Total synthesis of (-)-anamarine

Article abstract of DOI:10.1021/jo2010389

Total synthesis of polyhydroxy δ-pyranone natural product (-)-anamarine is accomplished from d-(-)-tartaric acid. The main feature of the synthesis is the utility of hitherto unexplored β-keto phosphonate derived from tartaric acid amide and further elaboration involving stereoselective reduction.

Full text of DOI:10.1021/jo2010389

NOTE
pubs.acs.org/joc
Total Synthesis of (À)-Anamarine
Kavirayani R. Prasad* and Kamala Penchalaiah
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
S Supporting Information
b
ABSTRACT: Total synthesis of polyhydroxy δ-pyranone natural
product (À)-anamarine is accomplished from D-(À)-tartaric acid.
The main feature of the synthesis is the utility of hitherto unexplored
β-keto phosphonate derived from tartaric acid amide and further
elaboration involving stereoselective reduction.
Scheme 1. Retrosynthesis for (À)-Anamarine 1
ihydro-2H-pyran-2-one (δ-pyranone) is an ubi-
5,6-Dquitous structural unit found in a number of
bioactive natural products of therapeutic significance. Natural
products and analogues possessing this moiety have been shown to
exhibit a number of biological activities including anticancer
activity.1 (+)-Anamarine (1), isolated from the flowers and leaves
of an unclassified Peruvian Hyptis species, is such a δ-pyranone with
a side chain comprising four contiguous hydroxy group substitu-
tions.2 (+)-Anamarine (1) is structurally similar to other members
of the polyhydroxy δ-pyranone natural product family such as
spicigerolide (2), synrotolide (3), synargentolide A (4), etc.
protected erythrulose derivative. Our efforts in the use of tartaric
acid as a four-carbon, four-hydroxy synthon culminated in the
synthesis of a variety of natural products including bioactive
lactones.8 Herein, we report the synthesis of (À)-anamarine
from D-(À)-tartaric acid based on a strategy of desymmetrization
of tartaric acid amide.
Our approach for the synthesis of (À)-anamarine is depicted
in Scheme 1. Synthesis of 1 is anticipated by deprotection of the
protecting groups in the lactone 5, the synthesis of which is
envisaged by ring-closing metathesis of the acryloyl ester derived
from 6. Formation of the 1,4-dienol unit in 6 is envisioned by
elaboration of the hitherto unknown β-keto phsophonate 7
derived from tartaric acid amide, while Grignard reagent addition
and stereoselective reduction is planned for the installation of the
other hydroxy group at the C11 position (Scheme 1).
Until now, five total syntheses were reported for (+)-anamar-
ine in the literature. Early syntheses by Valverde et al.3 and by
Lorenz and Lichtenthaler4 involved an arduous approach from
carbohydrate precursors and suffered from low yields. A recent
approach by Gao and O’Doherty5 relied on Sharpless’ asym-
metric dihydroxylation of sorbic acid ester, while Sabitha et al.6
disclosed a multistep sequence using asymmetric dihydroxyla-
tion and olefin cross-metathesis as the key steps in their synthesis
of 1. The synthesis by Marco’s group7 involved a boronate aldol
reaction of lactic acid derived aldehyde with an appropriately
Received: May 26, 2011
Published: July 08, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo2010389 J. Org. Chem. 2011, 76, 6889–6893
|

The Journal of Organic Chemistry
NOTE
Scheme 2. Synthesis of the 1,4-Dienol Unit 13
Scheme 3. Total Synthesis of (À)-Anamarine 1
Accordingly, the synthetic sequence commenced with the
addition of 1.5 equiv of the lithium anion derived from dimethyl-
methyl phosphonate to the bis-Weinreb amide 89 affording
the mono keto phosphonate 7 in 76% yield.10 HornerÀ
WadsworthÀEmmons olefination of (S)-2-benzyloxypent-4-enal11
with the phosphonate 7 yielded the R,β-unsaturated ketone 9 in
73% yield (based on 65% conversion). Reduction of the ketone
under Luche reduction conditions furnished the diastereomeric
alcohols 10 and 11 along with the diol 12 resulting from the
competing reduction of the Weinreb amide. Minor diasteroemer
10 was separated by column chromatography, and the major
diastereomer 11 which was nonseparable from 12 was purified as
its MOM ether 13 (Scheme 2).
alcohol 16 in 88% yield. Mitsunobu inversion of 16 furnished the
required diastereomer, which was purified as the silyl ether 17
using standard conditions. Deprotection of the benzyl ether in 17
under Na/liqNH3 conditions yielded the homoallylic alcohol 6
in 81% yield. Acryloylation of 6 furnished the ester 18, which on
ring-closing metathesis (RCM) reaction with Grubbs’ first-gen-
eration catalyst12 afforded the lactone 5 in 83% yield. Deprotec-
tion of the protecting groups in 5 with PPTS in aq MeOH yielded
the polyol, which was acylated under standard conditions to
afford (À)-anamarine 1 in 53% yield (Scheme 3). The spectral
data and specific rotation of (À)-1 are in complete agreement
with that reported in literature.2,3,7
In conclusion, a linear strategy for the synthesis of polyol-
containing δ-pyranone natural product (À)-anamarine is pre-
sented from D-(À)-tartaric acid. The synthetic sequence
Addition of MeMgBr to 13 afforded the ketone 15 in almost
quantitative yield. Reduction of 15 with K-Selectride yielded the
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The Journal of Organic Chemistry
NOTE
showcased the use of hitherto unknown β-keto phosphonate
derived from tartaric acid amide in the construction of the 1,4-
dienol unit. The synthesis depicted is useful for the synthesis of
the other structurally similar natural products and their
analogues.
Compound 10: [R]24 À23.8 (c 2.0, CHCl3); IR (neat) 3445, 2935,
D
1663, 1381, 1066, 990 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 7.38À7.20
(m, 5H), 5.89À5.72 (m, 2H), 5.67 (dd, J = 15.7, 4.8 Hz, 1H), 5.05 (dd,
J = 15.6, 9.1 Hz, 2H), 4.75 (brs, 1H), 4.69 (brs, 1H), 4.52, 4.30 (ABq, J =
11.9 Hz, 2H), 4.48 (brs, 1H), 3.81 (q, J = 6.7 Hz, 1H), 3.71 (s, 3H), 3.14
(s, 3H), 2.48À2.34 (m, 2H), 2.33À2.20 (m, 1H), 1.49 (s, 3H), 1.44
(s, 3H); 13C NMR (100 MHz, CDCl3) 170.2, 138.6, 134.4, 132.7, 130.1,
128.3, 127.7, 127.5, 117.0, 111.1, 79.9, 78.9, 78.8, 72.1, 70.4, 70.0, 61.3,
40.1, 32.3, 26.9, 26.0, 14.2; HRMS for C22H31NO6 + Na calcd 428.2049,
found 428.2043.
’ EXPERIMENTAL SECTION
Preparation of 7. To a stirred solution of dimethyl methylpho-
sphonate (0.77 mL, 7.19 mmol) in THF (5 mL) was added LHMDS
(5.4 mL of 1 M solution in THF, 5.4 mmol) at À78 °C. The reaction
mixture was stirred at the same temperature for 40 min. A solution of 8
(1.00 g, 3.6 mmol) in THF (10 mL) was added dropwise at À78 °C and
stirred at the same temperature for 1 h. After completion of the reaction
(monitored by TLC), it was cautiously quenched by the addition of
saturated NH4Cl (2 mL) and dried over Na2SO4. Evaporation of solvent
followed by silica gel column chromatography of the resultant residue
with EtOAc as eluent furnished 7 (0.93 g, 76%) as a yellow colored oil:
Preparation of 13 and 14. To a precooled (0 °C) solution of a
mixture of 11 and 12 (0.42 g, obtained above) in DCM (5 mL) were
added DMAP (0.025 g, 0.20 mmol) and iPr2NEt (0.9 mL, 9.35 mmol)
dropwise followed by MOMCl (0.3 mL, 4.13 mmol). The reaction
mixture was slowly allowed to warm to room temperature and stirred at
room temperature for 3 h. After completion of the reaction (TLC), it
was poured into water (10 mL) and extracted with EtOAc (2 Â 20 mL).
The combined organic layers were washed with brine (5 mL) and dried
over Na2SO4. Evaporation of solvent gave the crude residue which was
purified and separated by silica gel column chromatography using
petroleum ether/EtOAc (4:1) as eluent to furnish 13 (0.34 g, 74% yield
for two steps) as a colorless oil and 14 (0.046 g) in 10% yield.
[R]24 À31.5 (c 1.3, CHCl3); IR (neat) 2939, 1721, 1670, 1261,
D
1030 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 5.11 (d, J = 4.5 Hz, 1H),
4.97 (d, J = 4.4 Hz, 1H), 3.81 (d, J = 5.4 Hz, 3H), 3.79 (d, J = 5.3 Hz, 3H),
3.72 (s, 3H), 3.53 (dd, J = 22.6, 14.3 Hz, 1H), 3.23 (s, 3H), 3.21 (dd, J =
22.6, 11.5 Hz, 1H), 1.50 (s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz,
CDCl3) 200.1, 169.4, 113.0, 82.3, 73.8, 61.7, 53.1 (d, J = 7 Hz), 53.03 (d,
J =7 Hz), 36.9 (d, J =130 Hz), 32.4, 26.6, 26.2; HRMSfor C12H22NO8P+
Na calcd 362.0981, found 362.0982.
Compound 13: [R]24 +16.2 (c 1.2, CHCl3); IR (neat) 2987, 2935,
D
1
1669, 1381, 1070, 1030, 987 cmÀ1; H NMR (400 MHz, CDCl3) δ
7.37À7.20 (m, 5H), 5.75 (ddt, J = 17.1, 10.4, 7.0 Hz, 1H), 5.70 (dd, J =
15.6, 7.4 Hz, 1H), 5.59 (dd, J = 15.7, 7.5 Hz, 1H), 5.04 (dd, J = 15.3, 8.4
Hz, 2H), 4.76À4.61 (brm, 2H), 4.67, 4.58 (ABq, J = 6.7 Hz, 2H), 4.50,
4.30 (ABq, J = 11.8 Hz, 2H), 4.23 (t, J = 6.5 Hz, 1H), 3.82 (q, J = 6.7 Hz,
1H), 3.70 (s, 3H), 3.36 (s, 3H), 3.14 (brs, 3H), 2.47À2.31 (m, 1H),
2.32À2.20 (m, 1H), 1.46 (s, 3H), 1.42 (s, 3H); 13C NMR (100 MHz,
CDCl3) 170.0, 138.4, 136.0, 134.2, 128.7, 128.3, 127.7, 127.5, 117.2,
111.5, 93.7, 79.1, 78.8, 76.1, 73.4, 70.1, 61.8, 55.5, 40.1, 32.3, 27.0, 26.1;
HRMS for C24H35NO7 + Na calcd 472.2311, found 472.2309. Com-
pound 14: [R]24D +28.0 (c 4.6, CHCl3); IR (neat) 2986, 2934, 2888,
1209, 1094, 1031, 917 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 7.40À7.21
(m, 5H), 5.79 (ddt, J = 16.6, 10.3, 6.6 Hz, 1H), 5.75 (dd, J = 15.5, 7.2 Hz,
1H), 5.60 (dd, J = 15.6, 7.6 Hz, 1H), 5.07 (dd, J = 13.9, 8.7 Hz, 2H), 4.71,
4.65 (ABq, J = 6.7 Hz, 2H), 4.66, 4.59 (ABq, J = 6.3 Hz, 2H), 4.57, 4.39
(ABq, J = 11.9 Hz, 2H), 4.24 (t, J = 6.2 Hz, 1H), 4.14 (td, J = 7.6, 2.1 Hz,
1H), 3.98À3.82 (m, 2H), 3.71 (dd, J = 10.6, 2.3 Hz, 1H), 3.60 (dd, J =
10.6, 6.6 Hz, 1H), 3.39 (s, 3H), 3.35 (s, 3H), 2.54À2.39 (m, 1H),
2.38À2.30 (m, 1H), 1.45 (s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz,
CDCl3) 138.4, 136.5, 134.2, 128.4, 128.0, 127.6, 127.5, 117.4, 109.8,
96.6, 93.5, 79.3, 78.8, 76.7, 75.9, 70.4, 68.3, 55.5, 55.3, 40.2, 27.2, 27.1;
HRMS for C24H36O7 + Na calcd 459.2359; found 459.2361.
Preparation of 9. To a solution of 7 (0.21 g, 0.62 mmol) in MeCN
(2 mL) was added Cs2CO3 (0.38 g, 1.17 mmol), and the reaction
mixture was stirred for 45 min at room temperature. It was cooled to
0 °C, and a freshly prepared solution of (S)-benzyloxypent-4-enal11
(0.58 mmol) in MeCN (5 mL) was added dropwise. The reaction
mixture was stirred at 0 °C for 1 h and was cautiously quenched by
addition of saturated citric acid (5 mL). The reaction mixture was then
poured into water (15 mL) and extracted with EtOAc (2 Â 15 mL). The
combined organic layers were washed with brine (5 mL) and dried over
Na2SO4. Evaporation of the solvent gave the crude residue which was
purified by silica gel column chromatography using petroleum ether/
EtOAc (3:2) as eluent to furnish 9 (0.12 g) in 48% yield as a colorless oil
along with 0.073 g (35%) of the unreacted phosphonate 7: [R]24
D
À18.3 (c 1.8, CHCl3); IR (neat) 2983, 2936, 1721, 1668, 1207, 1091,
1072 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 7.40À7.20 (m, 5H), 6.95
(dd, J = 15.9, 6.0 Hz, 1H), 6.65 (d, J = 15.9 Hz, 1H), 5.76 (ddt, J = 17.2,
10.0, 7.0 Hz, 1H), 5.13 (brd, J = 4.2 Hz, 1H), 5.08 (dd, J = 18.6, 9.3 Hz,
2H), 5.0 (brd J = 4.6 Hz, 1H), 4.56, 4.41 (ABq, J = 11.7 Hz, 2H), 4.05
(q, J = 6.2 Hz, 1H), 3.69 (s, 3H), 3.21 (s, 3H), 2.53À2.27 (m, 2H), 1.50
(s, 3H), 1.39 (s, 3H); 13C NMR (100 MHz, CDCl3) 196.3, 169.9, 148.5,
137.8, 133.3, 128.4, 127.8, 127.7, 125.9, 118.0, 113.0, 81.6, 77.9, 74.4,
71.2, 61.6, 39.2, 32.5, 26.7, 26.4; HRMS for C22H29NO6 + Na calcd
426.1894, found 426.1894.
Preparation of 15. To a precooled (0 °C) solution of 13 (0.293 g,
0.65 mmol) in THF (4 mL) was added a solution of methylmagnesium
bromide (0.4 mL of 2.5 M solution in THF, 1.0 mmol) under argon
atmosphere. The reaction mixture was stirred for 1 h at 0 °C, quenched
with saturated NH4Cl (3 mL), and extracted with ether (2 Â 15 mL).
The combined organic layers were washed with brine (5 mL) and dried
over Na2SO4. The residue obtained after evaporation of the solvent was
purified by column chromatography using petroleum ether/EtOAc
(9:1) as eluent to yield 15 (0.25 g) in 94% yield as a colorless oil: [R]
Preparation of 10À12. To a stirred solution of 9 (0.47 g,
1.15 mmol) in MeOH (1.5 mL) was added CeCl3 7H2O (0.65 g,
3
1.73 mmol), and the reaction mixture was stirred for 45 min at room
temperature. It was cooled to À78 °C, and NaBH4 (0.087 g, 2.3 mmol)
was added portionwise for over 5 min. The reaction mixture was stirred
at the same temperature for 1 h, and after completion of the reaction
(monitored by TLC), it was quenched by addition of water (1 mL) at
À78 °C, slowly warmed up to room temperature, and stirred at room
temperature for 10 min. The mixture was then poured into water
(10 mL) and extracted with EtOAc (2 Â 5 mL). The combined organic
layers were washed with brine (5 mL) and dried over Na2SO4.
Evaporation of the solvent gave the residue which was purified by silica
gel column chromatography using petroleum ether/EtOAc (1:1) as
eluent to furnish 10 (0.032 g, 7%) as a colorless oil and a nonseparable
mixture of 11 and 12 (0.42 g) which was used as such in the next step.
24
D +22.0 (c 1.1, CHCl3); IR (neat) 2989, 2935, 2893, 1716, 1211, 1152,
1086, 1029 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 7.38À7.20 (m, 5H),
5.76 (ddt, J = 17.0, 10.0, 7.0 Hz, 1H), 5.70 (dd, J = 15.9, 7.3 Hz, 1H), 5.61
(dd, J = 15.6, 6.8 Hz, 1H), 4.05 (dd, J = 16.0, 8.9 Hz, 2H), 4.70, 4.58
(ABq, J = 6.7 Hz, 2H), 4.51, 4.35 (ABq, J = 12.0 Hz, 2H), 4.32À4.15 (m,
3H), 3.86 (q, J = 6.7 Hz, 1H), 3.37 (s, 3H), 2.51À2.37 (m, 1H),
2.35À2.23 (m, 1H), 2.25 (s, 3H), 1.47 (s, 3H), 1.37 (s, 3H); 13C NMR
(100 MHz, CDCl3) 208.3, 138.5, 136.3, 134.2, 128.6, 128.3, 127.5,
127.4, 117.2, 111.1, 93.6, 81.6, 79.4, 78.8, 75.8, 70.2, 55.6, 40.1, 26.73,
26.67, 26.1; HRMS for C23H32O6 + Na calcd 427.2097, found 427.2093.
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Preparation of 16. To a stirred solution of the methyl ketone 15
(0.215 g, 0.53 mmol) in THF (5 mL) at À78 °C was added K-Selectride
(0.8 mL of 1 M solution in THF, 0.79 mmol) dropwise over 5 min, under
argon atmosphere. The reaction mixture was stirred for 1 h, quenched
with 2 N NaOH (0.8 mL) followed by 30% H2O2 (0.4 mL) at À78 °C,
and slowly allowed to warm to room temperature under stirring (∼3 h).
The reaction mixture was diluted with water (15 mL) and extracted with
ether (2 Â 15 mL). The combined ethereal layers were washed with
brine (5 mL) and dried over Na2SO4. Evaporation of solvent followed by
purification of the resultant residue using petroleum ether/EtOAc (4:1)
as eluent furnished the alcohol 16 (0.19 g) in 88% yield as a colorless oil:
[R]24D +34.8 (c 3.5, CHCl3); IR (neat) 3473, 2985, 2934, 1603, 1380,
1071, 1030 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 7.30À7.20 (m, 5H),
5.78 (ddt, J = 17.1, 10.2, 7.0 Hz, 1H), 5.72 (dd, J = 15.8, 7.2 Hz, 1H), 5.60
(dd, J = 15.6, 7.6 Hz, 1H), 5.14À5.0 (m, 2H), 4.70, 4.58 (ABq, J = 6.7 Hz,
2H), 4.56, 4.38 (ABq, J = 11.9 Hz, 2H), 4.21 (dd, J = 7.2, 5.9 Hz, 1H),
4.06 (t, J = 7.2 Hz, 1H), 3.89 (dd, J = 13.3, 6.6 Hz, 1H), 3.85À3.70
(m, 2H), 3.88 (s, 3H), 2.53À2.36 (m, 1H), 2.39À2.33 (m, 1H), 2.22
(d, J = 7.6 Hz, 1H), 1.44 (s, 3H), 1.43 (s, 3H), 1.23 (d, J = 6.4 Hz, 3H),
13C NMR (100 MHz, CDCl3) 138.3, 136.3, 134.1, 128.3, 128.2, 127.6,
127.5, 117.3, 109.5, 93.5, 81.0, 78.8, 76.0, 70.4, 66.8, 55.5, 40.1, 27.3,
27.2, 20.3; HRMS for C23H34O6 + Na calcd 429.2253, found 429.2254.
Preparation of 17. To a precooled (0 °C) solution of alcohol 16
(0.189 g, 0.46 mmol), triphenylphosphine (0.366 g, 1.39 mmol), and
p-nitrobenzoic acid (0.386 g, 2.32 mmol) in toluene (2 mL) was added a
solution of DIAD (0.36 mL, 1.86 mmol) in THF (2 mL). The reaction
mixture was stirred at room temperature for 5 h. After completion of the
reaction (TLC), most of the solvent was evaporated off and the residue
thus obtained was purified by silica gel column chromatography using
petroleum ether/EtOAc (9:1) to give p-nitrobenzoate as yellow colored
oil along with DIAD impurity.
and extracted with EtOAc (2 Â 10 mL). The combined organic layer
was washed with brine (5 mL) and dried over Na2SO4. Evaporation
of solvent followed by column chromatography of the resulting residue
using petroleum/EtoAc (3:2) as eluent furnished the homoallylic
alcohol 6 (0.105 g) in 81% yield as colorless oil: [R]24 +73.0 (c 1.0,
D
CHCl3); IR (neat) 3420, 2932, 2888, 1640, 1105, 1032, 833 cm-1; 1H
NMR (400 MHz, CDCl3) δ 5.85À5.70 (m, 2H), 5.66 (dd, J = 15.7, 8.3
Hz, 1H), 5.12 (dd, J = 17.1, 6.9 Hz, 2H), 4.70, 4.54 (ABq, J = 6.7 Hz,
2H), 4.21 (brs, 1H), 4.15 (dd, J = 8.1, 3.8 Hz, 1H), 3.99 (t, J = 4.0 Hz,
1H), 3.88 (t, J = 9.4 Hz, 1H), 3.79 (dq, J = 12.3, 5.9 Hz, 1H), 3.36 (s,
3H), 2.31À2.20 (m, 2H), 1.80 (brs, 1H), 1.42 (s, 3H), 1.37 (s, 3H), 1.21
(d, J = 5.9 Hz, 3H), 0.88 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR
(100 MHz, CDCl3) 137, 133.8, 127.4, 118.4, 109.6, 93.3, 81.8, 80.9, 75.6,
71.0, 70.5, 55.6, 41.7, 27.8, 27.2, 25.8, 21.2, 18.0, À4.3, À4.4; HRMS for
C22H42O6Si + Na calcd 453.2648, found 453.2638.
Preparation of 18. To a precooled (0 °C) solution of 6 (0.064 g,
0.14 mmol) in CH2Cl2 (2 mL) was added Et3N (0.06 mL, 0.44 mmol)
followed by acryloyl chloride (0.024 mL, 0.29 mmol) dropwise under
argon atmosphere and the reaction mixture stirred at same temperature
for 1 h. After completion of the reaction (TLC), it was poured into cold
water and extracted with ether (2 Â 10 mL). The combined ethereal
layer was washed with brine (5 mL) and dried over Na2SO4. Evaporation
of solvent followed by column chromatography of the resulting residue
with petroleum ether/EtOAc (85:15) as eluent furnished the acrylate
ester 18 (0.44 g) in 65% yield as colorless oil: [R]24 +57.1 (c 0.7,
D
CHCl3); IR (neat) 2902, 2894, 1729, 1188, 1093, 1072, 1031, 833 cmÀ1
;
1H NMR (400 MHz, CDCl3) δ 6.38 (d, J = 17.2 Hz, 1H), 6.09 (dd, J =
17.3, 10.4 Hz, 1H), 5.80 (d, J = 10.4 Hz, 1H), 5.78À5.55 (m, 3H), 5.41
(q, J = 6.1 Hz, 1H), 5.06 (dd, J = 17.3, 11.0 Hz, 2H), 4.67, 4.52 (ABq, J =
6.7 Hz, 2H), 4.15 (dd, J = 7.7, 3.7 Hz, 1H), 3.97 (dd, J = 6.0, 3.8 Hz, 1H),
3.83 (t, J = 6.6 Hz, 1H), 3.77 (dq, J = 12.3, 6.0 Hz, 1H), 3.32 (s, 3H),
2.53À2.31 (m, 2H), 1.40 (s, 3H), 1.36 (s, 3H), 1.19 (d, J = 5.8 Hz, 3H),
0.86 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3)
165.1, 133.3, 132.8, 130.8, 128.6, 128.5, 118.2, 109.5, 93.3, 81.4, 80.1,
75.4, 72.7, 70.3, 55.6, 38.9, 27.7, 27.2, 25.8, 21.1, 17.9, À4.3, À4.5;
HRMS for C25H44O7Si + Na calcd 507.2754, found 507.2755.
To a solution of the p-nitrobenzoate (obtained above) in MeOH
(3 mL) was added K2CO3 (0.32 g, 2.36 mmol) and the mixture stirred at
room temperature for 1 h. After completion of the reaction (monitored
by TLC), it was filtered through a short pad of Celite, and the Celite pad
was washed with ether (20 mL). Evaporation of the solvent gave the
crude residue which was usedin thenext step without further purification.
To a precooled (0 °C) solution of the alcohol (obtained above) in
CH2Cl2 (3 mL) were added DMAP (11 mg, 0.092 mmol) and imidazole
(0.094 g, 1.38 mmol) followed by TBSCl (0.138 g, 0.92 mmol) under
argon atmosphere. The reaction mixture was refluxed for 12 h. After
completion of the reaction (TLC), it was poured into cold water
(15 mL) and extracted with diethyl ether (2 Â 15 mL). The ethereal
layer was washed with brine (5 mL) and dried over Na2SO4. Evaporation
of the solvent and purification of the resulting residue by column
chromatography using petroleum ether/EtOAc (95:05) as eluent furn-
Preparation of 5. To a solution of the acrylate ester 18 (0.045 g,
0.092 mmol) in CH2Cl2 (10 mL) under stirring was added Grubbs first-
generation catalyst (0.008 g, 0.0092 mmol) under argon atmosphere,
and the reaction mixture was refluxed for 5 h. After completion of the
reaction, most of the solvent was evaporated off and the residue thus
obtained was purified by column chromatography using petroleum
ether/EtOAc (3:2) as eluent to furnish the lactone 5 (0.035 g) in 83%
yield as a brown oil: [R]24D +14.7 (c 3.5, CHCl3); IR (neat) 2933, 2892,
1730, 1379, 1249, 1091, 1031, 832 cmÀ1; 1H NMR (400 MHz, CDCl3)
δ 6.87 (dt, J = 8.6, 3.8 Hz, 1H), 6.03 (d, J = 9.8 Hz, 1H), 5.87 (d, J = 15.5
Hz, 1H), 5.83 (d, J = 15.3 Hz, 1H), 4.95 (brs, 1H), 4.67, 4.56 (ABq, J =
6.7 Hz, 2H), 4.20 (brd, J = 2.3 Hz, 1H), 3.98 (dd, J = 6.3, 3.0 Hz, 1H),
3.86 (t, J = 6.8 Hz, 1H), 3.79 (dq, J = 12.2, 6.0 Hz, 1H), 3.36 (s, 3H),
2.54À2.34 (brm, 2H), 1.41 (s, 3H), 1.36 (s, 3H), 1.21 (d, J = 5.9 Hz,
3H), 0.87 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz,
CDCl3) 163.7, 144.5, 131.4, 130.7, 121.6, 109.5, 93.7, 81.6, 80.7, 77.1,
75.1, 70.5, 55.7, 29.6, 27.6, 27.1, 25.8, 21.3, 18.0, À4.25, À4.4; HRMS for
C23H40O7Si + Na calcd 479.2441; found 479.2442.
Preparation of (À)-Anamarine (1). To a stirred solution of 5
(0.016 g, 0.035 mmol) in a mixture of MeOH/water (9:1, 2 mL) was
added PPTS (0.005 g, 0.017 mmol) at room temperature, and the
reaction mixture was refluxed for 12 h. After completion of the reaction
(TLC), NaHCO3 (0.1 g) was added and the mixture stirred for 5 min.
The reaction mixture was filtered through a short pad of Celite, and the
Celite pad was washed with CHCl3 (15 mL). The residue obtained after
evaporation of the solvent was purified by a short-path silica gel column
chromatography using EtOAc/MeOH (4:1) as eluent to furnish the
tetrol, which was used as such in the next step without characterization.
ished 17 (0.148 g) in 62% yield for three steps as colorless oil: [R]24
D
+38.9 (c 0.8, CHCl3); IR (neat) 2932, 2888, 1647, 1198, 1074, 1031,
1
833 cmÀ1; H NMR (400 MHz, CDCl3) δ 7.39À7.22 (m, 5H), 5.80
(ddt, J = 17.0, 9.8, 7.0 Hz, 1H), 5.70 (dd, J = 15.6, 5.4 Hz, 1H), 5.65 (dd,
J = 15.6, 4.7 Hz, 1H), 5.07 (dd, J = 16.9, 9.8 Hz, 2H), 4.74, 4.58 (ABq, J =
6.7 Hz, 2H), 4.58, 4.38 (ABq, J = 11.8 Hz, 2H), 4.23 (dd, J = 7.1, 4.3 Hz,
1H), 4.07 (dd, J = 6.0, 3.9 Hz, 1H), 3.97À3.85 (m, 2H), 3.82 (dq, J =
12.7, 6.2 Hz, 1H), 3.40 (s, 3H), 2.56À2.40 (m, 1H), 2.39À2.24 (m, 1H),
1.47 (s, 3H), 1.41 (s, 3H), 1.25 (d, J = 6.0 Hz, 3H), 0.91 (s, 9H), 0.10
(s, 3H), 0.09 (s, 3H); 13C NMR (100 MHz, CDCl3) 138.5, 136.0, 134.3,
130.0, 128.3, 127.7, 127.5, 117.1, 109.6, 93.3, 82.1, 81.0, 79.2, 75.5, 70.5,
70.3, 55.7, 40.2, 27.9, 27.3, 25.9, 21.3, 18.0, À4.2, À4.4; HRMS for
C29H48O6Si + Na calcd 543.3118, found 543.3113.
Preparation of 6. Lithium was added to precooled (À78 °C) liquid
NH3 followed by a THF (2 mL) solution of 17 (0.157 g, 0.3 mmol). The
reaction mixture was stirred at the same temperature for 1 h, and solid
NH4Cl (0.05 mg) was added followed by cautious addition of water
(15 mL). The reaction mixture was warmed up to room temperature
6892
dx.doi.org/10.1021/jo2010389 |J. Org. Chem. 2011, 76, 6889–6893

The Journal of Organic Chemistry
NOTE
To a precooled (0 °C) solution of the tetrol obtained above in
CH2Cl2 (1 mL) were added DMAP (0.001 g, 0.007 mmol) and Et3N
(0.047 mL, 0.35 mmol) followed by Ac2O (0.026 mL, 0.028 mmol)
under argon atmosphere. The reaction mixture was stirred at room
temperature for 1 h. After completion of the reaction (TLC), it was
poured into cold water and extracted with EtOAc (2 Â 10 mL). The
combined organic layers were washed with brine (5 mL) and dried over
Na2SO4. Evaporation of solvent followed by column chromatography
of the resultant residue using petroleum ether/EtOAc (1:1) as eluent
furnished (À)-anamarine (0.008 g) in 53% yield as a gummy mass:
[R]24D À16.0 (c 0.5, CHCl3); lit.3 [R]24D À15.0 (c 0.02, CHCl3); IR
(neat) 2935, 1745, 1223, 1028 cmÀ1; 1H NMR7 (400 MHz, CDCl3) δ
6.89 (ddd, J = 9.3, 5.0, 3.5 Hz, 1H), 6.07 (d, J = 9.5 Hz, 1H), 5.90À5.75
(m, 2H), 5.36 (dd, J = 7.0, 6.0 Hz, 1H), 5.31 (dd, J = 7.3, 3.5 Hz, 1H),
5.18 (dd, J = 6.9, 3.5 Hz, 1H), 4.97 (td, J = 12.6, 7.7 Hz, 1H), 4.91 (quint,
J = 6.5 Hz, 1H), 2.50À2.40 (m, 2H), 2.13 (s, 3H), 2.07 (s, 3H Â 2), 2.03
(s, 3H), 1.18 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) 170.0,
169.86, 169.83, 169.76, 163.5, 144.5, 133.0, 125.5, 121.5, 75.8, 71.9, 71.6,
Meyer, D. T.; Jadhav, P. K.; De Lucca, G. V.; Smyser, T. E.; Klabe, R. M.;
Bacheler, L. T.; Rayner, M. M.; Seitz, S. P. J. Med. Chem. 1996, 39, 2156.
(10) Formation of the C2-symmetric bis-phosphonate resulting
from the addition of lithium anion of methyldimethyl phosphonate
to both amide units is not observed. For synthesis of C2-symmetric
bis-phosphonate from diethyl tartrate, see: Narakunan, K.; Nagarajan,
M. J. Org. Chem. 1994, 59, 6386.
(11) (S)-2-Benzyloxypent-4-enal was synthesized according to the
procedure described: Mulzer, J.; Angermann, A. Tetrahedron Lett. 1983,
24, 2843.
(12) For a review on the application of Grubbs’ first-generation
catalyst in metathesis reactions, see: Grubbs, R. H.; Chang, S. Tetra-
hedron 1998, 54, 4413.
70.4, 67.3, 29.1, 21.0, 20.91, 20.86, 20.6, 15.8; HRMS for C20H26O10
Na calcd 449.1424, found 449.1422.
+
’ ASSOCIATED CONTENT
S
Supporting Information. General experimental proce-
b
dures and copies of 1H NMR and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Fax: +918023600529. E-mail: prasad@orgchem.iisc.ernet.in.
’ ACKNOWLEDGMENT
We thank the Department of Science and Technology (DST),
New Delhi for funding. K.R.P is a swarnajayanthi fellow of DST,
New Delhi. K.P. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi, for a senior research fellowship.
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