Formal total synthesis of (+)-didemniserinolipid B

Article abstract of DOI:10.1016/j.tetasy.2010.11.006

The formal total synthesis of (+)-didemniserinolipid B, a marine tunicate possessing a 6,8-dioxabicyclo[3.2.1]octane framework, was accomplished starting from l-(+)-tartaric acid. The key transformations in the synthesis include the elaboration of a γ-hyd

Full text of DOI:10.1016/j.tetasy.2010.11.006

Tetrahedron: Asymmetry 21 (2010) 2848–2852
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Formal total synthesis of (+)-didemniserinolipid B
⇑
Kavirayani R. Prasad , Vasudeva Rao Gandi
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The formal total synthesis of (+)-didemniserinolipid B, a marine tunicate possessing a 6,8-dioxabicy-
Received 26 October 2010
Accepted 8 November 2010
Available online 4 December 2010
clo[3.2.1]octane framework, was accomplished starting from
L-(+)-tartaric acid. The key transformations
in the synthesis include the elaboration of a -hydroxy-amide readily obtained by desymmetrization of
c
tartaric acid bis-amide via the controlled addition of a Grignard reagent followed by stereoselective
reduction of the resulting ketone.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Didemniserinolipid
B
1, is
a
6,8-dioxabicyclo[3.2.1]octane
Our approach for the synthesis of (+)-1 is based on the elabora-
tion of bicyclic acetal 3 via the known ester 2 as shown in Scheme 1.
The synthesis of the bicyclic acetal 3 was planned by intramolecu-
lar ketalization of the trihydroxy ketone 4. Extension of aldehyde 5
followed by hydrogenation was envisioned for the synthesis of ke-
framework containing natural product isolated from the marine
tunicate belonging to the genus Didemnum sp. reported by Gonz-
alez et al.1 Contrary to simple insect pheromones, which possess
similar bicylic skeletal framework with simple alkyl substituents,
didemniserinolipids comprise an extended alkyl chains, containing
tone 4. c-Hydroxy amide 6, derived from the bis-amide 7, was cho-
a 2-aminopropane 1,3-diol ether, and an
a
,b-unsaturated ester.
sen as the appropriate precursor for the synthesis of aldehyde 5.
The synthetic sequence started with the addition of 5-benzyl-
oxypentylmagnesium bromide to bis-dimethylamide 7 derived
from tartaric acid resulting in the ketoamide 8 in 82% yield.5 The
stereoselective reduction of the ketone in 8 with NaBH4 in the
presence of CeCl3Á7H2O afforded a mixture of diastereomeric alco-
hols (dr ꢀ 9:1 by NMR,6 with 6 being the major isomer) in 91%
yield. The hydroxy amide 6 was transformed into the rearranged
hydroxy ester 9 by employing a methodology developed by us pre-
viously for an analogous compound.5h Thus, treating the hydroxy
amide 6 with an excess of 2,2-dimethoxypropane and p-toluene-
sulfonic acid in refluxing benzene followed by column purification
Due to the bio-activity of related didemniserinolipids as inhibitors
of HIV-1 integrase,2 the synthesis of didemniserinolipids has at-
tracted the attention of synthetic chemists. Ley et al. reported
the early synthesis and structural revision of didemniserinolipid
B,3a while Burke et al. disclosed the synthesis of 1 employing their
ketalization/ring closing metathesis strategy.3b,c Ramana and Indu-
vadana reported a formal synthesis of didemniserinolipid B involv-
ing a Pd-mediated alkynediol cycloisomerization.3d Recently, we
have accomplished a formal total synthesis of (À)-didemniserinoli-
pid B, from
cient stereoselective formal total synthesis of (+)-1, starting from
the same chiral pool precursor -(+)-tartaric acid, thus enabling
L
-(+)-tartaric acid.4 Herein, we report an easy and effi-
L
resulted in pure a-hydroxy ester 9 in 81% yield. Mitsunobu inver-
the enantiodivergent syntheses of both antipodes of 1 from a com-
mon chiral source.
sion of the secondary alcohol in 9 furnished the epimeric alcohol
10 in 91% yield. Silver oxide mediated protection of the hydroxy
group in 10 as the benzyl ether, followed by reduction of the ester
with NaBH4 produced the primary alcohol 11 in 89% yield. Oxida-
tion of 11 with IBX gave aldehyde 5, which upon reaction with the
OH
phosphonate 127 resulted in a 3:1 E/Z mixture of the
a,b-unsatu-
O
O
H
4
NaO3SO
O
rated ketone 13 in 82% yield over two steps.8 Hydrogenation of
the olefin in 13 furnished the saturated ketone 4 in 87% yield.
Reaction of ketone 4 with FeCl3 affected the deprotection9 of the
acetonide with concomitant intramolecular ketalization furnishing
the bicyclic acetal 3 in 93% yield (31% overall yield over 10 steps
from 7). Conversion of the bicylic acetal 3 into didemniserinolipid
B 1, via ester 2 has already been described.3c,d,4 Hence the present
sequence constitutes a formal total synthesis of (+)-didemniserin-
olipid B (Scheme 2).
13
CO2Et
NH2
(+)-didemniserinolipid B 1
⇑
Corresponding author. Fax: +91 80 23600529.
E-mail address: prasad@orgchem.iisc.ernet.in (K.R. Prasad).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.11.006

K. R. Prasad, V. R. Gandi / Tetrahedron: Asymmetry 21 (2010) 2848–2852
2849
OH
H
OH
NBoc
O
O
O
O
O
H
4
O
NaO3SO
O
O
13
CO2Et
NH2
OEt
1
2
4
OBn
H
O
OBn
O
OBn
H
BnO
OH
14
BnO
O
O
O
HO
13
5
5
O
O
O
OBn
O
4
4
3
5
O
O
O
NMe2
OBn
Me2N
Me2N
4
O
O
O
OH
6
7
Scheme 1. Retrosynthesis for didemniserinolipid B.
O
O
O
O
NaBH4/CeCl3
MeOH, −78 °C
4 h, 93%
BnO
MgBr
3
NMe2
Me2N
OBn
Me2N
3
THF, −15 °C, 0.5 h
82%
O
O
O
O
7
8
MeO
MeO
Benzene, MeOH
1.5h, 60°C, 81%
i) PPh3, DIAD
PNBA, THF
0°C to rt, 1h
ii) K2CO3, MeOH
15 min, 91%
O
O
O
O
p-TSA
Me2N
OBn
MeO
OBn
3
3
O
OH
HO
O
O
9
6
i) Ag2O/BnBr
O
O
IBX, EtOAc
Δ, 4h
toulene, Δ, 5h, 94%
ii) NaBH4/MeOH
0°C to rt, 12h
89%
HO
OBn
MeO
OBn
HO
3
3
BnO
O
HO
O
11
10
OMe
P
OH
O
O
OMe
O
OBn
14
H2/Pd/C
NaHCO3, hexane
3h, 87%
O
O
12
OBn
Cs2CO3, iPrOH,-15 °C to rt
2h, 82%
O
3
14
4
BnO
O
BnO
O
5
13 (E:Z 3:1)
OBn
ref. 4
O
O
O
O
FeCl3. 6H2O
CH2Cl2, rt, 0.5h
93%
HO
HO
O
OBn
OBn
3
12
4
BnO
O
3
4
OH
NBoc
O
O
O
ref. 3c
O
1
OEt
4
2
Scheme 2. Formal total synthesis of didemniserinolipid B.
reactions in the synthetic sequence include the formation of the
6,8-dioxabicyclo[3.2.1]octane framework by elaboration of
-hydroxy amide obtained by desymmetrization of the tartaric
acid bis-amide. The synthetic sequence depicted herein, in
3. Conclusion
a
c
In conclusion, a concise approach for the formal total synthesis
of (+)-didemniserinolipid has been accomplished. The key
B

2850
K. R. Prasad, V. R. Gandi / Tetrahedron: Asymmetry 21 (2010) 2848–2852
combination with our earlier approach4 for the other enantiomer
provides amenable strategies for the synthesis of a number of ana-
logs in both enantiomeric forms.
4.4. Preparation of (R)-methyl 2-((4R,5R)-5-(5-(benzyloxy)-
pentyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyacetate 9
To a stirred solution of 6 (0.6 g, 1.58 mmol) in benzene (6 mL)
was added p-toluenesulfonic acid (0.33 g, 1.74 mmol) at room tem-
perature. It was then heated to 60 °C and kept at the same temper-
ature for 30 min. The reaction mixture was cooled to room
temperature, after which 2,2-dimethoxy propane (0.78 mL,
6.33 mmol) and methanol (0.78 mL) were introduced. The reaction
mixture was then stirred for 1 h at 60 °C, cooled to room tempera-
ture and solid K2CO3 (0.24 g) was added. The reaction mixture was
filtered through a short pad of Celite and the Celite pad was
washed with CH2Cl2 (2 Â 10 mL). Evaporation of the solvent fol-
lowed by silica gel column chromatography of the crude residue
with petroleum ether/EtOAc (7:3) as eluent gave the hydroxy ester
4. Experimental
4.1. General procedures
Column chromatography was performed on silica gel, Acme
grade 100–200 mesh. TLC plates were visualized either with UV,
in an iodine chamber, or with phosphomolybdic acid spray, unless
noted otherwise. Unless stated otherwise, all reagents were pur-
chased from commercial sources and used without additional puri-
fication. THF was freshly distilled over Na-benzophenone ketyl.
Melting points were uncorrected. Unless stated otherwise, all the
reactions were performed under inert atmosphere. Unless stated
otherwise, all the NMR spectra were recorded in CDCl3.
9 (0.48 g, 82%) as a colorless oil. [
a
]
D = +14.3 (c 1.5, CHCl3); IR
(neat) 3446, 2988, 2863, 1748, 1456, 1067 cmÀ1
;
1H NMR
(400 MHz, CDCl3) d 7.49–7.05 (m, 5H), 4.52 (s, 2H), 4.24–4.01 (m,
2H), 3.98–3.86 (m, 1H), 3.86 (s, 3H), 3.49 (t, J = 6.3 Hz, 2H), 3.03
(br s, 1H), 1.97–1.15 (m, 14H); 13C NMR (100 MHz, CDCl3) d
172.9, 138.6, 128.3, 127.6, 127.5, 109.3, 81.4, 76.4, 72.8, 70.2,
68.8, 52.8, 32.5, 29.6, 27.4, 26.5, 26.3, 25.8; HRMS for C20H30O6+Na
calcd 389.1940; found 389.1936.
4.2. Preparation of (4R,5R)-5-(6-(benzyloxy)hexanoyl)-N,N,2,2-
tetramethyl-1,3-dioxolane-4-carboxamide 8
In a two necked 100 mL, round bottomed flask equipped with a
magnetic stirrer bar, rubber septum, and argon inlet was placed 7
(1.6 g, 6.6 mmol). This was dissolved in 10 mL of THF and was
cooled to À10 °C to À15 °C. A freshly prepared THF solution of 5-
benzyloxy-pentylmagnesium bromide (20 mL of 0.5 M solution in
THF, 10 mmol) was added at such a rate that the internal temper-
ature does not rise above À10 °C. The progress of the reaction was
monitored by TLC and after the reaction was complete (ꢀ0.5 h), it
was cautiously quenched by the addition of a saturated solution of
NH4Cl (5 mL). It was then poured into water (10 mL) and extracted
with ethyl acetate (2 Â 20 mL). The combined EtOAc extracts were
washed with brine (10 mL) and dried (Na2SO4). Evaporation of the
solvent and silica gel column chromatography of the resulting res-
idue with petroleum ether/EtOAc (3:2) as eluent yielded 8 (2.05 g,
4.5. Preparation of 10
To a solution of 9 (0.36 g, 1 mmol) in dry THF (6 mL), were
added triphenyl phosphine (0.79 g, 3 mmol), and p-nitrobenzoic
acid (0.5 g, 3 mmol) under an argon atmosphere and stirred for
10 min at room temperature. The reaction mixture was cooled to
0 °C and DIAD (0.6 mL, 3 mmol) was introduced into the reaction
mixture over a period of 15 min. It was then warmed to room tem-
perature and stirred at room temperature for 1 h. After the reaction
was complete (TLC), most of the solvent was removed under re-
duced pressure and the crude ester thus obtained was purified
by column chromatography with petroleum ether/ether (9:1) as
eluent to yield the corresponding p-nitrobenzoate ester (0.45 g)
which was subjected to the next step immediately.
86%) as a colorless oil. [
a]
D = +10.1 (c 3.8, CHCl3); IR (neat) 3030,
2938, 1715, 1656, 1260 cmÀ1
;
1H NMR (400 MHz, CDCl3) d 7.49–
7.15 (m, 5H), 5.11 (d, J = 5.8 Hz, 1H), 4.77 (d, J = 5.8 Hz, 1H), 4.47
(s, 2H), 3.44 (t, J = 6.5 Hz, 2H), 3.11 (s, 3H), 2.96 (s, 3H), 2.78–
2.45 (m, 2H), 1.95–1.51 (m, 5H), 1.48–1.15 (m, 9H); 13C NMR
(100 MHz, CDCl3) d 209.3, 168.2, 138.6, 128.4, 127.6, 127.5,
112.1, 82.3, 75.2, 73.1, 70.4, 39.6, 37.3, 36.3, 29.8, 26.6, 26.3,
To a methanol (5 mL) solution of p-nitrobenzoate ester (0.45 g,
1 mmol) obtained above was added K2CO3 (0.21 g, 1.5 mmol) and
stirred for 15 min at 0 °C. After the reaction was complete (TLC),
the reaction mixture was poured into ice-cold water (5 mL) and ex-
tracted with ethyl acetate (2 Â 15 mL). The combined organic lay-
ers were washed with brine (5 mL) and dried over Na2SO4.
Evaporation of the solvent and silica gel column chromatography
of the crude residue with petroleum ether/EtOAc (7:3) as eluent
26.0, 23.1; HRMS for
400.2108.
C21H31NO5+Na calcd 400.2100; found
4.3. Preparation of 6
yielded 10 (0.34 g, 91%) as a colorless oil. [
a]
D = +27.9 (c 2.0,
CHCl3); IR (neat) 3447, 2938, 2862, 1747, 1456, 1217 cmÀ1
;
1H
To a stirred solution of 8 (1 g, 2.75 mmol) in methanol (10 mL)
was added CeCl3Á7H2O (1.23 g, 3.31 mmol) and stirred for 1 h at
room temperature. Then the reaction mixture was cooled to
À78 °C and NaBH4 (0.13 g, 3.31 mmol) was added portion wise
over a period of 0.5 h and stirred at the same temperature. It was
then cautiously quenched by the addition of water (20 mL) and ex-
tracted with EtOAc (3 Â 15 mL). The combined organic layers were
washed with brine (10 mL), dried over Na2SO4 and concentrated.
Silica gel column chromatography of the resulting residue with
petroleum ether/EtOAc (2:3) as eluent gave alcohol 6 (0.93 g,
NMR (400 MHz, CDCl3) d 7.49–7.15 (m, 5H), 4.52 (s, 2H), 4.34 (br
s, 1H), 4.19–4.05 (m, 1H), 3.98–3.84 (m, 1H), 3.82 (s, 3H), 3.48 (t,
J = 6.3 Hz, 2H), 3.00 (d, J = 4.5 Hz, 1H), 1.77–1.15 (m, 14H); 13C
NMR (75 MHz, CDCl3) d 172.3, 138.6, 128.3, 127.6, 127.5, 109.1,
82.0, 76.6, 72.8, 70.7, 70.2, 52.6, 33.3, 29.6, 27.4, 26.8, 26.2, 25.7;
HRMS for C20H30O6+Na calcd 389.1940; found 389.1938.
4.6. Preparationof(R)-2-(benzyloxy)-2-((4S,5R)-5-(5-(benzyloxy)-
pentyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol 11
93%) as a colorless oil. [
a
]
D = À12.8 (c 1.6, CHCl3); IR (neat) 3446,
To a stirred solution of the hydroxy ester 10 (0.35 g, 0.96 mmol)
in toluene (6 mL) was added Ag2O (0.55 g, 2.4 mmol) under an ar-
gon atmosphere at room temperature and stirred for 1 h at the
same temperature. Benzyl bromide (0.18 mL, 1.44 mmol) was then
introduced into the reaction mixture, stirred at room temperature
for 1 h and then for a further 3 h at reflux. It was then cooled to
room temperature, filtered through a short pad of Celite and the
Celite pad was washed with CH2Cl2 (2 Â 10 mL). Evaporation of
2987, 1651, 1373, 1069, 740 cmÀ1
;
1H NMR (400 MHz, CDCl3) d
7.49–7.15 (m, 5H), 4.74–4.50 (m, 2H), 4.49 (s, 2H), 3.58 (br s,
1H), 3.46 (t, J = 6.6 Hz, 2H), 3.13 (s, 3H), 2.96 (s, 3H), 2.08 (d,
J = 8.6 Hz, 1H, exchangable with D2O), 1.65–1.15 (m, 14H); 13C
NMR (100 MHz, CDCl3) d 168.9, 138.6, 128.3, 127.6, 127.4, 110.2,
80.1, 74.1, 72.7, 70.3, 69.9, 37.0, 35.6, 34.7, 29.6, 26.7, 26.1, 26.0,
25.6; HRMS for C21H33NO5+Na calcd 402.2256; found 402.2243.

K. R. Prasad, V. R. Gandi / Tetrahedron: Asymmetry 21 (2010) 2848–2852
2851
solvent followed by silica gel column chromatography of the crude
residue with petroleum ether/EtOAc (4:1) as eluent yielded the
corresponding benzyloxy ester (0.41 g, 94%) as a colorless oil.
J = 11.9 Hz, 1H), 3.98 (t, J = 6.1 Hz, 1H), 3.87–3.79 (m, 1H), 3.74–
3.66 (m, 1H), 3.62 (t, J = 6.6 Hz, 2H), 3.45 (t, J = 6.6 Hz, 2H), 2.57
(t, J = 7.4 Hz, 2H), 2.46 (m, 1H), 1.69–1.50 (m, 10H), 1.49–1.23
(m, 30H); 13C NMR (100 MHz, CDCl3) d 201.3, 200.4, 143.1, 142.2,
138.7, 138.61, 138.12, 137.4, 132.0, 130.0, 128.4, 128.3, 128.2,
128.1, 127.93, 127.90, 127.61, 127.55, 127.43, 127.40, 109.1,
108.8, 82.6, 82.1, 79.3, 79.2, 74.4, 72.8, 71.73, 71.66, 70.37, 70.26,
63.0, 44.2, 40.3, 34.0, 32.8, 29.59, 29.56, 29.53, 29.44, 29.39,
29.24, 29.16, 27.4, 26.9, 26.2, 25.9, 25.7, 24.1, 23.8; HRMS for
[
a]
D = À11.9 (c 1.2, CHCl3); IR (neat) 3032, 2936, 2860, 1749,
1370, 1100 cmÀ1 1H NMR (400 MHz, CDCl3) d 7.49–7.12 (m,
;
10H), 4.74 (d, J = 11.8 Hz, 1H), 4.52 (s, 2H), 4.48 (d, J = 11.8 Hz,
1H), 4.07 (d, J = 4.6 Hz, 1H), 3.94 (t, J = 7.2 Hz, 2H), 3.79 (s, 3H),
3.48 (t, J = 6.3 Hz, 2H), 1.77–1.15 (m, 14H); 13C NMR (100 MHz,
CDCl3) d 170.7, 138.6, 136.9, 128.4, 128.3, 128.1, 128.0, 127.6,
127.5, 109.3, 80.7, 78.8, 78.2, 72.9, 72.8, 70.3, 52.1, 33.6, 29.6,
27.5, 26.8, 26.2, 25.8; HRMS for C27H36O6+Na calcd 479.2410;
found 479.2409.
In a single necked round bottomed flask equipped with a mag-
netic stirrer bar and guard tube was placed a solution of the ben-
zyloxy ester (0.4 g, 0.88 mmol) in 5 mL of MeOH. Next, NaBH4
(0.17 g, 4.4 mmol) was then introduced in to the reaction mixture
portionwise at 0 °C. The reaction mixture was slowly warmed up to
room temperature and stirred overnight at the same temperature.
Most of the methanol was evaporated off; water (10 mL) was
added and extracted with EtOAc (2 Â 10 mL). The combined organ-
ic layers were washed with brine (5 mL) and dried over Na2SO4.
Evaporation of the solvent followed by silica gel column chroma-
tography of the crude residue with petroleum ether/EtOAc (7:3)
C43H66O6+Na calcd 701.4757; found 701.4747.
4.8. Preparation of (R,)-1-(benzyloxy)-1-((4R,5R)-5-(5-(benzyl-
oxy)pentyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-19-hydroxynona-
decan-4-one 4
To a solution of 13 (56 mg, 0.08 mmol) in hexane (2 mL) was
added solid NaHCO3 (30 mg) and palladium on activated charcoal
(20 mg). The reaction mixture was stirred for 2 h under a hydrogen
atmosphere, after which it was filtered through a short pad of Cel-
ite and the Celite pad was washed with ether (10 mL). Evaporation
of the solvent followed by silica gel column chromatography of the
residue with petroleum ether/EtOAc (4:1) as eluent afforded 4
(49 mg, 87%) as a colorless oil. [
a]
D = +14.1 (c 1.5, CHCl3); IR (neat)
;
as eluent gave alcohol 11 (0.33 g, 88%) as
D = À3.7 (c 1.9, CHCl3); IR (neat) 3447, 3031, 2935, 1456, 1251,
1073 cmÀ1 1H NMR (400 MHz, CDCl3) d 7.39–7.12 (m, 10H), 4.62
a colorless oil.
3422, 2927, 1718, 1369, 1071 cmÀ1
1H NMR (400 MHz, CDCl3) d
[a]
7.49–7.15 (m, 10H), 4.56 and 4.53 (ABq, J = 11.7 Hz, 2H), 4.49 (s,
2H), 3.88 (td, J = 7.7, 3.0 Hz, 1H), 3.74–3.59 (m, 3H), 3.58–3.49
(m, 1H), 3.44 (t, J = 5.8 Hz, 2H), 2.59–2.44 (m, 2H), 2.32 (td,
J = 7.4, 3.4 Hz, 2H), 2.19–1.75 (m, 2H), 1.73–1.48 (m, 8H), 1.44–
1.15 (m, 32H); 13C NMR (100 MHz, CDCl3) d 211.1, 138.7, 138.2,
128.63, 128.58, 128.3, 128.0, 127.9, 127.7, 108.5, 82.0, 79.6, 78.7,
73.1, 72.4, 70.6, 63.3, 43.2, 37.8, 34.7, 33.1, 29.9 (5C), 29.7 (4C),
29.5 (4C), 29.3 (3C), 27.6, 27.3, 26.5, 26.4, 26.0, 24.6, 24.1; HRMS
for C43H68O6+Na calcd 703.4914; found 703.4904.
;
and 4.53 (ABq, J = 11.6 Hz, 2H), 4.44 (s, 2H), 3.78 (ddd, J = 15.8,
12.0, 4.4 Hz, 2H), 3.74–3.63 (m, 2H), 3.51–3.42 (m, 1H), 3.40 (t,
J = 6.6 Hz, 2H), 2.0 (br s, 1H), 1.75–1.42 (m, 5H), 1.32 (d,
J = 12.1 Hz, 9H); 13C NMR (100 MHz, CDCl3) d 138.6, 137.7, 128.5,
128.3, 128.0, 127.6, 127.5, 108.8, 80.4, 80.0, 79.9, 72.8, 72.4, 70.3,
61.8, 34.1, 29.7, 27.3, 27.0, 26.2, 26.1; HRMS for C26H36O5+Na calcd
451.2460; found 451.2469.
4.7. Preparation of (R,E)-1-(benzyloxy)-1-((4S,5R)-5-(5-(benzyl-
oxy)pentyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-19-hydroxynona-
dec-2-en-4-one 13
4.9. Preparation of 15-((1R,2R,5S,7R)-2-(benzyloxy)-7-(5-
(benzyloxy)pentyl)-6,8-dioxa-bicyclo[3.2.1]octan-5-yl)-
pentadecan-1-ol 3
To a stirred solution of alcohol 11 (0.1 g, 0.23 mmol) in EtOAc
(4 mL) was added IBX (0.2 g, 0.69 mmol) at room temperature
and refluxed for 4 h. The reaction mixture was then filtered
through a short pad of Celite and the Celite pad was washed with
ether (2 Â 10 mL). The organic layer was washed with saturated
NaHCO3 solution (5 mL), brine (5 mL), and dried over Na2SO4.
Evaporation of the solvent followed by silica gel column chroma-
tography of the crude residue with petroleum ether/EtOAc (7:3)
as eluent afforded aldehyde 5 (0.08 g), which was used for the next
step immediately.
To a pre-cooled suspension of Cs2CO3 (0.3 g, 0.92 mmol) in
iPrOH (2 mL) was added the solid phosphonate 123c (0.17 g,
0.46 mmol) at 15 °C and was slowly warmed to room temperature,
stirred for 20 min at the same temperature. It was then cooled to
À15 °C, and a solution of the aldehyde 5 (0.08 g, 0.23 mmol) in
iPrOH (2 mL) was added at the same temperature. The reaction
mixture was slowly allowed to return to room temperature and
stirred for 1.5 h at room temperature. It was then quenched with
saturated NH4Cl solution (5 mL) and extracted with EtOAc
(3 Â 5 mL). The combined organic layers were washed with brine
(5 mL) and dried over Na2SO4. Evaporation of the solvent followed
by silica gel column chromatography of the crude residue with
petroleum ether/EtOAc (7:3) as eluent furnished 13 (0.13 g, 82%)
To a stirred solution of 4 (10 mg, 0.015 mmol) in CH2Cl2
(1.5 mL) was added FeCl3Á6H2O (10 mg, 0.04 mmol) at room tem-
perature under an argon atmosphere. The progress of the reaction
was monitored by TLC and after the reaction was complete
(ꢀ0.5 h), it was filtered through a short pad of Celite and the Celite
pad was washed with CH2Cl2 (5 mL). The organic layer was washed
with saturated solution of NaHCO3 (2 mL) followed by brine (3 mL)
and dried over Na2SO4. Evaporation of the solvent and silica gel
column chromatography of the residue with petroleum ether/ether
(4:1) as eluent yielded 3 (8 mg, 94%) as a colorless oil. [
(c 0.5, CHCl3); Lit4
D = À21.2 (c 3, CHCl3); IR (neat) 3373, 2927,
2854, 1543, 1027 cmÀ1 1H NMR (400 MHz, CDCl3) d 7.49–7.15
a]D = +23.5
[a]
;
(m, 10H), 4.62 and 4.59 (ABq, 12.9 Hz, 2H), 4.49 (s, 2H), 4.17 (br
s, 1H), 3.90–3.73 (m, 1H), 3.63 (t, J = 6.6 Hz, 2H), 3.46 (t,
J = 6.6 Hz, 2H), 3.29 (br s, 1H), 2.37 (t, J = 5.1 Hz, 1H), 1.99–1.15
(m, 40H); 13C NMR (100 MHz, CDCl3) d 138.7, 138.5, 128.42,
128.37, 127.68, 127.63, 127.51, 109.4, 80.1, 77.8, 72.9, 72.3, 70.4
(2C), 63.1, 37.4, 35.3, 32.8, 30.8, 29.8, 29.67, 29.62, 29.5, 26.1,
25.8, 25.5, 22.8, 22.0; HRMS for C40H62O5+Na calcd 645.4495;
found 645.4481.
Acknowledgments
as a colorless oil. [
a
]
D = À6.4 (c 3.3, CHCl3); IR (neat) 3446, 2986,
2854, 1694, 1682, 1455, 1072 cmÀ1
;
1H NMR (400 MHz, CDCl3) d
K.R.P. is a Swarnajayanthi fellow of the Department of Science
and Technology (DST), New Delhi and thanks DST for funding.
V.R.G. thanks CSIR for a research fellowship.
7.38–7.15 (m, 10H), 6.75 (dd, J = 16.1, 6.3 Hz, 1H), 6.27 (d,
J = 16.2 Hz, 1H), 4.63 (d, J = 11.9 Hz, 1H), 4.49 (s, 2H), 4.42 (d,

2852
K. R. Prasad, V. R. Gandi / Tetrahedron: Asymmetry 21 (2010) 2848–2852
Pawar, A. B. ARKIVOC 2010, 39; (c) Prasad, K. R.; Gandi, V. R.; Nidhiry, J. E.; Bhat,
References
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spectroscopy. The alcohols were inseparable at this stage.
7. Phosphonate 11 was synthesized by a procedure described by Burke et al.3b
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Prasad, K. R.; Chandrakumar, A. Tetrahedron 2007, 63, 1798; For recent
application of -keto amides derived from tartaric acid in natural product
synthesis see: (a) Prasad, K. R.; Pawar, A. B. Synlett 2010, 1093; (b) Prasad, K. R.;
c-keto amides from tartaric acid see:
c