Stereoselective total synthesis of putaminoxin

Article abstract of DOI:10.1055/s-0031-1290156

The stereoselective total synthesis of a phytotoxic macrolide putaminoxin, isolated from the culture of Phoma putaminum fungus, has been accomplished by utilization of Sharpless asymmetric epoxidation, Birch reduction, Jacobsens kinetic resolution of race

Full text of DOI:10.1055/s-0031-1290156

PAPER
585
Stereoselective Total Synthesis of Putaminoxin
T
otal
S
ynt
h
hesis of Puta
i
minox
l
in lu Singh Yadav,*a,b Ande Raju,a,c Kontham Ravindar,a Basi V. Subba Reddy,a Ahmad Al Khazim Al Ghamdib
a
Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 607, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
b
c
Engineer Abdullah Baqshan for Bee Research, King Saudi University, Saudi Arabia
University of Hyderabad, Hyderabad 500046, India
Received 14 October 2011; revised 2 December 2011
OH
S
OH
OH
Abstract: The stereoselective total synthesis of a phytotoxic mac-
rolide putaminoxin, isolated from the culture of Phoma putaminum
fungus, has been accomplished by utilization of Sharpless asym-
metric epoxidation, Birch reduction, Jacobsen’s kinetic resolution
of racemic epoxide, and Yamaguchi lactonization as key transfor-
mations.
E
*
O
O
R
O
O
O
O
2
1
OH
Key words: macrolide, necrotic leaf disease, Sharpless asymmetric
epoxidation, Birch reduction, Jacobsen’s kinetic resolution,
Yamaguchi lactonization
*
O
O
3
4
Natural products containing ten-membered macrolide
skeletons such as putaminoxin,1 aspinolide,2 and
nonenolide3 have been isolated from fungal sources and
are known to possess potent phytotoxic properties. In par-
ticular, putaminoxin (1) (Figure 1), a disubstituted phyto-
toxic nonenolide, was isolated by Evidente et al. from the
culture filtrates of Phoma putaminum fungus,1 which is
responsible for a necrotic leaf disease of Erigeron annuus
(annual fleabane). Putaminoxin (1) is known to exhibit a
range of phytotoxicities on mandarin and annual dog’s
mercury and also shows severe toxicity on Erigeron annu-
us. Putaminoxins B (2), D (3), and E (4) were also isolated
by the same research group1 from Phoma putaminum, and
are structurally closely related to putaminoxin (1).4 The
absolute stereochemistry of putaminoxin (1) was deter-
mined by its total synthesis, and the stereochemistry of C5
and C9 were revealed as S and R, respectively.5
Figure 1 Putaminoxin (1) and putaminoxins B (2), D (3), and E (4)
tention of synthetic chemists to develop elegant
approaches for the synthesis of these natural products and
their analogues, to develop leads for potent herbicides.
Following our interest on the total synthesis of biological-
ly active natural products, herein we wish to report an ef-
ficient synthetic approach for the total synthesis of the
phytotoxic natural product putaminoxin (1).
In our retrosynthesis, we assumed that the target molecule
1 could be obtained from hydroxy acid 5 via Yamaguchi
macrolactonization (Scheme 1). The hydroxy acid 5
would be prepared easily from a homopropargyl alcohol
6. The intermediate alcohol 6 could be synthesized by the
coupling reaction of terminal alkyne 7 with chiral oxirane
8, which could in turn be prepared from commercially
available pentane-1,5-diol (9) and the corresponding race-
mic 2-propyloxirane by using known transformations. In
Fascinating structural features coupled with inherent phy-
totoxic activities of these macrolides have attracted the at-
OH
O
OTBS
OH
5
1
9
HO
O
O
1
5
OTBS
OTBS
O
OH
BnO
+
BnO
6
7
8
HO
OH
9
Scheme 1 Retrosynthetic analysis of putaminoxin (1)
SYNTHESIS 2012, 44, 585–590
x
x
.x
x
.2
0
1
2
Advanced online publication: 16.01.2012
DOI: 10.1055/s-0031-1290156; Art ID: Z97611SS
© Georg Thieme Verlag Stuttgart · New York

586
J. S. Yadav et al.
PAPER
DET, Ti(Oi-Pr)4, t-BuOOH, CH2Cl2] of allyl alcohol 12
afforded epoxy alcohol 13 in 92% yield. Treatment of 13
with triphenylphosphine in anhydrous carbon tetrachlo-
ride afforded the corresponding a-chlorooxirane 14 in
90% yield.9a Compound 14 was then converted into prop-
argyl alcohol 15 under Birch reaction conditions11 (Li, liq-
uid NH3, THF, –33 °C) in 95% yield. Propargyl alcohol
15 was converted into its tert-butyldimethylsilyl ether 7 in
95% yield by reaction with tert-butylchlorodimethylsi-
lane and imidazole in dichloromethane.9a
a
b,c
HO
OH
BnO
BnO
OH
9
10
O
d
e
OH
BnO
OEt
12
11
13
O
O
f
BnO
g
OH
OH
BnO
Cl
14
OTBS
h
The terminal chiral oxirane 8 (prepared from the corre-
sponding racemic oxirane 16 by using Jacobsen’s kinetic
resolution)12,17 was opened13 regioselectively with termi-
nal alkyne 7 by using n-butyllithium and boron trifluo-
ride–diethyl ether complex in tetrahydrofuran to afford
the homopropargyl alcohol 6 in 70% yield (Scheme 3).
Debenzylation of compound 6 with sodium in liquid am-
monia with concomitant partial reduction14 of the ho-
mopropargyl alcohol gave the corresponding homoallyl
alcohol 17 with E stereochemistry in 90% yield. Selective
oxidation of the primary hydroxy15a group of diol 17 by
using 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) and
(diacetoxyiodo)benzene in anhydrous dichloromethane,
and a subsequent oxidation15b,c,17 with sodium chlorite and
sodium dihydrogen phosphate afforded the hydroxy acid
5 in 80% yield (over two steps). Hydroxy acid 5 was then
subjected to Yamaguchi macrolactonization16 by using
2,4,6-trichlorobenzoyl chloride, triethylamine, and 4-
(N,N-dimethylamino)pyridine in toluene to afford the
macrolide 18 in good yield (70%). Removal of the tert-bu-
tyldimethylsilyl group in macrolide 18 by using tetrabutyl-
ammonium fluoride in tetrahydrofuran gave the target
molecule putaminoxin (1) in 90% yield. The 1H NMR, 13C
NMR, IR, and mass spectral data of the synthetic putami-
noxin (1) were in good agreement with those of the natural
product reported in the literature.1,5
BnO
BnO
15
7
Scheme 2 Reagents and conditions: (a) NaH, TBAI, BnBr, THF, 0
°C to r.t., 75%; (b) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C to r.t.,
86%; (c) Ph3P=CHCO2Et, benzene, r.t., 82%; (d) LAH, AlCl3, Et2O,
–78 °C, 80%; (e) L-(+)-DET, Ti(Oi-Pr)4, t-BuOOH, CH2Cl2, –20 °C,
92%; (f) Ph3P, CCl4, NaHCO3, reflux, 3 h, 90%; (g) Li, liquid NH3,
THF, –33 °C, 1 h, 95%; (h) TBSCl, imidazole, CH2Cl2, 0 °C to r.t., 1
h, 95%.
this synthetic route, we planned to install stereocenters at
C5 and C9 using Sharpless asymmetric epoxidation and
Jacobsen’s kinetic resolution, respectively.
Accordingly, the synthesis of putaminoxin (1) began from
commercially available pentane-1,5-diol (9), which was
protected as its monobenzyl ether 10 (75% yield) by reac-
tion with benzyl bromide in the presence of sodium hy-
dride and tetrabutylammonium iodide (Scheme 2).6
Oxidation of alcohol 10 by using Swern reaction
conditions7 [(COCl)2, DMSO, Et3N, CH2Cl2] gave the
corresponding aldehyde (86% yield), which was subse-
quently
homologated
with
a
Wittig
ylide8
(Ph3P=CHCO2Et) to afford the a,b-unsaturated ester 11 in
82% yield. The selective reduction of ester 11 (LAH,
AlCl3, Et2O, –78 °C)9 gave allyl alcohol 12 in good yield
(80%). Sharpless asymmetric epoxidation9a,10 [L-(+)-
O
16
a
O
OTBS
OTBS
8
OH
c
b
BnO
d
BnO
HO
7
6
OTBS
OH
O
OTBS
OH
HO
17
5
OTBS
OH
e
f
O
O
O
O
18
1
Scheme 3 Reagents and conditions: (a) (R,R)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II), AcOH, toluene,
r.t., 42%; (b) n-BuLi, BF3·OEt2, THF, –78 °C to r.t., 70%; (c) Na, liquid NH3, THF, –33 °C, 90%; (d) (i) TEMPO, PhI(OAc)2, CH2Cl2, 20 min;
(ii) NaClO2, NaH2PO4, DMSO–H2O, 80% (over two steps); (e) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, toluene, reflux, 70%; (f) 1.0 M
TBAF in THF, THF, 6 h, 90%.
Synthesis 2012, 44, 585–590
© Thieme Stuttgart · New York

PAPER
Total Synthesis of Putaminoxin
587
1H NMR (200 MHz, CDCl3): d = 7.20–7.35 (m, 5 H), 6.83–6.99 (m,
1 H), 5.77 (d, J = 5.6 Hz, 1 H), 4.46 (s, 2 H), 4.15 (q, J = 7.0, 14.0
Hz, 2 H), 3.44 (t, J = 5.4, 11.7 Hz, 2 H), 2.22 (q, J = 7.3, 14.0 Hz, 2
H), 1.54–1.68 (m, 4 H), 1.29 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 166.4, 148.6, 138.3, 127.3, 127.2,
127.1, 121.2, 72.7, 69.5, 60.0, 31.6, 28.9, 24.5, 14.0.
In conclusion, we have demonstrated an efficient linear
synthetic approach to the total synthesis of the phytotoxic
macrolide putaminoxin (1). This approach utilizes readily
available precursors and follows simple and high yielding
protocols such as Sharpless asymmetric epoxidation,
Birch reduction, Jacobsen’s kinetic resolution of a racem-
ic epoxide, and Yamaguchi lactonization as key steps; this
makes it attractive for the generation of new derivatives of
the natural product.
ESI-MS: m/z = 285 [M + Na+].
(E)-7-(Benzyloxy)hept-2-en-1-ol (12)
A soln of AlCl3 (392 mg, 2.9 mmol) in Et2O (7 mL) was added over
5 min to a suspension of LAH (326 mg, 8.6 mmol) in anhyd Et2O
(10 mL) at –78 °C under N2. After complete addition, the mixture
was allowed to stir at r.t. for 30 min. To this stirred suspension was
added a soln of ester 11 (1.5 g, 5.73 mmol) in anhyd Et2O (10 mL)
over 10 min. After stirring at 0 °C for 30 min, the mixture was
quenched with sat. aq Na2SO4 (10 mL) and filtered through Celite.
The residue was washed with EtOAc (3 × 20 mL). The combined
organic layers were dried (Na2SO4) and concentrated under reduced
pressure. The crude residue was purified by column chromatogra-
phy (silica gel, hexanes–EtOAc, 8:2).
IR spectra were recorded on a Perkin-Elmer FT-IR 240-c spectro-
photometer using KBr optics. 1H NMR and 13C spectra were record-
ed on a Gemini-200 spectrometer (200 MHz) and a Bruker-300
spectrometer (300 MHz); CDCl3 was used as solvent and TMS as
internal standard. Mass spectra were recorded on a Finnigan MAT
1020 mass spectrometer operating at 70 eV. Column chromatogra-
phy was performed on Merck silica gel (60–120 mesh). Optical ro-
tations were measured on a JASCO DIP-370 polarimeter at 25 °C.
5-(Benzyloxy)pentan-1-ol (10)
Yield: 1.0 g (80%); colorless viscous liquid.
A soln of 9 (2.0 g, 19.2 mmol) in anhyd THF (25 mL) was added
dropwise to a stirred suspension of a 55% dispersion of NaH in min-
eral oil (0.92 g, 38.4 mmol) in anhyd THF (20 mL) for 15 min at
0 °C. The mixture was then allowed to stir at r.t. for 45 min. To this
soln, BnBr (2.32 mL, 19.2 mmol) was added at 0 °C over 10 min
and then TBAI (40 mg, 1.92 mmol) was added. The resulting mix-
ture was stirred at r.t. for 10 h and then quenched with cold H2O (20
mL) at 0 °C. The crude mixture was extracted with EtOAc (3 × 20
mL) and the organic layers were dried (Na2SO4) and concentrated
under reduced pressure. The resulting residue was purified by col-
umn chromatography (silica gel, hexanes–EtOAc, 70:30).
IR (neat): 3399, 3029, 2929, 2857, 1454, 1364, 1206, 1096, 1006,
971, 737, 697, 610 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.20–7.33 (m, 5 H), 5.54–5.70 (m,
2 H), 4.46 (s, 2 H), 4.03 (d, J = 3.7 Hz, 2 H), 3.43 (t, J = 6.0 Hz, 2
H), 2.05 (q, J = 6.7, 12.8 Hz, 2 H), 1.41–1.66, (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 138.4, 132.4, 129.2, 128.6, 127.5,
127.3, 72.7, 70.2, 63.2, 31.7, 29.0, 25.5.
ESI-MS: m/z = 243 [M + Na+].
{(2S,3S)-3-[4-(Benzyloxy)butyl]oxiran-2-yl}methanol (13)
L-(+)-DET (0.2 mL, 1.0 mmol) and Ti(Oi-Pr)4 (0.308 mL, 1.0
mmol) were added to a stirred suspension of activated 4 Å MS (1.0
g) in anhyd CH2Cl2 (10 mL), and the mixture was stirred for 30 min
at –20 °C. To this mixture, a soln of allyl alcohol 12 (0.9 g, 4.0
mmol) in anhyd CH2Cl2 (15 mL) was added dropwise and the mix-
ture was stirred for another 30 min at –20 °C. Then a 4.0 M soln of
t-BuOOH in toluene (4.3 mL, 9.0 mmol) was added and the result-
ing mixture was stirred at the same temperature for 8 h. It was then
warmed to 0 °C and quenched with H2O (5 mL) and a 20% aq soln
of NaOH (3 mL). The resulting mixture was vigorously stirred for
3 h at r.t. and then filtered through Celite. The residue was washed
well with CH2Cl2 (3 × 20 mL). The organic layer was separated and
the aqueous layer was extracted with CH2Cl2 (3 × 30 mL). The
combined organic layers were washed with brine (15 mL) and dried
(Na2SO4). The solvent was removed under reduced pressure and the
residue was purified by column chromatography (silica gel, hex-
anes–EtOAc, 7:3).
Yield: 2.78 g (75%); colorless liquid.
IR (neat): 3387, 3030, 2928, 2858, 1454, 1362, 1206, 1097, 737,
697, 610 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.17–7.34 (m, 5 H), 4.17 (s, 2 H),
3.61 (t, J = 5.1 Hz, 2 H), 3.45 (t, J = 6.6 Hz, 2 H), 1.37–1.71 (m, 6
H).
13C NMR (75 MHz, CDCl3): d = 138.3, 128.1, 127.5, 127.3, 72.7,
70.1, 62.2, 32.3, 29.3, 22.3.
ESI-MS: m/z = 194 [M + H+].
Ethyl (E)-7-(Benzyloxy)hept-2-enoate (11)
DMSO (1.58 mL, 22.3 mmol) was added dropwise over 10 min to
a soln of oxalyl chloride (1.64 mL, 18.6 mmol) in anhyd CH2Cl2 (10
mL) at –78 °C under a N2 atmosphere. The mixture was stirred for
an additional 10 min and then a soln of alcohol 10 (2.4 g, 12.4
mmol) in CH2Cl2 (20 mL) was added dropwise. The resulting mix-
ture was stirred for 30 min and then Et3N (10.3 mL, 74.4 mmol) was
added dropwise at –78 °C; stirring was continued at r.t. for 30 min.
After completion of the reaction, the mixture was quenched with
ice-cold H2O (10 mL), and the aqueous phase was extracted with
CH2Cl2 (3 × 25 mL). The combined organic layers were washed
with brine (20 mL) and dried (Na2SO4). Removal of the solvent
gave the crude product 5-(benzyloxy)pentanal as a colorless liquid;
yield: 2.04 g (86%). A soln of this aldehyde in benzene was added
dropwise to a soln of Ph3P=CHCO2Et (3.2 g, 9.4 mmol) in benzene
(15 mL) at 80 °C. After 1 h, the solvent was removed under reduced
pressure and the crude product was purified by column chromatog-
raphy (silica gel, hexanes–EtOAc, 90:10).
Yield: 888 mg (92%); colorless viscous liquid; [a]D25 –19.3 (c 1.0,
CHCl3).
IR (neat): 3422, 2928, 2859, 1727, 1455, 1365, 1276, 1099, 1026,
877, 740, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.17–7.32 (m, 5 H), 4.43 (s, 2 H),
3.74–3.82 (m, 1 H), 3.47–3.57 (m, 1 H), 3.41 (t, J = 6.0 Hz, 2 H),
2.83–2.89 (m, 1 H), 2.76–2.80 (m, 1 H), 1.44–1.70 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 138.3, 128.2, 127.5, 127.4, 72.7,
69.9, 61.6, 58.4, 55.8, 31.2, 29.3, 22.5.
ESI-MS: m/z = 259 [M + Na+].
Yield: 1.67 g (82%); colorless liquid.
(2S,3R)-2-[4-(Benzyloxy)butyl]-3-(chloromethyl)oxirane (14)
A soln of epoxy alcohol 13 (0.7 g, 3.0 mmol) in CCl4 (10 mL) fol-
lowed by NaHCO3 (25 mg, 0.3 mmol) were added to a stirred soln
of Ph3P (0.95 g, 3.6 mmol) in anhyd CCl4 (10 mL). The reaction
IR (neat): 2927, 2856, 1720, 1654, 1455, 1366, 1266, 1197, 1165,
1105, 1024, 982, 737, 698 cm–1.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 585–590

588
J. S. Yadav et al.
PAPER
mixture was stirred at reflux temperature for 3 h. After completion
of the reaction, the mixture was cooled to r.t. and then the solvent
was removed under reduced pressure. The crude product was puri-
fied by column chromatography (silica gel, hexanes–EtOAc,
9.5:0.5).
mL) and AcOH (84 mg, 0.140 mmol) was stirred under open air for
1 h at r.t. The resulting mixture was concentrated under reduced
pressure and the brown residue was dried under reduced pressure.
Then racemic 2-propyloxirane (16; 3.0 g, 34.8 mmol) was added in
one portion at 0 °C and dropwise addition of H2O (0.35 mL, 19.2
mmol) over 10 min followed. The mixture was then allowed to
warm to r.t. and was allowed to stir for 20 h. The desired (R)-2-pro-
pyloxirane (8) was isolated after distillation from the reaction mix-
ture at atmospheric pressure.
Yield: 0.678 g (90%); colorless liquid; [a]D25 +18.7 (c 1.0, CHCl3).
IR (neat): 3030, 2935, 2860, 1493, 1454, 1362, 1258, 1207, 1102,
1026, 739, 710, 649 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.21–7.35 (m, 5 H), 4.47 (s, 2 H),
4.35–4.42 (m, 1 H), 4.07–4.14 (m, 1 H), 3.86–4.00 (m, 1 H), 3.70–
3.77 (m, 1 H), 3.46 (t, J = 5.8 Hz, 2 H), 1.49–2.02 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 138.3, 128.2, 127.4, 127.3, 72.7,
69.7, 58.7, 56.9, 44.6, 31.0, 29.2, 22.4.
Yield: 1.26 g (42%); colorless liquid; [a]D25 +11.0 (c 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): d = 2.81–2.88 (m, 1 H), 2.69 (dd,
J = 3.7, 5.2 Hz, 1 H), 2.40 (dd, J = 2.6, 5.2 Hz, 1 H), 1.44–1.55 (m,
4 H), 0.98 (t, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 46.3, 41.0, 31.2, 23.4, 15.8.
ESI-MS: m/z = 255 [M + H+].
(4R,8S)-12-(Benzyloxy)-8-(tert-butyldimethylsiloxy)dodec-6-
yn-4-ol (6)
(S)-7-(Benzyloxy)hept-1-yn-3-ol (15)
Fe(NO3)3 (20 mg, cat.) was added to a freshly condensed soln of an-
hyd NH3 (20 mL) in a two-necked round-bottomed flask at –33 °C
fitted with a cold condenser; cautious addition of Li metal pieces
(100 mg, 14.16 mmol) followed. The resulting gray suspension was
stirred for 1 h at the same temperature. A soln of epoxy chloride 14
(0.6 g, 2.36 mmol) in anhyd THF (10 mL) was added dropwise and
then stirring was continued for another 2 h at –33 °C. To this mix-
ture, solid NH4Cl (10 g) was added and then NH3 was allowed to
evaporate slowly. The residue was dissolved in Et2O (15 mL) and
then filtered though small pad of Celite. The filtrate was dried
(Na2SO4) and the crude product was purified by column chromatog-
raphy (silica gel, hexanes–EtOAc, 8:2).
A soln of 1.6 M n-BuLi in hexane (1.04 mL, 1.65 mmol) was added
to a stirred soln of alkyne 7 (0.5 g, 1.5 mmol) in anhyd THF (10 mL)
under an N2 atmosphere at –78 °C. The mixture was allowed to stir
for 30 min at the same temperature. BF3·OEt2 (0.2 mL, 1.65 mmol)
was then added slowly. After 10 min, a soln of (R)-2-propyloxirane
(8; 0.5 g, 5.81mmol) in anhyd THF (10 mL) was added and the mix-
ture was stirred for a further 3 h at –78 °C. The mixture was then
quenched with sat. aq NaHCO3 (10 mL) and sat. aq NH4Cl (10 mL)
at –78 °C. The mixture was allowed to warm to r.t. and then extract-
ed with EtOAc (3 × 20 mL) and dried (Na2SO4). Removal of the
solvent was followed by purification by column chromatography
(silica gel, hexanes–EtOAc, 70:30).
Yield: 4.9 g (95%); colorless liquid; [a]D25 –7.3 (c 1.0, CHCl3).
25
Yield: 0.44 g (70%); colorless viscous liquid; [a]D –10.7 (c 1.0,
CHCl3).
IR (neat) 3416, 2927, 2858, 1697, 1456, 1385, 1259, 1214, 1175,
1096, 759, 697, 668 cm–1.
IR (neat): 3415, 2925, 2855, 1630, 1383, 1272, 1106, 840, 703 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.19–7.34 (m, 5 H), 4.48 (s, 2 H),
4.32 (t, J = 5.2 Hz, 1 H), 3.46 (t, J = 6.0 Hz, 2 H), 2.28 (d, J = 2.2
Hz, 1 H), 1.40–1.76 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 138.3, 128.2, 127.5, 127.4, 84.9,
72.8, 72.7, 70.0, 61.9, 37.26, 29.2, 21.7.
1H NMR (200 MHz, CDCl3): d = 7.21–7.35 (m, 5 H), 4.47 (s, 2 H),
4.26–4.36 (m, 1 H), 3.69 (m, 1 H), 3.44 (t, J = 6.2 Hz, 2 H), 2.21–
2.47 (m, 2 H), 1.24–1.81 (m, 10 H), 0.80–1.06 (m, 12 H), 0.09 (d,
J = 4.6 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 138.6, 128.2, 127.5, 127.4, 84.5,
80.5, 72.8, 70.2, 69.7, 63.0, 38.6, 38.3, 29.3, 27.7, 25.7, 22.0, 18.7,
18.2, 13.9, –4.5, –5.0.
ESI-MS: m/z = 241 [M + Na+].
ESI-MS: m/z = 441 [M + Na+].
[(S)-7-(Benzyloxy)hept-1-yn-3-yloxy](tert-butyl)dimethylsilane
(7)
Imidazole (20 mg, 2.76 mmol) followed by TBSCl (0.331 g, 2.20
mmol) were added to a soln of propargyl alcohol 15 (0.4 g,1.84
mmol) in anhyd CH2Cl2 (10 mL) under a N2 atmosphere at 0 °C, and
the stirring was continued for 1 h at r.t. The mixture was then
quenched with sat. aq NH4Cl (10 mL) and extracted with CH2Cl2
(2 × 20 mL). The organic layer was washed with H2O (1 × 20 mL)
and brine (1 × 20 mL), dried (Na2SO4), and concentrated under re-
duced pressure. The residue was purified by column chromatogra-
phy (silica gel, hexanes–EtOAc, 9.8:0.2).
(5S,9R,E)-5-(tert-Butyldimethylsiloxy)dodec-6-ene-1,9-diol (17)
Freshly cut Na (230 mg, 10 mmol) was cautiously and portionwise
added to a freshly condensed soln of anhyd NH3 (25 ml) in a two-
necked round-bottomed flask at –78 °C and fitted with a cold con-
denser. The resulting deep blue suspension was stirred for 30 min at
the same temperature. A soln of homopropargylic alcohol 6 (0.4 g,
1.0 mmol) in anhyd THF (10 mL) was added dropwise and then the
mixture was stirred for another 2 h at –78 °C. After completion of
the reaction, the mixture was quenched with solid NH4Cl (10 g) and
then NH3 was allowed to evaporate slowly. The residue was dis-
solved in Et2O and then filtered though small pad of Celite. The fil-
trate was dried (Na2SO4) and the crude product was purified by
column chromatography (silica gel, hexanes–EtOAc, 7:3).
Yield: 0.578 g (95%); colorless liquid; [a]D25 –9.3 (c 1.0, CHCl3).
IR (neat): 3308, 2930, 2857, 1461, 1361, 1254, 1104, 936, 837, 776,
736, 696, 665 cm–1.
1H NMR (200 MHz, CDCl3) d = 7.21–7.36 (m, 5 H), 4.47 (s, 2 H),
4.27–4.36 (m, 1 H), 3.45 (t, J = 6.2 Hz, 2 H), 2.31 (d, J = 2.3 Hz, 1
H), 1.43–1.77 (m, 6 H), 0.90 (s, 9 H), 0.10 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 136.7, 128.4, 127.5, 127.4, 85.5,
72.8, 72.0, 70.2, 62.6, 38.3, 29.3, 25.8, 21.8, 18.2, –5.17.
Yield: 0.284 g (90%); colorless liquid; [a]D25 +7.7 (c 2.0, CHCl3).
IR (neat): 3351, 2931, 2860, 1463, 1362, 1242, 1065, 973, 836, 775,
670 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.41–5.60 (m, 2 H), 4.03–4.15 (m,
1 H), 3.69–3.76 (m, 1 H), 3.61 (t, J = 6.7 Hz, 2 H), 2.00–2.29 (m, 2
H), 1.21–1.62 (m, 10 H), 0.94 (t, J = 7.5 Hz, 3 H), 0.89 (s, 9 H), 0.03
(d, J = 6.7 Hz, 6 H).
ESI-MS: m/z = 333 [M + Na+].
(R)-2-Propyloxirane (8)
A mixture of (R,R)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-
cyclohexanediaminocobalt(II) (42 mg, 0.069 mmol) in toluene (0.2
13C NMR (75 MHz, CDCl3): d = 137.1, 125.8, 73.2, 70.7 62.7, 40.2,
38.8, 37.9, 32.5, 25.8, 21.3, 18.8, 18.1, 14.0, –4.3, –4.7.
Synthesis 2012, 44, 585–590
© Thieme Stuttgart · New York

PAPER
Total Synthesis of Putaminoxin
589
ESI-MS: m/z = 353 [M + Na+].
(5 mL) and extracted with EtOAc (3 × 10 mL). The organic layers
were washed with brine (5 mL), dried (Na2SO4), and concentrated
in vacuo. The solvent was removed and the residue was purified by
column chromatography (silica gel, hexanes–EtOAc, 70:30).
(5S,9R,E)-5-(tert-Butyldimethylsiloxy)-9-hydroxydodec-6-en-
oic acid (5)
PhI(OAc)2 (0.3 g, 0.935 mmol) was added to a soln of 17 (0.28 g,
0.85 mmol) and TEMPO (0.014 g, 0.085 mmol) in anhyd CH2Cl2 (5
mL) at 0 °C. The mixture was stirred for 20 min at r.t. After com-
pletion of the reaction, the mixture was diluted with CH2Cl2 (20
mL), washed with sat. aq Na2S2O3 (10 mL), and then extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were washed
with sat. aq NaHCO3 (10 mL) followed by brine soln (10 mL), and
then dried (Na2SO4) and concentrated in vacuo. The crude aldehyde
was immediately used for the next reaction. A soln of NaClO2 (0.12
g, 1.275 mmol) in H2O (2 mL) was added dropwise within 5 min at
r.t. To a stirred soln of the above aldehyde in DMSO (3 mL) was
added NaH2PO4 (0.27 g, 1.7 mmol) in H2O (3 mL). The mixture was
left overnight at r.t., and then 5% aq NaHCO3 (10 mL) was added.
The aqueous phase was extracted with CH2Cl2 (3 × 30 mL) and the
organic layer was washed with brine (10 mL), dried (Na2SO4), and
concentrated in vacuo. The residue was purified by column chroma-
tography (silica gel, hexanes–EtOAc, 70:30).
Yield: 0.035 g (90%); colorless oil; [a]D25 –25.3 (c 1.0, CHCl3).
IR (neat): 3433, 2959, 2930, 2871, 1729, 1641, 1442, 1365, 1182,
1007 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.54 (ddd, J = 4.7, 10.4, 15.3 Hz,
1 H), 5.32 (dd, J = 9.3, 15.5 Hz, 1 H), 4.97–5.10 (m, 1 H), 4.01 (dt,
J = 3.4, 10.2, 19.8 Hz, 1 H), 2.31–2.50 (m, 2 H), 1.83–2.09 (m, 4 H),
1.20–1.75 (m, 6 H), 0.93 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 175.7, 137.2, 131.7, 75.4, 74.2,
40.3, 38.7, 36.4, 35.7, 22.3, 19.2, 13.9.
ESI-MS: m/z = 235 [M + Na+].
Acknowledgment
A.R. and K.R. thank the CSIR and UGC, New Delhi, for the award
of fellowships. The author acknowledges the partial support by
King Saudi University for Global Research Network for Organic
Synthesis (GRNOS).
25
Yield: 0.233 g (80%; two steps); yellow oil; [a]D –18.1 (c 0.33,
CHCl3).
IR (neat): 2956, 2927, 2855, 1712, 1463, 1253, 1084, 973, 835, 776,
668 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.44–5.59 (m, 2 H), 4.06–4.16 (m,
1 H), 3.56–3.66 (m, 1 H), 2.35 (t, J = 6.79 Hz, 2 H), 2.03–2.28 (m,
2 H), 1.19–1.74 (m, 8 H), 0.94 (t, J = 7.5 Hz, 3 H), 0.89 (s, 9 H),
0.03 (d, J = 7.5 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 178.8, 136.7, 126.0, 72.8, 70.7,
40.11, 38.8, 37.4, 31.8, 25.8, 22.5, 20.4, 18.7, 14.0, –4.7, –4.8.
ESI-MS: m/z = 367 [M + Na+].
References
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(6S,10R,E)-6-(tert-Butyldimethylsiloxy)-10-propyl-3,4,5,6,9,10-
hexahydro-2H-oxecin-2-one (18)
2,4,6-Trichlorobenzoyl chloride (0.13 ml, 0.71 mmol) was added to
a stirred soln of 5 (0.15 g, 0.47 mmol) and Et3N (100 mg, 0.71
mmol) in anhyd THF (3 ml) at r.t. The resulting mixture was stirred
at r.t. for 3 h, and then a soln of DMAP (0.29 g, 2.35 mmol) in anhyd
toluene (20 mL) was added. The mixture was refluxed for 10 h and
then cooled to r.t. After completion of the reaction, the mixture was
quenched with a sat. aq NaHCO3 and then the aqueous layer was ex-
tracted with EtOAc (3 × 20 mL). The combined organic layers were
washed with brine (10 mL), dried (Na2SO4), and concentrated in
vacuo. The crude product was purified by column chromatography
(silica gel, hexanes–EtOAc, 8.0:2.0).
Yield: 0.099 g (70%); colorless oil; [a]D25 –8.7 (c 0.30, CHCl3).
IR (neat): 3433, 2962, 2935, 2890, 1730, 1670, 1450, 1366, 1183,
1007 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.43 (ddd, J = 4.3, 10.0, 15.0 Hz,
1 H), 5.27 (dd, J = 9.0, 15.0 Hz, 1 H), 4.90–5.05 (m, 1 H), 4.00 (dt,
J = 3.0, 10.0, 19.0 Hz, 1 H), 2.37–2.57 (m, 2 H), 1.80–2.0 (m, 4 H),
1.22–1.75 (m, 6 H), 0.90 (t, J = 7.4 Hz, 3 H), 0.87 (s, 9 H), 0.03 (d,
J = 7.4 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 174.6, 138.3, 129.5, 75.6, 72.3,
40.3, 39.6, 36.7, 35.8, 22.2, 18.9, 18.2, 14.0, 13.8, –4.3, –4.7.
ESI-MS: m/z = 249 [M + Na+].
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(6R,10R,E)-6-Hydroxy-10-propyl-3,4,5,6,9,10-hexahydro-2H-
oxecin-2-one (Putaminoxin; 1)
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0 °C. The mixture was stirred for 6 h and then diluted with H2O
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Synthesis 2012, 44, 585–590

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Synthesis 2012, 44, 585–590
© Thieme Stuttgart · New York