Novel synthesis of stagonolide-F, putaminoxin and aspinolide-A

Article abstract of DOI:10.2174/157017811794697502

Novel synthesis of putaminoxin, stagonolide-F and aspinolide-A have been achieved by utilizing (S) and (R)- malic acid. The key feature of the synthetic strategy includes Horner-Wittig olefination, double bond reduction and Steglich esterification. Olefinic acid for putaminoxin and stagonolide-F was prepared from (S)-malic acid whereas olefinic acid for aspinolide-A was prepared from (R)-malic acid and olefinic alcohols for putaminoxin, stagonolide-F and aspinolide-A were prepared by using Brown's asymmetric allylboration.

Full text of DOI:10.2174/157017811794697502

Letters in Organic Chemistry, 2011, 8, 143-149
143
Novel Synthesis of Stagonolide-F, Putaminoxin and Aspinolide-A
Ahmed Kamal*, Papagari Venkat Reddy, Moku Balakrishna and Singaraboina Prabhakar
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India
Received May 28, 2010: Revised October 08, 2010: Accepted October 13, 2010
Abstract: Novel synthesis of putaminoxin, stagonolide-F and aspinolide-A have been achieved by utilizing (S) and (R)-
malic acid. The key feature of the synthetic strategy includes Horner-Wittig olefination, double bond reduction and
Steglich esterification. Olefinic acid for putaminoxin and stagonolide-F was prepared from (S)-malic acid whereas
olefinic acid for aspinolide-A was prepared from (R)-malic acid and olefinic alcohols for putaminoxin, stagonolide-F and
aspinolide-A were prepared by using Brown’s asymmetric allylboration.
Keywords: Decanolides, (S) and (R) malic acid, Horner-Wittig olefination, Steglich esterification, Brown’s asymmetric
allylboration, Ring closing metathesis (R.C.M.).
INTRODUCTION
of olefin geometry in their skeleton [7-9]. As part of our
studies directed towards the synthesis of biologically active
lactone compounds [10-14], herein we report an efficient and
convergent formal synthesis of stagonolide-F, putaminoxin
and aspinolide-A by employing (S), (R)-malic acid and
Brown’s asymmetric allylboration. Our initial retrosynthetic
plan is outlined in Scheme 1. All the three lactones inturn
could be obtained by the Steglich coupling of olefinic acid
fragments and olefinic alcohol. Olefinic acid fragments for
stagonolide-F and putaminoxin can be prepared from (S)-
malic acid and olefinic acid fragment for aspinolide-A can be
prepared from (R)-malic acid.
Ten-membered
lactones
commonly
known as
decanolides have attracted synthetic as well as bioorganic
chemists, due to their unique structural properties and
interesting biological activities. Some examples, like
herbarumin-I, II, III [1, 2], microcarpalide [3] belong to this
class of molecules. Stagonolide-F (1) [4] was isolated from
pycnidial fungus Stagonospora cirsii. While Putaminoxin (2)
[5], a phytotoxic lactone was isolated from the culture of
Phoma putaminum fungus and aspinolide-A (3) [6], was
isolated from the cultures of Aspergillus ochraceus. The
structures of stagonolide-F, putaminoxin and aspinolide-A
OH
OH
OH
O
O
O
O
O
O
1
2
3
Aspinolide-A
Stagonolide-F
Putaminoxin
Fig. (1). Chemical structures of putaminoxin, stagonolide-F and aspinolide-A.
(as shown in Fig. 1) were determined by spectroscopic,
Olefinic chiral homoallyl alcohols (2R)-4-penten-2-ol 14
chemical and synthetic methods [7-9].
and (4R)-1-hepten-4-ol 15 were synthesized in one step by
utilizing Brown’s asymmetric allylboration of acetaldehyde
and butyraldehyde with (–)-B-allyldiisopinocampheylborane
in Et2O-pentane (1:1) at –100 °C according to the previously
reported literature [15, 16] Scheme 2.
RESULTS AND DISCUSSION
To the best of our knowledge, synthetic routes have been
developed in the literature for the preparation of these ten-
membered lactones utilizing Sharpless asymmetric
epoxidation, Keck allylation and Jacobsen’s hydrolytic
kinetic resolution methods for introducing stereogenic
centers and ring-closing metathesis (RCM) for construction
Olefinic acid fragment for stagonolide-F and
putaminoxin was prepared from (S) malic acid. Accordingly,
(S) malic acid 4 was subjected to reduction by using
BH3.DMS and B(OMe)3 to give (2S) butane-1,2,4-triol 7
[17]. Selective 1,3-protection of the triol 5 with p-
methoxybenzaldehyde dimethyl acetal, CSA, in CH2Cl2
afforded
a
six membered acetal [18], as p-
*Address correspondence to this author at the Division of Organic
Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607,
India; Tel: +91-40-27193157; Fax: +91-40-27193189;
methoxybenzylidene acetal 6 in 80% yield, and 1,2-
protection of the triol afforded a five-membered acetal as p-
methoxybenzylidene acetal in 10% yield. These two acetals
E-mail: ahmedkamal@iict.res.in
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

144 Letters in Organic Chemistry, 2011, Vol. 8, No. 2
Kamal et al.
OH
O
For the synthesis of stagonolide-F and putaminoxin,
coupling of the olefinic acid fragment 13, which was
obtained from (S) malic acid with (2R)-4-penten-2-ol 14 and
(4R)-1-hepten-4-ol 15 by employing Steglich esterification
conditions [26] to give the diene compounds 16 and 17
respectively. PMB group of these dienes were deprotected
by using DDQ to give the diene alcohols 18 and 19. These
dienes (18 and 19) have allowed the stage to be set for the
macrolactonization to obtain stagonolide-F and putaminoxin
via ring-closing metathesis (R.C.M.) [27-34]. Treatment of
the bis-olefin compounds 18 and 19 with the use of the
Grubbs’ first generation catalyst (20 mol%) under high
dilution in dichloromethane at reflux conditions gave a 10:1
(E:Z) mixture of macrocyclic lactones; from which (E)-
isomers of 1 and 2 were isolated in 55% yield by silica gel
column chromatography. The spectral and analytical data of
stagonolide-F 1 and putaminoxin 2 were comparable to the
previously reported data in the literature [4, 7, 8] Scheme 4.
Stagonolide-F,
Putaminoxin and
Aspinolide-A
O
R
R= Methyl and
R= Propyl
OH
R
OPMB
O
+
OH
R= Methyl and
R= Propyl
OPMB
O
OH
OTBDPS
R
H
While for the synthesis of aspinolide-A, olefinic acid
fragment ent-13 was prepared from (R)-malic acid as the
starting material, followed by the same set of reactions as
illustrated in Scheme 2, and is depicted in Scheme 5.
Coupling of the olefinic acid fragment ent-13 with (2R)-4-
penten-2-ol 14 by employing Steglich esterification
conditions gave the diene compound 20. PMB group of this
diene was deprotected by using DDQ to give the diene
alcohol compound 21 and ring-closing metathesis of the
compound 21 can be achieved by using Grubbs’ first
generation catalyst as reported in the Scheme 4 furnished
aspinolide-A (3) in 55% yield after silica gel column
chromatography. The spectral and analytical data of
aspinolide-A (3) was comparable to the previously reported
(natural as well as synthetic compound) data in the literature
[6, 9] Scheme 5.
R= Methyl and
R= Propyl
S and R malic acid
Scheme 1. Retrosynthetic analysis of putaminoxin, stagonolide-F
and aspinolide-A.
O
OH
a
R
H
R
R=Methyl 14 and
R=Propyl 15
R=Methyl and
R=Propyl
Scheme 2. Reagents and conditions: (a) (-)-Ipc2BCl, allyl MgBr,
E2O-pentane (1:1), –100 oC, NaOH and H2O2, 70%.
were separated by column chromatography. Hydroxy group
of 6 was protected as TBDPS ether using TBDPSCl and
imidazole in DMF to afford TBDPS protected compound 7
in good yield. Regioselective ring opening of the PMP
protected acetal 7 by DIBAL–H proceeded at the sterically
less-hindered side to give the unmasked primary alcohol 8 in
81% yield according to the literature procedure [19-24].
Alcohol 8 was oxidized under Swern’s oxidative conditions
to give the corresponding aldehyde, which without
purification (as crude) on Horner-Wittig olefination by two-
carbon homologation using ethoxycarbonylmethylene
triphenylphosphorane in benzene gave the ꢀ,ꢁ-unsaturated
ester 9 in 78% yield over 2 steps Scheme 3.
EXPERIMENTAL SECTION
(3S)-4-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-3-[(4-methoxy-
benzyl)oxy]butan-1-ol (8)
To a stirred solution of compound 7 (8 g, 17.31 mmol) in
dry CH2Cl2 (100 mL) at –78 oC was added drop wise
DIBAL-H (28.86 mL, 34.63 mmol, 1.2 M in toluene). After
the reaction mixture had been stirred at the same temperature
for 6 h, methanol (10 mL) was added. The reaction mixture
was allowed to warm to room temperature then sat. aq.
Roche salt (50 mL) was added and the mixture was stirred
vigorously for 2 h. The mixture was extracted with
dichloromethane (3x100 mL) and organic layers were
washed with brine, dried over Na2SO4. After evaporation of
the solvent, the crude product was purified by column
chromatography (silica gel, 60–120 mesh, EtOAc–hexane
2:8) to afford the compound 8 (6.51 g, 81%) as a colorless
Olefin reduction of compound 9 with PtO2-H2 (NaHCO3)
(catalytic) in ethylacetate gave compound 10 in 92% yield ,
which on treatment with TBAF in THF afforded primary
alcohol 11 in 88% yield. Olefinic acid fragment 13 was
prepared from compound 11 in two steps. Accordingly,
Compound 11 was subjected to Swern’s oxidative conditions
to give the corresponding aldehyde, which on Wittig
olefination with MePh3Br and t-BuOK in THF gave the
olefinic ester 12 in 55% yield [25]. Finally, olefinic ester was
hydrolyzed with LiOH in THF-methanol-water (2:1:1) to
afford the desired olefinic acid fragment 13 in 86% yield for
stagonolide-F as well as putaminoxin.
25
oil. Rf = 0.5 (30% EtOAc/hexane); [ꢀ]D = –34 (c 1.1,
CHCl3). IR (neat): 3429, 2933, 2860, 1612, 1513, 1465,
1247, 1108, 1038, 820, 742, 703 cm-1; H NMR (300 MHz,
1
CDCl3): ꢁ = 7.68-7.6 (m, 4H), 7.43-7.31 (m, 6H), 7.16 (d, J
= 8.68 Hz, 2H), 6.8 (d, J = 8.68 Hz, 2H), 4.58 (d, J = 11.33
Hz, 1H), 4.39 (d, J = 11.33 Hz, 1H), 3.78 (s, 3H), 3.75-3.61
(m, 5H), 2.17 (br s, 1H), 1.81-1.69 (m, 2H), 1.06 (m, 9H);
13C NMR (75 MHz, CDCl3): ꢁ = 159.2, 135.58, 133.29,
130.5, 129.73, 129.44, 127.71, 113.82, 78.41, 71.79, 65.88,

Novel Synthesis of Stagonolide-F, Putaminoxin and Aspinolide-A
Letters in Organic Chemistry, 2011, Vol. 8, No. 2
145
PMP
O
PMP
OH
O
OH
OH
O
O
O
b
Ref 13
a
HO
HO
TBDPSO
HO
OH
O
4
5
6
7
S-Malic acid
c
OPMB
O
OPMB
O
OPMB
e
d
TBDPSO
TBDPSO
TBDPSO
OEt
OEt
OH
10
8
9
f
OPMB
O
OPMB
O
OPMB
O
g
h
HO
OEt
OEt
OH
11
12
13
o
Scheme 3. Reagents and conditions: (a) PMB(OMe)2, CSA, dry CH2Cl2, 0 C, 2 h, 80%; (b) TBDPSCl, imidazole, dry DMF, 6 h, 85%; (c)
DIBAL-H, dry CH2Cl2, –78 oC, 6 h, 81%; (d) (i) (COCl)2, DMSO, Et3N, –78 oC, 1 h; (ii) Ph3PCHCO2Et, benzene, 6 h, reflux, 78% over two
o
steps; (e) PtO2-H2, NaHCO3(cat), EtOAc, 12 h, 92%; (f) TBAF (1M), THF, 0.5 h, 88%; (g) (i) (COCl)2, DMSO, Et3N, –78 C, 1 h; (ii)
MePh3Br, t-BuOK, THF, 0 oC, 1 h, 55 % over two steps; (h) LiOH, MeOH:THF:H2O (1:2:1), 0 oC to rt, 4 h, 86%.
O
OPMB
OH
OPMB
O
O
a
R
OH
+
R
R= Methyl 14 and
R= Propyl 15
R= Methyl 16 and
R= Propyl 17
13
PCy3
Ph
Cl
Ru
Cl
PCy3
OH
O
OH
Ru-I
O
c
b
O
R
R
O
R= Methyl 18 and
R= Propyl 19
R= Methyl = Stagonolide- F
R= Propyl = Putaminoxin
1
2
Scheme 4. Reagents and conditions: (a) DCC, DMAP, CH2Cl2, 0 oC to rt, 3 h, 81%; (b) DDQ, H2O:CH2Cl2 (1:9), 0 oC to rt, 1 h, 78%; (c) 20
mol% Ru-1, CH2Cl2, reflux, 48 h, 55%.
60.62, 55.23, 34.07, 26.81, 19.16; MS-ESIMS: m/z
[M+NH4]+: 482; HRMS calcd for (C28H36O4NaSi) 487.228 ;
found. 487.229.
temperature for 30 min. Compound 8 (6 g, 12.93 mmol) in
dry CH2Cl2 (15 mL), was added at –78 C to the reaction
o
mixture and stirred for 1 h at the same temperature. After 1 h
o
triethylamine (5.39 mL, 38.79 mmol) was added at –78 C
and slowly allowed the reaction mixture to room temperature
for 30 min. The reaction mixture was diluted with water (50
mL) and extracted with CHCl3 (3 x 100 mL). The combined
organic layers were washed with brine (100 mL), dried over
anhydrous Na2SO4 concentrated under reduced pressure to
afford crude aldehyde as yellow syrup. Aldehyde in dry
Ethyl (E,5S)-6-[1-(tert-butyl)-1,1-diphenylsilyl]oxy-5-[(4-
methoxybenzyl)oxy]-2-hexenoate (9)
To a stirred solution of oxalyl chloride (1.64 mL, 19.39
mmol) in dry CH2Cl2 (150 mL), DMSO (2.75 mL, 38.79
mmol) was added at –78 oC and stirred at the same

146 Letters in Organic Chemistry, 2011, Vol. 8, No. 2
OH
Kamal et al.
O
OH
OPMB
O
HO
+
OH
OH
O
O
ent-13
14
R-malic acid
ent-4
O
OPMB
OH
O
a
O
b
20
21
c
OH
O
O
3
Aspinolide A
Scheme 5. Reagents and conditions: (a) DCC, DMAP, CH2Cl2, 0 oC to rt, 3 h, 81%; (b) DDQ, H2O:CH2Cl2 (1:9), 0 oC to rt, 1 h, 78%; (c) 20
mol% Ru-1, CH2Cl2, reflux, 48 h, 55%.
25
toluene, which is obtained in the above step was added C-2
Horner-Wittig reagent (5.39 g, 15.50 mmol) and stirred for 2
h. After 2 h toluene was evaporated and extracted with
EtOAc (3x 100 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated under vacuo.
The residue was purified by column chromatography (silica
gel, 60–120 mesh, EtOAc–hexane 5:95) to afford the
compound 9 (5.36 g, 78%) as a light yellow oil. Rf = 0.5
(20% EtOAc/hexane); [ꢀ]D –40.2 (c 1, CHCl3); IR (neat):
2933, 2859, 1734, 1612, 1513, 1247, 1110, 1037, 821, 742,
704 cm-1; H NMR (300 MHz, CDCl3): ꢁ = 7.67-7.63 (m,
1
4H), 7.43-7.35 (m, 6H), ꢁ 7.2 (d, J = 7.8 Hz, 2H), 6.82 (d, J
= 7.8 Hz, 2H), 4.58 (d, J = 10.73 Hz, 1H), 4.39 (d, J = 10.73
Hz, 1H), 4.09 (q, J = 6.8, 14.63 Hz, 2H), 3.78 (s, 3H), 3.72
(dd, J = 5.85, 10.73 Hz, 1H), 3.6 (dd, J = 5.85, 10.73 Hz,
1H), 3.46 (m, 1H), 2.25-2.20 (m, 2H), 1.74-1.48 (m, 4H),
1.23 (t, J = 6.8, 14.63 Hz, 3H), 1.05 (m, 9H); 13C NMR (75
MHz, CDCl3): ꢁ = 173.58, 159.02, 135.56, 133.47, 131.03,
129.6, 129.3, 127.62, 113.65, 78.84, 71.72, 66.06, 60.12,
55.19, 34.26, 31.08, 26.8, 20.91, 19.15, 14.2; MS-ESIMS:
m/z [M+NH4]+: 552; HRMS calcd for (C32H42O5NaSi)
557.269 ; found. 557.271.
25
(20% EtOAc/hexane); [ꢀ]D –20.2 (c 1, CHCl3); IR (neat):
2933, 2859, 1718, 1655, 1513, 1465, 1249, 1173, 1109,
1039, 821, 704 cm-1; 1H NMR (500 MHz, CDCl3): ꢁ = 7.66-
7.62 (m, 4H), 7.43-7.34 (m, 6H), 7.17 (d, J = 8.78 Hz, 2H),
6.98-6.92 (m, 1H), 6.8 (d, J = 8.78 Hz, 2H), 5.85 (d, 1H),
4.49 (d, J = 10.73 Hz, 1H), 4.39 (d, J = 10.73 Hz, 1H), 4.18
(q, J = 6.8 Hz, 2H), 3.79 (s, 3H), 3.72 (dd, J = 4.87, 9.75,
15.61 Hz, 1H), 3.61 (dd, J = 4.87, 9.75, 15.61 Hz, 1H), 3.57
(p, J = 4.87 Hz, 1H), 2.56-2.50 (m, 1H), 2.46-2.40 (m, 1H),
1.28 (t, J = 6.8 Hz, 1H), 1.05 (m, 9 H); 13C NMR (75 MHz,
CDCl3): ꢁ = 166.3, 159.11, 145.36, 135.55, 133.30, 133.22,
130.39, 129.68, 129.28, 127.67, 123.37, 113.7, 77.98, 71.62,
65.25, 60.09, 55.20, 34.65, 26.78, 19.16, 14.26; MS-ESIMS:
m/z [M+NH4]+: 550; HRMS calcd for (C32H40O5NaSi)
555.2542 ; found. 555.2563.
Ethyl (5S)-6-hydroxy-5-[(4-methoxybenzyl)oxy]hexan-
oate (11)
To a stirred solution of Compound 10 (4.5 g, 8.42 mmol)
in dry THF (50 mL) was added tetrabutylammoniumfluoride
(TBAF) (8.42 mL, 8.42 mmol, 1 M in toluene) at 0 oC for 30
min. After 30 min, the reaction mixture was quenched with
sat. aq. NH4Cl then THF was evaporated and extracted with
EtOAc (3x75 mL) and organic layers were washed with
brine, dried over Na2SO4. After evaporation of the solvent,
the crude product was purified by column chromatography
(silica gel, 60–120 mesh, EtOAc–hexane 3:7) to afford the
compound 11 (2.2 g, 88%) as a colorless oil. Rf = 0.5 (50%
Ethyl (5S)-6-[1-(tert-butyl)-1,1-diphenylsilyl]oxy-5-[(4-
methoxybenzyl)oxy]hexanoate (10)
Compound 9 (5 g, 9.39 mmol) dissolved in dry ethyl
acetate (75 mL) was added catalytic amount of PtO2 and
NaHCO3 under a hydrogen atmosphere and stirred for 12 h.
After completion of the reaction, it was filtered through a
celite pad. Concentration of the filtrate gives the crude
product, which was purified by column chromatography
(silica gel, 60–120 mesh, EtOAc/hexane 5:95) to afford the
compound 10 (4.62 g, 92%) as a light yellow oil. Rf = 0.5
25
EtOAc/hexane); [ꢀ]D –7.2 (c 1, CHCl3); IR (neat): 3445,
2937, 2872, 1730, 1612, 1513, 1461, 1248, 1175, 1034, 822,
755 cm-1; H NMR (500 MHz, CDCl3): ꢁ = 7.28 (d, J = 7.8
1
Hz, 2H), 6.88 (d, J = 7.8 Hz, 2H), 4.54 (d, J = 10.73 Hz, 1H),
4.49 (d, J = 10.73 Hz, 1H), 4.12 (q, J = 6.8 Hz, 2H), 3.8 (s,
3H), 3.69 (m, 1H), 3.54-3.49 (m, 2H), 2.3 (t, 3H), 1.74-1.50
(m, 4H), 1.25 (t, J = 6.8 Hz, 3H); 13C NMR (75 MHz,

Novel Synthesis of Stagonolide-F, Putaminoxin and Aspinolide-A
Letters in Organic Chemistry, 2011, Vol. 8, No. 2
147
CDCl3): ꢀ = 173.38, 159.09, 130.27, 129.28, 113.7, 78.73,
71.06, 63.76, 60.18, 55.08, 34.04, 30.13, 20.61, 14.07; MS-
ESIMS: m/z [M+Na]+: 319; HRMS calcd for (C16H24O5Na)
319.1521 ; found. 319.1535.
758 cm-1; 1H NMR (300 MHz, CDCl3): ꢀ = 7.25 (d, J = 8.30
Hz, 2H), 6.86 (d, J = 8.30 Hz, 2H), 5.78-5.66 (m, 1H), 5.30-
5.19 (m, 2H), 4.52 (d, J = 11.33 Hz, 1H), 4.25 (d, J = 11.33
Hz, 1H), 3.8 (s, 3H), 3.71 (q, J = 6.79, 13.59 Hz, 1H), 2.33
(m, 2H), 1.8-1.49 (m, 4H); 13C NMR (75 MHz, CDCl3): ꢀ =
179.63, 159.22, 138.87, 130.70, 129.29, 117.33, 113.70,
79.58, 69.62, 55.18, 34.62, 33.75, 20.57; MS-ESIMS: m/z
[M+Na]+: 287; HRMS calcd for (C15H20O4Na) 287.125 ;
found. 287.124.
Ethyl (5S)-5-[(4-methoxybenzyl)oxy]-6-heptenoate (12)
To a stirred solution of oxalyl chloride (0.9 mL, 10.64
mmol), in dry CH2Cl2 (40 mL) DMSO (1.5 mL, 21.28
o
mmol) was added at –78 C and stirred at the same
temperature for 30 min. Compound 11 (2.1 g, 7.09 mmol) in
dry CH2Cl2 (10 mL), was added at –78 C to the reaction
(1R)-1-Methyl-3-butenyl (5S)-5-[(4-methoxybenzyl)oxy]-
6-heptenoate (16)
o
mixture and stirred for 1 h at the same temperature. After 1h
o
triethylamine (2.96 mL, 21.28 mmol) was added at –78 C
To a stirred solution of the compound 13 (0.25 g, 0.947
mmol) in dry CH2Cl2 (10 mL), DCC (0.39 g, 1.89 mmol)
(2R)-4-penten-2-ol (0.09 g, 1.04 mmol) and DMAP
(catalytic amount) were added at 0 oC and stirred at room
temperature for 3 h. After completion of the reaction, the
reaction mixture was filtered through Celite pad and
extracted with CH2Cl2 (3x15 mL), dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel,
60–120 mesh, EtOAc–hexane 4:96) to afford 16 (0.255 g,
81%) as a liquid. Rf = 0.8 (20% EtOAc/hexane); [ꢁ]D25 –30.2
(c 1, CHCl3); IR (neat): 2976, 2935, 1730, 1612, 1513, 1247,
1174, 1074, 821, 757 cm-1; 1H NMR (300 MHz, CDCl3): ꢀ =
7.25 (d, J = 8.309 Hz, 2H), 6.87 (d, J = 8.309 Hz, 2H), 5.8-
5.65 (m, 2H), 5.24-5.17 (m, 2H), 5.11-5.03 (m, 2H), 4.95 (m,
1H), 4.51 (d, J = 11.33 Hz, 1H), 4.26 (d, J = 11.33 Hz, 1H),
3.79 (s, 3H), 3.71 (q, J = 6.79, 13.59, 19.64 Hz, 1H), 2.38-
2.20 (m, 4H), 1.75-146 (m, 4H), 1.19 (d, J = 6.04 Hz, 3H);
13C NMR (75 MHz, CDCl3): ꢀ = 173.13, 159.02, 138.81,
133.69, 130.71, 129.26, 117.59, 117.20, 113.70, 79.70,
69.76, 69.66, 55.21, 40.25, 34.79, 34.35, 20.94, 19.47; MS-
ESIMS: m/z [M+Na]+: 355; HRMS calcd for (C20H28O4Na)
355.188 ; found. 355.187.
and allowed the reaction mixture to room temperature for 30
min. The reaction mixture was diluted with water (20 mL)
and extracted with CHCl3 (3 x 40 mL). The combined
organic layers were washed with brine (50 mL), dried over
anhydrous Na2SO4 concentrated under reduced pressure to
afford
crude
aldehyde
as
yellow
syrup.
To
methyltriphenylphosphonium bromide (3.80 g, 10.66 mmol)
in dry THF (50 mL) under a nitrogen atmosphere at 0 oC was
added t-BuOK (1.03 g, 9.22 mmol) and stirred for 4 h at the
same temperature. To this orange yellow ylide solution, the
above crude aldehyde in dry THF (8 mL) was added and
stirred at same temperature for 1 h. The reaction mixture was
quenched with saturated aqueous NH4Cl solution (10 mL).
The mixture was filtered over a celite pad and the residue
was washed with ether (20 mL). THF was evaporated then
extracted with EtOAc (3 x 40 mL). The combined organic
layers were dried over anhydrous Na2SO4 and concentrated
under vacuo. The residue was purified by column
chromatography (silica gel, 60–120 mesh, EtOAc–hexane
5:95) to afford the compound 12 (1.15 g, 55%) as a colorless
25
liquid. Rf = 0.8 (10% EtOAc/hexane); [ꢁ]D –50.2 (c 1,
CHCl3); IR (neat): 2936, 2863, 1733, 1612, 1513, 1459,
1
1246, 1173, 1035, 820, 757 cm-1; H NMR (500 MHz,
CDCl3): ꢀ = 7.16 (d, J = 8.78 Hz, 2H), 6.86 (d, J = 8.78 Hz,
2H), 5.72 (m, 1H), 5.2 (m, 2H), 4.53 (d, J = 11.7 Hz, 1H),
4.28 (d, J = 11.7 Hz, 1H), 4.1 (q, J = 6.83, 14.63 Hz, 2H),
3.8 (s, 3H), 3.71 (q, J = 5.85, 12.68 Hz, 1H), 2.27 (m, 2H),
1.76-1.48 (m, 4H), 1.24 (t, J = 6.83, 14.63 Hz, 3H); 13C
NMR (75 MHz, CDCl3): ꢀ = 173.59, 158.89, 138.88, 130.55,
129.15, 117.13, 113.56, 79.55, 69.53, 60.02, 55.05, 34.68,
33.93, 20.76, 14.09; MS-ESIMS: m/z [M+H]+: 293; HRMS
calcd for (C17H24O4Na) 315.157; found. 315.158.
(1R)-1-Propyl-3-butenyl (5S)-5-[(4-methoxybenzyl)oxy]-
6-heptenoate (17)
Compound 17 was prepared from 13 (0.2 g, 0.75 mmol)
as a liquid in 81% yield according to the procedure described
for compound 16. IR (neat): 2956, 2868, 1731, 1612, 1513,
1459, 1246, 1173, 1082, 922, 821, 755 cm-1; 1H NMR (300
MHz, CDCl3): ꢀ = 7.2 (d, J = 8.3 Hz, 2H), 6.84 (d, J = 8.3
Hz, 2H), 5.71 (m, 2H), 5.2 (m, 2H), 5.04 (m, 2H), 4.9 (p, J =
5.8, 12.2, 18.12 Hz, 1H), 4.52 (d, J = 11.4 Hz, 1H), 4.27 (d, J
= 11.4 Hz, 1H), 3.8 (s, 3H), 3.69 (q, J = 6.3, 13.0, 20.4 Hz,
1H), 2.35-2.20 (m, 4H), 1.77-1.43 (m, 6H), 1.40-1.22 (m,
2H), 0.9 (t, J = 7.36, 14.54 Hz, 3H); 13C NMR (75 MHz,
CDCl3): ꢀ = 173.19, 158.97, 138.9, 133.77, 130.65, 129.21,
117.42, 117.14, 113.64, 79.63, 72.72, 69.61, 55.14, 38.64,
35.68, 34.78, 34.27, 20.95, 18.49, 13.83; MS-ESIMS: m/z
[M+Na]+ 383; HRMS calcd for (C22H32O4Na) 383.2198;
found. 383.2212.
(5S)-5-[(4-Methoxybenzyl)oxy]-6-heptenoic acid (13)
To a stirred solution of 12 (1 g, 3.42 mmol) in MeOH (5
mL): THF (10 mL): H2O (5 mL) (1:2:1) at 0 oC was added
Lithium hydroxide monohydrate (0.29 g, 6.84 mmol) was
added. The reaction mixture was allowed to stir at room
temperature for 4 h. After completion of the reaction; it was
poured in to 0.5 N HCl and extracted with EOAc (3x25 mL).
The combined organic layers were washed with brine and
dried over anhydrous Na2SO4 and concentrated under vacuo.
The residue was purified by column chromatography (silica
gel, 60–120 mesh, EtOAc–hexane 5:95) to afford the
compound 15 (0.78 g, 86%) as a colorless liquid. Rf = 0.5
(1R)-1-Methyl-3-butenyl (5S)-5-hydroxy-6-heptenoate
(18)
To a solution of 16 (0.175 g, 0.52 mmol) in CH2Cl2:H2O
[10:1 mL] was added dichlorodicyanoquinone (DDQ) (0.13
g, 0.58 mmol) at 0 oC. The solution was stirred for 1 h. After
25
(60% EtOAc/hexane); [ꢁ]D +26.2 (c 1, CHCl3); IR (neat):
3410, 1710, 1612, 1513, 1300, 1247, 1175, 1035, 929, 822,

148 Letters in Organic Chemistry, 2011, Vol. 8, No. 2
Kamal et al.
the reaction was completed, it was quenched with sodium
bicarbonate and the solution was filtered through a pad of
Celite. The Celite pad was washed with CH2Cl2 (3x10 mL).
The combined filtrate was concentrated, and purification by
column chromatography (silica gel, 60–120 mesh, EtOAc–
hexane 4:96) to afford the compound 18 (0.088 g, 78%)
ESIMS: m/z [M+Na]+: 235; HRMS calcd for (C12H20O3Na)
235.1310; found. 235.1320.
Spectral and analytical data of all the three lactones 1, 2
and 3 are comparable to the previously reported data in the
literature [4-9].
25
colorless liquid. Rf = 0.3 (30% EtOAc/hexane); [ꢀ]D + 7.2
(c 1, CHCl3); IR (neat): 3442, 2978, 2931, 1729, 1643, 1424,
CONCLUSION
1
1378, 1177, 920 cm-1; H NMR (300 MHz, CDCl3): ꢁ =
In conclusion all the three ten membered lactones namely
stagonolide-F, putaminoxin and aspinolide-A have been
synthesized combining the “ex-chiral pool” methodology,
which involved transformation of enantiopure malic acid and
Brown’s asymmetric allylboration. All the three ten
memberd lactones are prepared in a common synthetic route.
The syntheses of related compounds of ten membered
lactones are underway in our laboratory.
5.93-5.69 (m, 2H), 5.26-5.03 (m, 4H), 4.97 (m, 1H), 4.09 (q,
J = 6.04, 12.84 Hz, 1H), 2.4-2.2 (m, 4H), 1.84-1.63 (m, 2H),
1.61-1.51 (m, 2H), 1.2 (d, J = 6.04 Hz, 3H); 13C NMR (75
MHz, CDCl3): ꢁ = 173.11, 141.05, 133.83, 117.93, 115.10,
72.60, 69.91, 40.22, 36.17, 34.24, 20.70, 19.46; MS-ESIMS:
m/z [M+Na]+: 235; HRMS calcd for (C12H20O3Na) 235.131;
found. 235.131.
(1R)-1-Propyl-3-butenyl (5S)-5-hydroxy-6-heptenoate (19)
ACKNOWLEDGEMENTS
19 was prepared from 17 as a liquid in 79% yield
according to the procedure described for compound 18 IR
(neat): 3440, 2959, 2872, 1730, 1642, 1379, 1173, 993, 919;
1H NMR (300 MHz, CDCl3): ꢁ = 5.89-5.64 (m, 2H), 5.24-
5.01 (m, 4H), 5.91 (m, 1H), 4.06 (q, J = 6.04, 12.08 Hz, 1H),
2.31-2.25 (m, 4H), 1.78-1.61 (m, 2H), 1.59-1.47 (m, 4H),
1.39-1.25 (m, 2H), 0.916 (t, J = 7.55, 14.35 Hz, 3H); 13C
NMR (75 MHz, CDCl3): ꢁ =173.58, 140.85, 133.92, 117.47,
114.66, 72.91, 72.54, 38.63, 36.18, 35.67, 34.17, 20.72,
18.49, 13.82; HRMS calcd for (C14H24O3Na) 263.1623;
found. 263.1616.
The authors P.V.R., M.B. and S.P.R. wish to thank UGC
and CSIR, New Delhi for the award of research fellowships.
REFERENCES AND NOTES
[1]
Rivero-Cruz, J. F.; Macias, M.; Gerda-Garcia-Rojas, C. M.; Mata,
R. A new phytotoxic nonenolide from Phoma herbarum. J. Nat.
Prod., 2003, 66, 511-514.
[2]
Rivero-Cruz, J. F.; Macias, M.; Gerda-Garcia-Rojas, C. M.; Mata,
R. Conformational behavior and absolute stereostructure of two
phytotoxic nonenolides from the fungus Phoma herbarum.
Tetrahedron, 2000, 56, 5337-5344.
[3]
[4]
Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T.
The structure of microcarpalide, a microfilament disrupting agent
from an endophytic fungus. Org. Lett., 2001, 3, 3479-3481.
Evidente, A.; Cimmino, A.; Berestetskiy, A.; Matina, G.; Andolfi,
A.; Motta, A. Stagonolides B-F, nonenolides produced by
Stagonospora cirsii, a potential mycoherbicide of Cirsium arvense.
J. Nat. Prod., 2008, 71, 31-34.
Evidente, A.; Lanzetta, R.; Capasso, R.; Andolfi, A.; Bottalico, A.;
Vurro, M.; Zonno, M. C. Putaminoxin, a phytotoxic nonenolide
from Phoma putaminum. Phytochemistry, 1995, 40, 1637-1641.
Fuchser, J.; Zeeck, A. Aspinolides and Aspinonene/aspyrone co-
metabolites, new pentaketides produced by Aspergillus ochraceus.
Liebigs Ann. Recl., 1997, 87-95.
Perepogu, A. K.; Raman, D.; Murty, U. S. N.; Rao, V. J. Concise
synthesis of stagonolide-F by ring closing metathesis approach and
its biological evaluation. Bioorganic Chem., 2009, 37, 46-51.
Sabitha, G.; Yadagiri, K.; Swapna, R.; Yadav, J. S. The first total
synthesis of putaminoxin and determination of its absolute
configuration. Tetrahedron Lett., 2009, 50, 5417-5419.
Chowdhury, P. S.; Gupta, P.; Kumar; P. First asymmetric total
synthesis of aspinolide A. Tetrahedron Lett., 2009, 50, 7018-7020.
(a) Kamal, A.; Reddy, P. V.; Prabhakar, S. An efficient aldol-based
approach for the synthesis of dihydrokawain-5-ol. Tetrahedron
Asymmetry, 2009, 20, 1936-1939.
(1R)-1-Methyl-3-butenyl (5R)-5-[(4-methoxybenzyl)oxy]-
6-heptenoate) (20)
Compound 20 was prepared from ent-13 (0.2 g, 0.756
mmol) as a liquid in 81% yield according to the procedure
described for compound 16. Rf = 0.8 (20% EtOAc/hexane);
[5]
[6]
[7]
[8]
25
[ꢀ]D + 28.2 (c 1, CHCl3); IR (neat): 2976, 2935, 1730,
1612, 1513, 1246, 1174, 1074, 821, 757 cm-1; 1H NMR (300
MHz, CDCl3): ꢁ = 7.18 (d, J = 8.49 Hz, 2H), 6.80 (d, J =
8.49 Hz, 2H), 5.77-5.62 (m, 2H), 5.20-5.14 (m, 2H), 5.06-
5.01 (m, 2H), 4.92 (m, 1H), 4.49 (d, J = 11.52 Hz, 1H), 4.23
(d, J = 11.52 Hz, 1H), 3.75 (s, 3H), 3.65 (q, J = 6.6, 12.6 Hz,
1H), 2.34-2.18 (m, 4H), 1.72-1.41 (m, 4H), 1.17 (d, J = 6.23,
Hz, 3H); 13C NMR (75 MHz, CDCl3): ꢁ = 172.88, 158.86,
138.67, 133.52, 130.51, 129.07, 117.45, 117.03, 113.51,
79.46, 69.54, 54.97, 40.09, 34.62, 34.14, 20.77, 19.31; MS-
ESIMS: m/z [M+Na]+: 355; HRMS calcd for (C20H28O4Na)
355.1885 ; found. 355.1873.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
Kamal, A.; Reddy, P. V.; Prabhakar, S.; Suresh, P. Stereoselective
total synthesis of simplactone A. Tetrahedron Asymmetry, 2009,
20, 1798-1801.
Kamal, A.; Reddy, P. V.; Prabhakar, S. Total synthesis of
phytotoxic herbarumin-I from D-mannitol. Tetrahedron
Asymmetry, 2009, 20, 1120-1124.
Kamal, A.; Krishnaji, T.; Reddy, P. V. Enantioselective total
synthesis of both the stereoisomers of dihydrokawain-5-ol.
Tetrahedron Asymmetry, 2007, 18, 1775-1779.
Kamal, A.; Krishnaji, T.; Reddy, P. V. A new chemoenzymatic
Baylis-Hillman approach for the synthesis of enantiomerically
enriched umbelactones. Tetrahedron Lett., 2007, 48, 7232-7235.
(a) Reddy, M. V. R.; Yucel, A. J.; Ramachandran, P. V. An
Efficient asymmetric synthesis of tarchonanthuslactone. J. Org.
Chem., 2001, 66, 2512-2514.
(1R)-1-methyl-3-butenyl (5R)-5-hydroxy-6-heptenoate (21)
Compound 21 was prepared from 20 (0.15 g, 0.45 mmol)
as a yellow liquid in 78% yield according to the procedure
described for compound 18. Rf = 0.3 (30% EtOAc/hexane);
25
[ꢀ]D – 9.8 (c 1, CHCl3); IR (neat): 3436, 3079, 2978, 2934,
1
1729, 1643, 1424, 1378, 1177, 921 cm-1; H NMR (300
MHz, CDCl3): ꢁ 5.88-5.65 (m, 2H), 5.29-5.03 (m, 4H), 4.93
(m, 1H), 4.07 (q, 1H), 2.36-2.22 (m, 4H), 1.77-1.61 (m, 2H),
1.55-1.48 (m, 2H), 1.20 (d, J = 6.83, 14.63 Hz, 3H); 13C
NMR (75 MHz, CDCl3): ꢁ 173.05, 140.83, 133.5, 117.51,
114.45, 72.33, 69.78, 40.08, 36.05, 34.12, 20.61, 19.32; MS-

Novel Synthesis of Stagonolide-F, Putaminoxin and Aspinolide-A
Letters in Organic Chemistry, 2011, Vol. 8, No. 2
149
[16]
Brown, H. C.; Jadhav, P. K. Asymmetric carbon-carbon bond
formation via .beta.-allyldiisopinocampheylborane. Simple
synthesis of secondary homoallylic alcohols with excellent
enantiomeric purities. J. Am. Chem. Soc., 1983, 105, 2092-2093.
Hanessian, S.; Ugolini, A.; Dube, D.; Glamyan, A. Facile access to
(S)-1,2,4-butanetriol and its derivatives. Can. J. Chem., 1984, 62,
2146.
Thiam, M.; Slassi, A.; Chastrette, F.; Amouroux, R. Malic acid as a
chiral synthon : Synthesis of 1,2 and 1,3 optically active diols.
Synth. Commun., 1992, 22, 83-95.
Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. A facile
cleavage of benzylidine acetals with diisobutylaluminium hydride.
Chem. Lett., 1983, 12, 1593-1596.
Mikami, T.; Asano, H.; Mitsunobu, O. Acetal-bond cleavage of
4,6-O-alkylidienehexopyranosides by diisobutylaluminium hydride
and by lithium triethylborohydride-TiCl4. Chem. Lett., 1987, 16,
2033-2036.
[25]
Batty, D.; Crich, D. Acyl radical cyclizations in synthesis. Part 4.
Tandem Processes: The 7 ende/5-exo serial cyclization approach to
enantiomerically pure Bicyclo [5.3.0] decane-2-ones. J. Chem.
Soc., Perkin Trans. 1, 1992, 3193-3204.
Neises, B.; Steglich, W. Simple method for the esterification of
carboxylic acids. Angew. Chem. Int. ed. 1978, 17, 522-524.
(a) Fürstner, Olefin metathesis and beyond. Angew. Chem. Int. Ed.,
2002, 39, 3012-3043.
Liu, D.; Kozmin, S. S.; Synthesis of (-)-Pinolidoxin: Divergent
synthetic strategy exploiting a common silacyclic precursor. Org.
Lett., 2002, 4, 3005-3007.
Murga, J.; Falomir, E.; Garica-Fortanet, J.; Carda, M.; Marco, J. A.
Stereoselective synthesis of microcarpalide. Org. Lett., 2002, 4,
3447-3449.
[17]
[18]
[19]
[20]
[26]
[27]
[28]
[29]
[30]
Prunet, J. Recent methods for the synthesis of (E)-alkene units in
macrocyclic natural products. Angew. Chem. Int. Ed., 2003, 42,
2826-2830.
[21]
[22]
Corey, E. J.; Jones, G. B. Reductive cleavage of tert-
butyldimethylsilyl ethers by diisobutylaluminum hydride. J. Org.
Chem., 1992, 57, 1028-1029.
Toshima, H.; Maru, K.; Saito, M.; Ichihara, A. Total syntheses of
cepaciamides A and B, novel fungitoxic 3-amino-2-piperidinone-
containing lipids produced by Pseudomonas cepacia D-202.
Tetrahedron, 1999, 55, 5793-5808.
Breuilles, P.; Uguen, D.; Toward a Total synthesis of pristinamycin
IIB; A Chiron approach to a C-9/C-16 fragment. Tetrahedron Lett.,
1998, 39, 3145-3148.
[31]
[32]
Gurjar, M. K.; Nagaprasad, R.; Ramana, C. V. Total synthesis of
microcarpalide. Tetrahedron Lett., 2003, 44, 2873-2875.
Dieters, A.; Martin, S. F. Synthesis of oxygen and nitrogen-
containing heterocycles by Ring-Closing Metathesis. Chem. Rev.,
2004, 104, 2199-2238.
Garica-Fortanet, J.; Murga, J.; Falomir, E.; Carda, M.; Marco, J. A.
Stereoselective total synthesis and absolute configuration of the
natural decanolides (-)-microcarpalide and (+)-lethaloxin. Identity
of (+)-lethaloxin and (+)-pinolidoxin. J. Org. Chem., 2005, 70,
9822-9827.
Gradillas, A.; Perez-Castells, J. Macrocyclization by Ring-Closing
Metathesis in the total synthesis of natural Products: reaction
conditions and limitations. Angew. Chem. Int. Ed., 2006, 45, 6086-
6101.
[33]
[23]
[24]
Toshima, H.; Maru, K.; M Saito, M; Ichihara, A. Study on
[34]
fungitoxie
3-amino-2-piperidinone-containing
lipids:
total
syntheses of cepaciamides A and B. Tetrahedron Lett., 1999, 40,
939-942.