Asymmetric total synthesis of stagonolide G

Article abstract of DOI:10.1002/hlca.201000416

A simple asymmetric total synthesis of stagonolide G (1) is described. Asymmetric dihydroxylation, regioselective epoxide ring opening, and vinyl Grignard reactions are involved in generating the stereogenic centers C(4) and C(8), followed by Grubbs-II-ca

Full text of DOI:10.1002/hlca.201000416

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Helvetica Chimica Acta – Vol. 94 (2011)
Asymmetric Total Synthesis of Stagonolide G
by Dasari Ramesh, Singanaboina Rajaram, Peddikotla Prabhakar, Udugu Ramulu, Dorigondla Kumar
Reddy, and Yenamandra Venkateswarlu*
Natural Products Laboratory, Organic Chemistry Division-I, Indian Institute of Chemical Technology,
Hyderabad-500007, India
(phone: þ 91-40-27193167; fax: þ 91-40-27160512; e-mail: luchem@iict.res.in)
A simple asymmetric total synthesis of stagonolide G (1) is described. Asymmetric dihydroxylation,
regioselective epoxide ring opening, and vinyl Grignard reactions are involved in generating the
stereogenic centers C(4) and C(8), followed by Grubbs-II-catalyzed ring-closing metathesis (RCM).
Introduction. – Naturally occurring macrolides, particularly ten-membered-ring-
containing lactones have continued to attract synthetic chemists as well as biologists
during recent years [1], due to their interesting structural properties and potent
biological activities [2]. Owing to the scarce availability of these macrolides, only few of
them were evaluated for biological activity. Some examples, mainly ten-membered
macrolides such as putaminoxin and pinolidoxin displayed potent biological activities
[3]. The main metabolite, stagonolide A shows phytotoxic property [4], and
stagonolide F exhibits antibacterial and antifungal activity [5a,b]. Stagonolides G – I,
nonenolides were produced by Stagonopora crisis Dav i s, which is a fungal pathogen
isolated from Cirsium arvense and proposed as a potential mycoherbicide of this
perennial noxious weed, and produces phytotoxic metabolites in liquid and solid
cultures [5c].
Biological properties and interesting structural features, such as geometrically
defined C¼C bonds and with established configurations of OH-carrying centers render
stagonolides as significant synthetic targets. In continuation of our studies towards total
synthesis of lactone-containing molecules [6], we have synthesized ten-membered
macrolides, such as stagonolide A [6c], stagonolide B [6c], and herbarumin I [6d], and
we were subsequently interested in a concise synthesis of stagonolide G (1; Fig.). In this
article, we report a simple synthesis of stagonolide G (1), and while we were working on
the synthesis of 1, the first stereoselective synthesis of 1 has been reported [7].
Figure. Structure of stagonolide G
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Results and Discussion. – The retrosynthetic analysis of stagonolide G (1) is
outlined in Scheme 1. Compound 1 can be obtained from diene ester 15 by ring-closing
methathesis (RCM) protocol, a key reaction strategy that has been widely used for the
synthesis of macrolides. Furthermore, compound 15 in turn can be obtained by Steglich
esterification of acid 14 and alcohol 6. The intermediate 6 is envisaged from (þ)-(R)-
glyceraldehyde, and intermediate 14 can be easily prepared from commercially
available pent-4-en-1-ol. Thus, in the present strategy, the two stereogenic centers C(4)
and C(8) (Fig.) are constructed: one by dihydroxylation on 7 (cf. Scheme 3, below) and
the second by vinyl Grignard reaction on 2 (cf. Scheme 2, below), leading to (4S)- and
(8R)-configurations.
Scheme 1. Retrosynthetic Analysis
As outlined in Scheme 2, intermediate 6 was prepared from (þ)-(R)-2,3-di-O-
cyclohexylideneglyceraldehyde 2 [8]. The aldehyde 2 was reacted with CH2¼CHMgBr
in THF to give an inseparable mixture of alcohols in a ratio of 1:1 [9]. Benzylation of
the secondary alcohol with BnBr in the presence of NaH in THF afforded compound 3,
and the required isomer was separated by column chromatography. The hexylidene
protecting group in 3 was removed by using Dowex Hþ resin in MeOH to give the diol 4
Scheme 2
a) 1. CH2¼CHMgBr, THF, ꢀ 788, 2 h; 89%; 2. NaH, BnBr, THF, 08 to r.t., 4 h; 41% (separation of
isomers). b) Dowex Hþ resin, MeOH, r.t., 20 h; 91%. c) Et3N, TsCl, Bu2SnO, CH2Cl2, r.t., 4 h; 92%. d)
LiAlH4, THF, reflux, 1 h; 86%.

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Helvetica Chimica Acta – Vol. 94 (2011)
[10]. The primary OH group in 4 was selectively protected with TsCl/Et3N in the
presence of Bu2SnO in dry CH2Cl2 to afford the tosyl derivative 5 in 92% yield. The
latter was reduced with LiAlH4 in THF to provide the key intermediate 6 for the
synthesis of stagonolide G (1).
The pent-4-en-1-ol was protected with tBuMe2SiCl (TBSꢀCl) to give compound 7,
and the asymmetric dihydroxylation of the terminal olefine in 7 with AD-mix-a
(K2OsO2(OH)4, K3Fe(CN)6, K2CO3, hydroquinine phthalazine-1,4-diyl diether
((DHQ)2PHAL)) at 08 furnished diol 8 [11], which was further subjected to mono-
tosylation in the presence of a catalytic amount of Bu2SnO to give 9; the subsequent
exposure to K2CO3 afforded epoxide 10 (Scheme 3). The regioselective ring opening of
10 with CH2¼CHMgBr in the presence of CuI yielded alcohol 11 [12], which was
t
protected with BnBr using NaH to furnish compound 12. Deprotection of BuMe2Si
group in 12 afforded 13, which was oxidized with [bis(acetoxy)iodo]benzene (BAIB) to
give 14 [13].
Scheme 3
a) 1H-Imidazole, tBuMe2SiCl, CH2Cl2, r.t., 3 h; 93%. b) AD-mix-a (K2OsO2(OH)4, K3Fe(CN)6, K2CO3,
t
hydroquinine phthalizine-1,4-diyl diether ((DHQ)2PHAL)), BuOH/H2O 1:1, 08, 24 h; 94%. c) Et3N,
TsCl, Bu2SnO, CH2Cl2, r.t., 4 h; 91%. d) K2CO3, MeOH, r.t., 2 h; 89%. e) CH2¼CHMgBr, CuI, THF, ꢀ
788, 3 h; 86%. f) NaH, BnBr, THF, 08 to r.t., 4 h; 93%. g) tBu4NF, THF, r.t., 3 h; 92%. h)
[Bis(acetoxy)iodo]benzene (BAIB), 2,2,6,6-tetramethylpiperidin-1-yl oxide (TEMPO), MeCN/H2O
2 :1, r.t., 3 h; 84%. i) Dicyclohexylcarbodiimide (DCC), 4-(dimethylamino)pyridine (DMAP), CH2Cl2,
08, 12 h; 83%; see also [7]. j) Grubbs-II catalyst, CH2Cl2, 408, 3 h; 88%; see also [7]. k) TiCl4, CH2Cl2, 08,
3 h; 73%; see also [7].
The acid 14 was esterified with the alcohol 6 in the presence of dicyclohexylcarbo-
diimide (DCC) and 4-(dimethylamino)pyridine (DMAP) at 08 to provide the diene
ester 15 in 83% yield, which was subjected to RCM using Grubbs-II catalyst to afford
the doubly benzyl-protected macrolide 16. Deprotection of the Bn groups was achieved
with TiCl4 in CH2Cl2 at 08 to provide the natural product stagonolide G (1; Scheme 3) in

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73% yield. The spectroscopic data of synthetic stagonolide G (1) are identical to those
of the natural product reported in [5b].
Conclusions. – We have reported a simple and concise total synthesis of stagonolide
G (1). This protocol involves an asymmetric dihydroxylation, regioselective epoxide
ring opening, Grignard reaction and Grubbs-II-catalyzed ring-closing metathesis as key
steps. The synthesis and biological evaluation of structurally related macrolides are in
progress in our laboratory.
The authors are thankful to CSIR, New Delhi, India, for the financial support, and Dr. J. S. Yadav,
Director, Indian Institute of Chemical Technology (IICT), for his encouragement.
Experimental Part
General. Solvents were dried over standard drying agents and freshly distilled prior to use. The
reagents were purchased from Aldrich and Acros, and were used without further purification unless
otherwise stated. All moisture-sensitive reactions were carried out under N2. Org. solns. were dried (anh.
Na2SO4) and concentrated in vacuo below 408. Column chromatography (CC): silica gel (SiO2, Acmeꢂs
60 – 120 mesh and 100 – 200 mesh). Optical rotations: Horiba high-sensitive polarimeter SEPA-300 at
1
258. IR Spectra: PerkinꢀElmer IR-683 spectrophotometer with NaCl optics; ˜n in cmꢀ1. H- (300 MHz)
and 13C-NMR (75 MHz) spectra: Bruker Avance 300 instrument, in CDCl3; d in ppm rel. to Me4Si as
internal standard, J in Hz. ESI-MS: Agilent Technologies 1100 Series (Agilent Chemistation Software); in
m/z.
(2R)-2-[(1R)-1-(Benzyloxy)prop-2-enyl]-1,4-dioxaspiro[4.5]decane (3). To a soln. of (þ)-(R)-2,3-
di-O-cyclohexylideneglyceraldehyde (2; 1.5 g, 8.82 mmol) in dry THF was added 1.0m CH2¼CHMgBr
soln. (13.2 ml, 13.2 mmol) in THFat ꢀ 788. The mixture was stirred at the same temp. for 2 h and allowed
to reach r.t. After completion, the reaction was quenched with sat. NH4Cl soln. (150 ml), and the
resulting mixture was extracted with AcOEt (2 ꢁ 75 ml). The combined org. phases were washed with
brine and dried (anh. Na2SO4). The solvent was removed under reduced pressure to give an inseparable
mixture of alcohols in a ratio of 1:1 (1.55 g). The crude product was then used for the next step without
any purification. To a soln. of the crude alcohol mixture (1.3 g, 6.56 mmol) in dry THF (20 ml) was added
NaH (0.52 g, 13.13 mmol) at 08, and the mixture was stirred for 10 min at the same temp. To this, BnBr
(0.78 ml, 6.56 mmol) was added at 08 and stirred at r.t. for 4 h. After completion of the reaction, the
mixture was diluted with H2O (100 ml) and extracted with AcOEt (2 ꢁ 75 ml), dried (anh. Na2SO4), and
concentrated under reduced pressure. The crude residue was purified by CC (SiO2; hexane/AcOEt
9.8 :0.2) to give pure 3 (0.77 g, 41%). Colorless liquid. Rf (hexane/AcOEt 4 :1) 0.8. [a]2D5 ¼ ꢀ18.5 (c ¼
0.49, CHCl3). IR (neat): 2933, 2859, 1449, 1099, 929. 1H-NMR: 1.39 (br. s, 2 H); 1.56 (br. s, 8 H);
3.66 – 3.94 (m, 3 H); 4.11 – 4.19 (m, 1 H); 4.55 (AB, J ¼ 12.8, 2 H); 5.26 – 5.36 (m, 2 H); 5.64 – 5.80 (m,
1 H); 7.20 – 7.41 (m, 5 H). 13C-NMR: 23.68; 23.85; 25.03; 34.75; 36.01; 65.24; 70.15; 76.97; 80.95; 119.82;
127.35; 127.61; 128.14; 134.13; 138.21. ESI-MS: 306 ([M þ NH4]þ).
(2R,3R)-3-(Benzyloxy)pent-4-ene-1,2-diol (4). To a soln. of 3 (0.6 g, 2.08 mmol) in MeOH (15 ml)
was added Dowex Hþ resin (5 g), and the mixture was stirred at r.t. for 20 h. After completion of reaction,
the mixture was filtered, and MeOH was evaporated under reduced pressure to afford a crude product,
which was purified by CC (hexane/AcOEt 70 :30) to afford pure 4 (390 mg, 91%). Colorless liquid.
1
[a]2D5 ¼ ꢀ36.92 (c ¼ 0.25, CHCl3). IR (neat): 3426, 2924, 2852, 1637, 1067. H-NMR: 3.12 (br. s, 1 H);
3.43 – 3.68 (m, 3 H); 3.76 – 3.85 (m, 1 H); 4.46 (AB, J ¼ 11.5, 2 H); 5.30 – 5.43 (m, 2 H); 5.67 – 5.83 (m,
1 H); 7.20 – 7.37 (m, 5 H). 13C-NMR: 62.98; 70.43; 73.68; 81.33; 120.61; 127.85; 127.94; 128.47; 134.57;
137.72. ESI-MS: 226 ([M þ NH4]þ).
(2R,3R)-3-(Benzyloxy)-2-hydroxypent-4-en-1-yl 4-Methylbenzenesulfonate (5). To a soln. of
4
(350 mg, 1.68 mmol), Bu2SnO (41 mg, 0.168 mmol), and Et3N (0.23 ml, 1.68 mmol) in dry CH2Cl2 was
added TsCl (320 mg, 1.68 mmol) at 08 under N2, and the mixture was stirred for 4 h at r.t. After
completion, the reaction was quenched with NaHCO3 soln. (50 ml), and the mixture was extracted with

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Helvetica Chimica Acta – Vol. 94 (2011)
CH2Cl2 (2 ꢁ 25 ml). The org. extract was washed with brine, dried (anh. Na2SO4), and the solvent was
removed under reduced pressure. The crude residue was purified by CC (hexane/AcOEt 9 :1) to yield
pure 5 (560 mg, 92%). Colorless liquid. Rf (hexane/AcOEt 7:3) 0.7. [a]2D5 ¼ ꢀ16.6 (c ¼ 0.32, CHCl3). IR
1
(neat): 3459, 2924, 2851, 1637, 1360, 1176. H-NMR: 2.44 (s, 3 H); 3.68 – 3.77 (m, 1 H); 3.82 – 3.89 (m,
1 H); 3.94 – 4.11 (m, 2 H); 4.43 (AB, J ¼ 11.3, 2 H); 5.31 – 5.40 (m, 2 H); 5.70 – 5.83 (m, 1 H); 7.20 – 7.34
(m, 7 H); 7.73 – 7.79 (m, 2 H). 13C-NMR: 21.58; 69.88; 70.60; 71.44; 79.74; 120.84; 127.88; 127.94; 128.43;
129.80; 133.85; 137.46; 144.84. ESI-MS: 380 ([M þ NH4]þ).
(2R,3R)-3-(Benzyloxy)pent-4-en-2-ol (6). To a soln. of 5 (500 mg, 1.38 mmol), in dry THF (5 ml)
was added LiAlH4 (76 mg, 2.07 mmol), and the mixture was heated to reflux for 1 h. After completion of
the reaction (TLC), the mixture was cooled to r.t., diluted with H2O (100 ml), and extracted with AcOEt
(3 ꢁ 30 ml). The combined org. layer was dried (anh. Na2SO4), and the solvent was removed under
reduced pressure to afford a crude compound. The crude residue was purified by CC (hexane/AcOEt
9.4 :0.6) to give pure 6 (228 mg, 86%). Colorless liquid. Rf (hexane/AcOEt 9 :1) 0.5. [a]2D5 ¼ ꢀ48.6 (c ¼
0.14, CHCl3). IR (neat): 3448, 2977, 2928, 2870, 1453, 1259, 1068. 1H-NMR: 1.12 (d, J ¼ 6.3, 3 H); 2.66 (br.
s, 1 H); 3.50 (t, J ¼ 7.9, 1 H); 3.62 – 3.73 (m, 1 H); 4.47 (AB, J ¼ 11.5, 2 H); 5.28 – 5.39 (m, 2 H); 5.63 – 5.76
(m, 1 H); 7.22 – 7.37 (m, 5 H). 13C-NMR: 18.12; 69.50; 70.34; 85.99; 120.23; 127.68; 127.86; 128.38; 135.10;
137.95. ESI-MS: 215 ([M þ Na]þ).
(tert-Butyl)(dimethyl)(pent-4-en-1-yloxy)silane (7). To a soln. of the pent-4-en-1-ol (1 g,
11.62 mmol) in dry CH2Cl2 (20 ml) was added 1H-imidazole (1.18 g, 17.44 mmol), and the mixture was
stirred for 10 min at 08. To this soln., tBuMe2SiCl (2.1 g, 13.95 mmol) was added at 08, and the mixture was
stirred at r.t. for 3 h. After completion of the reaction, the mixture was diluted with H2O, extracted with
AcOEt (2 ꢁ 50 ml), dried (anh. Na2SO4), and concentrated under reduced pressure. The crude residue
was purified by CC (hexane/AcOEt 9.9 :0.1) to give pure 7 (2.16 g, 93%). Pale yellow liquid. Rf (hexane/
AcOEt 9 :1) 0.9. [a]2D5 ¼ ꢀ5.43 (c ¼ 0.53, CHCl3). IR (neat): 2930, 2858, 1642, 1472, 1255, 1101. 1H-NMR:
0.03 (s, 6 H); 0.89 (s, 9 H); 1.53 – 1.66 (m, 2 H); 2.03 – 2.18 (m, 2 H); 3.54 – 3.66 (m, 2 H); 4.89 – 5.04 (m,
2 H); 5.69 – 5.87 (m, 1 H). 13C-NMR: ꢀ 5.18; 26.09; 30.16; 32.08; 62.31; 114.79; 138.30. ESI-MS: 202
([M þ H]þ).
(2S)-5-{[(tert-Butyl)(dimethyl)silyl]oxy}pentane-1,2-diol (8). To a cooled (08) soln. of 7 (2.1 g,
t
10.5 mmol) in BuOH/H2O 1:1 (100 ml) was added AD-mix-a (K2OsO2(OH)4, K3Fe(CN)6, K2CO3,
(DHQ)2PHAL; 13 g), and the mixture was stirred at the same temp. for 24 h. To this mixture, Na2SO3
(15 g) was added, and the mixture was stirred for 30 min and then filtered. The org. layer was separated,
and the aq. layer was extracted with AcOEt (3 ꢁ 75 ml). The combined org. layer was dried (anh.
Na2SO4) and concentrated under reduced pressure. The residue was purified by CC (SiO2; hexane/
AcOEt 7:3) to afford pure 8 (2.3 g, 94%). Colorless liquid. Rf (hexane/AcOEt 7:3) 0.2. [a]2D5 ¼ ꢀ5.55
1
(c ¼ 0.45, MeOH). IR (neat): 3383, 2931, 2859, 1466, 1254, 1096. H-NMR: 0.04 (s, 6 H); 0.88 (s, 9 H);
1.41 – 1.69 (m, 4 H); 2.82 (br. s, 1 H); 3.32 – 3.45 (m, 1 H); 3.50 – 3.71 (m, 4 H); 4.01 (br. s, 1 H).
13C-NMR: ꢀ 5.32; 25.98; 29.09; 30.57; 63.44; 66.76; 71.94. ESI-MS: 235 ([M þ H]þ).
(2S)-5-{[(tert-Butyl)(dimethyl)silyl]oxy}-2-hydroxypentyl 4-Methylbenzenesulfonate (9). To a soln.
of 8 (2.2 g, 9.40 mmol), Bu2SnO (234 mg, 0.94 mmol), and Et3N (1.7 ml, 10.3 mmol) in dry CH2Cl2 was
added TsCl (1.79 g, 9.4 mmol) at 08 under N2, and the mixture was stirred for 4 h at r.t. After completion
of the reaction, the mixture was diluted with sat. NaHCO3 soln. and extracted with CH2Cl2 (2 ꢁ 75 ml).
The org. extract was washed with H2O and dried (anh. Na2SO4). The solvent was removed under reduced
pressure to afford a crude product. The residue was purified by CC (SiO2; hexane/AcOEt 8.4 :1.6) to
afford pure 9 (3.31 g, 91%). Colorless liquid. Rf (hexane/AcOEt 7:3) 0.6. [a]2D5 ¼ þ2.1 (c ¼ 0.48, CHCl3).
IR (neat): 3423, 2924, 1634, 1352, 1175. 1H-NMR: 0.04 (s, 6 H); 0.87 (s, 9 H); 1.39 – 1.73 (m, 4 H); 2.46 (s,
3 H); 3.11 (br. s, 1 H); 3.59 – 3.67 (m, 2 H); 3.75 – 3.87 (m, 1 H); 3.88 – 3.98 (m, 2 H); 7.34 (d, J ¼ 8.3,
2 H); 7.78 (d, J ¼ 8.3, 2 H). 13C-NMR: ꢀ 5.41; 21.7; 25.94; 28.66; 30.62; 63.26; 69.14; 73.53; 127.94; 129.80;
132.76; 144.83. ESI-MS: 389 ([M þ H]þ).
(tert-Butyl)(dimethyl){3-[(2S)-oxiran-2-yl]propoxy}silane (10). To a stirred soln. of 9 (3.2 g,
8.24 mmol) in dry MeOH (15 ml) was added K2CO3 (2.28 g, 16.49 mmol) under N2, and the mixture
was stirred for 2 h. After completion of the reaction, MeOH was removed under reduced pressure. The
residue was diluted with H2O (100 ml) and extracted with CH2Cl2 (2 ꢁ 100 ml). The combined org.
phases were washed with H2O and brine, and dried (anh. Na2SO4). After evaporation of the solvent, the

Helvetica Chimica Acta – Vol. 94 (2011)
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crude residue was purified by CC (SiO2; hexane/AcOEt 9.6 :0.4) to give pure 10 (1.58 g, 89%). Colorless
liquid. Rf (hexane/AcOEt 4 :1) 0.8. [a]2D5 ¼ ꢀ4.3 (c ¼ 0.19, CHCl3). IR (neat): 1252, 1098, 835, 773.
1H-NMR: 0.04 (s, 6 H); 0.88 (s, 9 H); 1.51 – 1.72 (m, 4 H); 2.44 – 2.48 (m, 1 H); 2.73 (t, J ¼ 4.0, 1 H); 2.88 –
2.95 (m, 1 H); 3.58 – 3.70 (m, 2 H). 13C-NMR: ꢀ 5.38; 25.89; 28.97; 29.08; 47.01; 52.07; 62.54. ESI-MS:
217 ([M þ H]þ).
(4S)-7-{[(tert-Butyl)(dimethyl)silyl]oxy}hept-1-en-4-ol (11). To a cooled (ꢀ 788) soln. of CuI (0.12 g,
0.65 mmol) in dry THF (5 ml) was added 1.0m CH2¼CHMgBr soln. (16.2 ml, 16.2 mmol) in THF. To this
soln. was added 10 (1.4 g, 6.48 mmol) in dry THF (15 ml), and the mixture was stirred at the same temp.
for 3 h and allowed to reach r.t. After completion, the reaction was quenched with sat. NH4Cl soln.
(50 ml), and the mixture was extracted with AcOEt (3 ꢁ 50 ml). The combined org. phases were washed
with H2O and brine, and dried (anh. Na2SO4). The solvent was removed under reduced pressure, and the
crude residue was purified by CC (SiO2; hexane/AcOEt 9.4 :0.6) to give pure 11 (1.36 g, 86%). Pale
yellow liquid. Rf (hexane/AcOEt 90 :10) 0.5. [a]2D5 ¼ ꢀ27.10 (c ¼ 0.24, CHCl3). IR (neat): 3422, 2931,
1
2858, 1640, 1253, 1098, 835. H-NMR: 0.05 (s, 6 H); 0.90 (s, 9 H); 1.40 – 1.70 (m, 4 H); 2.11 – 2.30 (m,
2 H); 2.40 (br. s, 1 H); 3.57 – 3.69 (m, 3 H); 5.03 – 5.16 (m, 2 H); 5.73 – 5.91 (m, 1 H). 13C-NMR: ꢀ 5.42;
25.88; 29.06; 33.80; 41.85; 63.38; 70.55; 117.43; 135.05. ESI-MS: 245 ([M þ H]þ).
{(4S)-[4-(Benzyloxy)hept-6-en-1-yl]oxy}(tert-butyl)(dimethyl)silane (12). To a cooled (08) soln. of
11 (1.2 g, 4.91 mmol) in dry THF (20 ml) was added NaH (0.39 g, 9.83 mmol) at 08, and the mixture was
stirred for 10 min. To this mixture, BnBr (0.59 ml, 4.91 mmol) was added and stirred at r.t. for 4 h. After
completion of the reaction, the mixture was diluted with H2O (100 ml), extracted with AcOEt (2 ꢁ
75 ml), dried (anh. Na2SO4), and concentrated under reduced pressure. The crude residue was purified
by CC (SiO2 ; hexane/AcOEt 9.7:0.3) to afford pure 12 (1.52 g, 93%). Colorless liquid. Rf (hexane/
1
AcOEt 9 :1) 0.8. [a]2D5 ¼ ꢀ9.04 (c ¼ 0.31, CHCl3). IR (neat): 2931, 2858, 1252, 1095. H-NMR: 0.03 (s,
6 H); 0.89 (s, 9 H); 1.48 – 1.71 (m, 4 H); 2.23 – 2.42 (m, 2 H); 3.41 – 3.52 (m, 1 H); 3.55 – 3.63 (m, 2 H);
4.52 (AB, J ¼ 11.3, 2 H); 5.01 – 5.15 (m, 2 H); 5.74 – 5.94 (m, 1 H); 7.28 – 7.41 (m, 5 H). 13C-NMR: ꢀ 5.28;
25.96; 28.58; 29.93; 38.30; 63.11; 70.78; 78.27; 116.89; 127.40; 127.63; 128.25; 134.89; 138.84. ESI-MS: 335
([M þ H]þ).
(4S)-4-(Benzyloxy)hept-6-en-1-ol (13). To a soln. of 12 (1.4 g, 4.19 mmol) in dry THF (15 ml) was
added 1m tBu4NF soln. (4.19 ml) in THF, and the mixture was stirred for 3 h at r.t. After completion, the
reaction was quenched with sat. NaHCO3 soln. (100 ml), and the mixture was extracted with AcOEt (2 ꢁ
50 ml), the org. layer was washed with brine, dried (anh. Na2SO4), and concentrated under reduced
pressure. The crude residue was purified by CC (SiO2; hexane/AcOEt 4 :1) to yield pure 13 (850 mg,
92%). Colorless liquid. Rf (hexane/AcOEt 7:3) 0.3. [a]2D5 ¼ ꢀ12.96 (c ¼ 0.24, CHCl3). IR (neat): 3401,
1
2934, 2865, 1449, 1060. H-NMR: 1.51 – 1.75 (m, 4 H); 2.23 – 2.48 (m, 2 H); 3.43 – 3.52 (m, 1 H); 3.54 –
3.61 (m, 2 H); 4.53 (AB, J ¼ 11.5, 2 H); 5.01 – 5.13 (m, 2 H); 5.72 – 5.92 (m, 1 H); 7.27 – 7.38 (m, 5 H).
13C-NMR: 28.19; 29.87; 37.81; 62.13; 70.57; 78.10; 116.80; 127.24; 127.47; 128.02; 134.39; 138.21. ESI-MS:
221 ([M þ H]þ).
(4S)-4-(Benzyloxy)hept-6-enoic Acid (14). To a soln. of 13 (750 mg, 3.40 mmol) in MeCN/H2O 2 :1
(10 ml) were added [bis(acetoxy)iodo]benzene (BAIB; 2.41 g, 7.49 mmol) and 2,2,6,6-tetramethylpiper-
idin-1-yl oxide (TEMPO; 106 mg, 0.68 mmol). The mixture was stirred at r.t. for 3 h. After completion of
the reaction (TLC), the mixture was filtered and extracted with AcOEt (2 ꢁ 25 ml). The combined org.
phases were dried and concentrated under reduced pressure. The crude residue was purified by CC
(SiO2; hexane/AcOEt 7.8 :2.2) to give pure 14 (660 mg, 84%). Pale yellow liquid. Rf (hexane/AcOEt 7:3)
0.25. [a]2D5 ¼ ꢀ26.7 (c ¼ 0.32, CHCl3). IR (neat): 3428, 2928, 1707, 1447, 1072, 916, 739. 1H-NMR: 1.72 –
1.96 (m, 2 H); 2.21 – 2.48 (m, 4 H); 3.43 – 3.54 (m, 1 H); 4.51 (AB, J ¼ 11.3, 2 H); 5.03 – 5.13 (m, 2 H);
5.72 – 5.88 (m, 1 H); 7.20 – 7.34 (m, 5 H). 13C-NMR: 28.50; 29.90; 37.95; 70.82; 77.0; 117.34; 127.41; 127.60;
128.17; 134.05; 138.21; 179.83. ESI-MS: 257 ([M þ Na]þ).
(2R,3R)-3-(Benzyloxy)pent-4-en-2-yl (4S)-4-(Benzyloxy)hept-6-enoate (15). To a cooled (08) soln.
of 6 (180 mg, 0.937 mmol), DCC (386 mg, 1.874 mmol), and DMAP (11 mg, 0.093 mmol) in dry CH2Cl2
(5 ml) was added 14 (219 mg, 0.937 mmol), and the mixture was stirred at same temp. for 12 h. After
completion of the reaction (TLC), the mixture was diluted with H2O (25 ml) and extracted with CH2Cl2
(2 ꢁ 15 ml). The combined org. phases were dried and concentrated under reduced pressure. The crude
residue was purified by CC (SiO2; hexane/AcOEt 9.6 :0.4) to afford pure 15 (317 mg, 83%). Liquid. Rf

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Helvetica Chimica Acta – Vol. 94 (2011)
(hexane/AcOEt 9 :1) 0.6. [a]2D5 ¼ ꢀ26.94 (c ¼ 0.28, CHCl3). IR (neat): 2923, 2853, 1731, 1636, 1457, 1070,
697. 1H-NMR: 1.15 (d, J ¼ 6.8, 3 H); 1.69 – 1.92 (m, 2 H); 2.19 – 2.41 (m, 4 H); 3.40 – 3.51 (m, 1 H); 3.71 –
3.77 (m, 1 H); 4.30 – 4.64 (m, 4 H); 4.93 – 5.12 (m, 3 H); 5.24 – 5.35 (m, 2 H); 5.65 – 5.87 (m, 2 H); 7.16 –
7.35 (m, 10 H). 13C-NMR: 15.97; 28.97; 30.37; 38.22; 70.36; 71.01; 71.27; 77.40; 81.39; 117.41; 119.50;
127.53; 127.71; 128.32; 134.40; 134.57; 172.88. ESI-MS: 431 ([M þ Na]þ).
(5S,7Z,9R,10R)-5,9-Bis(benzyloxy)-10-methyl-3,4,5,6,9,10-hexahydro-2H-oxecin-2-one (16). To a
soln. of 15 (100 mg, 0.245 mmol) in degassed anh. CH2Cl2 (250 ml) was added Grubbs-II catalyst (42 mg,
0.049 mmol), and the mixture was stirred at 408 for 3 h. After completion, the reaction was quenched
with CH2¼CHOEt, and the mixture was concentrated under reduced pressure to afford a dark brown
residue. The crude residue was purified by CC (SiO2; hexane/AcOEt 9.6 :0.4) to give pure 16 (82 mg,
88%). Liquid. Rf (hexane/AcOEt 9 :1) 0.5. [a]D25 ¼ ꢀ1.70 (c ¼ 0.32, CHCl3). IR (neat): 2931, 2861, 1729,
1451, 1251, 1073. 1H-NMR: 1.17 (d, J ¼ 6.8, 3 H); 1.76 – 1.92 (m, 1 H); 1.97 – 2.13 (m, 1 H); 2.14 – 2.36 (m,
3 H); 2.39 – 2.56 (m, 1 H); 3.53 – 3.64 (m, 1 H); 4.30 – 4.55 (m, 5 H); 5.01 – 5.13 (m, 1 H); 5.36 – 5.47 (m,
1 H); 5.50 (td, J ¼ 11.3, 4.3, 1 H); 7.13 – 7.32 (m, 10 H). 13C-NMR: 13.0; 26.34; 28.50; 32.40; 69.64; 70.28;
71.11; 76.74; 127.30; 127.50; 128.29; 128.90; 131.14; 138.15; 138.53; 173.18. ESI-MS: 403 ([M þ Na]þ).
Stagonolide G (¼(5S,7Z,9R,10R)-3,4,5,6,9,10-Hexahydro-5,9-dihydroxy-10-methyl-2H-oxecin-2-
one; 1). To a soln. of 16 (60 mg, 0.15 mmol) in dry CH2Cl2 (5 ml) was added a soln. of TiCl4 (0.05 ml,
0.47 mmol) in dry CH2Cl2 (2 ml) under N2 at 08, the mixture was stirred at same temp. for 2 h. After
completion of the reaction (TLC), the mixture was diluted with H2O (50 ml) and extracted with CH2Cl2
(2 ꢁ 20 ml). The combined org. phases were washed with NaHCO3 soln., dried, and solvent was removed
under reduced pressure. The crude compound was purified by CC (SiO2; hexane/AcOEt 7:3) to afford
pure 1 (23 mg, 73%). Viscous liquid. Rf (hexane/AcOEt 7:3) 0.1. [a]2D5 ¼ þ9.8 (c ¼ 0.18, CHCl3). IR
(neat): 3428, 2921, 2852, 1762, 1459, 1370, 760. 1H-NMR: 1.14 (d, J ¼ 6.4, 3 H); 1.90 – 2.09 (m, 1 H); 2.29 –
2.71 (m, 5 H); 3.65 – 3.72 (m, 1 H); 4.07 – 4.15 (m, 1 H); 4.50 – 4.62 (m, 1 H); 5.55 – 5.73 (m, 2 H).
13C-NMR: 18.64; 27.43; 28.75; 33.72; 70.82; 72.22; 79.58; 127.79; 132.51; 176.69. ESI-MS: 201 ([M þ H]þ).
REFERENCES
[1] I. Shiina, Chem. Rev. 2007, 107, 239.
[2] J. Piel, Nat. Prod. Rep. 2009, 26, 338; K. C. Nicolaou, J. S. Chen, S. M. Dalby, Bioorg. Med. Chem.
2009, 17, 2290; T. Arif, J. D. Bhosale, N. Kumar, T. K. Mandal, R. S. Bendre, G. S. Lavekar, R. Dabur,
J. Asian Nat. Prod. Res. 2009, 11, 621; H. Itokawa, S. L. Morris-Natschke, T. Akiyama, K.-H. Lee, J.
Nat. Med. 2008, 62, 263; F. Pietra, Nat. Prod. Rep. 1997, 453.
[3] A. Evidente, R. Capasso, A. Andolfi, M. Vurro, M. Chiara Zonno, Nat. Toxins 1999, 6, 183.
[4] O. Yuzikhin, G. Mitina, A. Berestetskiy, J. Agric. Food Chem. 2007, 55, 7707.
[5] a) A. Evidente, A. Cimmino, A. Berestetskiy, G. Mitina, A. Andolfi, A. Motta, J. Nat. Prod. 2008, 71,
31; b) A. K. Perepogu, D. Raman, U. S. N. Murthy, V. J. Rao, Bioorg. Chem. 2009, 37, 46; c) A.
Evidente, A. Cimmino, A. Berestetskiy, A. Andolfi, A. Motta, J. Nat. Prod. 2008, 71, 1897.
[6] a) K. Rajesh, V. Suresh, J. J. P. Selvam, C. B. Rao, Y. Venkateswarlu, Synthesis 2010, 1381; b) V.
Shekhar, D. K. Reddy, V. Suresh, D. Chanti Babu, Y. Venkateswarlu, Tetrahedron Lett. 2010, 51, 946;
c) P. Prabhakar, S. Rajaram, D. K. Reddy, V. Shekar, Y. Venkateswarlu, Tetrahedron: Asymmetry
2010, 21, 216; d) J. J. P. Selvam, K. Rajesh, V. Suresh, D. Chanti Babu, Y. Venkateswarlu,
Tetrahedron: Asymmetry 2009, 20, 1115; e) D. K. Reddy, V. Shekhar, T. S. Reddy, S. P. Reddy, Y.
Venkateswarlu, Tetrahedron: Asymmetry 2009, 20, 2315; f) K. Rajesh, V. Suresh, J. J. P. Selvam, C. B.
Rao, Y. Venkateswarlu, Helv. Chim. Acta 2009, 92, 1866; g) M. Narasimhulu, A. Sai Krishna, J. V.
Rao, Y. Venkateswarlu, Tetrahedron 2009, 65, 2989.
[7] P. Srihari, B. Kumaraswamy, D. C. Bhunia, J. S. Yadav, Tetrahedron Lett. 2010, 51, 2903.
[8] A. Chatopadhyay, B. Dhotare, S. Hassarajani, J. Org. Chem. 1999, 64, 6874; J. Jurczak, S. Pikul, T.
Bauer, Tetrahedron 1986, 42, 447.
´
[9] F. Bravo, M. Kassou, S. Castillon, Tetrahedron Lett. 1999, 40, 1187; N. Sarkar, A. Nayek, S. Ghosh,
Org. Lett. 2004, 6, 1903; J. Nokami, H. Ogawa, S. Miyamoto, T. Mandai, S. Wakabayashi, J. Tsuji,
Tetrahedron Lett. 1999, 29, 5181.

Helvetica Chimica Acta – Vol. 94 (2011)
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[10] S. C. Bergmeier, D. M. Stanchina, J. Org. Chem. 1999, 64, 2852.
[11] H. Takahata, M. Kubota, T. Momose, Tetrahedron: Asymmetry 1997, 8, 2801.
[12] A. Vincent, J. Prunet, Synlett 2006, 2269.
[13] J. B. Epp, T. S. Widlanski, J. Org. Chem. 1999, 64, 293.
Received November 11, 2010