Stereoselective total synthesis of 4-ketoclonostachydiol

Article abstract of DOI:10.1002/hlca.201200631

An efficient stereoselective total synthesis of the bioactive 14-membered natural macrocyclic bislactone 4-ketoclonostachydiol is described. The strategy involves a Jacobsen's hydrolytic kinetic resolution (HKR), epoxide opening, MacMillan α-hydroxylation, Horner-Wadsworth-Emmons olefination, a Grignard reaction, and Hoveyda-Grubbs-II-catalyzed ring-closing metathesis (RCM) as key steps.

Full text of DOI:10.1002/hlca.201200631

Helvetica Chimica Acta – Vol. 96 (2013)
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Stereoselective Total Synthesis of 4-Ketoclonostachydiol
by Singanaboina Rajaram, Udugu Ramulu, Dasari Ramesh, Peddikotla Prabhakar,
and Yenamandra Venkateswarlu*†1)
Division of Natural Products Chemistry, Natural Products Laboratory, Indian Institute of Chemical
Technology, Hyderabad – 500007, India
An efficient stereoselective total synthesis of the bioactive 14-membered natural macrocyclic
bislactone 4-ketoclonostachydiol is described. The strategy involves a Jacobsenꢀs hydrolytic kinetic
resolution (HKR), epoxide opening, MacMillan a-hydroxylation, HornerꢀWadsworthꢀEmmons olefi-
nation, a Grignard reaction, and HoveydaꢀGrubbs-II-catalyzed ring-closing metathesis (RCM) as key
steps.
Introduction. – Marine fungi are attractive sources for anticancer, antifungal, and
antibacterial secondary metabolites [1]. Macrocyclic bislactone-containing natural
products are receiving significant attention due to their potent biological activities [2].
4-Ketoclonostachydiol (1), a 14-membered macrocyclic bislactone belongs to the
colletol family, was isolated from alga-derived fungus Gliocladium sp. [3]. 4-
Ketoclonostachydiol (1) exhibits various biological properties, such as strong cytotox-
icity against P388 cells (IC50 0.55 mm) and significant activities against Bacillus subtilis,
the fungi Trichophyton mentagrophytes, and Cladosporium resinae. The synthesis of
compounds of colletol family have been carried out by many groups [2]. Previously, we
have synthesized clonostachydiol using the strategy of MacMillan a-hydroxylation,
HornerꢀWadsworthꢀEmmons olefination, Grignard reaction, and HoveydaꢀGrubbs-
II-catalyzed ring-closing metathesis (RCM). The structure of 1 has recently been
patented for its excellent cytotoxic and antibacterial activities [4]. Only one synthesis of
1 has been reported so far, and the absolute configuration was determined by She and
co-workers [5]. In continuation of our interest in total synthesis of lactone containing
molecules [6], 4-ketoclonostachydiol (1) with its promising biological properties and
interesting structural features prompted us to attempt its synthesis. In the present study,
we report a stereoselective synthesis of 1 utilising MacMillan a-hydroxylation,
HornerꢀWadsworthꢀEmmons olefination, Grignard reaction, and HoveydaꢀGrubbs-
II-catalyzed ring-closing metathesis (RCM). According to the retrosynthetic analysis
outlined in Scheme 1, 1 can be synthesized by RCM of compound 18, which in turn
could be obtained from the fragments 9 and 14 via esterification. The compounds 9 and
14 could be synthesized starting from (ꢁ)-propylene oxide (2) and ethyl (S)-2-
hydroxypropanoate (10), respectively.
1
)
Deceased, July 17, 2013; correspondence should be addressed to Dr. K. Suresh Babu (phone:
þ 91-40-27191881; e-mail: suresh@iict.res.in).
ꢁ 2013 Verlag Helvetica Chimica Acta AG, Zꢂrich

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Scheme 1. Retrosynthetic Analysis
Results and Discussion. – As outlined in Scheme 2, the synthesis of 1 started
with the commercially available (ꢁ)-propylene oxide (¼2-methyloxirane; 2), which
was subjected to Jacobsenꢀs hydrolytic kinetic resolution (HKR) [7] with [((S,S)-
salen)Co(OAc)] as catalyst to afford (S)-2-methyloxirane (3) as a single isomer
([a]2D5 ¼ þ11.6 (c ¼ 1, CHCl3), 43%), which was easily separated from the more polar
diol 3a by distillation.
Scheme 2
a) [(S,S)-salen)Co(OAc)] (0.5 mol-%), dist. H2O (0.55 equiv.), 08, 16 h (salen ¼ N,N’-ethylenebis(sa-
licylimine)).
The enantiomerically pure 3 was subjected to regioselective copper-catalyzed (CuI)
[8] opening with Grignard reagent, derived from benzyl (Bn)-protected bromopropan-
ol, to furnish alcohol 4 in 73% yield (Scheme 3). Compound 4 was protected with
TBSCl (tBu(Me2)SiCl) in the presence of 1H-imidazole in dry CH2Cl2 to afford the silyl
ether 5 in 95% yield. The Bn group in 5 was removed using Li in liquid NH3 to afford
alcohol 6. The primary alcohol 6 was subjected to Swern oxidation [9] to afford the
corresponding aldehyde in 81% yield, which was subjected to the crucial MacMillan a-
hydroxylation [10] using nitrosobenzene (PhNO) and 40% of d-proline in dry DMSO,

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followed by rapid HornerꢀWadsworthꢀEmmons olefination using 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) to furnish the unstable anilinoxy compound, which was
further treated with 20 mol-% of CuSO4 · 5 H2O in MeOH at room temperature to
cleave the OꢀN bond to give the g-hydroxy a,b-unsaturated ester 7 [11] in 55% yield
with high diastereoselectivity (de 96%). The sequence of the reactions for the
preparation of compounds 5 to 7 were already reported earlier by Yadav and co-
workers [12]. The OH group in 7 was protected as its methoxymethyl (MOM) ether to
give 8 in 85% yield, followed by hydrolysis of the ethyl ester with LiOH · H2O in
aqueous THF, leading to the corresponding a,b-unsaturated carboxylic acid 9 in 85%
yield (Scheme 3).
Scheme 3
a) PhCH2O(CH2)3MgBr, CuI, dry THF, ꢀ 788, 5 h; 73%. b) 1H-Imidazole, (tert-butyl)chlorodimethyl-
silane (tBuMe2SiCl, TBSCl), dry CH2Cl2, 08 to r.t., 6 h; 95%. c) Li/liq. NH3, dry THF, ꢀ 788, 10 min;
86%. d) 1. (COCl)2, dry DMSO, Et3N, dry CH2Cl2, ꢀ 788, 1 h; 81%; 2. PhNO (nitrosobenzene),
C5H9NO2 (d-proline), dry DMSO, 208, 25 min; then (EtO)2P(O)CH2CO2Et (triethyl phosphonoace-
tate), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), LiCl, 08, 1 h; then MeOH, CuSO4 · 5 H2O, r.t., 12 h;
55% (one pot). e) Chloromethyl methyl ether (MOMCl), EtNiPr2, dry CH2Cl2, 08 to r.t., 5 h; 85%. f)
LiOH · H2O, THF/H2O 1:1, 8 h; 85%.
The key intermediate 14 was prepared from ethyl (S)-2-hydroxypropanoate (10,
Scheme 4). The secondary OH group in 10 was protected as its silyl ether, 11, in 92%
yield, followed by reduction of the ester group using DIBAL-H to give the aldehyde in
88% yield, which, on reaction with CH2¼CHMgBr [13] in Et2O, led to an inseparable
mixture of alcohols 12 in 83% yield (dr 8.5 :1.5, determined by HPLC on a chiral solid
phase), which were separated by converting them to the benzyl ethers 13 and 13a in
70% and 13% yields, respectively. The TBS moiety in the major diastereisomer 13 was
t
removed with Bu4NF (TBAF) in dry THF to give the secondary alcohol 14 in 89%
yield (Scheme 4).
The acid 9 was esterified with alcohol 14 in the presence of dicyclohexylcarbodi-
imide (DCC) and 4-(dimethylamino)pyridine (DMAP) in dry CH2Cl2 to give the ester
15 in 80% yield (Scheme 5). The TBS protecting group in 15 was removed using TsOH
in MeOH to give the secondary alcohol 16 in 90% yield. The acrylation of the latter
with CH2¼CHCOCl and dry Et3N in dry CH2Cl2 at 08 afforded the acrylate 17 in 86%
yield. Compound 17 was subjected to oxidative debenzylation with 4,5-dichloro-3,6-

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Scheme 4
a) 1H-Imidazole, tBuMe2SiCl, dry CH2Cl2, 08 to r.t., 5 h; 92%. b) 1. DIBAL-H (¼diisobutylaluminium
hydride), dry CH2Cl2, ꢀ 788, 0.5 h; 88%. 2. CH2 ¼ CHMgBr, dry Et2O, ꢀ 788, 1 h; 83%. c) NaH, BnBr,
Bu4NI, dry THF, 08 to r.t., 8 h; 70%. d) tBu4NF, THF, 08 to r.t., 7 h; 89%.
Scheme 5
a) Dicyclohexylcarbodiimide (DCC), 4-(dimethylamino)pyridine (DMAP), dry CH2Cl2, 08, 12 h; 80%.
b) TsOH, MeOH, 08, 0.5 h; 90%. c) Dry Et3N, acryloyl chloride (CH2¼CHCOCl), dry CH2Cl2, 08, 1 h;
86%. d) 4,5-Dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (DDQ), dry CH2Cl2, 508, 4 h;
74%. e) HoveydaꢀGrubbs-II catalyst, dry toluene, 808, 0.5 h; 78%. f) DessꢀMartin periodinane (DMP),
dry CH2Cl2, 5 h; 72%. g) CF3COOH, dry CH2Cl2, 08 to r.t., 3 h; 82%.

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dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (DDQ) [14] in dry CH2Cl2 to afford ester
18 in 74% yield. Compound 18 was subjected to HoveydaꢀGrubbs-II-catalyzed
(10 mol-%) [15] RCM in toluene at 808 to afford the MOM-protected 14-membered
macrolide 19 (it is enantiomeric derivative in [16]) in 78% yield. The secondary alcohol
in compound 19 was subjected to DessꢀMartin periodinane (DMP) oxidation to afford
keto compound 20 in 72% yield, followed by deprotection of MOM moiety with
CF3COOH in dry CH2Cl2 to give 1.
The physical and spectroscopic data of synthetic 4-ketoclonostachydiol (1) were
identical to those reported in literature [3].
Conclusions. – In conclusion, the total synthesis of 4-ketoclonostachydiol (1) has
been accomplished by MacMillan a-hydroxylation, HornerꢀWadsworthꢀEmmons
olefination, Grignard reaction, and HoveydaꢀGrubbs-II-catalyzed ring closing meta-
thesis (RCM), starting from commercially available 2-methyloxirane and ethyl (S)-2-
hydroxypropanoate.
The authors are thankful to CSIR, New Delhi India, for financial assistance, and to the 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
(Na2SO4) and concentrated in vacuo below 408. Column chromatography (CC): silica gel (Acmeꢀs 60 –
120 mesh and 100 – 200 mesh). Optical rotations: Horiba high-sensitive polarimeter SEPA-300 at 258. IR
1
Spectra: Perkin-Elmer IR-683 spectrophotometer with NaCl optics; ˜n in cmꢀ1. H- and 13C-NMR (300
and 75 MHz, resp.) spectra: Bruker Avance 300 instrument; d in ppm rel. to Me4Si as internal standard in
CDCl3; J in Hz. MS: Agilent Technologies 1100 Series (Agilent Chemstation Software).
(2S)-6-(Benzyloxy)hexan-2-ol (4). To a suspension of Mg (0.93 g, 38.79 mmol) in dry THF (25 ml) at
r.t. equipped with condenser (cool water circulation) was added PhCH2O(CH2)3Br (8.88 g, 38.79 mmol)
dropwise within 15 min, and the mixture was stirred for 0.5 h. After cooling the mixture to ꢀ 788, the
enantiomerically pure 3 (0.9 g, 15.51 mmol) in dry THF (15 ml) and freshly flame-dried CuI (0.08 g,
0.46 mmol) were added, and the mixture was stirred for 4 h at ꢀ 788. After completion, the reaction was
quenched with sat. aq. NH4Cl soln. (20 ml), and the mixture was extracted with AcOEt (3 ꢂ 25 ml). The
combined org. extract was washed with brine, dried (Na2SO4), and concentrated. The crude residue was
purified by CC (AcOEt/hexane 2 :8) to give pure 4 (2.33 g, 73%). Colorless liquid. [a]2D5 ¼ þ3.8 (c ¼ 6.5,
CHCl3). IR (neat): 3442, 3027, 2927, 2854, 1493, 1451, 1342, 1261, 1163, 1042, 700. 1H-NMR: 7.39 – 7.24 (m,
5 H); 4.50 (s, 2 H); 3.85 – 3.72 (m, 1 H); 3.48 (t, J ¼ 6.8, 2 H); 1.74 – 1.36 (m, 7 H); 1.18 (d, J ¼ 6.8, 3 H).
13C-NMR: 138.5; 128.3; 127.6; 127.5; 72.9; 70.2; 67.8; 38.9; 29.6; 23.3; 22.3. ESI-MS: 231 ([M þ Na]þ).
Ethyl (2E,4S,7S)-7-{[(tert-Butyl)(dimethyl)silyl]oxy}-4-(methoxymethoxy)oct-2-enoate (8). To a
cooled (08) soln. of 7 (0.5 g, 15.82 mmol) in dry CH2Cl2 was added EtNiPr2 (0.82 ml, 4.74 mmol), then
MOMCl (0.24 ml, 3.16 mmol) was added dropwise, and the mixture was stirred at r.t. for 5 h. After
completion of the reaction, the mixture was diluted with CH2Cl2, washed with brine, dried (Na2SO4), and
concentrated. The crude residue was purified by CC (AcOEt/hexane 2 :8) to affor pure 8 (0.48 g, 85%).
Yellow liquid. [a]D25 ¼ ꢀ32.2 (c ¼ 1.3, CHCl3). IR (neat): 2934, 2892, 2858, 1723, 1658, 1466, 1369, 1260,
1159, 1039, 834, 775. 1H-NMR: 6.79 (dd, J ¼ 15.8, 6.8, 1 H); 5.95 (d, J ¼ 15.8, 1 H); 4.58 (q, J ¼ 6.8, 2 H);
4.22 – 4.12 (m, 3 H); 3.81 – 3.71 (m, 1 H); 3.35 (s, 3 H); 1.77 – 1.36 (m, 4 H); 1.28 (t, J ¼ 7.6, 3 H); 1.10 (d,
J ¼ 6.2, 3 H); 0.86 (s, 9 H); 0.02 (s, 6 H). 13C-NMR: 166.1; 147.7; 121.8; 94.5; 75.3; 68.3; 60.3; 55.5; 34.9;
30.9; 25.8; 23.8; 18.0; 14.1; ꢀ 4.4; ꢀ 4.8. ESI-MS: 383 ([M þ Na]þ).

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(2E,4S,7S)-7-{[(tert-Butyl)(dimethyl)silyl]oxy}-4-(methoxymethoxy)oct-2-enoic Acid (9). To a
cooled (08) soln. of 8 (0.3 g, 0.83 mmol) in THF (4 ml) and H2O (4 ml) was added LiOH · H2O
(0.12 g, 4.9 mmol), and the mixture was stirrred for 8 h at r.t. After completion of the reaction, the
solvent was removed under reduced pressure, and the residue was diluted with H2O (5 ml), acidified with
KHSO4, and extracted with AcOEt (2 ꢂ 10 ml). The combined org. extract was washed with brine, dried
(Na2SO4), and concentrated. The crude product was purified by CC (AcOEt/hexane 3 :7) to give pure 9
(0.23 g, 85%). Brown liquid. [a]2D5 ¼ ꢀ27.3 (c ¼ 0.8, CHCl3). IR (neat): 3448, 2954, 2931, 2890, 2857, 1700,
1656, 1466, 1253, 1038, 833, 774. 1H-NMR: 6.94 (dd, J ¼ 15.8, 6.2, 1 H); 5.99 (d, J ¼ 15.8, 1 H); 4.62 (q, J ¼
6.8, 2 H); 4.27 – 4.17 (m, 1 H); 3.84 – 3.72 (m, 1 H); 3.38 (s, 3 H); 1.78 – 1.38 (m, 4 H); 1.13 (d, J ¼ 6.2,
3 H); 0.88 (s, 9 H); 0.04 (s, 6 H). 13C-NMR: 171.3; 150.7; 120.9; 94.7; 75.3; 68.3; 55.6; 34.9; 30.8; 25.8;
23.8; 18.1; ꢀ 4.4; ꢀ 4.7. ESI-MS: 355 ([M þ Na]þ).
Ethyl (2S)-2-{[(tert-Butyl)(dimethyl)silyl]oxy}propanoate (11). To a cooled (08) soln. of 10 (1.0 g,
8.47 mmol) and 1H-imidazole (1.44 g, 21.1 mmol) in dry CH2Cl2 (15 ml) was added TBSCl (1.65 g,
11.01 mmol), and the mixture was stirrred for 5 h. After completion of reaction, the mixture was diluted
with H2O (10 ml) and extracted into CH2Cl2 (3 ꢂ 20 ml). The combined org. extract was washed with
brine, dried (Na2SO4), and concentrated. The crude residue was purified by CC (AcOEt/hexane 0.5 :9.5)
to afford pure 11 (1.8 g, 92%). Colorless liquid. [a]2D5 ¼ ꢀ24 (c ¼ 7.1, CHCl3). IR (neat): 2943, 2897, 2852,
1759, 1255, 1145, 835, 778. 1H-NMR: 4.16 (q, J ¼ 7.2, 2 H); 4.29 (q, J ¼ 6.8, 1 H); 1.38 (d, J ¼ 6.8, 3 H);
1.26 (t, J ¼ 7.2, 3 H); 0.89 (s, 9 H); 0.05 (s, 3 H); 0.08 (s, 3 H). 13C-NMR: 173.6; 68.2; 60.3; 25.5; 21.0; 18.0;
13.9; ꢀ 5.2; ꢀ 5.5. ESI-MS: 255 ([M þ Na]þ).
(4S)-4-{[(tert-Butyl)(dimethyl)silyl]oxy}pent-1-en-3-ol (12). To a cooled (ꢀ 788) soln. of 11 (1.7 g,
7.32 mmol) in dry CH2Cl2 (20 ml) was added slowly 1m DIBAL-H in toluene (6.58 ml, 6.58 mmol), and
the mixture was stirred for 0.5 h. After completion, the reaction was quenched with MeOH (1 ml) and
sat. KNaC4H4O6 · 4 H2O (sodium potassium tartarate; 10 ml), and the mixture was stirred for 1 h and
then extracted with CH2Cl2 (2 ꢂ 20 ml). The combined org. extract was washed with brine, dried
(Na2SO4), and concentrated. The crude residue was purified by CC (AcOEt/hexane 2 :8) to give a pure
aldehyde as a colorless liquid (1.21 g, 88%, which was used in the following reaction). To the aldehyde
(1.2 g, 6.38 mmol) in dry Et2O (20 ml) was added dropwise 1.0m in THF CH2¼CHMgBr (15.13 ml,
12.7 mmol) at ꢀ 78 8, and the mixture was stirred for 1 h. After completion, the reaction was quenched
with sat. NH4Cl soln. (10 ml), and the mixture was extracted with Et2O (3 ꢂ 20 ml). The combined org.
extract was washed with brine, dried (Na2SO4), and concentrated. The crude residue was purified by CC
(AcOEt/hexane 2 :8) to furnish an inseparable diastereoisomer mixture 12 (1.14 g, 83%). Colorless
liquid. IR (neat): 3445, 3087, 2954, 2932, 2895, 2857, 1635, 1388, 1253, 1095, 934, 836, 772. 1H-NMR: 5.88 –
5.75 (m, 1 H); 5.33 – 5.13 (m, 2 H); 4.06 – 3.99 (m, 1 H); 3.89 – 3.80 (m, 1 H); 1.08 (d, J ¼ 6.4, 3 H); 0.89
(s, 9 H); 0.08 (s, 6 H). 13C-NMR: 136.5; 116.4; 76.6; 71.2; 25.7; 18.0; 17.6; ꢀ 4.5; ꢀ 4.9. EI-MS: 239
([M þ Na]þ).
{[(2S,3R)-3-(Benzyloxy)pent-4-en-2-yl]oxy}(tert-butyl)dimethylsilane (13). To a cooled (08) soln. of
12 (0.9 g, 4.16 mmol) in dry THF (15 ml) was added NaH (60%) (0.13 g, 9.16 mmol), and the mixture was
stirred for 30 min. To this mixture, BnBr (0.54 ml, 4.58 mmol), and Bu4NI (cat. amount) were added, and
the soln. was stirred at r.t. for 8 h. After completion, the reaction was quenched with cold H2O (10 ml),
and the mixture was extracted with AcOEt (3 ꢂ 15 ml), dried (Na2SO4), and concentrated. The crude
product was purified by CC (AcOEt/hexane 1:9) to furnish pure 13 (0.89 g, 70%). Colorless liquid.
[a]2D5 ¼ ꢀ2.8 (c ¼ 0.9, CHCl3). IR (neat): 3075, 3041, 2946, 2930, 2895, 2856, 1635, 1462, 1252, 1073, 926,
745, 669. 1H-NMR: 7.37 – 7.18 (m, 5 H); 5.82 – 5.73 (m, 1 H); 5.29 – 5.19 (m, 2 H); 4.59 (d, J ¼ 12.0, 1 H);
4.39 (d, J ¼ 12.0, 1 H); 3.85 – 3.78 (m, 1 H); 3.54 (dd, J ¼ 7.5, 4.5, 1 H); 1.15 (d, J ¼ 6.0, 3 H); 0.86 (s, 9 H),
0.02 (d, J ¼ 4.5, 6 H). 13C-NMR: 138.7; 136.4; 128.3; 127.6; 127.3; 118.6; 85.1; 70.9; 70.4; 25.8; 20.2; 18.1;
ꢀ 4.4; ꢀ 4.6. ESI-MS: 329 ([M þ Na]þ).
(2S,3R)-3-(Benzyloxy)pent-4-en-2-ol (14). To a cooled (08) soln. of 13 (0.3 g, 0.98 mmol) in dry THF
t
(10 ml) was added 1m Bu4NF in THF (1.96 ml, 1.96 mmol), and the mixture was stirred for 7 h at r.t.
After completion of the reaction, the mixture was diluted with H2O (10 ml) and extracted with AcOEt
(3 ꢂ 10 ml). The combined org. extract was washed with brine, dried (Na2SO4), and concentrated. The
crude product was purified by CC (AcOEt/hexane 2 :8) to give pure 14 (0.16 g, 89%). Colorless liquid.
[a]2D5 ¼ ꢀ35.2 (c ¼ 1.8, CHCl3). IR (neat): 3446, 3073, 3029, 2977, 2928, 2871, 1637, 1452, 1078, 928, 741,

Helvetica Chimica Acta – Vol. 96 (2013)
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669. 1H-NMR: 7.39 – 7.24 (m, 5 H); 5.91 – 5.75 (m, 1 H); 5.45 – 5.26 (m, 2 H); 4.65 (d, J ¼ 12.0, 1 H); 4.39
(d, J ¼ 12.0, 1 H); 3.96 – 3.85 (m, 1 H); 3.7 (dd, J ¼ 8.1, 3.9, 1 H); 1.15 (d, J ¼ 6.4, 3 H). 13C-NMR: 138.2;
134.5; 128.3; 127.6; 127.5; 120.2; 84.2; 70.2; 69.2; 17.9. ESI-MS: 215 ([M þ Na]þ).
(2S,3R)-3-(Benzyloxy)pent-4-en-2-yl (2E,4S,7S)-7-{[(tert-Butyl)(dimethyl)silyl]oxy}-4-(methoxy-
methoxy)oct-2-enoate (15). To a cooled (08) soln. of 9 (0.2 g, 0.6 mmol), DCC (0.15 g, 0.72 mmol),
and DMAP (0.014 g, 0.12 mmol) in dry CH2Cl2 (10 ml) was added 14 (0.1 g, 0.5 mmol) in 5 ml of dry
CH2Cl2, and the mixture was stirred at (08) for 12 h. After completion of the reaction, the mixture was
diluted with H2O (15 ml) and extracted with CH2Cl2 (3 ꢂ 10 ml). The combined org. extract was washed
with brine, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by CC (AcOEt/
hexane 2 :8) to yield pure 15 (0.24 g, 80%). Colorless liquid. [a]2D5 ¼ ꢀ46.3 (c ¼ 1.0, CHCl3). IR (neat):
2954, 2930, 2889, 2857, 1722, 1657, 1458, 1373, 1256, 1154, 1099, 1044, 834, 775. 1H-NMR: 7.24 – 7.35 (m,
5 H); 6.79 (dd, J ¼ 15.4, 6.6, 1 H); 5.96 (d, J ¼ 15.4, 1 H); 5.82 – 5.73 (m, 1 H); 5.35 – 5.26 (m, 2 H); 5.10 –
5.03 (m, 1 H); 4.61 (q, J ¼ 6.6, 2 H); 4.60 (d, J ¼ 12.1, 1 H); 4.44 (d, J ¼ 12.1, 1 H); 4.22 – 4.14 (m, 1 H);
3.87 – 3.76 (m, 2 H); 3.37 (s, 3 H); 1.75 – 1.40 (m, 4 H); 1.27 (t, J ¼ 6.6, 3 H); 1.12 (d, J ¼ 5.5, 3 H); 0.88 (s,
9 H); 0.04 (s, 6 H). 13C-NMR: 165.5; 147.9; 138.3; 134.8; 128.2; 127.5; 127.4; 122.1; 119.4; 94.6; 81.8; 75.4;
72.0; 70.4; 68.3; 55.6; 34.5; 31.0; 25.9; 23.8; 18.1; 15.3; ꢀ 4.7; ꢀ 4.4. ESI-MS: 529 ([M þ Na]þ).
(2S,3R)-3-(Benzyloxy)pent-4-en-2-yl (2E,4S,7S)-7-Hydroxy-4-(methoxymethoxy)oct-2-enoate (16).
To a cooled (08) soln. of 15 (0.23 g, 0.45 mmol) in MeOH (10 ml) was added TsOH (cat.), and the
mixture was stirred for 0.5 h. After completion, the reaction was quenched with solid NaHCO3, the
mixture was filtered, and the filtrate was concentrated under reduced pressure to afford a crude product,
which was purified by CC (AcOEt/hexane 3 :6) to furnish pure 16 (0.16 g, 90%). Colorless liquid. [a]D25
¼
ꢀ68.2 (c ¼ 0.5, CHCl3). IR (neat): 3455, 2930, 1731, 1708, 1657, 1453, 1373, 1262, 1153, 1030, 926, 739, 700.
1H-NMR: 7.37 – 7.24 (m, 5 H); 6.80 (dd, J ¼ 15.8, 6.8, 1 H); 5.98 (d, J ¼ 15.8, 1 H); 5.85 – 5.71 (m, 1 H);
5.37 – 5.26 (m, 2 H); 5.12 – 5.02 (m, 1 H); 4.64 (q, J ¼ 6.8, 2 H); 4.61 (d, J ¼ 12.1, 1 H); 4.43 (d, J ¼ 12.1,
1 H); 4.30 – 4.20 (m, 1 H); 3.87 – 3.76 (m, 2 H); 3.39 (s, 3 H); 1.84 – 1.46 (m, 4 H); 1.28 (d, J ¼ 6.8, 3 H);
1.20 (d, J ¼ 6.1, 3 H). 13C-NMR: 165.5; 147.6; 138.2; 134.7; 128.2; 127.5; 127.4; 122.2; 119.5; 94.7; 81.8;
75.2; 72.1; 70.4; 67.8; 55.7; 34.5; 31.1; 23.5; 15.3. ESI-MS: 415 ([M þ Na]þ).
(2S,3R)-3-(Benzyloxy)pent-4-en-2-yl (2E,4S,7S)-4-(Methoxymethoxy)-7-(prop-2-enoyloxy)oct-2-
enoate (17). To a cooled (0o) soln. of 16 (0.14 g, 0.35 mmol) in dry CH2Cl2 (10 ml) were added dry
Et3N (0.15 ml, 0.53 mmol) and acryloyl chloride (0.038 ml, 0.53 mmol), and the mixture was stirred at
(08) for 1 h. After completion of the reaction, a sat. NaHCO3 soln. (5 ml) was added, and the mixture was
extracted with CH2Cl2 (3 ꢂ 15 ml). The combined org. extract was washed with brine, dried (Na2SO4),
and concentrated. The crude residue was purified by CC (AcOEt/hexane 2 :8) to give pure 17 (0.136 g,
86%). Colorless liquid. [a]2D5 ¼ ꢀ76.2 (c ¼ 0.8, CHCl3). IR (neat): 2979, 2932, 1721, 1406, 1295, 1274,
1
1200, 1042, 772. H-NMR: 7.36 – 7.24 (m, 5 H); 6.77 (dd, J ¼ 15.8, 6.2, 1 H); 6.39 (d, J ¼ 17.2, 1 H); 6.10
(dd, J ¼ 17.2, 10.4, 1 H); 5.97 (d, J ¼ 15.8, 1 H); 5.84 – 5.77 (m, 1 H); 5.37 – 5.26 (m, 2 H); 5.11 – 4.93 (m,
2 H); 4.61 (q, J ¼ 10.3, 1 H); 4.57 (d, J ¼ 12.2, 1 H); 4.43 (d, J ¼ 12.2, 1 H); 4.26 – 4.15 (m, 1 H); 3.87 – 3.80
(m, 1 H); 3.37 (s, 3 H); 1.73 – 1.55 (m, 4 H); 1.28 (d, J ¼ 6.0, 3 H); 1.26 (d, J ¼ 6.7, 3 H). 13C-NMR: 165.7;
165.4; 147.3; 138.3; 134.7; 130.4; 128.8; 128.3; 127.5; 127.4; 122.4; 119.5; 94.5; 81.8; 74.9; 72.1; 70.8; 70.4;
55.6; 31.4; 30.7; 19.9; 15.2. ESI-MS: 469 ([M þ Na]þ).
(2S,3R)-3-Hydroxypent-4-en-2-yl (2E,4S,7S)-4-(Methoxymethoxy)-7-(prop-2-enoyloxy)oct-2-enoate
(18). To a soln. of 17 (0.12 g, 0.26 mmol) in dry CH2Cl2 (10 ml) was added DDQ (0.73 g, 3.2 mmol), and
the mixture was stirred at 508 for 4 h. After completion of the reaction, the mixture was diluted with
CH2Cl2, and sat. NaHCO3 (10 ml) was added. The mixture was stirred for 30 min and extracted with
CH2Cl2 (2 ꢂ 15 ml). The combined org. extract was washed with brine, dried (Na2SO4), and
concentrated. The crude residue was purified by CC (AcOEt/hexane 4 :6) to give pure 18 (0.064 g,
74%). Liquid. [a]2D5 ¼ ꢀ57.1 (c ¼ 0.5, CHCl3). IR (neat): 3405, 2940, 2871, 1716, 1448, 1349, 1117, 1022,
941, 812. 1H-NMR: 6.83 (dd, J ¼ 15.9, 6.1, 1 H); 6.38 (d, J ¼ 17.4, 1 H); 6.10 (dd, J ¼ 17.4, 10.6, 1 H); 6.01
(d, J ¼ 15.9, 1 H); 5.92 – 5.84 (m, 1 H); 5.81 (d, J ¼ 9.8, 1 H); 5.37 (dd, J ¼ 17.4, 10.6, 1 H); 5.07 – 4.95 (m,
2 H); 4.61 (d, J ¼ 12.3, 1 H); 4.29 – 4.25 (m, 1 H); 4.24 – 4.19 (m, 1 H); 3.38 (s, 3 H); 1.72 – 1.60 (m, 4 H);
1.27 (d, J ¼ 6.0, 3 H); 1.25 (d, J ¼ 6.8, 3 H). 13C-NMR: 166.1; 165.0; 149.6; 145.5; 131.8; 128.7; 124.1; 121.4;
94.5; 74.8; 74.0; 72.8; 69.9; 55.5; 28.1; 27.0; 18.1; 17.8. ESI-MS: 379 ([M þ Na]þ).

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Helvetica Chimica Acta – Vol. 96 (2013)
(3E,5R,6S,9E,11S,14S)-5-Hydroxy-11-(methoxymethoxy)-6,14-dimethyl-1,7-dioxacyclotetradeca-
3,9-diene-2,8-dione (19). To a soln. of 18 (0.025 g, 0.07 mmol) in degassed dry toluene (110 ml) was added
HoveydaꢀGrubbs-II catalyst (0.004 g, 0.007 mmol), and the resulting mixture was heated under N2 at 808
for 0.5 h. After completion of the reaction, the mixture cooled to r.t., and the solvent was concentrated
under reduced pressure. The crude residue was purified by CC (AcOEt/hexane 4 :6) to afford pure 19
(0.017 g, 78%). Colorless liquid. [a]2D5 ¼ ꢀ13 (c ¼ 0.3, CHCl3). IR (neat): 3502, 2931, 1722, 1645, 1442,
1365, 1223, 1099, 915. 1H-NMR: 6.82 (dd, J ¼ 15.8, 4.5, 1 H); 6.72 (dd, J ¼ 15.8, 6.8, 1 H); 5.98 – 5.87 (m,
2 H); 5.21 – 5.10 (m, 1 H); 5.07 – 4.96 (m, 1 H); 4.61 (q, J ¼ 6.8, 1 H); 4.45 – 4.37 (m, 1 H); 4.16 – 4.06 (m,
1 H); 3.35 (s, 3 H); 1.96 – 1.69 (m, 4 H); 1.47 (d, J ¼ 6.0, 3 H); 1.21 (d, J ¼ 6.8, 3 H). 13C-NMR: 166.1;
164.9; 149.6; 145.5; 124.1; 121.4; 94.5; 76.6; 74.0; 72.1; 69.9; 55.5; 28.1; 27.1; 18.2; 17.9. ESI-MS: 351 ([M þ
Na]þ).
(3E,6S,9E,11S,14S)-11-(Methoxymethoxy)-6,14-dimethyl-1,7-dioxacyclotetradeca-3,9-diene-2,5,8-tri-
one (20). To a cooled (08) soln. of 19 (0.015 g, 0.045 mmol) in dry CH2Cl2 (10 ml) was added DessꢀMartin
periodinane (0.077 g, 0.18 mmol), and the mixture was stirred for 5 h at r.t. The mixture was diluted with
CH2Cl2, the reaction was quenched with sat. Na2S2O3 soln. (5 ml), and the mixture was washed with sat.
NaHCO3 soln. The org. extract washed with brine, dried (Na2SO4), and concentrated. The crude residue
was purified by CC (AcOEt/hexane 3 :6) to give pure 20 (0.01 g, 72%). Colorless liquid. [a]2D0 ¼ þ29.5
(c ¼ 0.2, CHCl3). IR (neat): 3445, 2932, 1724, 1262, 1047, 917. 1H-NMR: 7.30 (d, J ¼ 15.6, 1 H); 7.01 (dd,
J ¼ 15.6, 4.3, 1 H); 6.48 (d, J ¼ 15.6, 1 H); 6.13 (dd, J ¼ 15.6, 1.2, 1 H); 5.32 (q, J ¼ 6.9, 1 H); 5.08 – 5.02 (m,
1 H); 4.46 – 4.41 (m, 2 H); 4.16 – 4.08 (m, 1 H); 3.38 (s, 3 H); 1.96 – 1.81 (m, 3 H); 1.56 – 1.62 (m, 1 H);
1.54 (d, J ¼ 6.4, 3 H); 1.28 (d, J ¼ 6.4, 3 H). 13C-NMR: 199.4; 165.7; 164.1; 150.0; 135.3; 131.1; 120.5; 94.7;
75.5; 73.9; 71.9; 55.6; 28.2; 28.1; 18.5; 16.4. ESI-MS: 349 ([M þ Na]þ).
(3E,6S,9E,11S,14S)-11-Hydroxy-6,14-dimethyl-1,7-dioxacyclotetradeca-3,9-diene-2,5,8-trione (1). To
a cooled (08) soln. of 20 (0.01g, 0.03mmol) in dry CH2Cl2 (5 ml) was added CF3COOH (1.0 ml), and the
mixture was stirred for 3 h at r.t. After completion of the reaction, the mixture was diluted with CH2Cl2
(10 ml), and the reaction quenched by addition of solid NaHCO3. Then, the mixture was filtered, and the
filtrate was concentrated under reduced pressure. The crude residue was purified by CC (AcOEt/hexanes
1:1) to give compound 1. (0.007g, 82%). Colorless liquid [a]2D0 ¼þ 70.3 (c ¼ 0.2, MeOH). IR (neat): 3375,
2990, 1764, 1243, 1058, 970. 1H-NMR: 7.35 (d, J ¼ 16.9, 1 H); 7.12 (dd, J ¼ 16.0, 4, 1 H); 6.4 (d, J ¼ 16.0,
1 H); 6.14 (dd, J ¼ 16.0, 2, 1 H); 5.33 (q, J ¼ 6.9, 1 H); 5.05 – 5.0 (m, 1 H); 4.55 – 4.51 (m, 1 H) 2.07 – 1.97
(m, 1 H); 1.89 – 1.82 (m, 1 H); 1.78 – 1.70 (m, 2 H); 1.54 (d, J ¼ 6.9, 3 H); 1.29 (d, J ¼ 6.2, 3 H). 13C-NMR:
199.5; 165.6; 164.1; 151.3; 135.7; 130.9; 119.6; 75.6; 72.2; 70.3; 31.1; 28.2; 18.9; 16.5. ESI-MS: 283
([M þ H]þ).
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Received December 3, 2012