Total synthesis of (±)-sacidumlignan D

Article abstract of DOI:10.1021/jo1025749

The first total synthesis of (±)-sacidumlignan D featuring a Zn-mediated Barbier reaction and reverse Wacker oxidation to form the key γ-lactone, its diastereoselective α-methylation followed by reduction cyclization, was documented.

Full text of DOI:10.1021/jo1025749

NOTE
pubs.acs.org/joc
Total Synthesis of (()-Sacidumlignan D§
Sunil Kumar Pandey and C. V. Ramana*
National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
S Supporting Information
b
ABSTRACT: The first total synthesis of (()-sacidumlignan D
featuring a Zn-mediated Barbier reaction and reverse Wacker
oxidation to form the key γ-lactone, its diastereoselec-
tive R-methylation followed by reduction cyclization, was
documented.
n 2005, four new lignans, namely sacidumlignans A-D, were
isolated from the ethanolic extract of the whole plant of Sarcos-
The resulting fully elaborated key lactone 2 can be transformed
to sacidumlignan D (1) by carbonyl reduction and cyclization.
On the other hand, it is anticipated that subjecting 2 to Friedel-
Crafts conditions would lead to di- and tetrahydronaphthalenes
which could be used for the synthesis of other sacidumlignans.
The synthesis of lactone 3 was planned via crotylation of
benzophenone derivatives 5 under Barbier conditions and sub-
sequent hydroboration and oxidation. The synthesis of benzo-
phenone 5 has been identified as the intermediate goal in the
synthesis of sacidumlignan D.5 Initially, allyl protection for the
4,40-hydroxy groups of 5 has been opted, keeping in mind that it
is stable under a variety of conditions. The synthesis of 5-diallyl
was intended from the addition of lithiated 6 to amide 7.6
The synthesis of the coupling partner 6 started with the protection
of the free -OH of known bromo-o-vanillin 87 as its allyl ether by
using allyl bromide and K2CO3 in the presence of phase transfer
catalyst (TBAI) affording 9. After examining various reagents and
conditions, the Baeyer-Villiger oxidation of 9 was found to be facile
with m-CPBA in dichloromethane and the desired phenol 10 was
obtained in good yield.8 Treatment of 10 with K2CO3 and MeI
afforded the key bromo derivative 6. Synthesis of the coupling partner
7 was begun from commercially available syringic acid. Initial
allylation attempts with K2CO3 and allyl bromide in DMF resulted
in the isolation of a C-allylated product 11 along with the desired O-
allylated product 12, in a 3:1 ratio.9 When NaH was used as a base in
the presence of phase transfer catalyst TBAI, the allylation proceeded
smoothly to give 11 exclusively. Hydrolysis of 11 with aq KOH
followed by coupling of the resulting acid 13 with morpholine gave
the key amide partner 7 (Scheme 1).
I
temma acidum (Roxb.) collected from the Hainan Island of China.1
The structure and the relative configuration of these four new
compounds were elucidated by employing extensive 2D NMR
spectroscopic techniques. Sacidumlignan D (1) was identified with
a novel rearranged lignan skeleton and showed promising antimi-
crobial activities against Grampositive bacteria in vitro. Sacidum-
lignan D (1) is closely related to eupomatilones—another class of
neolignans with unusual biaryl skeleton having a butyrolactone with
C(2)-C(3)-dimethyl substituents.2 We have recently documented
the total synthesis of a putative structure and later the synthesis of
the unnatural eupomatilone-6 enantiomer.3,4
Our next concern was the synthesis of 5-diallyl. The treatment of 6
with nBuLi followed by addition of the amide 7 in excess (5 equiv)
afforded the required benzophenone derivative 5-diallyl and the
triarylcarbinol 14 along with the dehalogenated compound. The
deallylation of 5-diallyl with use of N,N0-dimethylbarbituric acid in the
presence of Pd(OAc)2 and triphenylphosphine gave 5 in good
yield.10
Eupomatilone-6 also presents trans-C(2)-C(3)-dimethyl sub-
stituents on the lactone ring and this has been addressed by a
diastereoselective R-methylation of a suitable lactone. Consider-
ing its unusual neolignan skeleton and its structural similarity
with that of eupomatilone-6, the total synthesis of sacidumlignan
D has been undertaken. Figure 1 provides the key retrosynthetic
disconnections. The planned total synthesis of sacidumlignan D
involves diastereoselective methylation of lactone 3 as a key step.
Received: December 28, 2010
Published: March 09, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
NOTE
Scheme 2. Synthesis of des-Sacidumlignan
The next task was the hydroboration-oxidation of homo-
allylic alcohol 4 to obtain a diol. Surprisingly, the hydroboration-
oxidation of 4 furnished the furan derivatve 16 (8-desmethyl-
sacidumulignan D) exclusively (Scheme 2). Various other
alternatives attempted in this regard met with failure. This
undesired cyclization prior to the oxidation has prompted us to
modify our synthetic strategy. A reverse Wacker oxidation of a
suitably protected homoallylic alcohol was planned to secure a
lactol that could be further oxidized to the requisite lactone.12
The revised synthetic strategy had as first step the crotylation
of 5-diAc. The Barbier reaction of 5-diAc under standard condi-
tions proceeded smoothly and homoallylic alcohol 17 was
obtained in excellent yields. A comparison of Barbier reaction
of 5 and its two derivatives indicates the influence of the
protecting group of the 4-OH group on the outcome of the
reaction. Next, after exploring various conditions,12b the reverse
Wacker oxidation of 17 was found to be promising with
Pd(CH3CN)2(Cl)(NO2), CuCl2, and O2.13 However, the reac-
tion gave a 1:1 mixure of lactols 18 and its t-Bu acetals 19. The
acetals 19 were hydrolyzed with TFA in CH2Cl2 to afford the
lactols 18 in quantitative yield. The oxidation of lactols 18 was
carried out by Celite supported silver carbonate to obtain the
lactone 20.14 Compound 20 was converted to the key lactone 3
by deacetylation, using K2CO3 in methanol followed by repro-
tection of both the resulting phenolic-OH with TBSCl. After
exploring different electrophiles, the diastereoselective methyla-
tion at C(3) of lactone 3 was successfully conducted by using
MeOTf and LiHMDS as a base to afford 2.15 Our next task was
the sequential reduction of the lactone, cyclization, and TBS
deprotection. As expected, the initially formed diol after the reduction
of lactone 2 with LAH, cyclized partially during the workup and
treatment of the crude with cat. TFA in dichloromethane, provides
exclusively the TBS-protected sacidumlignan 21. Finally, the desilyla-
tion of 21 with TBAF in THF gave sacidumlignan D (1, Scheme 3).
The spectral and the analytical data of 1 were in good agreement with
data reported for natural sacidumlignan D.
Figure 1. Key retrosynthetic disconnections.
Scheme 1. Synthesis and Coupling of 6 and 7
The crotylation of 5 was attempted in the next step. Under
various Barbier conditions explored, the ketone 5 was found to be
intact even after prolonged exposure.11 However, with the diallyl
derivative 5-diallyl, the Barbier reaction proceeded smoothly and
gave the requisite homoallylic alcohol 15 in respectable yields.
The selective di-O-deallylation of 15 could be carried out
employing Pd(OAc)2 in the presence of N,N0-dimethylbarbituric
acid; however, the yield was poor.
To conclude, the first total synthesis of (()-sacidumlignan D
has been completed. The adopted approach features the crotyla-
tion of a benzophenone and the reverse Wacker oxidation to
construct the central tetrahydrofuran framework and the diaster-
eoselective C(2)-methylation of intermediate butyro-lactone to
address the requisite trans-geometry of the C(2)- and C(3)-
methyl substituents.
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The Journal of Organic Chemistry
NOTE
Scheme 3. Total Synthesis of (()-Sacidumlignan D
’ EXPERIMENTAL SECTION
(s), 150.9 (s, 2C), 151.2 (s, 2C), 178.8 (s); ESI-MS m/z 669.4 (100%,
[M þ Na]þ). Anal. Calcd for C34H54O8Si2: C, 63.12; H, 8.41. Found: C,
63.42; H, 8.29.
0
4,4 -(3-Methyl-5-oxotetrahydrofuran-2,2-diyl)bis(2,6-dimethoxy-
4,1-phenylene) Diacetate (20). A suspension of lactols 18 (800 mg, 1.63
mmol) and Ag2CO3 impregnated on Celite (1.35 g, 4.89 mmol, contains 1 mmol
of Ag2CO3per 0.57 g of prepared reagent) in toluene (40 mL) was heated at reflux
for 3 h. The reaction mixture was cooled to room temperature and filtered through
a pad of Celite and the Celite pad was washed with ethyl acetate (3 ꢀ 30mL).The
combined filtrate was concentrated under reduced pressure and purified by silica gel
column chromatography (35% ethyl acetate in petroleum ether) to afford lactone
20 (600 mg, 76%) as a colorless crystalline solid.
(3R/3S,4R/3S)-3,4-(Dimethyltetrahydrofuran-2,2-diyl)bis(2,6-
dimethoxy-4,1-phenylene)bis(oxy)bis(tert-butyldimethylsilane)
(21). To a solution of diTBS lactone 2 (50 mg, 154.6 μmol) in anhydrous
THF (2 mL) at 0 °C was slowly added LAH (26 mg, 0.62 mmol). The
reaction mixture was vigorously stirred for 1 h. The reaction mixture was
quenched with saturated ammonium chloride and filtered through Celite
and the filtrate was diluted by EtOAc, washed with water and brine, dried
(Na2SO4), and concentrated. At 0 °C, a solution of the above crude product
in dry CH2Cl2 (2mL) wastreatedwithTFA(20μL) and the contents were
stirred for 5 min. The reaction mixture was quenched with sat. NaHCO3
and the organic phase was washed with water and brine, dried (Na2SO4),
and concentrated under reduced pressure. The crude was purified by silica
gel chromatography (10% ethyl acetate in petroleum ether) to give cyclized
product 21 (30 mg, 78%) as a colorless solid.
Mp 211-212 °C; IR (CHCl3) ν 3020, 2941, 2842, 1767, 1605, 1508,
1
1463, 1417, 1369, 1338, 1211, 1176, 1133, 759, 666 cm-1; H NMR
(200 MHz, CDCl3) δ 6.77 (s, 2H), 6.55 (s, 2H), 3.82 (s, 6H), 3.77 (s,
6H), 3.39-3.30 (m, 1H), 2.77 (dd, J = 12.8, 3.5 Hz, 1H), 2.35 (m, 1H),
2.33 (s, 3H), 2.32 (s, 3H), 0.93 (d, J = 6.9 Hz, 3H); 13C NMR (50 MHz)
δ 17.1 (q), 20.3 (q, 2C), 37.5 (t), 38.3 (d), 56.1 (q, 2C), 56.2 (q, 2C),
91.8 (s), 102.2 (d, 2C), 103.0 (d, 2C), 127.8 (s), 128.5 (s), 138.3 (s),
140.6 (s), 151.8 (s, 2C), 152.0 (s, 2C), 168.4 (s), 168.4 (s), 175.3 (s);
ESI-MS m/z 511.2 (100%, [M þ Na]þ), 527 (14%, [M þ K]þ), 506
(9%, [M þ H2O]þ), 469 (29%, [M - H - H2O]þ). Anal. Calcd for
C25H28O10: C, 61.47; H, 5.78. Found: C, 61.53; H, 5.91.
(3R/3S,4R/3S)-5,5-Bis(4-((tert-butyldimethylsilyl)oxy)-3,5-dim-
ethoxyphenyl)-3,4-dimethyldihydrofuran-2(3H)-one (2).
At -78 °C, a solution of diTBS-derivative 3 (100 mg, 0.158 mmol) in
anhydrous THF (1 mL) was treated with LiHMDS (1 M solution in THF,
1.55 mL), the contents were then stirred at the same temperature for 1 h and
treated with MeOTf (18 μL, 0.158 mmol), and the stirring was continued
for additional 2 h at -78 °C. The reaction mixture was warmed to rt and
quenched with saturated ammonium chloride, extracted with ethyl acetate,
washed with brine, dried (Na2SO4), and concentrated. The crude was
purified by silica gel chromatography (10% ethyl acetate in petroleum
ether) to afford 2 (66 mg, 65%) as a colorless crystalline solid.
Mp 114-117 °C; IR (CHCl3) ν 3019, 2966, 2931, 2875, 1620, 1583,
1489, 1446, 1383, 1335, 1223, 1082, 1048, 1030, 928, 845, 757, 669 cm-1
;
1H NMR (200 MHz, CDCl3) δ 6.62 (s, 2H), 6.32 (s, 2H), 4.30 (t, J = 7.8
Hz, 1H), 3.76 (s, 6H), 3.67 (s, 6H), 3.48 (dd, J = 10.5, 8.4 Hz, 1H),
2.37 (dq, J = 10.6, 6.8 Hz, 1H), 2.04 (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 = 6.7 Hz,
3H), -0.13 (s, 6H), -0.09 (s, 6H); 13C NMR (50 MHz) δ -4.7 (q,
4C), 14.5 (q), 15.6 (q), 18.7 (s, 2C), 25.8 (q, 6C), 40.6 (d), 49.6 (d),
55.6 (q, 2C), 56.0 (q, 2C), 73.9 (t), 90.9 (s), 104.8 (d, 2C), 105.0 (d,
2C), 132.9 (s), 133.5 (s), 137.7 (s), 139.5 (s), 150.5 (s, 2C), 151.0 (s,
2C) ppm; ESI-MS m/z 655.3 (100%, [M þ Na]þ). Anal. Calcd for
C34H56O7Si2: C, 64.51; H, 8.92. Found: C, 64.60; H, 8.79.
(()-Sacidumlignan D (1). Compound 21 (30 mg) was dissolved
in dry THF (0.5 mL) and treated with TBAF (27 mg 0.66 mmol) at 0 °C.
After the mixture was stirred for 10 min at the same temperature, the
reaction mixture was quenched with saturated ammonium chloride,
extracted with EtOAc (2 ꢀ 5 mL), washed with brine, and dried over
Na2SO4 then solvent was evaporated under reduced pressure. The crude
residue was purified by silica gel column chromatography by eluting with
light petroleum ether/ethyl acetate (40% ethyl acetate in petroleum
ether) to procure sacidumlignan D (1) (15 mg, 89%) as a colorless solid.
Mp 149-153 °C; IR (CHCl3) ν 3025, 2927, 2847, 1565, 1514, 1457,
1406, 1327, 1253, 1121, 785 cm-1; 1H NMR (400 MHz, CD3COCD3)
δ 7.21 (s, 1H), 7.11 (s, 1H), 6.79 (s, 2H), 6.54 (s, 2H), 4.30 (t, J = 7.7 Hz,
Mp 172-174 °C; IR (CHCl3) ν 3023, 2930, 2850, 1760, 1590, 1515,
1465, 1412, 1334, 1248, 1126, 780 cm-1; 1H NMR (200 MHz, CDCl3)
δ 6.61 (s, 2H), 6.20 (s, 2H), 3.76 (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), 1.28 (d, J = 7.0 Hz, 3H), 1.03
(d, J = 6.7 Hz, 3H), 1.01 (s, 9H), 0.99 (s, 9H), -0.13 (s, 6H), -0.11
(s, 6H); 13C NMR (50 MHz) δ -4.7 (q, 4C), 13.2 (q), 16.2 (q), 18.7
(s, 2C), 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), 104.8 (d, 2C), 132.7 (s), 133.7 (s), 134.5 (s), 135.5
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NOTE
1H), 3.81 (s, 6H), 3.74 (s, 6H), 3.34 (dd, J = 10.1, 8.2 Hz, 1H), 2.43 (dq,
J = 9.6, 6.9 Hz, 1H), 2.04-1.94 (m, 1H), 0.99 (d, J = 6.5 Hz, 3H), 0.87
(d, J = 6.9 Hz, 3H); 13C NMR (50 MHz) δ 15.4 (q), 17.1 (q), 42.3 (d),
51.2 (d), 56.9 (q, 2C), 57.1 (q, 2C), 74.3 (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; ESI-MS m/z 427.2 (29%, [M þ Na]þ), 405.4
(100%, [M þ 1]þ). Anal. Calcd for C22H28O7: C, 65.33; H, 6.98. Found:
C, 65.25; H, 7.11.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, full
b
characterization for all new compounds, and 1H, 13C NMR, and
MS spectra for selected compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) Uenishi, J.; Tatsumi, Y.; Kobayashi, N.; Yonemitsu, O. Tetra-
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: vr.chepuri@ncl.res.in.
’ ACKNOWLEDGMENT
We thank the Ministry of Science and Technology for funding
through the Department of Science and Technology under the
Green Chemistry Program (No. SR/S5/GC-20/2007). S.K.P.
thanks CSIR, New Delhi for the financial assistance in the form of
a research fellowship.
’ DEDICATION
§Dedicated to Professor M. Nagarajan on the occasion of his 60th
birthday.
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