Stereoselective total synthesis of simplactone A

Article abstract of DOI:10.1016/j.tetasy.2009.07.008

The efficient and simple stereoselective approach toward the total synthesis of simplactone A is described. The key features of this synthetic strategy include stereoselective C-ethylation, selective triol protection, and Wittig olefination for the format

Full text of DOI:10.1016/j.tetasy.2009.07.008

Tetrahedron: Asymmetry 20 (2009) 1798–1801
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective total synthesis of simplactone A
*
Ahmed Kamal , Papagari Venkat Reddy, Singaraboina Prabhakar, Paidakula Suresh
Chemical Biology Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The efficient and simple stereoselective approach toward the total synthesis of simplactone A is
described. The key features of this synthetic strategy include stereoselective C-ethylation, selective triol
protection, and Wittig olefination for the formation of the six-membered ring.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 1 June 2009
Accepted 7 July 2009
Available online 5 August 2009
1. Introduction
OH
O
OH
O
The d lactone ring system is found in many natural products and
is also featured in many intermediates used for the synthesis of
biologically active important compounds. The d lactones have been
shown to exhibit a wide range of biological activities such as anti-
biotic, anticancer, anti-inflammatory, and bactericidal activities. In
view of their interesting structural features and biological activi-
ties, different synthetic routes have been developed for these
compounds.
O
O
simplactone A 1
simplactone B 2
Figure 1.
2. Results and discussion
The d lactones, simplactones A 1 and B 2 have been isolated
from the Caribbean sponge,1 plakortis simplex (as shown in
Fig. 1). Their structures have been proposed on the basis of their
spectroscopic data, and they are known to possess in vitro cyto-
toxic activity against WEHI 164. Some approaches have been
developed in the literature2a–d for the synthesis of these d lactones
by employing different procedures. Ogasawara synthesized sim-
plactones A and B from enantiopure 4-cumyloxy-2-cyclopentene-
1-one.2a Ogasawara also proposed that their spectroscopic values
are identical with those of the proposed (isolated) simplactones
B and A, respectively. Recently, Olivo and coworkers synthesized
the simplactones A and B utilizing a doubly diastereoselective ace-
tate aldol reaction in five steps from N-acyl thiazolidinethione chi-
ral auxiliaries2d and in order to avoid confusion, the reference has
been made to these lactones based on their absolute configuration.
As part of our studies directed toward the synthesis of lactones and
other biologically active molecules,3 we herein report a new syn-
thetic route to simplactone A utilizing a stereoselective ethylation
and selective protection of the triol from commercially available
(S)-malic acid.
(S)-Malic acid 2 was subjected to esterification using BF3ꢀOEt2 in
methanol to give dimethyl malate 3 in 98% yield. The dianion of 3,
formed on treatment with LHMDS in THF, was alkylated with ethyl
iodide according to Seebach’s procedure to provide 4 as the pre-
dominant diastereomer (anti/syn 9:1) in 76% yield after flash col-
umn chromatography.4 Treatment of the anti-diastereomer 4
with lithium aluminum hydride in THF afforded the desired triol
5 in 82% yield. Selective 1,3-protection of triol 5 afforded a six-
membered acetal,5 as p-methoxybenzylidene acetal 6a (p-methoxy-
benzaldehyde dimethylacetal, CSA, CH2Cl2) in 85% yield, and
1,2-protection afforded a five-membered acetal as p-methoxyben-
zylidene acetal 6b in 12% yield. These two acetals 6a and 6b were
separated by column chromatography (Scheme 2).
Alcohol 6a was oxidized under Swern’s oxidative conditions to
give the corresponding aldehyde, which without purification (as
a crude) on Wittig olefination with MeTPPI and n-BuLi in THF gave
the olefin 7 in 72% yield. Selective hydroboration of the terminal
olefin 7 was achieved with dicyclohexylborane [(Cy)2BH] followed
by oxidative workup to provide the homologated primary alcohol 8
(88% yield) as the exclusive product.6 Primary alcohol in 8 was oxi-
dized under Swern’s oxidative conditions to provide the aldehyde,
which without further purification underwent further oxidation
with NaClO2, NaH2PO4, and DMSO to give the acid in 77% yield,
which was treated with diazomethane to afford the ester in 87%
yield. This compound 10 was treated with AcOH/H2O (4:1) which
resulted in p-methoxybenzylidene deprotection and subsequent
The present approach for the synthesis of simplactone A is de-
picted in Scheme 1. The key for this approach is the synthesis of
4 and 6a starting from the commercially available (S)-malic acid.
* Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189.
E-mail address: ahmedkamal@iict.res.in (A. Kamal).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.07.008

A. Kamal et al. / Tetrahedron: Asymmetry 20 (2009) 1798–1801
1799
PMP
PMP
PMP
O
OH
O
O
O
O
O
O
O
OH
OH
OMe
O
1
10
8
6a
O
OH
OMe
MeO
(S)-Malic acid
O
2
4
Scheme 1. Retrosynthetic analysis of 1.
O
OH
O
OH
OH
OMe
OH
OMe
c
b
a
MeO
HO
MeO
(S)-Malic acid
O
O
5
2
3
4
d
PMP
PMP
O
PMP
O
PMP
O
OH
O
O
O
O
O
e
f
+
OH
OH
8
7
6a
6b
g
PMP
O
PMP
O
OH
O
O
O
O
i
h
OMe
OH
O
O
9
10
1
Scheme 2. Reagents and conditions: (a) BF3ꢀOEt2, MeOH, 0 °C to rt, 6 h, 98%; (b) LHMDS, EtI, THF, ꢁ78 °C to 0 °C, 24 h, 76%; (c) LAH, THF, 55 °C, 12 h, 82%; (d) PMB(OMe)2, CSA,
CH2Cl2, 0 °C, 2 h, 85%; (e) (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢁ78 °C, 1 h; (ii) MeTPPBr, n-BuLi, THF, ꢁ78 °C, 1 h, 72% over two steps; (f) Cy2BH, THF, 0 °C to rt, 6 h, then H2O2,
NaOH, 0 °C to rt, 2 h, 88%; (g) (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢁ78 °C, 1 h; (ii) NaClO2, NaH2PO4, DMSO, 0 °C to rt, 10 h, 77% over two steps; (h) CH2N2, ether, 0 °C, 1 h, 87%; (i)
4:1 AcOH/H2O, 0 °C to rt, 6 h, 85%.
lactonization afforded the target molecule. The spectroscopic and
analytical data were comparable to the previously reported data
in the literature.2a,d
recorded on Perkin–Elmer 683 spectrometer. Optical rotations
were obtained on a Horiba 360 digital polarimeter. 1H and 13C
NMR spectra were recorded in CDCl3 solution on a Varian Gemini
200, Brucker Avance 300. Chemical shifts are reported in parts
per million with respect to the internal TMS. Mass spectra were re-
corded on VG micromass-7070H (70 Ev).
3. Conclusion
In conclusion, we have developed a simple, convenient, and effi-
cient approach for the synthesis of naturally occurring simplactone
A utilizing stereoselective ethylation and selective protection of a
triol from commercially available (S)-malic acid. The synthesis of
related compounds of this family is underway in our laboratory.
4.2. Dimethyl (2R,3S)-2-ethyl-3-hydroxybutanedioate 4
To a stirred solution of dimethyl malate 3 (4 g, 24.69 mmol) in
dry THF (40 mL) at ꢁ78 °C LHMDS (54.3 mL, 54.32 mmol, 1 M in
THF) was added slowly and stirred for 1 h at the same temperature.
Ethyl iodide (2.96 mL, 37.03 mmol) in THF (7 mL) was added
slowly and stirred at ꢁ78 °C for 3 h. Then the temperature was
gradually increased to 0 °C for 20 h. After completion of the reac-
tion, the reaction mixture was quenched with aqueous NH4Cl at
ꢁ78 °C. Later the reaction mixture was acidified with dil HCl,
THF was evaporated and extracted with EtOAc (2 ꢂ 60 mL). The
combined organic layers were dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified by column
4. Experimental
4.1. General
Reagents and chemicals were purchased from Aldrich. All sol-
vents and reagents were purified by standard techniques. THF
was freshly distilled from LiAlH4. Crude products were purified
by column chromatography on 60–120 silica gel. IR spectra were

1800
A. Kamal et al. / Tetrahedron: Asymmetry 20 (2009) 1798–1801
chromatography (silica gel, 60–120 mesh, EtOAc/hexane 10:90) to
(20 mL) and extracted with ether (2 ꢂ 50 mL). The combined or-
ganic layers were dried over anhydrous Na2SO4 and concentrated
in vacuo. The residue was purified by column chromatography (sil-
ica gel, 60–120 mesh, EtOAc/hexane 5:95) to afford the compound
afford the compound 4 (3.56 g, 76%) as a yellow oil. ½a D20
¼ þ9:3 (c
ꢃ
1.1, CHCl3); IR (neat): mmax
: 3490, 2959, 1741, 1440, 1205,
1135 cmꢁ1 1H NMR (200 MHz, CDCl3): d = 1.01 (t, J = 7.5 Hz, 3H),
;
1.71 (m, 1H), 1.86 (m, 1H), 2.72 (td, J = 7.5 Hz, 1H), 3.07 (d,
J = 7.5 Hz, 1H), 3.68 (s, 3H), 3.8 (s, 3H), 4.24 (dd, J = 7.5 Hz, 1H);
13C NMR (75 MHz, CDCl3): d = 11.8, 21.2, 50.1, 51.7, 52.5, 70.6,
173.2, 173.8; MS-EIMS: m/z 213 (M+Na)+.
7 (1.69 g, 72%) as a colorless liquid. ½a D25
ꢃ
¼ þ15:5 (c 1.1, CHCl3); IR
(neat): m ;
max: 2962, 2925, 1615, 1516, 1248, 1032, 823 cmꢁ1 1H
NMR (400 MHz, CDCl3): d = 0.901 (t, J = 7.3 Hz, 3H), 1.01 (m, 1H),
1.46 (m, 1H), 1.72 (m, 1H), 3.56 (t, 1H), 3.78 (s, 3H), 3.92 (dd,
J = 7.3 Hz, 1H), 4.29 (dd, J = 10.9 Hz, 1H), 5.26 (m, 2H), 5.47 (s,
1H), 5.88 (m, 1H), 6.85 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H);
13C NMR (75 MHz, CDCl3): d = 10.9, 20.5, 40.0, 55.2, 71.2, 83.5,
100.8, 113.5, 118.2, 127.4, 131.1, 136.3, 159.9; MS-EIMS: m/z 271
(M+Na)+.
4.3. (2S,3S)-3-Ethylbutane-1,2,4-triol 5
To a stirred suspension of LiAlH4 (1.97 g, 52.10 mmol) in dry
THF (40 mL) at 0 °C compound 4 (3.3 g, 17.36 mmol) in THF
(10 mL) was added slowly and allowed to stir at 55 °C for 12 h.
After completion of the reaction, it was quenched with aqueous
NH4Cl and filtered. THF and water were evaporated and the residue
was purified by column chromatography (silica gel, 60–120 mesh,
EtOAc/hexane 80:20) to afford compound 5 (1.90 g, 82%) as a col-
4.6. 2-[(2S,4R,5S)-5-Ethyl-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]-
1-ethanol 8
To a stirred solution of alkene 7 (1.4 g, 5.64 mmol) in dry THF
(15 mL) at 0 °C dicyclohexylborane (13.54 mL, 6.77 mmol, 0.5 M
in THF) was added slowly. The mixture was stirred at room tem-
perature for 12 h. Then it was cooled to 0 °C and treated with aque-
ous NaOH (28.22 mL, 28.22 mmol, 1.0 M aqueous solution)
followed by H2O2 (1.91 mL, 28.22 mmol, 50% aqueous solution).
The reaction mixture was stirred for 2 h at room temperature.
Aqueous NH4Cl was added and the reaction mixture was extracted
with EtOAc (2 ꢂ 30 mL). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated in vacuo. The residue
was purified by column chromatography (silica gel, 60–120 mesh,
EtOAc/hexane 30:70) to afford the compound 8 (1.32 g, 88%) as a
orless liquid. ½a D25
ꢃ
¼ þ19:5 (c 1.1, CHCl3); IR (neat):
mmax: 3356,
2932, 1461, 1016 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d = 0.946 (t,
J = 7.54 Hz, 3H), 1.23–1.46 (m, 2H), 1.52 (m, 1H), 2.33 (br s, 1H),
3.62 (m, 2H), 3.68–3.86 (m, 3H), 3.95 (br s, 1H); 13C NMR
(75 MHz, CDCl3): d = 11.6, 21.1, 43.9, 62.6, 65.1, 74.5; MS-EIMS:
m/z 167 (M+Na)+.
4.4. [(2S,4S,5S)-5-Ethyl-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]-
methanol 6a
To a stirred solution of compound 5 (1.7 g, 12.68 mmol) in dry
dichloromethane (30 mL) at 0 °C, p-methoxybenzylidene dimeth-
ylacetal (2.58 mL, 15.22 mmol) and a catalytic amount of CSA were
added. The mixture was stirred at 0 °C for 2 h. After completion of
the reaction, it was quenched with Et3N and extracted with dichlo-
romethane (2 ꢂ 40 mL). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated in vacuo. The residue
was purified by column chromatography (silica gel, 60–120 mesh,
EtOAc/hexane 20:80) to afford the compound 6a (2.71 g, 85%) as a
colorless liquid. ½a D25
ꢃ
¼ þ81:5 (c 1.1, CHCl3); IR (neat): mmax
:
3419, 2924, 1361, 1176, 977, 815 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d = 0.921 (t, J = 7.5 Hz, 3H), 1.06 (m, 1H), 1.45 (m, 1H), 1.8 (m, 2H),
2.02 (m, 1H), 2.38 (br s, 1H), 3.55 (t, J = 11.3 Hz, 1H), 3.73–3.85 (m,
6H), 4.28 (dd, J = 4.5, 11.3 Hz, 1H), 5.4 (s, 1H), 6.89 (d, J = 7.0 Hz,
2H), 7.37 (d, J = 7.0 Hz, 2H); 13C NMR (75 MHz, CDCl3): d = 10.7,
20.6, 34.6, 39.9, 55.3, 60.6, 71.2, 81.3, 100.8, 113.7, 127.1, 130.8,
160.0; MS-EIMS: m/z 289 (M+Na)+.
colorless liquid. ½a D25
ꢃ
¼ þ31:5 (c 1.1, CHCl3); IR (neat):
mmax: 3457,
2964, 1615, 1517, 1248, 1081, 985, 829 cmꢁ1
;
1H NMR (300 MHz,
4.7. 2-[(2S,4R,5S)-5-Ethyl-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]-
CDCl3): d = 0.948 (t, J = 7.4 Hz, 3H), 1.08 (m, 1H), 1.43 (m, 1H),
1.91 (m, 1H), 3.5 (t, J = 11.3 Hz, 1H), 3.61 (m, 2H), 3.74–3.85 (m,
4H), 4.27 (dd, J = 4.9, 11.3 Hz, 1H), 5.4 (s, 1H), 6.84 (d, J = 8.6 Hz,
2H), 7.33 (d, J = 8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3): d = 10.8,
20.4, 36.1, 55.2, 63.1, 70.8, 81.9, 100.9, 113.5, 127.4, 130.8, 159.9;
MS-EIMS: m/z 275 (M+Na)+.
acetic acid 9
To a stirred solution of oxalyl chloride (0.7 mL, 8.27 mmol), in
dry CH2Cl2 (20 mL), DMSO (1.17 mL, 16.54 mmol) was added at
ꢁ78 °C and stirred at the same temperature for 30 min. Compound
8 (1.1 g, 4.13 mmol) in dry CH2Cl2 (4 mL) was added at ꢁ78 °C to
the reaction mixture and stirred for 1 h at the same temperature.
Next, Et3N (2.30 mL, 16.54 mmol) was added at ꢁ78 °C and the
reaction mixture was allowed to warm to room temperature for
30 min. The reaction mixture was diluted with water (10 mL)
and extracted with CHCl3 (2 ꢂ 40 mL). The combined organic lay-
ers were washed with brine (30 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure to afford crude aldehyde
as a yellow syrup. To the above crude aldehyde in DMSO (1.0 mL)
at 0 °C NaClO2 (0.55 g, 6.19 mmol, dissolved in 2 mL water) was
added slowly followed by NaH2PO4 (0.736 g, 6.19 mmol, dissolved
in 2 mL water) and allowed to stir at room temperature for 10 h.
The reaction mixture was quenched with saturated aqueous NaH-
CO3 solution and extracted with EtOAc (2 ꢂ 25 mL). The combined
organic layers were dried over anhydrous Na2SO4 and concen-
trated in vacuo. The residue was purified by column chromatogra-
phy (silica gel, 60–120 mesh, EtOAc/hexane 40:60) to afford the
4.5. (2S,4R,5S)-5-Ethyl-2-(4-methoxyphenyl)-4-vinyl-1,3-dioxane 7
To a stirred solution of oxalyl chloride (1.69 mL, 19.04 mmol), in
dry CH2Cl2 (30 mL), DMSO (2.7 mL, 38.09 mmol) was added at
ꢁ78 °C and stirred at the same temperature for 30 min. Compound
6 (2.4 g, 9.52 mmol) in dry CH2Cl2 (10 mL) was added at ꢁ78 °C to
the reaction mixture and stirred for 1 h at the same temperature.
Then Et3N (5.29 mL, 38.09 mmol) was added at ꢁ78 °C, and the
reaction mixture was allowed to warm to room temperature for
30 min. The reaction mixture was diluted with water (15 mL)
and extracted with CHCl3 (2 ꢂ 50 mL). The combined organic lay-
ers were washed with brine (30 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure to afford crude aldehyde
as
a yellow syrup. To methyltriphenylphosphonium bromide
(10.1 g, 28.56 mmol) in dry THF (50 mL) at ꢁ78 °C n-BuLi
(14.87 mL, 23.8 mmol, 1.6 M in hexane) was added and stirred
for 45 min at ꢁ78 °C. Then to the orange yellow ylide, the above
crude aldehyde (3.96 g, 15.84 mmol) in dry THF (10 mL) was added
slowly, and stirring was continued for 1 h at ꢁ78 °C. The reaction
mixture was quenched with saturated aqueous NH4Cl solution
compound 9 (0.89 g, 77%) as a colorless liquid. ½a D25
¼ þ55:5 (c
ꢃ
1.1, CHCl3); 1H NMR (400 MHz, CDCl3): d = 0.931 (t, J = 7.5 Hz,
3H), 1.11 (m, 1H), 1.44 (m, 1H), 1.77 (m, 1H), 2.61 (dd,
J = 15.9 Hz, 1H), 2.78 (dd, J = 15.9 Hz, 1H), 3.57 (t, J = 11.3 Hz, 1H),
3.79 (s, 3H), 4.02 (td, J = 3.8 Hz, 1H), 4.27 (dd, J = 4.6, 11.3 Hz,

A. Kamal et al. / Tetrahedron: Asymmetry 20 (2009) 1798–1801
1801
1H), 5.47 (s, 1H), 6.86 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 9.0 Hz, 2H); 13
NMR (75 MHz, CDCl3): d = 10.7, 20.7, 38.4, 39.8, 55.3, 70.9, 78.0,
101.0, 113.5, 127.3, 130.6, 159.9, 176.1; MS-EIMS: m/z 303
(M+Na)+.
C
(400 MHz, CDCl3): d = 0.99 (t, J = 7.32 Hz, 3H), 1.34 (m, 1H), 1.47
(m, 1H), 1.83 (m, 1H), 2.63 (dd, J = 3.1 Hz, 18.3, 1H), 2.71 (dd,
J = 3.1 Hz, 18.3, 1H), 2.85 (br s, 1H), 4.17 (br s, 1H), 4.22 (dd,
J = 5.2, 11.1 Hz, 1H), 4.36 (dd, J = 10.8, 11.1 Hz, 1H). 13C NMR
(75 MHz, CDCl3): d = 11.2, 19.5, 39.2, 39.3, 64.14, 69.1, 170.9; MS-
EIMS: m/z 145 (M+H)+.
4.8. Methyl 2-[(2S,4R,5S)-5-ethyl-2-(4-methoxyphenyl)-1,3-dioxan-
4-yl]acetate 10
Acknowledgments
To a stirred solution of acid 9 (0.6 g, 2.14 mmol) in dry ether
(10 mL) at 0 °C freshly generated ethereal solution of diazometh-
ane was added slowly and stirred for 10 min. After completion of
the reaction, the ether was evaporated carefully. The residue was
purified by column chromatography (silica gel, 60–120 mesh,
EtOAc/hexane 5:95) to afford the compound 10 (0.55 g, 87%) as a
The authors P.V.R., P.S, and S.P.R. wish to thank UGC and CSIR,
New Delhi, respectively, for the award of research fellowships.
References
colorless liquid. ½a D25
ꢃ
¼ þ82:0 (c 1.1, CHCl3); IR (neat): mmax
:
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;
1H NMR
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(400 MHz, CDCl3): d = 0.923 (t, J = 7.5 Hz, 3H), 1.1 (m, 1H), 1.42
(m, 1H), 1.74 (m, 1H), 2.57 (dd, J = 15.8 Hz, 1H), 2.70 (dd,
J = 15.8 Hz, 1H), 3.57 (t, J = 11.3 Hz, 1H), 3.69 (s, 3H), 3.79 (s, 3H),
4.04 (td, J = 3.0, 9.0 Hz, 1H), 4.28 (dd, J = 4.6, 11.3 Hz, 1H), 5.46 (s,
1H), 6.85 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 9.0 Hz, 2H); 13C NMR
(75 MHz, CDCl3): d = 10.8, 20.5, 38.6, 39.9, 51.7, 55.2, 70.9, 78.3,
100.6, 113.4, 127.2, 130.8, 159.8, 171.6; MS-EIMS: m/z 295 (M+H)+.
4.8.1. (4R,5S)-5-Ethyl-4-hydroxytetrahydro-2H-2-pyranone 1
To the ester 10 (0.4 g, 1.36 mmol) at 0 °C, AcOH/H2O (4:1,
10 mL) was added and then stirred at room temperature for 6 h.
After completion of the reaction, it was quenched with saturated
aqueous NaHCO3 solution and extracted with EtOAc (2 ꢂ 20 mL).
The combined organic layers were dried over anhydrous Na2SO4
and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, 60–120 mesh, EtOAc/hexane 30:70)
to afford the compound (0.16 g, 85%) as
a
colorless liquid.
¼ þ23:3 (c 1.0, CHCl3)}; IR
(neat): m ;
max: 3424, 2966, 1718, 1400, 1195, 1057 cmꢁ1 1H NMR
½
a 2D2
ꢃ
¼ þ22:9 (c 1.1, CHCl3); {lit.2d
½ ꢃ
a 2D2
6. Razavi, H.; Polt, R. J. Org. Chem. 2000, 65, 5693–5706.