Synthesis of Luffarin L and 16- epi -Luffarin L Using a Temporary Silicon-Tethered Ring-Closing Metathesis Reaction

Article abstract of DOI:10.1021/acs.joc.5b00876

The first synthesis of luffarin L (1) and 16-epi-luffarin L (2) by a silicon-tethered ring closing metathesis as a key step has been achieved. The stereochemistry and absolute configuration of the natural sesterterpenolide luffarin L (1) and a new route f

Full text of DOI:10.1021/acs.joc.5b00876

Article
pubs.acs.org/joc
Synthesis of Luffarin L and 16-epi-Luffarin L Using a Temporary
Silicon-Tethered Ring-Closing Metathesis Reaction
Aitor Urosa,† Isidro S. Marcos,† David Díez,† Jose M. Padron,‡ and Pilar Basabe*,†
́
́
†Departamento de Química Organ
Salamanca, Spain
‡BioLab, Instituto Universitario de Bio-Organ
(CIBICAN), Universidad de La Laguna, C/Astrofísico Francisco San
́
ica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caídos, 1-5, 37008,
́
ica “Antonio Gonzal
́
ez” (IUBO-AG), Centro de Investigaciones Biomed
́
icas de Canarias
́
chez 2, 38206, La Laguna, Spain
S
* Supporting Information
ABSTRACT: The first synthesis of luffarin L (1) and 16-epi-luffarin L (2) by a silicon-tethered ring closing metathesis as a key
step has been achieved. The stereochemistry and absolute configuration of the natural sesterterpenolide luffarin L (1) and a new
route for the stereoselective synthesis of sesterterpenolides with a luffarane skeleton have been established.
skeleton and some stereogenic centers present in the molecule
objective. Several enantiopure bioactive sesterterpenoid com-
pounds have been synthesized by us starting from natural
chiral building blocks such as ent-halimic acid, isolated from
Halimium viscosum,12 and (−)-sclareol,13−18 a commercial com-
pound isolated from Salvia sclarea. In Figures 1 and 2 are found
the structures of sesterterpenes synthesized from (−)-sclareol13−18
and from ent-halimic acid, respectively.19−21 In previous work, we
have carried out the synthesis of the sesterterpenolides with the
luffarane skeleton luffalactone15 and luffarin I.17
Herein we report the first enantioselective synthesis of
luffarin L (1) and 16-epi-luffarin L (2) involving the combination
of temporary silicon-tethering methodology22,23 with ring-closing
metathesis,24−26 the key step of this synthesis. This methodology
has been demonstrated to be a useful method for natural product
synthesis.27−29
INTRODUCTION
■
The synthesis of natural products is a fundamental pillar of
organic and biological chemistry. During the most recent
decades, many contributions related to natural products,
especially terpenes, have been reported.1−3 Among them, the
sesterterpenes have been attractive as synthetic objectives due to
their structural diversity and biological activities.4
Luffarin L (1) is a sesterterpenolide with a luffarane skele-
ton isolated by Butler and Capon5 from the sponge Luffariella
geometrica. This sesterterpene can be considered an excellent
synthetic objective in order not only to confirm its structure and
absolute configuration but to study its biological activity as
analogous with the butenolide fragment in the side chain.6−11
Therefore, SAR studies will be conducted not only with the
natural compound but with various synthetic analogues.
RESULTS AND DISCUSSION
■
The retrosynthetic route that appears in Scheme 1 was designed
for the synthesis of luffarin L (1) and its epimer 16-epi-luffarin L
(2). As depicted in Scheme 1, in the retrosynthetic analysis of the
synthesis of luffarin L (1) and 16-epi-luffarin L (2) the key step
to obtain the luffarane skeleton is a temporary silicon-tethered
ring-closing metathesis intramolecular reaction of intermediates
3 and 4. These compounds can be obtained from the nor-diterpenic
fragment 10, synthesized from commercial (−)-sclareol (Scheme 2),
A useful alternative to the total synthesis is to use natural
products as starting material, as they possess part of the carbon
Received: April 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00876
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Figure 1. Active sesterterpenoids synthesized from (−)-sclareol.
Figure 2. Antitumor sesterterpenolides analogous to dysidiolide synthesized from ent-halimic acid.
and furanones 5 and 6, obtained from 2-deoxy-D-ribose
(Schemes 3 and 4).
Wittig30,31 reaction of 2-deoxy-D-ribose (Scheme 3) gave
triol 11 in excellent yield, the intermediate for the synthesis of
lactones 5 and 6 (Schemes 3 and 4). The 1,2-protection of 11
was carried out with 2,2-dimethoxypropane32 and p-toluene-
sulfonic acid in order to obtain 12 that by a Mitsunobu-
type inversion33−35 led to intermediate 7. This compound was
deprotected with PPTS to give triol 13 that by treatment with
Starting from (−)-sclareol, ketone 8 was obtained as reported
previously.17 This compound was readily transformed into
allylic alcohol 10 in two steps by a Wittig reaction of 8 to
obtain 9 and the subsequent deprotection of the THP group
(Scheme 2).
B
DOI: 10.1021/acs.joc.5b00876
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Scheme 1. Retrosynthetic Analysis of Luffarin L (1) and 16-epi-Luffarin L (2)
a
Scheme 2. Synthesis of Nor-diterpenic Intermediate 10
a
Reagents and conditions: (a) Ph3PMeBr, NaHMDS, THF,−78 °C to rt (57%); (b) pTsOH, MeOH, rt (99%).
benzaldehyde dimethyl acetal in the presence of camphorsulfonic
acid gave 14. Oxidation of 14 with Dess−Martin periodinane36−39
led to ketone 1540 that without isolation was transformed by
Wittig reaction into compound 16Z. The olefination reaction was
optimized under diverse conditions41 using several reactants,
bases, and temperatures to obtain the desired regioisomer 16Z.
The best conditions were obtained using methyl P,P-bis(2,2,2-
trifluoroethyl)phosphonoacetate42 and KHMDS in THF at
−78 °C. Thus, 16Z was obtained in 46% yield, while the cor-
responding E-isomer was in 18% yield. Both isomers were
separated bycolumn chromatography. The double bond geometry
of bothesters was determinedbyROESYexperiments. Reaction of
16Z with camphorsulfonic acid in MeOH (Scheme 3) and in the
presence of H2O not only produced the deprotection but caused
the transesterefication reaction in order to give the desired product
of CSA gave 17. This compound was oxidized to ketone 18 and
without isolation it was transformed under the same Wittig
conditions as before, into a 45:11 mixture of 19Z:19E in favor of
the required double bond stereochemistry. Final deprotection
with CSA in aqueous MeOH led to the desired lactone 6.
Ring-Closing Metathesis Silicon-Assisted and Syn-
thesis of Luffarin L (1) and 16-epi-Luffarin L (2). Once
lactones 5 and 6 were obtained, the synthesis of luffarin L and
16-epi-luffarin L was continued using the following methodology.
In order to carry out the RCM reaction between nor-diterpenic
fragment 10 and lactones 5 and 6, these compounds were linked
through the formation of a silicon tether (Scheme 5), a technique
widely used with satisfactory results.44−46 In this manner inter-
mediates 3 and 4 were obtained in satisfactory yield, with lactones
5 and 6 recovered to some extent but not terpene intermediate 10.
With these compounds in hand, it was necessary to establish the
appropriate conditions of the ring-closing metathesis (RCM) in
order to obtain compounds 20 and 21. Several conditions were
tested, and the best ones are shown in Table 1.
5
43 in 83% yield.
The synthesis of lactone 6 was carried out starting from 11
by an analogous sequence as described above (Scheme 4). The
protection of 11 with benzaldehyde dimethylacetal in the presence
C
DOI: 10.1021/acs.joc.5b00876
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a
Scheme 3. Synthesis of Lactone 5
a
Reagents and conditions: (a) Ph3PMeBr, tBuOK, THF, 40 °C (85%); (b) Me2C(OMe)2, acetone, pTsOH (78%); (c) i: PhCOOH, Ph3P, DIAD,
THF, 0 °C to rt. ii: KOH/MeOH 10%, MeOH (42%); (d) PPTS, MeOH, 70 °C; (e) PhCH(OMe)2, DCM, CSA (35% over two reactions);
(f) DMP, DCM, rt; (g) (CF3CH2O)2P(O)CH2COOMe, KHMDS, THF. −78 °C to −10 °C (46% for 16Z and 18% for 16E over two steps);
(h) CSA, H2O, MeOH, rt (83%).
Deprotection of 20 with HF−pyridine47 in THF at 0 °C gave
a
Scheme 4. Synthesis of Lactone 6
compound 1, that showed 1H NMR and 13C NMR identical to
the ones described by Butler and Capon5 for the natural product
luffarin L. The specific optical rotation of 1 ([α]2D0 = +22.0; c 0.2,
CHCl3) was in agreement with that described for luffarin L
([α]2D0 = +25.1; c 2.1, CHCl3). Similarly, deprotection of 21 led to
2 ([α]2D0 = +92.4; c 0.2, CHCl3) identified as 16-epi-luffarin L.
The antiproliferative activity of compounds 1/2 and 20/21
was tested against a panel of representative human solid tumor
cell lines within our program directed at the discovery of new
antitumor agents.48 The results expressed as GI50 are shown in
Table 2. Luffarin L (1) was slightly more active than its C-16
epimer 2 in terms of GI50 against all cell lines (17−31 μM vs
28−51 μM). Notably, the corresponding precursors 20/21
displayed an enhanced activity profile with GI50 values in the
range 12−19 μM. This result is consistent with our previous
findings that silyl ethers represent a plausible strategy to enhance
a
the antiproliferative activity of natural products.49
Reagents and conditions: (a) PhCH(OMe)2, CSA, DCM (81%); (b)
DMP, DCM, rt; (c) (CF3CH2O)2P(O)CH2COOMe, KHMDS, THF,
−78 °C to −10 °C (45% for 19Z and 11% for 19E in two reactions);
(d) CSA, H2O, MeOH, rt (91%).
CONCLUSIONS
■
In summary, we have reported for the first time the synthesis of
luffarin L, a natural product isolated from Luffariella geometrica.
The commercially available natural compound (−)-sclareol
served as starting material. This synthesis permits confirmation
of the structure and absolute stereochemistry of the natural
product. The synthetic route involves a silicon-tethered intra-
molecular ring-closing metathesis that allowed the synthesis of
the isomer 16-epi-luffarin L. In addition, these compounds show
remarkable biological activity toward human cancer cell lines.
Different experiments varying the concentration of diene, the
amount of catalyst, the temperature, and the solvent were tested. The
best conditions were obtained with the use of 20% of Grubbs second
generation catalyst, at 3 mM concentration of diene in toluene, and
heating at 80 °C. Under these conditions, 20 and 21 were prepared
in good yields and transformations, 63% and 79%, with some
quantities of 3 and 4 recovered, respectively. The stereochemistry
Z for C-13 established for compound 21 shows an NOE between
H-12 and H-14; see ROESY in Supporting Information.
Furthermore, deprotection of 20 gave luffarin L, as discussed later,
having significant differences with the natural product luffarin K with
E stereochemistry at C-13.5 Therefore, we were able to obtain the
required stereochemistry of olefin Δ13 and the unsaturated lactone of
the side chain with the correct stereochemistry of C-16 in place.
EXPERIMENTAL SECTION
■
General Methods. NMR spectra were recorded on a 200 and
400 MHz (1H) and 50 and 100 MHz (13C) spectrometers. FTIR spectra
were recorded as films. HRMS spectra were recorded by using Q-TOF
using electrospray ionization.
D
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a
Scheme 5. Synthesis of Luffarin L (1) and 16-epi-Luffarin L (2)
a
Reagents and conditions: (a) iPr2SiCl2, imidazole, DCM, 0 °C, 3 (49%), 4 (60%); (b) Grubbs second generation catalyst, toluene, 80 °C,
20 (63%), 21 (79%); (c) HF−pyridine, THF, 0 °C, 1 (57%), 2 (81%).
organic layer washed with water and brine, dried (Na2SO4), filtered, and
concentrated in vacuo. The resulting crude residue was purified by flash
chromatography (silica gel, hexane/AcOEt, 99/1) to obtain 29 mg of 9
as yellow oil (0.08 mmol, 57%). [α]2D0 = +89.7 (c 0.5, CHCl3); IR (film)
3075, 2941, 1684, 1647, 1456, 1375, 1026 cm−1; 1H NMR (400 MHz,
CDCl3) δ 5.03 (1H, s, HA-14), 4.92 (1H, s, HB-14), 4.62 (1H, bs, H-2′),
4.21 (1H, d, J = 12.8 Hz, HA-16), 3.93 (1H, d, J = 12.8 Hz, HB-16), 3.53−
3.50 (2H, m, H-6′), 2.20−1.00 (21H, m), 1.58 (3H, s, Me-17), 0.94
(3H, s, Me-20), 0.88 (3H, s, Me-18), 0.83 (3H, s, Me-19); 13C NMR
(100 MHz, CDCl3) δ 147.0 (C), 140.2 (C), 126.0 (C), 110.3 (CH2),
97.8 (CH), 69.7 (CH2), 62.0 (CH2), 51.9 (CH), 41.8 (CH2), 39.0 (C),
36.9 (CH2), 34.0 (CH2), 33.6 (CH2), 33.3 (2, C and CH3), 30.6/30.4
(CH2), 26.7 (CH2), 25.6/25.5 (CH2), 21.7 (CH3), 20.0 (CH3), 19.4
(CH3), 19.3 (CH2), 19.0 (2, CH2); HRMS (EI) calcd for C24H44NO2
requires (M + NH4)+ 378.3367; found 378.3375.
15-Norlabda-8,13-dien-16-ol: 10. To a solution of 9 (27 mg,
0.08 mmol) in MeOH (7.5 mL) was added p-toluenesulfonic acid (4 mg,
0.023 mmol). The mixture was stirred for 4 h, quenched with water, and
extracted with AcOEt. The combined organic layer was washed with
water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to
obtain 22 mg of 10 as a yellow oil (0.08 mmol, 99%). [α]2D0 = +40.8
(c 0.9, CHCl3); IR (film) 3343, 3075, 2926, 1653, 1458, 1373, 1070,
Table 1. Experimental Conditions of RCM Reaction
a
b
b
c
c
entry cat. (equiv)
concn (solvent) T (°C)
3
4
20
21
1
2
3
4
5
0.10
0.20
0.20
0.20
0.20
15 mM (DCM)
3 mM (DCM)
3 mM (DCM)
3 mM (toluene)
3 mM (toluene)
40
40
40
80
80
32
−
38
18
−
−
−
−
−
−
8
−
−
−
−
d
33
63
−
24
b
79
a
Equivalents of second generation Grubbs catalyst. Percentage of
recovered starting material. Yield in percentage. Addition of catalyst
was done in two portions (0.06 equiv + 0.14 equiv).
c
d
15-Nor-16-(2-tetrahydropyranyloxy)labda-8,13-diene: 9. To
a suspension of triphenylmethylphosphonium bromide (73 mg,
0.19 mmol) in THF (350 mL) at −20 °C under an argon atmosphere
was added slowly 2 M THF solution of NaHMDS (308 mL, 0.19 mmol).
The mixture was warmed to room temperature and was stirred for
30 min. Then a solution of 8 (52 mg, 0.14 mmol) in THF (0.1 mL) was
added dropwise at −78 °C and stirred for 2.5 h at rt. A saturated aqueous
solution of NH4Cl (1 mL) was added at −78 °C and allowed to warm to
room temperature. It was extracted with AcOEt and the combined
a
Table 2. Antiproliferative Activity of Compounds 1/2 and 20/21
cell line (type)
compound
A549 (lung)
HBL-100 (breast)
HeLa (cervix)
SW1573 (lung)
T-47D (breast)
WiDr (colon)
1
2
31 ( 6.7)
48 ( 3.9)
17 ( 2.2)
16 ( 1.4)
22 ( 6.2)
39 ( 9.6)
18 ( 4.9)
17 ( 1.6)
17 ( 1.8)
28 ( 3.3)
12 ( 1.4)
14 ( 1.2)
25 ( 1.2)
39 ( 16)
17 ( 3.2)
17 ( 1.2)
20 ( 4.3)
51 ( 3.1)
18 ( 1.0)
19 ( 1.6)
21 ( 2.4)
40 ( 13)
18 ( 0.8)
19 ( 1.3)
20
21
a
Values are given in μM and are means of two to three experiments; standard deviation is given in parentheses.
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1026 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.01 (1H, s, HA-14), 4.90
(1H, s, HB-14), 4.10 (2H, s, H-21), 2.20−1.00 (15H, m), 1.57 (3H, s,
Me-17), 0.95 (3H, s, Me-20), 0.88 (3H, s, Me-18), 0.83 (3H, s, Me-19);
13C NMR (100 MHz, CDCl3) δ 149.9 (C), 140.1 (C), 126.1 (C), 108.4
(CH2), 65.9 (CH2), 51.9 (CH), 41.8 (CH2), 39.0 (C), 36.9 (CH2), 33.6
(2, CH2), 33.3 (2, C and CH3), 26.6 (CH2), 21.7 (CH3), 20.1 (CH3),
19.4 (CH3), 19.0 (2, CH2); HRMS (EI) calcd for C19H32ONa requires
(M + Na)+ 299.2345; found 299.2342.
2R,3S-Hex-5-ene-1,2,3-triol: 11. To a suspension of triphenylme-
thylphosphonium bromide (17 g, 46.8 mmol) in THF (190 mL) at 0 °C
was added 20% THF solution of tBuOK (26.5 mL, 44.8 mmol). The
mixture was stirred for 30 min at 0 °C, and 2-deoxy-D-ribose (2.5 g,
18.7 mmol) was added. It was warmed to 40 °C and stirred for 24 h.
Then NH4Cl (2.5 g) was added at 0 °C, and it was stirred for 12 h. It was
filtered and concentrated in vacuo. The resulting crude residue was
purified by column chromatography (silica gel, DCM/MeOH, 9/1) to
obtain 2.1 g of 11 as a white powder (15.8 mmol, 85%). mp: 54−55 °C;
[α]2D0 = −9.3 (c 1.9, MeOH); IR (film) 3227, 2901, 1464, 1065, 1030,
914, 870 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.85 (1H, tdd, J = 17.0,
10.3, and 7.6 Hz, H-5), 5.18 (1H, d, J = 17.0 Hz, HA-6), 5.16 (1H, d, J =
10.3 Hz, HB-6), 3.81−3.76 (3H, m, H-1, H-2), 3.63 (1H, q, J = 4.8 Hz,
H-3), 2.45−2.25 (2H, m, H-4); 13C NMR (50 MHz, CDCl3) δ 134.8
(CH), 118.2 (CH2), 74.1 (CH), 72.5 (CH), 63.3 (CH2), 37.7 (CH2);
HRMS (EI) calcd for C6H12O3Na requires (M + Na)+ 155.0679; found
155.0680.
(2R,3S)-1,2-Dimethylmethylenedioxyhex-5-en-3-ol: 12. To
a solution of 11 (403 mg, 3.04 mmol) in acetone (15 mL) were added
2,2-dimethoxypropane (1.5 mL, 12.2 mmol) and p-toluenesulfonic
acid (62 mg, 0.32 mmol). The reaction was stirred for 1 h under an
anhydrous atmosphere. Then Et3N (1 mL) was added, and it was
concentrated in vacuo. The resulting crude residue was purified by
column chromatography (silica gel, hexane/AcOEt, 9/1) to obtain
453 mg of 12 as a colorless oil (2.38 mmol, 78%). [α]2D0 = +16.6 (c 1.4,
CHCl3); IR (film) 3460, 3076, 2986, 1674, 1456, 1215, 1067, 907 cm−1;
1H NMR (200 MHz, CDCl3) δ 5.89 (1H, tdd, J = 17.1, 10.2, and 7.8 Hz,
H-5), 5.15 (1H, d, J = 17.1 Hz, HA-6), 5.14 (1H, d, J = 10.2 Hz, HB-6),
4.02−3.96 (2H, m, HA-1, H-2), 3.94−3.86 (1H, m, HB-1), 3.77 (1H, dt,
J = 8.6 and 4.6 Hz, H-3), 2.40−2.10 (2H, m, H-4), 1.42 (3H, s, C-CH3),
1.36 (3H, s, C-CH3); 13C NMR (100 MHz, CDCl3) δ 134.0 (CH),
118.1 (CH2), 109.0 (C), 78.1 (CH), 70.4 (CH), 65.2 (CH2), 37.6
(CH2), 26.4 (CH3), 25.2 (CH3); HRMS (EI) calcd for C9H16O3Na
requires (M + Na)+ 195.0992; found 195.0988.
(2R,3R)-1,2-Dimethylmethylenedioxyhex-5-en-3-ol: 7. To a
solution of 12 (1.3 g, 7.14 mmol) in THF (20 mL) were added
triphenylphosphine (2.8 g, 10.71 mmol) and benzoic acid (1.57 g,
7.85 mmol). Then DIAD (2.15 mL, 10.71 mmol) was added under an
argon atmosphere at 0 °C. The reaction was stirred for 1.5 h at rt. It was
quenched with water and extracted with AcOEt. The combined organic
layer was washed with water and brine, dried (Na2SO4), filtered, and
concentrated in vacuo.
70 °C and stirred for 14 h. It was allowed to cool to room temperature,
Et3N (2.5 mL) was added, and the solvent was evaporated under
pressure.
To a solution of resulting triol in DCM (14 mL) were added
benzaldehyde dimethyl acetal (533 μL, 3.93 mmol) and CSA (210 mg,
0.91 mmol). The mixture was stirred for 22 h at rt. Then Et3N (2.5 mL)
was added and concentrated in vacuo. The resulting crude residue was
purified by column chromatography (silica gel, hexane/AcOEt, 9/1
and 85/15) to afford 231 mg of 14 as a colorless oil (1.05 mmol, 35%).
[α]2D0 = +24.3 (c 1.6, CHCl3); IR (film) 3441, 3073, 2978, 2858, 1643,
1
1454, 1360, 1092, 1028, 918, 750, 698 cm−1; H NMR (200 MHz,
CDCl3) δ 7.55−7.35 (5H, m, Ph), 5.86 (1H, tdd, J = 17.2, 10.9, and 7.4
Hz, H-5), 5.56 (1H, s, CH-Ph), 5.21 (1H, d, J = 17.2 Hz, HA-6), 5.14
(1H, d, J = 10.9 Hz, HB-6), 4.13 (1H, dd, J = 11.8 and 2.0 Hz, HA-1), 4.02
(1H, d, J = 11.8 Hz, HB-1), 3.93 (1H, t, J = 10.8 Hz, H-3), 3.49 (1H, d, J =
10.8 Hz, H-2), 2.86 (1H, d, J = 10.8 Hz, OH), 2.53−2.45 (2H, m, H-4);
13C NMR (50 MHz, CDCl3) δ 138.2 (C), 133.7 (CH), 129.2/128.5/
126.2 (CH), 118.2 (CH2), 101.6 (CH), 79.9 (CH), 73.0 (CH2),
65.0 (CH), 35.9 (CH2); HRMS (EI) calcd for C13H16O3Na requires
(M + Na)+ 243.0992; found 243.0996.
Compounds 16Z and 16E. To a solution of 14 (430 mg,
1.93 mmol) in DCM (101 mL) was added a 15% DCM solution of DMP
(10.7 mL, 3.87 mmol). The reaction was stirred for 1 h under an argon
atmosphere at rt. Then it was diluted with AcOEt and washed with a
10% NaHCO3 (aq)/10% Na2S2O3 (aq) 1:1 solution. The organic layer
was dried (Na2SO4) and concentrated in vacuo.
A solution of methyl P,P-bis(2,2,2-trifluoroethyl)phosphonoacetate
(900 μL, 4.26 mmol) in THF (13.3 mL) under an argon atmosphere
at −78 °C was added slowly dropwise 0.7 M THF solution of KHMDS
(5.7 mL, 3.86 mmol). Then a solution of previous obtained 15 in THF
(2.7 mL) was added via cannula. The reaction was stirred for 30 min
at −78 °C and 30 min at −10 °C. It was quenched with saturated
aqueous solution of NH4Cl (5 mL) and extracted with Et2O. The
combined organic layer was dried (Na2SO4) and concentrated in vacuo.
The resulting crude residue was purified by flash chromatography (silica
gel, hexane/AcOEt, 98/2) to obtain 242 mg of 16Z (0.88 mmol, 46%)
and 96 mg of 16E (0.35 mmol, 18%), both as a colorless oils.
16Z: [α]2D0 = +104.4 (c 0.8, CHCl3); IR (film) 3075, 2959, 2859,
1721, 1661, 1456, 1381, 1227, 1103, 1028, 918, 746, 698 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.49−7.35 (5H, m, Ph), 6.01 (1H, tdd, J = 17.2,
10.2, and 7.1 Hz, H-6), 5.88 (1H, bs, H-2), 5.69 (1H, s, CH-Ph), 5.59
(1H, t, J = 4.8 Hz, H-4), 5.16 (1H, d, J = 17.2 Hz, HA-7), 5.10 (1H, d, J =
10.2 Hz, HB-7), 4.86 (1H, dt, J = 12.8 and 1.8 Hz, HA-8), 4.36 (1H, dt, J =
12.8 and 1.1 Hz, HB-8), 3.74 (3H, s, COOMe), 2.67 (2H, t, J = 6.0 Hz,
H-5); 13C NMR (100 MHz, CDCl3) δ 165.4 (C), 157.1 (C), 138.4 (C),
133.7 (CH), 128.9/128.3/126.1 (CH), 117.6 (CH2), 116.3 (CH), 97.6
(CH), 77.5 (CH), 67.4 (CH2), 51.5 (CH3), 38.8 (CH2); HRMS (EI)
calcd for C16H18O4Na requires (M + Na)+ 297.1097; found 297.1099.
16E: [α]2D0 = +20.5 (c 0.6, CHCl3); IR (film) 3075, 2951, 2841, 1721,
1655, 1435, 1381, 1211, 1026, 918, 750, 698 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.51−7.34 (5H, m, Ph), 6.00−5.87 (1H, m, H-6), 5.84 (1H, s,
H-2), 5.76 (1H, s, CH-Ph) 5.63 (1H, d, J = 15.4 Hz, HA-8), 5.19 (1H, d,
J = 17.2 Hz, HA-7), 5.15 (1H, d, J = 10.2 Hz, HB-7), 4.68 (1H, dd, J = 15.4
and 1.4 Hz, HB-8), 4.55 (1H, t, J = 6.2 Hz, H-4), 3.73 (3H, s, COOMe),
2.64 (2H, q, J = 6.2 Hz, H-5); 13C NMR (100 MHz, CDCl3) δ 165.9
(C), 152.8 (C), 137.9 (C), 133.5 (CH), 128.9/128.2/126.1 (CH), 117.7
(CH2), 114.4 (CH), 100.3 (CH), 77.2 (CH), 66.2 (CH2), 51.5 (CH3),
36.9 (CH2); HRMS (EI) calcd for C16H18O4Na requires (M + Na)+
297.1097; found 297.1099.
3-Hydroxymethylhepte-2,6-dien-1,4R-olide: 5. To a solution of
16Z (109 mg, 0.4 mmol) in MeOH (2.2 mL) were added H2O (45 μL)
and CSA (16 mg, 0.07 mmol). The mixture was stirred for 20 h. It was
quenched with NaHCO3 (40 mg) and stirred 15 min. The crude residue
was purified by column chromatography (silica gel, hexane/AcOEt, 9/1
and 8/2) to obtain 51 mg of 5 as a pale yellow oil (0.33 mmol, 83%).
[α]2D0 = −75.8 (c 0.3, CHCl3); IR (film) 3418, 3084, 2918, 1748, 1643,
912 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.04 (1H, bs, H-2), 5.72 (1H,
tdd, J = 17.1, 10.2, and 7.0 Hz, H-6), 5.14 (1H, d, J = 17.1 Hz, HA-7), 5.11
(1H, d, J = 10.2 Hz, HB-7), 5.07 (1H, t, J = 4.7 Hz, H-4), 4.56 (1H, d,
J = 16.8 Hz, HA-8), 4.46 (1H, d, J = 16.8 Hz, HB-8), 2.73−2.67 (1H, m,
To a solution of the resulting crude ester in MeOH (142 mL) was
added a 10% MeOH solution of KOH (71 mL, 7.1 mmol). The mixture
was stirred for 30 min at rt. The solvent was evaporated under pressure,
and water was added. It was extracted with AcOEt, and the combined
organic layer was washed with water, until neutral pH was reached,
and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The
resulting crude residue was purified by column chromatography (silica
gel, hexane/AcOEt, 8/2) to afford 550 mg of 7 as a pale yellow oil
(3.02 mmol, 42%). [α]2D0 = +8.1 (c 0.7, CHCl3); IR (film) 3483, 3078,
2986, 1641, 1381, 1215, 1067, 907 cm−1; 1H NMR (400 MHz, CDCl3) δ
5.84 (1H, tdd, J = 17.2, 10.2, and 7.1 Hz, H-5), 5.11 (1H, d, J = 17.2 Hz,
HA-6), 5.09 (1H, d, J = 10.2 Hz, HB-6), 4.05−3.90 (2H, m, HA-1, H-2),
3.75−3.70 (1H, m, HB-1), 3.57 (1H, bs, H-3), 2.19 (2H, t, J = 6.6 Hz,
H-4), 1.41 (3H, s, C-CH3), 1.34 (3H, s, C-CH3); 13C NMR (100 MHz,
CDCl3) δ 134.0 (CH), 117.8 (CH2), 109.3 (C), 78.4 (CH), 71.5 (CH),
66.0 (CH2), 38.2 (CH2), 26.5 (CH3), 25.3 (CH3); HRMS (EI) calcd for
C9H16O3Na requires (M + Na)+ 195.0992; found 195.0988.
(2R,3R)-1,3-Benzylidenedioxyhex-5-en-2-ol: 14. To a solution
of 7 (550 mg, 3.02 mmol) in MeOH (280 mL) was added pyridinium
p-toluenesulfonate (830 mg, 3.32 mmol). The solution was warmed to
F
DOI: 10.1021/acs.joc.5b00876
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The Journal of Organic Chemistry
Article
HA-5), 2.46−2.41 (1H, m, HB-5); 13C NMR (100 MHz, CDCl3) δ 172.3
(C), 170.8 (C), 130.5 (CH), 119.6 (CH2), 116.1 (CH), 81.2 (CH), 58.8
(CH2), 36.4 (CH2); HRMS (EI) calcd for C8H11O3 requires (M + H)+
155.0703; found 155.0708.
2.73−2.67 (1H, m, HA-5), 2.47−2.40 (1H, m, HB-5); 13C NMR (100
MHz, CDCl3) δ 172.6 (C), 170.8 (C), 130.4 (CH), 119.7 (CH2), 115.5
(CH), 81.7 (CH), 58.5 (CH2), 36.2 (CH2); HRMS (EI) calcd for
C8H11O3 requires (M + H)+ 155.0703; found 155.0708.
(2R,3S)-1,3-Benzylidenedioxyhex-5-en-2-ol: 17. To a solution
of 11 (156 mg, 1.18 mmol) in DCM (5 mL), benzaldehyde dimethyl
acetal (210 μL, 1.53 mmol) and camphorsulfonic acid (82 mg, 0.35 mmol)
were added. The solution was stirred for 22 h at rt. It was quenched with
Et3N (1 mL) and concenterd in vacuo. The resulting crude residue was
purified by column chromatography (silica gel, hexane/AcOEt, 9/1) to
obtain 210 mg of 17 as a colorless oil (0.95 mmol, 81%). [α]2D0 = −19.0
(c 1.7, CHCl3); IR (film) 3437, 3073, 2978, 2857, 1641, 1398, 1217,
1074, 1028, 916, 758, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.50−
7.34 (5H, m, Ph), 6.01 (1H, tdd, J = 17.2, 10.2, and 7.1 Hz, H-5), 5.49
(1H, s, CH-Ph), 5.21 (1H, d, J = 17.2 Hz, HA-6), 5.14 (1H, d, J = 10.2
Hz, HB-6), 4.26 (1H, dd, J = 10.4 and 4.6 Hz, HA-1), 3.58 (1H, t, J = 10.4
Compound 3. To a solution of imidazole (78 mg, 1.14 mmol) in
DCM (0.49 mL) under an argon atmosphere at 0 °C was added
iPr2SiCl2 (76 μL, 0.38 mmol), and the mixture was stirred for 5 min. A
solution of 5 (46 mg, 0.3 mmol) in DCM (0.32 mL) was added slowly
dropwise for 2 h at 0 °C. The mixture was stirred for 8 h at 0 °C. A
solution of 10 (83 mg, 0.3 mmol) in DCM (0.32 mmol) was added, and
the reaction was stirred for 14 h at 0 °C. Finally, it was filtered, washing
with hexane, and concentrated in vacuo. The resulting crude residue was
purified by flash chromatography (silica gel, hexane/AcOEt, 98/2 and
97/3) to obtain 53 mg of 3 as a colorless oil (0.098 mmol, 49%) and
15 mg of 5 as a pale yellow oil (0.1 mmol). [α]2D0 = +34.7 (c 1.0, CHCl3);
IR (film) 3080, 2943, 2866, 1761, 1647, 1464, 1099, 913 cm−1; 1H NMR
(200 MHz, CDCl3) δ 6.02 (1H, s, H-18), 5.71 (1H, tdd, J = 17.0, 10.2,
and 6.9 Hz, H-15a), 5.17 (1H, d, J = 17.0 Hz, HA-15b), 5.15 (1H, d, J =
10.2 Hz, HB-15b), 5.05−5.00 (1H, m, H-16), 5.02 (1H, s, HA-14), 4.87
(1H, s, HB-14), 4.65 (1H, dd, J = 16.8 and 1.7 Hz, HA-20), 4.54 (1H,
ddd, J = 16.8, 1.7, and 0.6 Hz, HB-20), 4.19 (2H, s, H-21), 2.80−2.60
(1H, m, HA-15), 2.45−2.30 (1H, m, HB-15), 2.10−1.90 (4H, m, H-11,
H-12), 1.80−1.00 (13H, m), 1.56 (3H, s, Me-22), 1.07 (12H, s, Me-iPr),
0.94 (3H, s, Me-23), 0.88 (3H, s, Me-25), 0.85 (3H, s, Me-24); 13C
NMR (50 MHz, CDCl3) δ 172.6 (C), 171.4 (C), 149.0 (C), 140.3 (C),
130.9 (CH), 126.4 (C), 119.8 (CH2), 116.0 (CH), 108.4 (CH2), 81.3
(CH), 65.9 (CH2), 59.4 (CH2), 52.1 (CH), 42.0 (CH2), 39.2 (C), 37.2
(CH2), 36.8 (2, CH2), 33.8 (CH2), 33.6 (2, C and CH3), 26.8 (CH2),
21.9 (CH3), 20.3 (CH3), 19.7 (CH3), 19.3 (2, CH2), 17.5 (4, CH3), 12.3
(2, CH); HRMS (EI) calcd for C33H54O4SiNa requires (M + Na)+
565.3684; found 565.3687.
Compound 4. To a solution of imidazole (68 mg, 0.99 mmol) in
DCM (0.43 mL) under an argon atmosphere at 0 °C was added
iPr2SiCl2 (66 μL, 0.36 mmol), and the mixture was stirred for 5 min. A
solution of 6 (41 mg, 0.27 mmol) in DCM (0.28 mL) was added slowly
dropwise for 2 h at 0 °C. The mixture was stirred for 6 h at 0 °C. A
solution of 10 (72 mg, 0.27 mmol) in DCM (0.28 mmol) was added,
and the reaction was stirred for 18 h at 0 °C. Finally, it was filtered,
washing with hexane, and concentrated in vacuo. The resulting crude
residue was purified by flash chromatography (silica gel, hexane/AcOEt,
98/2 and 97/3) to obtain 58 mg of 4 as a colorless oil (0.11 mmol, 60%)
and recover 13 mg of 6 (0.084 mmol). [α]2D0 = +48.6 (c 0.7, CHCl3); IR
(film) 3078, 2943, 2866, 1763, 1649, 1466, 1094, 909 cm−1; 1H NMR
(400 MHz, CDCl3) δ 6.02 (1H, s, H-18), 5.71 (1H, tdd, J = 17.1, 10.2,
and 7.0 Hz, H-15a), 5.19 (1H, d, J = 17.1 Hz, HA-15b), 5.15 (1H, d, J =
10.2 Hz, HB-15b), 5.03−5.01 (1H, m, H-16), 5.02 (1H, s, HA-14), 4.87
(1H, s, HB-14), 4.65 (1H, dd, J = 16.8 and 1.7 Hz, HA-20), 4.54 (1H,
ddd, J1 = 16.8, 1.7, and 0.6 Hz, HB-20), 4.20 (2H, s, H-21), 2.75−2.60
(1H, m, HA-15), 2.45−2.35 (1H, m, HB-15), 2.10−1.90 (4H, m, H-11,
H-12), 1.80−1.00 (13H, m), 1.56 (3H, s, Me-22), 1.07 (12H, s, Me-iPr),
0.94 (3H, s, Me-23), 0.88 (3H, s, Me-25), 0.83 (3H, s, Me-24); 13C
NMR (50 MHz, CDCl3) δ 172.6 (C), 171.5 (C), 149.0 (C), 140.3 (C),
130.9 (CH), 126.5 (C), 119.8 (CH2), 116.0 (CH), 108.3 (CH2), 81.3
(CH), 65.9 (CH2), 59.4 (CH2), 52.1 (CH), 42.0 (CH2), 39.2 (C), 37.2
(CH2), 36.8 (CH2), 36.5 (CH2), 33.8 (CH2), 33.6 (2, C and CH3),
26.8 (CH2), 21.9 (CH3), 20.3 (CH3), 19.7 (CH3), 19.3 (2, CH2), 17.5
(4, CH3), 12.3 (2, CH); HRMS (EI) calcd for C33H54O4SiNa requires
(M + Na)+ 565.3684; found 565.3687.
Hz, HB-1), 3.70−3.60 (2H, m, H-2, H-3), 2.66−2.44 (2H, m, H-4); 13
C
NMR (50 MHz, CDCl3) δ 138.0 (C), 134.0 (CH), 129.2/128.5/126.4
(CH), 117.8 (CH2), 101.0 (CH), 81.4 (CH), 71.3 (CH2), 65.8 (CH),
36.8 (CH2); HRMS (EI) calcd for C13H17O3 requires (M + H)+
221.1172; found 221.1178.
Compounds 19Z and 19E. To a solution of 17 (21 mg,
0.095 mmol) in DCM (4.7 mL) was added 15% DCM solution of
DMP (395 μL, 0.143 mmol). The mixture was stirred for 1 h under an
argon atmosphere. It was diluted with AcOEt, washed with a 10%
NaHCO3 (aq)/10% Na2S2O3 (aq) 1:1 solution, dried (Na2SO4),
filtered, and concentrated in vacuo.
To a solution of methyl P,P-bis(2,2,2-trifluoroethyl)phosphonoacetate
(42 μL, 0.19 mmol) in THF (620 μL) under an argon atmosphere
at −78 °C were added 0.7 M toluene solution of KHMDS (260 mL,
0.19 mmol) and a solution of previously obtained ketone in THF
(130 μL) via cannula. The mixture was stirred for 20 min at −78 °C and
30 min at −10 °C, quenched with a saturated aqueous solution of
NH4Cl (1 mL), and extracted with Et2O. The combined organic layer
was dried (Na2SO4) and concentrated in vacuo. The resulting crude
residue was purified by flash chromatography (silica gel, hexane/AcOEt,
98/2) to obtain 12 mg of 19Z (0.044 mmol, 45%) and 3 mg of 19E
(0.011 mmol, 11%), both as a colorless oils.
19Z: [α]2D0 = −102.3 (c 1.1, CHCl3); IR (film) 3073, 2953, 2859,
1
1721, 1659, 1437, 1227, 910 cm−1; H NMR (400 MHz, CDCl3) δ
7.50−7.35 (5H, m, Ph), 6.04−5.96 (1H, m, H-6), 5.88 (1H, bs, H-2),
5.69 (1H, s, CH-Ph), 5.59 (1H, bs, H-4), 5.16 (1H, d, J = 17.0 Hz, HA-7),
5.10 (1H, d, J = 10.3 Hz, HB-7), 4.77 (1H, d, J = 12.4 Hz, HA-8), 4.36
(1H, d, J = 12.4 Hz, HB-8), 3.75 (3H, s, COOMe), 2.67 (2H, t, J = 5.9 Hz,
H-5); 13C NMR (100 MHz, CDCl3) δ 165.4 (C), 157.1 (C), 138.4 (C),
133.7 (CH), 128.9/128.3/126.1 (CH), 117.6 (CH2), 116.3 (CH), 97.6
(CH), 77.5 (CH), 67.4 (CH2), 51.5 (CH3), 38.8 (CH2); HRMS (EI)
calcd for C16H18O4Na requires (M + Na)+ 297.1097; found 297.1099.
19E: [α]2D0 = −22.3 (c 0.8, CHCl3); IR (film) 3075, 2951, 2841, 1721,
1655, 1435, 1381, 1211, 1026, 918, 750, 698 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.50−7.36 (5H, m, Ph), 6.05−5.90 (1H, m, H-6), 5.84 (1H, s,
H-2), 5.76 (1H, s, CH-Ph), 5.63 (1H, d, J = 15.4 Hz, HA-8), 5.18 (1H, d,
J = 17.2 Hz, HA-7), 5.15 (1H, d, J = 10.2 Hz, HB-7), 4.68 (1H, d, J = 15.4
Hz, HB-8), 4.55 (1H, t, J = 6.2 Hz, H-4), 3.74 (3H, s, COOMe), 2.70−
2.60 (2H, m, H-5); 13C NMR (100 MHz, CDCl3) δ 165.9 (C), 152.8
(C), 137.9 (C), 133.5 (CH), 128.9/128.2/126.1 (CH), 117.7 (CH2),
114.4 (CH), 100.3 (CH), 77.2 (CH), 66.2 (CH2), 51.5 (CH3), 36.9
(CH2); HRMS (EI) calcd for C16H18O4Na requires (M + Na)+
297.1097; found 297.1099.
3-Hydroxymethylhepte-2,6-dien-1,4S-olide: 6. To a solution
of 19Z (360 mg, 1.32 mmol) in MeOH (7.3 mL) were added H2O
(147 μL) and CSA (51 mg, 0.22 mmol). The mixture was stirred for 22 h
at rt. It was quenched with NaHCO3 (110 mg) and stirred for 15 min.
The reaction was purified by column chromatography (silica gel,
hexane/AcOEt, 9/1 and 8/2) to obtain 199 mg of 6 as a pale yellow oil
(1.2 mmol, 91%). [α]2D0 = +73.4 (c 1.1, CHCl3); IR (film) 3418, 3084,
2918, 1748, 1643, 908 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.05 (1H, s,
H-2), 5.72 (1H, tdd, J = 17.1, 10.2, and 7.0 Hz, H-6), 5.20 (1H, d, J =
17.1 Hz, HA-7), 5.17 (1H, d, J = 10.2 Hz, HB-7), 5.07 (1H, t, J = 4.7 Hz,
H-4), 4.56 (1H, d, J = 16.8 Hz, HA-8), 4.46 (1H, d, J = 16.8 Hz, HB-8),
Compound 20. To a solution of 3 (53 mg, 0.1 mmol) in toluene
(31.4 mL) under an argon atmosphere at 80 °C was added dropwise a
solution of Grubbs second generation catalyst (20 mg, 0.02 mmol, 20%)
in toluene (1 mL) via cannula. The reaction was stirred for 16 h. Then it
was allowed to cool to room temperature and concentrated in vacuo.
The resulting crude residue was purified by column chromatography
(silica gel, hexane/AcOEt, 97/3 and 9/1) to afford 25 mg of 20 as a
colorless oil (0.052 mmol, 63%) and recover 10 mg of 3 (0.018 mmol).
[α]2D0 = −63.0 (c 0.2, CHCl3); IR (film) 2943, 2866, 1757, 1638, 1466,
1086, 885 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.88 (1H, bs, H-18),
5.28−5.23 (1H, m, H-14), 5.22−5.20 (1H, m, H-16), 4.71 (2H, s,
H-20), 4.45 (1H, d, J = 11.7 Hz, HA-21), 4.00 (1H, d, J = 11.7 Hz,
G
DOI: 10.1021/acs.joc.5b00876
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The Journal of Organic Chemistry
Article
HB-21), 3.05 (1H, ddd, J = 14.7, 11.2, and 4.0 Hz, HA-15), 2.65 (1H, dt,
J = 14.7, 9.0, and 4.3 Hz, HB-15), 2.20−1.90 (4H, m, H-11, H-12), 1.80−
1.00 (13H, m), 1.55 (3H, s, Me-22), 1.10 (6H, s, Me-iPr), 1.04 (6H, s,
Me-iPr), 0.93 (3H, s, Me-23), 0.88 (3H, s, Me-25), 0.83 (3H, s, Me-24);
13C NMR (100 MHz, CDCl3) δ 172.6 (C), 171.2 (C), 143.0 (C), 140.1
(C), 126.1 (C), 119.4 (CH), 115.6 (CH), 82.8 (CH), 60.3 (CH2), 59.2
(CH2), 51.9 (CH), 41.8 (CH2), 38.9 (C), 37.0 (CH2), 36.5 (CH2), 33.6
(CH2), 33.3 (2, C and CH3), 29.8 (CH2), 26.9 (CH2), 21.6 (CH3), 20.1
(CH3), 19.4 (CH3), 19.0 (2, CH2), 17.4/17.3/17.2 (4, CH3), 12.0/11.8
(CH); HRMS (EI) calcd for C31H54NO4Si requires (M + NH4)+
532.3817; found 532.3802.
Compound 21. To a solution of 4 (15 mg, 0.029 mmol) in toluene
(8.4 mL) under an argon atmosphere at 80 °C was added dropwise a
solution of Grubbs second generation catalyst (6 mg, 0.006 mmol, 20%)
in toluene (1 mL) via cannula. The reaction was stirred for 16 h. Then it
was allowed to cool to room temperature and concentrated in vacuo.
The resulting crude residue was purified by column chromatography
(silica gel, hexane/AcOEt, 97/3 and 9/1) to afford 9 mg of 21 as a
colorless oil (0.017 mmol, 79%) and recover 4 mg of 4 (0.007 mmol).
[α]2D0 = +113.9 (c 0.6, CHCl3); IR (film) 2941, 2926, 2866, 1757, 1649,
1462, 1055 cm−1; 1H NMR (200 MHz, CDCl3) δ 5.87 (1H, s, H-18),
5.30−5.23 (1H, m, H-14), 5.23−5.15 (1H, m, H-16), 4.71 (2H, s,
H-20), 4.46 (1H, d, J = 11.6 Hz, HA-21), 4.00 (1H, d, J = 11.6 Hz,
HB-21), 3.05 (1H, ddd, J = 14.5, 10.9, and 4.8 Hz, HA-15), 2.65 (1H, dt,
J = 14.5, 9.2, and 4.8 Hz, HB-15), 2.10−1.90 (4H, m, H-11, H-12), 1.80−
1.00 (13H, m), 1.55 (3H, s, Me-22), 1.10 (6H, s, Me-iPr), 1.04 (6H, s,
Me-iPr), 0.92 (3H, s, Me-23), 0.88 (3H, s, Me-25), 0.83 (3H, s, Me-24);
13C NMR (50 MHz, CDCl3) δ 173.0 (C), 171.6 (C), 143.2 (C), 140.3
(1H, m, HB-15), 2.20−1.90 (4H, m, H-11, H-12), 1.80−1.00 (11H, m),
1.55 (3H, s, Me-22), 0.93 (3H, s, Me-23), 0.88 (3H, s, Me-25), 0.82
(3H, s, Me-24); 13C NMR (100 MHz, CDCl3) δ 172.4 (C), 171.0 (C),
144.3 (C), 139.9 (C), 126.2 (C), 119.2 (CH), 116.1 (CH), 81.6 (CH),
60.4 (CH2), 58.7 (CH2), 51.8 (CH), 41.7 (CH2), 39.0 (C), 36.9 (CH2),
36.4 (CH2), 33.6 (CH2), 33.3 (2, C and CH3), 30.2 (CH2), 27.3 (CH2),
21.7 (CH3), 20.1 (CH3), 19.5 (CH3), 19.0 (2, CH2); HRMS (EI) calcd
for C25H38O4Na requires (M + Na)+ 425.2662; found 425.2652.
ASSOCIATED CONTENT
* Supporting Information
■
S
Copies of IR, NMR, and HRMS spectra are included. This
material is available free of charge via the Internet at http://pubs.
acs.orgThe Supporting Information is available free of charge on
the ACS Publications website at DOI: 10.1021/acs.joc.5b00876.
AUTHOR INFORMATION
Corresponding Author
*Fax: 34 923 294574. E-mail: pbb@usal.es.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank FSE and Junta de Castilla y Leon
■
́
(GR178,)
for financial support. AUG is grateful to the JCyL-FSE for his
fellowship. J.M.P. thanks the EU Research Potential (FP7-
REGPOT-2012-CT2012-31637-IMBRAIN), the European Re-
gional Development Fund (FEDER), and the Spanish Instituto
de Salud Carlos (III PI11/00840) for financial support.
(C), 126.4 (C), 120.0 (CH), 115.8 (CH), 83.1 (CH), 60.5 (CH2), 59.5
(CH2), 52.1 (CH), 42.0 (CH2), 39.2 (C), 37.1 (CH2), 37.0 (CH2), 33.8
(CH2), 33.6 (2, C and CH3), 30.0 (CH2), 27.5 (CH2), 21.9 (CH3), 20.3
(CH3), 19.7 (CH3), 19.3 (2, CH2), 17.7/17.6/17.5 (4, CH3), 12.3/12.0
(CH); HRMS (EI) calcd for C31H54NO4Si requires (M + NH4)+
532.3817; found 532.3802.
REFERENCES
■
20,21-Dihydroxyluffara-8,13Z,17(18)-trien-19,16R-olide: 1
(Luffarin L). To a solution of 20 (9 mg, 0.018 mmol) in THF (940 μL)
under an argon atmosphere at 0 °C was added HF−pyridine (5 drops).
The reaction was stirred for 40 min at 0 °C. Then NaHCO3 was added
slowly at 0 °C until gas liberation stops. It was diluted with Et2O and
filtered through a pad of silica gel eluting with AcOEt. The solvent was
evaporated under pressure, and the resulting crude residue was purified
by column chromatography (silica gel, hexane/AcOEt, 4/6) to afford
4 mg of 1 as a colorless oil (0.01 mmol, 57%). [α]2D0 = +22.0 (c 0.2,
CHCl3); IR (film) 3404, 2924, 2853, 1740, 1645, 1462, 1067 cm−1; 1H
NMR (400 MHz, CDCl3) δ 6.03 (1H, s, H-18), 5.26 (1H, t, J = 7.6 Hz,
H-14), 5.10 (1H, t, J = 4.6 Hz, H-16), 4.57 (1H, d, J = 16.2 Hz, HA-20),
4.50 (1H, d, J = 16.2 Hz, HB-20), 4.19 (1H, d, J = 12.0 Hz, HA-21), 4.15
(1H, d, J = 12.0 Hz, HB-21), 2.85−2.50 (2H, m, H-15), 2.15−1.90 (4H,
m, H-11, H-12), 1.80−1.00 (11H, m), 1.56 (3H, s, Me-22), 0.93 (3H, s,
Me-23), 0.88 (3H, s, Me-25), 0.83 (3H, s, Me-24); 13C NMR (100 MHz,
CDCl3) δ 172.2 (C), 170.8 (C), 144.3 (C), 139.9 (C), 126.3 (C), 119.2
(CH), 116.2 (CH), 81.6 (CH), 60.4 (CH2), 58.7 (CH2), 51.9 (CH),
41.8 (CH2), 39.0 (C), 37.0 (CH2), 36.4 (CH2), 33.6 (CH2), 33.3 (2, C
and CH3), 30.3 (CH2), 27.3 (CH2), 21.7 (CH3), 20.1 (CH3), 19.5
(CH3), 19.0 (2, CH2); HRMS (EI) calcd for C25H38O4Na requires
(M + Na)+ 425.2662; found 425.2652.
20,21-Dihydroxyluffara-8,13Z,17-trien-19,16S-olide: 2 (16-
epi-Luffarin L). To a solution of 21 (8 mg, 0.016 mmol) in THF
(850 μL) under an argon atmosphere at 0 °C was added HF-pyridine
(4 drops) slowly. The solution was stirred for 40 min at 0 °C, and
NaHCO3 was added slowly at 0 °C until gas liberation stops. It was
diluted with Et2O and filtered through a pad of silica gel eluting with
AcOEt. The resulting crude residue was purified by column
chromatography (silica gel, hexane/AcOEt, 1/1) to obtain 5 mg of 2
as a colorless oil (0.013 mmol, 81%). [α]2D0 = +92.4 (c 0.2, CHCl3); IR
(film) 3402, 2936, 1732, 1651, 1454, 1142, 1067 cm−1; 1H NMR (400
MHz, CDCl3) δ 6.02 (1H, s, H-18), 5.26 (1H, t, J = 7.7 Hz, H-14), 5.11
(1H, t, J = 4.5 Hz, H-16), 4.57 (1H, dd, J = 16.7 and 1.4 Hz, HA-20), 4.50
(1H, dd, J = 16.7 and 1.4 Hz, HB-20), 4.17 (1H, d, J = 12.1 Hz, HA-21),
4.15 (1H, d, J = 12.1 Hz, HB-21), 2.85−2.75 (1H, m, HA-15), 2.60−2.50
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