Total synthesis of (-)-sacidumlignans B and D

Article abstract of DOI:10.1021/jo2021696

The first total synthesis of naturally occurring sacidumlignans A (1), B (2), and D (4) was executed and the absolute configuration of 2 and 4 was determined. A diastereoselective α- methylation of a lactone was used as the key step for the control of the chiral centers of the central lignan core. An acid mediated dehydrative cyclization of an aldehyde to construct the dihydronaphthalene unit of 2 and the aromatization of the intermediate dihydronaphthalene derivative to synthesize 1 are the key reactions employed in this regard.

Full text of DOI:10.1021/jo2021696

Note
pubs.acs.org/joc
Total Synthesis of (−)-Sacidumlignans B and D
Jeetendra Kumar Rout and C. V. Ramana*
National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune 411 008, India
S
* Supporting Information
ABSTRACT: The first total synthesis of naturally occurring sacidumlignans A (1), B (2), and D (4) was executed and the
absolute configuration of 2 and 4 was determined. A diastereoselective α- methylation of a lactone was used as the key step for
the control of the chiral centers of the central lignan core. An acid mediated dehydrative cyclization of an aldehyde to construct
the dihydronaphthalene unit of 2 and the aromatization of the intermediate dihydronaphthalene derivative to synthesize 1 are the
key reactions employed in this regard.
are closely related (Figure 1) and indicate that they all originate
from a common precursor. The three sacidumlignans A, B, and
C contain naphthalene and di- and tetrahydronaphthalene
rings, respectively, and the sacidumlignan D was identified as a
rearranged tetrahydrofuran lignan with an unprecedented
skeleton. The isolation of a natural product viz. orthosilignin
having the constitution of the sacidumlignan B was reported in
2002; however, its relative stereochemistry has not been
investigated.1b
Inspired by its unprecedented structure, the ( )-sacidumli-
gnan D has been synthesized in our group which led to the
confirmation of its proposed relative configuration.2 In
continuation, we have been interested in developing an
asymmetric synthesis of sacidumlignan D to elucidate its
absolute configuration, thereby devising an approach that
would enable the synthesis of other sacidumlignans.
n 2005, Yue and co-workers reported the isolation of four
Inew lignans 1−4 (named respectively as sacidumlignans A−
D) from the plant Sarcostemma acidum (Roxb).1a The plant S.
acidum is one among the known 10 species of the genus
Sarcostemma and used in folklore medicine as a remedy for
chronic cough and postnatal hypogalactia in China. With the
help of extensive 2D NMR experiments, the structures of
sacidumlignans A−D and their relative configuration were
proposed (Figure 1). The structures of sacidumlignans A−D
To this end, retrosynthetic analyses of the sacidumlignans B
and D were done, leading to an advanced intermediate 6
(Scheme 1) from which either of 2 and 4 could be made. For
the synthesis of 4, the previously established synthetic route will
be followed from 6, whereas the synthesis of 2 will feature a
dehydrative cyclization of γ-aryl aldehyde3 (a carbon variant of
Pomeranz−Fritsch isoquinoline/isoquinolinone synthesis4)
leading to the dihydronaphthalene core 8 and subsequent
TBS-ether deprotection. To the best of our knowledge, this
reaction has been not used in the synthesis of aryldihydronaph-
thalene lignans.5 The synthesis of sacidumlignan A (1) was
Figure 1. Structures of sacidumlignans A−D (1−4) and of related
orthosilignin (5).
Received: October 19, 2011
Published: January 3, 2012
© 2012 American Chemical Society
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Note
the known benzyl ester 117 to afford the required diaryl
addition product 13 in 63% yield. The moderate yield was
accounted for by the identification of the formation of a
dehalogenated compound and the corresponding benzophe-
none 14 (10%) as the side products. The benzophenone side
product is assumed to occur as a result of elimination of a
carbanion.8
Scheme 1. Retrosynthetic Disconnections for
Sacidumlignans A, B, and D
Subsequently, compound 13 was subjected to deallylation
using the palladium(II) acetate, triphenylphosphine, and N,N'-
dimethylbarbituric acid as the allyl scavenger.9 The resulting
product was found to be unstable in CDCl3 solution and thus
was subjected for phenolic O-TBS protection using TBSCl and
imidazole in DMF to obtain the intermediate 10. The next key
intermediate lactone 9 was obtained from 10 in 77% yield by a
two-stage sequence involving a one-pot osmium tetroxide
catalyzed dihydroxylation−sodium periodate mediated diol
cleavage,10 followed by the oxidation of intermediate lactols
15 with Celite-supported silver carbonate11 in toluene at
reflux.12 The diastereoselective α-methylation of lactone 9 was
carried out under the established conditions (HMDS, n-BuLi,
MeOTf) and gave the key intermediate lactone 6 in 94% yield.
The latter served as the starting point for the synthesis of
sacidumlignans B and D. As has been established in the
synthesis of ( )-sacidumlignan D, the LAH reduction of 6
followed by TFA treatment of the crude diol gave the di-O-TBS
protected sacidumlignan D (16), which upon TBS deprotection
afforded the (−)-sacidumlignan D (4). The chiral-HPLC
analysis of racemic and optically active sacidumlignans revealed
the ee as 96%. The physical and spectral data of synthetic
(−)-sacidumlignan D (4) were in full agreement with the data
reported for the natural product and the similarity in the sign
and magnitude of the optical rotation [[α]25D = −138.2 (c 1.37,
planned via the aromatization6 of the dihydronaphthalene
derivative 8 prior to deprotection. Scheme 1 saliently presents
the key retrosynthetic disconnections. In our previous synthesis
of ( )-sacidumlignan D,2 the synthesis of ( )-6 involved the
reverse Wacker oxidation of a homoallylic alcohol which, in
turn, was prepared by using Zn-mediated Barbier crotylation of
a benzophenone derivative. To have a fixed absolute
configuration at C(3), we have opted for the preparation of
the intermediate lactone 9 from the oxidative olefin cleavage of
a pent-4-en-1-ol derivative 10 which, in turn, was planned via
the addition of an aryllithium to the corresponding (2R)-benzyl
2-methylpent-4-enoate (11), tentatively proposing an R-
configuration at C(3) in 2 and 4.
25
1
acetone); lit. [α] = −115 (c 1.14, acetone)] revealed that
D
the naturally occurring sacidumlignan D indeed had been
synthesized.
We next proceeded with the total synthesis of sacidumlignans
A (1) and B (2) (Scheme 3). The main concern in the
proposed retrosynthetic strategy was the deoxygenation of the
benzylic-OH group without cyclization, using triethylsilane in
the presence of BF3·Et2O.13 This reaction had been optimized
The synthesis of lactone 6 (Scheme 2) commenced with the
lithiation of the bromo derivative 12 followed by its addition to
Scheme 2. Total Synthesis of (−)-Sacidumlignan D (4)
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Note
In summary, the total synthesis of naturally occurring
sacidumlignans B and D was completed, and their relative
and/or absolute configurations were established. Furthermore,
we have also executed the synthesis of sacidumlignan A from an
intermediate used in the synthesis of sacidumlignan B. For the
total synthesis of the sacidumlignan B, a dehydrative cyclization
of a γ-aryl aldehyde leading to the aryldihydronaphthalene units
has been used, which is the first of its kind. The adopted
strategy employed a single advanced intermediate for all the
targets executed.
Scheme 3. Total Synthesis of Sacidumlignans A (1) and B
(2)
EXPERIMENTAL SECTION
■
All of the moisture- and air-sensitive reactions were carried out in
anhydrous solvents under argon atmosphere. The commercially
available reagents were used without further purification except
boron trifluoride etherate and hexamethyldisilazane, which were
distilled prior to use. The reactions were monitored by TLC plate
under UV light and anisaldehyde solution for charring purpose.
Purifications were carried out by column chromatography using 100−
200 mesh (0.075−0.150 mm) and 230−400 mesh (0.037−0.063 mm)
silica gel. The NMR spectra of all of the compounds were recorded on
200, 400, and 500 MHz spectrometers in CDCl3 or in acetone-d6
solutions using TMS as internal standard. The signal multiplicities are
abbreviated as s = singlet, d = doublet, t = triplet, q = quartet, st =
sextet, dd = doublet of doublet, ddd = doublet of doublet of doublet,
dddd = doublet of doublet of doublet of doublet, ddt = doublet of
doublet of triplet, ddq = doublet of doublet of quartet, tq = triplet of
quartet, m = multiplet and br = broad.
(R)-1,1-Bis(4-(allyloxy)-3,5-dimethoxyphenyl)-2-methylpent-
4-en-1-ol (13). At −78 °C, a solution of 12 (2.94 g, 10.8 mmol) in
THF (15 mL) was treated with n-BuLi in hexane (6.43 mL, 10.3
mmol). After 1 h of vigorous stirring at −78 °C, a solution of the ester
11 (1.0 g, 4.9 mmol) in THF (15 mL) was added drop by drop, and
stirring was continued at the same temperature for 2 h. The reaction
mixture was quenched with satd NH4Cl solution and warmed to rt.
The reaction mixture was partitioned between water/CH2Cl2, and the
aqueous layer was extracted with CH2Cl2. The combined organic layer
was dried (Na2SO4) and concentrated under reduced pressure. The
crude product was purified by column chromatography (100−200
silica gel, 20% EtOAc in petroleum ether) to procure 13 (1.49 g, 63%)
as a low melting solid and the ketone 14 (200 mg, 10%) as byproduct.
using the crude diol resulting from the LAH reduction of
lactone 6. The optimized conditions involve the addition of diol
to a solution of triethylsilane in CH2Cl2 at 0 °C followed by the
slow addition of BF3·Et2O and quenching of the reaction after 5
min of addition. Under these conditions, the requisite alcohol 7
was obtained in 74% yield along with the cyclization product 16
in 11% yield. Decreasing the reaction temperature was found to
favor the formation of the cyclization product, and at −78 °C,
the cyclization product 16 was predominantly obtained. With
the increase in temperature, the monoalcohol became less
prominent in competition with the TBS deprotection.
Oxidation of the alcohol 7 with 2-iodoxybenzoic acid (IBX)14
followed by p-TSA-mediated cyclization cum elimination3,4 in
toluene at room temperature gave the di-O-TBS-sacidumlignan
8 in excellent yields and with more than 99% diastereose-
lectivity without any damage to the protecting group. Here, the
cyclization occurred in a manner such that the methyl and
aromatic groups became anti to each other, thus making the
central dihydronaphthalene skeleton of the sacidumlignan B.
The final desilylation of 8 with TBAF completed the synthesis
of (−)-sacidumlignan B (2). The similarity in the spectral and
optical rotation data of 2 [[α]25D = −65.9 (c 0.8, acetone); lit.1
13: Rf = 0.3 (25% EtOAc in petroleum ether); mp 73−75 °C; [α]25
=
D
−13.6 (c 0.2, CHCl3); IR (CHCl3) ν 3501, 2935, 2854, 1589, 1504,
1463, 1415, 1320, 1237, 1124, 988, 923, 724 cm−1; H NMR (400
1
MHz, CDCl3) δ 6.73 (s, 2H), 6.69 (s, 2H), 6.09 (2 x dddd, J = 17.2,
10.3, 8.1, 6.1 Hz, 2H), 5.86 (dddd, J = 16.9, 10.2, 8.0, 6.3 Hz, 1H),
5.29 (ddt, J = 17.2, 3.5, 1.6 Hz, 2H), 5.17 (br d, J = 10.3 Hz, 2H),
5.03−4.97 (m, 2H), 4.50−4.48 (m, 4H), 3.82 (br s, 12H), 2.58 (tq, J =
6.8, 2.5 Hz, 1H), 2.23 (br.dd, J = 13.8, 5.6 Hz, 1H), 2.14 (s, 1H), 1.84
(br dt, J = 13.8, 8.9 Hz, 1H), 0.90 (d, J = 6.6 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 14.0 (q), 36.2 (t), 40.8 (d), 56.1 (q, 4C), 74.0 (t,
2C), 81.0 (s), 103.1 (d, 2C), 103.2 (d, 2C), 116.1 (t), 117.4 (t), 117.5
(t), 134.5 (d, 2C), 135.2 (s), 135.3 (s), 137.4 (d), 141.8 (s, 2C), 152.9
(s, 2C), 153.0 (s, 2C) ppm; HRMS (m/z) calcd for C28H36O7Na
507.2359, found 507.2317.
(R)-1,1-Bis(4-((tert-butyldimethylsilyl)oxy)-3,5-dimethoxy-
phenyl)-2-methylpent-4-en-1-ol (10). To a solution of PPh3 (13
mg, 0.05 mmol) in EtOH (5 mL) was added Pd(OAc)2 (6 mg, 0.025
mmol) followed by 1,3-dimethylbarbituric acid (213 mg, 1.36 mmol),
and the contents were stirred at rt. After 10 min of stirring, the color of
the solution was changed to orange. At that time, 13 (300 mg, 0.62
mmol) in ethanol (10 mL) was introduced, and stirring was continued
for additional 2 h. As the reaction proceeded, the color of the solution
was changed to red and to blood red. The ethanol was evaporated and
the crude was purified by column chromatography (100−200 silica gel,
40% EtOAc in petroleum ether) to procure compound intermediate
triol (210 mg, 84%) as a pale yellow syrup (Rf = 0.3, 50% EtOAc in
petroleum ether) which was used for the next reaction without any
characterization.
[α]25 = −116 (c 1.44, acetone)] with that of the natural
D
product confirmed the assigned relative configuration and
established the absolute configuration of sacidumlignan B.
Finally, subjecting the dihydronaphthalene intermediate 8 to
a one-pot aromatization with DDQ in CH2Cl2 and desilylation
by adding TBAF gave the sacidumlignan A (1) in 80% yield.
The spectral data of 1 are in complete agreement with the data
reported for the natural product, except for the appearance of
extra phenolic OH peaks, which were confirmed by deuterium
exchange studies.
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To an ice-cooled solution of above triol (500 mg, 1.24 mmol) in
anhydrous DMF (5 mL) were added imidazole (340 mg, 4.9 mmol)
and TBSCl (470 mg, 3.1 mmol), and the mixture was stirred for 1 h at
rt. After the completion of reaction as indicated by TLC, the reaction
mixture was partitioned between water−EtOAc and the aqueous layer
was extracted with EtOAc. The combined organic layer was washed
with brine, dried (Na2SO4), and concentrated under reduced pressure.
The crude was purified by column chromatography (100−200 silica
gel, 10% EtOAc in petroleum ether) to obtain 10 (750 mg, 96%) as
yellow liquid: Rf = 0.8 (30% EtOAc in petroleum ether); [α]25D = −5.8
(c 2.8, acetone); IR (CHCl3) ν 3525, 2933, 2857, 1587, 1511, 1463,
1415, 1328, 1249, 1186, 1131, 914, 838, 782, 753 cm−1; 1H NMR (200
MHz, CDCl3) δ 6.66 (s, 2H), 6.63 (s, 2H), 5.85 (dddd, J = 16.2, 10.8,
7.9, 6.4 Hz, 1H), 5.01−4.93 (m, 2H), 3.75−3.74 (br s, 12H), 2.52 (tq,
J = 6.7, 2.6 Hz, 1H), 2.26 (dd, J = 13.5, 5.8 Hz, 1H), 2.03 (s, 1H), 1.79
(ddd, J = 13.5, 7.9, 4.0 Hz, 1H), 1.00 (s, 18H), 0.89 (d, J = 6.7 Hz,
3H), 0.11 (br s, 12H) ppm; 13C NMR (50 MHz, CDCl3) δ −4.7 (q,
4C), 14.2 (q), 18.7 (s, 2C), 25.8 (q, 6C), 36.5 (t), 41.0 (d), 55.8 (q,
4C), 81.1 (s), 103.7 (d, 2C), 103.8 (d, 2C), 115.9 (t), 132.9 (s), 133.0
(s), 137.8 (d), 138.9 (s, 2C), 151.0 (s, 2C), 151.1 (s, 2C) ppm; HRMS
(m/z) calcd for C34H56O7Si2Na 655.3462, found 655.3469.
6.38 (s, 2H), 3.78 (s, 6H), 3.71 (s, 6H), 3.34−3.26 (m, 1H), 2.75 (dd,
J = 17.2, 7.5 Hz, 1H), 2.34 (dd, J = 17.2, 5.0 Hz, 1H), 1.0 (s, 9H), 0.99
(s, 9H), 0.89 (d, J = 7.0 Hz, 3H), 0.12 (s, 6H), 0.11 (s, 6H) ppm; 13C
NMR (100 MHz, CDCl3) δ −4.7 (q, 4C), 17.2 (q), 18.6 (s, 2C), 25.7
(q, 6C), 37.7 (t), 38.3 (d), 55.7 (q, 2C), 56.0 (q, 2C), 92.7 (s), 103.1
(d, 2C), 104.1 (d, 2C), 133.1 (s), 133.5 (s), 134.4 (s), 135.1 (s), 151.1
(s, 2C), 151.3 (s, 2C), 176.1 (s) ppm; HRMS (m/z) calcd for
C33H52O8Si2Na 655.3099, found 655.3107.
(3R,4R)-5,5-Bis(4-((tert-butyldimethylsilyl)oxy)-3,5-dime-
thoxyphenyl)-3,4-dimethyldihydrofuran-2(3H)-one (6). At −78
°C, a solution of freshly distilled hexamethyldisilazane (0.09 mL, 0.44
mmol) in anhydrous THF (1 mL) was treated with n-BuLi (0.21 mL,
0.33 mmol) and the mixture stirred for 30 min at the same
temperature. To this was introduced a solution of 9 (70 mg, 0.11
mmol) in THF (1 mL). After 1 h of stirring, MeOTf (0.02 mL, 0.17
mmol) was added, and the contents were stirred for an additional 4 h
at −78 °C. The reaction was quenched with satd NH4Cl solution and
allowed to warm to rt. The contents were partitioned between water−
EtOAc. The organic layer was separated, and the aqueous layer
extracted with EtOAc. The combined organic layer was washed with
brine, dried (Na2SO4), and concentrated under reduced pressure. The
crude was purified (230−400 silica gel, 10% EtOAc in petroleum
ether) to procure lactone 6 (67 mg, 94%) as colorless solid by column
chromatography: Rf = 0.5 (20% EtOAc in petroleum ether), mp 116−
(4R)-5,5-Bis(4-((tert-butyldimethylsilyl)oxy)-3,5-dimethoxy-
phenyl)-4-methyltetrahydrofuran-2-ol (15). To a suspension of
compound 10 (250 mg, 0.39 mmol), 2,6-lutidine (0.1 mL, 0.79
mmol), and NaIO4 (127 mg, 0.59 mmol) in dioxane (5 mL)−water (1
mL) was added a solution of OsO4 (2 mg) in toluene (10 μL) and
stirred at rt for 2 h. After completion, the reaction mixture was
partitioned between water and CH2Cl2. The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2. The
combined organic layer was washed with brine, dried (Na2SO4), and
concentrated. Purification of the crude product by silica gel column
chromatography (100−200, 20% EtOAc in petroleum ether) gave 15
(210 mg, 84%) as a colorless syrup: Rf = 0.2 (20% EtOAc in petroleum
117 °C; [α]25 = −60.9 (c 2.3, acetone); IR (CHCl3) ν 2934, 2857,
D
1776, 1588, 1514, 1463, 1338, 1249, 1207, 1131, 914, 839, 782 cm−1;
1H NMR (400 MHz, CDCl3) δ 6.62 (s, 2H), 6.20 (s, 2H), 3.77 (s,
6H), 3.67 (s, 6H), 2.86 (dq, J = 11.8, 6.7 Hz, 1H), 2.43 (dq, J = 11.8,
7.0 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H), 1.03 (d, J = 6.7, 3H), 1.01 (s,
9H), 0.99 (s, 9H), 0.13 (s, 6H), 0.11 (s, 6H) ppm; 13C NMR (100
MHz, CDCl3) δ −4.7 (q, 4C), 13.2 (q), 16.2 (q), 18.6 (s), 18.7 (s),
25.7 (q, 6C), 41.1 (d), 46.2 (d), 55.7 (q, 2C), 56.0 (q, 2C), 91.0 (s),
104.1 (d, 2C), 104.7 (d, 2C), 132.7 (s), 133.7 (s), 134.5 (s), 135.4 (s),
150.9 (s, 2C), 151.2 (s, 2C), 178.7 (s) ppm; HRMS (m/z) calcd for
C34H54O8Si2Na 669.3255, found 669.3254.
((((3R,4R)-3,4-Dimethyltetrahydrofuran-2,2-diyl)bis(2,6-di-
methoxy-4,1-phenylene))bis(oxy))bis(tert-butyldimethylsi-
lane) (16). To an ice-cooled solution of lactone 6 (32 mg, 0.05 mmol)
in THF (1 mL) was added LAH (6 mg, 0.15 mmol) slowly and the
mixture stirred for 30 min at rt. Subsequently, the reaction mixture was
quenched with satd NH4Cl solution and filtered through Celite pad,
and the filtrate was partitioned between water−CH2Cl2. The organic
layer was separated, and the aqueous layer was extracted with CH2Cl2.
The combined organic layer was washed with brine, dried (Na2SO4),
and concentrated under reduced pressure. The resulting crude diol was
directly utilized in the next step without further purification.
A solution of above crude residue in CH2Cl2 (1 mL) was cooled to
0 °C and treated with 7 μL of TFA. Within 5 min, the reaction was
quenched with satd NaHCO3 solution. The layers were separated, and
the aqueous layer was extracted with CH2Cl2. The combined organic
layer was dried (Na2SO4) and concentrated under reduced pressure,
and the resulting residue was purified by column chromatography
(100−200 silica gel, 5% EtOAc in petroleum ether) to afford 16 (28
mg, 89%, two steps) as a colorless solid: Rf = 0.2 for reduction (20%
EtOAc in petroleum ether), 0.8 for cyclization (20% EtOAc in
petroleum ether); mp 72−74 °C; [α]25D = −114.2 (c 1.8, acetone); IR
(CHCl3) ν 2957, 2930, 2857, 1586, 1511, 1463, 1412, 1333, 1249,
1183, 1130, 1040, 915, 838, 782 cm−1; 1H NMR (400 MHz, CDCl3) δ
6.61 (s, 2H), 6.31 (s, 2H), 4.30 (t, J = 7.8 Hz, 1H), 3.76 (s, 6H), 3.67
(s, 6H), 3.48 (dd, J = 10.5, 8.3 Hz, 1H), 2.37 (dq, J = 10.6, 6.8 Hz,
1H), 2.03 (ddq, J = 13.6, 10.6, 7.1 Hz, 1H), 1.02 (d, J = 7.0 Hz, 3H),
1.01 (s, 9H), 0.99 (s, 9H), 0.83 (d, J = 6.8 Hz, 3H), 0.13 (s, 6H), 0.09
(s, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ −4.7 (q, 2C), −4.7 (q,
2C), 14.4 (q), 15.5 (q), 18.7(s), 18.7 (s), 25.8 (q, 6C), 40.6 (d), 49.6
(d), 55.6 (q, 2C), 55.9 (q, 2C), 73.9 (t), 90.9 (s), 104.7 (d, 2C), 105.0
(d, 2C), 132.8 (s), 133.4 (s), 137.7 (s), 139.4 (s), 150.4 (s, 2C), 151.0
(s, 2C) ppm; HRMS (m/z) calcd for C34H56O7Si2H 633.3643, found
633.3628.
ether); [α]25 = −82.5 (c 2.1, acetone); IR (CHCl3) ν 3418, 2932,
D
2857, 1587, 1514, 1463, 1455, 1415, 1337, 1249, 1130, 910, 838, 782,
756 cm−1.
Major isomer: 1H NMR (400 MHz, CDCl3) δ 6.67 (s, 1.4H), 6.29
(s, 1.4H), 5.79 (br t, J = 4.9 Hz, 0.7H), 3.76 (s, 4.5H), 3.68 (s, 4.1H),
3.27 (tq, J = 12.8, 6.9 Hz, 0.8H), 2.46 (d, J = 4.9 Hz, 0.7H), 2.08 (ddd,
J = 12.8, 6.5, 1.4 Hz, 0.7H), 1.94 (ddd, J = 12.8, 9.8, 5.0 Hz, 0.7H),
1.00 (s, 10.3H), 0.99 (s, 8.1H), 0.83 (d, J = 6.9 Hz, 2.3H), 0.12 (s,
6.2H), 0.10 (s, 5.6 H) ppm; 13C NMR (100 MHz, CDCl3) δ −4.7 (q,
2C), −4.6 (q, 2C), 17.0 (q), 18.7 (s, 2C), 25.8 (q, 6C), 39.0 (d), 42.0
(t), 55.7 (q, 2C), 55.9 (q, 2C), 91.6 (s), 98.0 (d), 104.4 (d, 2C), 104.5
(d, 2C), 132.9 (s), 133.5 (s), 136.1 (s), 139.5 (s), 150.6 (s, 2C), 151.0
(s, 2C) ppm.
1
Minor isome:r. H NMR (400 MHz, CDCl3) δ 6.63 (s, 0.6H),
6.60 (s, 0.5H), 5.61 (dd, J = 9.9, 4.7 Hz, 0.3H), 3.75 (s, 1.5H), 3.70 (s,
1.9H), 3.22 (d, J = 4.7 Hz, 0.2H), 2.99 (br st, 0.3H), 2.29 (ddd, J =
13.0, 6.9, 5.6 Hz, 0.3H), 1.77 (ddd, J = 13.0, 7.6, 4.9 Hz, 0.3H), 1.00
(s, 10.3H), 0.99 (s, 8.1H), 0.89 (dd, J = 6.9 Hz, 1H), 0.12 (s, 6.2H),
0.1 (s, 5.6 H) ppm; 13C NMR (100 MHz, CDCl3) δ −4.7 (q, 2C),
−4.6 (q, 2C), 17.6 (q), 18.7 (s, 2C), 25.8 (q, 6C), 40.1 (d), 41.0 (t),
55.7 (q, 2C), 55.9 (q, 2C), 91.9 (s), 97.9 (d), 104.2 (d, 2C), 104.9 (d,
2C), 132.9 (s), 133.5 (s), 136.3 (s), 139.5 (s), 150.5 (s, 2C), 151.0 (s,
2C) ppm; HRMS (m/z) calcd for C33H54O8Si2K 673.2994, found
673.2996.
(R)-5,5-Bis(4-((tert-butyldimethylsilyl)oxy)-3,5-dimethoxy-
phenyl)-4-methyldihydrofuran-2(3H)-one (9). To a solution of
lactols 15 (70 mg, 0.11 mmol) in toluene (5 mL) was added silver
carbonate on Celite (152 mg, 0.55 mmol contains 1 mmol of Ag2CO3
per 0.57 g of prepared reagent). The reaction mixture was refluxed at
130 °C for 2 h in the dark. The reaction mixture was cooled and
filtered, and the filtrate was concentrated under reduced pressure. The
crude product was purified by column chromatography (100−200
silica gel, 15% EtOAc in petroleum ether) to afford 9 (64 mg, 92%) as
a colorless solid: Rf = 0.5 (30% EtOAc in petroleum ether); mp 145−
146 °C; [α]25 = −97.2 (c 3.1, acetone); IR (CHCl3) ν 2997, 2933,
D
2895, 2857, 1767, 1587, 1514, 1463, 1417, 1336, 1249, 1129, 972, 920,
(−)-Sacidumlignan D (4). At 0 °C, a solution of 16 (36 mg, 0.06
mmol) in THF (1 mL) was treated with TBAF (37 mg, 0.14 mmol)
839, 783, 760, 666 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.66 (s, 2H),
1569
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The Journal of Organic Chemistry
Note
and stirred for 30 min. The reaction was quenched with satd NH4Cl
solution and extracted with EtOAc. The combined organic layer was
dried (Na2SO4) and concentrated under reduced pressure. The crude
product was purified by column chromatography (100−200 silica, 40%
EtOAc in petroleum ether) to obtain (−)-sacidumlignan D (4) (22
mg, 96%) as a white amorphous solid: Rf = 0.3 (50% EtOAc in
petroleum ether); mp 150−152 °C; [α]25D = −138.2 (c 1.37, acetone);
IR (CHCl3) ν 3535, 3429, 3009, 2962, 2936, 2873, 2840, 1614, 1515,
of 8 (20 mg). Usual workup and purification by column
chromatography gave (−)-sacidumlignan B (2) (12 mg, 95%) as a
colorless solid: Rf = 0.5 (50% EtOAc in petroleum ether); [α]25
=
D
−65.9 (c 0.8, acetone); IR (CHCl3) ν 3510, 3439, 2956, 2928, 2846,
1
1722, 1613, 1514, 1459, 1314, 1209, 1111, 757, 661 cm−1; H NMR
(400 MHz, acetone-d6) δ 7.31 (s,1H), 6.95 (s, 1H), 6.50 (s, 1H), 6.46
(d, J = 1.2 Hz, 1H), 6.42 (s, 2H), 3.81 (s, 3H), 3.74 (s, 3H), 3.71 (s,
6H), 3.67 (d, J = 3.0 Hz, 1H), 2.41 (dq, J = 7.0, 3.0, 1H), 1.82 (d, J =
1.2 Hz, 3H), 1.05 (d, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz,
acetone-d6) δ 18.9 (q), 22.7 (q), 42.5 (d), 52.0 (d), 52.0 (q), 56.4 (q,
2C), 60.9 (q), 105.9 (d, 2C), 109.4 (d), 116.1 (d), 121.4 (s), 127.1 (s),
135.1 (s), 137.1 (s), 138.8 (s), 139.1 (s), 143.9 (s), 147.8 (s), 148.3 (s,
2C) ppm; HRMS (m/z) calcd for C22H26O6Na 409.1627, found
409.1639.
1
1455, 1327, 1215, 1115, 1050, 1008, 912, 840, 753, 666 cm−1; H
NMR (400 MHz, acetone-d6) δ 7.17 (s, 1H), 7.06 (s, 1H), 6.78 (s,
2H), 6.53 (s, 2H), 4.26 (t, J = 7.7 Hz, 1H), 3.80 (s, 6H), 3.73 (s, 6H),
3.33 (dd, J = 10.1, 8.2 Hz, 1H), 2.42 (dq, J = 9.6, 6.9 Hz, 1H), 2.04−
1.94 (m, 1H), 0.98 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H) ppm;
13C NMR (100 MHz, acetone-d6) δ 15.4 (q), 17.0 (q), 42.3 (d), 51.1
Sacidumlignan A (1). A solution of 8 (8 mg, 0.013 mmol) and
DDQ (5 mg, 0.02 mmol) in CH2Cl2 (1 mL) were stirred at room
temperature and under argon atmosphere. After 5 min, TBAF (9 mg,
0.032 mmol) was added and the mixture stirred for 10 min and then
quenched with satd NH4Cl solution. Usual workup followed by
chromatographic purification (100−200 silica gel, 25% EtOAc in
petroleum ether) gave sacidumlignan A (1) (4 mg, 80%) as a colorless
solid: Rf = 0.5 (50% EtOAc in petroleum ether); IR (CHCl3) ν 3543,
3439, 2957, 2925, 2853, 1722, 1611, 1518, 1464, 1288, 1215, 1116,
(d), 56.9 (q, 2C), 57.0 (q, 2C), 74.2 (t), 91.5 (s), 106.0 (d, 2C), 106.4
(d, 2C), 135.7 (s), 136.2 (s), 137.1 (s), 139.4 (s), 148.0 (s, 2C), 148.4
(s, 2C) ppm; HRMS (m/z) calcd for C22H28O7H 405.1913, found
405.1900.
(2R,3S)-4,4-Bis(4-((tert-butyldimethylsilyl)oxy)-3,5-dime-
thoxyphenyl)-2,3-dimethylbutan-1-ol (7). The reduction of
lactone 6 with LAH was carried out according to the procedure
used for the preparation of compound 16. After that, the crude residue
was directly employed in the next step without further purification. At
0 °C, a solution of the above crude product (55 mg) in CH2Cl2 (1
mL) was treated slowly with Et3SiH (0.07 mL, 0.43 mmol) followed
by BF3·Et2O (0.03 mL, 0.25 mmol) and stirred for 5 min before
quenching with satd NaHCO3 solution, and the aqueous layer was
extracted with CH2Cl2. The combined organic layer was dried
(Na2SO4) and concentrated under reduced pressure, and the crude
was purified by column chromatography (100−200 silica gel, 25%
EtOAc in petroleum ether) to afford the alcohol 7 (40 mg, 74%) as
colorless oil and the compound 16 (6 mg, 11%): Rf = 0.4 for 7, 0.7 for
16 (20% EtOAc in petroleum ether); [α]25D = −16.7 (c 3.4, acetone);
IR (CHCl3) ν 3450, 2956, 2934, 2857, 1588, 1508, 1465, 1421, 1330,
1248, 1127, 1037, 913, 834, 784 cm−1; 1H NMR (500 MHz, CDCl3) δ
6.50 (s, 2H), 6.47 (s, 2H),3.76 (s, 12H), 3.47 (dd, J = 10.6, 8.4 Hz,
1H), 3.44 (dd, J = 10.6, 6.4 Hz, 1H), 3.42 (d, J = 11.4 Hz, 1H), 2.50
(ddq, J = 11.4, 6.8, 2.1 Hz, 1H), 1.77−1.69 (m, 1H), 1.64 (br s, 1H),
0.99 (br s, 18H), 0.75 (d, J = 6.9 Hz, 3H), 0.65 (d, J = 6.8 Hz, 3H),
0.11 (br s, 6H), 0.10 (s, 6H) ppm; 13C NMR (125 MHz, CDCl3) δ
−4.6 (q, 2C), − 4.7 (q, 2C), 9.8 (q), 11.8 (q), 18.7 (s, 2C), 25.8 (q,
6C), 36.2 (d), 36.3 (d), 55.8 (q, 2C), 55.9 (q, 2C), 56.7 (d), 67.0 (t),
105.3 (d, 2C), 105.4 (d, 2C), 132.6 (s, 2C), 136.9 (s), 137.4 (s), 151.2
(s, 2C), 151.3 (s, 2C) ppm; HRMS (m/z) calcd for C34H58O7Si2Na
657.3619, found 657.3571.
1
911, 759 cm−1; H NMR (400 MHz, acetone-d6) δ 7.77 (s, 1H), 7.73
(s, 1H), 7.32 (s, 1H), 6.58 (s, 1H), 6.49 (s, 2H), 3.97 (s, 3H), 3.84 (s,
6H), 3.67 (s, 3H), 2.45 (s, 3H), 2.11 (s, 3H) ppm; 13C NMR (100
MHz, acetone-d6) δ 17.6 (q), 21.4 (q), 55.9 (q), 56.7 (q, 2C), 60.7
(q), 101.8 (d), 106.2 (d, 2C), 120.5 (d), 123.9 (s), 127.4 (s), 131.7
(s), 131.8 (s), 133.7 (s), 135.7 (s), 138.1 (s), 138.7 (s), 140.7 (s),
148.9 (s, 2C), 149.1 (s) ppm; HRMS (m/z) calcd for C22H24O6Na
407.1471, found 407.1442.
ASSOCIATED CONTENT
* Supporting Information
■
S
1H, 13C, DEPT NMR and LR-/HRMS of all new compounds,
LC chromatograms for (−)-sacidumlignan D (4) and
( )-sacidumlignan D, and COSY and NOESY of (−)-saci-
dumlignan B (2). This material is available free of charge via the
Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
*E-mail: vr.chepuri@ncl.res.in.
■
tert-Butyl(((5R,6S)-5-(4-((tert-butyldimethylsilyl)oxy)-3,5-di-
methoxyphenyl)-1,3-dimethoxy-6,7-dimethyl-5,6-dihydro-
naphthalen-2-yl)oxy)dimethylsilane (8). A suspension of 7 (35
mg, 0.06 mmol) and IBX (24 mg, 0.08 mmol) in EtOAc (5 mL) was
refluxed for 1 h. The reaction mixture was cooled to room temperature
and was filtered through Celite. The resulting aldehyde was dissolved
in toluene (1 mL) and treated with p-TSA (0.5 mg, 0.002 mmol, 5 mol
%). After being stirred at rt for 15 min, the reaction mixture was
concentrated, and the residue was purified by column chromatography
(100−200 silica gel, 5% EtOAc in petroleum ether) to afford 8 (27
mg, 80% in two steps) as a colorless syrup: Rf = 0.6 (10% EtOAc in
ACKNOWLEDGMENTS
■
Dedicated to Dr. Mukund K. Gurjar on the occasion of his 60th
birthday. We thank the NCL-IGIB Joint Research Initiative
Program (CSIR-NWP-0013) for funding. Financial support
from CSIR (New Delhi) in the form of a research fellowship to
J.K.R. is gratefully acknowledged.
REFERENCES
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1.2 Hz, 1H), 6.29 (s, 1H), 6.23 (s, 2H), 3.78 (s, 3H), 3.67 (br s, 9H),
3.60 (d, J = 4.3 Hz, 1H), 2.38 (dq, J = 7.0, 4.3 Hz, 1H), 1.78 (d, J = 1.2
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the preparation of compound 4 was followed for the silyl deprotection
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The Journal of Organic Chemistry
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