PCC, and Dess−Martin, failed to afford the target product.
Methylenation with Eschenmoser’s salt using Et3N as the base
installed the methylene functionality in 23 in a single step.18 23
could then be used for an aldol reaction with 3-hydroxy-3-
methyl-2-butanone (S2). Intermediate 13 was synthesized in
gram quantities.
B
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Scheme 3. Synthesis of the Monomer 12
Scheme 4. Bioinspired [4 + 2] Dimerization of Diene Latone 12 to Aphadilactones A−D
With key precursor 13 in hand, the synthesis of 12 was then
accomplished in a three-step tandem sequence. Acid-catalyzed
cleavage of the acetal was followed by oxidation of MnO2. The
filtrate of the reaction mixture was then treated with p-TsOH.
Thus, through a short and high yielding synthetic sequence,
diene lactone 12 was synthesized in 40% yield (3 steps, Scheme
3).
rotation of synthetic aphadilactones A−D and that reported in
the literature may be due to differences in purity of the samples
(comparing the purity of natural compounds and synthetic
samples by 1H NMR), which would cause significant
underestimation of its own chiral properties.
In summary, we have accomplished the first total synthesis of
aphadilactones A−D, diterpenoid dimers discovered by Yue
and co-workers,1 in 11 steps from known compounds 16 and
17 in 6.6% overall yield. Key features of the synthesis include
(i) a catalytic asymmetric hetero-Diels−Alder reaction to form
the dihydropyran ring; (ii) a tandem reaction of acid-catalyzed
cleavage of the acetal, oxidation, and cyclization to install the
lactone and furan rings simultaneously; and (iii) an
intermolecular Diels−Alder reaction to forge the target
products aphadilactones A−D.
Having accessed monomer 12, the stage was now set to
explore the bioinspired [4 + 2] dimerization/1,3 σ-hydrogen
migration sequence to reach our target. Reaction conditions
were optimized for solvent, Lewis acid, temperature, and
reaction time. To our great satisfaction, when the reaction was
performed in toluene with BHT at 170 °C for 17 h,
aphadilactones A−D were formed in an approximate 1:1:1:1
mixture in 65% yield (Scheme 4). The single isomers were
obtained by semipreparative HPLC separation (C18 silica gel
column and then chiral AD-H column as reported1). Our
EXPERIMENTAL SECTION
■
1
synthetic samples matched the H and 13C NMR spectra of
General Methods. All reactions sensitive to air or moisture were
carried out under argon or nitrogen atmosphere in dry and freshly
distilled solvents under anhydrous conditions, unless otherwise noted.
Anhydrous THF, toluene and Et2O were distilled over sodium
benzophenone ketyl under Ar. Anhydrous CH2Cl2 was distilled over
calcium hydride under Ar. All other solvents and reagents were used as
obtained from commercial sources without further purification.
Optical rotations were measured on a polarimeter using a 10 cm
cell at approximately 25 °C. NMR spectra were recorded at 300 and 75
natural aphadilactones A−D (see Tables 1−3). The assign-
ments of the synthetic samples were further secured by analyses
of specific optical rotations, as measured in MeOH solution
22
according to the reference (A, [α]D −8.3 c 0.145 MeOH; B,
[α]D2202 −40.7 c 0.150 MeOH; C, [α]D20 +4.0 c 0.125 MeOH; D,
[α]D −15.1 c 0.185 MeOH). The synthetic samples were
22
found to exhibit an optical rotation of A, [α]D 22 −0.6 c 0.137
MeOH; B, [α]D22 −28 c 0.150 MeOH; C, [α]D −1.0 c 0.088
MHz for 1H and 13C nuclei, or at 600 and 150 MHz for for 1H and 13
C
22
MeOH; D, [α]D −23 c 0.088 MeOH, respectively. The
nuclei, respectively. Chemical shifts are reported in parts per million
(ppm) relative to the tetramethylsilane peak recorded as δ 0.00 ppm in
observed difference in absolute values between the optical
C
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Table 1. H NMR Data Comparison of 1 and 2 [δH (mult, J in Hz)] in CD3OD
a
b
a
b
proton
1
1
2
2
2
5.79 (m)
5.79 (br s)
5.79 (br s)
5.79 (br s)
2.38 (m)
4a
2.35 (dd, 18.0, 4.3)
2.43 (dd, 18.0, 10.9)
5.21 (m)
2.35 (dd, 18.6, 4.2)
2.43 (dd, 18.0, 10.2)
5.21 (m)
2.38 (m)
4b
2.45 (dd, 18.1, 10.2)
5.22 (m)
2.45 (dd, 18.0, 10.8)
5.21 (m)
5
6
5.35(br d, 8.5)
2.09 (m, 2H)
1.53 (m, 2H)
1.54 (m)
5.35(br d, 9.6)
2.09 (m, 2H)
1.53 (m, 2H)
1.54 (m)
5.36 (br d, 8.1)
2.10 (m, 2H)
1.53 (m, 2H)
1.53 (m)
5.36 (br d, 10.8)
2.10 (m, 2H)
1.53 (m, 2H)
1.53 (m)
8
9
10a
10b
11
1.76 (m)
1.76 (m)
1.79 (m)
1.79 (m)
2.74 (m)
2.74 (m)
2.75 (m)
2.74 (m)
16
1.38 (s, 3H)
1.39 (s, 3H)
2.03 (m)
1.38 (s, 3H)
1.39 (s, 3H)
2.03 (m)
1.38 (s, 3H)
1.39 (s, 3H)
1.48 (m)
1.38 (s, 3H)
1.39 (s, 3H)
1.48 (m)
17
18α
18β
19
1.48 (m)
1.48 (m)
2.05 (m)
2.05 (m)
1.73 (d, 0.8, 3H)
2.02 (br s, 3H)
5.79 (br s)
1.73 (d, 0.6, 3H)
2.02 (br s, 3H)
5.79 (br s)
1.73 (br s, 3H)
2.02 (br s, 3H)
5.79 (br s)
1.73 (d, 1.2, 3H)
2.02 (br s, 3H)
5.79 (br s)
20
2′
4′a
4′b
5′
2.34 (dd, 18.0, 4.2)
2.43 (dd, 18.0, 10.9)
5.21 (m)
2.34 (dd, 18.6, 4.2)
2.43 (dd, 18.0, 10.8)
5.21 (m)
2.34 (dd, 18.1, 4.4)
2.45 (dd, 18.1, 10.2)
5.20 (m)
2.34 (dd, 18.0, 4.2)
2.45 (dd, 18.0, 10.8)
5.21 (m)
6′
8′
5.33 (br d, 8.5)
2.06 (m, 2H)
1.29 (m)
5.33 (br d, 8.4)
2.06 (m, 2H)
1.29 (m)
5.34 (br d, 8.2)
2.06 (m, 2H)
1.24 (m)
5.34 (br d, 8.4)
2.06 (m, 2H)
1.24 (m)
9′a
9′b
10′a
10′b
13′
16′
17′
18′α
18′β
19′
20′
1.50 (m)
1.50 (m)
1.50 (m)
1.50 (m)
1.89 (ddd, 13.0, 13.0, 4.4)
2.09 (m)
1.89 (ddd, 13.2, 13.2, 4.8)
2.09 (m)
1.82 (m)
1.82 (m)
2.16 (m)
2.16 (m)
5.29 (s)
5.29 (s)
5.27 (s)
5.28 (s)
1.33 (s, 3H)
1.36 (s, 3H)
1.82 (ddd, 13.4, 13.4, 2.7)
2.11 (m)
1.33 (s, 3H)
1.36 (s, 3H)
1.82 (ddd, 13.2, 13.2, 3.0)
2.11 (m)
1.33 (s, 3H)
1.36 (s, 3H)
2.07 (m)
1.33 (s, 3H)
1.36 (s, 3H)
2.07 (m)
1.86 (m)
1.86 (m)
1.71 (d, 0.7, 3H)
2.02 (br s, 3H)
1.71 (d, 1.2, 3H)
2.02 (br s, 3H)
1.69 (br s, 3H)
2.01 (br s, 3H)
1.69 (d, 1.2, 3H)
2.01 (br s, 3H)
a
b
Natural product. Synthesized compound.
CDCl3/ TMS solvent, or the residual chloroform (δ 7.26 ppm) or
methanol (δ 3.31 ppm) peaks. The 13C NMR values were referenced
to the residual chloroform (δ 77.0 ppm), or methanol (δ 49.0 ppm)
peaks. 13C NMR values are reported as chemical shift δ, multiplicity
and assignment. 1H NMR shift values are reported as chemical shift δ,
relative integral, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet), coupling constant (J in Hz) and assignment. Analytical
gas chromatography (GC) was performed on Dex 120 capillary
column, column temperature = 105 °C (isothermal), inject temper-
ature = 220 °C, detector temperature = 220 °C. Flow = 1.2 mL/min.
High resolution mass spectroscopy (HRMS) was performed on a TOF
instrument with ESI in positive ionization mode. Semipreparative
reversed-phase high-performance liquid chromatography: the flow rate
was 1 mL/min mobile phase, acetonitrile/water = 50/50, UV
detection at 266 nm. Semipreparative normal-phase high-performance
liquid chromatography: the flow rate was 1 mL/min mobile phase,
hexane/ethanol = 90/10, UV detection at 266 nm.
Synthetic Procedures and Characterization Data. Aphadi-
lactones A−D (1−4). To a solution of monomer 12 (65 mg, 0.20
mmol) in toluene (2.0 mL) was added BHT (5 mg) under argon, and
the mixture was heated in a sealed tube (ø = 1.0 cm, length = 9.0 cm,
the section below the level of solution was immersed in the oil bath) at
170 °C for 17 h. The reaction was left to cool to room temperature.
The mixture was purified by column chromatography on silica gel
(hexane:EtOAc:CH2Cl2 = 1:1.5:1) to afford 42 mg dimer products
(65%). (6.0 mg, 9% of 12 recovered). The dimer products were
further separated by semipreparative reversed-phase high-performance
liquid chromatography and semipreparative normal-phase high-
performance liquid chromatography in sequence. Compounds 1, 2,
3 and 4 can be gained separately.
Optical rotations. 1: [α]D22 −0.6 c 0.137 MeOH. 2: [α]D22 −28.0 c
0.150 MeOH. 3: [α]D22 −1.0 c 0.088 MeOH. 4: [α]D22 −23.0 c 0.088
MeOH.
HRMS (TOF ESI). 1: calcd for C40H52NaO8 683.3560 [M + Na]+,
found 683.3566. 2: calcd for C40H52NaO8 683.3560 [M + Na]+, found
683.3572. 3: calcd for C40H52NaO8 683.3560 [M + Na]+, found
683.3555. 4: calcd for C40H52NaO8 683.3560 [M + Na]+, found
683.3557.
tert-Butyldimethyl(pent-4-en-1-yloxy)silane (S5). To a suspension
of 4-penten-1-ol S4 (4.30 g, 50.0 mmol, 1.00 equiv) in CH2Cl2 (90
mL) at room temperature was added imidazole (4.42 g, 65.0 mmol,
1.30 equiv). Then TBSCl (9.80 g, 65.0 mmol, 1.30 equiv) was added.
The mixture was stirred at room temperature for 12 h, then diluted
with CH2Cl2 (100 mL), washed with H2O, and brine, then dried
(MgSO4) and filtered. The residue was purified by flash chromatog-
raphy on silica gel (hexane:Et2O = 20:1) to give S5 (9.51 g, 47.6
1
mmol, 95%) as a colorless oil: H NMR (CDCl3, 300 MHz) δ 5.86−
5.78 (m, 1H), 5.02 (d, J = 9.0 Hz, 1H), 4.95 (d, J = 6.0 Hz, 1H), 3.62
(t, J = 6.0 Hz, 2H), 2.13−2.08 (m, 2H), 1.64−1.58 (m, 1H), 0.90 (s,
9H), −0.05 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 138.6, 114.5, 62.5,
32.0, 30.0, 26.0 (3C), 18.34, −5.30 (2C).
(S,E)-6-(6-(5,5-Dimethyl-4-oxo-4,5-dihydrofuran-3-yl)-2-methyl-
hepta-1,6-dien-1-yl)-4-methyl-5,6-dihydro-2H-pyran-2-one (12). To
a solution of 13 (194.0 mg, 0.492 mmol, 1.00 equiv) in a mixture of
acetone/water (3/1) (40 mL), PPTS (123.5 mg, 0.492 mmol, 1.00
equiv) was added, and the resulting solution stirred at room
D
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Table 2. H NMR Data Comparison of 3 and 4 [δH (mult, J in Hz)] in CD3OD
a
b
a
b
proton
3
3
4
4
2
5.78 (br s)
5.78 (br s)
5.78 (br s)
2.37 (m)
5.78 (br s)
2.37 (m)
4a
2.35 (dd, 18.2, 4.7)
2.44 (m)
2.35 (dd, 18.0, 4.2)
2.44 (m)
4b
2.44 (m)
2.44 (m)
5
5.23 (m)
5.23 (m)
5.23 (m)
5.22 (m)
6
5.39 (br d, 8.6)
2.14 (br t, 7.1, 2H)
1.63 (m, 2H)
1.56 (m)
5.39 (br d, 8.4)
2.14 (br t, 7.8, 2H)
1.63 (m, 2H)
1.56 (m)
5.39 (br d, 8.6)
2.14 (m, 2H)
1.63 (m, 2H)
1.60 (m)
5.39 (br d, 9.0)
2.14 (m, 2H)
1.63 (m, 2H)
1.60 (m)
8
9
10a
10b
11
1.78 (m)
1.78 (m)
1.76 (m)
1.76 (m)
2.64 (m)
2.64 (m)
2.65 (m)
2.65 (m)
16
1.37 (s, 3H)
1.37 (s, 3H)
1.92 (m)
1.37 (s, 3H)
1.37 (s, 3H)
1.92 (m)
1.37 (s, 3H)
1.38 (s, 3H)
1.82 (m)
1.37 (s, 3H)
1.37 (s, 3H)
1.82 (m)
17
18α
18β
19
1.82 (m)
1.82 (m)
1.92 (m)
1.92 (m)
1.76 (d, 1.3, 3H)
2.02 (br s, 3H)
5.78 (br s)
1.76 (d, 1.2, 3H)
2.02 (br s, 3H)
5.78 (br s)
1.76 (d, 1.2, 3H)
2.02 (br s, 3H)
5.78 (br s)
2.34 (dd, 18.1, 4.5)
2.44 (m)
1.76 (br s, 3H)
2.02 (br s, 3H)
5.78 (br s)
20
2′
4′a
4′b
5′
2.34 (dd, 18.2, 4.7)
2.42 (m)
2.34 (dd, 18.0, 4.2)
2.42 (m)
2.34 (dd, 18.6, 4.2)
2.44 (m)
5.21 (m)
5.21 (m)
5.21 (m)
5.21 (m)
6′
8′
5.32 (br d, 8.6)
2.07 (br t, 7.4, 2H)
1.35 (m)
5.33 (br d, 9.0)
2.07 (br t, 7.2, 2H)
1.35 (m)
5.35 (br d, 8.6)
2.09 (m, 2H)
1.33 (m)
5.35 (br d, 8.4)
2.09 (m, 2H)
1.33 (m)
9′a
9′b
10′a
10′b
13′
16′
17′
18′α
18′β
19′
20′
1.47 (m)
1.47 (m)
1.46 (m)
1.46 (m)
1.87 (m)
1.87 (m)
1.84 (m)
1.84 (m)
2.03 (m)
2.03 (m)
2.05 (m)
2.05 (m)
5.34 (s)
5.34 (s)
5.33 (s)
5.33 (s)
1.31 (s, 3H)
1.35 (s, 3H)
1.92 (m)
1.31 (s, 3H)
1.35 (s, 3H)
1.92 (m)
1.31 (s, 3H)
1.35 (s, 3H)
1.92 (m)
1.31 (s, 3H)
1.35 (s, 3H)
1.92 (m)
1.92 (m)
1.92 (m)
1.92 (m)
1.92 (m)
1.71 (d, 1.2, 3H)
2.02 (br s, 3H)
1.71 (d, 1.2, 3H)
2.02 (br s, 3H)
1.68 (d, 1.2, 3H)
2.02 (br s, 3H)
1.68 (br s, 3H)
2.02 (br s, 3H)
a
b
Natural product. Synthesized compound.
temperature for 4 h. The reaction was diluted with water, extracted
with EtOAc (3 × 50 mL), and the combined organic layer dried
(Na2SO4) and concentrated. The crude semiacetal was dissolved in
dried DCM (30 mL), and then neutral activated MnO2 (856 mg, 9.84
mmol, 20.0 equiv) was added. The mixture was stirred in room
temperature for 16 h and was filtered over Celite, washed with
CH2Cl2. PTSA (1.00 equiv) was added to the filtrate, and the mixture
was stirred in room temperature for 3 h. Then the reaction mixture
was quenched with saturated NaHCO3 aqueous solution (3 mL), the
layers were separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 50 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(hexane:EtOAc = 2:1) providing 12 (65.0 mg, 0.197 mmol, 40%,
3 h at −40 °C. The mixture was then cooled to −78 °C, and a solution
of 23 (741 mg, 2.54 mmol, 1.00 equiv) in THF was added dropwise
over 20 min. After another 20 min, the flask was moved to −40 °C for
1.5 h. The reaction was quenched by the addition of saturated NH4Cl
aqueous (20 mL), the layers were separated, and the aqueous layer was
extracted with Et2O (3 × 40 mL). The combined organic layer was
separated, and the aqueous layer was extracted with ether. The
combined organic solution was washed with brine, dried (Na2SO4)
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane:EtOAc = 5:1 → 2:1) providing
13 (760 mg, 1.93 mmol, 76%) as a clear, colorless oil that was a 1:1
mixture of diastereomers at the position of hydroxyl (inseparable by
1
flash column chromatography): H NMR (CDCl3, 300 MHz) δ 5.42
(s, 1H), 5.21 (d, J = 9.0 Hz, 1H), 5.11 (s, 1H), 5.06 (s, 1H), 4.90 (s,
1H), 4.71−4.63 (m, 1H), 4.54 (d, J = 12.0 Hz, 1H), 4.02−3.94 (m,
1H), 3.73 (d, J = 6.0 Hz, 1H), 2.94−2.84 (m, 1H), 2.67 (dd, J = 3.0,
18.0 Hz, 1H), 2.08−1.96 (m, 5H), 1.77 (dd, J = 3.0, 18.0 Hz, 1H),
1.71 (br s, 3H), 1.69 (br s, 3H), 1.66−1.56 (m, 2H), 1.36 (br s, 6H),
1.21 (d, J = 6.0 Hz, 3H), 1.15 (d, J = 6.0 Hz, 3H); 13C NMR (CDCl3,
75 MHz) δ 214.8, 214.8, 150.0(2C), 139.6, 139.5, 137.2, 125.1, 125.1,
120.0, 110.1, 110.0, 98.6, 93.2, 70.8, 68.9, 68.9, 63.4, 41.9, 41.8, 39.1,
39.0, 35.7, 31.4, 31.2, 26.3, 25.6, 25.5, 23.8, 22.8, 21.9, 16.5, 16.5;
1
over 3 steps): H NMR (CDCl3, 300 MHz) δ 6.01 (s, 1H), 5.82 (s,
1H), 5.55 (s, 1H), 5.43 (s, 1H), 5.35 (d, J = 9.0 Hz, 1H), 5.15−5.07
(m, 1H), 2.41 (dd, J = 12.0, 18.0 Hz, 1H), 2.30 (t, J = 9.0 Hz, 2H),
2.21 (dd, J = 3.0, 18.0 Hz, 1H), 2.09 (t, J = 6.0 Hz, 2H), 1.99 (s, 3H),
1.71 (s, 1H), 1.68−1.64 (m, 2H), 1.40 (s, 6H); 13C NMR (CDCl3, 75
MHz) δ 207.6, 183.3, 165.2, 156.9, 141.8, 138.2, 122.5, 121.0, 116.7,
99.9, 88.4, 74.1, 38.8, 35.1, 31.9, 26.2, 23.1 (2 C), 23.00, 16.72; [α]22
D
−19.5 (c 0.625, MeOH); HRMS (TOF ESI) calcd for C20H26NaO4
[α]20 −4.0 (c 0.10, CHCl3); HRMS (TOF ESI) calcd for
353.1723 [M + Na]+, found 353.1749.
D
C23H38NaO5 417.2611 [M + Na]+, found 417.2612.
(E)-2,5-Dihydroxy-11-((2S,6S)-6-isopropoxy-4-methyl-3,6-dihy-
dro-2H-pyran-2-yl)-2,10-dimethyl-6-methyleneundec-10-en-3-one
(13). To a solution of LiN(SiMe3)2 in THF at −40 °C, 3-hydroxy-3-
methyl-2-butone S2 (777 mg, 7.62 mmol, 3.00 equiv) in THF (3 mL)
was added dropwise. After the addition, the stirring was continued for
(2S,6S)-2-((E)-2-Iodoprop-1-en-1-yl)-6-isopropoxy-4-methyl-3,6-
dihydro-2H-pyran (14). A solution of the above vinylstannane 19
(2.32 g, 4.78 mmol) in THF (50 mL) was cooled to −17 °C (NaCl/
ice) followed by addition of NIS (1.61 g, 7.17 mmol, 1.50 equiv) in
E
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Table 3. 13C NMR Data Comparison of 1, 2, 3 and 4 in CD3OD
a
b
a
b
a
b
a
b
carbon
1
1
2
2
3
3
4
4
1
168.1
116.4
161.2
35.8
168.1
116.5
161.2
35.8
168.0
116.4
161.2
35.7
168.0
116.5
161.2
35.7
167.9
116.5
161.1
35.8
168.0
116.5
161.1
35.8
167.9
116.4
161.1
35.8
168.0
2
116.5
161.1
35.8
3
4
5
76.0
76.0
75.9
75.9
76.0
76.1
76.0
76.0
6
123.6
143.6
40.2
123.7
143.6
40.2
123.7
143.5
40.2
123.7
143.6
40.2
123.9
143.4
40.0
123.9
143.4
40.0
123.8
143.5
40.1
123.8
143.6
40.1
7
8
9
25.0
25.1
24.9
24.9
25.9
25.9
25.9
25.9
10
11
12
13
14
15
16
17
18
19
20
1′
31.2
31.2
31.1
31.1
32.1
32.2
32.1
32.1
37.7
37.7
37.6
37.6
36.5
36.6
36.6
36.6
193.1
112.4
206.9
89.4
193.1
112.4
206.9
89.4
193.2
112.3
206.8
89.4
193.2
112.3
206.8
89.4
193.1
112.1
206.6
89.2
193.1
112.1
206.7
89.2
193.1
112.0
206.6
89.2
193.2
112.0
206.7
89.2
23.1
23.1
23.1
23.1
23.1
23.1
23.1
23.1
23.4
23.4
23.4
23.4
23.5
23.4
23.4
23.4
25.9
25.9
25.9
25.9
24.9
25.0
24.8
24.8
16.7
16.7
16.6
16.6
16.6
16.6
16.6
16.6
23.0
23.0
23.0
23.0
23.0
23.0
23.0
23.0
168.1
116.4
161.2
35.8
168.0
116.5
161.1
35.8
168.0
116.4
161.2
35.8
168.0
116.5
161.1
35.8
167.9
116.5
161.1
35.8
168.0
116.5
161.1
35.9
167.9
116.5
161.2
35.8
168.0
116.5
161.2
35.8
2′
3′
4′
5′
76.0
76.0
76.0
76.0
76.0
76.0
76.0
76.0
6′
7′
8′
123.6
143.5
40.4
123.6
153.5
40.4
123.9
143.4
40.5
123.9
143.4
40.5
123.6
143.4
40.4
123.6
143.4
40.4
124.0
143.3
40.5
124.0
143.3
40.5
9′
23.4
23.4
23.2
23.2
23.7
23.7
23.6
23.6
10′
11′
12′
13′
14′
15′
16′
17′
18′
19′
20′
35.6
35.6
35.2
35.3
35.8
35.8
35.6
35.6
43.5
43.5
43.4
43.5
43.1
43.1
43.1
43.1
197.9
102.2
209.8
90.6
197.9
102.2
209.7
90.5
198.0
102.2
209.7
90.5
198.0
102.2
209.7
90.5
197.5
101.9
209.8
90.3
197.6
101.9
210.0
90.3
197.6
101.9
209.9
90.5
197.7
101.9
210.0
90.4
23.0
23.0
23.0
23.0
23.0
23.0
23.0
23.0
23.0
23.0
23.0
23.0
23.0
23.0
23.0
23.0
31.6
31.6
31.5
31.5
30.4
30.5
30.5
30.5
16.6
16.6
16.5
16.5
16.8
16.8
16.5
16.5
23.0
23.0
23.0
23.0
23.0
23.0
23.0
23.0
a
b
Natural product. Synthesized compound).
THF (5 mL), to give an almost clear yellow solution. After 20 min, a
mixture of saturated aqueous Na2S2O3 (5 mL) and saturated aqueous
NaHCO3 (5 mL) was added followed by Et2O (50 mL). Stirring was
continued for 2 min until two clear, colorless phases were formed. The
phases were separated, and the aqueous phase was extracted with Et2O
(3 × 50 mL). The combined organic extracts were dried over MgSO4
and then concentrated under reduced pressure. The residue was
purified by flash chromatography on deactivated silica gel
(hexane:EtOAc = 50:1) to afford the desired product 14 (ca. 1.46g)
as a yellow oil. The crude vinyl iodide can also be used directly in the
sieves (4.0 g), catalyst S320 (730 mg, 1.50 mmol, 3.00 mol %), 2-
butynal 17 (3.5 g, 50.0 mmol, 1.00 equiv). The mixture was stirred for
1.5 h at room temperature. Then 1-methoxy-3-methyl-1, 3-butadiene
16 (4.9 g, 50.0 mmol, 1.00 equiv) was added, and the mixture was
stirred at room temperature for 18 h. The reaction was diluted with
Et2O, filtered through Celite and concentrated under atmospheric
pressure at 43 °C. The residue was purified by flash chromatography
on silica gel (pentane:Et2O = 15:1) to give 15 (7.0 g, 42.2 mmol, 84%)
as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 5.40−5.39 (m, 1H),
5.01−5.00 (m, 1H), 4.50−4.45 (m, 1H), 3.48 (s, 3H), 2.30 (dd, J =
9.0, 18.0 Hz, 1H), 2.10 (dd, J = 3.0, 18.0 Hz, 1H), 1.84 (d, J = 3.0 Hz,
3H), 1.73 (d, J = 1.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 136.8,
120.9, 98.2, 80.7, 78.3, 61.9, 55.4, 36.4, 22.9, 3.9; [α]25D −44.8 (c 0.86,
CHCl3); HRMS (TOF ESI) calcd for C10H14NaO2 189.0886 [M +
Na]+, found 189.0863.
1
next step without purification: H NMR (CDCl3, 300 MHz) δ 6.23
(dd, J = 3.0, 9.0 Hz, 1H), 5.42 (br s, 1H), 5.06 (br s, 1H), 4.67−4.59
(m, 1H), 4.03−3.95 (m, 1H), 2.48 (d, J = 3.0 Hz, 3H), 2.05 (dd, J =
9.0, 18.0 Hz, 1H), 1.81 (dd, J = 3.0 Hz, 18.0 Hz), 1.73 (s, 3H), 1.21 (d,
J = 6.0 Hz, 3H), 1.16 (d, J = 6.0 Hz, 3H); 13C NMR (CDCl3, 75
MHz) δ 140.9, 120.1, 98.8, 93.3, 89.5, 69.3, 64.3, 34.8, 28.3, 23.8, 22.7,
GC (β-dex chiral column) (T = 105 °C): tR1(minor) = 28.05 min,
tR2 (major) = 28.71 min, and ee = 98.0.
1-Methoxy-3-methylbuta-1,3-diene (16). To a suspension of t-
BuOK (9.12 g, 80.0 mmol) in anhydrous Et2O (100 mL) under argon
at 0 °C was added (methoxymethyl)triphenylphosphonium chloride
21.9; [α]24 −26.8 (c 0.45, CHCl3); HRMS (TOF ESI) calcd for
D
C12H19INaO2 345.0322 [M + Na]+, found 345.0329.
(2S,6R)-6-Methoxy-4-methyl-2-(prop-1-yn-1-yl)-3,6-dihydro-2H-
pyran (15). In a 100 mL flask under argon was added 4 Å molecular
F
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The Journal of Organic Chemistry
Article
(28.8 g, 60.0 mmol) over 5 min. The resultant reddish suspension was
stirred for 1 h at 0 °C, and a solution of S9 (5.0 mL, 60.0 mmol) in
Et2O (5 mL) was then added. Stirring was continued for 10 min, and
then warmed to room temperature for 0.5 h, The resultant solution
was poured into brine (50 mL) and pentane (100 mL).
Triphenylphosphine oxide was filtered off through a pad of Celite.
The filtrate was extracted twice with a pentane/ether (1:1) mixture
(totally 100 mL). The combined organic layer was washed with brine
(50 mL) and dried over MgSO4. After careful distillation under
atmospheric pressure, the residue was distilled under reduced pressure
to give 1-methoxy-l, 3-pentadiene 16 in 62% yield (∼3.64 g, E:Z =
NEt3 (v/v)) gave the vinylstannane 19 (2.32 g, 4.78 mmol, 77%) as a
colorless oil: 1H NMR (CDCl3, 300 MHz) δ 5.57 (d, J = 6.0 Hz, 1H),
5.44 (br s, 1H), 5.09 (br s, 1H), 4.89−4.82 (m, 1H), 4.05−3.96 (m,
1H), 1.98 (dd, J = 6.0, 12.0 Hz, 1H), 1.91 (s, 3H), 1.80 (dd, J = 3.0,
18.0 Hz, 1H), 1.73 (s, 3H), 1.54−1.44 (m, 6H), 1.35−1.25 (m, 6H),
1.22 (d, J = 6.0 Hz, 3H), 1.16 (d, J = 6.0 Hz, 3H), 0.92−0.86 (m, 9H);
13C NMR (CDCl3, 75 MHz) δ 142.4, 140.2, 137.3, 120.1, 93.5, 69.1,
62.5, 35.4, 29.1 (3C), 27.3 (3C), 23.8, 22.9, 22.1, 19.7, 13.7 (3C), 9.1
(3C); [α]24 −20.2 (c 0.50, CHCl3); HRMS (TOF ESI) calcd for
D
C24H46NaO2Sn 509.2412 [M + Na]+, found 509.2422.
tert-Butyl(((E)-7-((2S,6S)-6-isopropoxy-4-methyl-3,6-dihydro-2H-
pyran-2-yl)-6-methylhept-6-en-1-yl)oxy)dimethylsilane (20). In a
flame-dried 10 mL conical flask equipped with a magnetic stir bar,
septum, and argon inlet needle, olefin S5 (1.36 g, 6.80 mmol, 1.50
equiv) was dissolved in anhydrous THF (2 mL). A freshly prepared
solution of 9-BBN (0.5 M in THF, 27.2 mL, 13.6 mmol, 3.00 equiv)
was added dropwise at room temperature. Then it was stirred at room
temperature for 1.5 h. In a separate 100 mL conical flask, Cs2CO3
(4.43 g, 13.59 mmol, 3.0 equiv) and AsPh3 (278 mg, 0.91 mmol, 0.20
equiv) was dissolved in DMF (25 mL) and water (10 mL) followed by
the addition of hydroboration reaction mixture. Then the crude vinyl
iodide 14 (1.46 g, 4.53 mmol, 1.00 equiv) was added and argon inlet
needle. Pd(dppf)Cl2 (665 mg, 0.91 mmol, 0.20 equiv) was added at
last. The reaction was stirred for 15 h at room temperature, and then
diluted with Et2O (100 mL), washed with H2O, and brine, then dried
(MgSO4) and filtered. Evaporation of solvent, and the residue was
filtered through short flash chromatography deactivated silica gel
(hexane:EtOAc = 30:1) to give 20 as a colorless oil: 1H NMR (CDCl3,
300 MHz) δ 5.42 (br s, 1H), 5.19 (d, J = 9.0 Hz, 1H), 5.07 (br s, 1H),
4.70−4.62 (m, 1H), 4.04−3.95 (m, 1H), 3.58 (t, J = 6.0 Hz, 2H),
2.03−1.98 (m, 3H), 1.83 (dd, J = 3.0, 18.0 Hz, 1H), 1.72 (s, 3H), 1.68
(s, 3H), 1.55−1.40 (m, 4H), 1.35−1.25 (m, 2H), 1.21 (d, J = 6.0 Hz,
3H), 1.14 (d, J = 6.0 Hz, 3H), 0.87 (s, 9 H), 0.03 (s, 6 H); 13C NMR
(CDCl3, 75 MHz) δ 140.0, 137.3, 124.6, 120.0, 98.7, 93.2, 68.8, 63.4,
63.2, 39.5, 35.7, 32.7, 27.4, 25.9 (3 C), 25.4, 23.8, 22.8, 21.8, 16.5, −5.3
1
5:4). E: H NMR (CDCl3, 300 MHz) δ 1.81 (m, 3H), 3.59 (s, 3H),
4.69 (m, 1H), 4.77 (m, 1H), 5.64 (d, J = 12.9 Hz, 1H), 6.58 (d, J =
1
12.9 Hz, 1H). Z: H NMR (300 MHz, CDCl3) δ 1.95 (m, 3H), 3.64
(s, 3H), 4.77 (m, 1H), 4.81 (d, J = 6.9 Hz, 1H), 4.99 (m, 1H),5.87(d, J
= 6.9 Hz, 1H).19
But-2-ynal (17). To a solution of compound S10 (3.50 g, 50.0
mmol, 1.00eq ) in CH2Cl2 (150 mL) was added PCC (19.44 g, 90.0
mmol, 1.80 equiv) at 0 °C, and then warmed to room temperature
slowly. The mixture was stirred for 2 h at room temperature and
filtered through a short silica gel column. It was washed with 150 mL
of CH2Cl2. Filtrate was condensed under reduced pressure at 0 °C
until 15 mL of solution was left. The crude aldehyde 17 can be used
directly in the next step without CH2Cl2 completely removed: 1H
NMR (CDCl3, 300 MHz) δ 9.15 (s, 1H), 2.07 (s, 3H).
(2S,6S)-6-Isopropoxy-4-methyl-2-(prop-1-yn-1-yl)-3,6-dihydro-
2H-pyran (18). To a solution of compound 15 (7.0 g, 42.2 mmol,
1.00eq ) in i-PrOH (100 mL) was added p-TsOH (76.0 mg, 0.40
mmol, 1.00 equiv), and the solution was stirred at room temperature
for 3 h. The reaction was quenched with dilute NaHCO3 and extracted
with Et2O (2 × 100 mL). The organic layer was washed with water (3
× 100 mL); water layer was extracted with Et2O (2 × 100 mL);
organic layer was washed with water again (3 × 100 mL); all organic
layers were dried (MgSO4), filtered and concentrated under
atmospheric pressure at 43 °C. The residue was purified by flash
chromatography on silica gel (pentane:Et2O = 20:1) to give 18 (6.86
g, 35.4 mmol, 84%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ
5.43 (br s, 1H), 5.11 (br s, 1H), 4.65 (br d, J = 6.0 Hz, 1H), 4.07−4.03
(m, 1H), 2.33 (dd, J = 9.0, 12.0 Hz, 1H), 2.02 (dd, J = 3.0, 12.0 Hz,
1H), 1.88 (d, J = 3.0 Hz, 3H), 1.73 (d, J = 1.2 Hz, 3H), 1.27 (d, J = 3.0
Hz, 3H), 1.18 (d, J = 3.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ
136.5, 119.9, 93.3, 80.8, 78.2, 69.4, 57.5, 36.4, 23.8, 22.6, 21.9, 3.6;
(2 C); [α]25 −7.8 (c 0.96, CHCl3); MS (EI) m/z 396 (M+); HRMS
D
(EI) calcd for C23H44SiO3 396.3060, found m/z 396.3068.
(E)-7-((2S,6S)-6-Isopropoxy-4-methyl-3,6-dihydro-2H-pyran-2-yl)-
6-methylhept-6-en-1-ol (21). The TBS ether 20 (ca. 1.6 g, 4.04
mmol, 1.00 equiv) was placed in a flame-dried two-neck round-bottom
flask, under argon atmosphere. To this was added anhydrous THF (50
mL), and then TBAF (1.0 M in THF, 4.85 mL, 4.85 mmol, 1.20
equiv) was added slowly at room temperature. The mixture was
allowed to stir at room temperature for 6 h. After complete conversion,
the mixture was diluted with Et2O (100 mL), washed with H2O, and
brine, and then dried (Na2SO4) and filtered. Solvent was evaporated,
and the residue was purified by flash chromatography deactivated silica
(hexane:EtOAc = 10:1 → 5:1 → 3:1) to give 21 (7.0 g, 42.2 mmol,
[α]25 −34.3 (c 0.36, CHCl3); HRMS (EI) calcd for C12H18O2
D
194.1307, found m/z 194.1312.
Tributyl((E)-1-((2S,6S)-6-isopropoxy-4-methyl-3,6-dihydro-2H-
pyran-2-yl)prop-1-en-2-yl)stannane (19). To a suspension of CuCN
(2.78 g, 30.93 mmol, 5.00 equiv) in THF (90 mL) at −78 °C was
added a solution of n-BuLi (1.6 M in hexane, 38.6 mL, 61.80 mmol,
10.00 equiv). After 5 min the flask was immersed in a cooling bath at
−40 °C, resulting in the formation of a pale-yellow, almost clear
solution. The mixture was cooled back to −78 °C after 10 min, which
made it become slightly heterogeneous. Neat Bu3SnH (16.6 mL, 61.80
mmol, 10.00 equiv) was then added dropwise, immediately leading to
a turbid yellow solution with liberation of gas. After 20 min at −78 °C
the mixture was stirred for 5 min at −40 °C, giving an almost clear
golden-yellow solution. After 10 min at −40 °C the solution was
cooled back to −78 °C followed by addition of MeOH (27.5 mL,
680.0 mmol, 110.00 equiv) under vigorous stirring. After 10 min at
−78 °C the flask was immersed in a cooling bath at −40 °C; the
reaction mixture now was a clear red solution. After 40 min at −40 °C
this solution was cooled back to −78 °C, and a solution of 18 (1.20 g,
6.18 mmol, 1.00 equiv) in THF (5 mL) was added. The mixture was
stirred for 15 h, during which period the temperature was allowed to
rise to −15 °C. Saturated aqueous NH4Cl (30 mL) and 25% aqueous
NH4OH (6 mL) were then added together with Et2O (50 mL).
Stirring was continued for 30 min, the two almost clear phases were
separated, and the aqueous phase was extracted with Et2O (2 × 150
mL). The combined organic extracts were dried over MgSO4, and the
solution was concentrated under reduced pressure. Purification of the
residue by flash chromatography on deactivated silica gel (hexane 2%
1
84%, over 3 steps) as a colorless oil: H NMR (CDCl3, 300 MHz) δ
5.40 (br s, 1H), 5.18 (dd, J = 3.0, 9.0 Hz, 1H), 5.06 (br s, 1H), 4.69−
4.61 (m, 1H), 4.02−3.94 (m, 1H), 3.60 (t, J = 6.0 Hz, 2H), 2.05−1.98
(m, 3H), 1.75 (dd, J = 3.0, 18.0 Hz, 1H), 1.70 (s, 3H), 1.67 (d, J = 1.2
Hz, 3H), 1.60−1.50 (m, 2H), 1.48−1.40 (m, 2H), 1.38−1.30 (m, 2H),
1.20 (d, J = 6.0 Hz, 3H), 1.13 (d, J = 6.0 Hz, 3H); 13C NMR (CDCl3,
75 MHz) δ 139.9, 137.3, 124.6, 120.0, 93.2, 68.9, 63.4, 62.8, 39.4, 35.7,
32.6, 27.3, 25.3, 23.8, 22.8, 21.8, 16.5; [α]24 −14.6 (c 0.35, CHCl3);
D
HRMS (TOF ESI) calcd for C17H30NaO3 305.2087 [M + Na]+, found
305.2106.
(E)-7-((2S,6S)-6-Isopropoxy-4-methyl-3,6-dihydro-2H-pyran-2-yl)-
6-methylhept-6-enal (22). Anhydrous powdered 4 Å molecular sieves
(1.8 g, ∼0.5 g/mmol) were placed in flame-dried round-bottom flask
under argon atmosphere, and then it was cooled to 0 °C, and
anhydrous CH2Cl2 (40 mL) was added. Alcohol 21 (980 mg, 3.47
mmol, 1.00 equiv) in anhydrous CH2Cl2 (10 mL) was added and
stirred for 10 min. Then 4-methylmorpholine-N-oxide (610 mg, 5.21
mmol, 1.50 equiv) was added, followed by tetrapropylammoniumper-
ruthenate (74 mg, 0.21 mmol, 6.0 mol %) at 0 °C, and the mixture was
allowed to stir at room temperature for 2 h. After the completion of
the reaction, the reaction mixture was filtered through Celite and
concentrated. The residue was purified by flash chromatography on
G
dx.doi.org/10.1021/jo501117k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
silica gel (hexane:EtOAc = 5:1) to give 22 (750 mg, 2.68 mmol, 77%)
as a colorless oil: H NMR (CDCl3, 300 MHz) δ 9.75 (t, J = 1.2 Hz,
(7) Yamaguchi, K.; Yang, L.; McCall, S.; Huang, J.; Yu, X. X.; Pandey,
S. K.; Bhanot, S.; Monia, B. P.; Li, Y.-X.; Diehl, A. M. Hepatology 2007,
45, 1366−1374.
1
1H), 5.42 (br s, 1H), 5.20 (dd, J = 0.9, 9.0 Hz, 1H), 5.06 (br s, 1H),
4.68−4.63 (m, 1H), 4.03−3.95 (m, 1H), 2.43 (dt, J = 0.9, 6.0 Hz, 2H),
2.07−1.97 (m, 3H), 1.78 (dd, J = 3.0, 18.0 Hz, 1H), 1.71 (s, 3H), 1.68
(s, 3H), 1.66−1.58 (m, 2H), 1.52−1.44 (m, 2H), 1.21 (d, J = 6.0 Hz,
3H), 1.14 (d, J = 6.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 202.6,
139.2, 137.2, 125.1, 120.1, 93.3, 68.9, 63.4, 43.7, 39.1, 35.7, 27.0, 23.8,
(8) Matsuda, D.; Tomoda, H. Curr. Opin. Invest. Drugs 2007, 8, 836−
841.
(9) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 1999, 38, 2398−2400.
(10) Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2001, 40,
3667−3670.
22.8, 21.9, 21.6, 16.5; [α]20 −15.9 (c 0.50, CHCl3); HRMS (TOF
D
ESI) calcd for C17H28NaO3 303.1931 [M + Na]+, found 303.1933.
(E)-7-((2S,6S)-6-Isopropoxy-4-methyl-3,6-dihydro-2H-pyran-2-yl)-
6-methyl-2-methylenehept-6-enal (23). To a solution of 22 (750 mg,
2.68 mmol, 1.00 equiv) in dried CH2Cl2 (40 mL) and Et3N (1.9 mL,
13.4 mmol, 5.00 equiv) was added Eschenmoser’s salt (2.48 g, 13.4
mmol, 5.00 equiv). After stirring for 10 h, the reaction mixture was
quenched with saturated NaHCO3 aqueous solution (20 mL), the
layers were separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 40 mL). The combined organic layers were washed with
brine, dried over anhydrous MgSO4 and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(hexane:EtOAc = 5:1) providing 23 (741 mg, 2.54 mmol, 95%) as a
(11) Chavez, D. E.; Jacobsen, E. N. Org. Lett. 2003, 5, 2563−2565.
(12) Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772−
10773.
(13) Bonazzi, S.; Guttinger, S.; Zemp, I.; Kutay, U.; Gademann, K.
̈
Angew. Chem., Int. Ed. 2007, 46, 8707−8710.
(14) Bonazzi, S.; Eidam, O.; Guttinger, S.; Wach, J.-Y.; Zemp, I.;
̈
Kutay, U.; Gademann, K. J. Am. Chem. Soc. 2010, 132, 1432−1442.
(15) Zurwerra, D.; Gertsch, J. r.; Altmann, K.-H. Org. Lett. 2010, 12,
2302−2305.
(16) Potuzak, J. S.; Tan, D. S. Tetrahedron Lett. 2004, 45, 1797−
1801.
(17) Ravindar, K.; Reddy, M. S.; Lindqvist, L.; Pelletier, J.;
Deslongchamps, P. Org. Lett. 2010, 12, 4420−4423.
(18) Douelle, F.; Capes, A. S.; Greaney, M. F. Org. Lett. 2007, 9,
1931−1934.
(19) Mikami, K.; Motoyama, Y.; Terada, M. J. Am. Chem. Soc. 1994,
116, 2812−2820.
(20) Gademann, K.; Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2002, 41, 3059−3061.
1
colorless oil: H NMR (CDCl3, 300 MHz) δ 9.53 (s, 1H), 6.25 (s,
1H), 5.99 (s, 1H), 5.42 (s, 1H), 5.21 (d, J = 9.0 Hz, 1H), 5.07 (s, 1H),
4.70−4.63 (m, 1H), 4.03−3.95 (m, 1H), 2.22 (t, J = 6.0 Hz, 2H),
2.06−1.96 (m, 2H), 1.78 (dd, J = 3.0, 18.0 Hz, 1H), 1.72 (s, 3H), 1.69
(s, 3H), 1.58 (t, J = 6.0 Hz, 2H), 1.21 (d, J = 6.0 Hz, 3H), 1.15 (d, J =
6.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 194.6, 150.1, 139.2, 137.3,
134.1, 125.3, 120.1, 93.3, 68.9, 63.4, 39.0, 35.7, 27.4, 25.7, 23.8, 22.8,
21.9, 16.5; [α]20 −8.1 (c 0.20, CHCl3); HRMS (TOF ESI) calcd for
D
C18H28NaO3 315.1931 [M + Na]+, found 315.1956.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of the novel precursors. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: liying@lzu.edu.cn
*E-mail: fjnan@simm.ac.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from the National Science
and Technology Major Projects for Major New Drugs
Innovation and Development (2012ZX09304011) and the
National Natural Science Foundation of China (30725049).
Authors thank Prof. Zhaoguo Zhang (Shanghai Jiaotong
University) for the GC−MS analysis.
REFERENCES
■
(1) Liu, J.; He, X.-F.; Wang, G.-H.; Merino, E. F.; Yang, S.-P.; Zhu,
R.-X.; Gan, L.-S.; Zhang, H.; Cassera, M. B.; Wang, H.-Y.; Kingston, D.
G. I.; Yue, J.-M. J. Org. Chem. 2013, 79, 599−607.
(2) Zhang, H.-J.; Luo, J.; Shan, S.-M.; Wang, X.-B.; Luo, J.-G.; Yang,
M.-H.; Kong, L.-Y. Org. Lett. 2013, 15, 5512−5515.
(3) He, X.-F.; Wang, X.-N.; Fan, C.-Q.; Gan, L.-S.; Yin, S.; Yue, J.-M.
Helv. Chim. Acta 2007, 90, 783−791.
(4) Zhang, Y.; Wang, J. S.; Wei, D. D.; Gu, Y. C.; Wang, X. B.; Kong,
L. Y. J. Nat. Prod. 2013, 76, 1191−1195.
(5) Zammit, V. A.; Buckett, L. K.; Turnbull, A. V.; Wure, H.; Proven,
A. Pharmacol. Ther. 2008, 118, 295−302.
(6) Hubbard, B. K.; Enyedy, I.; Gilmore, T. A.; Serrano-Wu, M. H.
Expert Opin. Ther. Pat. 2007, 17, 1331−1339.
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