Synthetic studies towards NG-121: Diastereoselective synthesis of NG-121 methyl ether

Article abstract of DOI:10.1055/s-0032-1317544

Starting from unsymmetrically O-protected methyl 4-bromo-3,5- dihydroxybenzoate, a facile synthesis of the methyl ether of bioactive natural product NG-121 was accomplished in very good overall yield. The key steps were: Stille coupling reaction of the farnesyl unit with the electron-rich phenolic segment; hydroxy-directed selective epoxidation of the farnesyl chain along with concomitant phenol-driven intramolecular regio- and diastereoselective ring closure to the corresponding hydroxybenzopyran; and regioselective formylation followed by in situ reductive lactonization. Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317544

PAPER
▌3797
paper
Synthetic Studies towards NG-121: Diastereoselective Synthesis of NG-121
Methyl Ether
Diastereoselective Synthesis of NG-121 Methyl Ether
Mandeep Singh, Narshinha P. Argade*
Division of Organic Chemistry, National Chemical Laboratory (CSIR), Pune 411 008, India
Fax +91(20)25902629; E-mail: np.argade@ncl.res.in
Received: 27.09.2012; Accepted after revision: 19.10.2012
from Stachybotrys (SC-710-1) and possess antibacterial
Abstract: Starting from unsymmetrically O-protected methyl 4-
and antifungal activity.3 SMTP congeners were isolated
bromo-3,5-dihydroxybenzoate, a facile synthesis of the methyl
from Stachybotrys microspora and are effective plasmin-
ether of bioactive natural product NG-121 was accomplished in
very good overall yield. The key steps were: Stille coupling reaction
ogen modulators.4 Retrobiogenetically, Nature may be
of the farnesyl unit with the electron-rich phenolic segment; hy- utilizing 3,4-dihydroxyphthalide, farnesal, an appropriate
droxy-directed selective epoxidation of the farnesyl chain along
with concomitant phenol-driven intramolecular regio- and diastere-
oselective ring closure to the corresponding hydroxybenzopyran;
model skeleton and the stachybotrin A–C core structure
and regioselective formylation followed by in situ reductive lactoni-
zation.
amine/amino acid, and enzymes to design these novel
multifunctional architectures. A synthesis of the NG-121
have been reported by Inoue et al., respectively utilizing
[2,3]-sigmatropic rearrangement of a sulfur ylide and the
Key words: 4-bromo-3,5-dihydroxybenzoate, Stille coupling, in-
Mannich reaction/Claisen rearrangement as the key
tramolecular cyclization, formylation, lactonization, NG-121 meth-
yl ether
steps.5,6 However, total syntheses of these target com-
pounds have not yet been accomplished and this is imper-
ative from the point of view of advanced biological
screenings. The real challenges in the synthesis of these
A large number of structurally interesting and biologically
natural products are: (i) regioselective introduction of
important natural and unnatural benzopyrans are known
farnesyl unit, (ii) stereoselective creation of two adjacent
in the literature.1 Naturally occurring, novel multifunc-
asymmetric carbon centers in the chromane ring, (iii) lac-
tional NG-121 and stachybotrin C were isolated from the
tonization with the regioselective introduction of a formyl
culture broth of Stachybotrys parvispora F-47082 (Figure
group, and (iv) preservation of the C=C bonds throughout
1).
the sequence. In continuation of our studies on selective
couplings of phenolic substrates with long-chain hydro-
OH
carbons and their application in the synthesis bioactive
OH
natural products,7 we herein report the first synthesis of
NG-121 methyl ether (Schemes 1–3).
O
O
O
OH
OH
NG-121
OH
R2
O
O
OH
O
OH
O
O
4,6-dihydroxyiso-
benzofuran-1(3H)-one
(E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-5-hydroxy-
2-methyl-2H-furo[3,4-h]chromen-7(9H)-one (A)
O
O
N
R1
stachybotrin A (R1 = H, R2 = OH)
stachybotrin B (R1 = R2 = H)
O
known
stachybotrin C (R1 = C2H4C6H4OH, R2 = H)
SMTP congeners (R1 = alkyl/aryl/amino acid moieties, R2 = H)
(ref. 7d)
O
OH
Figure
1
Naturally occurring multifunctional bioactive
O
chromanols2–4
(E)-7-(4,8-dimethylnona-3,7-dien-1-yl)-4-hydroxy-
7-methyl-3,7-dihydro-1H-furo[3,4-f]chromen-1-one (B)
NG-121 has been effective against Alzheimer’s disease,
while stachybotrin C prevents hypoxic neuronal injury
caused by ischemia.2 Stachybotrin A and B were isolated
Scheme 1 Reported regioselective coupling of 4,6-dihydroxy-
phthalide and farnesal
Retrosynthetically, regioselective condensation of 4,6-di-
hydroxyphthalide with farnesal to constitute benzopyran
A (Scheme 1), followed by selective hydroxy-directed
SYNTHESIS 2012, 44, 3797–3804
Advanced online publication: 31.10.2012
DOI: 10.1055/s-0032-1317544; Art ID: SS-2012-Z0764-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

3798
M. Singh, N. P. Argade
PAPER
epoxidation and oxirane ring opening with metal hydride of the formyl unit. The reaction of symmetrical amide 5
would formulate a concise approach to NG-121. Howev- with tert-butyllithium and N,N-dimethylformamide selec-
er, as depicted in Scheme 1, the reaction of 4,6-dihy- tively yielded the desired mono-formylated benzaldehyde
droxyphthalide with farnesal is known to produce the derivative 6 in 85% yield. Sodium cyanoborohydride re-
regioisomer B.7d Hence, we decided to initiate our synthe- duction of benzaldehyde derivative 6 to the corresponding
sis with an appropriate resorcinol derivative, introducing intermediate benzyl alcohol and in situ lactonization fur-
the farnesyl unit first and then stepwise lactonization fol- nished the required phthalide 7 in 81% yield. Selective
lowed by chromanol generation (Scheme 2). The symmet- mono-MOM deprotection of compound 7 was studied us-
rically double MOM-protected benzyl alcohol 1 on ing known literature protocols (CSA/MeOH, 2 M
selective o-lithiation using tert-butyllithium as the base HCl/MeOH, CBr4/i-PrOH,9a I2/MeOH9b). Unfortunately,
followed by reaction with farnesyl bromide gave the de- all attempts were unsuccessful and resulted in double-
sired coupling product 2 in 62% yield. Pyridinium chloro- MOM deprotection to yield the farnesylated dihy-
chromate oxidation of benzyl alcohol 2 to the droxyphthalide 8 in 62% yield. Plausibly the mono-MOM
corresponding aldehyde 3 (88%) and subsequent Pinnick deprotected intermediate under goes second deprotection
oxidation (NaClO2/NaH2PO4)8 provided the required car- at a rate faster than the starting material itself. Alas, mono-
boxylic acid 4 in 95% yield. At this stage, for selectivity MOM protection of biphenolic compound 8 using differ-
reasons it appeared appropriate to generate the lactone ent molar concentrations of MOMCl also resulted in di-
ring first by applying the o-formylation strategy. N-(3-Di- MOM-protected compound 6 as the major product. The
methylaminopropyl)-N′-ethylcarbodiimide hydrochloride hydroxy-directed vanadyl acetylacetonate catalyzed se-
(EDCI) induced coupling of carboxylic acid 4 with dieth- lective epoxidation conditions developed by Lattanzi et
ylamine gave the appropriate amide 5 for the introduction al.10 to obtain the chromanol were extended to biphenolic
OMOM
OMOM
t-BuLi, TMEDA
CuBr⋅Me2S
OMOM
PCC, CH2Cl2, 25 °C
3 h (88%)
H
farnesyl bromide
OMOM
OMOM
OMOM
OMOM THF, –20 °C, 2 h
(62%)
O
OH
OH
3
2
1
H
N
OMOM
NaH2PO4, NaClO2
2-methylbut-2-ene
EDCI, HOBt, DIPEA, CH2Cl2
25 °C, 24 h (78%)
N
HO
t-BuOH–H2O (5:1)
OMOM
OMOM
25 °C, 8 h (95%)
O
O
4
5
OMOM
t-BuLi, THF
–78 °C, 15 min
CSA, MeOH
25 °C, 24 h
NaBH3CN
MeOH–AcOH
OMOM
N
DMF, 24 h
(85%)
OMOM
(62%)
100 °C, 2 h
O
CHO
(81%)
O
OMOM
6
O
7
OH
OH
O
O
OH
VO(acac)2
TBHP
O
( )-NG-121 (9)
or
O
OH
TFA, CH2Cl2
25 °C, 1 h
OH
O
OH
8
O
O
O
( )-10
Scheme 2 Attempted synthesis of chromanol (±)-NG-121
Synthesis 2012, 44, 3797–3804
© Georg Thieme Verlag Stuttgart · New York

PAPER
Diastereoselective Synthesis of NG-121 Methyl Ether
3799
compound 8 in an attempt diastereoselectively synthesize the yield of the desired Stille coupling product 14 to 70%.
either the (±)-NG-121 (9) or its regioisomer 10; however, As described in Scheme 2, o-formylation of ether 14 was
all attempts met with failure and the highly reactive biphe- planned for the generation of the requisite γ-lactone moi-
nolic substrate 8 underwent instantaneous excessive de- ety. However, tert-butyllithium/N,N-dimethylformamide
composition.
driven o-formylation of methyl and MOM ether protected
unsymmetrical amide 14 was unselective and resulted in
the formation of a mixture of the corresponding desired
and undesired isomeric benzaldehyde derivatives utilizing
To circumvent the above-mentioned difficulty involved in
selective MOM-deprotection, we altered our plans and de-
cided to commence the synthesis with the unsymmetrical
methyl benzoate derivative 11 containing two different
protecting groups, the methyl and MOM ethers (Scheme
3). The base-catalyzed hydrolysis of ester 11 to give cor-
responding carboxylic acid 12 (99%) followed by N-(3-
dimethylaminopropyl)-N′-ethylcarbodiimide hydrochlo-
ride induced coupling with diethylamine provided the ap-
propriate amide 13 in 95% yield. Palladium-catalyzed
Stille coupling reaction of electron-rich bromoresorcinol
derivative 13 with tributyl(farnesyl)tin furnished the re-
quired coupling product 14, but in 10–15% yield only.11
However, as according to the literature report,12 addition
of cesium fluoride (2.0 equiv) as an accelerator improved
1
both the available o-positions (3:2, by H NMR). Hence
deprotection of the MOM group was planned to generate
the chromanol and then the formyl unit would be intro-
duced. Camphorsulfonic acid driven selective MOM de-
protection of compound 14 gave the desired phenol 15 in
88% yield. The hydroxy-directed vanadyl acetylaceto-
nate/tert-butyl hydroperoxide (TBHP) mediated regiose-
lective epoxidation of the C2=C3 bond in the farnesyl
chain followed by concomitant regio- and diastereoselec-
tive intramolecular oxirane ring opening exclusively
formed the pair of chromanol enantiomers (±)-16 in 73%
yield.
OMe
OMe
OMe
H
N
Br
aq KOH, MeOH
25 °C, 8 h
Br
Br
SnBu3
N
(99%)
EDCI, HOBt
DIPEA, DMF
25 °C, 12 h
(95%)
PdCl2(PPh3)2, CsF, DMF, 90 °C
36 h (70%)
MOMO
MOMO
COOH
MOMO
COOMe
O
11
12
13
OMe
OMe
CSA, MeOH
25 °C, 12 h
VO(acac)2, TBHP
TFA, CH2Cl2
N
N
(88%)
N
25 °C, 1 h (73%)
OMOM
OH
O
O
O
14
15
OMe
OMe
t-BuLi, THF
DMF, –78 °C
OH
OMOM
MOMCl, DIPEA
CH2Cl2
N
25 °C, 8 h (94%)
4 h (90%)
O
O
O
( )-17
( )-16
OMe
OMe
OMOM
OMOM
NaBH3CN
MeOH–AcOH
N
O
O
O
100 °C, 2 h
(87%)
O
CHO
O
( )-18
( )-19
OMe
CSA, MeOH
25 °C, 12 h
OH
O
O
( )-NG-121 methyl ether (20)
(92%)
O
Scheme 3 Diastereoselective synthesis of NG-121 methyl ether
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3797–3804

3800
M. Singh, N. P. Argade
PAPER
A pseudo-SN2 epoxide opening resulted in the cis orienta- tem, regio- and diastereoselective ring closure with the
tion of the secondary hydroxy group and the tertiary meth- generation of two adjacent chiral centers, and selective o-
yl group in compound (±)-16, which was established on formylation were the key steps involved. We feel that our
the basis of NOESY studies; we propose that the present present approach to NG-121 methyl ether is general in na-
outcome is on the basis of thermodynamic stability (Fig- ture and would be useful to access the NG-121 and stachy-
ure 2).13 The formed free secondary hydroxy group in botrin analogues, and SMTP congeners for SAR studies.
compound (±)-16 was MOM protected to obtain product
(±)-17 in 94% yield. Fortunately, the tert-butyllithium/
N,N-dimethylformamide o-formylation of (±)-17 was
completely regioselective and exclusively furnished the
requisite benzaldehyde derivative (±)-18 in 90% yield.
The presence of a formyl group at the 8-position in com-
pound (±)-18 was confirmed on the basis of NOESY stud-
ies. NOESY data revealed the interaction of the OMe
group with an adjacent aromatic proton through space.
Herein exclusive formylation at the 8-position in the start-
ing material (±)-17 could be due to the effective participa-
tion of the locked ring oxygen atom of the chromane
system in the o-lithiation step. Sodium cyanoborohydride
reduction of aldehyde (±)-18 to the corresponding alcohol
and in situ lactonization gave phthalide (±)-19 in 87%
yield. MOM deprotection of (±)-19 provided NG-121
methyl ether (±)-20 in 92% yield. The obtained spectral
data for NG-121 methyl ether (±)-20 was in concurrence
with the data reported for the model compound.5 We also
prepared the 3,5-dinitrobenzoyl derivative of compound
(±)-20 with the prospect of establishing the structure by
X-ray crystallography, but unfortunately the product was
also a thick oil. We carefully studied the demethylation of
compound (±)-19/20 to get the actual natural product
1H NMR: 200, 400, and 500 NMR spectrometers (TMS internal
standard); 13C NMR: 200 (50 MHz), 400 (100 MHz), and 500 NMR
spectrometers (125 MHz); MS: MS-TOF mass spectrometer;
HRMS (ESI): TOF mass analyzer; IR: FT-IR spectrophotometer.
Column chromatographic separations were carried out on silica gel
(100–200 mesh); PE = petroleum ether. Commercially available t-
BuLi, farnesyl bromide, TMEDA, CuBr·Me2S, PCC, 2-methylbut-
2-ene, Et2NH·HCl, EDCI, HOBt, CsF, PdCl2(PPh3)2, CSA,
VO(acac)2, MOMCl, TBHP, NaBH3CN, B(C6F5)3, and Et3SiH were
used. [3,5-Bis(methoxymethoxy)phenyl]methanol (1), methyl 4-
bromo-3-methoxy-5-(methoxymethoxy)benzoate (11), and tribu-
tyl(farnesyl)tin were prepared by known procedures.15
{3,5-Bis(methoxymethoxy)-4-[(2E,6E)-3,7,11-trimethyldodeca-
2,6,10-trien-1-yl]phenyl}methanol (2)
A 1.60 M t-BuLi in pentane soln (30.15 mL, 48.24 mmol) was
added dropwise to a soln of alcohol 1 (5.00 g, 21.92 mmol) and
TMEDA (6.86 mL, 46.05 mmol) in THF (60 mL) at –20 °C under
argon; the mixture was stirred at –20 °C for 1 h. CuBr·Me2S (9.44
g, 46.05 mmol) was added and the mixture was stirred at –20 °C for
a further 1 h. A soln of farnesyl bromide (6.87 g, 24.12 mmol) in
THF (20 mL) was added dropwise to this mixture, which was stirred
at –20 °C for 2 h. The reaction was quenched with sat. aq NH4Cl
soln (10 mL) and then concentrated in vacuo. EtOAc (80 mL) was
added to the residue and the organic soln was washed with H2O (30
mL) and brine (30 mL), dried (Na2SO4), and concentrated in vacuo.
Purification of the residue by column chromatography (silica gel,
NG-121 (BCl3, BBr3, TMSI/DCM,14a LiCl/DMF,14b EtSNa/ PE–EtOAc, 1:1) afforded pure 2 as a thick oil; yield: 5.87 g (62%).
HMPA,14c BuSLi/HMPA,14d B(C6F5)3/Et3SiH14e) howev-
er, the result was always recovery of starting material
and/or decomposition. Hence, we have accomplished the
diastereoselective synthesis of the methyl ether of natural
product NG-121.
IR (neat): 3427, 1611, 1589 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.56 (s, 3 H), 1.59 (s, 3 H), 1.67
(s, 3 H), 1.78 (s, 3 H), 1.80–2.14 (m, 8 H), 3.39 (d, J = 8 Hz, 2 H),
3.47 (s, 6 H), 4.61 (s, 2 H), 5.01–5.14 (m, 2 H), 5.14–5.25 (m, 1 H),
5.19 (s, 4 H), 6.78 (s, 2 H).
13C NMR (50 MHz, CDCl3): δ = 16.0, 16.1, 17.6, 22.5, 25.7, 26.6,
26.7, 39.7, 39.8, 56.0, 65.5, 94.4, 106.5, 119.5, 122.6, 124.2, 124.4,
131.3, 134.7, 134.9, 140.0, 155.7.
MS (ESI): m/z = 455 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C26H40O5Na: 455.2773;
OH
H
H
Hax
Heq
OMe
found: 455.2776.
O
3,5-Bis(methoxymethoxy)-4-[(2E,6E)-3,7,11-trimethyldodeca-
2,6,10-trien-1-yl]benzaldehyde (3)
To a stirred suspension of PCC (3.74 g, 17.36 mmol) and 4 Å mo-
lecular sieves in CH2Cl2 (60 mL) at 0 °C was added a soln of alcohol
2 (5.00 g, 11.57 mmol) in CH2Cl2 (20 mL) under argon. The mixture
was stirred at 25 °C for 3 h, and then diluted with Et2O (20 mL). The
resulting mixture was filtered through a pad of Celite and the filtrate
was concentrated in vacuo. Purification of the residue by column
chromatography (silica gel, PE–EtOAc, 4:1) afforded pure alde-
hyde 3 as a thick oil; yield: 4.37 g (88%).
N
O
( )-16
Figure 2 NOESY interaction between Hax and methylene protons
In summary, the diastereoselective first synthesis of meth-
yl ether of natural product NG-121 has been achieved in
nine steps with 29% overall yield (an average of 88%
yield each step) using an appropriate reactions sequence
and essential protecting groups. Stille coupling to intro-
duce the farnesyl chain on the electron-rich phenolic sys-
IR (CHCl3): 2723, 1699, 1586 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.56 (s, 3 H), 1.58 (s, 3 H), 1.67
(s, 3 H), 1.80 (s, 3 H), 1.85–2.10 (m, 8 H), 3.46 (d, J = 8 Hz, 2 H),
3.48 (s, 6 H), 5.06 (t, J = 8 Hz, 2 H), 5.15–5.28 (m, 1 H), 5.26 (s, 4
H), 7.29 (s, 2 H), 9.87 (s, 1 H).
Synthesis 2012, 44, 3797–3804
© Georg Thieme Verlag Stuttgart · New York

PAPER
Diastereoselective Synthesis of NG-121 Methyl Ether
3801
13C NMR (50 MHz, CDCl3): δ = 16.0, 16.1, 17.6, 23.2, 25.7, 26.5,
26.7, 39.7, 39.8, 56.1, 94.4, 108.9, 121.2, 124.0, 124.3, 127.5,
131.3, 135.0, 135.5, 135.7, 156.0, 191.6.
MS (ESI): m/z = 453 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C26H38O5Na: 453.2617;
with H2O (20 mL) and brine (20 mL), dried (Na2SO4), and concen-
trated in vacuo. Purification of the residue by column chromatogra-
phy (silica gel, PE–EtOAc, 3:2) afforded pure 6 as a thick oil; yield:
2.69 g (85%).
IR (CHCl3): 2857, 1740, 1684, 1634, 1594 cm–1.
found: 453.2611.
1H NMR (500 MHz, CDCl3): δ = 1.03 (t, J = 10 Hz, 3 H), 1.33 (t,
J = 10 Hz, 3 H), 1.58 (s, 3 H), 1.60 (s, 3 H), 1.68 (s, 3 H), 1.79 (s, 3
H), 1.93–2.11 (m, 8 H), 3.09 (q, J = 10 Hz, 2 H), 3.42 (d, J = 5 Hz,
2 H), 3.45 (s, 3 H), 3.53–3.64 (m, 2 H), 3.59 (s, 3 H), 5.06 (s, 2 H),
5.08 (t, J = 5 Hz, 1 H), 5.09 (t, J = 5 Hz, 1 H), 5.16 (t, J = 10 Hz, 1
H), 5.25 (s, 2 H), 6.83 (s, 1 H), 10.21 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 12.1, 13.5, 16.0, 16.3, 17.7, 23.2,
25.7, 26.6, 26.7, 38.8, 39.7 (2 C), 42.5, 56.2, 58.0, 94.1, 101.6,
108.7, 120.8, 121.5, 124.0, 124.3, 125.1, 131.3, 135.2, 136.1, 138.6,
159.9, 160.5, 169.5, 189.0.
3,5-Bis(methoxymethoxy)-4-[(2E,6E)-3,7,11-trimethyldodeca-
2,6,10-trien-1-yl]benzoic Acid (4)
To a stirred soln of aldehyde 3 (4.00 g, 9.30 mmol) in t-BuOH–H2O
(5:1, 40 mL) was added 2-methylbut-2-ene (5.91 mL, 55.81 mmol)
at 25 °C, the mixture was stirred for 15 min, and then NaH2PO4
(1.67 g, 13.95 mmol) was added. After stirring at 25 °C for 10 min,
NaClO2 (3.36 g, 37.20 mmol) was added and stirring was continued
for 8 h. The mixture was concentrated in vacuo, the EtOAc (60 mL)
was added to the residue, and the organic soln was washed with
brine (3 × 20 mL), dried (Na2SO4), and concentrated in vacuo. Pu-
rification of the residue by column chromatography (silica gel, PE–
EtOAc, 2:3) afforded pure 4 as white solid; yield: 3.94 g (95%); mp
78–80 °C.
MS (ESI): m/z = 530 [M + H]+, 552 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C31H48NO6: 530.3482; found:
530.3484.
IR (CHCl3): 1726, 1693, 1586 cm–1.
4,6-Bis(methoxymethoxy)-5-[(2E,6E)-3,7,11-trimethyldodeca-
2,6,10-trien-1-yl]isobenzofuran-1(3H)-one (7)
1H NMR (500 MHz, CDCl3): δ = 1.56 (s, 3 H), 1.58 (s, 3 H), 1.67
(s, 3 H), 1.79 (s, 3 H), 1.90–2.10 (m, 8 H), 3.46 (d, J = 5 Hz, 2 H),
3.48 (s, 6 H), 5.07 (t, J = 10 Hz, 2 H), 5.19 (t, J = 10 Hz, 1 H), 5.25
(s, 4 H), 7.49 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 16.0, 16.1, 17.6, 23.1, 25.7, 26.6,
26.7, 39.7, 39.8, 56.1, 94.5, 109.5, 121.5, 124.1, 124.3, 126.7,
127.9, 131.3, 135.0, 135.6, 155.4, 170.9.
To a stirred soln of 6 (2.00 g, 3.78 mmol) in AcOH–MeOH (1:1, 20
mL) was added NaBH3CN (356 mg, 5.67 mmol) and the mixture
was heated at 100 °C for 2 h. The reaction was allowed to attain 25
°C and concentrated in vacuo. EtOAc (40 mL) was added to the res-
idue and the organic soln was washed with H2O (15 mL) and brine
(15 mL), dried (Na2SO4), and concentrated in vacuo. Purification of
the residue by column chromatography (silica gel, PE–EtOAc, 9:1)
afforded pure 7 as a thick oil; yield: 1.40 g (81%).
MS (ESI): m/z = 447 [M + H]+, 469 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C26H38O6Na: 469.2566;
IR (CHCl3): 1768, 1619 cm–1.
found: 469.2578.
1H NMR (400 MHz, CDCl3): δ = 1.56 (s, 3 H), 1.58 (s, 3 H), 1.67
(s, 3 H), 1.80 (s, 3 H), 1.90–2.12 (m, 8 H), 3.47 (s, 3 H), 3.48 (d, J =
8 Hz, 2 H), 3.54 (s, 3 H), 5.07 (s, 2 H), 5.07 (t, J = 8 Hz, 2 H), 5.14
(t, J = 8 Hz, 1 H), 5.26 (s, 2 H), 5.37 (s, 2 H), 7.38 (s, 1 H).
N,N-Diethyl-3,5-bis(methoxymethoxy)-4-[(2E,6E)-3,7,11-tri-
methyldodeca-2,6,10-trien-1-yl]benzamide (5)
A soln of EDCI (1.64 g, 8.63 mmol) and HOBt (1.32 g, 8.63 mmol)
in CH2Cl2 (20 mL) was added dropwise to a stirred suspension of
acid 4 (3.50 g, 7.84 mmol) and Et2NH·HCl (946 mg, 8.63 mmol) in
CH2Cl2 (40 mL) at 0 °C under argon atmosphere. DIPEA (2.95 mL,
17.26 mmol) was added dropwise to the mixture, which was then
stirred at 25 °C for 24 h. To the mixture was added EtOAc (60 mL)
and the organic soln was washed with H2O (20 mL) and brine (20
mL), dried (Na2SO4), and concentrated in vacuo. Purification of the
residue by column chromatography (silica gel, PE–EtOAc. 3:1) af-
forded pure 5 as a thick oil; yield: 3.06 g (78%).
13C NMR (100 MHz, CDCl3): δ = 16.0, 16.2, 17.6, 23.8, 25.6, 26.4,
26.7, 39.6, 39.7, 56.1, 56.7, 69.0, 94.4, 97.1, 105.2, 121.2, 123.9,
124.2, 125.4, 129.5, 131.3, 135.1, 136.0, 150.3, 156.9, 171.0.
MS (ESI): m/z = 481 [M + Na]+, 513 [M + Na + MeOH]+.
HRMS (ESI): m/z [M + Na]+ calcd for C27H38O6Na: 481.2566;
found: 481.2566.
4,6-Dihydroxy-5-[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-
1-yl]isobenzofuran-1(3H)-one (8)
IR (CHCl3): 1732, 1619, 1581 cm–1.
To a stirred soln of 7 (1.00 g, 2.18 mmol) in MeOH (30 mL) was
added camphorsulfonic acid (cat., 50 mg) and the mixture was
stirred at 25 °C under argon for 24 h. The reaction was quenched by
the addition of sat. aq NaHCO3 (1 mL) and concentrated in vacuo.
EtOAc (30 mL) was added to the residue and the organic soln was
washed with brine (10 mL), dried (Na2SO4), and concentrated in
vacuo. Purification of the residue by column chromatography (silica
gel, PE–EtOAc, 4:1) afforded pure 8 as a thick oil; yield: 500 mg
(62%).
1H NMR (200 MHz, CDCl3): δ = 1.05–1.33 (m, 6 H), 1.57 (s, 3 H),
1.59 (s, 3 H), 1.67 (s, 3 H), 1.78 (s, 3 H), 1.90–2.15 (m, 8 H), 3.15–
3.60 (m, 4 H), 3.40 (d, J = 8 Hz, 2 H), 3.46 (s, 6 H), 5.00–5.28 (m,
3 H), 5.18 (s, 4 H), 6.79 (s, 2 H).
13C NMR (50 MHz, CDCl3): δ = 12.9, 14.0, 15.9, 16.1, 17.6, 22.6,
25.6, 26.6, 26.7, 39.3, 39.7, 39.8, 43.3, 55.9, 94.5, 106.1, 121.1,
122.1, 124.2, 124.3, 131.2, 134.87, 134.93, 135.7, 155.5, 171.0.
MS (ESI): m/z = 524 [M + Na]+.
IR (CHCl3): 3380, 1735, 1618 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C30H48NO5: 502.3532; found:
502.3529.
1H NMR (400 MHz, CDCl3): δ = 1.58 (s, 3 H), 1.59 (s, 3 H), 1.67
(s, 3 H), 1.84 (s, 3 H), 1.90–2.20 (m, 8 H), 3.55 (d, J = 8 Hz, 2 H),
5.06 (t, J = 8 Hz, 1 H), 5.07 (t, J = 8 Hz, 1 H), 5.24 (s, 2 H), 5.30 (t,
J = 8 Hz, 1 H), 6.48 (br s, 1 H), 7.07 (s, 1 H), 7.33 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 16.1, 16.3, 17.6, 23.1, 25.6, 26.1,
26.6, 39.6 (2 C), 68.8, 103.3, 120.3, 120.8, 123.3, 124.2, 124.4,
126.1, 131.4, 135.9, 140.7, 150.4, 156.4, 173.0.
N,N-Diethyl-2-formyl-3,5-bis(methoxymethoxy)-4-[(2E,6E)-
3,7,11-trimethyldodeca-2,6,10-trien-1-yl]benzamide (6)
A 1.60 M t-BuLi in pentane soln (5.23 mL, 8.38 mmol) was added
to a stirred soln of 5 (3.00 g, 5.98 mmol) in THF (30 mL) at –78 °C
under argon, stirring was continued for a further 15 min, and then
DMF (2.31 mL, 29.94 mmol) was added. The mixture was allowed
to warm up to 25 °C and stirred for 24 h. The reaction was quenched
with sat. aq NH4Cl soln (10 mL) and concentrated in vacuo. EtOAc
(50 mL) was added to the residue and the organic soln was washed
MS (ESI): m/z = 393 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C23H30O4Na: 393.2042;
found: 393.2041.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3797–3804

3802
M. Singh, N. P. Argade
PAPER
4-Bromo-3-methoxy-5-(methoxymethoxy)benzoic Acid (12)
Ester 11 (5.00 g, 16.44 mmol) was added to a mixture of 10% aq
KOH soln (40 mL) and MeOH (40 mL) and the mixture was stirred
at 25 °C for 8 h. The mixture was concentrated in vacuo and the res-
idue was diluted with EtOAc (50 mL), acidified with 2 M HCl (100
mL), and extracted with EtOAc (3 × 20 mL). The combined organic
layers were washed with H2O (25 mL) and brine (25 mL), dried
(Na2SO4), and concentrated in vacuo. Purification of the residue by
column chromatography (silica gel, PE–EtOAc, 2:3) afforded pure
12 as a white solid; yield: 4.72 g (99%); mp 160–162 °C.
IR (nujol): 2700–2500, 1687, 1588 cm–1.
1H NMR (200 MHz, DMSO-d6): δ = 3.41 (s, 3 H), 3.90 (s, 3 H), 5.33
(s, 2 H), 7.24 (s, 1 H), 7.37 (s, 1 H), 13.26 (br s, 1 H).
13C NMR (50 MHz, DMSO-d6): δ = 56.1, 56.5, 94.8, 106.0, 106.6,
N,N-Diethyl-3-hydroxy-5-methoxy-4-[(2E,6E)-3,7,11-trimeth-
yldodeca-2,6,10-trien-1-yl]benzamide (15)
To a stirred soln of 14 (2.00 g, 4.24 mmol) in MeOH (50 mL) was
added camphorsulfonic acid (100 mg) and the mixture was stirred
at 25 °C under argon for 12 h. The reaction was quenched by the ad-
dition of sat. aq NaHCO3 soln (1 mL) and concentrated in vacuo.
EtOAc (50 mL) was added to the residue and the organic soln was
washed with brine (20 mL), dried (Na2SO4), and concentrated in
vacuo. Purification of the residue by column chromatography (silica
gel, PE–EtOAc, 2:1) afforded pure 15 as a thick oil; yield: 1.59 g
(88%).
IR (CHCl3): 3272, 1615, 1586 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.00–1.35 (m, 6 H), 1.57 (s, 3 H),
1.58 (s, 3 H), 1.66 (s, 3 H), 1.76 (s, 3 H), 1.35–2.15 (m, 8 H), 3.20–
3.40 (m, 2 H), 3.40–3.60 (m, 2 H), 3.33 (d, J = 8 Hz, 2 H), 3.77 (s,
3 H), 5.00 (t, J = 6 Hz, 1 H), 5.08 (t, J = 6 Hz, 1 H), 5.19 (t, J = 6
Hz, 1 H), 6.37 (d, J = 2 Hz, 1 H), 6.55 (d, J = 2 Hz, 1 H), 7.35 (s, 1
H).
108.8, 131.3, 154.3, 156.6, 166.7.
HRMS (ESI): m/z [M + Na]+ calcd for C10H11BrO5Na: 312.9688;
found: 312.9695.
13C NMR (50 MHz, CDCl3): δ = 12.8, 14.2, 15.9, 16.1, 17.6, 22.2,
25.6, 26.6, 26.7, 39.3, 39.7, 39.8, 43.3, 55.7, 100.5, 107.5, 117.4,
122.0, 124.1, 124.4, 131.2, 134.9, 135.0, 136.3, 155.6, 158.0, 171.9.
MS (ESI): m/z = 450 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C27H42NO3: 428.3165; found:
4-Bromo-N,N-diethyl-3-methoxy-5-(methoxymethoxy)benz-
amide (13)
A soln of EDCI (3.26 g, 17.06 mmol) and HOBt (2.61 g, 17.06
mmol) in DMF (15 mL) was added dropwise to a stirred suspension
of acid 12 (4.50 g, 15.51 mmol) and Et2NH·HCl (1.87 g, 17.06
mmol) in DMF (30 mL) at 0 °C under argon. DIPEA (5.84 mL,
34.13 mmol) was added dropwise to the mixture, which was stirred
at 25 °C for 12 h. EtOAc (80 mL) was added and the organic layer
was washed with brine (4 × 20 mL), dried (Na2SO4), and concen-
trated in vacuo. Purification of the residue by column chromatogra-
phy (silica gel, PE–EtOAc, 3:2) afforded pure 13 as a thick oil;
yield: 5.08 g (95%).
428.3154.
(±)-2-[(E)-4,8-Dimethylnona-3,7-dien-1-yl]-N,N-diethyl-3-hy-
droxy-5-methoxy-2-methyl-3,4-dihydro-2H-chromene-7-car-
boxamide (16)
VO(acac)2 (14 mg, 1.50 mol%) was added to a stirred soln of phenol
15 (1.50 g, 3.51 mmol) in CH2Cl2 (20 mL) at 25 °C under argon. Af-
ter 15 min, a ~5.50 M TBHP in decane soln (0.83 mL, 4.56 mmol)
was added to mixture followed by the dropwise addition of TFA
(0.05 mL, 20 mol%) and the mixture was further stirred at 25 °C for
1 h. The mixture was concentrated in vacuo and the residue was pu-
rified by column chromatography (silica gel, PE–EtOAc, 13:7) to
afford pure 16 as a thick oil; yield: 1.13 g (73%).
IR (neat): 1634, 1581 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.05–1.35 (m, 6 H), 3.15–3.35 (m,
2 H), 3.40–3.60 (m, 2 H), 3.49 (s, 3 H), 3.91 (s, 3 H), 5.25 (s, 2 H),
6.62 (d, J = 2 Hz, 1 H), 6.82 (d, J = 2 Hz, 1 H).
13C NMR (50 MHz, CDCl3): δ = 12.8, 14.1, 39.4, 43.3, 56.3, 56.5,
95.1, 103.0, 103.7, 106.3, 137.3, 154.8, 157.1, 170.1.
MS (ESI): m/z = 368 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C14H20BrNO4Na: 368.0473;
found: 368.0471.
IR (CHCl3): 3393, 1612, 1579 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.00–1.30 (m, 6 H), 1.27 (s, 3 H),
1.50–1.65 (m, 2 H), 1.58 (s, 6 H), 1.66 (s, 3 H), 1.90–2.15 (m, 6 H),
2.20–2.45 (br s, 1 H), 2.61 (dd, J = 16, 4 Hz, 1 H), 2.81 (dd, J = 16,
4 Hz, 1 H), 3.20–3.40 (m, 2 H), 3.40–3.60 (m, 2 H), 3.73 (t, J = 8
Hz, 1 H), 3.81 (s, 3 H), 5.02–5.12 (m, 2 H), 6.41 (s, 1 H), 6.45 (s, 1
H).
13C NMR (100 MHz, CDCl3): δ = 12.8, 14.3, 15.9, 17.6, 19.0, 21.5,
25.6, 26.2, 26.6, 36.9, 39.1, 39.6, 43.2, 55.5, 67.5, 78.7, 100.2,
107.8, 109.2, 123.8, 124.2, 131.4, 135.5, 136.5, 153.3, 158.2, 171.1.
N,N-Diethyl-3-methoxy-5-(methoxymethoxy)-4-[(2E,6E)-
3,7,11-trimethyldodeca-2,6,10-trien-1-yl]benzamide (14)
Pd(PPh3)2Cl2 (200 mg, 10 mol%) was added to a stirred soln of aryl
bromide 13 (1.00 g, 2.89 mmol) and tributyl(farnesyl)tin (2.86 g,
5.79 mmol) in DMF (14.5 mL) at 25 °C under argon. CsF (880 mg,
5.79 mmol) was added to the mixture, which was heated at 90 °C
for 36 h. EtOAc (60 mL) was added to the mixture and the insoluble
residue was removed by filtration. The organic layer was washed
with brine (4 × 20 mL), dried (Na2SO4) and concentrated in vacuo.
Purification of the residue by column chromatography (silica gel,
PE–EtOAc, 7:3) afforded pure 14 as a thick oil; yield: 955 mg
(70%).
MS (ESI): m/z = 466 [M + Na]+, 482 [M + K]+.
HRMS (ESI): m/z [M + H]+ calcd for C27H42NO4: 444.3114; found:
444.3109.
(±)-2-[(E)-4,8-Dimethylnona-3,7-dien-1-yl]-N,N-diethyl-5-
methoxy-3-(methoxymethoxy)-2-methyl-3,4-dihydro-2H-
chromene-7-carboxamide (17)
IR (neat): 1636, 1581 cm–1.
MOMCl (0.25 mL, 3.38 mmol) was added to a stirred soln of 16
(1.00 g, 2.25 mmol) in CH2Cl2 (15 mL) at 0 °C under argon and the
mixture was stirred for 30 min. DIPEA (0.77 mL, 4.51 mmol) was
added dropwise and the mixture was further stirred at 25 °C for 8 h
and then quenched with H2O (5 mL). The organic layer was sepa-
rated and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL).
The combined organic layers were washed with brine (20 mL),
dried (Na2SO4), and concentrated in vacuo. Purification of the resi-
due by column chromatography (silica gel, PE–EtOAc, 7:3) afford-
ed pure 17 as a thick oil; yield: 1.03 g (94%).
1H NMR (200 MHz, CDCl3): δ = 1.05–1.35 (m, 6 H), 1.56 (s, 3 H),
1.58 (s, 3 H), 1.66 (s, 3 H), 1.76 (s, 3 H), 1.85–2.12 (m, 8 H), 3.15–
3.60 (m, 4 H), 3.36 (d, J = 6 Hz, 2 H), 3.44 (s, 3 H), 3.81 (s, 3 H),
5.00–5.22 (m, 3 H), 5.16 (s, 2 H), 6.58 (s, 1 H), 6.73 (s, 1 H).
13C NMR (50 MHz, CDCl3): δ = 12.8, 14.1, 15.9, 16.0, 17.6, 22.3,
25.6, 26.6, 26.7, 39.2, 39.6, 39.7, 43.3, 55.7, 55.8, 94.5, 102.9,
105.2, 120.3, 122.2, 124.2, 124.3, 131.1, 134.75, 134.83, 135.6,
155.3, 158.1, 171.2.
MS (ESI): m/z = 494 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C29H46NO4: 472.3427; found:
IR (CHCl3): 1637, 1581 cm–1.
472.3424.
Synthesis 2012, 44, 3797–3804
© Georg Thieme Verlag Stuttgart · New York

PAPER
Diastereoselective Synthesis of NG-121 Methyl Ether
3803
1H NMR (400 MHz, CDCl3): δ = 1.10–1.30 (m, 6 H), 1.28 (s, 3 H),
1.58 (s, 6 H), 1.60–1.70 (m, 2 H), 1.66 (s, 3 H), 1.92–2.00 (m, 2 H),
2.00–2.08 (m, 2 H), 2.13 (q, J = 8 Hz, 2 H), 2.65 (dd, J = 16, 8 Hz,
1 H), 2.93 (dd, J = 16, 8 Hz, 1 H), 3.20–3.40 (m, 2 H), 3.40–3.60
(m, 2 H), 3.40 (s, 3 H), 3.81 (s, 3 H), 3.81 (t, J = 8 Hz, 1 H), 4.66 (d,
J = 8 Hz, 1 H), 4.82 (d, J = 8 Hz, 1 H), 5.07 (t, J = 8 Hz, 1 H), 5.09
(t, J = 8 Hz, 1 H), 6.41 (s, 1 H), 6.46 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 12.8, 14.3, 15.9, 17.6, 19.0, 21.4,
23.2, 25.6, 26.6, 37.4, 39.0, 39.6, 43.2, 55.5, 55.8, 72.5, 77.9, 95.3,
100.0, 107.8, 109.4, 123.9, 124.2, 131.2, 135.3, 136.3, 153.3, 157.9,
171.1.
MS (ESI): m/z = 483 [M + K]+, 499 [M + Na + MeOH]+.
HRMS (ESI): m/z [M + H]+ calcd for C26H37O6: 445.2590; found:
445.2585.
(±)-2-[(E)-4,8-Dimethylnona-3,7-dien-1-yl)-3-hydroxy-5-meth-
oxy-2-methyl-3,4-dihydro-2H-furo[3,4-h]chromen-7(9H)-one
(NG-121 Methyl Ether, 20)
To a stirred soln of 19 (250 mg, 0.56 mmol) in MeOH (10 mL) was
added camphorsulfonic acid (cat., 20 mg) and the mixture was
stirred at 25 °C for 12 h under argon. The reaction was quenched by
the addition of sat. NaHCO3 (1 mL) and concentrated in vacuo.
EtOAc (20 mL) was added to the residue and the organic soln was
washed with brine (10 mL), dried (Na2SO4), and concentrated in
vacuo. Purification of the residue by column chromatography (silica
gel, PE–EtOAc, 4:1) afforded pure 20 as a thick oil; yield: 207 mg
(92%).
MS (ESI): m/z = 510 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C29H46NO5: 488.3376; found:
488.3380.
IR (neat): 3460, 1770, 1621 cm–1.
(±)-2-[(E)-4,8-Dimethylnona-3,7-dien-1-yl]-N,N-diethyl-8-for-
myl-5-methoxy-3-(methoxymethoxy)-2-methyl-3,4-dihydro-
2H-chromene-7-carboxamide (18)
1H NMR (400 MHz, CDCl3): δ = 1.36 (s, 3 H), 1.57 (s, 6 H), 1.59–
1.65 (m, 2 H), 1.66 (s, 3 H), 1.89 (br s, 1 H), 1.92–2.18 (m, 4 H),
2.13 (q, J = 8 Hz, 2 H), 2.77 (dd, J = 18 and 4 Hz, 1 H), 2.98 (dd,
J = 18 and 4 Hz, 1 H), 3.88 (s, 3 H), 3.95 (s, 1 H), 5.06 (t, J = 8 Hz,
1 H), 5.08 (t, J = 8 Hz, 1 H), 5.17 (d, J = 16 Hz, 1 H), 5.22 (d, J =
16 Hz, 1 H), 6.90 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 15.9, 17.6, 19.1, 21.5, 25.7, 26.6,
26.9, 36.9, 39.6, 55.9, 67.3, 68.0, 79.5, 97.2, 114.7, 123.4, 124.1,
125.4, 127.8, 131.5, 136.0, 147.9, 159.5, 171.7.
A 1.60 M t-BuLi in pentane soln (0.89 mL, 1.43 mmol) was added
to a stirred soln of 17 (500 mg, 1.02 mmol) in THF (10 mL) at –78
°C and the mixture was stirred for 15 min. DMF (0.39 mL, 5.13
mmol) was added and the mixture was allowed to attain 25 °C and
stirred for a further 4 h. The reaction was quenched with sat. aq
NH4Cl soln (5 mL) and then concentrated in vacuo. EtOAc (20 mL)
was added to the residue and the organic soln was washed with H2O
(10 mL) and brine (10 mL), dried (Na2SO4), and concentrated in
vacuo. Purification of the residue by column chromatography (silica
gel, PE–EtOAc, 3:2) afforded pure 18 as a thick oil; yield: 475 mg
(90%).
MS (ESI): m/z = 423 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C24H32O5Na: 423.2147;
IR (neat): 1682, 1639, 1599 cm–1.
found: 423.2141.
1H NMR (200 MHz, CDCl3): δ = 1.01 (t, J = 8 Hz, 3 H), 1.25–1.42
(m, 6 H), 1.59 (s, 6 H), 1.67 (s, 3 H), 1.65–1.80 (m, 2 H), 1.90–2.25
(m, 6 H), 2.55–2.75 (m, 1 H), 2.85–3.05 (m, 1 H), 3.08 (q, J = 6 Hz,
2 H), 3.43 (s, 3 H), 3.45–3.75 (m, 2 H), 3.86 (t, J = 6 Hz, 1 H), 3.88
(s, 3 H), 4.69 (d, J = 8 Hz, 1 H), 4.84 (d, J = 8 Hz, 1 H), 5.00–5.20
(m, 2 H), 6.31 (s, 1 H), 10.35 (s, 1 H).
Acknowledgment
M.S. thanks CSIR, New Delhi for the award of a research fellow-
ship. N.P.A. thanks the Department of Science and Technology,
New Delhi, for financial support.
13C NMR (125 MHz, CDCl3): δ = 12.1, 13.6, 16.0, 17.6, 21.5, 23.1,
25.6, 26.6, 37.6, 38.5, 39.6, 42.3, 55.87, 55.94, 72.1, 79.4, 95.5,
101.3, 115.0, 123.4, 124.2, 131.4, 135.8, 138.9, 157.0, 162.3, 170.1,
187.9.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
MS (ESI): m/z = 538 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C30H45NO6Na: 538.3145;
References
found: 538.3135.
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(±)-2-[(E)-4,8-Dimethylnona-3,7-dien-1-yl)-5-methoxy-3-(meth-
oxymethoxy)-2-methyl-3,4-dihydro-2H-furo[3,4-h]chromen-
7(9H)-one (19)
To a stirred soln of aldehyde 18 (400 mg, 0.77 mmol) in AcOH–
MeOH (1:1, 10 mL) was added NaBH3CN (73 mg, 1.16 mmol) and
the mixture was heated at 100 °C for 2 h. The reaction was allowed
to warm up to 25 °C and concentrated in vacuo. EtOAc (25 mL) was
added to the residue and the organic soln was washed with H2O (15
mL) and brine (15 mL), dried (Na2SO4), and concentrated in vacuo.
Purification of the residue by column chromatography (silica gel,
PE–EtOAc, 2:1) afforded pure 19 as a thick oil; yield: 300 mg
(87%).
IR (CHCl3): 1770, 1619 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.35 (s, 3 H), 1.58 (s, 6 H), 1.55–
1.75 (m, 2 H), 1.66 (s, 3 H), 1.90–2.22 (m, 6 H), 2.78 (dd, J = 18, 6
Hz, 1 H), 2.99 (dd, J = 18, 4 Hz, 1 H), 3.42 (s, 3 H), 3.88 (t, J = 8
Hz, 1 H), 3.88 (s, 3 H), 4.68 (d, J = 8 Hz, 1 H), 4.84 (d, J = 8 Hz, 1
H), 5.00–5.16 (m, 2 H), 5.16 (d, J = 14 Hz, 1 H), 5.25 (d, J = 14 Hz,
1 H), 6.90 (s, 1 H).
13C NMR (50 MHz, CDCl3): δ = 15.9, 17.6, 19.4, 21.5, 23.8, 25.6,
26.6, 37.3, 39.6, 55.93, 55.96, 68.0, 72.1, 78.9, 95.5, 97.1, 114.8,
123.4, 124.1, 125.3, 127.8, 131.4, 135.7, 148.0, 159.4, 171.7.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3797–3804

3804
M. Singh, N. P. Argade
PAPER
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