Total Synthesis of Tetraketide and Cryptorigidifoliol i via a Sequential Allylation Strategy

Article abstract of DOI:10.1021/acs.jnatprod.6b00443

A unified and efficient synthetic route for both tetraketide (1) and cryptorigidifoliol I (2) has been devised successfully from commercially available starting materials in 11 and 17 steps, with 16% and 11% overall yields, respectively. Highlights of the syntheses involved sequential Lewis acid-catalyzed highly regio- and diastereoselective allylations and intramolecular Mitsunobu lactonization.

Full text of DOI:10.1021/acs.jnatprod.6b00443

Article
pubs.acs.org/jnp
Total Synthesis of Tetraketide and Cryptorigidifoliol I via a
Sequential Allylation Strategy
Birakishore Padhi,†,‡ G. Sudhakar Reddy,†,‡ and Debendra K. Mohapatra*,†,‡
†Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
‡Academy of Scientific and Innovative Research, New Delhi 110025, India
S
* Supporting Information
ABSTRACT: A unified and efficient synthetic route for both tetraketide
(1) and cryptorigidifoliol I (2) has been devised successfully from
commercially available starting materials in 11 and 17 steps, with 16% and
11% overall yields, respectively. Highlights of the syntheses involved
sequential Lewis acid-catalyzed highly regio- and diastereoselective
allylations and intramolecular Mitsunobu lactonization.
The retrosynthetic analysis of 1 and 2 is illustrated in Scheme
icyclic tetrahydro-α-pyrones are an important class of
Boxygenated natural products isolated from different 1. A close assessment of the structures of tetraketide (1) and
cryptorigidifoliol I (2) showed that both contain a similar
bicyclic lactone moiety. The bicyclic lactone of both 1 and 2
could be derived from an intramolecular Mitsunobu lactoniza-
tion of a seco acid obtained from the intermediates 12 and 16,
respectively, which could be, in turn, accessed individually from
lactols 13 and 17 via a gold-catalyzed diastereoselective
allylation reaction developed by our group.12 Precursors 13
and 17 could be obtained separately from the known alcohols
14 and 19 via different allylation sequences, namely, the
Maruoka allylation and chelation-controlled allylation.
biological origins such as plants, insects, and marine
organisms.1 Several members of this class bear a common
structural entity (bicyclic lactone), where a 2,6-trans-tetrahy-
dropyran ring is fused to a pyran-2-one unit (Figure 1). This
class of molecules exhibits vast biological properties including
analgesic, antibacterial, antifungal, anti-inflammatory, antipar-
asitic, and cytotoxic activities.1 In addition, some of them have
been used in traditional medicine for treating arthritis,
headache, and hepatitis infections.1h Owing to their interesting
chemical framework and promising biological profiles, these
compounds have attracted much attention from the chemical
synthesis community over the past decade.2−6
RESULTS AND DISCUSSION
■
Tetraketide (1) and cryptorigidifoliol I (2) are two aliphatic
polyketides isolated during the isolation process from the leaves
of Euscaphis japonica1f in 2000 and the root wood of
Cryptocarya rigidifolia1k in 2015, respectively. The structures
of 1 and 2 were assigned mainly on the basis of extensive
spectroscopic studies, electronic circular dichroism (ECD), and
The work toward the synthesis of tetraketide (1) commenced
with the readily available (S)-pent-4-en-2-ol (14) as shown in
Scheme 2. The hydroxy functionality of 14 was protected as its
benzyl ether to furnish compound 20 in 85% yield.7 One-pot
oxidative cleavage of the terminal double bond in 20 using Jin’s
protocol8 afforded the corresponding aldehyde, which was then
subjected to a Reetz allylation9 by treatment with TiCl4 and
allyltrimethylsilane to provide the homoallylic alcohol 21 in
80% yield over two steps with good diastereoselectivity (dr =
93:7 by HPLC). The spectroscopic and analytical data of the
newly generated secondary alcohol 21 were closely comparable
with those reported by Keck.9c Silylation10 of secondary alcohol
21 to its tert-butyldimethylsilyl ether 22 and subsequent
deprotection of benzyl ether using Li/naphthalene11 afforded
1
the H NMR spectroscopy of Mosher acid derivatives. The
biological activity of 1 is still not known, whereas 2 possesses
antimalarial activity against the Dd2 strain of Plasmodium
falciparum and antiproliferative activity against certain human
cancer cells.1k However, further biological evaluation of
compounds 1 and 2 is hampered due to their limited
availability from natural resources. Hence, a new sequential
allylation approach has been developed toward the total
synthesis of 1 and 2, which could provide sufficient amounts
of the target compounds for further biological evaluation and
confirmation of their structures.
Received: May 16, 2016
© XXXX American Chemical Society and
American Society of Pharmacognosy
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Figure 1. Natural products containing a bicyclic lactone structural unit.
With good quantities of lactol 13 in hand, our established
diastereoselective allylation reaction was carried out at the
anomeric position using AuCl3 and allyltrimethylsilane via
formation of an oxocarbenium ion intermediate to provide the
desired 2,6-trans-tetrahydropyran 24 in 92% yield with an
excellent diastereoselectivity (dr >95:5, confirmed by NMR
spectroscopy).12 OsO4-catalyzed oxidative cleavage8 (OsO4,
NaIO4, 2,6-lutidine, dioxane/H2O) of the olefin moiety of 24 in
one pot furnished aldehyde 25, and further oxidation of the
resulting aldehyde 25 under Pinnick’s conditions13 gave the
carboxylic acid 12 in 78% yield over two steps. Removal of the
TBS group using HF·pyridine in tetrahydrofuran (THF)
afforded the corresponding seco acid 26 in impure form,
which was taken forward without further characterization.14
Intramolecular Mitsunobu lactonization15 of seco acid 26 using
diethyl azodicarboxylate in the presence of Ph3P provided
bicyclic compound tetraketide (1) in 58% yield over two steps
(Scheme 3). The analytical and spectroscopic data of 1 were in
good agreement with those of the isolated natural product.1f
After successful achievement of total synthesis for tetraketide
(1), it was decided to examine further the synthetic efficacy of
this particular approach toward the total synthesis of
cryptorigidifoliol I (2) via different allylation reactions. The
synthesis began from the commercially available cetyl alcohol
19 (Scheme 4). The oxidation of 1-hexadecanol (19) with o-
Scheme 1. Retrosynthetic Analysis
Scheme 2. Synthesis of Lactol Precursor 13
Scheme 3. Total Synthesis of the Tetraketide
the corresponding alcohol 23 in a 72% yield over two steps.
Oxidative cleavage8 of the double bond ultimately provided the
desired lactol 13 in 76% yield, which is the requisite precursor
for gold-catalyzed allylation.
B
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provided the homoallylic alcohol 33 in 80% yield (over two
steps) with excellent diastereoselectivity (dr = 99:1 by
HPLC).21 Similarly, before proceeding further, it was necessary
to confirm the relative stereochemistry of the homoallylic
alcohol 33. The configuration of 33 was determined by 13C
NMR analysis of the acetonide derivative 34 formed via
subsequent deprotection of PMB ether22 and further protection
using 2,2-dimethoxypropane.19 The chemical shifts of the
acetonide methyl group (δ 24.89 and 24.91) and acetal carbon
(δ 100.2) were in accordance with Rychnovsky’s method15 for
1,3-trans-stereochemistry (Scheme 5).
Scheme 4. Synthesis and Stereochemical Assignment of 29
The hydroxy group of 33 was protected as the TBS ether10
to furnish 35 followed by selective deprotection of the PMB
ether in the presence of benzyl ether using DDQ, providing
secondary alcohol 36 (86% yield, over two steps).22 Oxidative
cleavage of terminal olefin 36 was performed smoothly utilizing
OsO4-catalyzed Jin’s protocol8 to furnish lactol 17 in 82% yield.
With lactol precursor 17 in hand, gold-catalyzed diastereose-
lective allylation then was carried out (Scheme 6).
iodoxybenzoic acid (IBX)16 afforded palmitaldehyde (27) in
92% yield. With aldehyde 27 in hand, asymmetric Maruoka
allylation17 was performed using allyltributyltin in the presence
of Ti(iPrO)4 and (S)-BINOL at −20 °C to give the desired
homoallylic alcohol 18 in 87% yield. Benzylation of the
secondary alcohol of 18 under basic conditions (BnBr, NaH,
and catalytic TBAI) in dimethylformamide (DMF) provided
compound 28 in 95% yield with an enantiomeric excess of
97%.7 Oxidative cleavage of the terminal olefin 28 was
accomplished using Jin’s protocol8 to furnish the resultant
aldehyde, which was immediately subjected to the chelation-
controlled allylation using allyltrimethylsilane under Reetz
conditions9 (TiCl4, CH2Cl2, −78 °C), to obtain product 29
in 81% yield (over two steps) with high diastereoselectivity (dr
= 98:2 by HPLC). Using Rychnovsky’s method,18 the relative
configuration of the major isomer 29 was confirmed by
examining the 13C NMR spectrum of acetonide 31, which was
prepared by deprotecting the benzyl group with Li/
naphthalene,11 followed by protection of the corresponding
1,3-diol 30 as its acetonide 31 in 73% yield over two steps.19
Inspection of the 13C NMR spectrum of acetonide 31 showed
chemical shifts of the acetonide methyl groups at δ 24.75 and
24.83 ppm and the ketal carbon at δ 100.1 ppm, indicating an
anti-1,3-diol acetonide, in accordance with Rychnovsky’s model
for 1,3-anti stereochemistry (Scheme 4).
Scheme 6. Synthesis of the Lactol Precursor 17
Next, the stereogenic center at the anomeric position of 17
was introduced by using AuCl3 and allyltrimethylsilane via
formation of an oxocarbenium ion, providing allylated product
37 in 92% yield with high diastereoselectivity (dr = 96:4 by
HPLC).12 Oxidative cleavage8 of the terminal double bond
followed by further oxidation of the subsequent aldehyde 38
under Pinnick’s conditions13 furnished acid 16 in 71% yield
over two steps. To access the bicyclic compound 15, HF·
pyridine was used for the deprotection of the TBS ester14
followed by the intramolecular Mitsunobu lactonization15 of
the resultant seco acid 39 using diethyl azodicarboxylate and
Ph3P to provide 15 in 59% yield (over two steps).
Debenzylation of 15 was achieved using Pd/C catalyst23 in
MeOH to produce 2 in 92% yield, which completed the first
total synthesis of cryptorigidifoliol I (2) (Scheme 7). A
After confirming the 1,3-anti relationship of the stereo-
centers, homoallylic alcohol 29 was protected as its p-
methoxybenzyl ether to provide compound 32 in 88% yield
(Scheme 5).20 Manipulation of the terminal olefin in 32 via
Jin’s dihydroxylation−oxidation protocol8 followed by a
chelation-controlled Sakurai allylation using MgBr2·Et2O
Scheme 5. Synthesis and Stereochemical Assignment of 33
1
comparison of the H NMR spectroscopic and analytical data
of synthetic compound 2 with those of the natural product
showed that they were identical.1 Due to low availability of
compound 2 during the isolation process, the Kingston group
1a
1
provided only the H NMR spectrum. Herein, compound 2
has been synthesized in pure form in a ≥ 30 mg quantity, and
complete spectroscopic and analytical data were obtained (see
Supporting Information).
In summary, a linear synthesis of both tetraketide (1) and
cryptorigidifoliol I (2) was achieved using a fully practical and
stereocontrolled sequential allylation approach. The use of
selected reagents as well as substrate-controlled allylation
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Na2SO4, and concentrated under reduced pressure. The crude material
was purified by silica gel column chromatography (ethyl acetate−
hexane, 1:19) to furnish the desired compound 20 (6.96 g, 85%) as a
colorless liquid: [α]20D −35 (c 2.2, CHCl3); IR νmax 2924, 2854, 1636,
1382, 1251, 766 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.73−7.21 (5H,
m), 5.84 (1H, m), 5.12−5.02 (2H, m), 4.53 (2H, ABq, J = 14.8, 11.7
Hz), 3.58 (1H, m), 2.38 (1H, m), 2.28 (1H, m), 1.20 (3H, d, J = 6.1
Hz); 13C NMR (CDCl3, 100 MHz) δ 138.9, 135.0, 128.2, 127.5, 127.3,
116.8, 74.4, 70.3, 40.8, 19.4; anal. C 81.77, H 9.15%, calcd for
C12H16O, C 81.65, H 9.23%.
Scheme 7. Total Synthesis of the Cryptorigidifoliol I
(4S,6S)-6-(Benzyloxy)hept-1-en-4-ol (21). To a solution of 20
(4.0 g, 22.73 mmol) in dioxane and water (3:1) (60 mL) were added
sequentially 2,6-lutidine (10.5 mL, 90.91 mmol), OsO4 (0.45 mL,
0.454 mmol, 1 M solution in toluene), and then NaIO4 (19.45 g, 90.91
mmol) at room temperature, and the mixture was stirred for 2 h. After
the completion of the reaction (monitored by TLC), 1,4-dioxane was
removed under reduced pressure and the residual aqueous layer was
extracted with CH2Cl2 (3 × 150 mL). The CH2Cl2 layer was quickly
washed with 1 N HCl (2 × 100 mL) to remove excess 2,6-lutidine
followed by brine (2 × 100 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure to afford the crude aldehyde. On
purification using a short flash chromatographic column containing
silica gel (ethyl acetate−hexane, 1:19), this furnished the correspond-
ing aldehyde as a colorless liquid, 3.47 g (86%), which was used
immediately without further characterization.
strategies served as powerful tools for the generation of highly
diastereoselective 1,3-anti-alcohol derivatives and a 2,6-trans-
allylated tetrahydropyran core employing methodology devel-
oped in-house. This work offers a unified strategy to access
tetraketide (1) and cryptorigidifoliol I (2) and further has
provided scalable amounts of target compounds (76 and 31 mg,
respectively) for further biological activity studies.
To a solution of the above aldehyde (3.47 g, 19.49 mmol) in
CH2Cl2 (150 mL) was added a 1.0 M solution of TiCl4 in CH2Cl2
(21.44 mL, 21.44 mmol) slowly at −78 °C. After 15 min,
allyltrimethylsilane (4.65 mL, 29.24 mmol) was added, and the
reaction mixture was stirred at −78 °C for 1 h. After completion of the
reaction (monitored by TLC), the reaction mixture was quenched
using a saturated aqueous solution of NaHCO3 (50 mL) and was
stirred vigorously for 3 h at room temperature. The layers were
separated, and the aqueous layer further extracted with CH2Cl2 (2 ×
75 mL). The combined organic layer was dried with Na2SO4 and
evaporated under reduced pressure. The residue was purified by
column chromatography over silica gel (ethyl acetate−hexane, 1:9) to
afford allylic alcohol 21 (3.98 g, 93%, dr 93:7) as a colorless liquid:
EXPERIMENTAL SECTION
■
General Experimental Procedures. Air- and/or moisture-
sensitive reactions were carried out in anhydrous solvents under an
atmosphere of argon or nitrogen in oven- or flame-dried glassware. All
anhydrous solvents were distilled prior to use: THF from Na and
benzophenone; CH2Cl2, DMF, and hexane from CaH2; and MeOH
from Mg cake. Commercially available reagents were used without
purification. Column chromatography was carried out using silica gel
(60−120 mesh). Analytical thin-layer chromatography (TLC) was run
on silica gel 60 F254 precoated plates (250 μm thickness).
Diastereomeric ratio was recorded on a Shimadzu LC-MS-8040
instrument with different chiral stationary-phase columns and different
solvent systems (for further information, see the Supporting
Information). Melting points were determined using a Stuart SMP3
apparatus. Specific rotations [α]D were measured with an Anton Paar
MCP 200 digital polarimeter at 20 °C. Infrared spectra were recorded
in CHCl3/neat with a Thermo Nicolet Nexus 670 spectrometer and
[α]20 +38.5 (c 2.5, CHCl3); IR νmax 3449, 2968, 2860, 1636, 1450,
D
1377, 1089 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.73−7.25 (5H, m),
5.83 (1H, m), 5.14−5.04 (2H, m), 4.59 (1H, d, J = 11.6 Hz), 4.45
(1H, d, J = 11.6 Hz), 3.98 (1H, m), 3.88 (1H, m), 2.71 (1H, br s),
2.25−2.19 (2H, m), 1.70−1.63 (2H, m), 1.26 (3H, d, J = 6.2 Hz); 13C
NMR (CDCl3, 125 MHz) δ 138.3, 135.0, 128.3 127.6, 127.5, 117.3,
72.5, 70.5, 67.5, 42.3, 42.0, 19.2; HRESIMS m/z 243.1352 [M + Na]+
calcd for C14H20O2Na, 243.1355.
(((4S,6S)-6-(Benzyloxy)hept-1-en-4-yl)oxy)(tert-butyl)-
dimethylsilane (22). To a stirred solution of 21 (2.5 g, 11.36 mmol)
in dry CH2Cl2 (50 mL) were added imidazole (1.16 g, 17.05 mmol)
and TBSCl (2.57 g, 17.05 mmol) followed by dimethylaminopyridine
(DMAP) (138 mg, 1.14 mmol) at 0 °C. After 6 h of stirring at room
temperature, the reaction was then quenched with saturated aqueous
NaHCO3 (30 mL). The layers were then separated and the aqueous
layer was extracted with CH2Cl2 (2 × 50 mL). The combined organic
layer was dried over Na2SO4 and concentrated under reduced
pressure. The crude product was purified by silica gel column
chromatography (ethyl acetate−hexane, 1:20) to obtain compound 22
1
reported in wave numbers (cm−1). H and 13C NMR spectra were
recorded on a Varian 300 or 400 or Bruker Avance 500 MHz
spectrometer, chemical shifts are reported in ppm downfield from
tetramethylsilane, and coupling constants (J) are reported in hertz
(Hz). The following abbreviations are used to designate signal
multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad. CHN analysis was recorded on a Thermo
Finnigan Flash EN 1112 instrument. HRESIMS data were recorded on
an ESI-QTOF mass spectrometer.
(S)-((Pent-4-en-2-yloxy)methyl)benzene (20). To a stirred
solution of alcohol 14 (4.0 g, 46.55 mmol) in dry DMF (100 mL)
was added 60% NaH (2.29 g, 69.77 mmol) at 0 °C. The reaction
mixture was then allowed to reach room temperature and stirred for 1
h. To this was added benzyl bromide (6.64 mL, 55.81 mmol) followed
by tetrabutylammonium iodide (1.72 g, 4.65 mmol) at 0 °C, and the
mixture was stirred at room temperature for 12 h. After completion of
the reaction (monitored by TLC), it was quenched with an aqueous
solution of NH4Cl (50 mL) at 0 °C and diluted with tert-butyl methyl
ether (150 mL). The layers were separated, and the aqueous layer was
extracted with tert-butyl methyl ether (2 × 150 mL). The combined
organic layers were washed with brine (200 mL), dried over anhydrous
(3.52 g, 93%) as a colorless liquid: [α]20 +28.7 (c 1.7, CHCl3); IR
D
νmax 2930, 2857, 1730, 1462, 1377, 1152, 1060 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 7.32−7.20 (5H, m), 5.80 (1H, m), 5.04−4.97
(2H, m), 4.56 (1H, d, J = 11.4 Hz), 4.38 (1H, d, J = 11.4 Hz), 3.98
(1H, m), 3.69 (1H, m), 2.29−2.14 (2H, m), 1.71 (1H, m), 1.47 (1H,
m), 1.19 (3H, d, J = 6.1 Hz), 0.87 (9H, s), 0.03 (6H, d, J = 9.6 Hz);
13C NMR (CDCl3, 75 MHz) δ 139.0, 134.7, 128.2, 127.4, 127.3, 116.9,
72.0, 70.0, 68.6, 44.7, 42.5, 25.8, 20.1, 18.0, −4.0, −4.5; HRESIMS m/z
335.2401 [M + H]+ calcd for C20H35O2Si, 335.2400.
(2S,4S)-4-((tert-Butyldimethylsilyl)oxy)hept-6-en-2-ol (23).
To a stirred solution of naphthalene (5.38 g, 42.04 mmol) in dry
THF (40 mL) was added Li metal (174 mg, 21.02 mmol) at room
temperature. After 30 min, a dark green color developed, which turned
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dark blue after 1 h. To this was added slowly compound 22 (1.76 g,
5.25 mmol) in dry THF (15 mL) at −20 °C. The resulting mixture
was stirred for 1 h at the same temperature. After completion of the
reaction (monitored by TLC), it was quenched with a saturated
aqueous solution of NH4Cl (30 mL) and diluted with ethyl acetate (50
mL). The resulting mixture was stirred for 1 h at room temperature.
The organic layer was separated, and the aqueous layer extracted with
ethyl acetate (2 × 50 mL). The combined organic layers were dried
over Na2SO4 and concentrated under reduced pressure to obtain the
crude mass, which on purification by silica gel column chromatography
(ethyl acetate−hexane, 1:9) furnished the desired alcohol 23 (1.0 g,
78%) as a colorless liquid: [α]20D +14.9 (c 2.5, CHCl3); IR νmax 3447,
2926, 1640, 1384, 1218, 1087, 771 cm−1; 1H NMR (CDCl3, 500
MHz) δ 5.74 (1H, m), 5.11−5.03 (2H, m), 4.15 (1H, m), 4.03 (1H,
m), 3.25 (1H, br s), 2.38−2.32 (2H, m), 1.62−1.57 (2H, m), 1.16
(3H, d, J = 6.2 Hz), 0.90 (9H, s), 0.10 (6H, d, J = 8.2 Hz); 13C NMR
(CDCl3, 125 MHz,) δ 134.6, 117.3, 71.1, 64.3, 43.1, 41.0, 25.7, 23.8,
17.9, −4.6, −4.9; HRESIMS m/z 267.1752 [M + Na]+ calcd for
C13H28O2SiNa, 267.1761.
washed with 1 N HCl (2 × 15 mL) to remove excess 2,6-lutidine
followed by brine (2 × 15 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure to produce a crude aldehyde. On
purification by short column flash chromatography over silica gel
(ethyl acetate−hexane, 1:19) this afforded corresponding aldehyde 25
as a yellow liquid, 172 mg (92%), which was used immediately without
further characterization.
2-((2R,4R,6S)-4-((tert-Butyldimethylsilyl)oxy)-6-methyl-
tetrahydro-2H-pyran-2-yl)acetic acid (12). To a stirred solution of
aldehyde 25 (172 mg, 0.63 mmol) in tert-butyl alcohol (15 mL) was
added 2-methyl-2-butene (0.95 mL, 0.95 mmol, 1 M solution in THF)
at room temperature. NaH2PO4 (227 mg, 1.89 mmol) and sodium
chlorite (170 mg, 1.89 mmol) were dissolved in water (10 mL) to
make a clear solution, which was subsequently added to the reaction
mixture at 0 °C. It was then allowed to stir for a further 6 h at room
temperature. After completion of the reaction (monitored by TLC), it
was diluted with water (15 mL). The organic solvent was removed
under reduced pressure, and the aqueous layer extracted with ethyl
acetate (3 × 30 mL). The combined organic layer was washed with
brine (40 mL), dried over anhydrous Na2SO4, and evaporated under
reduced pressure. The crude product was purified by silica gel column
chromatography (ethyl acetate−hexane, 3:7) to afford an acid, 12 (155
(4R,6S)-4-((tert-Butyldimethylsilyl)oxy)-6-methyltetrahydro-
2H-pyran-2-ol (13). To a solution of 23 (620 mg, 2.54 mmol) in
dioxane and water (3:1) (16 mL) were sequentially added at room
temperature 2,6-lutidine (1.17 mL, 1.02 mmol), OsO4 (56 μL, 0.056
mmol, 1 M solution in toluene), and NaIO4 (2.18 g, 1.02 mmol), and
the mixture was stirred for 2.5 h. After completion of the reaction
(monitored by TLC), 1,4-dioxane was removed under reduced
pressure and the residual aqueous layer was extracted with CH2Cl2
(3 × 50 mL). The CH2Cl2 layer was quickly washed with 1 N HCl (2
× 25 mL) to remove excess 2,6-lutidine followed by brine (2 × 20
mL), dried over anhydrous Na2SO4, and concentrated under reduced
pressure to get the crude lactol. On purification by short flash
chromatographic column over silica gel (ethyl acetate−hexane, 1:19)
this afforded the corresponding lactol 13 (475 mg, 76%) as a pale
yellow liquid: [α]20D −15.0 (c 0.9, CHCl3); IR νmax 3424, 2955, 2856,
mg, 85%), as a colorless oil: [α]20 −15.8 (c 1.3, CHCl3); IR νmax
D
1
3448, 2929, 2857, 1640, 1715, 1254, 1109 cm−1; H NMR (CDCl3,
500 MHz) δ 4.51 (1H, m), 4.01 (1H, m), 3.93 (1H, m), 2.72 (1H, dd,
J = 15.1, 9.0 Hz), 2.49 (1H, dd, J = 15.1, 5.2 Hz), 1.86 (1H, m), 1.71−
1.65 (2H, m), 1.36−1.26 (4H, m), 0.89 (9H, s), 0.06 (6H, d, J = 2.1
Hz); 13C NMR (CDCl3, 125 MHz) δ 175.7, 66.9, 68.8, 64.7, 38.3,
38.1, 29.6, 25.7, 21.1, 18.0, −4.7, −4.8; HRESIMS m/z 311.1656 [M +
Na]+ calcd for C14H28O4SiNa, 311.1664.
(1S,5R,7S)-7-Methyl-2,6-dioxabicyclo[3.3.1]nonan-3-one (1).
To a stirred solution of acid 12 (242 mg, 0.84 mmol) in THF (10 mL)
in a vial was added HF·pyridine (0.6 mL) in THF (8 mL) at 0 °C. The
reaction mixture was stirred for 12 h at room temperature. After
completion of the reaction (monitored by TLC), it was quenched with
H2O (10 mL) and diluted with ethyl acetate (20 mL). The layers were
separated, and the aqueous layer was extracted with ethyl acetate (3 ×
20 mL). The combined organic layers were washed with brine (2 × 50
mL), dried over anhydrous Na2SO4, and evaporated under reduced
pressure. The crude product was purified by silica gel column
chromatography (ethyl acetate−hexane, 4:1) to afford seco acid 26
(116 mg) as a colorless oil, which was used immediately without
further characterization.
1
1466, 1383, 1254, 1096 cm−1; H NMR (CDCl3, 400 MHz) δ 5.38
(0.6H, br s), 4.68 (0.4H, m), 4.12 (1H, m), 3.79 (0.6H, m), 3.50
(0.4H, m), 2.05 (1H, m), 1.90−1.72 (1.6H, m), 1.56−1.31 (1.4H, m),
1.26 (1.2H, d, J = 6.2 Hz), 1.18 (1.8H, d, J = 6.2 Hz), 0.88 (9H, s),
0.07 (6H, d, J = 2.9 Hz); 13C NMR (CDCl3, 125 MHz) δ 94.4, 92.9,
68.3, 67.3, 64.2, 64.0, 43.4, 42.8, 42.4, 39.5, 25.8, 25.7, 21.4, 21.2, 18.0,
18.0, −4.6, −4.6; HRESIMS m/z 247.1721 [M + H]+ calcd for
C12H27O3Si 247.1724.
(((2S,4R,6S)-2-Allyl-6-methyltetrahydro-2H-pyran-4-yl)oxy)-
(tert-butyl)dimethylsilane (24). To a stirred solution of lactol 13
(297 mg, 1.21 mmol) and allyltrimethylsilane (0.36 mL, 1.81 mmol) in
CH2Cl2 (20 mL) was added AuCl3 (18.2 mg, 0.06 mmol) at room
temperature, and the mixture was allowed to stir for 3 h. After
completion of the reaction (monitored by TLC), it was quenched with
H2O (10 mL). The organic layer was separated, and the aqueous layer
extracted with CH2Cl2 (2 × 20 mL). The combined organic layer was
dried over anhydrous Na2SO4 and concentrated under reduced
pressure to give a pale yellow oil, which was purified by column
chromatography over silica gel (ethyl acetate−hexane, 1:19) to furnish
To a stirred solution of Ph3P (524 mg, 1.98 mmol) in anhydrous
THF (50 mL) was added diethylazodicarboxylate (0.32 mL, 1.98
mmol) at 0 °C under an argon atmosphere. After the reaction mixture
was stirred for 0.5 h at room temperature, it was cooled to 0 °C. To
this reaction mixture, crude seco acid 26 (116 mg) dissolved in THF
(20 mL) was added, and the mixture was stirred for 12 h at room
temperature. After completion of the reaction (monitored by TLC), it
was quenched with H2O (25 mL) and diluted with ethyl acetate (50
mL). The organic layer was separated, and the aqueous layer extracted
with ethyl acetate (2 × 50 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by silica gel column
chromatography (ethyl acetate−hexane, 1:4) to furnish the desired
lactone 1 (76.2 mg, 58% over two steps) as a white amorphous solid:
the desired compound 24 (300 mg, 92%) as a colorless liquid: [α]20
D
−22.9 (c 2.3, CHCl3); IR νmax 2927, 2855, 1638, 1384, 1218, 769
1
cm−1; H NMR (CDCl3, 300 MHz) δ 5.79 (1H, m), 5.12−5.02 (2H,
m), 4.12−3.91 (2H, m), 3.79 (1H, m), 2.44 (1H, m), 2.22 (1H, m),
1.81 (1H, m), 1.75−1.51 (3H, m), 1.21 (3H, d, J = 6.2 Hz), 0.89 (9H,
s), 0.06 (6H, s); 13C NMR (CDCl3, 75 MHz) δ 135.2, 116.6, 70.9,
65.6, 65.0, 42.2, 37.5, 37.1, 25.8, 21.6, 18.1, −4.6; HRESIMS m/z
293.1908 [M + Na]+ calcd for C15H30O2SiNa, 293.1912.
mp 86−87 °C; [α]20 −12.7 (c 0.9, MeOH); IR νmax 2927, 1737,
D
1
1390, 1229, 1070 cm−1; H NMR (CDCl3−C6D6, 1:1, 300 MHz) δ
4.40 (1H, m), 3.89 (1H, br s), 3.68 (1H, ddq, J = 11.5, 5.6, 2.8 Hz),
2.60 (1H, br d, J = 19.0 Hz), 2.33 (1H, dd, J = 19.0, 5.2 Hz), 1.68 (1H,
m), 1.34 (1H, br dt, J = 13.5, 2.0 Hz), 1.13 (1H, br s), 1.12 (1H, ddd, J
= 13.9, 11.5, 2.0 Hz), 0.99 (3H, d, J = 6.0 Hz); 13C NMR (CDCl3−
C6D6, 1:1, 100 MHz) δ 169.7, 73.0, 65.8, 61.9, 38.5, 36.4, 29.5, 21.3;
anal. C 61.45, H 7.81%, calcd for C8H12O3, C 61.52, H 7.74%.
Palmitaldehyde (27). To a stirred solution of alcohol 19 (10.0 g,
41.32 mmol) in ethyl acetate was added IBX (17.35 g, 61.98 mmol).
The resulting mixture was refluxed for 12 h. After completion of the
reaction (monitored by TLC), the reaction mixture was cooled to
room temperature and filtered through a Celite bed and washed with
2-((2R,4R,6S)-4-((tert-Butyldimethylsilyl)oxy)-6-methyl-
tetrahydro-2H-pyran-2-yl)acetaldehyde (25). To a solution of 24
(186 mg, 0.69 mmol) in dioxane and water (3:1) (12 mL) were added
sequentially 2,6-lutidine (0.32 mL, 2.75 mmol), OsO4 (14 μL, 0.014
mmol, 1 M solution in toluene), and NaIO4 (588 mg, 2.75 mmol) at
room temperature, and the mixture was stirred for 2.5 h. After
completion of the reaction (monitored by TLC), 1,4-dioxane was
removed under reduced pressure and the residual aqueous layer was
extracted with CH2Cl2 (3 × 25 mL). The CH2Cl2 layer was quickly
E
DOI: 10.1021/acs.jnatprod.6b00443
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
ethyl acetate. The solvent was evaporated under reduced pressure and
purified by silica gel column chromatography over silica gel (ethyl
acetate−hexane, 1:19) to obtain aldehyde 27 (9.12 g, 92%), as a white
solid, which was used immediately without further characterization.
(R)-Nonadec-1-en-4-ol (18). To a stirred solution of TiCl4 (0.41
mL, 3.743 mmol) in CH2Cl2 (25 mL) was added Ti(iPrO)4 (3.32 mL,
11.230 mmol) at 0 °C under argon. The solution was allowed to warm
to room temperature. After 3 h, silver oxide (1.73 g, 7.49 mmol) was
added, and the reaction mixture was stirred in the dark for 6 h. The
reaction mixture was diluted with CH2Cl2 (50 mL) and treated with
(S)-binaphthol (2.143 g, 7.486 mmol) at room temperature for 3 h to
furnish a chiral bis(S)-TiIV oxide. The in situ-generated bis(S)-TiIV
oxide in CH2Cl2 was cooled to −15 °C and added sequentially to
palmitaldehyde (9.0 g, 37.44 mmol) dissolved in CH2Cl2 (30 mL) and
allyltributyltin (17.4 mL, 56.16 mmol). The reaction mixture was
warmed to 0 °C and stirred for 24 h. After completion of the reaction
(monitored by TLC), the reaction mixture was quenched with
saturated NaHCO3 solution (100 mL) and extracted with CH2Cl2 (3
× 150 mL). The combined organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude product
was purified by silica gel column chromatography (ethyl acetate−
hexane, 1:19) to afford the homoallylic alcohol 18 (9.2 g, 87%) as a
white solid: mp 44−45 °C; [α]20D +2.5 (c 1.5, CHCl3); IR νmax 3231,
TiCl4 in CH2Cl2 (21.55 mL, 20.56 mmol) slowly at −78 °C. After 15
min, allyltrimethylsilane (4.46 mL, 28.02 mmol) was added, and the
reaction mixture was stirred at −78 °C for 1 h. After completion of the
reaction (monitored by TLC), the reaction mixture was quenched
with a saturated aqueous solution of NaHCO3 (60 mL) and was
stirred vigorously for 3 h at room temperature. The layers were
separated, and the aqueous layer was further extracted with CH2Cl2 (2
× 100 mL). The combined organic layer was dried over Na2SO4 and
evaporated under reduced pressure. The residue was purified by
column chromatography over silica gel (ethyl acetate−hexane, 1:9) to
furnish allylic alcohol 29 (7.39 g, 81% over two steps, dr 98:2 by
HPLC) as a colorless liquid: [α]20 −12.8 (c 2.5, CHCl3); IR νmax
D
3450, 2925, 2855, 1647, 1491, 1395, 1071, 770 cm−1; 1H NMR
(CDCl3, 400 MHz) δ 7.38−7.26 (5H, m), 5.82 (1H, m), 5.14−5.07
(2H, m), 4.55 (2H, ABq, J = 23.5, 11.4 Hz), 3.96 (1H, m), 3.71 (1H,
m), 2.25−2.20 (2H, m), 1.77−1.45 (4H, m), 1.38−1.15 (26H, m),
0.88 (3H, t, J = 7.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 138.4, 134.9,
128.4, 127.8, 127.6, 117.4, 77.0, 71.2, 67.7, 42.1, 39.3, 33.4, 31.9, 29.7,
29.7, 29.6, 29.3, 25.4, 22.6, 14.1; HRESIMS m/z 417.3723 [M + H]+
calcd for C28H49O2, 417.3727.
(4R,6R)-4-Allyl-2,2-dimethyl-6-pentadecyl-1,3-dioxane (31).
To a stirred solution of naphthalene (492 mg, 3.84 mmol) in
anhydrous THF (10 mL) was added Li metal (13 mg, 1.92 mmol) at
room temperature. After 30 min, a dark green color developed that
turned dark blue after 1 h. To this reaction mixture was added slowly
compound 22 (200 mg, 0.480 mmol) in anhydrous THF (5 mL) at
−20 °C. The resulting mixture was stirred for 1 h at the same
temperature. After completion of the reaction (monitored by TLC), it
was quenched with saturated aqueous NH4Cl solution (15 mL) and
diluted with ethyl acetate (30 mL). The resulting mixture was stirred
for 1 h at room temperature. The organic layer was separated, and the
aqueous layer extracted with ethyl acetate (2 × 30 mL). The combined
organic layers were dried over Na2SO4 and concentrated under
reduced pressure to obtain a crude mass. On purification by silica gel
column chromatography (ethyl acetate−hexane, 1:4), this afforded the
desired diol 30 as a colorless liquid, 141 mg (90%), which was used
immediately without further characterization.
To a solution of the above-mentioned diol 30 (141 mg, 0.43 mmol)
in CH2Cl2 (10 mL) was added CSA (10 mg, 0.043 mmol) and 2,2-
dimethoxypropane (0.16 mL, 1.30 mmol) at 0 °C. The reaction
mixture was stirred at room temperature for 2 h. After completion of
the reaction (monitored by TLC), the reaction was quenched with
saturated aqueous NaHCO3 solution (10 mL), diluted with CH2Cl2
(10 mL), and stirred for 30 min at room temperature. The layers were
separated, and the aqueous layer was extracted with CH2Cl2 (2 × 15
mL). The combined organic layer was dried over Na2SO4 and
evaporated under reduced pressure. The residue was purified by silica
gel column chromatography (ethyl acetate−hexane, 1:19) to obtain
compound 31 (128 mg, 81%) as a colorless liquid: 1H NMR (CDCl3,
400 MHz) δ 5.80 (1H, m), 5.12−5.02 (2H, m), 3.85 (1H, m), 3.75
(1H, m), 2.30 (1H, m), 2.19 (1H, m), 1.65−1.46 (3H, m), 1.41 (1H,
m), 1.35 (6H, s), 1.31−1.21 (26H, m), 0.88 (3H, t, J = 7.0 Hz); 13C
NMR (CDCl3, 100 MHz) δ 134.5, 116.7, 100.1, 66.6, 66.2, 40.2, 38.2,
35.9, 31.9, 29.7, 29.6, 29.6, 29.3, 25.3, 24.8, 24.7, 22.7, 14.1.
1-((((4R,6R)-6-(Benzyloxy)henicos-1-en-4-yl)oxy)methyl)-4-
methoxybenzene (32). To a stirred solution of alcohol 29 (6.7 g,
16.08 mmol) in anhydrous DMF (60 mL) was added 60% NaH (964
mg, 24.12 mmol) at 0 °C. The reaction mixture was then allowed to
reach room temperature and stirred for 1 h. To this reaction mixture
was added p-methoxybenzyl chloride (2.6 mL, 19.29 mmol), followed
by tetrabutylammonium iodide (593 mg, 1.61 mmol) at 0 °C with
stirring at room temperature for 12 h. After completion of the reaction
(monitored by TLC), it was quenched with an aqueous solution of
NH4Cl (100 mL) at 0 °C and was diluted with tert-butyl methyl ether
(150 mL). The layers were separated, and the aqueous layer was
extracted with tert-butyl methyl ether (2 × 150 mL). The combined
organic layers were washed with brine (200 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The crude material
was purified by silica gel column chromatography (ethyl acetate−
hexane, 1:19) to furnish the desired compound 32 (7.6 g, 88%) as a
1
2919, 2850, 1617, 1466, 1401, 1253, 1074 cm−1; H NMR (CDCl3,
300 MHz) δ 5.82 (1H, m), 5.19−5.09 (2H, m), 3.65 (1H, m), 2.31
(1H, m), 2.14 (1H, m), 1.62 (1H, br s), 1.52−1.40 (2H, m), 1.39−
1.20 (26H, m), 0.88 (3H, t, J = 7.0 Hz); 13C NMR (CDCl3, 100 MHz)
δ 134.9, 117.9, 70.7, 41.9, 36.8, 31.9, 29.7, 29.6, 29.6, 29.3, 25.6, 22.7,
14.1; anal. C 80.65, H 13.48%, calcd for C19H38O, C 80.78, H 13.56%.
(R)-((Nonadec-1-en-4-yloxy)methyl)benzene (28). To a stirred
solution of alcohol 18 (7.0 g, 24.82 mmol) in anhydrous DMF (70
mL) was added 60% NaH (1.49 g, 37.23 mmol) at 0 °C. The reaction
mixture was then allowed to reach room temperature and stirred for 1
h. To this reaction mixture was added benzyl bromide (3.54 mL, 29.78
mmol) followed by tetrabutylammonium iodide (915 mg, 2.48 mmol)
at 0 °C, with stirring conducted at room temperature for 12 h. After
completion of the reaction (monitored by TLC), it was quenched with
an aqueous solution of NH4Cl (140 mL) at 0 °C and was diluted with
tert-butyl methyl ether (150 mL). The layers were separated, and the
aqueous layer was extracted with tert-butyl methyl ether (2 × 150 mL).
The combined organic layers were washed with brine (200 mL), dried
over anhydrous Na2SO4, and concentrated under reduced pressure.
The crude material was purified by silica gel column chromatography
(ethyl acetate−hexane, 1:20) to furnish the desired compound 28
(8.77 g, 95%) as a yellow liquid: [α]20 +8.1 (c 3.2, CHCl3); IR νmax
D
3446, 2925, 2854, 1632, 1460, 1266, 1096, 1026 cm−1; 1H NMR (500
MHz, CDCl3) δ 7.37−7.22 (5H, m), 5.85 (1H, m), 5.12−5.02 (2H,
m), 4.5 (2H, ABq, J = 39.9, 11.7 Hz) 3.43 (1H, m), 2.38−2.27 (2H,
m), 1.52 (1H, m), 1.40 (1H, m), 1.36−1.19 (26H, m), 0.88 (3H, t, J =
7.0 Hz); 13C NMR (CDCl3, 125 MHz) δ 138.9, 135.0, 128.2, 127.6,
127.3, 116.7, 78.5, 70.8, 38.3, 33.8, 31.9, 29.7, 29.6, 29.4, 25.3, 22.7,
14.1; HRESIMS m/z 373.3469 [M + H]+ calcd for C26H45O,
373.3464.
(4R,6R)-6-(Benzyloxy)henicos-1-en-4-ol (29). To a stirred
solution of 28 (8.2 g, 22.04 mmol) in dioxane and water (3:1) (80
mL) were added sequentially 2,6-lutidine (10.19 mL, 88.17 mmol),
OsO4 (0.44 mL, 0.440 mmol, 1 M solution in toluene), and NaIO4
(18.87 g, 88.17 mmol) at room temperature, and the mixture was
stirred for 2.5 h. After completion of the reaction (monitored by
TLC), 1,4-dioxane was removed under reduced pressure and the
residual aqueous layer was extracted with CH2Cl2 (3 × 100 mL). The
CH2Cl2 layer was quickly washed with 1 N HCl (2 × 100 mL) to
remove excess 2,6-lutidine followed by brine (2 × 100 mL), dried over
anhydrous Na2SO4, and concentrated under reduced pressure to
produce the crude aldehyde. On purification by short flash column
chromatography over silica gel (ethyl acetate−hexane, 1:19), this
afforded the corresponding aldehyde (7.0 g) as a colorless liquid,
which was used immediately without further characterization.
To the stirred solution of the above-mentioned aldehyde (7.0 g,
18.686 mmol) in CH2Cl2 (180 mL) was added a 1.0 M solution of
F
DOI: 10.1021/acs.jnatprod.6b00443
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
pale yellow liquid: [α]20 +61.3 (c 2.4, CHCl3); IR νmax 2925, 2854,
aqueous layer was further extracted with CH2Cl2 (2 × 15 mL). The
combined organic layer was dried over Na2SO4 and evaporated under
reduced pressure. The residue was purified by column chromatog-
raphy over silica gel (ethyl acetate−hexane, 1:20) to afford compound
34 (91 mg, 83%) as a colorless liquid: 1H NMR (CDCl3, 400 MHz) δ
7.35−7.24 (5H, m), 5.79 (1H, m), 5.12−5.01 (2H, m), 4.50 (2H, ABq,
J = 49.5, 11.2 Hz), 4.06 (1H, m), 3.84 (1H, m), 3.61 (1H, m), 2.30
(1H, m), 2.18 (1H, m), 1.69−1.49 (6H, m), 13.4 (6H, d, J = 5.4 Hz),
1.31−1.19 (26H, m), 0.88 (3H, t, J = 7.0 Hz); 13C NMR (CDCl3, 125
MHz) δ 138.9, 134.5, 128.3, 127.8, 127.4, 116.7, 100.2, 75.6, 71.4,
66.2, 63.4, 41.4, 40.1, 38.4, 34.1, 31.9, 29.9, 29.7, 29.6, 29.3, 24.9, 24.9,
24.7, 22.7, 14.1.
D
1
1616, 1516, 1247, 1068, 771 cm−1; H NMR (CDCl3, 400 MHz) δ
7.34−7.24 (5H, m), 7.21 (2H, d, J = 8.5 Hz), 6.83 (2H, d, J = 8.5 Hz),
5.85 (1H, m), 5.14−5.04 (2H, m), 4.54−4.48 (2H, m), 4.33−4.23
(2H, m), 3.76 (3H, s), 3.71 (1H, m), 3.62 (1H, m), 2.38−2.30 (2H,
m), 1.67−1.44 (4H, m), 1.36−1.20 (26H, m), 0.88 (3H, t, J = 7.0 Hz);
13C NMR (CDCl3, 125 MHz) δ 159.0, 139.0, 134.6, 130.9, 129.4,
128.2, 127.7, 127.3, 117.1, 113.7, 75.7, 74.8, 70.8, 70.6, 55.1, 40.0, 38.6,
34.0, 31.9, 29.9, 29.7, 29.6, 29.4, 24.9, 22.6, 14.1 ppm; HRESIMS m/z
559.4115 [M + Na]+ calcd for C36H56O3Na, 559.4121.
(4S,6R,8R)-8-(Benzyloxy)-6-((4-methoxybenzyl)oxy)tricos-1-
en-4-ol (33). To a solution of 32 (6.2 g, 11.549 mmol) in dioxane and
water (3:1) (80 mL) were added sequentially 2,6-lutidine (5.34 mL,
46.19 mmol), OsO4 (0.23 mL, 0.230 mmol, 1 M solution in toluene),
and NaIO4 (9.89 g, 46.19 mmol) at room temperature, and the
mixture was stirred for 3 h. After completion of the reaction
(monitored by TLC), 1,4-dioxane was removed under reduced
pressure, and the residual aqueous layer was extracted with CH2Cl2
(3 × 100 mL). The CH2Cl2 layer was quickly washed with 1 N HCl (2
× 100 mL) to remove excess 2,6-lutidine followed by brine (2 × 100
mL), dried over anhydrous Na2SO4, and concentrated under reduced
pressure to produce a crude aldehyde. On purification by short column
flash chromatography over silica gel (ethyl acetate−hexane, 1:19), this
afforded the corresponding aldehyde (5.41 g) as a colorless liquid,
which was used immediately without further characterization.
(((4S,6S,8R)-8-(Benzyloxy)-6-((4-methoxybenzyl)oxy)tricos-
1-en-4-yl)oxy)(tert-butyl)dimethylsilane (35). To a stirred sol-
ution of 33 (3.5 g, 6.04 mmol) in anhydrous CH2Cl2 (50 mL) were
added imidazole (614 mg, 9.06 mmol) and TBSCl (1.36 g, 9.06
mmol) followed by DMAP (73 mg, 0.60 mmol) at 0 °C. After 24 h of
stirring at room temperature, the reaction was then quenched with a
saturated aqueous NaHCO3 solution (50 mL). The layers were then
separated and the aqueous layer was further extracted with CH2Cl2 (2
× 100 mL). The combined organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The crude product was purified
by silica gel column chromatography (ethyl acetate−hexane, 1:19),
providing the product 35 (3.97 g, 95%) as a colorless liquid: [α]20
D
+13.2 (c 1.2, CHCl3); IR νmax 2926, 2854, 1743, 1618, 1462, 1249,
1
1066, 771 cm−1; H NMR (CDCl3, 500 MHz) δ 7.34−7.24 (5H, m),
To the stirred solution of the above-mentioned aldehyde (5.41 g,
10.04 mmol) in CH2Cl2 (130 mL) at 0 °C were added MgBr2·OEt2
(6.48 g, 25.10 mmol) and allyltrimethylsilane (9.59 mL, 60.24 mmol).
The resultant mixture was stirred at 0 °C overnight. After completion
of the reaction (monitored by TLC), it was quenched with 1 M
aqueous HCl (30 mL) solution at 0 °C. The resultant mixture was
warmed to room temperature. The organic layer was separated, and
the aqueous layer extracted with CH2Cl2 (2 × 30 mL). The combined
organic layer was washed with a saturated aqueous solution of
NaHCO3 (50 mL) and dried over anhydrous Na2SO4. The solvent was
evaporated under reduced pressure to give a pale yellow oil that was
purified by column chromatography over silica gel (ethyl acetate−
hexane, 1:9) to furnish the homoallylic alcohol 33 (5.37 g, 80% over
7.21 (2H, d, J = 8.7 Hz), 6.84 (2H, d, J = 8.7 Hz), 5.81 (1H, m), 5.07−
4.99 (2H, m), 4.52 (1H, d, J = 11.4 Hz), 4.43−4.30 (3H, m), 3.92
(1H, m), 3.77 (3H, s), 3.72 (1H, m), 3.56 (1H, m), 2.30−2.17 (2H,
m), 1.84−1.64 (3H, m), 1.62−1.45 (3H, m), 1.37−1.20 (26H, m),
0.90−0.86 (12H, m), 0.06 (6H, d, J = 2.9); 13C NMR (CDCl3, 75
MHz) δ 159.0, 139.0, 134.7, 131.1, 129.2, 128.2, 127.7, 127.3, 117.0,
113.7, 76.1, 73.2, 70.9, 70.1, 68.9, 55.2, 42.3, 42.2, 40.2, 34.1, 31.9,
29.9, 29.7, 29.3, 25.9, 25.0, 22.7, 18.1, 14.1, −4.1, −4.5; HRESIMS m/z
717.5249 [M + Na]+ calcd for C44H74O4SiNa, 717.5248.
(4S,6S,8R)-8-(Benzyloxy)-4-((tert-butyldimethylsilyl)oxy)-
tricos-1-en-6-ol (36). To a stirred solution of compound 35 (2.5 g,
3.597 mmol) in CH2Cl2 (30 mL) and water (3 mL) at 0 °C was added
DDQ (2.04 g, 8.992 mmol) in one portion. The reaction mixture was
stirred at room temperature for 2.5 h, quenched with saturated
aqueous NaHCO3 solution (40 mL), and diluted with CH2Cl2 (30
mL). The resulting mixture was stirred vigorously for 4 h. The layers
were separated, and the aqueous layer was extracted with CH2Cl2 (2 ×
70 mL). The combined organic layer was washed with brine (80 mL),
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was purified by silica gel column chromatog-
raphy (ethyl acetate−hexane, 1:9) to afford alcohol 36 (1.88 g, 91%)
two steps, dr 99:1) as a colorless liquid: [α]20 +28.0 (c 1.8, CHCl3);
D
1
IR νmax 3448, 2925, 2853, 1685, 1606, 1386, 1249, 1032 cm−1; H
NMR (CDCl3, 400 MHz) 7.36−7.24 (5H, m), 7.20 (2H, d, J = 8.5
Hz), 6.84 (2H, d, J = 8.5 Hz), 5.82 (1H, m), 5.14−5.05 (2H, m),
4.55−4.58 (2H, m), 4.32−4.24 (2H, m), 3.97 (1H, m), 3.91 (1H, m),
3.77 (3H, s), 3.55 (1H, m), 2.28−2.14 (2H, m), 1.88−1.76 (2H, m),
1.68−1.48 (4H, m), 1.38−1.20 (26H, m), 0.88 (3H, t, J = 7.1 Hz); 13C
NMR (CDCl3, 125 MHz) δ 159.2, 138.8, 134.8, 130.2, 129.6, 128.3,
127.8, 127.5, 117.3, 113.8, 75.8, 74.4, 71.1, 70.6, 68.0, 55.2, 42.2, 39.5,
39.3, 33.8, 31.9, 29.9, 29.7, 29.6, 29.3, 24.8, 22.6, 14.1; HRESIMS m/z
603.4383 [M + Na]+ calcd for C38H60O4Na, 603.4383.
as a colorless liquid: [α]20 +1.6 (c 1.3, CHCl3); IR νmax 3508, 2925,
D
1
2854, 1637, 1462, 1382, 1253, 1071 cm−1; H NMR (CDCl3, 400
MHz) δ 7.30−7.12 (5H, m), 5.66 (1H, m), 4.99−4.89 (2H, m), 4.47
(2H, ABq, J = 16.0, 11.4 Hz), 4.08 (1H, m), 3.94 (1H, m), 3.59 (1H,
m), 3.40 (1H, d, J = 2.4 Hz), 2.33−2.26 (2H, m), 1.67−1.34 (6H, m),
1.28−1.10 (26H, m), 0.84−0.76 (12H, m), 0.01 (6H, d, J = 6.1 Hz);
13C NMR (CDCl3, 75 MHz) δ 138.7, 134.8, 128.3, 127.8, 127.5, 117.2,
77.0, 71.4, 70.0, 64.8, 43.0, 41.8, 41.4, 33.9, 31.9, 29.8, 29.7, 29.6, 29.3,
25.9, 25.4, 22.7, 18.0, 14.1, −4.4, −4.8; HRESIMS m/z 575.4849 [M +
H]+ calcd for C36H67O3Si, 575.4854.
(4R,6S)-6-((R)-2-(Benzyloxy)heptadecyl)-4-((tert-
butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-ol (17). To a
solution of 36 (850 mg, 1.48 mmol) in dioxane and water (3:1) (16
mL) were added sequentially 2,6-lutidine (0.68 mL, 5.91 mmol), OsO4
(29.6 μL, 0.029 mmol, 1 M solution in toluene), and NaIO4 (1.26 g,
5.91 mmol) at room temperature, and the mixture was stirred for 2.5
h. After completion of the reaction (monitored by TLC), 1,4-dioxane
was removed under reduced pressure and the residual aqueous layer
was extracted with CH2Cl2 (3 × 40 mL). The CH2Cl2 layer was
quickly washed with 1 N HCl (2 × 60 mL) to remove excess 2,6-
lutidine followed by brine (2 × 60 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure to afford a crude lactol. On
purification by short flash column chromatography over silica gel
(4S,6S)-4-Allyl-6-((R)-2-(benzyloxy)heptadecyl)-2,2-dimeth-
yl-1,3-dioxane (34). To a stirred solution of compound 33 (150 mg,
0.26 mmol) in CH2Cl2 (15 mL) and water (2 mL) at 0 °C was added
DDQ (147 mg, 0.646 mmol) in one portion. The reaction mixture was
stirred at room temperature for 3 h, quenched with saturated aqueous
NaHCO3 (15 mL), and diluted with water (20 mL) and CH2Cl2 (30
mL). The resulting mixture was stirred vigorously for 4 h. The layers
were separated, and the aqueous layer was extracted with CH2Cl2 (2 ×
40 mL). The combined organic layer was washed with brine (20 mL),
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was purified by silica gel column chromatog-
raphy (ethyl acetate−hexane, 2:3) to afford the corresponding diol
(101 mg, 85%) as a colorless liquid that was used immediately without
further characterization.
To a solution of the above-mentioned diol (101 mg, 0.22 mmol) in
CH2Cl2 (10 mL) were added CSA (5 mg, 0.022 mmol) and 2,2-
dimethoxypropane (0.08 mL, 0.66 mmol) at 0 °C. The mixture was
stirred at room temperature for 3 h. After completion of the reaction
(monitored by TLC), the reaction mixture was quenched with a
saturated aqueous solution of NaHCO3 (10 mL) and was stirred for
30 min at room temperature. The layers were separated, and the
G
DOI: 10.1021/acs.jnatprod.6b00443
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
(ethyl acetate−hexane, 1:9), this gave lactol 17 (699 mg, 82%) as a
(26H, m), 0.92−0.80 (12H, m), 0.04 (6H, d, J = 1.1 Hz); 13C NMR
(CDCl3, 100 MHz) δ 174.9, 139.0, 128.3, 127.9, 127.4, 75.7, 71.3,
67.8, 65.2, 64.6, 39.9, 38.9, 38.4, 34.1, 31.9, 29.9, 29.7, 29.6, 29.3, 25.8,
24.8, 22.7, 18.0, 14.1, −4.8, −4.9; HRESIMS m/z 641.4565 [M + Na]+
calcd for C37H66O5SiNa, 641.4571.
(1S,5R,7S)-7-((R)-2-(Benzyloxy)heptadecyl)-2,6-dioxabicyclo-
[3.3.1]nonan-3-one (15). To a stirred solution of acid 16 (110 mg,
0.18 mmol) in THF (6 mL) in a vial was added HF·pyridine (0.3 mL)
in THF (2 mL) at 0 °C. The solution mixture was stirred for 12 h at
room temperature. After completion of the reaction (monitored by
TLC), it was quenched with H2O (10 mL) and diluted with ethyl
acetate (15 mL). The layers were separated, and the aqueous layer was
extracted with ethyl acetate (3 × 20 mL). The combined organic layers
were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4,
and evaporated under reduced pressure. The crude product was
purified by silica gel column chromatography (ethyl acetate−hexane,
4:1) to afford the seco acid 39 (70.8 mg) as a colorless oil, which was
used immediately without further characterization.
yellow liquid: [α]20 +48.2 (c 0.8, CHCl3); IR νmax 3445, 2926, 2854,
D
1
1634, 1462, 1253, 1079 cm−1; H NMR (CDCl3, 400 MHz) δ 7.41−
7.22 (5H, m), 5.22 (0.6 H, br s), 4.58 (1H, m), 4.47−4.43 (1.4H, m),
4.08 (1H, m), 3.80−3.58 (1.6H, m), 3.49 (0.4H, m), 1.99 (1H, m),
1.81−1.43 (7H, m), 1.39−1.08 (26H, m), 0.93−0.78 (12H, m), 0.09−
0.01 (6H, m); 13C NMR (CDCl3, 75 MHz) δ 139.0, 139.0, 128.4,
128.3, 128.2, 127.6, 127.4, 94.1, 92.7, 74.3, 74.0, 71.0, 70.7, 68.2, 67.4,
64.2, 64.0, 42.7, 42.3, 41.2, 41.1, 40.8, 39.7, 33.9, 33.8, 31.9, 29.9, 29.6,
29.3, 25.8, 25.7, 24.8, 24.8, 22.7, 18.0, 14.1, −4.6, −4.7 ppm;
HRESIMS m/z 599.4459 [M + Na]+ calcd for C35H64O4SiNa,
599.4466.
(((2S,4S,6S)-2-Allyl-6-((R)-2-(benzyloxy)heptadecyl)-
tetrahydro-2H-pyran-4-yl)oxy)(tert-butyl)dimethylsilane (37).
To a stirred solution of lactol 17 (500 mg, 0.87 mmol) and
allyltrimethylsilane (0.20 mL, 1.30 mmol) in CH2Cl2 (8 mL) was
added AuCl3 (13 mg, 0.043 mmol) at room temperature, and the
mixture was stirred for 5 h. After completion of the reaction
(monitored by TLC), it was quenched with H2O (10 mL). The
organic layer was separated, and the aqueous layer extracted with
CH2Cl2 (2 × 30 mL). The combined organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pressure to give a
pale yellow oil. This was purified by column chromatography over
silica gel (ethyl acetate−hexane, 1:19) to furnish the desired
compound 37 (479 mg, 92%, dr 96:4) as a colorless liquid: [α]20
+41.5 (c 1.1, CHCl3); IR νmax 2925, 2854, 1462, 1253, 1070, 771 cm−1D;
1H NMR (CDCl3, 400 MHz) δ 7.36−7.23 (5H, m), 5.79 (1H, m),
5.12−5.01 (2H, m), 4.52 (2H, ABq, J = 42.8, 11.3 Hz), 4.04−3.89 (3H,
m), 3.65 (1H, m), 2.41−2.16 (2H, m), 1.99−1.77 (2H, m),1.72−1.43
(6H, m), 1.34−1.18 (26H, m), 0.93−0.81 (12H, m), 0.04 (6H, s); 13C
NMR (CDCl3, 75 MHz) δ 139.1, 135.3, 128.3, 127.8, 127.4, 116.6,
75.9, 71.4, 69.9, 66.5, 65.0, 40.9, 40.6, 38.0, 37.6, 34.2, 31.9, 29.9, 29.7,
29.3, 25.8, 24.9, 22.7, 18.1, 14.1, −4.7; HRESIMS m/z 601.5010 [M +
H]+ calcd for C38H69O3Si, 601.5010.
To a stirred solution of Ph3P (110 mg, 0.42 mmol) in anhydrous
THF (20 mL) was added diethylazodicarboxylate (66 μL, 0.42 mmol)
at 0 °C under an argon atmosphere. After the reaction mixture was
stirred for 0.5 h at room temperature, it was cooled to 0 °C. To this
reaction mixture was added dropwise crude seco acid 39 (70.8 mg) in
THF (15 mL), and the mixture was stirred for 12 h at room
temperature. After completion of the reaction (monitored by TLC), it
was quenched with H2O (15 mL). THF was removed under reduced
pressure, and the aqueous layer extracted with ethyl acetate (3 × 20
mL). The combined organic layer was dried over anhydrous Na2SO4
and concentrated under reduced pressure. The crude product was
purified by silica gel column chromatography (ethyl acetate−hexane,
1:4) to furnish the desired lactone 15 (50 mg, 59% over two steps) as
a white solid: [α]20D −21.0 (c 0.7, CHCl3); IR νmax 2924, 2854, 1737,
1
1458, 1386, 1077, 766 cm−1; H NMR (CDCl3, 500 MHz) δ 7.40−
2-((2R,4R,6S)-6-((R)-2-(Benzyloxy)heptadecyl)-4-((tert-
butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)-
acetaldehyde (38). To a solution of 37 (250 mg, 0.415 mmol) in
dioxane and water (3:1) (12 mL) were sequentially added 2,6-lutidine
(0.19 mL, 1.66 mmol), OsO4 (8.3 μL, 0.008 mmol, 1 M solution in
toluene), and NaIO4 (356 mg, 1.66 mmol) at room temperature, and
the mixture was stirred for 2.5 h. After completion of the reaction
(monitored by TLC), 1,4-dioxane was removed under reduced
pressure and the residual aqueous layer was extracted with CH2Cl2
(3 × 30 mL). The CH2Cl2 layer was quickly washed with 1 N HCl (2
× 40 mL) to remove excess 2,6-lutidine followed by brine (2 × 40
mL), dried over anhydrous Na2SO4, and concentrated under reduced
pressure to get the crude aldehyde, which on purification by short flash
column chromatography over silica gel (ethyl acetate−hexane, 1:19)
afforded corresponding aldehyde 38 as a pale yellow liquid, 214 mg
(85%), which was used immediately without further characterization.
2-((2R,4R,6S)-6-((R)-2-(Benzyloxy)heptadecyl)-4-((tert-
butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)acetic Acid
(16). To a solution of aldehyde 38 (214 mg, 0.354 mmol) in tert-
butyl alcohol (10 mL) was added 2-methyl-2-butene (0.53 mL, 0.532
mmol, 1 M solution in THF) at room temperature. NaH2PO4 (137
mg, 1.064 mmol) and sodium chlorite (103 mg, 1.064 mmol) were
dissolved in water (8 mL) to make a clear solution, which was added
subsequently to the reaction mixture at 0 °C. This was then allowed to
stir for a further 6 h at room temperature. The reaction mixture was
diluted with water (15 mL). The organic solvent was removed under
reduced pressure, and the aqueous layer extracted with ethyl acetate (3
× 30 mL). The combined organic layer was washed with brine (50
mL), dried over anhydrous Na2SO4, and evaporated under reduced
pressure. The crude product was purified by silica gel column
chromatography (ethyl acetate−hexane, 3:7) to afford the acid 16
7.25 (5H, m), 4.86 (1H, m), 4.50 (2H, ABq, J = 71.8, 11.4 Hz), 4.29
(1H, m), 4.02 (1H, m), 3.60 (1H, m), 2.72−2.66 (2H, m), 2.04−1.85
(3H, m), 2.64−1.45 (5H, m), 1.35−1.21 (26H, m), 0.88 (3H, m, J =
7.1 Hz), 0.04 (6H, d, J = 1.1 Hz); 13C NMR (CDCl3, 125 MHz) δ
169.4, 138.5, 128.5, 127.9, 127.6, 74.7, 73.0, 71.2, 65.7, 62.6, 41.4, 37.4,
36.4, 34.0, 31.9, 29.8, 29.7, 29.6, 29.3, 24.8, 22.6, 14.1; HRESIMS m/z
487.3774 [M + H]+ calcd for C31H51O4, 487.3781.
(1S,5R,7S)-7-((R)-2-Hydroxyheptadecyl)-2,6-dioxabicyclo-
[3.3.1]nonan-3-one (2). To a stirred solution of compound 15 (42
mg, 0.086 mmol) in MeOH (4 mL) was added Pd/C (10%) (8.0 mg).
The mixture was stirred for 3 h at room temperature under a hydrogen
atmosphere. After complete consumption of the starting material
(monitored by TLC), the reaction mass was filtered through a small
pad of Celite and then thoroughly washed with MeOH (3 × 5 mL).
The filtrate was concentrated under reduced pressure and purified by
silica gel column chromatography (ethyl acetate−hexane, 3:7) to
furnish the lactone 2 (31.4 mg, 92%) as a colorless oil: [α]20D −9.1 (c
0.8, MeOH); IR νmax 3451, 2920, 2852, 1727, 1460, 1384, 1261, 1080
1
cm−1; H NMR (CDCl3, 500 MHz) δ 4.90 (1H, m), 4.39 (1H, br s),
4.12 (1H, m), 3.81 (1H, m), 2.90 (1H, br d, J = 9.2 Hz), 2.81 (1H, dd,
J = 19.2, 5.3 Hz), 2.08−1.90 (3H, m), 1.74−1.56 (3H, m), 1.51−1.36
(2H, m), 1.34−1.21 (26H, m), 0.88 (3H, m, J = 7.0 Hz); 13C NMR
(CDCl3, 125 MHz) δ 169.5, 72.9, 68.3, 65.9, 63.6, 41.9, 37.6, 36.7,
36.3, 31.9, 29.7, 29.6, 29.6, 29.3, 25.7, 22.7, 14.1; HRESIMS m/z
414.3585 [M + NH4]+ calcd for C24H48O4N, 414.3577.
ASSOCIATED CONTENT
■
S
* Supporting Information
(183 mg, 83%) as a colorless liquid: [α]20 +17.4 (c 1.8, CHCl3); IR
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.6b00443.
D
νmax 3449, 2926, 2854, 1712, 1463, 1217, 1074 cm−1; 1H NMR
(CDCl3, 400 MHz) δ 7.38−7.21 (5H, m), 4.55 (1H, d, J = 11.2 Hz),
4.46−4.37 (2H, m), 4.10−3.94 (2H, m), 3.60 (1H, m), 2.58 (1H, m),
2.46 (1H, m), 2.36−1.78 (3H, m), 1.70−1.42 (5H, m), 1.37−1.13
NMR spectra (PDF)
H
DOI: 10.1021/acs.jnatprod.6b00443
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
(k) Yadav, V. K.; Agrawal, D. Chem. Commun. 2007, 5232−5234. See
for the synthesis of goniopypyrone.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mohapatra@iict.res.in. Tel: +91-40-27193128. Fax:
+91-40-27160512.
Notes
■
(6) (a) Tsubuki, M.; Kanai, K.; Honda, T. J. Chem. Soc., Chem.
Commun. 1992, 1640−1641. (b) Friesen, R. W.; Bissada, S.
Tetrahedron Lett. 1994, 35, 5615−5618. (c) Mukai, C.; Hirai, S.;
Hanaoka, M. J. Org. Chem. 1997, 62, 6619−6626. (d) Surivet, J. P.;
Vatele, J. M. Tetrahedron Lett. 1998, 39, 7299−7300. (e) Tsubuki, M.;
Kanai, K.; Nagase, H.; Honda, T. Tetrahedron 1999, 55, 2493−2514.
(f) Chen, J.; Lin, G. Q.; Wang, Z. M.; Liu, H. Q. Synlett 2002, 1265−
1268. (g) Ramachandran, P. V.; Chandra, J. S.; Reddy, M. V. R. J. Org.
Chem. 2002, 67, 7547−7550. (h) Yamashita, Y.; Saito, S.; Ishitani, H.;
Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3793−3798. (i) Chen, J.;
Lin, G. Q.; Liu, H. Q. Tetrahedron Lett. 2004, 45, 8111−8113.
(j) Chen, J.; Lin, G. Q.; Liu, H. Q. Tetrahedron Lett. 2004, 45, 8111−
8113. (k) Prasad, K. R.; Dhaware, M. G. Synlett 2007, 2007, 1112−
1114. (l) Prasad, K. R.; Gholap, S. L. Tetrahedron Lett. 2007, 48,
4679−4682. (m) Nagaiah, K.; Sreenu, D.; Purnima, K. V.; Rao, R. S.;
Yadav, J. S. Synthesis 2009, 2009, 1386−1392. (n) Paioti, P. H. S.;
Coelho, F. Tetrahedron Lett. 2011, 52, 6180−6184. (o) Sabitha, G.;
Reddy, T. R.; Yadav, J. S. Tetrahedron Lett. 2011, 52, 6550−6553.
(p) Kumaraswamy, G.; Kumar, R. S. Helv. Chim. Acta 2013, 96, 1366−
1375. See for the synthesis of parvistone D and its stereoisomers.
(7) Sato, M.; Takeuchi, S.; Ishibashi, M.; Kobayash, J. Tetrahedron
1998, 54, 4819−4826.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Council of Scientific and Industrial Research
(CSIR), New Delhi, India, for financial support as part of the
XII Five Year Plan Programme under the title ORIGIN (CSC-
0108). B.P. and G.S.R. thank CSIR and University Grants
Commission (UGC), New Delhi, India, for financial assistance
in the form of fellowships.
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